M. tuberculosis                                                                  EM Photo

Forthcoming Meetings

15^th Conference of the Union North America Region: Vancouver, Canada

24-26 February 2011

42^nd Union World Conference on Lung Health :  Lille,   France

26-30 October 2011

6^th Conference of the Union Europe Region:  London,  United Kingdom

4-6 July 2012

3^rd Asia  Pacific Region Conference of IUATLD: Hong Kong, China

8-11 July 2011

Editorial  Group:

Dr  John Thompson      Canberra

Prof Adrian Sleigh  Australian National University, Canberra

A/Prof Paul Kelly   Australian National University, Canberra

Address for correspondence

Email: jtjnj@grapevine.net.au

Website >http://tbreview.wordpress.com

Contents

Population Studies                          Immunology

Extrapulmonary TB                       Prognosis

TB and HIV                                        Diagnostic Methods

Imaging                                               NonTB Mycobacteria

Zoonoses                                            Drug Reactions

Treatment                                          Socio-political  Issues

Microbiology                                    Catastrophe Corner

Editorial

Vitamin D  has come a long way since its discovery by Edward Mellanby  nearly ninety years ago.  Its presence in fish liver oils takes us back to the days of what was called “the white plague”, aka tuberculosis.   In the nineteenth century  the empirical use of cod liver oil enjoyed  great popularity in the treatment of tuberculosis; so much so that one pharmaceutical company, Felton Grimwade  in Victoria made so money from this remedy it was able to endow what is still the richest art gallery in Australia.  But while the use of cod liver oil  proved so beneficial in the twentieth century for the young dwellers in ‘those dark satanic  mills”  the medical profession in sunny Australia lost interest in such treatments.  After all we had plenty of sunlight as well as fresh meat and diary products.  This view was not always shared by mothers who continued to administer various forms of fish liver oil, often to their children’s disgust.

Now we are being told  that popular opinion may have been correct all along.   Surveys of those both at risk from Vitamin D deficiency  and those not at risk show significant numbers with low Vitamin D blood levels.  We are also informed that Vitamin D can longer be described  a fat soluble vitamin, but functions most like a hormone, particularly in preserving the integrity of the immune system.  Indeed  its presence in the lung plays a role in macrophage activation with the implication that it could help inactivate M. tuberculosis, the “white plague bacillus”

What’s going on? Studies in experimental animals have shown the scavenging effects of vitamin D binding protein (VDBR) in tuberculosis.  So far, Vitamin D supplementation in humans with active tuberculosis has failed to demonstrate  improved outcomes  when they are so treated.  Paradoxically  one study showed increased risk of developing tuberculosis when Vitamin D levels were either too high or too low.   To make matters worse, there is no agreement on the definition of Vitamin D deficiency as measured by serum 25 (OH) D because of laboratory imprecision.  This imprecision has been addressed in bone fracture studies in the elderly where inconsistent risks have been found. Certainly levels below 30nmol are associated with bone disease, but some  would argue that levels below 50 nmol represent deficiency.  Until  a consistent lower limit of normal for serum 25(OH)D has been agreed on there seems little point in urging Vitamin D supplementation  to prevent tuberculosis even in those most at risk of this disease.   This is not to say that those at risk of Vitamin D deficiency  should not have this risk addressed.

Population Studies

Revisiting rates of reactivation  tuberculosis: a population–based approach.

Horsburgh et al   Boston  MA    USA

Am J Crit Care Med 2010; 182: 420

Rationale: Reactivation tuberculosis(TB) occurs as a result of reactivation of latent TB infection (LTBI) , and was reported to occur in the United States at a rate of 0.10 to 0.16 cases per 100 person-years in the 1950s; it has not been measured since.

Objectives: To calculate the rate of reactivation TB in a US community.

Methods: A population-based tuberculin skin test survey for LTBI was performed in western Palm Beach County, Florida, from 1998 to 2000 along with a cluster analysis of TB case isolates in the same area from 1997 to 2001.  Reactivation (unclustered) TB was presumed to have arisen from the population with LTBI.

Measurements and Main Results: The rate of reactivatilon TB among persons with LTB without HIV infection  was 0.040 cases per 100 person-years  (95% CI, 0.024-0.067) using the n method and 0.058 cases per 100 person-years (95% CI, 0.038-0.089) using the n-1 method.  HIV infection was the strongest risk factor for reactivation (rate ratio [RR]. 57; 95% CI, 27-120; P< 0.001).  Among persons without HIV infection, reactivation was increased among those older than 50 years (RR 3.8; 95% CI, 1.3-11) and among those born in the United States (RR 3.2; 95%CI, 1.1-9.3).

Conclusions: Rates of reactivation TB in this area have declined substantially since the 1950s.  The greatest part of this decline may be attributed to the disappearance of old,  TB in the population.  If similar declines are seen in other areas of the United States, the cost effectiveness of screening and treatment of LTBI may be substantially less than previously estimated .

Comment: This study suggests that the chance of an infected adult developing tuberculous disease  has halved to about 5% in a lifetime.  This could reflect increasing affluence in the population during this time, despite the advent of HIV.  Unfortunately the tuberculin used to diagnose LTBI 50 years ago is not the same as today.   It is important that this study be repeated  not just once but in many regions of the affluent world  to confirm or deny that we may be overusing chemoprophylaxis.

JT

EpiReview: tuberculosis in NSW, 2008

Roberts-Witteveen et al   Sydney NSW

NSW Public Health Bull 2010; 21: 174

Aim : To describe the epidemiology  of tuberculosis cases notified in NSW In 2008.

Method: Data on tuberculosis cases resident in NSW that were reported in 2008 were extracted from the Notifiable Diseases Database.  Demographic, microbiological, clinical and other characteristics of cases were described.  Incidence rates per 100,00 were calculated.

Results: In 2008, 498 tuberculosis cases were notified in NSW (7.1 cases per 100,000 population).  Most cases were newly diagnosed (n=479, 96%).  The lung was the most common site of disease (n=304, 61%).  Eight of 269 tested cases (1.6%) had a HIV-tuberculosis co-infection.  One case had multi-drug–resistant tuberculosis.  Most cases reported past residence ( n=429, 86%) or birth (n=378 , 76%) in a country with a high incidence of tuberculosis.

Conclusion: The incidence of tuberculosis in NSW increased slightly in 2008.  Most cases had links to countries with a high tuberculosis incidence.

Comment: It is of concern that  only a little over a half were tested for HIV infection.

JT

Extrapulmonary Tuberculosis

Isoniazid resistance and death in patients with tuberculous meningitis: retrospective cohort study.

Vinnard et al    Philadelphia  PA    USA

BMJ  2010; 341:c4451

Objective: To determine whether initial isoniazid resistance is associated with death during the treatment of tuberculous meningitis.

Design: Retrospective cohort study.

Setting: National Tuberculosis Surveillance System at the Centers for Disease Control in the United States.

Participants: Patients with a clinical diagnosis of tuberculous meningitis, reported to the National  Tuberculosis Surveillance System between 1 January 1993 and 31 December 2005.

Main outcome measure: All cause mortality during antituberculous treatment.

Results: Between 1993 and 2005, 1896 patients had a clinical diagnosis of tuberculous meningitis and positive cultures from any site.  In 123 (6%) of these patients, isoniazid resistance was present on initial susceptibility testing.  The unadjusted association between initial isoniazid resistance and subsequent death among these 1896 patients did not reach statistical significance (odds ratio 1.38, 95% CI 0.94-2.02).  However, among 1614 patients  with positive cerebrospinal cultures, a significant unadjusted association was found between initial isoniazid resistance and subsequent death (odds ratio 1.61, 1.08 to 2.4).  This association increased after adjustment for age, race, sex and HIV status (odds ratio 2.07, 1.30 to 3.29).

Conclusions: Isoniazid resistance on initial susceptibility testing was associated with subsequent death among cases of tuberculous meningitis with positive cerebrospinal cultures.  Randomised controlled trials are needed to evaluate the optimal empirical regimen for treating patients with tuberculous meningitis  who are at high risk for both initial isoniazid resistance and poor clinical outcome.

Comment: How much does this finding also reflect the fact that CSF culture positive TB meningitis has a worse prognosis than CSF culture negative disease.

In other words should they have compared those   patients who had a positive isoniazid resistant culture from another site and those with isoniazid resistant cultures from their CSF.

JT

Comparative analysis of cerebrospinal fluid adenosine deaminase in tuberculous and non-tuberculous meningitis.

Moghtaderi  et al    Zahedan    Iran

Clin Neurol Neurosurg 2010; 112: 459

Objective: To calculate cut-off point for the adenosine deaminase (ADA) activity in the CSF of patients with tuberculous meningitis. (TBM)

Patients and Methods: The ADA assay was based on the automatic indirect method in which ADA catalyzes adenosine to inosine.  ADA activity in the CSF was calculated based on ammonia  liberated from adenosine and quantified spectrophoto-metrically.  Arithmetic mean values  and standard deviation of each variable was measured. Mann-Whitney U and Fisher exact tests were applied to compare continuous and dichotomous variables between tuberculous and nontuberculous groups.  A receiver operating characteristic curve was plotted to identify various cut-off points to determine the best level of ADA activity.

Results:  Totally, 42 patients were enrolled into the study.  The median of ADA activity in the TBM group was 22 and in the non-TBM group was 8.0.  The mean CSF–ADA activity was found to be significantly higher in TBM group (23.05+/- 13/1IU/L) than in the CSF from non-TBM patients. (9.39+/- 5.18 IU/L).The highest accuracy is at the cut-off value of 10.5 IU/L.  The sensitivity and specificity of the test at this cut-off to differentiate TBM from non-TBM is 81 and 86% respectively.

Conclusion: Considering that a high positive value activity of ADA cannot confirm TBM, however, in suspected patients it may lead the physician to treat patients earlier before the confirmatory diagnostic reports are received..  The suggested cut-off value in this pilot study is 10.51IU/L with high sensitivity and specificity.

Comment: Any test that helps the diagnosis of this disease is welcome.  It would be helpful to measure ADA activity in those cases with a presumptive diagnosis of TBM, where there is response to antituberculosis treatment but no bacteriological confirmation.

JT

A review of tuberculous meningitis at Auckland City  Hospital, New Zealand.

Anderson et al   Auckland  New Zealand

J Clin Neurosci 2010;17: 1018

Abstract: The clinical features, investigations, treatment and outcome were studied in 104 patients with definite or probable tuberculous meningitis.  The diagnosis of definite tuberculous meningitis required the growth of Mycobacterium tuberculosis from cultures, or a positive polymerase chain reaction (PCR) assay for M. tuberculosis.  In probable tuberculous meningitis, cultures and PCR assay were negative, but other causes of meningitis were excluded  and there was a response to anti-tuberculosis treatment.  Of the 104 patients, 36% had a poor outcome (severe disability, persistent vegetative state or death), 12% moderate disability and 52% good recovery.  A diagnosis of definite tuberculous meningitis, the severity of the symptoms at presentation  and the occurrence of a stroke were significant predictors of a poor outcome.  The most common reasons for a delayed diagnosis were presentation with mild symptoms  wrongly attributed to a systemic infection, incorrectly attributing CSF abnormalities to non-tuberculous bacterial meningitis and failure to diagnose extra neural tuberculosis associated with meningitis.  Recognition of the difficulties in making a diagnosis of tuberculous meningitis may facilitate earlier diagnosis in the future.

Comment: Despite their closing remarks, the outcome for this group’s patients is no worse than in most reported series.

JT

TB and HIV

African Australians living with HIV: a case series from Victoria.

Lemoh et al  Melbourne  Australia

Sex Health  2010; 7: 142

Background: This research aimed to describe the characteristics of African-born Victorians living with HIV, identify associations with delayed HIV diagnosis and describe their response to combination antiretroviral therapy (cART).

Methods: A case series of African-born adults living with HIV in Victoria was conducted.  Data was collected in interviews and reviews of case notes.  Associations with delayed HIV diagnosis (CD4 below 200 cells microL (-1) at diagnosis and/or AIDS within 3 months of HIV diagnosis) were explored using univariate regression.  AIDS-defining illnesses and response to cART were described.

Results: Fourteen males and six females were included.  Ten were born in the Horn of Africa (nine in Ethiopia).  Sixteen had sexual exposure (12 heterosexual; four male to male sex.  Seven reported acquiring HIV in Australia.  Median CD4 count at diagnosis was 145 cells microL (-1). Ten had delayed HIV diagnosis, of whom eight were born in the Horn of Africa.  Delayed HIV diagnosis was associated with birth in the Horn of Africa (odds ratio 11.56).  Nine had a diagnosis of AIDS, including three cases of tuberculosis, three of Pneumocystis jiroveci pneumonia and two of cerebral toxoplasmosis. Eighteen had received cart, of which 16 achieved virological suppression and 15 achieved a CD4 count above 200 cells microL(-1`).  Clinical failure and virological failure occurred in seven and five cases, respectively.

Conclusions:HIV prevention strategies for Victoria’s African communities should address HIV exposure in Australia.  Ethiopian-born Victorians with HIV appear to be at particular risk of delayed diagnosis.  Response to cART in this series was comparable to that observed in other industrialized countries.

Comment: It is to be hoped that all cases of tuberculosis among Africans who  come to Australia  have HIV testing carried out.

JT

Imaging

A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis.

Ralph et al   Darwin    NT    Australia

Thorax 2010; 65: 863

Background: The grading of radiological severity in clinical trials in tuberculosis (TB)  remains unstandardised.  The aim of this study was to generate and validate a numerical score for grading chest x-ray (CXR) severity and predicting response to treatment in adults with smear-positive pulmonary TB.

Methods: At a TB clinic in Papua, Indonesia, serial CXRs were performed at diagnosis, 2 and 6 months in 115 adults with smear-positive positive pulmonary TB.  Radiographic findings predictive of 2-month sputum microscopy status were used to generate a score.  The validity of the score was then assessed in a second data set of 139 comparable adults with TB, recruited 4 years later  at the same site.  Relationships between the CXR score and other measures of TB severity were examined.

Results: The estimated proportion of lung affected and presence of cavitation, but not cavity size or other radiological findings, significantly predicted outcome and were combined to derive a score given by percentage of lung affected plus 40 if cavitation was present.  As well as predicting 2-month outcome, scores were significantly associated with sputum smear grade at diagnosis (p< 0.001), body mass index, lung function, haemoglobin, exercise tolerance and quality of life (p<0.02 for each).  In the validation data set, baseline CXR score predicted 2-month smear status significantly more accurately  than did the proportion of lung affected alone.  In both data sets, CXR scores decreased over time (p<0.001).

Conclusion: This simple, validated method for grading CXR severity in adults with smear-positive pulmonary TB correlates with baseline clinical and microbiological severity and response to treatment, and is suitable for use in clinical trials.

Comment:  Yes indeed, although recently doubt has been expressed as to whether the WHO guidelines of 2 month sputum smear status does reflect  the final outcome of treatment.

JT

Low yield of chest radiography in a large tuberculosis screening program.

Eisenberg et al  Boston  MA  USA

Radiology 2010; 256: 998

Purpose: To assess the frequency and spectrum of abnormalities  on routine screening chest radio-graphs in the pre-employment evaluation of health care workers with positive tuberculin skin tests (TST) results.

Materials and methods: The institutional review board this HIPAA-compliant retrospective study  and waived the need for written informed patient consent.  Chest radiographic reports of all 2586 asymptomatic  with positive TST results who underwent pre-employment evaluation between January 1, 2003 and December 231, 2007, were evaluated to determine the frequency of detection  of evidence of active tuberculosis (TB) or latent TB infection (LTBI) and the spectrum of imaging findings.  All chest radiographs interpreted as positive were reviewed by an experienced board-certified radiologists.  If there was a discrepancy between the two readings, a second experienced radiologist served as an independent and final arbiter.  Any follow-up  chest radiographs or computed tomographic images that had been acquired by employee health services or by the employee’s private physician as a result of a suspected abnormality detected at initial screening were also evaluated.

Results: Of the 159 (6.1%) chest radiographic examinations that yielded abnormal results, there were no findings that were consistent with active TB.  There were 92 cases of calcified granulomas, calcified lymph nodes, or both; 25 cases of apical pleural thickening, 16 cases of fibrous scarring; and 31 cases of noncalcified nodules.  All cases of fibrous scarring involved an area smaller than 2 cm(2).  All noncalcified nodules were 4 mm in diameter or smaller, with the exception of one primary lung malignancy and one necrotizing granuloma (negative for acid-fast bacilli) that grew Mycobacterium kansasii on  culture.

Conclusion: Universal chest radiography in a large pre-employment TB screening program was of low yield in the detection of active TB or increased LTBI reactivation risk , and it provided no assistance in deciding which individual to prioritize for LTBI treatment.

Comment: One would expect similar findings for health care workers in Australia.  Not only does the  present conventional cut point for tuberculin sensitivity render the test very nonspecific, but our predictions  that 10% of tuberculin positive  adults will develop active TB in their lifetime are based on old data, that may not reflect the current  reality for HIV-negative health care workers in an affluent society.                                                        JT

Dual time-point FDG PET-CT for differentiating benign  from malignant solitary pulmonary nodules in a TB endemic area.

Sathekde et al    Pretoria   South Africa

S Afr Med J  2010; 100: 598

Objective: Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an accurate non-invasive imaging test for differentiating benign from malignant solitary pulmonary nodules (SPNs).  We aimed to assess its diagnostic accuracy  for differentiated benign from malignant SPNs in a tuberculosis (TB)-endemic area.

Methods: Thirty patients, 22 men and 8 women, mean age 60 years, underwent dual time point FDG-PET/computed tomography (CT) imaging, followed by histological examination of the SPN.  Maximum standard uptake values (SUVmax) with the greatest uptake in the lesion were calculated for two time points (SUV1 and SUV2), and the percentage change over time per lesion was calculated (%DSUV).  Routine histological findings served as the gold standard.

Results: Histological examination showed that 14 lesions were malignant and 16 benign, 12 of which were TB.  SUVmax for benign and malignant lesions were 11.02 (SD 6.6 ) v 10.86 (SD8.9); however, when tuberculomas were excluded from the analysis,  a significant difference in mean SUV1max values between benign and  malignant lesions was observed(p=0.0059).  Using an SUVmax cut-off value of 2.5, a sensitivity of 85.7% and a specificity of 25% was obtained.  Omitting the TB patients from analysis resulted in a sensitivity of 85.7 % and a specificity of 100%.   Mean %DSUV of benign lesions did not differ significantly  from mean %DSUV of malignant lesions (17.1% (SD 16.3%) v 19.4%(SD 23.7%)).  Using a cutoff  of %DSUV > 10% as indicative of malignancy , a sensitivity of 85.7% and a specificity of 50% was obtained.  Omitting the TB patients from the analysis yielded a sensitivity of 85.7% and a specificity of 75%.

Conclusion: Our findings suggest that FDG-PET cannot distinguish malignancy from tuberculosis and therefore cannot reliably be used to reduce futile biopsy/ thoracotomy.

Comment:  It seems that FNA biopsy under CT control cannot yet be bypassed.

JT

Zoonoses

Zoonotic Tuberculosis: on the decline

Ingram et al    Perth  WA    Australia

CDI 2010; 34: 339

Abstract: Mycobacterium bovis is a zoonotic member of the Mycobacterium tuberculosis complex responsible for a clinical syndrome indistinguishable from that due to M. tuberculosis.  In Australia, infection with M. bovis has historically been associated with employment in the livestock industry or immigration from countries in which animal disease is endemic.  It currently accounts for 0.2% of all human cases of tuberculosis within Australia.  This paper describes a case of pulmonary M. bovis in a butcher and reviews factors responsible for the declining incidence of this disease in Australia.

Comment: It is a mystery why the possum in Australia does not act as a reservoir of M.bovis as in New Zealand.

JT

Treatment

Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis.

Caminero et al      Las Palmas   Spain

Lancet Infect Dis 2010; 10: 621

Abstract: Multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis are generally thought to have high mortality rates.  However, many cases can be treated with the right combination and rational use of available antituberculosis drugs.  This review describes the evidence available for each drug  and discusses the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis.  The recommended regimen is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible.  Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety and cost.  Among the first group (the oral first line drugs) high dose isoniazid, pyrazinamide and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis.  The second group is the quinolones, of which the first choice is high-dose levofloxacin.  The third group are the injectable drugs, which should be used in the following order: capreomycin, kanamycin, then amikacin.  The fourth group are called the second-line drugs and should be used in the following order: thioamides, cycloserine, then aminosalicylic acid.  The fifth group includes drugs that are not very effective or for which there are sparse clinical data/  Drugs in group five should be used in the following order: clofazamine, amoxicillin with clavulanate, linezolid, carbapenins, thiocetazone, then clarithromycin.

Comment: It is interesting that of the two thioamides, prothionamide and ethionamide, one is not preferred over the other.  Some might argue that the macrolides like clarithromycin should be higher up the list .

JT

Short, highly effective and inexpensive standardized treatment of multidrug-resistant tuberculosis.

Van Deun et al   Antwerp    Belgium

Am J Respir Crit Care Med 2010; 182: 684

Rationale: Based on expert opinion, the global guidelines for management of multidrug-resistant tuberculosis impose lengthy and often poorly tolerated treatments.

Objectives: This observational study evaluates the effectiveness of standardized regimens for patients with proven multidrug-resistant tuberculosis previously untreated with second-line drugs in low-income countries.

Methods: Consenting patients were sequentially assigned to one of six standardized treatment regimens.  Subsequent cohorts were treated with regimens adapted to results in prior cohorts.  The study was designed to minimize failure and default while reducing total treatment duration without increasing relapse frequency.

Measurements and Main Results: We report the treatment outcome of all patients with laboratory-confirmed, multidrug-resistant tuberculosis enrolled from May 1997 to December 2007.  The most effective treatment regimen required a minimum of 9 months of treatment with gatifloxacin, clofazamine, ethambutol and pyrazinamide throughout the treatment period supplemented by prothionamide, kanamycin and high dose isoniazid during an intensive phase of a minimum of 4 months, giving a relapse-free cure of 87.9% (95%CI, 82.7-91.6) among 206 patients.  Major adverse drug reactions were infrequent and manageable.  Compared with the 221 patients treated with regimens based on ofloxacin and commonly prothionamide throughout, the hazard ratio of any adverse outcome was 0.39 (95% CI ,0.26-0.59).

Conclusions: Serial regimen formulation guided by overall treatment effectiveness resulted in treatment outcomes comparable with those obtained by first line treatment.  Confirmatory formal trials in populations with high levels of human immunodeficiency virus coinfection  and in populations with a higher initial prevalence of resistance to second line drugs are required.

Comment: After much trial and error this seems to be an effective regimen.  It may take longer to decide which fluoroquinolones are the best.

JT

Role of corticosteroids in the treatment of tuberculosis: an evidence-based update

Kadhiravan et al   Puducherry   India

Indian J Chest Dis Allied Sci 2010; 52: 153

Abstract: Corticosteroids are often used as an adjunct in the treatment of various forms of tuberculosis(TB) and for the prevention of complications, such as constrictive pericarditis, hydrocephalus, focal neurological defects, pleural adhesions and intestinal strictures.  Notwithstanding, they have been proven in clinical trials to improve the following outcomes only- death or disability in human immunodeficiency virus (HIV)-seronegative patients with tubercular meningitis and tubercular pericarditis.  Despite a lack of specific evidence for efficacy in HIV co-infected patients with tubercular meningitis or pericarditis, corticosteroids are generally recommended in them as well.  Corticosteroids significantly decrease of pleural thickening in patients with tubercular pleural effusion; the clinical significance of this finding, however, is unclear.  Recently, it has been demonstrated that use of corticosteroids improve the morbidity in HIV co-infected patients with paradoxical immune reconstitution inflammatory syndrome (IRIS).  However, evidence favouring the use of corticosteroids in other clinical situations is sparse of lacking.  Likewise, the biological mechanisms underlying their beneficial effect in TB meningitis and pericarditis remain poorly understood.

Comment: As far as I am aware, corticosteroids are not used for TB pleural effusion in this country.

JT

Microbiology

Microscopic-observation for drug susceptibility and thin layer assays for the detection of drug resistant tuberculosis: a systematic review and meta-analysis.

Minion  et al  Montreal     QC      Canada

Lancet Infect Dis 2010; 10: 688

Background: Simple, rapid and affordable tests are needed to detect drug resistance to Mycobacterium tuberculosis.  We did a systematic review and meta-analysis to investigate the accuracy of microscopic –observation drug susceptibility (MODS) and thin layer agar (TLA) assays for rapid screening of patients at risk of drug-resistant tuberculosis.

Methods: In accordance with protocols and methods recommended by the Cochrane Diagnostic Test Accuracy Working Group, we systematically searched PubMed, Embase and Biosis for reports published between January, 1990 and February 2009.  We included studies investigating detection of drug resistance in M.tuberculosis with the MODS or TLA assay, and in which an accepted reference standard was used.  Data extracted from the studies were combined by use of bivariate random-effects regression models and hierarchical summary receiver operating characteristic curves to estimate sensitivity and specificity for detection of resistance to specific drugs.

Findings: We identified 12 studies, of which nine investigated the MODS assay and three the TLA assay.  For the MODS assay of rifampicin resistance, pooled estimates were 98%(95% CI 94.5-99.3) for sensitivity and 99.4% (95.7-99.9) for specificity.  For the MODS assay of isoniazid resistance with a 0.1 mcg/ml cutoff, pooled sensitivity was 97.7% (94.4-99.1) and pooled specificity was 95.8% (88.1-98.6), but with a 0.4 mcg/ml cutoff, sensitivity decreased to

90.0% (84.5-93.7) and specificity increased to 98.6% (96.9-99.4).  All assessments of rifampicin and isoniazid resistance with the TLA assay yielded 100% accuracy.  Mean turnaround time was 9.9 days (95% CI4.1-15.8) for the MODS assay 11.1 days (10.1-12.0) for the TLA assay.

Interpretation: MODS  and TLA assays are inexpensive, rapid alternatives to conventional methods for drug susceptibility testing of M.tuberculosis.  Our data and expert opinion informed WHO’s recommendation for use of selected non-commercial drug susceptibility  tests, including MODS, as an interim solution  until capacity for genotypic or automated liquid culture drug susceptibility testing is developed.

Comment: Yes but these studies used skilled laboratory personnel to conduct the tests.  How will such skills be obtained in low income settings?

JT

Rapid molecular detection of tuberculosis and rifampin resistance.

Boehme et al  Geneva   Switzerland

N Engl J Med  2010; 363: 1005

Background: Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug resistant forms and in patients with human immunodeficiency virus infection.  Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect.

Methods: We assessed the performance of Xpert MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and resistance to rifampin (RIF) with fully integrated sample processing in 1730 patients with suspected drug sensitive or multidrug-resistant pulmonary tuberculosis.  Eligible patients in Peru, Azerbaijan, South Africa and India provided three sputum specimens each.  Two specimens were processed with N-acetyl-L-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and one specimen was used for direct testing with microscopy and the MTB/RIF test.

Results: Among culture positive patients, a single, direct MTB/RIF test identified 551 of 561 patients with smear positive tuberculosis (98.2%) and 124 of 171 with smear negative tuberculosis (72.5%).  The test was specific in 604 of 609 patients without tuberculosis (99.2%)  Among patients with smear negative, culture-positive tuberculosis, the addition of a second MTB/RIF test increased sensitivity by 12.6 percentage points and a third by 5.1 percentage points, to a total of 90.2 %.  As compared with phenotypic drug-susceptibility testing, MTB/RIF testing correctly identified 200 of 205 patients (97.6%)  with rifampin–resistant bacteria  and 504 out of 514 (98.1%) with Rifampin –sensitive bacteria. Sequencing resolved all but two cases in favour of the MTB/RIF assay.

Conclusions: The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours minimal hands-on time.

Comment: It would be nice to know if these results are reproducible.

JT

Detection of Mycobacteria tuberculosis in corneas from donors with active tuberculosis disease through poly-merase chain reaction and culture.

Catedral et al     Quezon City  Philippines

Br J Ophthamol  2010; 94: 894

Objective: To determine if Mycobacterium tuberculosis can be detected  in corneas of donors who have active tuberculosis (TB) disease using polymerase chain reaction  (PCR) or culture.

Design: This is a prospective cross-sectional study.

Participants: 25 corneas (12 from TB-negative donors and 13 from TB-positive donors) from the Sta. Lucia International Eye Bank were submitted to the TB Research Laboratory, Medical Research Laboratory, Department of Medicine, UP-PGH, for diagnostic evaluation.

Intervention: Corneas were evaluated using PCR test for M.tuberculosis.  Acid-fast bacilli smear  and culture were also done.

Main Outcome Measures: Result of laboratory findings.

Results: Among 12 TB-negative donors, there were 2 (16%) corneas that were PCR negative for M.tuberculosis, whereas 10 (83%) corneas were PCR positive for M. tuberculosis.  Among 13 TB-positive donors, there were 7 (54%) corneas that were PCR negative for M. tuberculosis, whereas 6(46%) corneas were PCR positive for M. tuberculosis.  All cultures were negative,

Conclusion: PCR for M. tuberculosis was positive for some TB-positive donors as well as TB-negative donors.  However, all cultures were negative.  It is recommended that further studies be done to investigate if recipients with PCR-positive corneas will eventually lead to disease transmission or not.  It is further recommended that such findings be used to re-evaluate criteria for suitability of donors with tuberculosis.

Comment: The main investigation should be directed at the laboratory concerned.

JT

Does bleach processing increase the accuracy of sputum smear microscopy for diagnosing pulmonary tuberculosis?

Cattamanchi et al   San Francisco   USA

J Clin Microbiol 2010; 48: 2433

Abstract: Bleach digestion of sputum prior to smear preparation has been reported to increase the yield of microscopy for diagnosing pulmonary tuberculosis, even in high-prevalence settings.  To determine the diagnostic accuracy of bleach microscopy, we updated a systematic review published in 2006 and applied the Grading of Recommendations, Assessment, Development and Evaluation framework to rate the overall quality of the evidence.  We searched multiple databases (as of January 2009) for primary studies in all languages comparing bleach and direct microscopy.  We assessed study quality using a validated tool and heterogeneity by standard methods.  We used hierarchical  summary receiver operating characteristic (HSROC) analysis to calculate summary estimates of diagnostic accuracy  and random-effects meta-analysis to pool sensitivity and specificity differences.  Of 14 studies (11 papers) included, 9 evaluated bleach centrifugation and 5 evaluated bleach sedimentation.  Overall, examination of bleach-processed versus direct smears led to small increases (for bleach centrifugation , 6% [95% CI, 3-10%, P=0.001]; for bleach sedimentation, 9% [95% CI, 4-14%, P=0.001]) and small decreases in specificity ( for bleach centrifugation,-3% [95% CI= -4 to -1%, P=0.004]; for bleach sedimentation, -2% [95%CI=-5 to 0%, P=0.05%)]). Similarly, analysis of HSROC curves suggested little or no improvement in diagnostic accuracy.  The quality of evidence was rated very low for both bleach centrifugation and bleach sedimentation.  This updated systemic review suggests that the benefits of bleach processing are less than those described previously.  Further research should focus on alternative approaches to optimizing smear microscopy, such as light–emitting diode fluorescence and same day sputum collection strategies.

Comment: As I understand it, bleach is recommended as a cheap way of enhancing sputum smear microscopy in third world counties, who cannot even afford centrifugation, let alone fluorescent microscopy.

JT

Immunology

Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy?

Behar et al    Boston    MA     USA

Nat Rev  Microbiol  2010; 8: 668

Abstract: Virulent Mycobacterium tuberculosis inhibits apoptosis and triggers necrosis of host macrophages to evade innate immunity and delay the initiation of adaptive immunity.  By contrast, attenuated M.tuberculosis induces macrophage apoptosis, an innate defence mechanism that reduces bacterial viability.  In this Opinion article, we describe how virulent M. tuberculosis blocks production of the eicosanoid lipid mediator prostaglandin E (2) (PGE(2)).  PGE(2) production by infected macrophages prevents mitochondrial damage and initiates plasma membrane repair, two processes that are crucial for preventing necrosis and inducing apoptosis.  Thus, M.tuberculosis-mediated modulation  of eicosanoid production determines the death modality of the infected macrophage, which in turn has a substantial impact on the outcome of infection.

Comment: Did our macrophages always have an innate defence mechanism to M. tuberculosis?

Prognosis

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts.

Kik et al   The Hague     Netherlands

Eur Respir J 2010; 35: 1346

Abstract: The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-gamma release assays (IGRAs), QuantiFERON-TB Gold In-tube (QFT-GIT) and T-SPOT.TB, and the tuberculin skin test (TST) in immigrants’ contacts.  Immigrant close contacts of sputum smear positive TB patients were included when aged >/=16 yrs and their TST result was >/=5 mm 0-3 months after diagnosis of the index patients.  Contacts were followed for the next 2yrs for development of TB disease.  Of 339 immigrant contacts with TST >/=5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT,TB, respectively.  Nine contacts developed active TB.  One patient had not been tested  with TST, while another patient had not been tested with QFT and T-SPOT.TB.  PPV for progression to TB during this period was 9.288 =3.1 % (95% CI 1.3-5.0%) for TST >/=10mm, 7/184 =3.8% (95% CI 1.7-5.9%) for TST>/=15 mm, 5/178 =2.8 % (95% CI 1.0-4.6%) for QFT-GIT and 6/181 = 3.3% (95%  CI 1.3-5.3%)  for T-SPOT.TB.  Sensitivity was 100% , 88%, 63% and 75%, respectively.  The predictive values of QFT-GIT, T-SPOT.TB and TST for progression to TB disease among immigrant close contacts were comparable.

Comment: That’s one side of the coin.  On the other is NPPV, best expressed as specificity.

JT

Diagnostic Methods

Screening for tuberculosis in asylum seekers: comparison of chest radiography with an interview – based system

Schneeberger Geisler et al   Berne  Switzerland

Int J Tuberc Lung Dis 2010; 14: 1388

Setting: Mandatory initial screening of asylum seekers for tuberculosis (TB) in Switzerland, 2004-2005 and 2007-2008.

Objective: To compare the yield of screening by chest radiography with an individual assessment based on geographical origin, personal history and symptoms.

Design: Cross-sectional retrospective comparison of two 2-year periods.

Results: The prevalence of detected TB cases was defined as the proportion of screenees starting antituberculosis treatment for culture-confirmed  pulmonary  TB  within 90  days.  TB  prevalence  was 14.3 per 10,000 asylum seekers screened (31  /21727) using  chest  radiography  and  12.4 (29 /23402) using individual assessment.  The sensitivity of radiography was 100%  vs. 55% for individual assessment, but its specificity was lower  (89.9%) vs 96 %, respectively). The higher sensitivity of radiography meant shorter delays between screening and treatment (median 6 vs. 25 days).  Its lower specificity led to a larger proportion of those needing further investigations for suspicion of TB (12% vs 4%).

Conclusion: The interview–based system initially missed more cases, but the ultimate 90-day yield was comparable for the two periods.  The main difference is the delay until the start of treatment, which potentially increases transmission and secondary cases.  The radiograph system was more burdensome to both the health system and the screenees, as more suspects require further investigations.

Comment: This was designed as a cost cutting exercise, but given the many studies across the world  that condemn delays in beginning TB treatment, it is hard to justify a change to this interview system.

JT

Direct comparison of the diagnostic yield of ultrasound-assisted Abrams and Tru-Cut needle biopsies for pleural tuberculosis

Koegelenberg   et al  Cape Town   South Africa

Thorax  2010; 65: 857

Background: Tuberculous pleuritis remains the commonest cause of exudative effusions in areas with a high prevalence of tuberculosis and histological and /or microbiological confirmation on pleural tissue is the gold standard for its diagnosis.  Uncertainty remains regarding the choice of closed pleural biopsy needles.

Objectives: This prospective study compared ultrasound-assisted Abrams and Tru-Cut needle biopsies with regard to their diagnostic yield for pleural tuberculosis.

Methods: 89 patients (54 men) of mean +/- SD age 38.7 +/- 16.7 years with pleural effusions and a clinical suspicion of tuberculosis were enrolled in the study.  Transthoracic ultrasound was performed on all patients, who were then randomly assigned to undergo >/=4 Abrams needle biopsies followed by >/=4 Tru-Cut biopsies or vice versa.  Medical thoracoscopy was performed on cases with non-diagnostic closed biopsies.  Histological and /or microbiological proof of tuberculosis on any pleural specimen was considered the gold standard  for pleural tuberculosis.

Results: Pleural tuberculosis was diagnosed in 66 patients, alternative diagnoses were established in 20 patients and 3 remained undiagnosed.  Pleural biopsy specimens obtained with Abrams needles contained pleural tissue in 81 patients (91%) and were diagnostic for tuberculosis in 54 patients (sensitivity 81.8%), whereas Tru-Cut needle biopsy specimens only contained pleural tissue in 70 patients (78.1%, p=0.015) and were diagnostic in 43 patients (sensitivity 65.2%, p=0.022).

Conclusions: Ultrasound assisted pleural biopsies performed with an Abrams needle are more likely to contain pleura and have a significantly higher diagnostic sensitivity for pleural tuberculosis.

Comment: In experienced hands, the Abrams needle is to be preferred.  This study also demonstrates the old finding that the more specimens you take the greater chance of making a diagnosis.

JT

Non Tuberculous Mycobacteria

Host  immune responses to rapidly growing mycobacteria, an emerging cause of chronic lung disease.

Chan et al  Denver   CO    USA

Am J Respir Cell Mol Biol 2010; 43: 387

Abstract: Rapidly growing mycobacteria (RGM) are environmental organisms classified under the broader category of nontuberculous mycobacteria. The most common RGM to cause human diseases are Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium massiliense.  Infections due to the RGM are an emerging health problem in the United States.  Chronic pulmonary disease and skin/soft tissue infections are the two most common disorders due to these organisms.  Clinical outcomes in the treatment of M. abscessus infections are generally disappointing.  Because less is known about the nature of the immune response to M. abscessus than for tuberculosis, we herein highlight the major clinical features associated with infections due to M. abscessus and other RGM, and review the known host immune response to RGM, drawing from experimental animal and clinical studies.  Based on an in vitro and in vivo murine models, Toll-like receptor 2, dectin-1, tumor necrosis factor (TNF)-alpha, IFN-gamma, leptin, T cells, and possibly neutrophils are important components in the host defence against RGM infections.  However, excessive induction of TNF-alpha by the R morphotype of M. abscessus may allow it to be more pathogenic than the S morphotype.  Clinical observations and/or genetic studies in humans corroborate many of the findings in animals in that those  with cell-mediated immunodeficiency, genetic defects in IFN-gamma-IL- 12 axis, and those individuals on TNF-alpha blockers are at increased risk for nontuberculous mycobacteria infections, including the RGM.  However, much remains to be discovered on why seemingly healthy individuals, particularly postmenopausal women with thoracic cage anomalies, appear to be at increased risk.

Comment: While the isolation of RGM from the human body generally indicates invasion, we still need to learn more about the significance of isolating slower growing mycobacteria from the body.

JT

Drug Reactions

Age related risk of hepatotoxicity in the treatment of latent tuberculosis infection: a systematic review.

Kunst et al     Birmingham    UK

Int J Tuberc Lung Dis  2010; 14: 1374

Objective: To determine the age related risk of hepatotoxicity  under currently recommended regimens for latent tuberculosis infection (LTBI).

Methods: A systematic review of the MEDLINE and EMBASE databases (from database inception to 2008) was performed to determine the risk of isoniazid (INH) and /or rifampicin hepatotoxicity  in LTBI stratified by patient age.  Study selection, study quality assessment and data extraction were performed using piloted proformas.  Rate data were meta-analysed to generate summary rates with 95% CI within age-related subgroups using a random effects model.

Results: Seven relevant studies (18610 participants including 115 cases of hepatotoxicity) met the selection criteria.  The median rate of hepatotoxicity was 1.8% ( range 0.07-11.9).  On average, rates were higher among those aged >/=35 years(1.7%, 95% CI 1.4-2.2)  than those aged < 35 years (0.2%, 95%CI 0.1-0.3%.

Conclusion : The rates of hepatotoxicity were low. Summary estimates of risks generated in this review can be used for counseling individuals for who chemoprophylaxis recommended.  The use of INH for the treatment of LTBI is safe in older patients with clinical or biochemical monitoring.

Comment: Would anyone regard a drug as safe with  a hepatotoxicity rate of up to11.9%?    But then if one study regards an ALT level of  5 times above upper limit of normal as representing hepatotoxicity, and another only 3 times that, it is obvious that the rates of hepatotoxicity will vary greatly.

JT

Socio-political Issues

Is wealthier always healthier?  The impact of national income level, inequality and poverty on public health in Latin America.

Biggs et al  Cambridge   UK

Soc Sci Med 2010; 71: 266

Abstract: Despite findings indicating that both national income level and income inequality are each determinants of public health, few have studied how national  income level, poverty and inequality interact with each other to influence public health outcomes.  We analyzed the relationship between gross domestic product (GDP) per capita in purchasing power parity, extreme poverty rates, the gini coefficient for personal income and three common measures of public health:  life expectancy, infant mortality rates and tuberculosis (TB) mortality rates.  Introducing poverty and inequality as modifying factors, we then assessed whether the relationship between GDP and health differed during times of increasing, decreasing, or constant poverty and inequality.  Data were taken from twenty two Latin American countries from 1960 to 2007 from the December 2008 World Bank World Development Indicators, World Health Organisation Global Tuberculosis Database 2008 and the Socio-Economic Database for Latin America and the Caribbean.  Consistent with previous studies, we found increases in GDP have a sizeable positive impact on population health.  However, the strength of the relationship is powerfully influenced by changing levels of poverty and inequality.  When poverty was increasing, greater GDP had no significant effect on life expectancy  or TB mortality, and only led to a small reduction in infant mortality rates.  When inequality was rising, greater GDP had only a modest effect on life expectancy and infant mortality rates, and no effect on TB mortality rates.  In sharp contrast, during times of decreasing or constant poverty and inequality, there was a very strong relationship between increasing GDP and higher life expectancy and lower TB and infant mortality rates.  Finally, inequality and poverty were found to exert independent, substantial effects on the relationship between national income level and health.  Wealthier is indeed healthier, but how much healthier depends on how increases in wealth are distributed.

Comment: It is interesting to see how such data analysis supports what many of us already believe.

JT

“ It is more than the issue of taking tablets”: the interplay between migration policies and TB control in Sweden.

Kulane et al   Stockholm    Sweden

Health Policy 2010; 97: 26

Objectives: Tuberculosis is re-emerging as a critical public health concern in Sweden among the immigrants.  The aim of this study was to explore the experiences of the Somali community of TB care in the Stockholm area.

Methods: Focus group discussions were conducted with 34 adult women and men by a Somali speaking moderator.  Each group consisted of 6-9 participants –men and women separately.  The audiotaped discussions were transcribed , translated  and read many times and in the process patterns and codes were identified and migration emerged as an important theme in the context of TB control.

Results: Fear of being deported emerged as a barrier to sharing of complete health information with the doctor.  The routine contact tracing and follow up of infected cases in TB control was expressed as a source of concern since it was feared the health care providers could share the information with the immigration authorities.  Interpreter use was expressed as a barrier particularly if of the same female gender.

Conclusion: It is important to be aware of how a country’s immigration policies impact on TB control activities among immigrants.  The existing TB control measures, such as contact tracing, assume new meanings for immigrants.  Further research is therefore needed to understand this emerging complexity in order to make TB control more effective.

Comment: Some might argue that fear of being deported impels many refugees to be more compliant with whatever measures the health authorities direct them to take.

JT

Catastrophe Corner

Incidence of malignant diseases in humans injected with radium-224.

Nekolla et al   Neuherberg   Germany

Radiat Res  2010; 174: 377

Abstract: The “Spiess study”   (one of the authors, Ed) follows the health of 899 persons who received multiple injections of the short-lived alpha-particle emitter (224) Ra mainly between 1945 and 1955 for the treatment of tuberculosis, ankylosing spondylitis and some other diseases.  In December 2007, 124 persons were still alive.  The most striking health effect, observed shortly after (224)Ra injections, was a temporal wave of 57 malignant bone tumours.  During the two most recent decades of observation , a significant excess of non-skeletal malignant diseases has become evident.  Expected numbers of cases were computed from the age, gender and calendar year distribution of person years at risk and incidence rates from the German Saarland Cancer Registry.  Poisson statistics were applied to test for statistical significance of the standardized incidence ratios.  Up to the end of December 2007, the total number of observed malignant non-skeletal diseases was 270 (248 specified cases of non-skeletal solid cancers and 22 other malignant diseases, among these 16 malignant neoplasms of lymphatic and hematopoietic tissue, six without specification of site) compared to 192 expected cases.  Accounting for a 5-year minimum latent period and excluding 13 cases of non-melanoma skin cancer, 231 non-skeletal solid cancers were observed compared to 151 expected cases.  Significantly  increased cancer rates were observed for breast (32 compared to 9.7), soft and connective tissue (11 compared to 1.0). thyroid (7 compared to 1.0), liver  (10 compared to 2.4), kidney (13 compared to 5.0). pancreas (9 compared to 4.1), bladder (16 compared to 8.0) and female genital organs (15 compared to 7.8).

Comment: It is salutary to be reminded what damage alpha particles with only a half life of less than 4 days can do once they penetrate the body.

JT

Cavitating tuberculosis (courtesy IUATLD)

The    Australian Tuberculosis Review

October   2010

M. tuberculosis                EM Photo

Forthcoming Meetings

41 st   Union World Conference on Lung Health:   Berlin   Germany

11-15 November 2010

Website: Berlin 2010

42 nd   Union World Conference on Lung Health :  Lille   France

26-30 October 2011

6^th Conference of the Union Europe Region:  London  UK

4-6 July 2012

Editorial  Group:

Dr  John Thompson      Canberra

Prof Adrian Sleigh  Australian National University, Canberra

A/Prof Paul Kelly   Australian National University, Canberra

Address for correspondence

Email: jtjnj@actewagl.net.au

Website >http://tbreview.wordpress.com

Contents

Infection

Diagnosis

HIV/AIDS and TB

Socio-political issues

Immune Studies

Prevention

Zoonoses

Risk Factors

Control

Treatment

Microbiology

Nontuberculous Mycobacteria

Editorial

In the May 22 and June 11  editions of the 2010 Lancet, this journal has continued its excellent service to those critically interested in the prevention and control of tuberculosis.  In particular, the articles tell us where we are at in terms of tuberculosis worldwide.  The news is very mixed indeed. Prevention by means of vaccination has not advanced.  Some vaccines are undergoing clinical trials (including one from Warwick Britten’s group in Sydney), but it is far too early to see widespread application.  Meanwhile, the number of notified cases across the world still tops 9 million with a decline in the incidence rate of less than 1% per annum.  80% of all tuberculosis can be found in 22% of the world’s nations.  The ongoing HIV/AIDS epidemic together with widespread poverty in these countries and increasing drug resistance, all help to reinforce the realization that we will not achieve the goal of eliminating TB by 2050.  There are other disappointments: the WHO guidelines for treatment failure by persistence of sputum smear positivity after 2 months of treatment has now been shown to be unreliable.  The good news is that more countries are able to cure a minimum of 85% of cases as well as detecting at least 70% of active pulmonary disease.  This disease has been with us a long time and will not readily  yield  to our present efforts.

Infection

Updated guidelines for using Interferon gamma release assays to detect Mycobacterium tuberculosis infection-United States, 2010.

Mazurek et al      CDC   Atlanta  GA     USA

MMWR Recommen Rep 2010; 59: 1

Abstract: CDC published guidelines for using the QuantiFERON-TB Gold test (QFT_G) (Cellistis,Carnegie, Victoria, Australia) (CDC: Guidelines for using the QuantiFERON –TB Gold test for detecting Mycobacterium tuberculosis infection, United States MMWR).  Subsequently, two new interferon gamma release (IFN-gamma) assays (IGRAs) were approved by the Food and Drug Administration (FDA) as aids in diagnosing M. tuberculosis infection, both latent infection and infection manifesting as M. tuberculosis. These tests are the QuantiFERON-TB Gold-in-tube test (QFT-GIT)(Cellistis Ltd, Carnegie ,Victoria, Australia) and the T-SPOT.TB test(T-Spot) (Oxford Immunotec Ltd., Abingdon, United Kingdom).  The antigens, methods and interpretation criteria for these assays differ from those for IGRAs approved previously by FDA.  For assistance in developing recommendations related to IGRA use, CDC convened a group of experts to review the scientific evidence and provide opinions regarding use of IGRAs.  Data submitted to FDA, published reports and expert opinion related to IGRAs were used in preparing these guidelines.  Results of studies examining sensitivity, specificity and agreement for IGRAs  and TST vary with respect to which test is better.  Although data on the accuracy of IGRAs and their ability to predict subsequent active tuberculosis are limited, to date, no major deficiencies have been reported in studies involving various populations.  This report provides guidance to US public health officials, health-care providers and laboratory workers for use of FDA-approved IGRAs in the diagnosis of M.tuberculosis infections in adults and children.  In brief, TSTs and IGRAs (QFT-G, QFT-GIT and T-Spot) may be used as aids in diagnosing M. tuberculosis infection.  They may be used for surveillance purposes and to identify persons likely to benefit from treatment.  Multiple additional recommendations are provided  that address quality control, test selection and medical management after testing.  Although substantial progress has been made in documenting the utility of IGRAs, additional research is needed that focuses on the value and limitations of IGRAs in situations of importance to medical care of tuberculosis control.  Specific areas needing additional research are listed.

Comment: The major limitation is that we don’t have a gold standard.

JT

Interferon gamma release assays: principles and practice.

Lalvani et al   London   UK

Enferm Infect Microbiol Clin  2010; 28: 245

Abstract: The last decade has witnessed significant advances in mycobacterial genomics and cellular research which have resulted in the development of two new blood tests, the enzyme-linked immunospot assay (ELISpot) (TSPOT.TB), Oxford Immunotec, Oxford,UK) and the enzyme-linked immunoabsorbent assay (ELISA)( QuantiFERON-TB Gold inTube,Cellestis, Carnegie, Australia).  These tests, which are collectively known as interferon gamma release assays (IGRAs) detect latent tuberculosis infection (LTBI) by measuring interferon (IFN)-gamma release in response to antigens present in Mycobacterium tuberculosis, but not bacille Calmette-Guerin (BCG) vaccine and most nontuberculous mycobacteria.  This is done  through enumeration of IFN-gamma-secreting T cells (ELISpot) or by measurement of IFN-gamma concentration (ELISA).  The evidence base for these tests has expanded rapidly and now demonstrates that IGRAs are more specific than the tuberculin skin test(TST) as they are not confounded by previous BCG vaccination.  In addition, with active tuberculosis (TB) as a surrogate for LTBI, it appears that the ELISA has a similar sensitivity to the TST, whereas the ELISpot is more sensitive.  Using degree of exposure as a surrogate for LTBI, both assays correlate at least as well with TB exposure as the TST.  Recent longitudinal data have now demonstrated the prognostic power of positive IGRA results in recent contacts for the subsequent progression to active TB.  Deployment of IGRAs, driven by new guidelines internationally, will impact on clinical practice in several ways.  Their high specificity means that BCG-vaccinated individuals with a false positive TST will not receive unnecessary preventive treatment, whereas improved sensitivity in individuals with weakened cellular immunity at highest risk of progressing to active TB (for example HIV-positive individuals) enables more reliable targeted testing and treatment of these vulnerable groups.  The role of IGRAs in active TB is less clear, but they may be useful as adjunctive tests in the diagnostic work-up of an individual with suspected TB.  Finally, recent developments and future developments in IGRA development  are reviewed.

Comment: In wealthy countries like Australia, we should be using both tests to detect LTBI.  If the tuberculin test (PPD 10units) is less than 15 mm induration,  then a QuantiFERON –TB gold in tube is called for .  This should considerably reduce the number of people treated unnecessarily.

JT

Tuberculin skin-test reactions are unaffected by the severity of hyperendemic intestinal Helminth infections and co-infections.

Zevallos  et al         Lima   Peru

Am J Top Med Hyg  2010; 83: 319

Abstract: The tuberculin skin test (TST) quantifies cell-mediated immunity to tuberculosis antigens.  Helminths suppress cell-mediated immunity, so we studies the effect of Helminth infection and deworming on the TST in a randomised, double blind, placebo controlled study in an indigenous Amazon community (n=195).  Stool microscopy diagnosed Helminths in 98% and co-infection with multiple species in 24% of study subjects.  The TST was positive (>/= 10mm) for 49%, and responses increased with age (P=0.001), bacille Calmette Guerin (BCG) vaccination (P=0.01) and tuberculosis contact ( P=0.05).  TST results had no association with Helminth-egg concentrations, species, or co=infections (all P>0.1)  One month after deworming  with albendazole (three daily 400-mg doses), Helminths were reduced , but 63  remained infected with Helminths.  Albendazole did not cause a change in TST size (P=0.8) or positivity (P=0.9) relative to placebo.  Thus, TST reactions were unaffected by albendazole therapy that partly cured intestinal Helminth infections, and TST interpretation was unaffected by high-burden Helminth infections and co-infection with multiple agents.

Comment Would  IGRA testing give similar results ?

JT

Diagnosis

Pitfalls of diagnostic laparoscopy in abdominal tuberculosis.

Meshikes A Dammam Saudi Arabia

Surg Endosc 2010; 24: 908

Background: Diagnostic laparoscopy currently is emerging as an important tool in the diagnostic armamentarium  for abdominal tuberculosis. (TB).  However, the laparoscopic view may be deceiving even to the most experienced eyes, and it is not uncommon for TB to be diagnosed erroneously before the final histologic confirmation is received.

Methods: A retrospective review of 20 diagnostic laparoscopies was conducted.  The cases erroneously diagnosed at laparoscopy were collected and analysed.

Results: Five cases were identified.  For two patients, the laparoscopic findings were thought to be those of carcinomatosis, but histology showed TB.  For the other three patients, TB was suspected laparoscopically, but the final diagnoses were carcinomatosis, spontaneous bacterial peritonitis and panniculitis.  Two patients died; one due to delayed diagnosis and treatment of abdominal TB and the other due to carcinomatosis.

Conclusion: For a percentage of patients, the laparoscopic features of abdominal TB at diagnostic laparoscopy may be mistaken for other pathologies.  Caution should be exercised before disclosure of the provisional diagnosis to the patient based on laparoscopy alone without histological confirmation.

Comment: If they can’t get the diagnosis right in Saudi Arabia where the TB is common, we in Australasia must  be even more cautious  in similar circumstances.

JT

The role of chest CT scanning  in TB outbreak investigation.

Lee  et al      Seoul         ROK

Chest  2010; 137: 1057

Background: In TB outbreaks, detecting active cases is the key step in stopping transmission of the disease.  The aim of this study was to evaluate the role of high-resolution  CT (HRCT) scanning of the chest in the investigation of a TB outbreak that developed in a cohort of 92 soldiers  in the South Korean army.

Methods: Outbreak investigation, including tuberculin skin test(TST), QuantiFERON TB GOLD-in-Tube (QFT) test and simple chest radiograph (CXR) was performed.  For participants with any abnormal findings in these tests, HRCT scanning was done.  Active pulmonary tuberculosis was diagnosed based on sputum studies or HRCT scan findings.  In addition, participants with positive results in both TST and QFT were treated as having a latent YB infection (LTBI).  TST and QFT were repeated in participants with a positive result in one of these tests.  CXR was repeated in all participants at 3 and 6 months of follow-up

Results:  Eighty seven participants completed the study protocol.  Among them, 18 active TB cases were diagnosed.  Nine of these had normal CXR, but had lesions that were suggestive  of active TB on HRCT scan.  Twenty two participants with normal HRCT scans and positive results in either TST or QFT, nine completed a 3 month investigation.  All but one of nine participants revealed positive results in both tests.

Conclusion: Inclusion of HRCT scanning in the outbreak investigation of TB may be helpful in differentiating active TB from LTBI more reliably.

Comment: Until we know the dose of  radiation exhibited by these particular HRCT scans and the size of the supposedly active lesions  detected by scan, it is difficult accept that this modality is suitable for screening in TB contact action.

JT

HIV/AIDS

Self-reported HIV testing practice among physicians treating tuberculosis in Australia and New Zealand.

Emerson et al   Randwick    NSW

Int J STD AIDS  2010; 21: 346

Abstract: Not all people with tuberculosis have their HIV status ascertained  despite the interaction between these infections.  We investigated the self-reported HIV testing practice among physicians  treating tuberculosis in Australia and New Zealand and used logistic regression to assess factors associated with a routine offer of HIV testing in cases of tuberculosis.  Of 290 subjects, 61% always recommended an HIV test for a 38 year –old married man with smear-positive pulmonary tuberculosis.  A lower proportion (40%) always tested a 78-year old man or a female patient(58%), and more always tested a South African case(85%), a patient with oral candidiasis(87%)  or an unmarried male patient (66%).  No scenario was associated with a universal offer of HIV testing.  Clinician factors such as specialty (odds ratio [OR] 3.09),, jurisdiction of practice (OR 4.09) and number of HIV tests requested in the last year (OR 0.29) predicted the self-reported frequency of always HIV testing tuberculosis patients.  At least 48% of respondents reported  that epidemiological or clinical factors influenced their decision to offer testing.  Strategies to increase HIV testing in cases of tuberculosis need to consider clinician factors.

Comment: The authors correctly assume that all cases of tuberculosis should be tested for the HIV virus.  Is the low frequency of testing due to the fact that in the 1990s in Australia, clinicians were almost intimidated not to offer routine HIV testing?  What is also remarkable is that in a population of some 26 million, a rare disease is being managed by no less than  290 clinicians.

JT

Socio-political issues

Impact of treatment completion, intolerance and adverse events on health system costs in a randomised trial of 4 months rifampin or 9 months isoniazid for latent TB.

Aspler et al      Montreal   Canada

Thorax  2010; 65: 582

Rationale: Treatment for latent tuberculosis infection with isoniazid for 9 months (9H) has poor completion and serious adverse events, while treatment for 4 months with daily rifampin (4R) has significantly higher completion (rates) and fewer adverse events.

Objectives: To compare the health system costs of 4R and 9H.

Methods: In a randomised trial conducted in five Canadian centres, one Brazilian and one Saudi Arabian centre, consenting subjects were randomised to receive 4R or 9H.  Health system costs were estimated from healthcare utilisation including scheduled and unscheduled visits, investigations and drugs.  All activities for all subjects were evaluated using financial information from 2007 from the Montreal Chest Institute.  Costs were expressed in Canadian dollars.

Results: Total health system cost per patient allocated to 4R was 4854 compared with $970 for 9H (p< 0.0001).  The average cost per patient for the 328 of the 420 (78%) who completed 4R therapy was $1094 compared with $ 1625 for the 254 of 427 (60o%) completing 9H (p< 0.0001).  Costs were modestly increased in patients with minor intolerance and substantially increased if the treating physician stopped treatment because of possible adverse events.  Total costs related to management of adverse events with 9H were $ 48,142 compared with  $25,684 for 34R (p=0.008). Using these data, incremental cost-effectiveness showed that 4R would be cast saving and prevent more cases within 2 years if efficacy exceeded 74% and cost saving if efficacy exceeded 65%.

Conclusions: The 4R regimen was significantly cheaper per patient completing treatment because of better completion and fewer adverse events.

Comment: Yes. there are savings here, but they seem pretty trivial when compared to the daily cost of a hospital bed in Australia of A$ 1200, or a single dose of carboplatin for non-small cell lung cancer of A$415 or a single injection of an anti-TNF drug of A$900 or a treatment for pulmonary artery hypertension  of A$2000 a week.  Besides the savings for an Australian 6H would be less.

JT

Immune Studies

The Vitamin D axis in the lung: a key role for Vitamin D-binding protein.

Chishimba et al   Birmingham   UK

Thorax  2010; 65: 456

Abstract: There has been much recent interest in the role of the vitamin D  axis in lung disease, which includes vitamin D, vitamin D receptor(VDR) and vitamin D-binding protein (VDBP, also known as Gc-globulin).  VDBP is a serum protein which has immunomodulatory functions  relevant in the lung, predominantly relating to macrophage activation and neutrophil chemotaxis.  Variations within its gene are also associated with airways disease, implying a role for the protein product in pathogenesis.  Thus far the majority of evidence relates to chronic obstructive pulmonary disease (COPD), but is scant in other airways diseases such as asthma and bronchiectasis.  VDBP also acts as a scavenger protein to clear extra-cellular G-actin released from necrotic cells, which may be of relevance in severe lung infections and acute lung injury.  Vitamin D protects against the development of cancer and tuberculosis, although optimal levels are unknown.  The majority of circulating vitamin D is bound to VDBP and its uptake into cells occurs in both bound and unbound forms, which suggests the role of VDBP warrants further study in these conditions as well..  This article reviews the evidence of the role of VDBP and its gene in a range of lung diseases, including asthma, COPD and tuberculosis.

Comment:  As the next article confirms we have to  have to regard Vitamin D as a hormone rather than a vitamin.

JT

Does vitamin D make the world go ‘round’ ?

Wagner et al   Charleston  SC  USA

Breastfeed Med  2008; 3: 239

Abstract: Vitamin D has emerged from obscurity , and its effects on various organ systems throughout the body down to the cellular level are being discovered.  What was thought to be a agent affecting only bone and calcium metabolism has shifted.  We no longer see vitamin D as a ‘vitamin’ important only in childhood, but as a complex hormone that is involved not only in calcium homeostasis but also in the integrity of the innate immune system.  Vitamin D deficiency is linked to inflammatory and long-latency diseases such as multiple sclerosis, rheumatoid arthritis, tuberculosis, diabetes and various cancers, to named a few.  In this review we trace how we came to view vitamin\ D and how that view led to one of the largest epidemics of nutrient deficiency beginning in the late 20^th century.  We then discuss the need  for  Vitamin D in the context  of the breast feeding mother and her infant and child, why breastfed are particularly at risk and what to do about it.

Comment: But do serum Vitamin D levels truly reflect the body stores?

JT

Prevention

New Vaccines for tuberculosis

Kaufmann et al  Berlin   Germany

Lancet  2010; 375: 2110

Abstract: New vaccines are urgently needed if we want to reach the goal of substantially reducing the incidence of tuberculosis by 2050.  Despite a steady increase in funding over the past decade, there is still a striking financial shortfall for vaccine research and development for tuberculosis.  Yet, around ten vaccine candidates have left the laboratory stage and entered clinical trials.  These vaccines are either aimed at replacing the present vaccine, BCG, or at enhancing immunity induced by BCG.  However, these pre-exposure candidates are designed for prevention of disease and will therefore neither eradicate the pathogen nor prevent stable infection.  Long-term vaccination strategies need to target these ambitious goals.  Even though vaccine development will have a price, the return of investment will greatly exceed original costs.

Comment: But will they first be used on those most  at need?

JT

Zoonoses

Tuberculosis in humans and animals: an overview.

Lobule et al  Atlanta GA & Iowa  USA,  Paris  France.

Int J Tuberc Lung Did  2010; 14: 1075

Abstract: Tuberculosis (TB) is a significant disease for both humans and animals.  Susceptibility to Mycobacterium tuberculosis is relatively high in humans, other primates and guinea pigs.  Cattle rabbits, rabbits and cats are susceptible to M.bovis are quite resistant to M.tuberculosis.  Wild, hoofed stock is susceptible to M.bovis, but few reports are available on the isolation of M.tuberculosis.  Swine and dogs are susceptible to both M.bovis and M.tuberculosis.  M.bovis accounts for only a small percentage of the reported cases of TB in Humans; however, it is a pathogen of significant economic importance in wild and domestic animals around the globe, especially in countries where little information is available on the incidence of M. bovis infection in humans.  Unlike transmission of M.bovis from cattle to humans, the role of human-to-human airborne transmission in the spread of M.bovis has been somewhat controversial.  Investigations are needed to elucidate the relative importance of M.bovis on TB incidence in humans, especially in developing countries. Efforts should be concentrated  in countries where human immunodeficiency virus (HIV) infection is widespread, as HIV-infected individuals are more susceptible to mycobacterial disease.  Eradication of M.bovis and pasteurisation of dairy products are the cornerstones of the prevention of human disease.

Comment: Certainly, but it took Australia well over a hundred years to complete the second part of the cornerstone.

JT

Risk Factors

Silicosis in automobile foundry workers: a 29 year cohort study .

Zhang et al    Beijing     China

Biomed Environ Sci  2010; 23: 121

Objectives: The purposes were to determine the relationship between silicosis among foundry workers and their cumulative exposure to silica dust, and to establish a regression model to predict the risk for developing silicosis by a given length of employment and air concentration of silica at work sites.

Methods: A 29-year cohort study was conducted, including all those employed for more than one year  January 1, 1980 to December 31, 1996 and all members of the cohort were followed-up to December 31, 2008.  In total, 2009 workers of an automobile factory in Shiyan, Hubei province  were recruited into the study, 1300 at eight worksites including sand preparation, cast shakeout, and finishing, melting ,moulding,coremaking, overhead crane operation and pouring as exposed group, and the other 709 auxiliary workers at the same factory such as electricians, inspectors, fitters and so on, as control group.  Person-years of observation were calculated by persons observed and years followed up for each of them.  Person-year incidence of silicosis and its relative risk(RR) or odds ratio (OR) and 95% confidence intervals (CI)among the workers were estimated, adjusted for relevant factors with logistic regression model using  SPSS version 15.0 software.

Results: Totally, 2009 workers were followed up  for 37151 person-years and 48 cases of silicosis were found with an overall incidence of 1.34 per thousand, 2.02 per thousand in the exposed group and 0.15 per thousand in the control group (RR13.13, 95%CI 3.18-54.13), higher in men than that in women(RR= 13.92, 95% CI=1.92-100.93).  Risks of silicosis varied by job, highest in those exposed to cast shakeout and finishing (RR =28.14, 95% CI=6.43-123.11)) followed by those exposed to pouring (RR=22.23,95% CI=5.01-98.55) in the foundry.   The average length of employment at onset of silicosis was 25.94 years, and silicosis incidence increased with length of employment.  Average age at onset of silicosis was  47.83 years..  The risk of pulmonary tuberculosis in workers with silicosis was increased 2.57 fold (P<0.01) Ten deaths were recorded in those with silicosis, with a case fatality rate of 20.83 per cent.  Three of them died of lung cancer, three of liver cancer, two of ischaemic heart disease and two of other diseases.  Incidence of silicosis in foundry positively correlated with their cumulative silica  exposure (OR=3.0,95% CI=2.34-3.83)  Risks of silicosis increased 4.38 fold with an increase of 1mg/m3-year of cumulative silica exposure and by 3.79 fold with smoking, respectively, adjusted for alcohol drinking and age.  Based on a logistic regression model fitted, incidence of silicosis is expected to be 44.6 per thousand with daily exposure  to silica of 4.18 mg/m3 on average for 30 years, and if incidence of silicosis is expected to be less than 1 per thousand , daily exposure to silica should be controlled below0.2 mg/cm3 for those with 20 years of employment, or below 0.1 mg/cm3 with 30-40 years of silica exposure.

Conclusions: At present, foundry workers in china still face high risk of developing silicosis.  For lowering occurrence of silicosis in exposed workers, it seems necessary that current occupational exposure limits for silica at worksites in China should be re-examined and silica dust control measures be strengthened.

Comment This could be a report on silicosis and tuberculosis among rock miners in Australia 100 years ago.

JT

Control

Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis.

Horne et al   Seattle  WA    USA

Lancet Infect Dis 2010; 10: 387

Abstract: WHO has previously recommended sputum-smear examination at the end of the second month of treatment in patients with recently diagnosed pulmonary tuberculosis, extension of the intensive therapy phase.  We did a systematic review and meta-analysis to assess the accuracy of a positive sputum smear or culture during treatment for predicting failure or relapse in pulmonary tuberculosis.  We searched PubMed, EMBase and the Cochrane Library for studies published in English  through December ,2009.  We included randomised controlled trials, cohort, and case controlled studies of previously untreated pulmonary tuberculosis patients who had received a standardised regimen with rifampin in the initial phase.  Accuracy results were summarised in forest plots and pooled by use of a hierarchical regression approach.  15 papers (28 studies) met the inclusion criteria.  The pooled sensitivities  for both 2-month smear (24% [95% CI 12-42%], six studies) and culture (40% [95% CFI 25-56%],four studies) to predict relapse were low. Corresponding specificities (85%[95%CI 72-90%] and 85%[95%CI 77-91%]) were higher but modest. For failure , 2-month smear (seven studies) had low sensitivity  (57%[95%CI41-73%]) and higher though modest specificity (81%[95%CI72-87%]).  Both sputum smear microscopy and mycobacterial culture during tuberculous treatment have low sensitivity and modest specificity for predicting failure and relapse.Although we pooled a diverse group of patients, the individual studies had similar performance characteristics. Better predictive markers are needed.

Comment: The WHO recommendations apply to countries where sputum culture is not available.  In view of the modest specificity of positive smears at two months of treatment to predict failure, as found by this study, it would be wise not to abandon the WHO recommendation yet.

JT

Tuberculosis control and elimination 2010-2050: cure, care and social development.

Lonroth et al  Geneva  Switzerland

Lancet  2010; 375: 1814

Abstract: Rapid expansion of the standardised approach to tuberculosis diagnosis and treatment that is recommended by WHO allowed more than 36 million people to be cured between 1995 and 2008, averting up to 6 million deaths. Yet tuberculosis remains a severe global public health threat.  There are more than 9 million new cases every year worldwide, and the incidence is falling at less than 1% per year.  Although the overall target related to the Millennium Development Goals of halting and beginning to reverse the epidemic might have already been reached by 2004, the more long term elimination target set for 2050 will not be met with present strategies and instruments.  Several key challenges persist.  Many vulnerable people do not access to affordable services of sufficient quality.  Technologies for diagnosis, treatment and prevention  are old and inadequate. Multi-drug resistant  tuberculosis is a serious threat in many settings in many settings.  HIV/AIDS continues to fuel the tuberculosis epidemic, especially in Africa. Furthermore, other risk factors and underlying social determinants help to maintain tuberculosis in the community.  Acceleration  of the decline towards elimination of this disease will need invigorated actions in four broad areas: continued scale up of early diagnosis and proper treatment of all forms of tuberculosis in line with the Stop TB Strategy; development and enforcement  of bold health system policies; establishment of links with the broader development agenda; and promotion and intensification of research towards innovations.

Comment: Some technologies may be old and inadequate but others have never been used properly.

JT

Active Screening at entry for tuberculosis  among new immigrants: systematic review and meta-analysis.

Ashad et al        London     UK

Eur Resp J  2010; 35: 1336

Abstract: Although there is no evidence that imported tuberculosis increases the incidence of the disease in host countries, the rise in migration worldwide raises concerns regarding the adequacy of surveillance and control of immigrant-associated tuberculosis in low-incidence countries.  Assessing the performance of screening of immigrants for tuberculosis is key to rationalizing control policies for the detection and management  of immigrant –associated tuberculosis. We performed a systematic review  and meta-analysis to determine the yield of active screening for tuberculosis among new immigrants at the point of entry.  The yield for pulmonary tuberculosis was 3.5 cases per 1000 screened (95% CI 2.9-4.1; I(2)=94%); for refugees, asylum seekers and regular immigrants the estimates were 11.9 (95% CI 6.7-17.2; I(2)92%), 2.8 (95% CI 2.0-3.7; I(2) =96%) and 2.7 (95% CI 2.0-3.4; I92)=81%), respectively.  The yield estimates for immigrants from Europe, Africa and Asia were 2.4 (95% CI 1.3-3.4; I92)51.5%), 6.5 (95% CI 3.2-10.0; I920= 62%) and 11.2 (95% CI 6.2-16.1; I(2)=95%), respectively.  These results provide useful data to inform the development of coherent policies and rational screening services for the detection of immigrant–associated tuberculosis.

Comment: So very little has changed  over the years.

JT

Treatment

Inconsistent dosing of anti-tuberculosis drugs in Taipei, Taiwan

Chiang et al  Taipei   Taiwan

Int J Tuberc Lung Dis 2010; 14: 878

Setting: Taipei City, Taiwan

Objectives: To evaluate prescribing practices for anti-tuberculosis drugs in the treatment of tuberculosis (TB).

Method: Medical audit of the medical charts of all patients notified and treated for TB in Taiwan in 2003 to determine the treatment regimens prescribed and compare these with recommended dosages.

Results: A total of 24 different anti-tuberculosis regimens were prescribed.  Of 1700 patients notified, 1096 (64.5%) had their body weight recorded.  Of 506 patients prescribed a three-drug fixed-dose combination (FDC), the dosage was adequate in 374 (73.9%), too low in 100 (19.8%), and too high in 32 (6.3%).  Of 75 patients prescribed a two-drug FDC, the dosage was adequate in 57 (76.0%), too low in 15 (20%) and too high in 3 (4%).  Of 481 patients prescribed rifampicin, the dosage was adequate in 302 (62.8%), too low in 152 (31.6%) and too high in 27 (5.6%).  Of 451 patients prescribed isoniazid, the dosage was adequate in 396 (87.8%), too low in 29 (6.4%) and too high in 26 (5.8%).

Conclusion: The prescribing practices for anti-tuberculosis drugs were substandard and need improvement.  These findings imply that the National TB Programme needs strengthening.

Comment: In those patients not weighed, could the drug dose estimates have been even sloppier ?

JT

Follow-up of patients with multidrug resistant tuberculosis four years after standardized first-line drug treatment.

He et al       Beijing        China

PLoS One  2010;5:e10799

Background: In 2004, an anti-tuberculosis (TB) drug resistance survey in Heilongjiamg province China, enrolled 1574  (79%) new and 421 (21%) retreat5ment patients.  Multidrug resistant (MDR ) TB was detected in 7.2% of new and 30.4% of retreatment patients. All received treatment with standardized first-line (FLD) regimens.

Methodology/Principal findings: We report treatment outcomes of the 2004 cohort, and long-term outcomes as assessed in the second half of 2008.  The reported cure rate for MDR-TB patients was 83% (94/113) among new and 66% (85/128) among retreatment patients(P<0.001).  Ten of 241 MDR-TB patients died during treatment.  Of the remaining 231, 129 (56%) could be traced  in 2008.  The overall recurrence rates among new and retreatment cases were 46% and 66% , respectively(P=0.03).  The overall death rates among new and retreatment cases were 25 and 46% ,respectively (P=0.02).  Forty percent of the traced new cases and 24% of the retreatment cases were alive and without recurrent TB(P=0.01).  Of the 16 patients who failed or defaulted from treatment in 2004, only two patients were not re-diagnosed with TB  by 2008.  Of the 111 (86%) patients with an initial successful treatment outcome, 63  (57%) had developed recurrent TB, 40 (36%( had died, 27 (24%) of them died of TB.  The follow-up period of four years precluded follow-up of all patients .  In a highly conservative sensitivity analysis in which we assumed that all non-included patients were alive and did not have recurrent TB, the recurrence and death rate were 33% and 21%.

Conclusions/Significance: Documentation of cure based on conventional smear microscopy was a poor predictor of long term outcomes.  MDR-TB patients in Heilongjiang province in China had high recurrence and death rates four years after treatment with standardised FLD regimens, reinforcing the need for early diagnosis and treatment of MDR-TB, including assessment of treatment outcomes with more sensitive laboratory methods.

Comment: Given the natural history of TB, in which patients follow a long course of relapses and remissions, it is likely there will be even more recurrences after 8 years.

JT

Microbiology

Use of simulated sputum specimens to estimate the specificity of laboratory-diagnosed tuberculosis.

Demers et al   Quebec & Montreal Canada, Cape town & Tygerberg South Africa, The Hague & Amsterdam  Netherlands.

Int J Tuberc Lung Dis  2010; 14: 1016

Setting: Cross-contamination is not uncommon in mycobacteriology laboratories of high-income countries, as documented by bacterial genotyping. The extent of this problem in low-income countries is largely unknown where this method is impractical.

Objective: To estimate the rate of cross-contamination in a high-volume tuberculosis (TB) laboratory in South Africa.

Design: Simulated sputum specimens labelled with false names were sent from a TB clinic, interspersed with patient samples, and processed for culture and microscopy.  Results were interpreted in the context of the observed proportion of samples with positive microscopy and culture results.

Results: With microscopy, 6/190 (3.2%) simulated specimens were positive (estimated specificity =96.8%).  Considering the 881 positive microscopy results in  6093 clinical samples, we extrapolate that 19.3% (95% CI 7.0-42.8) of positive smears were false positives. On culture, 2/190 (1.1%) of the simulated specimens were positive for Mycobacterium tuberculosis. (estimated specificity=98.9%).  Considering the 1862 positive cultures from 6093 clinical samples, we estimate that 2.4% (95% CI 0.3-8.8) of positive cultures were false –positives.

Conclusion: Simulated specimens offer a means of estimating the proportion of false positive results, providing information on all sources of potential error  from the clinic, through the laboratory and to reporting of results.

Comment: A further reminder to the clinician not to make a  firm diagnosis on the basis of an abnormal laboratory test alone.

JT

Nontuberculous  Mycobacteria

Impact of human activities on the ecology of nontuberculous mycobacteria.

Falkinham J O  Blacksburg VA  USA

Future Microbiol 2010; 5: 951

Abstract: Nontuberculous mycobacteria (NTM) are environmental opportunistic pathogens of humans and animals.  They are found in a wide variety of habitats to which humans are exposed, including drinking water distribution systems and household water and plumbing.  In that regard, they are distinct from their obligate pathogenic relatives, the members of the Mycobacterium tuberculosis complex.  Owing to the presence of NTM in the human environment, human activities have had direct impacts on their ecology and thereby their epidemiology.  NTM are oligotrophic, able to grow at low organic matter concentrations and over a wide range of temperatures, and even at low oxygen concentrations.  Thus NTM are normal inhabitants of natural waters and drinking waters.  Discovery of the presence of NTM-polluted soils is not surprising in light of the ability of NTM to degrade a variety of hydrocarbon pollutants.  A major human activity selecting for the growth and predominance of mycobacteria in habitats is disinfection.  In comparison to other bacteria, NTM are disinfectant , heavy metal and antibiotic resistant.  Therefore, the use of any antimicrobial agent selects for mycobacteria.  Use of disinfectant in drinking water treatment  selects for mycobacteria that can grow and come to proliferate in drinking water distribution systems in the absence of disinfectant-sensitive competing micro-organisms.  NTM selection may also occur as a consequence of antibiotics in drinking water sources.

Comment: The author has given us plausible reasons why NTM are being isolated from sputum specimens more frequently than in the past, although not necessarily leading to an increased rate of disease caused by these organisms.

JT

Cavitating Pulmonary TB- courtesy  IUATLD

June   2010

M. tuberculosis                              EM Photo

Forthcoming Meetings

41 th   Union World Conference on Lung Health:   Berlin   Germany

11-15 November 2010

Website: Berlin 2010

Editorial  Group:

Dr  John Thompson      Canberra

Prof Adrian Sleigh  Australian National University, Canberra

A/Prof Paul Kelly   Australian National University, Canberra

Address for correspondence

Email: jtjnj@actewagl.net.au

Website http://tbreview.wordpress.com

Contents

Editorial

Treatment

Risk Factors

TB and HIV/Aids

Adverse Reactions

Extrapulmonary TB

Zoonoses

Surgery

Immune Studies

Epidemiology

Infection

Diagnosis

Pharmacokinetics and Imaging

Microbiology

Control

Prevention

Catastrophe Corner

Editorial

The report from Japan in the “Infection section”  of this edition tells us of attempts to diagnose TB infection in health care workers exposed to tuberculous patients.  They used one of the better Interferon-gamma tests (QFT-G) and followed the health care workers for  between two and four years.  As expected, a small number converted their test from negative to positive, but only by small amounts.  What was surprising to the authors was that nearly half (41%) of the subjects reverted to negative during follow-up.  The numbers in this study are small, but we should not be surprised at the results.  They mirror those of the Prophit study over half a century before, where in a much larger population, follow-up tuberculin testing showed that nearly half of those considered positive, eventually reverted.  We had hoped that the new diagnostic tests would not show this trend, but remember that in the Prophit study, the larger the tuberculin reaction, the less likely it would revert.  In the present study the same may well be true, but larger numbers are needed to confirm this. We should not be  naïve enough to think that we can set an absolute value on any test to diagnose TB infection and expect  that the so called “cut point” will exclude  or include all such infections. More follow-up studies on interferon-gamma positive subjects are needed to find out if we have been setting the bar too low.

Treatment

Adding moxafloxacin is associated with a shorter time to sputum conversion in pulmonary tuberculosis.

Wang et al  Taipei  Taiwan

Int J Tuberc Lung Dis 2010; 14: 65

Objective: To investigate whether adding moxafloxacin (MXF) to the standard anti-tuberculosis regimen can shorten the time to sputum culture conversion in pulmonary tuberculosis (PTB).

Methods: Adults with sputum culture positive PTB were divided into two treatment groups by their choice: standard regimen alone (HERZ group) and standard regimen plus daily MXF in the first two months (MXF group).  Sputum samples were collected thrice weekly in the first 8 weeks.  The propensity score was calculated to estimate the conditional probability of entering the MXF group.  Factors influencing time to sputum conversion were investigated using Cox proportional hazards regression analysis stratified by propensity score.

Results: Sixty two patients were enrolled in the MXF group and 88 in the HERZ group; respectively 51 and 72 completed the study..  The regimen was modified before sputum conversion in respectively 6 (12%) and 12 (16%; P=0.47) patients, due to adverse effects..  The time to culture conversion was shorter in the MXF group ( HR 2.1, 95% CI 1.4-3.2).  The culture conversion rate after 6 weeks of treatment was respectively 89% and 61%  (P=0.011), < 0.05/4, calculated using the modified Bonferroni method).

Conclusions: Adding MXF to the standard anti-tuberculosis regimen in the first 2 months was associated with a shorter time to culture conversion, a higher 6-week culture conversion and reduced transmission of tuberculosis.

Comment: An interesting pilot study!

JT

Risk Factors

Passive smoking and tuberculosis

Leung et al      Hong Kong     China

Arch Intern Med 2010; 170: 287

Background: Increasing evidence has incriminated active smoking as a causal factor for tuberculosis(TB).  However, the effect of secondhand tobacco smoke exposure on TB has not been similarly elucidated.

Methods: A cohort of 15,486 female never-smokers aged 65 to 74 years and living with their surviving husband were enrolled at 18 Elderly Health Centers in Hong Kong from 2000 to 20003 and followed up prospectively  through linkage with the territory-wide notification registry and death registry for TB and death until December 23 2008, using an identity card number as a unique identifier.  The relationship between passive smoking and development of TB was assessed with adjustment for other baseline characteristics.

Results: Passive exposure to secondhand tobacco smoke in the household was independently associated with obstructive lung disease (odds ratio [OR], 1.43; 95% CI,1.16-1.77) and diabetes mellitus (OR,1.13; 95% CI 1.02-1.26) at baseline and with the development of both active TB (HR,1.49; 95% CI, 1.01-2.19) and culture confirmed TB (HR 1.70; 95% CI,1.04-2.80) on prospective follow up after potentially confounding background variables were controlled for.  Passive smoking accounted for 13.7% of active TB and for 18.% % of culture –positive TB in this cohort.Conclusions: Similar to active smoking, passive exposure to secondhand tobacco smoke in the household also predisposes to the development of TB.  Increased emphasis should therefore be put on tobacco control in national TB programs.

Comment: I am not certain that all confounding factors have been allowed for .

JT

Tumour necrosis factor inhibitors and risk of serious infection in rheumatoid arthritis.

Katikireddi  et al   Adelaide   South Australia

Int J Rheum Dis 2010;13: 12

Abstract: Tumour necrosis factor inhibitors have demonstrated significant clinical and radiological benefits in rheumatoid arthritis (RA).  However, they have important adverse events including an association with infection.  Results from current studies, including meta-analyses of randomized controlled trials and observational studies, are conflicting regarding the risk of serious infection in RA patients treated with TNF inhibitors.  The majority of data suggest an increased risk, in particular of respiratory , skin and soft tissue infections, including tuberculosis.  This increased risk of tuberculosis is of particular concern in the APLAER region.  However, adverse event analysis remains a difficult area to study and decisions regarding initiation of TNF inhibitors must be made on a case-by-case basis after carefully considering the risks and benefits.

Comment: And adequate screening for TB.

JT

Mycobacterium tuberculosis infection in transplant recipients: early diagnosis and treatment of resistant tuberculosis.

Holty et al    Stanford    CA       USA

Curr Opin Organ Transplant 2009;14: 613

Purpose of review: To provide a better understanding and summarize recent advances in the diagnosis and treatment of Mycobacterium tuberculosis (MTB) infection in solid organ transplant (SOT) candidates and recipients.

Recent Findings: Despite advances in SOT medicine, MTB causes substantial morbidity and mortality in SOT recipients, with reported prevalence rates of 0.4-6%.  The primary source of post transplant MTB is reactivation of pretransplant latent MTB infection.  The short-term mortality rate in SOT recipients with drug-susceptible active MTB is 30%.  In immunocompromised persons with extensively drug-resistant MTB, the mortality rate approaches 100%. Clinical presentation is often atypical with more than half of SOT recipients presenting with extrapulmonary or disseminated disease.  Pretransplant latent MTB infection screening is the cornerstone for preventing reactivation and dissemination of active MTB post transplant.  Treatment of active MTB in SOT recipients is problematic, given significant drug toxicity and interaction with immunosuppressive agents.

Summary: A high degree of suspicion for latent and active MTB infection in SOT  candidates and recipients is warranted to establish a timely diagnosis and initiate life-saving appropriate therapy.

Comment: Worse still, some recipients are already immunosuppressed and have diminished tuberculin or interferon activity.

JT

Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review.

Liang et al     Shenyang    China

Int J Cancer 2009; 125: 2936

Abstract: There has been conflicting evidence  concerning the possible association between tuberculosis(TB) and subsequent risk of lung cancer.  To investigate whether currently published epidemiological studies can clarify this association, we performed a systematic review of 37 case-control and 4 cohort studies (published between January 1966 and January 2009) and a meta-analysis of risk estimates, with particular attention to the role of smoking, passive smoking and the timing of diagnosis of TB on this relationship.  Data for the review show a significantly increased lung cancer risk associated with preexisting TB.  Importantly, the association was not due to confounding by the effects of tobacco use (RR=1.8, 95%CI=1.4-2.2, among  never smokers), lifetime environmental  tobacco smoke exposure (RR=2.9, 95% CI= 1.6-5.3, after controlling) or the timing of diagnosis of TB (the increased lung cancer risk remained 2-fold elevated for more than 20 years after TB diagnosis).  Interestingly, the association was significant with adenocarcinoma (RR=1.6, 95% CI=1.2-2.1), but no significant associations with squamous and small cell type of lung cancer were observed.  Although no causal mechanism has been demonstrated for such an association , present study supports a direct relation between TB and lung cancer, especially adenocarcinomas.

Comment:  So the association still holds up after all these years!

JT

TB and HIV/AIDS

Treatment of latent tuberculosis infection in HIV infected persons.

Akolo et al  Oxford  United Kingdom

Cochrane Database Syst Rev 2010; 1: CD000171

Background: Individuals with human immunodeficiency virus (HIV) infection are at increased risk of developing active tuberculosis (TB) .  It is known that treatment of latent TB infection (LTBI), also referred to as TB preventive therapy or chemoprophylaxis, helps to prevent progression to active disease in HIV negative populations.  However, the extent and magnitude of protection, if any,  associated with preventive treatment in those infected with HIV should be quantified. This present study is an update of the original review.

Objectives: To determine the effectiveness of TB preventive therapy in reducing the risk of active tuberculosis and death in HIV-infected persons.

Search Strategy: This review was updated using the Cochrane Controlled Trials Register (CCTR), Medline, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway and AIDSDRUGS (publication date from 1 July 2002 to 4 April 2008).  We also scanned reference lists of articles and contacted authors and other researchers in the field in an attempt to identify additional studies that might be eligible for inclusion in this review.

Selection Criteria: We included randomized controlled trials in which HIV positive individuals were randomly allocated to TB preventive therapy or placebo, or to alternative TB preventive therapy regimens.  Participants could be tuberculin skin test positive or negative, bur without active tuberculosis.

Data Collection and Analysis: Three reviewers independently applied the study selection criteria, assessed study quality and extracted data.  Effects were assessed using relative risk for dichotomous data mean differences for continuous data.

Main Results: 12 trials were included with a total of 8578 randomized  participants. TB preventive therapy (any anti-TB drug) versus placebo was associated with a lower incidence of active TB (RR 0.68, 95% CI 0.54-0.85). This benefit was more pronounced in individuals with a positive tuberculin skin test (RR 0.38,95% CI 0.25—0.57) than in those who had a negative test (RR 0.89, 955 CI 0.64-1.24).  Efficacy was similar for all regimens (regardless of drug type, frequency or duration of treatment).  However, compared to INH monotherapy, short course multi-drug regimens were more likely to require discontinuation of treatment due to adverse effects.  Although there was reduction in mortality with INH monotherapy versus placebo  among individuals with a positive tuberculin skin test(RR 0.74, 95% CI 0.55 -1.0) and with INH plus rifampicin versus placebo regardless of tuberculin skin test status(RR 0.69, 95% CI 0.50-0.50), overall, there was no evidence that TB preventive therapy versus placebo reduced all-cause mortality(RR 0.94, 95%CI 0.85- 1.05).

Authors’ Conclusions: Treatment of latent tuberculosis infection reduces the risk of active TB in HIV positive individuals especially in those with a positive tuberculin skin test.  Future studies should assess these aspects.  In addition, trials evaluating the long term effects of anti-tuberculosis chemoprophylaxis, the optimum duration of TB preventive therapy, the influence  of level of immunocompromise on effectiveness and combination of anti-tuberculosis chemoprophylaxis  with antiretroviral therapy are needed.

Comment: One can be persuaded that there is little point in giving preventive therapy to HIV individuals who are tuberculin negative, unless severely immunosuppressed.

JT

Timing of initiation of antiretroviral drugs during tuberculosis therapy.

Abdool Karim et al   Durban    South    Africa

N Engl J Med 2010; 362: 697

Background: The rates of death are high among patients with coinfection with tuberculosis  and the human immunodeficiency virus (HIV).  The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial.

Methods: In an open label, randomized, controlled trial in Durban South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy  (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group).  The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli.  Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included .  All patients received standard tuberculosis therapy, prophylaxis with trimethoprim-sulphamethoxazole, and a once daily antiretroviral regimen of didanosine., lamivudine and efavirenz.  The primary end point was death from any cause.

Results: This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy.  There was a reduction in the rate of death among the 429 patients  in the combined integrated –therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential –therapy group 12.1 per 100 person-years), or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated –therapy groups, 0.44; 95% CI 0.25-0.79; P=0.003).  Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata.  Rates of adverse events during follow-up were similar in the two study groups.

Conclusions: The initiation of antiretroviral treatment during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services.

Comment: So it seems in this series that the reconstitution syndrome frequency was not increased by starting HAART early.

JT

Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis.

Muller  et al   Bern   Switzerland

Lancet Infect Dis 2010; 10: 25

Abstract: In patients with HIV-1 infection who are starting antiretroviral therapy (ART) , the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well defined.  We did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections, and examined the relationship between occurrence  and the degree of immunodeficiency.  Systematic review identified 54 cohort studies of 13,103 patients starting ART, of whom 1,699 developed IRIS,  We calculated pooled cumulative incidences with 95% credibility intervals (Crl) by Bayesian methods and did a random effects metaregression to analyse the relation between D4 count and incidence of IRIS, In patients with previously diagnosed AIDS-defining illnesses, IRIS  developed in 37.7% (95% Crl 26.6-49.4) of those with cytomegalovirus, 19.5% (2.3-50.7) of those with progressive cryptococcal meningitis,15.7% (9.7-24.5) of those with tuberculosis, 16.7% (2.3-50.7) of those with progressive multifocal leuko-encephalopathy, and 6.4 %(1.2-24.7) of those with Kaposi’s syndrome, and 12.2 %(6.8-19.6) of those with herpes zoster.  16.1% (11.1-22.9) of unselected patients starting ART developed any type of IRIS.  4.5% (2.1-8.6) of patients with any type of IRIS died, 3.2% (0.7-9.2) of those with tuberculosis-associated died, and 20.8% (5.0-52.7) of those with cryptococcal meningitis died.  Metaregression analyses showed that the risk of IRIS is associated with CD4 count at the start of ART, with a high risk to patients with fewer than 50 cells per microL.  Occurrence of IRIS might therefore be reduced by initiation of ART before immunodeficiency becomes advanced.

Comment: As in wealthy countries.

JT

Adverse Reactions

Drug-induced optic neuropathy – TB or not TB.

Pradhan et al    Auckland      New Zealand

Surv Ophthalmol 2010; Jan 16 (E pub)

Abstract: Autosomal dominant optic atrophy is an inherited optic neuropathy manifesting with variable penetrance and expressivity.   Other genetic and environ mental factors are postulated to contribute to more marked visual loss in some affected individuals.  Optic neuropathy is also a known adverse effect of ethambutol treatment for tuberculosis.  This case report demonstrates an atypical presentation of ethambutol toxicity, with progressive profound loss of vision despite drug cessation .  A subsequent diagnosis of autosomal dominant optic atrophy was made when the proband’s sons presented with mild visual disturbance and colour vision defects, confirmed with electrophysiology and OPA1 gene mutational analysis. This case emphasizes the importance of avoiding potentially neurotoxic therapy in predisposed individuals and the influence of environmental factors in patients with inherited optic neuropathies.

Comment: Hence the importance of an adequate family history .

JT

Extra pulmonary tuberculosis

Simultaneous scrofuloderma and intracranial tuberculomas: a rare presentation of systemic tuberculosis.

Wong et al   Auckland     New Zealand

Australas J Dermatol  2010; 51: 39

Abstract: Tuberculosis can involve multiple organ systems concurrently.  We report a case of simultaneous brain tuberculomas and scrofuloderma occurring in the same patient.  Skin biopsies confirmed scrofuloderma and the patient was successfully treated for tuberculosis with resolution of the brain masses.  This case illustrates importance of dermatological manifestations of systemic disease as an accessible source for diagnosis and guidance in appropriate therapy.

Comment: When a biopsy is taken, some must always be saved for culture.

JT

Meningeal tuberculosis: high long–term mortality despite standard therapy.

Shaw et al     Dallas  TX        USA

Medicine (Baltimore)  2010; 89: 189

Abstract: The long-term outcomes of patients with tuberculous meningitis treated with modern chemotherapy are poorly defined.  We conducted this retrospective case-control study to determine the long-term survival in patients with proven tuberculous meningitis treated by directly observed therapy in the state of Texas.  The patients had been diagnosed and treated for tuberculous  meningitis between 2000 and 2005 in the state of Texas.  Cases were patients with microbiologically proven tuberculous meningitis; controls were patients in whom Mycobacterium could not be isolated but met the Centers for Disease Control and Prevention(CDC) criteria for nonproven tuberculous meningitis.  There were 135 cases and 75 controls, with average observation periods of 3.76 +/- 2.63 years and 4.51 +/- 2.09 years ,respectively .  At the end of the observation period, 39.76 % of cases were still alive compared to 85.07% of controls.  The long-term outlook in patients with proven tuberculous meningitis adequately treated with current standard tuberculous therapy is bleak.  A re-examination of treatment strategies is urgently needed.

Comment: It seems we can no longer congratulate ourselves in achieving a short term-mortality of 30%.

JT

Zoonoses

Sensitivity, specificity and confounding factors  of novel serological tests used for the rapid diagnosis of bovine tuberculosis in farmed red deer (Cervus elaphus).

Buddle et al     Palmerston North  New Zealand

Clin Vaccine Immunol 2010; 17: 626

Abstract: In this study, novel serological tests were used to detect tuberculosis (TB) in groups of farmed red deer (Cervus elaphus) varying in disease status or possible confounding factors.  Groups of deer naturally or experimentally infected with Mycobacterium bovis and animals vaccinated against paratuberculosis were studied, as were uninfected animals naturally and experimentally infected  with Mycobacterium avium subsp paratuberculosis.  Sera were assayed using two rapid rapid-flow tests.  Chembio’s CervidTB STAT-PAK and DPP VetTB tests, and results were compared to those from tuberculin skin tests.  Both serological test had a high sensitivity, but specificity was adversely affected  after animals had received a vaccine against paratuberculosis and were subsequently skin tested.  The specificity of the DPP VetTB test was higher than that of the CervidTB STAT-PAK test, with natural infection with M.avium subsp para-tuberculosis adversely affecting the specificity of only the Cervid TB STAT-PAK test.  The sera from M. avium subsp paratuberculosis- infected deer that produced false positive reactions in the Cervid TB STAT-PAK test were retested with a multiantigen print immunoassay (MAPIA), and some of these sera were shown to react with the MPB83 antigen.  Combining the results from the serological tests and the skin tests showed only a slight increase in the sensitivity in the sensitivity of detection of M.bovis-infected animals.  It is concluded that both the CervidTB STAT-PAK and DPP VetTB tests offer rapid, convenient and easy detection of bovine tuberculosis in deer, albeit with significant interference from paratuberculosis vaccination status and subsequent skin testing.  The latter finding illustrates one of the limitations of currently available vaccines against paratuberculosis.

Comment: In view of the increase in numbers of wild  red and fallow deer in Australia, do we know how many have bovine tuberculosis?

JT

Surgery

Late extrusion of pulmonary plombage outside the thoracic cavity.

Yadav  et al     Townsville   Qld

Interact Cardiovasc Thorac Surg 2010; 10: 808

Abstract : Plombage, a variant of collapse therapy for patients with pulmonary tuberculosis that uses a variety of foreign materials was undertaken until the 1950s before the introduction of effective antimicrobial therapy.  Complications related to previous plombage procedures are not uncommon.  Management of these complications can be challenging.  We report a patient presenting with extrusion of plombage 59 years later and managed successfully with removal of the plomb and pectoral muscle flap transposition.

Comment: It is worth being reminded of this complication.

JT

Immune Studies

TB: screening for responses to a vile visitor.

Behr et al     Montreal       Canada

Cell   2010; 140: 615

Abstract: Mycobacteria, the pathogens that cause tuberculosis and leprosy, establish long-term infections in host macrophages.  Recent studies, including including two genetic screens reveal that virulent mycobacteria evade the host immune system by stimulating production of anti-inflammatory molecules and inhibiting autophagy.

Comment: They are almost the perfect parasite!

JT

LIGHT contributes to early but not late control of Mycobacterium tuberculosis infection.

Musicki et al     Sydney    Australia

Int Immunol 2010; 22: 353

Abstract: The TNF superfamily member, LIGHT, contributes to optimal T-cell activation in vitro through co-stimulation of dendritic cell cytokine production; however ,its role in T-cell-mediated control of intracellular bacterial infections is unknown.  Protective immunity against Listeria monocytogenes and Mycobacterium tuberculosis infection requires both antigen specific CD4+ and CD8+ T cells.  Using LIGHT-deficient mice we determined that LIGHT was necessary for optimal  re-stimulation of anti-listerial CD8+ T cells in vitro.  By contrast, LIGHT (-/-) mice infected with L. monocytogenes  generated equivalent T-cell responses and the infection  as effectively as normal C57BL/6 mice.  Following M. tuberculosis infection, LIGHT (-/-) mice showed a significant increase in bacterial replication in the lungs at 4 weeks, but by 6 weeks had controlled the infection.  Analysis of T-cell responses in vivo revealed that LIGHT was dispensable for the activation  of primary T-cell responses and the production of IL-12 and IFN-gamma.  In addition, LIGHT was not required for the induction of memory T-cell responses to anti-mycobacterial DNA or BCG vaccines and for subsequent protection against tuberculosis challenge.  Therefore, LIGHT contributes to the optimal co-stimulation of anti-listerial CD8+ T-cell responses in vitro and to the early control of M. tuberculosis; however, other mechanisms compensate for LIGHT deficiency in the control of these pathogens in vivo.

Comment: In mice, that is.

JT

Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB.

Eum et al     Masan       Korea

Chest  2010; 137: 122

Background: The exact role of neutrophils in the pathogenesis of TB is poorly understood.  Recent evidence suggests that neutrophils are not simply scavenging phagocytes in Mycobacterium tuber-culosis (Mtb) infection.

Methods: Three different types of clinical specimens from patients with active pulmonary TB who underwent lung surgery were examined: sputum, BAL fluid and cavity contents.  Differential cell separation and quantification were performed for intracellular and extracellular bacteria, and bacterial length was measured using microscopy.

Results: Neutrophils were more abundant than macrophages in sputum (86.6% +/- 2.2% vs 8.4% +/- 1.3%) and in BAL fluid (78.8% +/- 5.8% vs 11.8% +/- 34.1%).  Inside the cavity, lymphocytes (41.3% +/- 11.2%) were the most abundant cell type, followed by neutrophils (38.8% +/- 9.4%) and macrophages (19.5% +/- 7.5%).  More intracellular bacilli were found in neutrophils than macrophages in sputum (67.6% +/- 5.6% vs 25.2% +/- 6.5%), in BAL fluid (65>1% +/- 14.4%  vs 28.3% +/- 11.6%) and in cavities (61.8% +/- 13.3% vs 23.9 % +/- 9.3%).  The lengths of Mtb were shortest in cavities (1.9 +/- 0.1 microm), followed by sputum (2.9 +/- 0.1 microm) and in BAL fluid (3.6 +/- 0.2 microm).

Conclusions: Our results show that neutrophils are the predominant cell types infected with Mtb in patients with TB and that these intracellular bacteria appear to replicate rapidly.  These results are consistent with a role for neutrophils in providing a permissive site for a final burst of active replication of the bacilli prior to transmission.

Comment: Should we allow for the fact that these were multidrug-resistant mycobacteria?

JT

Epidemiology

Tuberculosis and air travel: a systematic review and analysis of policy.

Abubakar I     Norwich      U K

Lancet Infect Dis 2010; 10: 176

Abstract: WHO international guidelines for the control of tuberculosis in relation to air travel require –after a risk assessment- tracing of patients who sat for longer than 8h in rows adjacent to people with pulmonary tuberculosis who are smear positive or smear negative. A further recommendation is that all commercial air travel should be prohibited until the person has two consecutive negative sputum smears for drug-susceptible tuberculosis  or two consecutive cultures for multidrug–resistant tuberculosis.  In this review I examine the evidence put forward to support these recommendations and assess whether such an approach is justifiable.  A systematic review identified 39 studies of which 13 were included.  The majority of studies found no evidence of transmission.  Only two studies reported reliable evidence of transmission. Te analysis suggests that there is reason to doubt the value of actively screening air passengers for infection with Mycobacterium tuberculosis and that the resources used might be better spent addressing other priorities for the control of tuberculosis.

Comment: That may be, but such issues leave the sphere where EBM rules and enter the political sphere where the “precautionary principle”  is paramount.

JT

Mortality of tuberculosis in very old people.

Salvado et al    Barcelona      Spain

J Am Geriatr Soc 2010; 58: 18

Objectives: To describe the clinical characteristics and outcomes of tuberculosis (TB) in elderly people.

Design: Observational analysis of a prospective cohort of adults with TB (1995-2004). A case control study to determine attributable mortality to Tb in very old people was done.

Results: Of 319 patients with TB, 109(34.2%) were aged 65 and older.  The older group was more likely to have co-morbidities (1.4% vs 0.4%; P<0.001), extrapulmonary and disseminated TB (50.4% vs 26.1%; P<0.001), toxicity (22% vs 9.8%; P=0.006) ,and 30=day mortality (18.3% vs 1.6%);P<0.001).  When patients aged 65 to 79 were compared with those aged 80 and over, only differences in TB-related mortality were detected (9.8% vs 44.4%; P=0.01).  In the attributable mortality analysis, 30 day and 6-month mortality were higher in very old patients with TB than in controls without TB  (41.7% vs 11.1%; P=0.005; 45.8% and 19.4%; P=0.01, respectively). No differences in mortality were shown when excluding patients with post mortem TB diagnosis or those who died within the first 72 hours of diagnosis.

Conclusion: Older people with TB had a higher frequency of atypical features, more adverse drug reactions and greater TB-related mortality than younger people.  Data suggest that very old patients with TB have higher mortality , but if diagnosed early and adequately treated, very old patients with TB  do not have greater mortality than those without.

Comment: No surprises here, but the numbers of subjects may not give the study much strength.

JT

Three-year longitudinal study of genotypes of Mycobacterium tuberculosis in a low prevalence population.

Gallego et al  Sydney    NSW   Australia

J Med Microbiol 2010; 42: 267

Objective: To investigate the molecular epidemiology of tuberculosis, temporal and spatial distribution of Mycobacterium tuberculosis isolates and associations between genotypes and clinical characteristics, in a low prevalence population.

Methods: A total of 930 M. tuberculosis isolates referred to the New South Wales (NSW), Australia) Mycobacterium Reference Laboratory in 2004-2006 were characterized by mycobacterial interspersed repetitive unit (MIRU) and spacer oligo-nucleotide(spolig) typing.  Associations between genotypes, patient age, disease site and drug resistance were explored  and the predictive power of molecular typing was analysis using Bayesian Belief Networks.

Results: Among isolates from 855 NSW residents, there were 287 spoligotypes, 494 MIRU types and 643 unique spoligotype-MIRU type combinations.  They formed 73 spoligotype, 104 MIRU type and 76 Spoligo-MIRU clusters, most of which contained only two isolates.  The majority (87.7%) of spoligotype clusters contained several MIRU profiles and 64.4% of MIRU clusters contained several spoligotypes.  The three most common M. tuberculosis clades were Beijing (24.1%), East African Indian (11.8%) and central Asian (6.5%); 6.9% and 0.7% isolates were resistant to isoniazid and rifampicin, respectively.  There was no proof of association between genotype and drug resistance, but isoniazid resistance increased independently over time.  Given the low rates of genotype clustering, statistical analysis of genotype-phenotype associations was limited.  Potential associations were not confirmed by Bayesian classifiers.

Conclusions: Spoligo and MIRU typing demonstrated low levels of M.tuberculosis clustering in NSW ; temporal and spatial changes  in M. tuberculosis genotypes reflected migration patterns to Australia.  No analytically significant associations between M. tuberculosis genotypes and clinical phenotypes were detected.

Comment: Are we to conclude that timely treatment and contact action in Australia has resulted in little transmission of Mtb disease?

JT

Infection

Estimation of incidence of tuberculosis infection in health-care workers using repeated interferon-gamma assays.

Yoshiyama et al    Tokyo      Japan

Epidemiol Infect  2009; 137: 1691

Abstract: The aim was to estimate the incidence of Mycobacterium tuberculosis (Mtb) infection in health-care workers(HCWs) in Japan.  We repeated cross-sectional surveys of HCWs with QuantFERON-TB (QFT-G) in 2003, 2005 and 2007 at a hospital with tuberculosis wards and 311 HCWs who underwent QFT-G testing two or three times were included in the study.  Five HCWs (1.8%) converted from negative to positive. Incidence of new TB infection was estimated to be 0.6/100 person-years by the CDC’s definition.  Thirteen positive persons (41%) reverted from positive to negative. Multivariable logistic regression analysis identified a significant association between QFT-G conversion and working in TB wards.  The IFN-gamma levels of all but two subjects with reverting or converting QFT-G results were close to the test’s cut-off.  The incidence of Mtb infection in HCWs at our hospital was higher than that estimated for the general population in Japan.  Criteria for defining QFT-G conversion and reversion need further investigation  considering the high proportion of reversion, as the incidence of infection would have changed if we had applied other definitions.

Comment: See editorial

A prospective large-scale study of methods  for the detection of latent Mycobacterium tuberculosis infection in refugee children.

Lucas et al   Perth   Western Australia

Thorax 2010; 65: 442

Background: Diagnosis of latent tuberculosis infection (LTBI) is a cornerstone of the health assessment of resettled high incidence populations, particularly in children.  Two blood-based interferon gamma release assays (IFGRAs) , T.SPOT.TB and QFT gold in tube (QFT-GIT) have greater sensitivity and specificity than the tuberculin skin test(TST), but their performance as screening tools for LTBI in children, especially refugee children, remains unclear.

Methods: 524 African and ethnic Burmese children, including 107 under 3 years of age, were prospectively enrolled in a comparison of the T.SPOT.TB and QFT-GIT.  The TST was also performed in 342 of the children.

Results: The T.SPOT.TB and QFT-GIT had similar rates of positivity  (8% and 10%,respectively) and showed good concordance when both tests gave definitive results  (kappa 0.78, P< 0.0001).  However, the IGRAs had significant failure rates: 15% of QFT_GIT gave indeterminate results due to failed mitogen response and 14%  of T.SPOT.TB results were inconclusive, largely because of insufficient mononuclear leukocyte yields. Failure of the GFT-GIT mitogen response was associated with African ethnicity and co-morbid infections, particularly with helminthes.  The TST tests showed poor concordance (approximately 50% ) with both IGRAs.

Conclusions: It is reasonable to screen using either  IGRA with follow-up by the alternative if the test fails.  In general the QFT-GIT is the preferred option for non-African populations but the T.SPOT.TB is recommended  when there are epidemiological  and /or high risk factors for TB infection.  However, both IGRAs have methodological and performance characteristics that limit their usefulness in refugee children, highlighting the need  for continued development of screening strategies.

Comment: Of course, if you change the cut off point for TST positivity you will get varying concordance with IGRAs.  There is a case to be made for using both groups of tests.

JT

Contact tracing by RFLP

Diagnosis

An algorithm for tuberculosis screening and diagnosis in people with HIV.

Cain et al    Atlanta GA    USA

N Engl J Med 2010; 362: 707

Background: Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy .  No internationally accepted, evidence –based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common.

Methods: We consecutively enrolled people with HIV infection from eight outpatient clinics in Cambodia, Thailand and Vietnam.  For each patient, three samples of sputum and one each of urine, stool, blood and lymph node aspirate (for patients with lymphadenopathy) were obtained for mycobacterial culture.  We compared the characteristics of patients who received a diagnosis of tuberculosis (on the basis of having one or more specimens that were culture positive) with those of patients who did not have tuberculosis to derive an algorithm for screening and diagnosis.

Results: Tuberculosis was diagnosed in 267 (15%) of 1748 patients (median CD4+ T-lymphocyte count, 242 per cmm; interquartile range, 82-396).  The presence of a cough for 2 or 3 weeks or more during the preceding 4 weeks had a sensitivity of 22 to 33% for detecting tuberculosis.  The presence of cough of any duration, fever of any duration or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive and 36 % specific for tuberculosis.  In the 1199 patients with any of these symptoms, a combination of two negative sputum smears, a normal chest radiograph, and a CD4+ cell count of 350 or more helped rule out a diagnosis of tuberculosis, whereas a positive diagnosis could be made only for the 113 patients(9%)  with one or more positive sputum smears; mycobacterial culture was required for most other patients.

Conclusions: In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough.  It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

Comment: If cultures are available.

JT

Pharmacokinetics and Imaging

Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons.

Liu et al   Stony Brook  New York  USA

J Med Chem 2010;53: 2882

Abstract: The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin(RIF) and pyrazinamide(PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET).  Each radiosynthesis and formulation has been accomplished in 1h, using  [(11)C]CH(3)I to label RIF and [(11)C]HCN to label INH and PZA.  Following IV administration , INH,PZA and/or their radiolabel led metabolites accumulate in the bladder while RIF and/or its radiolabel led metabolites accumulates in the liver and gall bladder, consistent with the known routes of excretion of the drugs.   In addition, the biodistribution data demonstrate the ability of the three drugs and their radiolabel led metabolites to cross the blood-brain barrier decreases in the order PZA>INH>RIF, although in all cases the estimated drug concen-trations are greater than the minimum inhibitory concentration(MIC) values for inhibiting bacterial growth of Mycobacterium tuberculosis(MTB).  The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain and pave the way for imaging the distribution of the pathogen in vivo.

Comment: No longer do we have to postulate a breakdown of the blood-brain barrier to explain why these drugs are effective in TB meningitis.

JT

Microbiology

Diagnostic accuracy of the microscopic observation drug susceptibility assay: a pilot study from India.

Michael et al    Vellore     India

Int J Tuberc Lung Dis 2010; 14: 482

Setting: The microscopic observation drug susceptibility test (MODS) assay is a rapid, sensitive, low-cost liquid culture technique.

Objective: To establish the accuracy of MODS for the detection of active pulmonary tuberculosis (TB) and to document the costs and challenges of setting up this assay in a low-income setting.

Design: Prospective blinded pilot study of 200 adult TB suspects at a tertiary referral hospital in India.  Reference standard included culture (Lowenstein-Jensen and automated liquid culture) and clinical diagnosis.

Results: Patients were mostly male (n=122) and outpatients (n=184), with a mean age of 40.4 Years (SD 16.2)  Seventeen (8.5%) were HIV infected and 47 (23.5%) were reference culture positive. Compared to reference culture, MODS was 78.9% sensitive (95% CI,62.2-90.0( and 96.7 % specific (95% CI, 92.0-98.8).  Clinical assessment suggested that MODS was false –negative in 3/8 reference culture-positive  MODS-negatives and true positive in 4/6 reference culture-negative MODS-positives.  MODS was faster than solid (P<0.001) and liquid culture (P=0.088), and cheaper than both.

Conclusion: MODS may be a good alternative to automated liquid culture, but there were several challenges in setting up the assay.  Prior training and validation, setup costs and inability to rule out cross-contamination need to be taken into account before the test can be established.

Comment: The quoted P value suggests that MODS is not faster than liquid automated culture.

JT

The transcriptome of Mycobacterium tuberculosis.

Haller et al          Seattle    WA     USA

Appl Microbiol Biotechnol 2010; 86: 1

Abstract: In this review ,we summarize the present understanding of the Mycobacterium tuberculosis transcriptome and catalogue both experimentally verified findings and computationally derived predictions .  We also provide a new analysis for a range of discoveries  by comparing the results of previously independent research papers.  Bringing these data together and improving their accessibility should help catalyze further discoveries.  This minireview also provides some general insights that may be valuable to those working to characterize the transcriptome of less-studied prokaryocytes.

Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains.

Parwati  et al     Bandung       Indonesia

Lancet Infect Dis 2010; 10: 103

Abstract: The wide geographic distribution of one clade of Mycobacterium tuberculosis, the Beijing genotype family, and its genetic homogeneity, suggests that strains belonging to this grouping might have a selective advantage over other M. tuberculosis strains.  This hypothesis was addressed by reviewing molecular-epidemiological, experimental and clinical studies.  Beijing strains represent about 50% of strains in east Asia and at least 13% of strains worldwide.  Their emergence  might be linked to escape from BCG vaccination, and to multidrug resistance, which is associated with the Beijing genotype in many areas.  Different animal models have shown Beijing strains to be more virulent, and to cause more histopathological changes, higher outgrowth and increased mortality.  At a molecular level, Beijing strains have specific properties in terms of protein and lipid structures and their interaction with the human immune system.  Finally, the Beijing genotype has been linked to polymorphisms in immune genes, suggesting the possibility of human-mycobacterial co-evolution.  The emergence of the Beijing genotype family might represent an evolutionary response of M.tuberculosis to vaccination or antibiotic treatment or antibiotic treatment, with an important negative impact on tuberculosis control.  More research is needed to further unravel the mechanisms underlying the emergence of M. tuberculosis Beijing genotype strains and examine the implications for future control strategies.

Comment: We are told that the Beijing genotype is the most common clade of M. tuberculosis in Australia and no doubt will become more common.

JT

Detection of Mycobacterium tuberculosis from paraffin-embedded tissues by INNO-LiPA Rif TB assay; retrospective analyses of Health Protection Agency National Mycobacterium Reference Laboratory data.

Reddy et al   London    United Kingdom

J Med Microbiol 2010;59: 563

Abstract: Molecular diagnostic methods are of potential value in identifying tuberculosis (TB) and drug resistance where tissue specimens have been submitted for histology  but not for microbiological culture.  All paraffin-embedded tissue (PRT) specimens (n=60) referred to a single national centre over a 42 month study period were analysed using the INNO-LIPA Rif.TB assay; 29/60 patients had been reported to the UK Enhanced Tuberculosis Surveillance database with a diagnosis of TB based on clinical, radiological and histological evidence.  Mycobacterium tuberculosis (Mtb) DNA detectable in 5/29 reported TB cases (17.2%); 12 out of 29 had a positive MTB culture from a secondary clinical specimen and Mtb DNA was detectable 2 of the 12 (16.7%) laboratory confirmed TB cases.  Referring clinicians should be aware of the limitations of this assay on PETs and should request molecular testing only in patients with a high clinical probability of TB and when acid-fast bacilli are seen in tissue specimens.

Comment: Quite.

JT

Control

An analysis of the costs and treatment success of collaborative arrangements among public and private providers for tuberculosis control in Indonesia.

Johns et al          Jakarta     Indonesia

Health Policy 2009; 93: 214

Objectives: To identify the cost-effectiveness of collaborative arrangements among public and private providers to employ the Directly Observed Treatment Short-Course (DOTS) strategy for tuberculosis (TB) control in Indonesia.

Methods: Three strategies were assessed: hospital out-patient diagnosis with referral to public health centres (PHCs) for treatment, hospital outpatient diagnosis and treatment, and private practitioner  referral of suspects to PHCs.  The outcome was the number of sputum smear positive cases successfully treated.  Costs included direct costs to providers and patients.  Uncertainly analysis was done for both costs and effectiveness data.

Results: The average cost per case successfully treated ranged from US $169 to $ 567 for different strategies.  The cost per additional case successfully treated  incremental to existing TB programs ranged from US$ 152 to $982.  In three of four provinces assessed, there was a clearly preferred strategy of strategies, although the preferred strategy differed by province; in one province a preferred strategy could not be identified.

Conclusions: All strategies increased TB case finding, although attribution is tentative because of the study design.  Neither collaboration among private practitioners nor among  hospitals is clearly preferred based on cost-effectiveness.  For hospitals, this study suggests that having hospitals refer patients to health centres is preferable over hospitals administering treatment.

Comment: A difficult topic to analyse, and still does not address the issue  of when private practitioners do not refer for treatment.

JT

Prevention

Trade-off between BCG vaccination and the ability to detect and treat latent tuberculosis

Gerberry D   West Lafayette  IN  USA

J Theor Biol 2009; 261: 548

Abstract: policies regarding the use of the bacille Calmette-Guerin (BCG) vaccine for tuberculosis vary greatly throughout the international community.  The arguments against mass vaccination are that the effectiveness of BCG in preventing tuberculosis is uncertain and that BCG vaccination can interfere with the detection and treatment of latent tuberculosis.  In this work, we pose a dynamical systems model for the population-level dynamics of tuberculosis in order to study the trade-off which occurs between vaccination and detection/treatment of latent tuberculosis.  We assume that latent infection in vaccinated individuals is completely undetectable.  For the case of a country with very low levels of tuberculosis, we establish analytic thresholds, via stability analysis and the basic reproductive number, which determine the optimal vaccination policy, given the effectiveness of the vaccine and the detection/treatment rate of latent tuberculosis.  The results of this work suggest that is unlikely that a country detects and treats latent tuberculosis at a high enough rate to justify the discontinuation of mass vaccination from this perspective.

Comment: This is a different perspective!

Catastrophe Corner

Mycobacterium bovis abdominal aortic and femoral artery aneurysms following intravesical bacillus Calmette-Guerin therapy for bladder cancer.

Costiniuk et al    Ottowa     Canada

Cardiovasc Pathol 2010; 19: e29

Background: Infectious complications of intravesical bacillus Calmette-Guerin (BCG) therapy are rare, but these have included a handful of cases of mycotic aneurysm.

Methods and Results: We present the case of a patient  with a ruptured abdominal aortic aneurysm and a femoral artery aneurysm who had previously received intravesical BCG therapy for bladder carcinoma.  Histopathologic examination of resected tissue revealed numerous acid-fast bacilli, and subsequent mycobacterial culture of blood and resected tissue revealed BCG strain M.bovis.

Conclusions: Clinicians should be aware of the possible extravesical complications, albeit rare, of BCG therapy.  Therapy should consist  of  combined medical and surgical management.

Comment: Given that the particular bladder cancer for which BCG is given, is uncommon, I suspect that dissemination of BCG disease following such treatment, is not as rare as the authors suggest.

JT

Cavitating Pulmonary   Tuberculosis

(courtesy  IUATLD)

Feb.   2010



M. tuberculosis                              EM Photo

Forthcoming Meetings

14 th Conference of the Union North America Region:  Orlando Fl  USA

11-13 March 2010

Website:www.bc.lung.ca/lungdiseases/tuberculosis_iuatld.html

41 th    Union World Conference on Lung Health:   Berlin   Germany

11-15 November 2010

Website: Berlin 2010

Dr  John Thompson      Canberra

Prof Adrian Sleigh  Australian National University, Canberra

A/Prof Paul Kelly   Australian National University, Canberra

Address for correspondence

Email: jtjnj@actewagl.net.au

Website: http://tbreview.wordpress.com

Contents

Editorial

TB notifications in Australia

Diagnosis

DOTS

Risk Factors

Children

Control

TB & HIV

Immunity

Treatment

PopulationStudies

Social Issues

NonTuberculous Mycobacteria

Microbiology

Surgery

ExtraPulmonary TB

Drug Reactions

Editorial: A report from the Centers  for   Disease Control in the USA  on page  10    of this edition shows that extrapulmonary  tuberculosis in that country makes up an increasing proportion of notified tuberculosis cases when viewed over 13 years.  The authors are unable to explain this finding, although the difference in risk factors between the two forms of tuberculosis, does help to provide an explanation.   Were they to look at similar Australian data, the reason could become clearer.  As in the USA, the proportion of extra-pulmonary tuberculosis notified has risen from 34% of all cases  in 1993 to 39 % in 2007, whereas those cases with lung involvement have fallen from a 65% of notifications in 1993 to 61% in 2007. Over the same time, those born outside Australia   represented an increasing proportion of notified TB cases; from 59% in 1993 to nearly 86% in 2007.   Most cases of extrapulmonary TB (EPTB) occur in a younger population and most of these have come to Australia , often within 5 years.  The US study shows that this foreign born population  of EPTB cases don’t  have the same risk factors as those with pulmonary disease, such as alcoholism, homelessness and male sex.     It can be predicted that as long as Australia (and the USA) continues its intake refugees and migrants from high TB prevalent countries, that  the trend towards an increasing proportion of EPTB  in younger people will continue.

Tuberculosis notifications in Australia

Barry et al   Canberra

CDI 2009; 33: 304

Abstract: The National Notifiable Diseases Surveillance System received 1135  tuberculosis (TB) notifications in 2007, of which 1086 were new cases and 48 were relapsed cases.  The incidence of TB in Australia in 2007 was 5.4 cases per 100,000 population, similar to rates since 1986.  In 2007, 86.4% of cases occurred in the overseas-born population.  The incidence in the Indigenous Australian population The National Notifiable Diseases Surveillance System received 1135  tuberculosis (TB) notifications in 2007, of which 1086 were new cases and 48 were relapsed cases.  The incidence of TB in Australia in 2007 was 5.4 cases per 100,000 population, similar to rates since 1986.  In 2007, 86.4% of cases occurred in the overseas-born population.  The incidence in the Indigenous Australian population  was 6.6 per 100,000 population.  By contrast, the incidence of TB in the non-Indigenous population was 0.9 cases per 100,000 population.  Household or other close contact with TB or past residence in a high risk country were the most commonly reported risk factors for TB infection.  In 2007, 31 cases of TB were reported in health care workers, 29 of whom were born overseas.  There were no reports of TB transmission in Australian health care settings.  Outcome data of the 2006 TB cohort indicate that treatment success was attained in more than 95 % of cases.  As Australia continues to contribute to global TB control it is important to maintain good centralized reporting of TB to identify populations at risk and for early detection of reversal of trends in TB.

Comment: Definitely, but we must distinguish between TB infection and disease.

JT

Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2007.

Lumb et al  The Australian Mycobacterium Reference Laboratory Network

CDI 2009; 33: 298

Abstract: The Australian Mycobacterium Reference Laboratory Network collects and analyses laboratory data on new cases of  disease caused by Mycobacterium tuberculosis complex.  In 2007, a total of 872 cases were identified by bacteriology; an annual reporting rate of 4.1 cases per 100,000 population..  Isolates were identified as M. tuberculosis (n=867), M. africanum (n=4) and M.bovis (n=1).  Fifteen children aged under 10 years had bacteriologically confirmed tuberculosis.  Results of in vitro drug susceptibility testing were available were available for 871 of 872 isolates for isoniazid (H), rifampicin(R), ethambutol (E) and pyrazinamide (Z).  A total of 98 (11.3%) isolates of M.tuberculosis were resistant to at least one of these anti-tuberculosis agents.  Resistance to at least H and R was detected in 24 (2.8%) isolates , all from overseas born patients; 17 were from the respiratory tract (sputum n=16, endotracheal aspirate (n=1).  Thirteen patients with MDR-TB were from the Papua New Guinea-Torres Strait Islands zone.  Of the 98 M. tuberculosis isolates resistant to at least one of the standard drugs, 54 (55.1%) were from new cases, 9 (9.2%) from previously treated cases and no information was available  on the remaining 35 cases.  Seven were Australian born , 90 were overseas born and the country of birth of one was unknown.  Of the 90 overseas-born persons with drug resistant disease, 66 (73.3%) were from 5 countries: India (n=16), Papua NewGuinea (n=15), the Philippines (n=12), Vietnam ) n=12)and China (n=11_.  No XDR-TB was detected in 2007.

Comment: Given the increasing burden of HIV in PNG, it is likely more drug resistant TB cases will enter the Torres Strait islands from that direction.

JT

Diagnosis

Longitudinal assessment of an ELISPOT test for Mycobacterium tuberculosis infection.

Hill et al  The Gambia, San Francisco USA

PLoS Med 2007; 4: e192

Background: Very little longitudinal information is available regarding the performance of T cell-based studies for Mycobacterium tuberculosis infection.  To address this deficiency, we conducted a longitudinal assessment of the enzyme linked immunosorbent spot test (ELISPOT)  in comparison to the standard tuberculin skin test (TST).

Methods and Findings: In tuberculosis (TB) contacts we repeated ELISPOT tests 3 mo (n=341) and 18 mo (n=240) after recruitment and TSTs at 18 mo (n=130).  We evaluated factors for association with conversion and reversion and investigated suspected cases of TB.  Of 207 ELISPOT-negative contacts, 51 (24.6%)  had 3 mo ELISPOT conversion, which was associated with a positive recruitment TST (odds ration [OR] 2.2, 95% confidence interval [CI] 1.0-5.0. p=0.48) and negatively associated with bacillus Calmette-Guerin (BCG) vaccination (OR 0.5,95% CI0.2-1.0, p=0.06).  Of 134 contacts, 54(40.2%) underwent 3-mo ELISPOT reversion, which was less likely in those with a positive recruitment TST (OR 0.3, 95% CI 0.1-0.8, p=0.014).  Between 3 and 18 mo, 36/132 (26.5%) contacts underwent ELISPOT conversion and 28/78 (35.9%) underwent ELISPOT reversion.  Of the 210 contacts with complete results, 73 (34.8%) were ELISPOT negative at all three time points; 36 (17.1%) were positive at all three time points..  Between recruitment and 18 mo, 20 (27%) contacts had ELISPOT conversion , 37 (50%) had TST conversion, which was associated with a positive recruitment ELISPOT (OR 7.2, 95%CI 1.4-37.1, p=0.019); 18 (32.7%) underwent ELISPOT reversion, and five (8.9%) underwent TST reversion.  Results in 13 contacts diagnosed as having TB were mixed, but suggested higher TST sensitivity.

Conclusions: Both ELISPOT conversion and reversion occur after tuberculosis exposure.  Rapid ELISPOT reversion may reflect M.tuberculosis clearance or translation into dormancy and may contribute to the relatively low reported ELISPOT conversion rate.  Therefore a negative ELISPOT test for M tuberculosis infection should be interpreted with caution.

Comment: Presumably QUANTIferon tests would give a similar result.

JT

The strengths and weaknesses of diagnostic tools for tuberculous uveitis

Vasconcelos-Santos et al        Los Angeles    CA        USA

Ocul Immunol Inflamm 2009; 17: 351

Summary: Diagnostic criteria for tuberculous uveitis encompass exclusion of other known etiologies of uveitis, suggestive clinical history and signs, supportive systemic investigations, positive response to empiric antituberculosis treatment and evidence of Mycobacterium tuberculosis or its DNA in ocular fluids/tissues.  Recent advances in diagnostic  tools for tuberculous infection, including molecular biology techniques for detection of M tuberculosis DNA and interferon-gamma release assays, have improved the specificity of the diagnosis and the ability to ascertain exposures to the infecting agent.  However, even with such advances, establishing the diagnosis of tuberculous uveitis remains a challenging issue because each of these available investigations  has its strengths and limitations and tuberculous infection can present with clinical features of any type of extraocular or intraocular inflammation.  This article critically analyzes the role of these test in supporting the diagnosis of tuberculous uveitis and proposes a practical diagnostic approach , based on a judicious combination of these tests.

Comment:  I suspect that across the world TB uveitis is either under- or over-diagnosed.

JT

DOTS

Food incentives to improve completion of tuberculosis treatment: randomised controlled trial in Dili, Timor-Leste.

Martins et al   Darwin NT  Australia

BMJ 2009; 339: b4248

Objective: To determine the effectiveness of the provision of whole food to enhance completion of treatment for tuberculosis.

Design: Parallel group randomized controlled trial.

Setting: Three primary care clinics in Dili, Timor-Leste.

Participants: 270 adults aged >/== 18 with previously untreated newly diagnosed pulmonary tuberculosis.

Main outcome measures: Completion of treatment (including cure).  Secondary outcomes included adherance to treatment, weight gain and clearance of sputum smears.  Outcomes were assessed remotely, blinded to allocation status.

Interventions: Participants started standard tuberculosis treatment and were randomly assigned to intervention(nutritious, culturally apprpriate daily meal (weeks 1-8) and food package  (weeks 9-32) (n=137) or control (nutritional advice, n=133) groups. Randomisation sequence was computor generated with with allocation concealment by sequentially numbered, opaque, sealed envelopes.

Results:Most patients with tuberculosis were poor, malnourished men living close to the clinics; 265/270 contributed to the analysis.  The intervention had no significant beneficial or harmful impact on the outcome of treatment (76% v 78%, completion, p=0.7) or adherance (93% for both groups, p=0.7) but did lead to improved weight gain at the end of treatment (10.1% v 7.5% improvement, p=0.04).  Itch was more common in the intervention group (21%v 9%, p<0.01).  In a subgroup analysis of patients with positive results on sputum smears, there were clinically important improvements in one month sputum clearance (85% v 67%, p=0.13) and completion of treatment (78%v 68%, p=0.3).

Conclusion: Provision of food did not improve outcomes with tuberculosis treatment in these patients in Timor–Leste.  Further studies in different settings and measuring different outcomes are required.

Comment: Even the best study can be undone by civil unrest.  However one must agree with the authors that the time of administration of chemotherapy could be a major explanation for failure to show a difference between the two groups.

JT

Risk Factors

Diabetes  mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies.

Jeon et al  Boston  Mass    USA

PLoS 2009; 5: e152

Background: Several studies have suggested that diabetes mellitus (DM) increases the risk of active tuberculosis (TB).  The rising prevalence of DM in TB-endemic areas may adversely affect TB control.  We conducted a systematic review and a meta-analysis of observational studies assessing the association of DM and TB in order to summarize the existing evidence and to assess the methodological quality of the studies.

Methods and Findings: We searched the PubMed and EMBASE databases to identify observational studies that had reported an age-adjusted quantitative estimate of the association between DM and active TB disease.  The search yielded 13 observational studies (n=1,786, 212 participants) with 17,698 TB cases.  Random effects meta-analysis of cohort studies showed that DM was associated with an increased risk of TB (RR=3.11, 95% CI 2.27-4.26).  Case-control studies were heterogeneous and odds ratios ranged from 1.16 to 7.83.  Subgroup analyses showed that effect estimates were higher in non-North American studies.

Conclusion: DM was associated with an increased risk of TB regardless of study design and population.  People with DM may be important targets for interventions such as active case finding and treatment of latent TB and efforts to diagnose, detect and treat DM may have a beneficial impact on TB control.

Comment: The next step is to investigate whether those with well controlled DM are less likely to develop TB.

JT

Children

Toxicity of first-line drugs for treatment of tuberculosis in children: review.

Frydenberg et al    Melbourne   Vic.

Trop Med Int Health 2009; 14: 1329

Objective: To determine the frequency and manifestations of adverse events associated with recommended first-line anti-TB drugs in children.

Methods: Literature Review

Results: Overall, children tolerate anti-TB drugs very well when using currently recommended dosages.  Serious adverse events are rare and even mild symptoms such as nausea and vomiting are uncommon.  There are occasional case reports of severe hepatotoxicity.

Conclusions: Surveillance and reporting of adverse events will need to be improved when recommended dosages of the main first-line anti-TB therapy for children are increased.  Co-morbidities such as HIV infection and severe malnutrition may affect the incidence and complicate the management  of possible adverse events to anti-TB therapy.

Comment:  It is reassuring when a meta-analysis tells us what we already believe.

JT

Control

Upper-room ultra violet light and negative air ionization to prevent tuberculosis transmission.

Escombe  et al   London & Leeds, UK, Lima,  Peru, Baltimore & Washington, USA

PLoS Med 2009; 6: e1000043

Background: Institutional tuberculosis (TB) is an important public health problem highlighted by the HIV/AIDS pandemic and the emergence of multidrug and extensively drug-resistant TB.  Effective TB infection control measures are urgently needed.  We evaluated the the efficacy of upper-room ultraviolet (UV) lights and negative air ionization for preventing airborne TB transmission using a guinea pig air-sampling model to measure the TB infectiousness of ward air.

Methods and findings: For 535 consecutive days, exhaust air from an HIV/TB ward in Lima ,Peru was passed through three guinea pig air-sampling enclosures each housing approximately 150 guinea pigs, using a 2-d cycle.  On UV-off days, ward air passed in parallel through a control animal enclosure and a similar enclosure containing negative ionizers..  On UV-on days, UV lights and mixing fans were turned on in the ward, and a third animal enclosure alone received ward air.  TB infection in guinea pigs was defined by monthly tuberculin tests.  All guinea pigs underwent autopsy to test for TB disease, defined by characteristic autopsy changes or by culture of Mycobacterium tuberculosis fdrom organs.  35% (106/305) of guinea pigs in the control group developed TB infection, and this was reduced to 14% (43/303) by ionizers, and to 9.5% (29/307) by UV lights (both p<0.0001) compared with the control group.  TB disease was confirmed in 8.6 % (26/304) of control group animals, and this was reduced to 4.3% (13/303) by ionizers, and to 3.6% (11/307) by UV lights (both p<0.03 compared with the control group. Time to event analysis demonstrated that TB infection was prevented by ionizers (log-rank 27, p<0.0001) and by UV lights (log-rank 46, p<0.0001).  Time to event  analysis also demonstrated that TB disease was prevented by Ionizers (log-rank, p=0.055) and by UV lights (log-rank 5.4, p=0.02).  An alternative analysis using an airborne infection model demonstrated that ionizers prevented  60 % of TB infection and  51% of TB disease, and that UV lights prevented 70 % of TB infection and 54% of TB disease.  In all analysis strategies, UV lights tended to be more protective than ionizers.

Conclusions: Upper-room UV lights and negative air ionization each prevented most air-borne TB transmission detectable by guinea pig air sampling.  Provided there is adequate mixing of room air, upper-room UV light is an effective low-cost intervention for use in TB infection control in high –risk  clinical settings.

Comment: Given the susceptibility of guinea pigs to M. tuberculosis, it is remarkable how few of the animals became infected, let alone diseased.

JT

TB and HIV

Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early retroviral therapy.

Elliott et al       Sydney    Australia

J Infect Dis 2009; 200: 1736

Background:In many settings, the benefits of antiretroviral therapy (ART) are reduced by the high early incidence of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS)

Methods: We used tuberculin skin testing  and the QuantiFERON Gold In-tube assay to investigate cellular immune responses to purified protein derivative (PPD) and region of difference1 (RD1) antigens during the first 24 weeks of ART.

Results: TB-IRIS and ART-associated tuberculosis occurred in 15 of 75 (20%) and 11 of 231(4.8%)  participants at risk, respectively. Greater increases in interferon gamma (IFN-gamma) and skin test responses to PPD were seen at week 24 and 12 in participants with TB-IRIS (P</=0.04), respectively.  Raw IFN-gamma responses to RD1 antigens and PPD and PPD corrected for pre-ART CD4(+) T cell counts were higher at all time points  in individuals with ART-associated tuberculosis (p<0.001) and were associated with areas under receiver operator characteristic curves of 0.9 for RD1 (95% CI 0.78—1.0) and 0.92 for PPD (95% CI 0.83-1.00) for the diagnosis of ART-associated tuberculosis.  Pre-ART IFN-gamma responses enabled stratification of participants into groups with risks of subsequent tuberculosis of 0.7%, 9.3%, and 30%.

Conclusions : Type 1 effector T cell responses are prominent in ART-associated tuberculosis, but additional immune defects may be more important in paradoxical TB-IRIS.  IFN-gamma release assays may contribute to the prediction and diagnosis of tuberculosis during early ART.

Comment: Any test that can do this is welcome, but at best 70% of cases were not predicted.

JT

Immunity

The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis.

Caws et al  Ho Chi Minh City, Vietnam,  Oxford, UK, Washington & Seattle, USA,  Bilthoeven, Netherlands

PLoS Pathog 2008; 4: e1000034

Abstract: The factors that govern the development of tuberculosis disease are incompletely understood.  We hypothesized that some strains of Mycobacterium tuberculosis (M tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection.  We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis.  The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population.  Isolates of M.tuberculosis were  genotyped by large sequence polymorphisms.  The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2).  We found a significant protective association between the Euro-American lineage of M tuberculosis and pulmonary rather than meningeal tuberculosis  (OR for causing TBM 0.395, 95% CI 0.193-0.806, P=0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population.  We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype(OR=1.57 [95% CI 1.15- 2.15]) than other individuals.  The study provides evidence that M tuberculosis genotype influences clinical disease phenotype and demonstrates for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis.

Comment The overlap is considerable.

JT

Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin.

Yuk et al        Daejeon    Korea

Cell Host Microbe 2009; 6: 231

Summary: Autophagy and Vitamin D3-mediated innate immunity have been shown to confer protection against infection with intracellular Mycobacterium tuberculosis.  Here, we show that these two antimycobacterial defences are physiologically linked via a regulatory function of human cathelicidin (hCAP-18/LL-37), a member of the cathelicidin family of antimicrobial proteins.  We show that 1,25 dihydroxyvitamin D3 (1,25D3), the active form of Vitamin D, induced autophagy in human monocytes via cathelicidin, which activated transcription of the autophagy-related genes Beclin-1 and Atg5.  1,25D3 also induced the co-colonization of mycobacterial  phagosymes with autophagosomes in human macrophages in a cathelicidin –dependent manner.  Furthermore, the antimycobacterial activity in human macrophages mediated by physiological levels of 1,25 D3 required autophagy and cathelicidin.  These results indicate that human cathelicidin, a protein that has direct antimicrobial activity, also serves as a mediator of Vitamin D3-induced autophagy.

Comment: The role of Vitamin D3 in the body’s  defence against M tuberculosis is becoming well delineated.  It remains to be seen if Vitamin D deficiency is a risk factor for the disease, but before that can bew determined we need to define Vitamin D deficiency.

JT

Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis.

Cobat et al     Paris           France

J Exp Med 2009; 206: 2583

Summary: Approximately 20% of persons living in areas hyperendemic for tuberculosis (TB) display persistent lack of tuberculin skin test (TST) reactivity and appear to be naturally resistant to infection by Mycobacterium tuberculosis.  Among those with a positive response, the intensity of TST reactivity varies greatly.  The genetic basis of TST reactivity is not known.  We report on a genome-wide linkage search for loci that have an impact on TST reactivity, which is defined either as a zero vs nonzero (TST-BINaq) or as an extent of TST in millimeters (TST-quantitative trait locus [QTL]) in a panel of 128 families, including 350 siblings, from an area of South Africa hyperendemic for TB. We detected a major locus (TST-1) on chromosomal region 11p14 (P =1.4 *(-5)) , which controls TST-BINaq, with a lack of responsiveness indicating indicating T cell independent resistance to M. tuberculosis. We also detected a second major locus (TST2) on chromosomal region 5p15 (P < 10(-5)) which controls TST-QTL or the intensity of T cell-mediated delayed type hypersensitivity (DTH) to tuberculin.  Fine mapping of this region identified SLC6A3, encoding the dopamine transporter DAT1, as a promising gene for further studies.  Our studies pave the way for the understanding of the molecular mechanisms involved in resistance to  M. tuberculosis indection endemic areas (TST1) and for the identification of critical regulators of T cell-dependant DTH to tuberculin (TST2).

Comment: This study opens up a whole range of possibilities, including how one gene can code for a protein that may have multiple functions.

JT

Treatment

Effect of duration and intermittency of Rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis.

Menzies et al    Montreal   Canada

PLoS  Med  2009; 6: e1000140

Background: Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned.  We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes.

Methods and Findings: PubMed, Embase and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French or Spanish. Between 1965 and June 2008.Selected studies utilized standardized treatment with rifampin-containing regimens.  Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analysis.  Meta-regression was performed using a negative binomial regression model.  A total of 57 trials with 312 arms and 21,472 participants were included in the analysis.  Regimens utilizing rifampin only for the first 1-2 mo had significantly higher rates of failure, relapse and acquired drug resistance, as compared to regimens that used rifampin for 6 mo.  This was particularly evident when there was initial drug resistance to isoniazid, streptomycin or both.  On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient evidence of the efficacy of twice weekly rifampin administration throughout therapy.

Conclusions: TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid  and/or streptomycin.  Treatment outcomes were similar with all intermittent regimens evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy.

Comment: In other words , the 8 weeks intensive phase of treatment should include daily rifampicin(rifampin).

JT

Linezolid: a review of safety and tolerability.

Vinh et al      Winnipeg     Canada

J Infect 2009; 59 Suppl 1: S59

Summary: Linezolid has demonstrated activity against antibiotic-susceptible and antibiotic –resistant Gram-positive cocci.  The availability of intravenous and oral formulations, with near 100% bioavailability of the latter, is hoped to facilitate the management of multiple drug-resistent Gram-positive infections.  Linezolid was approved for clinical use in the United States in April 2000 and has subsequently been approved in other countries for the management of community acquired and nosocomial pneumonia, complicated and uncomplicated skin and soft tissue infections, and infections caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, including cases with concurrent bacteremia.  Additional studies have demonstrated potential use in febrile cancer patients with neutropenia and case reports have demonstrated some efficacy in the management of endocarditis, tuberculosis, nocardiasis and in anaerobic infections.  Given the potential for significantly increased increased use of linezolid, a thorough review ands update of its tolerability and safety profile is warranted.

Comment: At one time we had hoped that linezolid would be reserved for drug resistant tuberculosis.

JT

Population Studies

Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006.

Peto et al     Atlanta,    Ga          USA

Clin Infect Dis 2009; 49: 1350

Background: Almost one fifth of United States tuberculosis cases are extrapulmonary; unexplained slower annual case count decreases have occurred in extrapulmonary tuberculosis (EPTB), compared with annual case count decreases in pulmonary tuberculosis (PTB) cases.  We describe the epidemiology of EPTB by means of US national TB surveillance data.

Methods: US tuberculosis cases reported from 1993 to 2006 were classified as either EPTB or PTB.  EPTB encompassed lymphatic, pleural, bone and/or joint, genito-urinary, meningeal, peritoneal and unclassified EPTB cases. We excluded cases with concurrent extra-pulmonary-pulmonary tuberculosis and cases of disseminated (miliary) tuberculosis.  Demographic characteristics, drug suscep-tibility test results, and risk factors, including human immunodeficiency virus (HIV) status, were compared for EPTB and PTB cases.

Results: Among 253,299 cases, 73.6% were PTB and 18.7%  were EPTB, including lymphatic 4 (40.4%), pleural (19.8%), and/or joint (11.3%), genitourinary (6.5%), meningeal(5.4%), peritoneal (4.9%) and unclassified EPTB (11.8%) cases. Compared with PTB, EPTB was associated with female sex (odds ratio [OR], 1.7, 95%CI 1.7-1.8, and foreign birth (OR 1.5; CI 1.5-1.6), almost equally associated with HIV status (OR 1.1;CI 1.1-1.1), and negatively associated with multi-drug resistance. (OR 0.6: 95% CI ).5-0.6) and several tuberculosis risk factors, especially homelessness (OR 0.3; CI 0.3-0.3) and excess alcohol use (OR 0.3; CI 0.3-0.3).  Slower annual decreases in EPTB case counts, compared with annual decreases in PTB case counts, from 1993 through 2006 have caused EPTB to increase from 15.7 % of tuberculosis cases in 1993 to 21.0 % in 2006.

Conclusions:  EPTB epidemiology and risk factors differ from those of PTB and the proportion of EPTB has increased from 1993 through 2006 .  Further study is needed to identify causes of the proportional increase in EPTB.

Comment: See  editorial

JT

Social Issues

Confinement for extensively drug-resistant tuberculosis: balancing protection of health systems, individual rights and the public’s health.

London L   Cape Town South Africa

Int J Tuberc Lung Dis 2009; 13: 1200

Summary: In the context of an expanding tuberculosis (TB) and human immunodeciency virus HIV) epidemic in South Africa, enforcing involuntary admission for extensively drug-resistant TB raises many ethical and human rights dilemmas, principally because it trades off  the human rights of individuals for the public good.  However, the dichotomy may as well be conceptualised as being about competing rights claims and the rights obligation of the state to control infectious diseases.  Superficial analysis of the ethical and rights issues in managing drug-resistant TB patients are more likely to do harm than good.  This paper argues for a more nuanced dialogue about these difficult policy choices, providing a more careful human rights analysis, using established analytical frameworks, to tease out the possible criteria that could justify limitation of individual rights.  Generally only in very restricted situations, where there is a clearly defined risk to one or more third parties, based on evidence, and conditional on careful consideration of available alternatives, should involuntary admission be considered.  Community-based strategies will need to be developed to cope with infection control without forced admission for most cases, particularly in high prevalence settings typical of many developing countries.  Even when involuntary admission is indicated, strict adherence to administratively just procedures would be required.  Confinement has no place as a strategy for the broader control of the epidemic, which is contingent on sustained commitment to improved health system functioning and action to address the abysmal investment in research and development for drugs for neglected diseases worldwide.

Comment: Who will define what is “a clearly defined risk”?     I suspect that the lawyer, the medical clinician, the ethicist, the sociologist, even the medical administrator will all respond differently.

JT

Costs incurred by patients with pulmonary tuberculosis in rural India.

John et al          Vellore           India

Int J Tuberc Lung Dis 2009; 2009; 13: 1281

Setting: Vellore district, Tamil Nadu, India

Objective: To measure patient costs associated with diagnosis and the complete treatment of tuberculosis (TB)

Design: Prospective structured interview pof 100 new smear-positive adult patients being treated for TB in Tamil Nadu, India, selected evenly from 10 representative health facilities in the state Direct (out of pocket) and indirect (lost time) costs were quantified by period of illness using a standardized questionnaire , and univariate analysis investigated predictors of total cost.

Results: Seventy-four per cent of patients were male, with a mean age of 40.2 Years.  All were given a fisrstr-line regimen, and none had been previously treated.  The mean direct cost was US$ 34.91 (SD $46.94), the mean indirect cost was  $526.87 (SD 375.71), and the total mean cost per patient was $ 562.66 (SD 287.48).  Twenty five patients were admitted to hospital, at a mean cost of $ 279.43 (SD 142.88) per admission.  Variation in costs was associated with admission.

Conclusion: TB patients in India incur large costs associated with TB illness.  The greatest single cost was time lost during admission.  Total patient costs represent 193% of the estimated monthly income of a manual labourer/

Comment: The poor from yet another country to add to the list.

JT

NonTuberculous Mycobacteria

Pulmonary Mycobacterium xenopi infection in non-HIV infected patients: a systematic review.

Varadi et al    Toronto     Canada

Int J Tuberc Lung Dis 2009;13: 1210

Setting:The incidence of Mycobacterium xenopi infections is increasing worldwide.  The characteristics and optimal management of patients with pulmonary M. xenopi infections has not been well established.

Methods: Systematic review of English- and French language studies reporting at least two cases of microbiologically confirmed M. xenopi lung infection .  Studies were independantrly reviewed by 2 reviewers.  We decribe the risk factors and clinical presentation of advanced infection, and examined the impact on clinical success and mortality of including individual antimycobacterial drugs in the treatment regimen.  The majority were retrospective case series.  There was a marked heterogeneity among the studies.  Patients were generally middle-aged men with a history of obstructive lung disease or prior tuberculosis, presenting with an upper lobe cavitary infection.   There was no clear association between administration of particular drugs and clinical success or mortality.

Conclusion: We could not demonstrate any advantage of specific drugs in the treatment of pulmonary M.xenopi infection.  Observations from the pooled data are likely subject  to significant confounding and selkection biases.  The inability to make firm conclusions on the optimal management of this increasingly common infection strongly underscores the need for further research.

Comment: For “infection”, please read “disease”

JT

Contact    tracing     by        RFLP

Microbiology

Cytological  and transcript analysis reveal fat and lazy persister-like bacilli in tuberculous sputum.

Garton et al   Leicester, Birmingham & London, UK, Banjul, the Gambia,

Paris, France

PLoS Med 2008;  5: e75

Background: Tuberculous sputum provides a sample of bacilli that must be eliminated by chemotherapy and that may go on to transmit infection.  A preliminary observation  that Mycobacterium tuberculosis cells contain triacylglycerol  lipid bodies in sputum, but not when growing in vitro, led us to investigate the extent of this phenomenon and its physiological basis.

Methods and findings: Microscopy-positive sputum samples from the UK and the Gambia were investigated for their content of lipid body-positive mycobacteria by combined Nile red and auramine staining.  All samples contained a lipid body-positive population varying from 3% to 86% of the population present.  The recent finding that triacylglycerol synthase is expressed by mycobacteria when they enter in vitro nonreplicating persistence led us tio investigate whether this state was also associated with lipid body formation.  We found that when placed in laboratory conditions inducing nonreplicating persistence, two tuberculosis strains had lipid body levels comparable to those found in sputum.  We investigated these physiological findings further by comparing the M tuberculosis transcriptome of growing and nonreplicating  persistence cultures with that directly obtained from sputum samples.  Although sputum has traditionally been thought  to contain actively growing tubercle bacilli, our transcript analyses refute the hypothesis that these cells predominate.  Rather, they reinforce the results of the lipid body analyses by revealing transcriptional signatures that can be clearly attributed to slowly replicating or nonreplicating mycobacteria.  Finally, the lipid body count was highly correlated (R2=0.64, p<0.03) with time to positivity in diagnostic liquid cultures, thereby establishing this cytological feature and the size of a potential nonreplicating population.

Conclusion: As nonreplicating tubercle bacilli are tolerant to the cidal action of antibiotics and resistant to multiple stresses, identification of this persister-like population of tubercle bacilli in sputum presents exciting and tractable new opportunities to investigate both responses to chemotherapy  and the transmission of tuberculosis.

Comment:  For example, are these persisters more or less likely to evolve into drug resistant organisms?

JT

Surgery

The current of thoracic surgery in tuberculosis

Sihoe et al     Hong Kong      China

Respirology 2009;14:954

Summary: Although tuberculosis is mainly managed medically today, thoracic surgery continues to play a key  in its diagnosis and treatment in selected subgroups of patients.  In certain scenarios such as multidrug-resistant tuberculosis, advanced tuberculous empyema and symptomatic bronchial stenosis, modern thoracic surgery may represent the only effective means of management in selected patients.  Advances in thoracic surgery in recent years, in particular the use of Video-assisted Thoracic  Surgery, not only reduce postoperative morbidity for individual patients, but may potentially allow a wider range of tuberculosis patients to benefit from surgery.  Respiratory physicians and thoracic surgeons should continue to work together to ensure that tuberculosis patients who may benefit from surgery are identified for prompt and effective intervention.

Comment: Certainly VAT has been a great advance in diagnosis where lung or pleural tuberculosis cannot be completely excluded.

JT

Extrapulmonary tuberculosis

Tuberculous arthritis of the finger: a forgotten disease.

Janssens et al    Brussels    Belgium

JBR-BTR 2009; 92” 242

Summary: We present a case of a 64 b-year-old man of Belgian origin with a chronic painful swelling of the third finger.  A chronic arthritic from an unusual germ was suspected at the third metacarpo-phalangeal joint on the plain radiograph, ultrasound and MRI.  A few months later , he developed thoracic back pain  Plain radiographs, a Technetium -99m bone scan  and MRI examination of the thoracic spine revealed a spondylodiscitis of the dorsal spine.  A tuberculous origin was found on biopsy of the affected dorsal vertebral bodies T9 and T10 as suspected on the first imaging examinations of the finger.  The patient was found to be HIV-positive.  This case shows gthat it is important to think of musculosketal particularly in high-risk persons.

Comment: And not just in the HIV-positive, but in all meat workers who come to Australia.

JT

Drug Reactions

The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection.

Bliven et al     Atlanta  GA    USA

Int J Tuberc Lung Dis 2009;13: 1054

Background: To examine chronic viral hepatitis (CVH) as a risk factor for hepatotoxicity during isoniazid (INH) treatment for latent tuberculosis infection (LTBI()

Methods: A search of MEDLINE (1966-May 2008) was conducted using the terms ‘tuberculosis’, ‘antitubercular’, ‘therapeutics’, ‘treatment’, ‘prevention’, ‘prophylaxis’, ‘hepatitis’, ‘toxic hepatitis’, ‘hepatotoxic’, ‘liver’, and ‘injury’.  Peer-reviewed, English –language articles  describing the relationship between a history of CVH and occurrence of hepatotoxicity  during LTBI treatment were selected.  We limited CVH diagnosis to positive serological test or biopsy for hepatitis B or C.  Risk ratios and 945% Confidence Intervals were abstracted or derived.

Results: We reviewed 486 abstracts and 11 studies met the selection criteria.  Populations included in the study were the general population (n=6) and transplant recipients (n=5).  The variability in study designs and case finding practices precluded performing a quantitative meta-analysis.  Two studies of former or current drug users reported a consistent positive association between chronic hepatitis C infection and INH hepatotoxicity.  Other risk ratios did not significantly or consistently show any association between CVH in patients treated for LTBI and the development of INH toxicity.

Conclusion: Owing to the limited number of published papers, CVH was not established as a risk factor for INH hepatotoxicity during LTBI .  Controlled studies are needed to define the safety and tolerability of LTBI treatment in those with CVH and to provide an evidence base for recommendations  for LTBI treatment in persons with CVH.

Comment: I would think the association between Hepatitis C in illicit drug injectors and H hepatotoxicity  will hold up in further studies.  In any case I would be reluctant to offer H prophylaxis to this group of people where compliance is likely to be negligible.

JT

Cavitary       Pulmonary       Tuberculosis

]]> http://tbreview.wordpress.com/2010/02/01/the-australian-tuberculosis-review-february-2010/feed/ 0 tbreview image002 image005 image006 http://tbreview.wordpress.com/2009/10/08/australian-tuberculosis-review-october-2009/ http://tbreview.wordpress.com/2009/10/08/australian-tuberculosis-review-october-2009/#comments Wed, 07 Oct 2009 23:06:59 +0000 tbreview http://tbreview.wordpress.com/?p=90 ]]> M. tuberculosis                           EM Photo

Editorial  Group:
Dr  John Thompson      Canberra

Prof Adrian Sleigh  Australian National University, Canberra

A/Prof Paul Kelly   Australian National University, Canberra

Address for correspondence
Email: jtjnj@actewagl.net.au

Forthcoming Conferences

41st World Conference on Lung Health
11-15 November 2010, Berlin, Germany

13th Conference of the Union North America
11-13 March, Orlando, Florida, USA

American Thoracic Society 2010
14-19 May 2010 New Orleans, USA

Contents

Editorial                                                       P   2

Control                                                          P   2

Diagnosis                                                     P   3

Risk Groups                                               P   4

Socio-Political issues                             P    6

Immune Studies                                      P    6

Drug Resistance                                      P    7

Non-Tuberculous  Mycobacteria     P    8

Children                                                    P    9

Prevention                                               P    9

Microbiology                                          P   10

Extra-pulmonary   Tuberculosis     P   11

Nursing                                                     P   12

Editorial
It is not unexpected that the first case of extensively resistant tuberculosis (XDR-TB) has been reported in Australia.  Such cases have been increasing, particularly in Africa, where they are frequently associated with HIV/AIDS.  Our intake of African migrants and refugees has increased in recent years, and those found to have active tuberculosis have a higher prevalence of multidrug resistant disease (MDR-TB), than expected.  Fortunately we have been able to keep the overall proportion of MDR-TB cases in Australia to just under 1%, just as approximately 10% of M. tuberculosis isolated in this country are resistant to one antituberculosis drug.  These figures incidentally are the same as those for Cuba and better than the USA.  One wonders if the US embargo of Cuba has done them a favour in TB control at least!
It is inevitable that if our migration program does not change,  more XDR-TB will arrive here.  While XDR does not mean total resistance to all antituberculosis drugs, the results of treatment with those drugs still sensitive are very poor indeed.  Thus the patient continues to be infectious at the best for a very long time or until their death.  They must be nursed in isolation, but how can that be  maintained, let alone enforced? The current individual human rights agenda has changed much in public health control.  Some states still have legislation in place to compulsorily confine such patients, but are very reluctant to use it, particularly if it won’t stand up to legal challenge.  Others have repealed such laws.  In Victoria, an attempt to confine such a patient could be regarded as assault.
In South Africa the compulsory detention of XDR-TB patients has been met by severe criticism from human rights activists, and the same could happen here.   We should make preparations to counter such an event.  This is not to advocate a change in our refugee and migrant programs, which are very efficient in screening for TB, but to urge the Commonwealth to consult with the States and consider legislation  that applies communal rights over individual ones in this particular context.

Control

Tuberculosis into the 2010s: is the glass half full?

Ralph et al      Casuarina         N T          Australia

Clin Infect Dis   2009; 49: 574

Summary: During the 16 years since the World Health Organization declared tuberculosis  (TB) a global emergency, major new challenges have emerged- in particular the spread of extensively  drug-resistant (XDR)-TB and its overlap with human immunodeficiency virus infection.  However, during this period, we have also witnessed the creation of-and major commitments from- agencies dedicated to TB control, research and funding, and tangible positive achievements have occurred; these include improvements in new and existing TB diagnostics, a developmental pipeline of new candidate TB drugs, better treatment outcomes for multidrug-resistant  and XDR-TB, heightened recognition of the importance of nosocomial transmission, and improved strategies to reduce mortality associated with concurrent human immunodeficiency virus infection and TB,  We suggest updates to the 2006 International Standards of Tuberculosis Care to embrace these developments.  The incorporation of these recent advances into optimised directly observed treatment, short course (DOTS), programs, in conjunction with more widespread deployment and enhanced political will, all provide grounds for improved control.
Comment: So it’s not all gloom and doom.
JT

Diagnosis

Performance of nucleic acid amplification tests for diagnosis of tuberculosis in a large urban setting.

Laraque et al     New York      USA

Clin Infect Dis 2009; 49: 46

Background: A diagnosis of tuberculosis (TB) relies on acid-fast bacilli (AFB) smear and culture results.  Two rapid tests that use nucleic amplification (NAA) have been approved by the US Food and Drug Administration for the diagnosis of TB based on detection of Mycobacterium tuberculosis from specimens obtained from the respiratory tract.  We evaluated the performance of NAA testing under field conditions in a large urban setting with moderate TB prevalence.
Methods: The medical records of patients with suspected TB  during 2000-2004 were reviewed.  Analysis was restricted to the performance of NAA on specimens collected within 7 days after the initiation of treatment for TB.  The assay’s sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were evaluated.
Results: The proportion of patients with confirmed or suspected TB whose respiratory tract specimens were tested by use of NAA increased from 429 (12.9%) of 3334 patients in 2000 to 527 (15.6%) of 3386 patients in 2006; NAA testing among patients whose respiratory tract specimens tested positive for AFB increased from  415 (43.6%) of 952 patients in 2000 to 487 (55.7%) of 877 in 2004 (P<0.001 for both trends).Of the 16,511 patients being evaluated for pulmonary TB, 4642 (28.1%) had specimens that tested positive on smear.  Of those 4642 patients, 2241 (48.3%) had NAA performed on their specimens.  Of those 2241 patients, 1279 (57.1%) had positive test results.  Of those 1279 patients, 1262 (98.7%) were confirmed to have TB.  For 1861 (40.1%) of the 4642 patients whose specimens tested positive for AFB on smear, the NAA test had a sensitivity of 96.0%.  For 158 patients whose specimens tested negative for AFB on smear, the NAA test had a sensitivity of 79.3 % , a specificity of 80.3%, a PPV of 83.1%  and an NPV of 76.0%, respectively.  For the 215 specimens that tested positive for AFB by smear, we found a sensitivity, specificity, PPV and NPV of 97.5%, 93.6%, 95.1% and 96.8%, respectively.  A high grade smear was associated with a better test performance.
Conclusion: NAA testing was helpful for determining whether patients whether patients  whose specimens tested positive for AFB on smear had TB or not.  This conclusion supports the use of this test for early diagnosis of pulmonary and extrapulmonary TB.
Comment: The use of NAA may be effective, but is it cost-effective?
JT

Use of a T cell interferon gamma release assay in the investigation for suspected active tuberculosis in a low prevalence area.

Wingvist et al      Malmo        Sweden

BMC  Infect Dis 2009; 9: 105

Background : In settings with low background prevalence of tuberculosis (TB) infection, interferon-gamma release assays (IGRA) could be useful for diagnosing active TB.  This study aims to evaluate the performance of QuantiFERON-TB Gold (QFT-G) in the investigation of suspected active TB, with particular attention to patients originating in high-incidence countries.  Furthermore, factors associated with QFT-G results in patients with active TB were assessed.
Methods: From patients investigated for clinically suspected active TB, blood was obtained for QFT-G testing, in addition to routine investigations..  Positive (PPV) and negative (NPV) predictive values for QFT-G were calculated, comparing patients with confirmed TB and those with other final diagnoses.  QFT-G results in TB patients originating from countries with intermediate or high TB incidence were compared with QFT-G results from a control group  of recently arrived asymptomatic immigrants from high incidence countries..  Factors associated with QFT-G outcome in patients with confirmed TB were assessed.
Results: Among 141 patients, 41/70 (58.6%) with confirmed TB had a positive QFT-G test, compared to 16/71 (22.6%) patients with other final diagnoses, resulting in overall PPV of 71.9% and NPV of 67.6%.  For patients with pulmonary disease, PPV and NPV were 61.1% and 67.7%, respectively,  90/5% and 66.7% for subjects with extrapulmonary manifestations.  Comparing patients from high-incidence countries with controls yielded a PPV for active TB of 76.7% and a NPV of 82.7%.  Patients with confirmed TB and positive QFT-G results were characterized by a lower median peripheral white cell blood count (5.9 x 10(9) /L vs. 8.8 x 10(9)/L; P<0.001 and a higher median body mass index (22.7vs 20.7; P=0.043) as compared to QFT-G negative TB patients.
Conclusion: The overall PPV and NPV of QFT-G for identifying active TB were unsatisfactory, especially for pulmonary disease.  Thus, the usefulness of QFT-G for this purpose is questionable.  However, a high PPV was observed for extrapulmonary TB  and QFT-G might be considered in the diagnostic process in this situation.  The PPV and NPV for identifying active TB  among persons originating from regions with high to intermediate TB incidence was similar to that observed in subjects originating in the low-incidence region.
Comment:  In other words we should be looking to QFT-G to help diagnose TB infection, but not disease.
JT

Risk Groups

Barriers to implementation of effective tuberculosis control in prisons.

Moller et al       Copenhagen        Denmark

Public Health  2009; 123: 419

Summary: The high prevalence and mortality from tuberculosis (TB) in prisons in Europe make them a priority target for the StopTB strategy.  Implementation however is difficult and requires a whole prison approach, with due attention to the values and understanding of all staff and to prisoners’ health literacy levels.
Comment: Why this is not a concern in Australia seems to be linked to the extraordinarily low prevalence of TB in injecting drug users in this country.
JT

The profile of health problems in African immigrants attending an infectious disease unit in Melbourne , Australia.

Gibney et al      Melbourne       Australia

Am J Trop Med Hyg  2009; 80: 805

Summary: The number of African immigrants living in Western countries is increasing.  A  retrospective  audit of sub-Saharan African patients attending the infectious diseases clinics of a Melbourne teaching hospital was performed.  A total of 375 patients were included.  H, pylori gastritis was diagnosed in 60%  of those tested (35/58), schistosomiasis in 41% (84/206), chronic hepatitis B in 19% (32/167), and strongyloidiasis in 18% (32/179).  Active tuberculosis (TB) affected 18% (51/276) and latent TB 55% (152/276).  Pathologic parasites were detected in stool in 21% (31/145), Vitamin D deficiency (< 50nmol/L) affected 73%(139/191), anaemia 17% (52/312), iron deficiency 15% (22/151), and low neutrophil count 25% (78/312). Infectious diseases, Vit D deficiency, anaemia and latent TB were common in Sub-Saharan African immigrants.  Clinicians need to be aware of these conditions to meet the health needs of this group.  Comprehensive health checks should be encouraged for new arrivals, particularly from high risk areas.
Comment: It is disturbing that 99/376 (26%) were not screened  for tuberculosis, so given the high prevalence in those screened, how many cases were missed?
JT

Regional survey of tuberculosis risk assessment in rheumatology outpatients commencing anti-TNF-alpha treatment in relation to British Thoracic Society guidelines.

John et al    Dudley      United Kingdom

Clin Med  2009; 9: 225

Summary: The aim of this study was to analyse tuberculosis (TB) risk assessment for rheumatology patients commencing anti-tumour necrosis factor-alpha (anti-TNF-alpha) therapy using the British Thoracic Society (BTS) guidelines.  Data were obtained retrospectively on 856 outpatients regionally receiving anti-TNF-alpha.  Prior to commencing treatment, patients had the following assessments documented: respiratory examination, 47.4%; chest X-ray, 84.5%; TB history, 92.9%; and advice about TB risk, 45.8%.  Of the 856 patients, 94.3% were on immunosuppressants but 27% had a tuberculin test; 12.6% had > or=1 high-risk factors for TB.  In total, 3.4% were referred to a TB specialist and of these 24.1% had no risk factors for TB.  Of patients with > or =1 risk factor, 76.9% were not referred.  Only 4/28 patients at high risk for TB due to ethnicity or birthplace received chemoprophylaxis.  Marked inter-unit variation was demonstrated and it was evident that patients require improved screening for TB.  Greater awareness is necessary of patients with risk factors, particularly ethnicity, to facilitate more appropriate targeting of chemoprophylaxis. Multi-centre audit is a valuable clinical governance tool.
Comment: Would the rheumatology units in Australia do any better?
JT

Overseas screening for tuberculosis in US-bound immigrants and refugees.

Liu et al      Atlanta     GA      USA

N Engl J Med  2009; 360: 2406

Background : In 2007, a total of 57.8% of the 13,293 new cases of tuberculosis in the United States were diagnosed in foreign-born persons, and the tuberculosis rate among foreign-born persons was 9.8 times as high as that among US-born persons (20.6 vs. 2.1 cases per 100,000 population).  Annual arrivals of approximately 400,000 immigrants and 50,000 to 70,000 refugees from overseas are likely to contribute substantially to the tuberculosis burden among foreign-born persons in the United States.
Methods: The Centers for Disease Control and Prevention (CDC) collects information on overseas screening for tuberculosis   among US-bound immigrants and refugees, along with follow-up evaluation after their arrival in thew United States.  We analysed screening and follow-up data from the CDC to study the epidemiology of tuberculosis in these populations.
Results: From  1999 through 2005, a total  of 26,075 smear-negative cases of tuberculosis (i.e., cases in which a chest radiograph was suggestive of active tuberculosis but sputum smears were negative for acid fast bacilli on three consecutive days) .  and 22,716 cases of inactive tuberculosis (i.e., cases in which a chest radiograph was suggestive of tuberculosis that was no longer clinically active) were diagnosed by overseas medical screening of 2,714,223 US-bound immigrants, representing prevalences of 961 cases per 100,000 persons (95% confidence interval [CI], 949 to 973) and 837 cases per 100,000 persons (95% CI, 826 to 848), respectively.  Among 378,506 US-bound refugees, smear-negative tuberculosis was diagnosed in 3923 and inactive tuberculosis in 10,743, representing prevalences of 1036 and 2838 cases per 100,000 persons (95% CI, 2785 to 2891), respectively.  Active pulmonary tuberculosis was diagnosed in the United States in 7.0% of immigrants and refugees with an overseas diagnosis of smear-negative tuberculosis and in 1.6 % of those with an overseas diagnosis of inactive tuberculosis.
Conclusions: Overseas screening for tuberculosis with follow-up evaluation after arrival in the United States is a high-yield intervention for identifying tuberculosis in US-bound immigrants and refugees and could reduce the number of tuberculosis cases among foreign-born persons in the United States.
Comment: Encouraging findings to want to continue  Australia’s similar screening program.
JT

Socio-Political Issues

Tracking and decomposing  health and disease inequality in Thailand.

Yiengprugsawan et al       Canberra   Australia,   Nonthaburi   Thailand

Ann Epidemiol  2009; Sept 9

Purpose: In middle-income countries, interest in the study of inequalities in health has focused on aggregate types of health outcomes, like rates of mortality.  This work moves beyond such measures to focus on disease-specific health outcomes with the use of national health survey data.
Methods: Cross-sectional data from the National Health and Welfare Survey 2003, covering 52,030 adults aged 15 or older, were analysed.  The health outcomes were the 20 most commonly reported diseases.  The age-sex adjusted concentration index (C*) of ill health was used as a measure of socio-economic health inequality (values ranging from -1 to +1).  A negative  (or positive ) concentration index shows that a disease was more concentrated among the less well off (or better off).  Crude concentration indices © for four of the most common diseases were also decomposed to quantify to quantify determinants of inequalities.
Results: Several diseases, such as malaria (C*=-0,462), goitre (C* = -0.352(, kidney stone (C* = -0.261), and tuberculosis (C* = -0.233), were strongly concentrated among those with lower incomes, whereas allergic conditions (C*=0.174) and migraine (C*= 0.085) were disproportionately reported by the better off.  Inequalities were found to be associated with older age, low education and residence in the rural Northeast and rural north of Thailand.
Conclusions: Pro-equity health policy in Thailand and other middle-income countries with health surveys can now be informed by national data combining epidemiological and health statistics in ways not previously possible.
Comment: Provided that geographic influences are allowed for.
JT

Immune Studies

Allergic sensitisation in tuberculosis patients at the time of diagnosis and following chemotherapy.

Ellertsen  et al         Oslo        Norway

BMC Infect Dis 2009; 9: 100

Background : It is still a matter of debate whether there is an association between infection with Mycobacterium tuberculosis (M tuberculosis) and allergy.  Previously, we have shown higher levels of specific IgE to different inhalant allergens and total IgE in tuberculosis (TB) patients compared to controls.  The objectives of this study were to evaluate a possible change in allergic sensitisation in TB patients after successful TB treatment and to confirm the finding of our previous study of enhanced allergic sensitisation in TB patients compared to controls in a more controlled setting.  Additionally, we wanted to determine the cytokine profile in the same groups and finally to evaluate the association between the presence of Bacillus Calmette-Guerin vaccination (BCG) scar and allergic sensitisation among controls.
Methods Sera were analysed for specific IgE to inhalant allergens (Phadiatop) and total IgE by the use of ImmunoCAP 1000 (Pharmacia Diagnostics).  Thirteen different cytokines were also analysed in the sera by multiplex bead immunoassay (Luminex 100, Luminex Corporation), and clinical symptoms of allergy and BCG scar were reported in a questionnaire.
Results: A reduction in levels of specific and total IgE were observed after successful TB treatment.  TB patients also had higher levels of specific and total IgE compared to healthy controls.  Both interleukin (IL)-6 and interferon (IFN) gamma were higher in TB patients compared to healthy controls.  The levels of IL-6 were reduced after successful TB treatment.  The presence of a BCG scar was associated with a reduced risk of developing allergic sensitisation.
Conclusion: We observed a reduced level of allergic sensitisation after successful TB treatment.  TB patients seem to be more allergically sensitised than healthy controls, confirming our previous finding.  Furthermore, we observed an inverse association between allergic sensitisation and visible BCG scar, which adds additional support to the hygiene hypothesis.
Comment: So the hygiene hypothesis is not being allowed to die.                                                                    JT

High levels of human antigen-specific CD4 cells in peripheral blood revealed by stimulated co- expression of CD25 and CD 134 (0X40)

Zaunders et al       Sydney        Australia

J Immunol  2009; 183: 2827

Summary: Ag specific human CD4 (+) memory T lymphocytes have mostly been studied using assays of proliferation in vitro.  Intracellular cytokine and ELISPOT assays quantify effector cell populations but barely elicit responses to certain recall Ags that elicit strong proliferative responses, eg , tetanus toxoid, that comprise non-Th1 CD4(+) cells.  We have found that culturing whole blood with Ag for 40-48 h induces specific CD4(+) T cells to simultaneously express CD25 and CD134.  This new technique readily detects responses to well described CD4(+) T cell recall AGs, including preparations of mycobacteria, CMV, HSV-1, influenza, tetanus toxoid, Candida albicans and streptokinase, as well as HIV-1 peptides, with high specificity. The assay detects much higher levels of Ag-specific cells than intracellular cytokine assays, plus the cells retain viability and can be sorted for in vitro expansion.  Furthermore, current in vitro assays for human CD4(+) memory T lymphocytes are too labor –intensive and difficult to standardize for routine diagnostic laboratories, whereas the whole- blood CD-25(+)CD134(+) assay combines simplicity of set-up with a straightforward cell surface flow cytometry readout.  In addition to revealing the true extent of Ag-specific human CD4(+) memory T lymphocytes, its greatest use will be as a simple in vitro monitor of CD(+) T cell responses to Ags such as tuberculosis infection or vaccines.
Comment: We still lack a test that will detect TB infection with more sensitivity and specificity than the currently available TST and QFTs.
JT

Drug Resistance

Predictors of extensively drug-resistant pulmonary tuberculosis.

Kliiman et al    Tartu       Estonia

Ann Intern Med 2009; 150: 766

Background: About 40,000 cases of extensively drug-resistant tuberculosis  emerge worldwide annually, but the predictors of extensive drug resistance are unclear.
Objective: To identify risk factors for extensively drug-resistant tuberculosis and multidrug-resistant  but non-extensively drug-resistant tuberculosis in patients with culture- confirmed pulmonary tuberculosis.
Design: Cross-sectional, countrywide study.
Setting: Estonia, a country with one of the highest rates of extensively drug-resistant and multidrug-resistant tuberculosis.
Patients: All patients  with culture-confirmed pulmonary tuberculosis with clinical or radiologic evidence of active TB detected from January 2003 to December 2005..
Measurements: Risk determinants from patients’ demographic characteristics, socio-economic variables and tuberculosis –selected data or HIV status.
Results: Of 1163 patients, 60 (5.2%) had extensively drug-resistant tuberculosis and 196 (16.9%) had multidrug-resistant  but nonextensively drug-resistant tuberculosis.  Previous antituberculosis treatment (adjusted odds ratio [OR], 10.54 [95%CI, 5.97 18.62]), HIV infection (OR,3.12 [CI, 1.31 to 7.42]), homelessness (OR 2.73  [OR, 1.15 to 6.48]), and alcohol abuse (OR, 1.98 [CI 1.08 to 3.64]) increased risk for extensive drug resistance.  Previous treatment (OR, 4.11[CI, 2.77 to 6.08]) and age 24 years and younger (OR, 2.57[ CI,1.09 to 6.06]) 25 to 44 years (OR, 2.62[ CI 1.35 to 5.16]), and 45 to 64 years (OR2.06[CI, 1.06 to 3.999]) were determinants of multidrug resistance.  In patients 24 years or younger, female sex (OR 6.23[ CI, 1.02 to 37.99]) and birth outside of Estonia (OR, 82.04 [CI 3.46 to 1945.47]) increased risk for multidrug resistance.
Limitation: Patients’ co-morbid conditions and drug abuse history were not incorporated into analyses because of inconsistent source data.
Conclusion: Previous treatment is a common risk factor for extensively drug-resistant  and multidrug-resistant tuberculosis.  Reducing relapses; screening persons younger than 65 years  and immigrants; and combating against HIV infection, alcoholism and homelessness are key issues  for decreasing the spread of highly drug-resistant tuberculosis.
Comment:  One can scarcely disagree with these conclusions, but the CIs are so wide as to make this study’s  findings  rather weak.
JT

The epidemiological fitness cost of drug resistance in Mycobacterium tuberculosis.

Luciani et al      Sydney         Australia

Proc Natl Acad Sci USA  2009; 106: 14711

Summary : The emergence of antibiotic resistance in Mycobacterium tuberculosis has raised the concern that pathogen strains that are virtually untreatable may become widespread.  The acquisition of resistance to antibiotics results in a longer duration of infection in a host, but this resistance may come at a cost through a reduced transmission rate.  This raises the question of whether the overall fitness of drug-resistant strains is higher than that of sensitive strains- essential information for predicting the spread of the disease.  Here , we directly estimate the transmission cost of drug resistance, the rate at which resistance evolves, and the relative fitness of resistant strains.  These estimates are made using explicit models of the transmission and evolution of sensitive and resistant strains of M. tuberculosis, using Bayesian computation and molecular epidemiology data from Cuba, Estonia and Venezuela.  We find that the transmission cost of drug resistance relative to sensitivity can be as low as 10%, that resistance evolves at rates of approximately 0.0025-0.02 per case per year, and that the overall fitness of resistant strains of resistant strains is comparable with that of sensitive strains.  Furthermore, the contribution of transmission to the spread of drug resistance is very high compared with acquired resistance due to treatment failure (up to 99%).  Estimating such parameters directly from in vivo data will be critical to understanding and responding to antibiotic resistance.  For instance, projections using our estimates suggest that the prevalence of tuberculosis may decline with successful treatment, but the proportion of cases associated with resistance is likely to increase.
Comment: So the resistant organism has evolved without sacrificing any of its old virulence.
JT

Non-tuberculous Mycobacteria

Mycobacterium interjectum as a cause of lung disease mimicking tuberculosis.

Lacasa et al   Barcelona    Spain

Int J Tuberc Lung Dis  2009; 13: 1048

Summary
An increasing number of nontuberculous mycobacteria has recently been documented.  M. interjectum has been seen most often in cervical lymph nodes, and occasionally in the sputum of those with chronic lung disease.  A case of M. interjectum pulmonary disease in an immunocompetent patient is described.
A 48 year old previously healthy male presented with a 2 week history of cough, fever, night sweats and dyspnoea, and, 48 hours before admission , blood stained sputum and chest pain.  CXR revealed cavities in the right upper lobe.  Sputum was positive on smear for AFB and he was treated for tuberculosis with  three first line drugs for 2 months, then rifampicin and isoniazid for a total of 6 months.  Although laboratory identified M. interjectum, sputum  conversion soon occurred and by 6 months, the cavities on CXR had collapsed and cure seemed evident.  Eighteen months later the patient was readmitted with the same symptoms as his earlier presentation. A new CXR and CT scan  showed fresh cavities, while sputum was positive for M. interjectum.  Sensitivity testing showed resistance to R,H,Z,E,linezolid and doxycycline, but sensitivity to clarithromycin (CLM), levofloxacin(LVX) and S.
CLM,LVX,R and S were started and were to be given 2 years.  By 9 months, his disease appeared in remission.  Only one other case of pulmonary involvement by M. interjectum has been described but that was in a patient with  long standing bronchiectasis.
Comment:  It seems odd that the laboratory did not carry out resistance studies in the first place.
JT

Children

Congenital tuberculosis after in-vitro fertilisation

Stuart et al       Melbourne    Australia

Med J Aust  2009; 191: 41

Summary: A 6-week old infant who had been conceived through in-vitro fertilisation (IVF) presented with a skin lesion and enlarged lymph nodes, and developed severe respiratory distress.  Mycobacterium tuberculosis was identified; his mother was the only potential source identified.  To our knowledge, this is the first case of congenital tuberculosis after IVF reported in Australia and the second world wide.  It highlights the importance of adequate screening during investigation of infertility and the difficulties in diagnosing congenital tuberculosis.
Comment: Indeed!
JT

Toxicity of first-line drugs for treatment of tuberculosis in children: review.

Frydenberg et  al    Melbourne       Australia

Trop Med Int Health  2009; Sept 7

Summary Objective: To determine the frequency and manifestations of adverse events associated with recommended first-line anti-TB drugs in children.
Method: Literature review
Results: Overall, children tolerate anti-TB drugs very well when using currently recommended dosages.  Serious adverse events are rare and even mild symptoms such as nausea and vomiting are uncommon.  There are occasional case reports of severe hepatotoxicity.
Conclusions: Surveillance and reporting of adverse events will need to be improved when recommended dosages of the main first-line anti-TB therapy for children are increased.  Co-morbidities such as HIV infection and severe malnutrition may affect the incidence and complicate the management of possible adverse events to anti-TB therapy
Comment: There is little in this review to support routine liver function tests in children receiving recommended dosages of anti-TB drugs.
JT

Prevention

Mapping  the global use of different BCG vaccine strains.

Ritz et al     Melbourne     Australia

Tuberculosis (Edinb)  2009; 89: 248

Summary: Bacille Calmette-Guerin (BCG) vaccine is one of the oldest and most commonly administered vaccines worldwide.  Different BCG vaccine strains exist as a result of genetic changes that occurred during repeated subculture in different countries before lyophilization was introduced for the storage of seed lots in the 1960s.  Increasing evidence suggests that these genetically divergent BCG strains are associated with different protective efficacy against tuberculosis (TB), different rates of adverse events and variable susceptibility to anti-tuberculous drugs.  Information on which BCG vaccine strains are used  in each country worldwide has not previously been collated.    This report summarised data from the EuroTB network and from WHO/UNICEF in the first map depicting the BCG strains used globally.  In 83 (44%) of 188 countries , more than one BCG vaccine strain was used during the five year period.  In the countries that only used one strain, BCG Denmark was used in 32, BCG Russia/Bulgaria in 30, BCG Japan in eight, BCG Connaught in two.  Twelve countries used their locally- produced BCG vaccine strains.  The considerable variation in BCG vaccine strains used worldwide highlights the importance of documenting the particular vaccine strain used on an individual, local and national level.  This is important for the interpretation of changes in the epidemiology of adverse events after BCG immunisation, to interpret differences in the protective efficacy of BCG, and to inform the design of trials investigating novel TB vaccines.
Comment: And the same goes for   tuberculin.
JT

Comparable studies of immunostimulating activities in vitro among Mycobacterium bovis bacillus Calmette-Guerin (BCG) substrains.

Hayashi et al        Nagoya           Japan

FEMS Immunol Med Microbiol  2009; 56: 116

Summary: During the serial passage of Mycobacterium bovis bacillus Calmette-Guerin (BCG) in different countries after initial seed distribution from the Pasteur Institute, specific insertions and deletions in the genome among BCG substrains were observed and speculated to result in differences in immunological activities.  “Early shared strains” of BCG (Russia, Moreau, Japan, Sweden, Birkhaug), distributed by the Pasteur Institute, which conserve three types of mycolate (alpha, methoxy ,keto) in cell wall, exhibited stronger activities of induction of nitric acid, interleukin-1beta (IL-1beta), IL-6, IL-8, IL-12, and tumour necrosis factor (TNF-alpha), from human epithelial cell line A549, human myelomonocytic cell line THP-1 and mouse bone marrow cells in the presence of interferon-gamma (IFN-gamma) than did “late shared strains” of BCG (Danish, Glaxo, Mexico, Tice, Connaught, Montreal, Phipps, Australia, Pasteur).  The stronger induction of IL-12 and TNF-alpha in the presence of IFN-gamma was also observed by trihalose 6,6’-dimycolate (TDM) extracted from BCG-Japan than by TDM from BCG-Connaught, which lacks the methoxymycolate residue.  These results show “early shared strains” are more potent immunostimulating agents than “late shared strains), which could be attributed partially to methoxymycolate.  Our study provides the basic information for immunological characterization of various BCG strains and may contribute to a re-evaluation of them as a reference strain for vaccination against TB.
Comment: An important paper, but why wasn’t this work done years ago?
JT

Microbiology

A fast method for the identification of Mycobacterium tuberculosis in sputum and cultures based on thermally assisted hydrolysis and methylation followed by gas chromatography-mass spectrometry.

Kaal et al    Amsterdam         The Netherlands

J Chromatogr A  2009; 1219: 6319

Summary : A fast gas chromatography- mass spectrometry (GC-MS) method with minimal sample preparation is described for early diagnosis of tuberculosis (TB).  The automated procedure is based on the injection of sputum samples which are then methylated inside the GC injector by using thermally assisted hydrolysis and methylation (THM).  The THM-GC-MS procedure was optimised for the injection of sputum samples.  For the identification of Mycobacterium tuberculosis the known marker tuberculostearic acids (TBSA) and other potential markers were evaluated.  Hexacosanoic acid in combination with TBSA was found to be specific for the presence of M.tuberculosis.  For validation of the method several sputum samples with different  viscosities spiked with bacterial cultures were analysed.  Finally, 18 stored sputum samples collected in Vietnam from patients suspected to suffer from TB were re-analysed in Amsterdam by microscopy after decontamination/concentration and using the new THM-GC-MS method.  No false positives were found by THM-GC-MS and all patients who were diagnosed were also found pound positive by THM-GC-MS method.  These results show that the new fast and sensitive THM-MS-GS method holds great potential for the diagnosis of TB.
Comment: Encouraging!
JT

Extra-pulmonary tuberculosis

Rapid diagnosis of tuberculosis through the detection of mycobacterial DNA in urine by nucleic acid amplification methods.

Green et al       London      United Kingdom

Lancet Infect Dis  2009;  9: 505

Summary: Tuberculosis kills over 1.7 million people worldwide every year and nearly 40% of patients remain undiagnosed because of the poor sensitivity of the current, century old diagnostic method: sputum microscopy.  Sputum microscopy is not easily able to detect paediatric, extra-pulmonary or HIV –associated tuberculosis, which are now important causes of morbidity and mortality in developing countries.  Newer diagnostic methods for tuberculosis remain less sensitive than sputum microscopy.  Alternative strategies to diagnose tuberculosis by use of nucleic acid amplification methods to detect fragments of mycobacterial DNA in urine have been developed over the past decade with varying sensitivities and specificities.  Methods using quantitative  PCR on urine samples to detect transrenal DNA makes it possible to assay to assay the total body burden of mycobacterial infection in any age group and in extra-pulmonary tuberculosis with urine samples ,which can be collected noninvasively.  This review discusses the developments and application of nucleic acid amplification of mycobacterial transrenal DNA for improved tuberculosis diagnostics.
Comment: Sure, but it doesn’t come cheaply
JT

Diagnosis of tuberculous uveitis: clinical application of an interferon-gamma release assay.

Ang et al      Singapore

Ophthalmology  2009; 116: 1391

Purpose : To determine the role of the QuantiFERON-TB Gold In-Tube(QFT) assay in the diagnosis of tuberculous  (TB) uveitis.
Design: Retrospective cohort study.
Participants: The study included 157 patients with suspected TB uveitis seen over an 18 month period (August 1,2006 to  end of February, 2007) at the Singapore National Eye Center (SNEC) uveitis clinic.
Methods: We identified all cases of suspected TB uveitis in the above-mentioned time period and reviewed all medical records  of the cases.  Clinical findings, type of treatment instituted, response to treatment and results of investigations  such as QFT, tuberculin skin test (TST) and chest X-rays were recorded.   A novel method of using treatment response to determine the presumed diagnosis of TB was used to estimate the accuracy of QFT and TST.
Main Outcome Measures: The positive likelihood ratio (LR+), negative likelihood ratio (LR-), and area under the receiver operator characteristic curve (ROC) of the investigations were estimated.
Results: QFT is not superior to TST in sensitivity as a screening test or first –line study in TB-related uveitis; however QFT is more specific than the TST in identifying infections by Mycobacterium tuberculosis.  Negative QFT tests should be interpreted with caution, because they do not exclude the diagnosis.
Conclusions: The new QFT is only slightly superior to the TST in the diagnosis of TB uveitis.  Thus, there is an important role for interpreting the QFT together with the TST.  This is the first and largest study of its kind to evaluate the use of QFT in the clinical diagnosis of TB uveitis.
Comment: The evidence is mounting that in countries that can afford it, the two diagnostic tests, QFT and TST should be administered  together in the diagnosis of TB infection and in certain types of TB disease.
JT

Nursing

Institutionalised isolation: tuberculosis nursing at Westwood Sanatorium, Queensland, Australia 1919-55

Kirby et al     Bristol      United Kingdom

Nurs Inq  2009; 16: 122

Summary : From the mid nineteenth to mid twentieth century sanatoria loomed large in the popular consciousness as the space for the treatment of tuberculosis (TB).  A review of the historiography of sanatoria at the beginning of this paper shows that the nursing contribution to the care of TB patients is at best ignored and at worst attracts negative comment.  Added to this TB nursing was not viewed as prestigious by contemporaries, leading to problems attracting recruits.  Using a case study approach based on surviving archival material, this paper sets out to provide a glimpse of the work of TB nurses in a rural sanatorium at Westwood, Queensland, Australia.  For the nurses geographical isolation was compounded by professional stagnation, which created a working environment influenced by friction  and discord among the staff.  It reveals how despite this , nurses coped with working in hostile conditions, to make the long stay of their patients, separated from their families and familiar life style more bearable.
Comment: Before world war two, Westwood in central Queensland was very isolated indeed.
JT

Cavitating Pulmonary Tuberculosis         Courtesy    IUATLD

M. tuberculosis EM photo

Editorial Group:

Dr John Thompson   Canberra

Prof Adrian Sleigh    Australian National University, Canberra

A/Prof Paul Kelly       Australian National University, Canberra

Address for correspondence

Email: jtjnj@actewagl.net.au

Forthcoming Conferences

40th Union World Conference on Lung Health; 3-7 December 2009
Cancun, Mexico,
Contact: cancun2009@theunion.org

2nd Conference of the Union Asia Pacific Region 9-12 September 2009 Beijing
Contact: mail@iiuatld-apr.com

International Tuberculosis Course
31 August-18 September 2009-04-19 Hanoi, Vietnam
Contact: tb-lunghealth-courses@theunion.org

In this Edition

Editorial P 1 – 2

Microbiology P 2 – 3

Prevention and Control P 3 – 5

Infection P 5 – 6

TB and HIV P 6 – 7

Cell Biology P 7

Pharmacology P 7

Extra-Pulmonary TB P 8

Risk Factors P 9

Diagnosis P 10

Treatment P 10 – 11

Drug Resistance P 11

Population Studies P 11 – 12

Editorial

It is remarkable that 127 years have passed since Ziehl and in the following year Neelsen provided us with their test to identify M. tuberculosis, yet despite advances in other microbiological techniques, it still remains basic to finding acid fast bacilli. In most countries it remains the one criterion whereby TB is diagnosed or not. In those countries that can afford them, radiometric broth techniques have greatly advanced the isolation of M. tuberculosis on culture, while nuclear amplification has revolutionised the detection and differentiation of all mycobacteria.
But studies are still being published which seek to modify the ZN technique, particularly for poor countries. This is not just for the purpose of reducing cost also to reduce the persisting high error rate in interpretation, from which small laboratories in low incidence countries are not immune. We know that the fluorescent detection of AFB using an auramine stain is significantly superior, yet it is far from standard even in high income countries. In resource limited countries as we now call them, the cost of fluorescent microscopes severely limits their use even though there is now evidence that an increased detection rate leading to cure of more cases of TB and less transmission can more than compensate in cost for this equipment.
The prevention of contamination of TB cultures by non-mycobacteria still exists and bedevils the interpretation of drug trials where sputum culture conversion is seen as an endpoint. The study from Brazil on page 7 exemplifies this. We have not yet perfected the perfect decontamination method whereby all non-mycobacteria are destroyed but not a single Mycobacterium tuberculosis.
Thirdly we have not yet eradicated cross-contamination by another patient’s tubercle bacilli from our laboratories as the study from Marseilles tells us on page 2. Indeed the increasing use of nuclear amplication techniques across a wider range of laboratories will almost certainly see more cross contamination and more false positives. Only strong regulatory processes from a central authority together with inter-laboratory quality control measures can limit these problems. Australia is fortunate that such regulations are in place, but every clinician should be aware of whether the laboratory to which they send specimens, has the capacity for as little error as possible in processing and identifying M. tuberculosis. Once again good clinical practice dictates that no diagnosis should be made on the laboratory result alone.

Microbiology:

Fluorescent microscopy is less expensive than Ziehl-Neelsen microscopy in Thailand.

Sohn et al Nonthaburi, Thailand

Int J Tuberc Lung Dis 2009; 13: 266

Summary: Ziehl-Neelsen (ZN) microscopy is the primary method for acid-fast bacilli examination in resource–limited settings, including Thailand. Despite its considerably improved diagnostic performance, conventional fluorescent microscopy (FM) is rarely used due to its perceived high cost. An evaluation in Thailand found that the total cost of FM operated in thew National Tuberculosis Reference Laboratory (NTRL) in Bangkok, Thailand, is similar to that of ZN performed in the NTRL, and in four regional Thai laboratories. FM is therefore a cost effective alternative to ZN in resource –limited settings,
Comment: If these findings could be replicated at district level, case detection would be significantly enhanced.
JT

Evaluating the performance of basic fuchsin for the Ziehl-Neelsen stain.

Gordon et al Adelaide, South Australia, Paris, France

Int J Tuberc Lung Dis 2009; 13: 130

Setting: An investigation of commercially available basic fuchsin (BF) dye powders used for the detection of acid-fast bacilli (AFB).
Objective: to determine whether single or multiple assays may predict the performance of BF in the Ziehl-Neelsen (ZN) method.
Design: The composition and staining properties of six BF dye samples were assessed using continuous recording spectrophotometry, reverse phase thin-layer chromatography (RPTLC) and a standardised ZN biological staining test.
Results: Variable proportions of BF homologues could be demonstrated in the sample, but neither spectroscopy nor RPTLC was fully predictive of their staining quality. ZN staining of standard smears was needed to identify five powders that yielded satisfactory results and one powder with unsatisfactory performance. Increasing the BF concentration did not always result in improved staining.
Conclusions: Simple analytical methods, such as spectrophotometry and RPTLC , should be complemented by biological staining of control smears to assess the quality of BF dye powders. This allows tuberculosis control programmes to avoid procurement of BF dyes that would fail to detect AFB even when strictly adhering to current international guidelines for ZN staining.
Comment: Quite!
JT

Rapid detection of laboratory cross-contamination with Mycobacterium tuberculosis using multispacer sequence typing

Djelouadji et al Marseilles France

BMC Microbiol 2009; 9: 47

Background: The ability to culture Mycobacterium tuberculosis from clinical specimens serves as the gold standard for the diagnosis of tuberculosis. However, a number of false-positive diagnoses may be due to cross-contamination of such specimens. We herein investigate such episodes of cross-contamination by using a technique known as multispacer sequence typing (MST). This technique was applied to six M. tuberculosis isolates prepared within the same laboratory over a two-week period of time.
Results: MST analysis indicated a unique and common sequence profile between a strain isolated from a patient with proven pulmonary tuberculosis and a strain isolated from a patient diagnosed with lung carcinoma. Using this approach, we were able to provide a clear demonstration of laboratory cross-contamination within just four working days. Further epidemiological investigations revealed that the two isolates were processed for culture on the same day.
Conclusion: The application of MST has been demonstrated to serve as a rapid and efficient method to investigate cases of possible cross-contamination with M.tuberculosis.
Comment: We need all the tools we can get to identify cross-contamination.
JT

Fluoromycobacteriophages for rapid, specific and sensitive antibiotic testing of Mycobacterium tuberculosis.

Piuri et al Pittsburgh Pn USA

PLoS ONE 2009; 4: e4870

Summary: Rapid antibiotic susceptibility testing of Mycobacterium tuberculosis is of paramount importance as multiple and extensively –drug resistant strains of M tuberculosis emerge and spread. We describe here a virus-based assay in which fluoromycobacteriophages are used to deliver a GFP or Zs Yellow fluorescent marker gene to M. tuberculosis, which can then be monitored by fluorescent detection approaches including fluorescent microscopy and flow cytometry. Pre-clinical evaluations show that the addition of either Rifampicin or Streptomycin at the time of the phage addition obliterates fluorescence in susceptible cells but not in isogenic resistant bacteria enabling drug sensitivity in less than 24 hours. Detection requires no substrate addition, fewer than 100 cells can be identified, and resistant bacteria can be detected within mixed populations. Fluorescence withstands fixation by paraformaldehyde providing enhanced biosafety for testing MDR-TB and XDR-TB infections.
Comment: Will the need for a fluorescent microscope or more so a flow cytometer limit the use of this technique.
JT

Nontuberculous mycobacteria among patients who are suspected for multidrug-resistant tuberculosis-need for earlier identification of nontuber-culosis mycobacteria.

Tabarsi et al Teheran Iran

Am J Med Sci 2009; 337: 182

Background: In this study, we intended to find the prevalence of nontuberculosis mycobacteria (NTM) among patients who are referred as suspected multidrug-resistant tuberculosis (MDR-TB) cases to the only referral centre in Iran.
Methods: All patients referred to our center in 2002-2006 as MDR-TB with histories of treatment with standard and CATll World Health Organisation regimens were included in the study. Sputum smear and culture for acid-fast bacilli were performed for all patients 3 times. Sputum polymerase chain reaction was also performed for all patients. Mycobacterial identification was performed via polymerase chain reaction and routine identification tests for all culture-positive cases
Results: of the 105 patients in the study, 12 (11.4%) were identified to have NTM infection. The identified mycobacteria were classified in order of prevalence as Chelonae (8 cases), Simiae (2 cases), Aloei (1 case), and Farcinogen (1 case). Based on radiologic findings most of the cases demonstrated bilateral nodularity (83.3%) and also multifocal bronchiectasis (75%). Notably, cavitary lesions were present in 41.7% of the cases.
Conclusion: Based on the findings of this study, it is essential that such cases be identified before commencing MDR-TB treatment.
Comment: Are we to believe that in regional Iran, treatment decisions are made on sputum smear positivity alone? If so those with NTM disease caused by drug sensitive organisms eg M. kansasii would pass unnoticed.
JT

Prevention and Control

Preventive chemotherapy. Where has it got us? Where to go next?

Landry et al Montreal Canada

Int J Tuberc Lung Dis 2008; 12: 1352

Summary: The World Health organization estimates that a third of the world’s population is infected with Mycobacterium tuberculosis. Every second, one person becomes newly infected with tuberculosis (LTBI). In the past two decades, the spread of human immunodeficiency virus infection, worsening poverty and deteriorating health services have resulted in a steady increase in the overall incidence
Of TB globally. With treatment of LTBI, the number of infected persons who develop activeTB can be significantly reduced. Prevention through treatment of LTBI should therefore be an integral part of the control of TB.
Although only a minority of those with LTBI will develop active disease, the risk varies substantially according to the time since infection and medical risk factors. If persons at low risk for TB are selected for preventive chemotherapy, the individual and public health benefits are low, and a large number will have to be treated to prevent a single active case. It is therefore important to identify and treat patients who are high risk of disease.
Tools for rapid and reliable identification of persons with LTBI who are most likely to progress to active disease are urgently needed, as this will permit rational use of preventive treatment by restricting treatment to those patients with the most favourable risk/benefit ratio. The major challenges are efficient identification of those at highest risk of developing disease and ensuring treatment completion with a non-toxic regimen. If these can be overcome, preventive treatment holds the promise to substantially assist in the achievement of global control of TB.
Comment Recommended reading, although more emphasis should be given to realising that the larger the Mantoux reaction or the greater the release of IFN y, the greater the risk.
JT

Isoniazid completion rates for latent tuberculosis infection among college students managed by a community pharmacist.

Hess et al Pomona CA USA

J Am Coll Health 2009; 57: 553

Objective: The authors’ objective was to document 9-month and previously recommended 6-month treatment completion rates for latent tuberculosis infection (LTBI) in a pharmacist –managed LTBI clinic in a community pharmacy on a college campus, and to describe patient characteristics.
Participants: Participants were university students diagnosed with LTBI.
Methods: The authors conducted a retrospective review of pharmacy records from 2000 to 2006. Main outcome measures included 6-month and 9-month LTBI treatment completion rates, total isoniazid (INH) tablets taken, characteristics of completers versus noncompleters, average time to treatment completion and reported adverse drug events.
Results: The 9-month completion rate was 59 %, and the 6-month completion rate was 67 %. Among those not completing treatment, 15.2% experienced fatigue and 2.2 % experienced a rash (p=0.04 and p= 0.03, respectively).
Conclusion: LTBI clinics are a unique niche for community pharmacies and can provide individualised patient care to ensure LTBI treatment adherence, monitoring for disease progress and safety of isoniazid.
Comment: These completion rates might exceed the usual 50% but they are not all that encouraging.
JT

Inadequate ventilation for nosocomial tuberculosis prevention in public hospitals in central Thailand

Jiamjarasrangsi et al Bangkok Thailand

Int J Tuberc Lung Dis 2009; 13:454

Setting: Forty-two community and general hospitals in central Thailand.
Objective: To examine the adequacy of indoor ventilation for nosocomial tuberculosis (TB) prevention in public hospitals in central Thailand.
Design: A cross-sectional survey was conducted among 323 patient care and ancillary areas in the target hospitals. Data on indoor ventilation rate were collected by the tracer gas method and reported as air changes per hour (ACH). The adequacy of the measured ventilation rates were then determined by comparison with the international recommended standard values.
Results: Indoor ventilation rates were inadequate in almost half the studied areas ( 144/323, 44.6%). The inadequacy was particularly serious in the emergency rooms (ERs) and radiological areas, where 73.8 % (31/42 each) of the rooms had ACH below the recommended standards. Detailed analysis showed that most of the rooms with natural ventilation had air exchange rates that exceeded the recommended standards, while the opposite was the case for rooms with air-conditioning, particularly the window or wall-mount type.
Conclusion: Indoor ventilation in high risk nosocomial TB areas in public hospitals in Thailand was inadequate due to the installation of airconditioning systems in modern buildings.
Comment: Yet another study where the message is loud and clear. If the climate allows it, design hospitals with high ceilings and lots of open window space; otherwise spend large amounts on the best exhaust ventilation airconditioning money can buy.

JT

Impact of tuberculosis preventive therapy on tuberculosis in HIV-infected children

Gray et al Cape Town South Africa

Cochrane Database Syst Rev 2009; Jan 21; (1): CD006418

Background: Children with HIV are at increased risk of acquiring tuberculosis (TB), a common cause of acute and chronic respiratory disease and death in HIV-infected children living in areas where prevalence of the disease is high. Children infected with HIV and TB have worse outcomes than HIV-uninfected children who have TB; thus preventing the infection and disease in HIV-infected children is potentially an important public health intervention. Isoniazid, an anti-tuberculosis medication, has been used effectively to prevent TB in HIV-uninfected children, but currently there are no guidelines on the use of TB preventive therapy in HIV-infected children.
Objectives: To determine the impact of TB preventive therapy on TB-related incidence and death in HIV-infected children.
Search Strategy: We searched the Cochrane Controlled Trials Register (CENTRAL/CCTR), Cochrane HIV/AIDS Group Specialized Register, Medline/PubMed, EMBASE and AIDSearch. In addition, we scanned reference lists, manually searched conference abstracts, and contacted content experts.
Selection Criteria: We included studies of HIV-infected children randomised to receive TB preventive therapy or placebo, or an alternative TB preventive regimen. Participants could have a tuberculin test that was positive or negative..
Data Collection and Analysis: Two authors independently used the study selection criteria, assessed methodological quality and extracted data. Effects were assessed using hazard ratios.
Main results: One trial met the selection criteria for the review. The trial participants were HIV-infected children, most of whom were not taking antiretroviral therapy. Subjects were randomised to isoniazid and cotrimoxazole or placebo and tricomoxazole given daily or three times a week. The trial showed a marked reduction in TB incidence and death in the isoniazid group. As yet, however, there were no long term follow-up data on the durability of the protective effect or on possible long-term adverse events. This trial was unable to assess the impact of isoniazid prophylaxis on children receiving antiretroviral therapy.
Authors’ Conclusions: Isoniazid prophylaxis in HIV-infected children has the potential to play a major public health role by reducing TB incidence and death. As yet, however, data are insufficient to guide the duration of prophylaxis and to support its use in children using highly active antiretroviral therapy (HAART) and in those living in areas of low TB prevalence. Further studies are needed to assess whether TB preventive therapy is of benefit in all HIV-infected children, irrespective of use of antiretroviral treatment, the optimal duration of preventive therapy, or long term adverse events.
Comment: Nor do we know if the tuberculin status determines the outcome, particularly in regions of low TB prevalence.
JT

Infection

Comparison of QuantiFERON Gild In-Tube test and tuberculin skin test for identification of latent Mycobacterium tuberculosis infection in healthcare staff and association between positive test results and known risk factors for infection.

Vinton et al Melbourne Australia

Infect Control Hosp Epidemiol 2009; 30: 215

Objective: We compared a whole-blood interferon gamma release assay (QuantiFERON-TB Gold In-Tube test, hereafter “ QFT –in-tube test”) with a tuberculin skin test (TST) to determine which test more accurately identified latent Mycobacterium tuberculosis infection in healthcare staff.
Methods: A total of 481 hospital staff members were recruited from 5 hospitals in Melbourne ,Australia. They provided information about demographic variables and tuberculosis (TB) risk factors )i.e. birth or travel to a country with a high prevalence of TB, working in an occupation likely to involve contact with M.tuberculosis, or individuals with TB, or being a household contact of an individual with proven pulmonary TB.) The QFT-in tube test and the TST were administered in accordance with standardised protocols. Concordance between the test results was analysed using the kappa statistic, the McNemar test and logistic regression.
Results: A total of 358 participants had both a TST result and a QFT-in tube test result available for comparison. There were fewer positive QFT-in tube test results than positive TST results (6.7 % vs. 33.0%; P< .001). Agreement between the tests was poor (71%; kappa=0.16). A positive QFT-in tube test result was associated with birth in a country with a high prevalence of TB, the number of years an individual had lived in a country with a high prevalence of TB (i.e., the effect of each additional year, treated as a continuous variable), and high-risk occupational contact. A contact TST result was associated with older age, receipt of bacille Calmette-Guerin (BCG) vaccination, and working in an occupation that involved patient contact. Receipt of BCG vaccination was most strongly associated with discordant results in instances in which the TST result was positive and the QFT-in tube test result was negative.
Conclusion: In a population of healthcare staff with a low prevalence of TB and a significant rate of BCG vaccination, a positive QFT-in tube test result was associated with the presence of known risk factors for TB exposure, whereas a positive TST result was more strongly associated with a prior history of BCG vaccination.
Comment: There is no doubt QFT tests are more specific for detection of TB infection if the subject has received BCG. However their conclusion does not match their findings that those staff in contact with a tuberculous patient are more likely to have a positive TST result. It looks as if a negative QFT test will have to be followed by a TST and that 15 mm or more of induration will confirm infection.
JT

TB and HIV

HIV/AIDS: Immune reconstitution inflammatory syndrome: a reappraisal.

French M Perth Western Australia

Clin Infect Dis 2009; 1: 101

Summary: Individuals with human immunodeficiency virus infection who commence antiretroviral therapy when they are very immunodeficient are susceptible to immune reconstitution disorders. The most common disorders are the various forms of immune restoration disease (IRD) that appear to result from the restoration of a dysregulated immune response against pathogen specific antigens. Essentially, any pathogen that can cause an opportunistic infection as a result of cellular immunodeficiency can provoke IRD when pathogen-specific immune responses recover during antiretroviral therapy. In resource-poor countries, Mycobacterium tuberculosis and Cryptococcus neoformans are the most significant pathogens, because the former causes substantial morbidity and the latter substantial mortality. IRD associated with these pathogens is characterized by severe inflammatory responses and is often referred to as immune reconstitution inflammatory syndrome. Prevention and treatment strategies for IRD are being developed, but preliminary data have demonstrated the efficacy of corticosteroid therapy in sever cases. Immune reconstitution after antiretroviral therapy may also be associated with autoimmune disease or sarcoidosis, both of which appear to have an immunopathogenesis that is different from that of IRD.
Comment: A little more emphasis on delaying the introduction of antiretroviral therapy in cases with TB, would be helpful
JT

Timing of antiretroviral therapy initiation in tuberculosis patients with AIDS: a decision analysis.

Schiffer et al Seattle USA

J Acquir Immune Def Synd 2009; 44: 229

Summary: In HIV-infected tuberculosis patients with < 200 CD4 lymphocytes /cmm, highly active antiretroviral therapy (HAART) improves survival but can be complicated by immune reconstitution inflammatory syndrome (IRIS) and drug toxicity. We conducted a decision analysis in hypothetic cohorts of 1000 patients in which HAART was initiated during the first 2 months of antituberculosis therapy (early) or during months 2 through 6 of tuberculosis therapy (deferred) or was withheld until after tuberculosis therapy (no HAART). Out comes assessed were 1-year mortality and the combined outcome of 1-year mortality, new AIDS-defining illness, severe IRIS and severe drug toxicity. There 33, 48 and 147 deaths and 497, 501 and 501 combined outcome events in the early HAART, deferred HAART and no-HAART groups, respectively ; most events were drug toxicity in the early and deferred groups and HIV –related mortality or AIDS defining illness in the no-HAART group. In a 2-way sensitivity analysis of mortality , early HAART was favoured , even with the highest reported rates of IRIS (70%) and severe drug toxicity (56%). Deferred HAART as favoured over early HAART only if the IRIS-related mortality in the early group exceeded 4.6 %. These results support early initiation of HAART in patients with AIDS, except where IRIS-related mortality rates are high.
Comment: Should we compromise by delaying antiretroviral treatment for a month?
JT

Approaches to tuberculosis screening and diagnosis in people with HIV in resource-limited settings.

Reid et al New York USA

Lancet Infect Dis 2009; 9: 173

Summary: Tuberculosis is the main cause of morbidity and mortality in people living HIV/AIDS worldwide. Early diagnosis and treatment is essential in addressing the dual epidemic of tuberculosis and HIV. Increasing recognition of the importance of integrating tuberculosis services-including screening-into HIV care has led to global policies and the beginnings of implementation of activities at national level. However, debate remains about the best methods of screening for pulmonary tuberculosis among people living with HIV/AIDS in resource-limited settings. Mycobacterial culture, the gold standard for tuberculosis diagnosis, is too slow and complex to be a useful screening test in such settings. More widely available methods, such as symptom screening, sputum smear microscopy, chest radiography and tuberculin skin testing have important shortcomings, especially in people living with HIV/AIDS. However, until cheaper, simpler and more sensitive diagnostics for tuberculosis are available in peripheral healthcare settings., a strategy must be developed that uses current evidence to combine available screening tools.
Comment: In Australia our services are not integrated to the extent that we don’t know how many notified cases of TB are HIV positive.
JT

Cell Biology

How B cells shape the immune response against Mycobacterium tuberculosis

Maglione et al New York USA

Eur J Immunol 2009; 39: 676

Summary: Extensive work illustrating the importance of cellular immune mechanisms for protection against Mycobacterium tuberculosis has largely relegated B-cell biology to an afterthought within the tuberculosis (TB) field. However, recent studies have illustrated that B lymphocytes , through a variety of interactions with the cellular immune response, play previously underappreciated roles in sharing host defence against non-viral intracellular pathogens, including M.tuberculosis. Work in our laboratory has recently shown that, by considering these lymphocytes more broadly within their variety of interactions with cellular immunity, B cells have a significant impact on the outcome of airborne challenge with M. tuberculosis as well as the resultant inflammatory response. In this review we advocate for a revised view of TB immunology in which roles of cellular and humoral immunity are not mutually exclusive. In the context of our current understanding of host defence against non-viral intracellular infections, we review recent data supporting a more significant role of B cells during M. tuberculosis infection than previously thought.
Comment: Yet we have been singularly unsuccessful in finding specific immunoglobulins either for the diagnosis of TB or for protection against it.
JT

Cutinase -like proteins of Mycobacterium tuberculosis: characterization of their variable enzymatic functions and active site identification.

West et al Sydney, Australia, Wuxi, China, Bethesda, USA

FASEB J 2009; Feb 18

Summary: Discovery and characterization of novel secreted enzymes of Mycobacterium tuberculosis are important for understanding the pathogenesis one of the most important human bacterial pathogens. The proteome of M. tuberculosis contains over 400 potentially secreted proteins , the majority of which are uncharacterised. A family of seven cutinase-like proteins (CULPs) was identified by bioinformatic analysis, expressed and purified from Escherichia coli, and characterized in terms of their enzymatic activities. These studies revealed a functional diversity of enzyme classes based on differential preferences for substrate chain length. One member, CULP1, exhibited strong esterase activity, 40-fold higher than that of CULP6, which had strong activity as a lipase. Another, CULP4, performed moderately as an esterase and weakly as a lipase. CULP6 lipase activity was optimal above ph7, and fully maintained to ph5. None of the CULP members exhibited cutinase activity. Site-directed mutagenesis of each residue of the putative catalytic triad in CULP6 confirmed that each was essential for activity toward all fatty acid chain length of nitrophenol esters and lipolytic function. CULP1 and CULP2 were present only in culture supernatants of M tuberculosis., while CULP6, which is putatively essential for mycobacterial growth, was retained in the cell wall, suggesting the proteins play distinct roles in Mycobacterial biology.
Comment: But will any of them prove to be the weak links in attempts to destroy the organism and cure the person?
JT

Pharmacology

Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis.

Hugonnet et al New York USA

Science 2009; 323: 1215

Summary: Beta-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolysed by the chromosomally encoded blaC gene product. The carbapenem class of beta-lactams are very poor substrates for blaC, allowing us to determine the three-dimensional structure of the co-valent blaC-meropenem covalent complex at 1.8 angstrom resolution. When meropenem was combined with the beta-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [MIC {meropenem) less than 1 mcg /ml], and sterilization of aerobically cultures was observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the “persistent” state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. Meropenem and clavulanate are Food and Drug Administration-approved drugs and could be potentially used to treat patients with currently untreatable disease.
Comment: In combination, of course.
JT

Extra-Pulmonary Tuberculosis

Differentiating intestinal tuberculosis from Crohn’s disease: a diagnostic challenge.

Almadi et al Montreal Canada

Am J Gastroenterol 2009; 104: 1003

Summary: With the changing epidemiology of Crohn’s disease (CD) and intestinal tuberculosis (ITB), we are in an era where the difficulty facing physicians in discriminating between the two diseases has increased, and the morbidity and mortality resulting from a delayed diagnosis or misdiagnosis is considerably high. In this article we examine the changing trends in the epidemiology of CD and ITB, in addition to clinical features that aid in the differentiation of both diseases. The value of various laboratory, serological and tuberculin skin tests are reviewed as well. The use of an interferon-gamma-release assay, QuantiFERON-TB-Gold, in the work up of these patients and its value in populations where the bacillus Calmette-Guerin vaccine is still administered is discussed. Different radiological, endoscopic, and pathological similarities and features that can aid the clinician in reaching a rapid diagnosis are reviewed as well. The association between mycobacteria and CD, the concerns with the practice of antituberculosis medication trials in areas where tuberculosis (TB) is endemic, as well as the extrapulmonary TB induced by the use of antitumour necrosis factor-alpha agents are delineated in this article. Furthermore, we propose an algorithm for the investigation of patients in whom the differential diagnosis encompasses CD and ITB.
Comment: A timely review: as migrants and refugees continue to enter wealthy countries, so there will be more patients with intestinal tuberculosis.
JT

Pancreatic tuberculosis: a clinical and imaging review of 32 cases.

Nagar et al Mumbai India

J Comput Assist Tomogr 2009; 33: 136

Background: Tuberculosis of the pancreas is a rare entity, and anecdotal reports describing imaging features of pancreatic tuberculosis have been described in medical literature. The imaging features include computed tomography (CT) and ultrasonography in diagnosed cases of tubercular involvement of the pancreas are described, with an overview of clinical features and laboratory investigations.
Materials and Methods: We analysed records of 384 patients of diagnosed cases of abdominal tuberculosis for involvement of pancreas and detected 32 patients (8.33%) who had pancreatic involvement. This included 22 men and 10 women with an age range of 19 to 64 years ( mean age of 42,5 years) who were detected to have pancreatic from 1999 to 2004 in our institute. We reviewed the clinical, radiologic (ultrasonographic and CT features) and laboratory findings of all patients. The criteria for diagnosis of tuberculosis was based on ascitic fluid adenosine deaminase level in 14 patients, fine needle aspiration cytology of lymph nodes in 9 patients and the presence of pulmonary tuberculosis in 9 patients.
Results: The duration of symptoms spanned between 2 and 11 months, with a mean of 6 months. The most common symptom was abdominal pain localized to the epigastrium. Sixteen patients were HIV positive. Fourteen patients had a history of tuberculosis of the lungs, whereas 18 patients had pancreatic and peripancreatic involvement as the primary manifestation. Ultrasonography showed bulky inhomogeneous pancreas in 5 patients; solitary or multiple hypoechoic collections were observed in 7 and 20 patients respectively. CT findings demonstrated hypodense collections within the pancreas associated with peripancreatic lymphadenopathy in 29 patients. Three patients had a complex pancreatic mass lesion.
Conclusions: Pancreatic tuberculosis can present with a variable spectrum of imaging findings. Tuberculosis of the pancreas should be considered as a diagnostic possibility in patients who present with a pancreatic space occupying lesion associated with peripancreatic lymphadenopathy.
Comment: It seems that if you can’t diagnose tuberculosis elsewhere in the abdomen, there is no point looking for pancreatic involvement. This article seems to tell us that finding pancreatic TB won’t influence treatment anyway.
JT

Risk Factors

Tuberculosis and substance abuse in the United States, 1997-2006.

Oeltmann et al CDC Atlanta USA

Arch Intern Med 2009; 169: 189

Background: Tuberculosis (TB) control efforts are often ineffective in controlling TB among patients who use illicit drugs or abuse alcohol (substance abuse). This study examined the prevalence of substance abuse among TB cases reported in the United States and assessed the relationship between substance abuse and indicators of TB transmission.
Methods: A cross-sectional analysis was performed of data on US TB cases in patients 15 years or older reported from 1997 through 2006. Analyses included number and proportion of patients with TB characterized by substance abuse and associations between substance abuse, sputum smear status, treatment failure and inclusion in a county-level genotype cluster.
Results: Of 153,268 patients with TB, 28650 (18.7%) reported substance abuse, including 22,293 of 76,816 US born patients (29%). Multivariate analysis showed that, among patients negative for human immunodeficiency virus, odds of sputum smear-positive disease were 1.8 ( 99% CI, 1.7-1.9) times greater among those who reported substance abuse; this association was weaker among patients with human immunodeficiency virus infection (OR, 1.2; 99%CI, 1.1-1.4). Among female patients, odds of treatment failure were 2.4 (99% CI, 1.9-3.0) times greater among those who reported substance abuse. The association was weaker among male patients ( OR, 1.5; 99% CI, 1.3-1.7). Patients who abused substances were more likely to be involved in a county-level genotype cluster (US-born: OR, 2.3; 99% CI, 2.0-2.7; foreign-born: 1.5; 1.2-2,0).
Conclusions: Substance abuse is the most commonly reported behavioural risk factor among patients with TB in the United States. Patients who abuse substances are more contagious (smear positive) and remain contagious longer because treatment failure presumably extends periods of infectiousness. Increased transmission is consistent with our finding that patients who abuse substances were more likely to be involved in a localized genotype cluster, which can represent recent transmission.
Comment: This risk factor is going to be with us for a long time both in the US and Australia.
JT

Human genetic influence on susceptibility of tuberculosis: from infection to disease.

Cheepsattayakorn et al Bangkok Thailand

J Med Assoc Thai 2009;92: 136

Summary: There is substantial evidence from studies on racial variation in susceptibility to tuberculosis (TB) that human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis (Mtb). In only a minority of cases is there an obvious identifiable risk factor such as human immunodeficiency virus (HIV) infection, advanced age, diabetes, corticosteroid usage or alcohol abuse. In the remainder, a complex interaction of genetic and environmental factors causes the development of clinical TB. Assessment of the contribution of genetics of host resistance to human TB is a long standing challenge of human genetic research. Several studies demonstrated the association of various human leukocyte antigens (HLA) with disease susceptibility in different ethnic populations. There are likely to be many more TB-susceptibility genes to be identified.
Comment: Very true, but let us not forget poverty as a major risk factor.
JT

Impact of diabetes mellitus on treatment outcomes of patients with active tuberculosis.

Dooley et al Baltimore Md USA

Am J Trop Med Hyg 2009; 80: 634

Summary: Diabetes mellitus (DM) is an emerging chronic health condition of developed and developing countries. We conducted a retrospective cohort study of patients with active , culture-confirmed tuberculosis (TB) in Maryland to determine the impact of DM on TB treatment outcomes. Of 297 TB patients, 42 (14%) had DM. Patients with DM has 2.0 times higher odds of death than patients without DM (95% CI,0.74-5.2, P=0.18). Adjusting for human immunodeficiency virus (HIV), age, weight, and foreign birth, the odds of death were 6,5 times higher in patients with DM than patients without DM. (median 49 vs 39 days, P=0.039). In pulmonary TB patients, time to sputum culture conversion was longer in patients with DM than in patients without DM (Median 39 vs 29 days, P=0.09). Two month culture conversion proportions were similar (70% and 69%). Treatment failure occurred in 4.1% of patients without DM and 6.7% of patients with DM (P=0.51). In conclusion, DM was a risk factor for death in Maryland TB patients. There was a trend toward increased time to sputum conversion; two month culture conversion proportions were, however, similar.
Comment: Greater numbers are needed before it is possible to have confidence in these findings.
JT

Diagnosis

Pleural fluid adenosine deaminase and interferon gamma as diagnostic tools in tuberculous pleurisy.

Krenke et al Warsaw Poland

J Physiol Pharmacol 2008; 59: 349

Summary: Several biological markers have been proposed to improve the efficacy of diagnosing tuberculous pleurisy. The study was undertaken to evaluate the accuracy of pleural fluid adenosine deaminase (ADA) activity and interferon-gamma (IFN-gamma) in differentiating tuberculous pleural effusion (TPE) and non-tuberculous pleural effusion (non-TPE). Ninety four patients (50M and 44 F, mean age 60+/-18, range 18-95 years) with pleural effusion(PE) were studied. TPE was diagnosed in patients with : (i) positive pleural fluid or pleural biopsy culture or (ii) granulomas in the pleural biopsy specimen, after exclusion of other granulomatous diseases. Pleural fluid ADA activity was measured with the colorimetric method of giusti, while IFN-gamma was measured by ELISA. TPE was diagnosed in 28 patients. The non-TPE group consisted of 35 patients with malignant PE, 20 patients with parapneumonic effusion/pleural empyema, 5 with pleural transudate, and 6 with miscellaneous PE. The ADA activity and IFN-gamma concentrations were significantly higher in TPE than in non-TPE (614+/- 324 vs 15+/-36 pg/ml, P< 0.0001 and 75+/- 39 vs 11+/- 16 U/l respectively, P< 0.0001). The diagnostic sensitivity and specificity of IFN-gamma measurement ( cut-off value of 75 pg/ml) were 100% and 98.5% respectively and were similar to those of ADA (100% and 93.9% at the cut-off value of 40.3 U/L). We conclude that pleural fluid ADA activity and IFN-gamma concentration are highly sensitive and specific markers of tuberculous pleurisy.
Comment: These tests are now an important part of of our diagnostic armamentarium, even though few other studies have reached this degree of sensitivity.
JT

Pulmonary tuberculosis and disease-related pulmonary apical fibrosis in ankylosing spondylitis.

Ho et al Taoyuan Taiwan

J Rheumatol 2009; 36: 355

Objective: We investigated the etiological association and clinical characteristics of apical pulmonary fibrosis in ankylosing spondylitis (AS).
Methods: We reviewed medical records of 2136 consecutive patients diagnosed with AS at a tertiary medical center. Clinical and radiographic characteristics were analysed for evidence of apical lung fibrosis on chest radiographs.
Results: Of 2136 patients with AS, 63 (2.9%) developed apical lung fibrosis, of which chronic infections were the cause in 41 and AS inflammation in 22 patients. Tuberculosis (TB) was considered to be the cause of apical lung fibrosis in 40 patients (63.5%), including 19 with bacteriologically–proven TB and 21 with chest radiographs suggestive of TB. Two were identified as having non-TB mycobacterial infection and one as aspergillus infection. Lung cavities appeared to be crucial differentiators (P=0.009, odds ratio 7.4, 95% CI 1.5-365) between TB and AS inflammation induced apical fibrosis.
Conclusion: Our study suggests that TB, instead of aspergillus, is the most common pulmonary infection in patients with AS presenting with apical pulmonary fibrosis. AS-associated apical lung fibrosis may mimic pulmonary TB infection . Thus, bacteriological survey and serial radiological follow-up of lung fibrocavitary lesions are critical for accurate diagnosis and treatment.
Comment: It does not do to assume that upper lobe or apical segment shrinkage on a plain chest film is due to ankylosing spondylitis in a patient with that disease, even in a country with little TB.
JT

Treatment

Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis.

Orenstein et al Tugela KwaZulu-Natal South Africa

Lancet Infect Dis 2009; 9: 153

Summary: Multi-drug-resistant (MDR) tuberculosis is a growing clinical and public-health concern. To evaluate existing evidence regarding treatment regimens for MDR tuberculosis, we used a Bayesian random-effects meta-analysis to assess how the reported proportion of patients treated successfully is influenced by differences in treatment regimen, study methodology, and patient population. Successful treatment outcome was defined as cure or treatment completion. 34 clinical reports with a mean of 250 patients per report met the inclusion criteria. Our analysis shows that the proportion of patients treated successfully improved when treatment duration was at least 18 months, and if patients received directly observed therapy throughout treatment. Studies that combined both factors had significantly higher pooled success proportions (69%, 95% CI, 64-73%) than other studies of treatment outcomes (58%, 95%CI, 52-64%). Indivualised treatment regimens had higher treatment success (64%, 95% CI 59-68%) than standardised regimens( 54%, 95% CI, 43-68%), although the difference was not significant. Treatment approaches and study methodologies were heterogeneous across studies. Many important variables, including patients’ HIV status, were inconsistently reported between studies. These results underscore the importance of strong patient support and treatment follow-up systems to develop successful MDR tuberculosis treatment programmes.
Comment: We don’t know yet if treatment completion means cure, but these results seem more credible than those reported by the group in Lima, Peru.
JT

Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase ll trial.

Conde et al Rio de Janeiro Brazil

Lancet 2009; 373: 1183

Background: New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant strains. The fluoroquinolone, moxifloxacin is a promising new agent that might have additive activity to existing antituberculosis agents. We assessed the activity and safety of moxifloxacin in the initial stage of tuberculosis treatment.
Methods: We undertook a phase ll, double-blind ,randomised, controlled trial of a regimen that included moxifloxacin adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received isoniazid, rifampicin and pyrazinamide at standard doses and were assigned by permuted block randomisation to receive either moxifloxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15-20 mg/kg) plus moxifloxacin placebo (N=85) 5 days a week for 8 weeks. The primary endpoint was the proportion of patients whose sputum culture had converted to negative by week 8. Analysis was modified by intention to treat(ITT); patients whose baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered with Clinical Trials.gov, number NCT00082173.
Findings: 74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population . 125 patients had 8-week data )(moxifloxacin n=64, ethambutol n=61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59(80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17.2% , 95% CI 2.8-31.7; p=0.03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to the study drug (grade 3 cutaneous reaction in the ethambutol group).
Interpretation: Moxifloxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to assess whether moxifloxacin can be used to shorten the duration of tuberculosis treatment are justified.
Comment: Not on these results, I think. The differences are barely significant and the confident intervals far too wide. It seems the researchers underestimated the numbers of subjects they needed to enrol.
JT

Drug Resistant TB

Fitness cost of drug resistance in Mycobacterium tuberculosis.

Gagneux S London UK

Clin Microbiol Infect 2009; 15; Suppl1: 66

Summary: Multidrug-resistant (MDR)— and extensively drug-resistant (XDR)— forms of tuberculosis are growing public health problems. Mathematical models predict that the future of the MDR and XDR tuberculosis epidemics depends in part on the competitive fitness of drug-resistant strains. Here, recent experimental and molecular epidemiological data that illustrate how heterogeneity among drug-resistant strains of Mycobacterium tuberculosis can influence the relative fitness and transmission of this pathogen are reviewed.
Comment: It should be recalled that the very first strains of resistant M tuberculosis sacrificed fitness for resistance, but this state of affairs did not last.
JT

Population Studies

Major Mycobacterium tuberculosis lineages associate with patient country of origin.

Reed et al Montreal Canada

J Clin Microbiol 2009; 47: 1119

Summary: Over recent years , there has been an increasing acknowledgment of the diversity that exists among Mycobacterium tuberculosis clinical isolates. To facilitate comparative studies aimed at deciphering the relevance of this diversity to human disease, an unambiguous and easily interpretable method of strain classification is required. Presently, the most effective means of assigning isolates into a series of unambiguous lineages is the method of Gagneux et al, that involves the PCR-based detections of large sequence polymorphisms (LSPs). In this manner, isolates are classified into six major lineages, the majority of which display a high degree of geographic restriction. Here we describe an independent replicate of the Gagneux study carried out on 798 isolates collected over a 6-year period from mostly foreign-born patients resident on the island of Montreal, Canada. The original trends in terms of bacterial genotype and patient ethnicity are remarkably conserved within this Montreal cohort, even though the patient distributions between the two populations are quite distinct. In parallel with the LSP analysis, we also demonstrated that “clustered” tuberculosis (TB) cases defined through restriction fragment length polymorphism (RFLP) analysis ( for isolates with > or= 6 IS6110 copies) cor RFLP in combination with spoligotyping ( for isolates with <6 IS6110 copies) do not stray across the LSP-defined lineage boundaries. However, our data also demonstrate the poor discriminatory power of either RFLP or spoligotyping alone for these low-IS6110-copy-number isolates. We believe that this independent validation of the LSP method should encourage researchers to adopt this system in investigations aimed at elucidating the role of strain variation in TB.
Comment: Would these findings also hold up for Australia’s various imported strains?
JT

Human-to–human transmission of tuberculosis caused by Mycobacterium tuberculosis bovis in immunocompetent patients.

Sunder et al Tours France

J Clin Microbiol 2009; 47: 1249

Summary: Human-to-human transmission of Mycobacterium bovis in two immunocompetent patients from the same family was confirmed by spoligotyping (pattern F35, which was only observed in cattle from the same area in France). A single allelic difference between animal and human isolates
was observed with mycobacterial interspersed repetitive units containing variable-number tandem repeats, suggesting a jump across the species barrier.
Comment: Such a jump is rarely seen between humans and cattle and less often between us and other animals.
JT

Contact tracing by RFLP

February 2009

Editorial Group

Dr John Thompson Canberra

Prof. Adrian Sleigh Australian National University

A/Prof Paul Kelly Australian National University

Address for correspondence

Email: jtjnj@actewagl:net.au

Website http://tbreview.wordpress.com

Forthcoming Conferences
5th IUATLD Europe Region Conference
27 May – 30 May 2009 Dubrovnik Croatia
Email: info@depol.org

2nd IUATLD Asia Pacific Region Conference
9 Sept – 12 Sept 2009 Beijing China
Email: Chinatb1933@Yahoo.com

List of Contents

Risk Factors P 1

Treatment P 3

Differential Diagnosis P 4

Extra pulmonary TB P 4

Microbiology P 5

Contact Tracing P 6

TB and HIV P 6

Imaging P 7

Population Studies P 8

Control P 8

Non TB Mycobacteria P 9

Zoonoses P 9

Socio-political Issues P 9

Health Care Workers P 10

Children P 11

Prevention P 11

Cell Biology P 12

Editorial

A report from the USA in this edition (P2) shows that there is a slight but significant delay in sputum conversion among diabetic patients treated with effective antituberculous chemotherapy. An earlier study from Indonesia suggested treatment failure rates in their diabetic patients were higher than in nondiabetics because therapeutic blood levels of antituberculous agents were more difficult to maintain. We know that those with type 2 diabetes mellitus are between one and half and three times more likely to develop TB although evidence from Hong Kong suggests that those with excellent control (Hb1 Ac <7) are not at risk for TB. Few diabetics achieve this degree of control and there is anecdotal evidence that relapse and treatment failure following treatment for tuberculosis occurs more frequently than in nondiabetics. The literature is sparse and more studies are required to elucidate this issue.

Risk Factors

Risk of tuberculosis in screened subjects without known risk factors for active disease.

Cook et al Vancouver BC Canada

Int J Tuberc Lung Dis 2008; 12: 903

Setting: Tuberculosis (TB) referral clinic in Vancouver, British Columbia, Canada.
Background: Screening for and treatment of latent TB infection (LTBI) in at-risk populations are the cornerstone of TB control in low-incidence countries. Persons at low risk often undergo the tuberculin skin test for reasons other than contact. Little information exists on the actual risk of TB in this population
Objective: To determine the risk of TB in screened subjects without known risk factors.
Design: Retrospective descriptive analysis of demographics, TST reaction size and TB disease occurrence in 98,333 low-risk subjects screened from 1990 to 2002.
Results: The annual average disease rate was 0.4 per 100,000 population (cumulative rate 7.4 /100,000 ) from 1990 to 2006, and TB was diagnosed only in the foreign-born. Risk of TB in the foreign-born increased with larger TST reaction size (P<0.03). Completion of treatment for LTBI was not documented for any of the subsequent active TB cases.
Conclusion: In a low-risk screened population, active TB disease was found only in the foreign born. Treatment of LTBI is not recommended in persons with a positive TST and no additional risk factors.. Local screening programs should focus on populations with confirmed risk factors for disease.
Comment: These are compelling conclusions, although I am not sure that a TST reaction of > 15mm in a low risk , non-BCG vaccinated person should be ignored.
JT

Tumour necrosis factor antagonists: structure, function and tuberculosis risks.

Wallis RS Washington DC USA

Lancet Infect Dis 2008; 8:601

Summary: Our understanding of the infection risks presented by tumour necrosis factor (TNF) antagonists has continued to evolve in the 10 years since these drugs were first introduced. Several recent studies have confirmed the increased risk of tuberculosis posed by TNF antibodies compared with soluble TNF receptor, particularly with regard to reactivation of latent infection. Structural and functional differences seem to account for this finding. This review examines the potential relations between target specificity, stoichiometry and binding kinetics of TNF blockers and their associated risk of infection. Clinical strategies for prevention and management of tuberculosis in patients treated with TNF blockers may be improved based on our evolving understanding of these differences.
Comment: An important issue particularly as the range of these agents and the conditions they treat , continues to expand.
JT

Mycobacterial clearance from sputum is delayed during the first phase of treatment in patients with diabetes.

Restrepo et al Brownsville TX USA

Am J Trop Med 2008; 79: 541

Summary: Although type 2 diabetes (DM) is a recognized risk factor for development of tuberculosis (TB), the impact on treatment is unclear. Among the few published reports, some suggest that mycobacterial clearance is delayed in TB patients with DM. Using survival analysis on data from 469 culture-positive TB patients retrospectively identified in south Texas, we found DM to be an independent risk factor for a 5-day delay in mycobacterial clearance within the first 60 days of treatment.
Comment: Yet another report where response to TB treatment in diabetics is suboptimal.
JT

Tuberculosis associated with household crowding in a developed country.

Baker et al Wellington New Zealand

J Epidemiol Comm Hlth 2008; 62: 715

Background: Tuberculosis (TB) remains an important infectious disease in New Zealand (NZ) and globally, but risk factors for transmission are still poorly understood. This research aimed to identify whether household crowding contributes to TB transmission in NZ.
Methods: This ecological study used TB surveillance and census data to calculate the TB incidence rates by census area unit (CAU). Census data were used to determine CAU characteristics including proportion of household crowding (a bedroom deficit of one or more), proportion of population who are migrants born in high-TB-incidence countries, median household income, and deprivation level. A negative binomial regression model was used to estimate the association between TB incidence and household crowding.
Results: The analysis included 1898 notified TB cases for the 2000-2004 period. Univariate analysis showed TB incidence at the CAU level was associated with household crowding, for the total population and for all ethnic and age groups. After adjusting for the covariates of household income, existing TB burden and proportion of migrants from high TB –incidence countries, multivariate analysis showed statistically significant associations between TB incidence and household crowding. The incidence rate ratio (IRR) was 1.05 ( 95% CI, 1.02 to 1.08) in the total population and 1.08 (95% CI 1.04 to 1.12) for NZ-born people <40 years.
Conclusion: At the CAU level, TB incidence in NZ is associated with household crowding. An individual-based study (eg case-control) in recently infected cases (detected by molecular epidemiology) is suggested to complement these findings. Reducing or eliminating household crowding could decrease TB incidence in NZ and globally.
Comment: A good try, considering the host of confounding factors.
JT

Functional gene polymorphisms in Canadian Aboriginal populations with high rates of tuberculosis.

Larcombe et al Manitoba Canada

J Infect Dis 2008; 198: 1175

Summary: The present study determined whether a pattern of functional single nucleotide polymorphisms (SNPs) was present that could predispose a Dene cohort to a suboptimal response to Mycobacterium tuberculosis. Compared with a Caucasian cohort, the Dene and Cree were found to maintain a significantly higher frequency of SNPs associated with low expression of vitamin D receptor (VDR), interferon (IFN)-gamma and tumor necrosis factor-alpha (-308) and high production of monocyte chemoattractant protein (MCP)-1 (-2518) and interleukin (IL)-6 (-174). Given the roles played by IFN-gamma and VDR in facilitating macrophage containment of M. tuberculosis and the opposing role of MCP-1 and IL-6, the observed alleic variation by ethnicity may in part contribute to the high rates of tuberculosis among the Dene.
Comment: Are the Dene less subject to rheumatoid disease and ankylosing spondylitis?
JT

Tuberculosis in Thai renal transplant recipients.

Rungruanghiranya et al Nakornnayok
Thailand

Transplant Proc 2008;40: 2376

Objective: Tuberculosis (TB) is a leading cause of morbidity and mortality in renal transplant recipients, especially in developing countries. Its incidence and characteristics remain unknown in Thai recipients, and outcome of TB in Thailand.
Methods: We retrospectively reviewed case records of all renal transplant recipients from 1992 to 2007 to record demographic information, transplant characteristics, median time to diagnosis of TB, and outcomes.
Results: Among 270 recipients, 9 (3.84%, 95% CI, 1.18%-5.49%) developed TB. Their median age was 40 years (range = 23-62 years) and median time from transplantation to diagnosis was 36 months (range 4-115 months). Although pulmonary TB was the most common form (56%), 2 patients (22%) developed extrapulmonary disease. Disseminated TB occurred in 2 patients (22%). The diagnosis was made on respiratory specimen cultures in 3 cases (33.3%) and body fluid cultures in 3 (33.3%). Five patients were successfully treated with a four drug combination therapy. Two of the other subjects who received triple therapy were noncompliant, succumbing to graft failure and sepsis. Blood group AB (OR 10.95, 95% CI, 1.57-76.6) and the use of tacrolimus rescue therapy (OR 9.68, 95% CI, 2.13-43.94) were associated with an increased risk of TB.
Conclusion: TB is common among Thai renal transplant recipients with an incidence 27 times higher than among the general Thai population . The extrapulmonary form in particular occurs more frequently with an increased risk of mortality.
Comment: The widely divergent times of onset of TB after transplant suggests both transmission from the donor organ as well as reactivation of infection in the recipient.
JT

Treatment

The value of end-of-treatment chest radiograph in predicting pulmonary tuberculosis relapse.

Hamilton et al Durham, NC, New York, NY, Atlanta, GA, Cleveland OH, USA; Montreal Canada.

Int J Tuberc Lung Dis 2008; 12: 1059

Setting: Patients with cavitatory pulmonary tuberculosis (TB) on baseline chest radiograph (CXR) remain culture positive after 8 weeks of treatment are at high risk of relapse. The role of end-of-treatment (EOT) CXR in predicting relapse is unclear.
Objective: To determine whether EOT CXR independently predicts TB relapse.
Design: We conducted a secondary analysis of a randomized trial of intermittent treatment using rifapentine in the continuation phase of TB treatment among 1004 human immunodeficiency virus seronegative adults with culture positive TB.
Results: Relapse occurred in 17.3 % of subjects with persistent cavity on EOT CXR, 7.6% of subjects with a cavity that resolved by EOT CXR, and 2.5% (P=0.0002 for trend) of subjects who never had a cavity. In multivariable analysis, patients with persistent cavity on EOT CXR were significantly more likely to relapse than subjects whose early cavity had resolved by EOT CXR (HR 1.92, 95% CI 1.09-3.39).
Conclusion: A persistent cavity after 6 months of TB treatment was independently associated with disease relapse after controlling for other variables. EOT CXR may help predict those likely to relapse.
Comment: Indeed! Will these findings apply to those who have completed 6 months of daily chemotherapy?
JT

New anti-tuberculosis drugs with novel mechanisms of action.

Rivers et al Perth WA Australia

Curr Med Chem 2008; 15: 1956

Summary: It is estimated that a third of the world’s population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new antituberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area., with several new drug candidates entering clinical trials. This review considers new potential first-line antituberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure activity relationships , in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.
Comment: A timely review.
JT

Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes.

Blackmore et al Wellington New Zealand

Clin Infect Dis 2008; 47: e83

Summary: Paradoxical reactions are immune-mediated exacerbations of disease triggered by tuberculosis treatment. Paradoxical reactions involving the central nervous system may be life threatening. Infliximab ( tumor necrosis factor antibody) profoundly inhibits cellular immune responses to Mycobacterium tuberculosis. We describe a case in which infliximab was used to control steroid-resistant tuberculosis paradoxical reaction involving the central nervous system.
Comment: We look forward to hearing more.
JT

Differential Diagnosis

Tuberculosis mimicked by melioidosis

Vidyalakhsmi et al Mangalore India

Int J Tuberc Lung Dis 2008; 12: 1209

Background: In regions endemic for tuberculosis (TB) such as India, presumptive anti-tuberculosis treatment is often prescribed. Melioidosis, caused by Burkholderia pseudomallei, is underdiagnosed in India, due to lack of awareness and low index of suspicion.
Setting: A tertiary care hospital in south India.
Objective: To present our analysis of a series of 22 cases of suspected TB that was later confirmed to be melioidosis.
Design: Twenty two patients with culture proven melioidosis, who were originally given empirical anti-tuberculosis treatment, were retrospectively analysed regarding clinical presentation, laboratory findings and epidemiological features, with a view to determining any significant discriminatory parameter/s that would help to distinguish the two diseases.
Results: Eight cases mimicked pulmonary TB, five tubercular arthritis, three tubercular spondylitis, two splenic abscess, and one case mimicked tuberculous pericarditis and parotid abscess. Fever was the chief presenting complaint; all had high erythrocyte sedimentation rate (ESR) values (mean 111 mm +/- 23.7 SD); 15 (68.2% had neutrophil leucocytosis, 20 (90.9%) had diabetes mellitus. Subsequent to laboratory culture reports confirming melioidosis, appropriate treatment was instituted.
Conclusion: Fever in a diabetic patient with high ESR and neutrophil leukocytosis should raise suspicion of melioidosis while instituting presumptive antituberculosis treatment in areas where both diseases are prevalent.
Comment: Although Burkholderia pseudomallei is not particularly susceptible to rifampicin in vitro, there can be some response to this drug in localized pulmonary melioidosis.
JT

Extrapulmonary Tuberculosis

Temporal evolution of cerebrospinal fluid following initiation of treatment for tuberculous meningitis.

Patel et al Durban South Africa

S Afr Med J 2008; 98: 610

Objective: Clinicians often perform follow-up lumbar punctures (LPs) on patients with tuberculous meningitis (TBM) to document changes occurring in the cerebrospinal (CSF). Normalisation of the CSF then serves as indirect confirmation of the diagnosis. However, changes occurring in CSF following the initiation of of anti-tuberculosis (TB) treatment are not well described. We undertook a retrospective study to determine the temporal evolution of CSF in patients with TBM on anti-TB treatment in an attempt to provide a more rational basis for the interpretation of repeat LPs.
Methods: Patients diagnosed with TBM at King GeargeV hospital in Durban from 1994 to 2003 were identified. Demographic, clinical, laboratory and radiological data were recorded. We examined the change in CSF lymphocyte cell count, polymorphonuclear (PMN) cell count, glucose concentration and protein concentration. Initially, scatter plots of the data modelled over time were produced and random affects models were then used to model the predicted changes in CSF over time.
Results: Ninety nine patients were identified, and a total of 327 LPs were done. The average number of LPs per patient was 3 (range 3 to 9). Statistically significant changes in all four variables (lymphocytes, PMN cells, glucose and protein) were demonstrated, with a p value of < 0.001. The predicted models showed that lymphocyte count and protein concentration change slowly over time. PMN cells and glucose concentration changed rapidly in an exponential manner.
Conclusions: Our results demonstrate the tendency for CSF to normalize over time. The slow change in lymphocyte count and protein concentration limits clinical use. The rapid change in PMN cells and glucose concentration allows us to make reasonable clinical decisions. If a repeat LP does not show definite improvement in these two parameters, it should be considered atypical for TBM.
Comment: Useful when microbiological proof is not forthcoming JT

Orbital tuberculosis: a review of the literature.

Madge et al Adelaide SA Australia

Orbit 2008; 27: 267

Purpose: To provide an up-to-date review of the clinical presentations, investigations and manage-ment of orbital tuberculosis (OTB).
Methods: Systematic review of the literature concerning OTB, limiting the results to English language peer reviewed journals.
Results: Seventy nine patients from 39 publications were identified as cases of OTB. The conditions presents in one of five forms: classical periostitis; orbital soft tissue tuberculoma or cold abscess with no bony involvement; OTB with bony involvement; spread from the paranasal sinuses; and tuberculous dacryoadenitis. The ocular adnexa, including the nasolachrymal system and overlying skin ,may also be involved.
Conclusions: Diagnosis can be difficult and may necessitate an orbital biopsy, in which acid-fast bacilli and characteristic histopathology may be seen. Growth of Mycobacterium tuberculosis (Mtb)) from such a specimen remains the gold standard for diagnosis. Ancillary investigations include tuberculin skin tests and chest radiography, but more recently alternatives such as whole blood interferon-gamma immunological tests and PCR-based tests of pathological specimens have proved useful. The management of OTB is complex, requiring a stringent public health strategy and high levels of patient adherence, combined with long courses of multiple anti-tuberculous medications. The interaction of the human immunodeficiency virus (HIV) with TB may further complicate management.
Comment: This condition is sufficiently rare as to render a “trial of treatment “ in the absence of a tissue or microbiological diagnosis, very poor medical practice.
JT

Microbiology

An evaluation of the recovery of mycobacteria from urine specimens using the automated Mycobacteria Growth Indicator Tube system (BACTEC MGIT 960)

Chan et al Singapore

J Med Microbiol 2008; 57: 1220

Summary: The Mycobacteria Growth Indicator Tube (MGIT 960) system was evaluated against Lowenstein-Jensen (LJ) medium and the Bactec 460 TB system for the recovery of mycobacteria from 1393 consecutive urine specimens.
MGIT had a sensitivity of 91.3% (95% CI, 83.2-99.4) when the combination of Bactec 460 and LJ was used as the reference method. The mean time for positivity for MGIT and Bactec 460 was 19.3 days and 20 days, respectively, while that for LJ medium was 35 days. The incidence of contamination was highest for LJ medium )n=148), followed by MGIT 960 (n=81), and Bactec 460 had the lowest incidence of contamination (n =50). In conclusion, the isolation of mycobacteria from urine specimens by the MGIT 960 is comparable to that of the Bactec 460 TB system and solid media.
Comment: Contamination in urine specimens is always a problem, so it is helpful to learn that it can be greatly reduced by these automated broth techniques.
JT

Lessons from molecular epidemiology and comparative genomics

Mathema et al Newark NJ USA

Semin Resp Crit Care Med 2008; 29: 467

Summary: Molecular biology has revolutionized the field of tuberculosis (TB) research. Comparative genomics and molecular epidemiology are providing revelations about the evolutionary origins of Mycobacterium tuberculosis and phylogenetic relationships between different strains and strain families. Accumulating evidence indicates that distinct strains of M.tuberculosis (genotype) may be associated with differential transmissibility, virulence, and /or clinical manifestations (phenotype). As advances in our understanding of the relationship between genotype and phenotype progress, this knowledge will have important ramifications for TB control and the development of novel vaccines and improved diagnostics. Some of the greatest advantages of molecular epidemiological methods include our abilities to follow transmissions of particular strains within communities, track epidemics, and recognize the presence of historic outbreaks. Moreover, there are critical questions about TB that are essentially unanswerable in the absence of molecular techniques. These include our capacity to distinguish exogenous reinfection for endogenous reactivation in recurrent TB cases and to recognize primary transmission of drug resistant strains versus the acquisition of drug resistance via de novo mutations. Finally, an elucidation of the phylogenetic structure and evolutionary history of M. tuberculosis provides a necessary background for understanding the underlying mechanism responsible for the continued success of this deadly pathogen.
Comment : And to track the changing distribution of different strains across the world.
JT

The scent of Mycobacterium tuberculosis.

Syhre et al Christchurch New Zealand

Tuberculosis (Edin) 2008; 88: 317

Summary: Worldwide, tuberculosis (TB) kills nearly 2 million people annually, yet rapid diagnosis still relies on a 100-year-old method of sputum staining for acid-fast bacilli. The advent of solid phase micro-extraction and gas chromatography/mass spectrometry makes it possible to systematically investigate whether volatile metabolites from organisms belonging to the genus mycobacterium can be used as a rapid and highly selective alternative to the traditional diagnostic methods. We have identified four specific compounds (methyl phenylacetate, methyl p-anisate, methyl nicotinate and o-phenylanisole) from Mycobacterium tuberculosis and Mycobacterium bovis cultures grown in vitro that are distinctive volatile markers. These compounds are detectable before the visual appearance of colonies, potentially useful as the basis of a non-invasive diagnostic test for TB and have characteristic odours.
Comment: This seems worth pursuing
JT

Contact Tracing

Tuberculosis transmission by patients with smear-negative pulmonary tuber-culosis in a large cohort in the Netherlands.

Tostmann et al Nijmegen The Netherlands

Clin Infect Dis 2008; 47: 1135

Background: Sputum smear microscopy is commonly used for diagnosing tuberculosis (TB). Although patients with sputum-smear negative TB are less infectious than patients with smear-positive TB, they also contribute to TB transmission. The objective of this study was to determine the proportion of TB transmission events caused by patients with smear-negative pulmonary TB in the Netherlands.
Methods: All patients in the Netherlands with culture-confirmed TB during the period 1996 – 2004 were included in this study. Patients with identical DNA fingerprints in Mycobacterium tuberculosis isolates from sputum samples were clustered. The first patients in a cluster were considered to be the index patients; all other patients were considered to be secondary cases. In addition, we examined transmission from sources by conventional contact tracing.
Results: We analyzed 394 clusters with a total of 1285 patients. On the basis of molecular linkage only, 12.6% of the secondary cases were attributable to transmission from a patient with smear-negative TB. The relative transmission rate among patients with smear-negative TB, compared with patients with smear-positive TB, was 0.24 (95% CI 0.20-0.30). Secondary cases in clusters with an index patient with smear-negative TB more frequently had smear-negative status (OR, 1.86; 95% CI, 1.18-2.93), compared with secondary cases in clusters with an index patients with smear-positive TB. Conventional contact tracing revealed that 26 (6.2%) of the 417 sources, as identified by the Municipal Health Services, had smear –negative TB.
Conclusions: In the Netherlands, patients with smear-negative, culture-positive TB are responsible for 13 % of TB transmission. Countries that have ample resources should expand their TB-control efforts to include prevention of transmission from patients with smear-negative, culture-positive TB.
Comment: It is surprising to learn that such countries do not already do so.
JT

TB and HIV

To routinely offer testing for HIV infection in all cases of tuberculosis: a rational clinical approach?

Post et al Sydney NSW Australia

Med J Aust 2008; 188: 162

Summary: The strong interaction between the HIV and tuberculosis epidemics has been well described. Australian national surveillance data suggest that HIV status is ascertained by clinicians in less than 50% of people with tuberculosis. Clinicians are not able to reliably predict which people have HIV infection: risk factor assessment alone is insufficient. Because tuberculosis is an AIDS-defining condition and highly effective therapy for HIV infection is available, all patients with Mycobacterium tuberculosis infection should be offered HIV testing.
Comment: I believe the authors mean Mycobacterium tuberculosis disease rather than infection.
JT

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings.

Meintjes et al Cape Town South Africa

Lancet Infect Dis 2008; 8: 516

Summary: The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To this rectify problem, around a hundred researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists and public health specialists met in Kampala, Uganda, in November 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high income and resource limited settings.. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardization and comparability of data.
Comment: The title is a little misleading as the definitions are meant to be applied universally.
JT

Adenosine deaminase activity is a sensitive marker for the diagnosis of tuberculous pleuritis in patients with very low CD4 counts.

Baba et al Bergen Norway

PLos ONE 2008; 3: e2788

Background: Adenosine deaminase activity (ADA) is a commonly used marker for the diagnosis of tuberculous pleural effusion. There has been concern about its usefulness in immunocompromised patients, especially HIV positive with very low CD4 counts.
Materials and Methods: This was a retrospective case control study. Medical files of patients with tuberculous pleuritis and non-tuberculous pleuritis were reviewed . Clinical characteristics, CD4 counts in blood and biochemical markers in pleural fluid , including ADA were recorded.
Results: One ninety seven tuberculous pleuritis and 40 non-tuberculous pleuritis patients were evaluated. Using the cut-off value of 30 U/L, the overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ADA was 94%, 95%, 19, and 0.06, respectively. The mean CD4 counts among TB pleuritis patients was 29 and 153 cells/microL in patients with CD4 < 50 cells/microL and > 50 cells/ microL, (p< 0.05) respectively. The corresponding mean ADA values for these patients were 76 U/L and 72 U/L respectively. )p< 0.5). There was no correlation between ADA values and CD4 cell counts (r=-0.120, p=0.369).
Conclusion: ADA analysis is a sensitive marker of tuberculous pleuritis even in HIV patients with very low CD4 in a high TB endemic region. The ADA assay is inexpensive, rapid and simple to perform and is of great value for the immediate diagnosis of tuberculous pleuritis while waiting for the culture result and this has a positive impact on patient outcome.
Comment: The pleural fluid was taken from South African patients.
JT

Imaging

Restrictive cardiomyopathy versus constrictive pericarditis: making the distinction using tissue Doppler imaging.

McCall et al Westmead NSW Australia

Eur J Echocardiogr 2008; 9: 591

Summary: Although the primary cause of constrictive pericarditis is entirely different to that of restrictive cardiomyopathy, the two often present with very similar clinical findings. As such, making the distinction between the two is a diagnostic challenge. We report a case that highlights how tissue Doppler imaging may simplify the distinction between pericardial constriction and myocardial restriction.
Comment: A reminder that not all cases of TB constrictive pericarditis showed calcification on X-ray.
JT

Application of technetium-99m-sestamibi in differentiation of active from inactive pulmonary tuberculosis using a single photon emission computed tomography method.

Ahmadihosseini et al Mashad Iran

Nucl Med Commun 2008; 29: 690

Objective: We studied the usefulness of 99mTc-methoxyisobutylisonitrile (MIBI) scintigraphy for differentiation between active and inactive pulmonary tuberculosis.
Methods: Thirty six patients (aged 27-82 years, 16 males and 20 females) were included in our study. Each patient was injected with 740 MBq (20 mCi) 99mTc-MIBI and both planar and single photon emission computed tomography (SPECT) imaging were performed 15 and 290 minutes after injection. Twenty-four patients had active pulmonary tuberculosis (proven by sputum culture), and the remainder 12 had negative sputum culture. Semiquantitative as well as visual assessments were done on all sets of images.
Results: All of the 12 patients in the control group had negative scintigraphy on both planar and SPECT images. Twenty patients with active pulmonary tuberculosis had positive 99Tc-MIBI scintigraphy on planar images (sensitivity of 87.5%). SPECT images were positive in 23 patients with active pulmonary tuberculosis (sensitivity of 95.8%). Both semiquantitative and visual assessment of planar and SPECT images showed statistically significant differences between active and inactive pulmonary tuberculosis patients ( P<0.001). Comparison of 15 and 60 min image sets did not show any statistically difference (P=0.9956 and ).457 for planar and SPECT images, respectively)
Conclusion: 99Tc-MIBI has significant uptake in the active tuberculosis lesions and can be used to differentiate between active and inactive tuberculosis. The SPECT method is especially useful because of its higher sensitivity.
Comment: This pilot study should be followed by others.
JT

Population Studies

Epidemiology of laboratory confirmed tuberculosis in Victoria, 1990 to 2004

McPherson et al Canberra Australia

Commun Dis Intell 2008; 32: 237

Summary: In Australia, most cases of tuberculosis (TB) occur in migrants. To inform control strategies for this group, we investigated all laboratory confirmed tuberculosis cases diagnosed by the State TB reference laboratory in Victoria between 1990 and 2004. The laboratory data were matched to notification data to determine country of birth and a multivariate model was constructed to compare Australian and non-Australian born patients. The proportion of non-Australian-born cases increased over the period of the study and a shift in cases from South East Asia to African countries was observed. Non-Australian-born cases were likely to be young, female, have extrapulmonary disease and show first line drug resistance. The shift in country of birth of TB cases in Victoria reflects migration patterns and the corresponding epidemiology of TB in the country of origin of these migrants. Ongoing migration from countries with highTB incidence raises the question whether it is possible to eliminate TB from Australia and new control strategies should be considered.
Comment: Indeed. JT

Migrants and tuberculosis: analyzing epidemiological data with ethnography.

Littleton et al Auckland New Zealand

Aust NZ J Pub Hlth 2008; 32: 142

Objective: Media portrayals of tuberculosis (TB) in New Zealand are of immigrants who enter the country with active disease and pose a threat to inhabitants, which fosters a popular perception that border control is the best and only response to disease control. This paper reviews both New Zealand and international data on TB rates, causes and transmission among migrant populations to elucidate the precise nature of the link between immigration and TB rates.
Methods: Recent information from scholarly journals on immigration and TB was reviewed. Surveillance data from New Zealand and comparable information from other low incidence countries were reviewed.
Conclusions and implications: The importation of active TB is only a minor part of the total TB burden. While effective border control is essential, equally, if not more important, are the circumstance that promote the reactivation of latent TB infection in migrant communities, including migrants’ experience in transit and after arrival, structural conditions, and personal characteristics. For sound prevention strategies, attention needs to be paid to the existence of transnational communities and the conditions for migrants, rather than placing a singular focus on place of birth.
Comment: Even in the case of refugees, it is unwise to assume that their new country will somehow endow them with greater resistance to those M tuberculosis organisms they may be harbouring.
JT

Control

Adapting a generic tuberculosis control operational guideline and scaling it up to China: a quantitative case study.

Wei et al Leeds UK

BMC Public Health 2008; 8: 260

Background: The TB operational guideline (the deskguide) is a detailed action guide for country TB doctors aiming to improve the quality of DOTS, while the China national TB policy guide is a guide to TB control that is comprehensive but lacks operational usability for frontline TB doctors. This study reports the process of deskguide adaptation, its scale-up and lessons learnt for policy implications.
Methods: The deskguide was translated, reviewed and revised in a working group process. Details of the eight adaptation steps are reported here. An operational study was embedded in the adaptation process. Two comparable prefectures were chosen as pilot and control sites in each of two participating provinces. In the pilot sites, the deskguide was used with the national policy guide in routine in-service training and supervisory trips; while on the control sites, only the national policy guide was used. In-depth interviews and focus groups were conducted with 16 county TB doctors, 16 township doctors, 17 village doctors, 63 TB patients and 57 patient family members. Following piloting, the deskguide was incorporated into the National TB guidelines for county TB dispensary use.
Results: Qualitative research identified that the deskguide was useful in the daily practice of county TB doctors. Patients in the pilot sites had a better knowledge of TB and better treatment support compared with those in the control sites.
Conclusion: The adaptation process highlighted a number of general strategies to adapt generic guidelines into country specific ones: 1) local-policy makers and practitioners should have a leading role; 2) a systematic working process should be employed with capable focal persons; and 3) the guideline should be embedded within the current programmes so it is sustainable and replicable for further scaleup.
Comment: Nothing will work unless the people involved believe they own the process.
JT

Non- Tuberculous Mycobacteria

Susceptibility to nontuberculous mycobacterial lung disease.

Sexton et al Auckland New Zealand

Eur Respir J 2008; 31: 1322

Summary: The nontuberculous mycobacteria NTM) exhibit heterogeneous pathogenicity in humans. Articles on known and potential human factors capable of producing susceptibility to NTM lung disease (NTMLD) were identified by a systematic search of the medical literature, and are reviewed in the present study. Patients with pre-existing structural lung disease are known to be a risk of NTMLD. Other susceptible groups have become recognized since the 1980s, in particular middle-aged nonsmokers without previous lung disease (a group including those with Lady Windermere syndrome) and patients with genetically determined defects of the interleukin-12/ interleukin-gamma axis, certain human leukocyte antigen alleles, cystic fibrosis transmembrane conductance regulator mutations, and polymorphisms of solute carrier 11A1 (or natural resistance –associated macrophage protein 1) and the Vitamin D receptor. Information is also accruing about acquired system causes of susceptibility to NTMLD, including inhibitory antibodies directed against interferon-gamma, post-menopausal waning of endogenous oestrogen levels, celiac disease and exposure to the use of dietary phyto-oestrogens. It is not know whether immunosuppressive factors, such as oral corticosteroid treatment, chronic renal failure, diabetes mellitus and other known risk factors for pulmonary tuberculosis, are also risk factors for the development of NTMLD. Caution is appropriate in managing such patients.
Comment: In some circumstances it is necessary to determine if the NTM are colonizing tissues (as in bronchiectatic cavities) rather than actively invading their walls.
JT

Zoonoses

Isolation of Mycobacterium bovis and other mycobacterial species from ferrets and stoats.

De Lisle et al Upper Hutt New Zealand

Vet Microbiol 2008; 132: 402

Summary: As part of wildlife surveillance for bovine tuberculosis, pooled lymph nodes from 21,481 ferrets, 1056 stoats and 83 weasels were cultured for mycobacteria. A total of 268 isolates of Mycobacterium bovis were obtained from ferrets, 2 from stoats and none from weasels, demonstrating the presence of a wildlife reservoir of infection in ferrets. DNA typing by restriction endonuclease analysis (REA) of 48 selected isolates revealed 23 REA types. Twenty one of these types had previously been isolated from cattle and farmed deer, demonstrating a complex cycle of infection involving wildlife and domestic animals. Apart from M. bovis,a further 208 mycobacterial isolates were obtained, the majority of which were members of the M. avium complex. Speciation of the remaining mycobacterial isolates by DNA sequencing of the 16s rRNA gene, identified half the isolates as M. triplex. Other species identified included M. fortuitum, M. florentinum, M. interjectum, M intracellulare, M. holsaticum, and M. septicum/peregrinum.
Comment: Such reservoirs must make bovine TB all that much harder to eliminate in New Zealand.
JT

Socio-political issues

International Monetary Fund programs and tuberculosis outcomes in post-communist countries.

Stuckler et al Cambridge UK

PloS Med 2008; 5: e143

Background: Previous studies have indicated that International Monetary Fund (IMF) economic programs have influenced health-care infrastructure in recipient countries. The post-communist Eastern European and former Soviet Union countries experienced relatively similar political and economic changes over the past two decades, and participated in IMF programs of various size and duration. We empirically examine how IMF programs related to changes in tuberculosis incidence, prevalence and mortality changes among these countries.
Methods and Findings: We performed multivariate regression of two decades of tuberculosis incidence, prevalence and mortality data against variables potentially influencing tuberculosis program outcomes in 21 post-communist countries for which comparative data are available. After correcting for confounding variables, as well as potential detection, selection and ecological biases, we observed that participating in an IMF program was associated with increased tuberculosis incidence, prevalence and mortality rates by 13.9%, 13.2% and 16.6%, respectively. Each additional year of participation in an IMF program was associated with increased tuberculosis mortality rates by 4.1%, and each 1% increase in IMF lending was associated with increased tuberculosis mortality rates by 0.9%. On the other hand, we estimated a decrease in tuberculosis morality rates of 30.7% (95% CI, 18.3% to 49.5%) associated with exiting the IMF programs. IMF lending did not appear to be a response tp worsened health conditions; rather it appeared to be a precipitant of such outcomes (Granger and Sims causality tests), even after controlling for potential political ,socio-economic, demographic and health-related confounders. In contrast, non-IMF lending programs were connected with decreased tuberculosis mortality rates (-7.6%, 95% CI, -1.0% to -14.1%). The associations observed between tuberculosis mortality and IMF programs were similar to those observed when evaluating the impact of IMF programs on tuberculosis incidence and prevalence. While IMF programs were connected with large reductions in generalized government expenditures, tuberculosis program coverage, and the number of physicians per capita, non-IMF lending programs were not significantly associated with these variables.
Conclusions: IMF economic reform programs are associated with significantly worsened tuberculosis incidence, prevalence and mortality rates in post-communist Eastern European and former Soviet countries, independently of other political, socio-economic, demographic and health changes in these countries. Future research should attempt to examine how IMF programs may have related to other non-tuberculosis-related health outcomes.
Comment: What many of us have long thought has been confirmed by scientific analysis. Friedman has much to answer for.
JT

Mass incarceration can explain population increases in TB and multidrug-resistant TB in European and central Asian countries.

Stuckler et al Cambridge UK

Proc Natl Acad Sci USA 2008; 105: 13280

Summary: Several micro level studies have pinpointed prisons as an important site for tuberculosis (TB) and multidrug-resistant TB in European and central Asian countries. To date, no comparative analyses have examined whether rises in incarceration rates can account for puzzling differences in TB trends among overall populations. Using longitudinal TB and cross-sectional multidrug-resistant TB data for 26 eastern European and central Asian countries, we examined whether and to what degree increases in incarceration account for differences in population TB and multidrug-resistant TB burdens. We find that each percentage point increase in incarceration rates relates to an increased TB incidence of 0.34% (population attributable risk, 95% CI: 0.01-0.58%, P< 0.01), after controlling for TB infrastructure; HIV prevalence; and several surveillance, economic, demographic, and political indicators. Net increases in incarceration account for a 20.5% increase in TB incidence or nearly three-fifths of the average total increase in TB incidence in the countries studied from 1991 to 2002. Although the number of prisoners is a significant determinant of differences in TB incidence and multidrug-resistant TB prevalence among countries, the rate of prison growth is a larger determinant of these outcomes, and its effect is exacerbated but not confounded by HIV. Differences in incarceration rates are a major determination of differences in population TB outcomes among eastern European and central Asian countries, treatment expansion alone does not appear to resolve the effect of mass incarceration on TB incidence.
Comment: A plausible conclusion, although the confounders are many.
JT

Health Care Workers

Primary cutaneous inoculation in a health care worker as a result of a surgical accident.

Tapias et al Sanander Colombia

Int J Dermatol 2008; 47: 833

Summary: In May 2004, a 48-year-old surgeon suffered a superficial cut with a scalpel to the second finger of his left hand while performing a decortication for tuberculous empyema with pulmonary entrapment. The injury healed normally, but, approximately 2 weeks after the event, n erythematous, nonpainful papule of about 3 mm in diameter developed and increased progressively to 7 mm 3 days after its initial appearance. At this time, the papule secreted a clear liquid and began to ulcerate. Approximately 3 weeks after the injury , a gram stain of the liquid was performed; it showed no bacteria but a moderate leukocyte reaction. The liquid showed acid-fast bacilli and grew Mycobacterium tuberculosis. These were fully sensitive to all first line drugs. During this time, the patient developed ipsilateral painful axillary adenitis of about 2.5 cms in diameter. Directly observed short course therapy was begun . After 3 weeks of treatment the finger lesion had disappeared. A chest X-ray was normal. The axillary adenitis took about 6 months to disappear. At three and a half years followup the patient is free of disease.
Comment: Not a common scenario, where the organisms are susceptible, although not rare among meat workers in bovine TB endemic areas,.
JT

Discordant QuantiFERON-TB Gold test results among US health care workers with increased risk of latent tuberculosis infection: a problem or a solution?

Pollock et al Boston MA USA

Infect Control Hosp Epidemiol 2008; 29: 878

Objective: In late 2006, our hospital implemented use of the QuantiFERON-TB Gold (QFT-G) assay, a whole-blood interferon-gamma release assay, for detection of tuberculosis infection . All newly hired health care workers (HCWs) with positive Mantoux tuberculin skin tests (TST) results were routinely tested with the QFT-G assay, to take advantage of its higher specificity. We then undertook a quality assurance review to evaluate the QFT-G test results in HCWs with multiple risk factors for latent tuberculosis infection (LTBI).
Methods: The clinical records for TST-positive HCWs tested with the QFT-G assay were reviewed. HCWs with 2 or more risk factors commonly associated with LTBI were classified as increased risk. (IR). IR HCWs who had QFT-G test results underwent repeat QFT-G testing and were offered testing with a different interferon-gamma release assay (T-SPOT.TB) and with extended T cell stimulation assays.
Results: Of 143 TST-positive HCWs tested with the QFT-G assay, 26 (18%) had positive results, 115 (81%) had negative results, and 2 (1%) had indeterminate results. Of 82 IR HCWs, 23 (28%) had positive QFT-G test results, and 57 (70%) had negative results. Of the 57 IR HCWs with negative results, 43 underwent repeat QFT-G testing. 41 had negative results again and 2 were positive. The 43 HCWs were also offered additional testing with the T-SPOT.TB diagnostic and 36 consented: 31/36 tested negative, 5/36 tested positive. Extended assays using the antigens ESAT-6 and CFP-10 confirmed the positive results detected by the overnight assays and yielded positive results for an additional 7/36 19%) of individuals; strikingly , all 36 HCWs had strongly positive test results with assays using purified protein derivative.
Conclusions: The extreme discordance between the results of our clinical diagnostic algorithm and the results of QFT-G testing raises concern about the sensitivity of the QFT-G assay for detection of LTBI in our HCWs. Results of extended stimulation assays suggest that many of our IR HCWs have indeed been sensitized to Mycobacterium tuberculosis. It is possible that the QFT-G assay identifies those at higher reactivation risk rather than all previously infected, but, in the absence of long-term follow-up data, we should interpret negative QFT-G results with some caution.
Comment: There has never been a universal gold standard for LTBI using the TST and the same goes for QFT-G et al. Each region has to find its own cut off point.
JT

Children

Vitamin D deficiency and insufficiency in children with tuberculosis.

Williams et al London UK

Pediatr Infect Dis J 2008; 27:941

Summary: We examined the prevalence of Vitamin D deficiency in children attending our tuberculosis (TB) clinic during a 2-year period. Sixty-four patients were included with active TB (n=26) or latent TB infection (n=38). Eighty-six percent (n=55) were either vitamin D deficient ( serum 25-hydroxyvitamin D < 20nmol/L) or insufficient (serum 25-hydroxyvitamin D < 75 nmol/L). Only 1 child with active TB was vitamin D replete.
Comment: This is but one among many reports linking vitamin D deficiency and TB. Not only is there no unanimity about what represents “insufficiency”, but we don’t what comes first.
JT

Prevention

Derivation and validation of a clinical prediction score for isolation of inpatients with suspected pulmonary tuberculosis.

Rakoczy et al Sacramento USA

Infect Control Hosp Epidemiol 2008; 29: 927

Background: The use of clinical prediction score to improve the practice of instituting airborne-transmission precautions in patients with suspected tuberculosis holds promise for increasing appropriate isolation and decreasing unnecessary isolation. The objective of the study was to derive and validate a clinical prediction score for patients with suspected tuberculosis.
Methods: We used a case control study design to evaluate differences between patients with a diagnosis of tuberculosis and those placed under airborne precautions who had negative culture results. We developed risk scores based on a multivariable analysis of independently significant factors associated with tuberculosis. Subsequently, we evaluated the sensitivity and specificity in a separate (validation) cohort of patients.
Results: Within our population , we found 4 clinical factors associated with tuberculosis: chronic symptoms (OR, 10.2; 95% CI, 2.95-35.4), upper lobe disease on chest radiograph (OR, 5.27; 95%
CI , 1.6-17.23), foreign born status (OR, 7.01; 95% CI, 2.1-23.8), and immunocompromised state other than human immunodeficiency virus infection (OR, 8.14; 95% CI, 2.08-31.8). Shortness of breath (OR, 0.13; 95% CI, 0.04-0.45) was found to be associated with non-tuberculosis diagnoses and considered a negative predictor in the model. Using a cut-off point to maximize sensitivity, we applied the prediction rule to the validation cohort, resulting in a sensitivity of 97% and a specificity of 42%.
Conclusion: The tuberculosis prediction rule derived from our patient population could improve utilization of airborne precautions. Clinical prediction rules continue to show their utility for improvement in isolation practices in different demographic areas.
Comment: It would be reassuring if the confidence intervals were narrower.
JT

Cell Biology

Living on the edge: inhibition of host cell apoptosis by Mycobacterium tuberculosis.

Briken et al Maryland USA

Future Microbiol 2008; 3: 415

Summary: Tuberculosis is a human disease of global importance caused by infection with Mycobacterium tuberculosis. M. tuberculosis is a highly adapted human pathogen that has evolved to employ multiple strategies in its attempt to avoid an efficient host immune response. The induction of host cell death is an ancient immune defence strategy that is conserved throughout the animal and plant kingdoms. Here we review the current status of the research involving interaction of host cell death by apoptosis. We concluded that virulent strains of M.tuberculosis employ several strategies to avoid the induction of macrophage cell death, and success in this process is clearly important for bacterial virulence. The molecular mechanisms of host cell apoptosis inhibition are little understood, but the recent identification of anti-apoptosis genes in the genome of M. tuberculosis has provided the tools necessary to investigate the details of this host-pathogen interaction. The results of these future studies may prove useful for the development of new drug targets and /or vaccine candidates.
Comment: On the other hand a robust cytokine induced cell necrosis may make M.tuberculosis sick but makes us sick as well.

RFLP in contact tracing

June 2008 No 2

M. tuberculosis E M Photo

Editorial Group:

Drs John Thompson Canberra

Prof Adrian Sleigh Australian National University

A/Prof Paul Kelly Australian National University

Address for correspondence

Email: jtjnj@actewagl.net.au

Website http://tbreview.wordpress.com

Forthcoming Conferences

39th Union World Conference on Lung

Health Paris France 16-20 Oct 2008

Email: paris2008@iuatld.org

Contents

Editorial P 1

Correspondence P 2

New Books P 2

News from Australia P 2 – 3

World News P 3

Population Studies P 3

Treatment P 4

Immunity P 5

Risk factors P 6

Imaging P 6 – 7

Non Tuberculous Mycobacteria P 7

Diagnosis P 8

History P 8

Experimental therapeutics P 9

Nursing P 9

Prevention P 10

Children P 10

Social Issues P 10

Extra Pulmonary TB P 11

TB & HIV P 11

Editorial: An article from one of the leading cancer treatment centers in the world in page 8 of this edition reminds us how BCG given to prevent tuberculosis has been a mixed blessing, but that its use in superficial bladder cancer has been an outstanding success.
Initially we gave the BCG either as multiple intracutaneous injections or as a single intra vesical instillation. Much larger doses of BCG were used, so Th2 reactions were not uncommon. Eventually it was found that repeated BCG introduced directly into the bladder was far more effective. Some urologists repeat the treatment as often as monthly. However Mycobacterium bovis BCG can and does implant itself in the bladder and lower genito-urinary tract and mycobacterial disease sometimes results. In one large series the rate for BCG cystitis was 2% and for prostatitis 0.9%. In 0.4 % of cases dissemination takes place. Those practicing clinical tuberculosis should be aware of these complications. Although the BCG bacillus may be resistant to pyrazinamide, standard short course treatment seems to be curative, although it is felt that isoniazid should be continued for as long as BCG is instilled.

Correspondence

Dr Anastasios Konstantinos, Director Queensland Tuberculosis Control Centre, writes:
I dispute the Editorial advice given in the October 2007 issue of Australian Tuberculosis Review. On the basis of one study, you have suggested that the recommended dose of pyrazinamide should be further decreased to the lower limit of the 20 -30 mg/Kg currently recommended in many international guidelines which are lower than the 30-40 mg/Kg dose used in the BMRC randomized controlled trials that helped establish the modern 6-month regimen for tuberculosis. It is important to review the evidence.
Initial studies in the 1950s showed that high doses of pyrazinamide (~ 50 mg/Kg) combined with isoniazid had a potent sterilizing action but was unacceptably hepatotoxic. However 20-30 mg/Kg of pyrazinamide combined with isoniazid was found to lack such sterilizing ability as judged by the emergence of isoniazid resistant tubercle bacilli. Thus pyrazinamide was used as a second line antituberculosis agent until BMRC studies showed that 30-40 mg/Kg used in the first 2 months of treatment contributed potent sterilizing action, that dose being selected on the basis of prior research.

Additionally the BMRC trials showed that the 6 month regimens utilizing pyrazinamide for the first 2 months at 30-40 mg/Kg was no more hepatotoxic than a 25 mg/Kg dose when combined with isoniazid for 12 weeks (although definitely more toxic if the regimen was increased to 24 weeks).

While international guidelines have since decreased the recommended dose of pyrazinamide, the scientific basis for this eludes me. It is important to be aware of the dose-related hepatoxicity of pyrazinamide. The BMRC trial did not include elderly populations with significant co-morbidities or children and the results may not be generalizable to these groups. But, additionally, we should be aware that the dose used in these trials, 30-40 mg/Kg, was based on the hypothesis that this was the dose required to achieve the proposed sterilizing effect. It is premature to recommend that the standard dose of pyrazinamide should now be decreased to the lower limit of the 20-30 mg/Kg recommendation when the evidence is lacking. Many inexperienced clinicians will round down from this (with unfortunate consequences-Ed)

References Girling D Tubercle 1984; 23: 1
Zhang, Mitchison D Int J Tuberc Lung Dis 2003; 7: 6
US PHS TB Trial AM Rev Resp Dis 1959; 80: 371

New Books

W John Spicer
Clinical Microbiology and Infectious Diseases Second Edition
Churchill Livingstone 2008

This superbly illustrated text from Melbourne contains two succinct pages on the biology of mycobacteria and another short but lucid description of the diseases caused by these organisms. As a synopsis it should be invaluable for many in the health field.
JT

NEWS FROM AUSTRALIA

Tuberculosis notifications in Australia, 2006

Roche et al National Tuberculosis Committee Canberra

CDI 2008; 32: 1

Abstract: The National Notifiable Disease Surveillance System received 1,201 tuberculosis (TB) notifications in 2006, of which 1,142 were new cases and 59 were relapses. The incidence of TB in Australia was 5.8 cases per 100,000 population in 2006, up from 5.3 per 100,000 in 2005, but still below 6 per 100,000 as it has been since 1985. Eighty five percent of TB notifications in 2006 were in people born outside Australia. The incidence in people born overseas and Indigenous Australians were 20.7 and 6.6 cases per 100,000 population respectively. By contrast, the incidence of TB in the non-indigenous Australian-born population was 0.9 cases per 100,000 population. Household or other close contact was reported to be the most common risk factor for TB infection. The number of cases of TB reported in health care workers increased in 2006; these were mainly in health care workers born in TB-endemic countries and there were no reports of TB transmission in Australian health care settings.
Outcome data of the 2005 TB cohort indicates that treatment success was obtained in more than 95% of cases. Progress towards TB elimination in Australia will rely on continued TB awareness, maintenance of high standards of TB diagnostic and control practices, and promoting regional and global TB control activities.
Comment: This one of the best annual reports for some time. However the authors seem confused about the difference between infection and disease in TB. Their plea for all TB sufferers to be tested for HIV makes sense. If there is an true increase in the number of health care workers born overseas who are developing TB, what does this say about the efficiency of our screening procedures?
JT

Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2006.

Lumb et al The Australian Mycobacterium Reference Laboratory Network

CDI 2008; 32: 12

Abstract: In 2006, the Australian Mycobacterium Reference Laboratory Network identified 905 bacteriologically confirmed cases of disease caused by members of the Mycobacterium tuberculosis complex. The annual reporting rate was 4.4 cases per 100,000 population. Of the 905 isolates, 903 were Mycobacterium tuberculosis and two were Mycobacterium bovis. Fourteen children aged under 10 years (male n=5, female n=9) had bacteriologically confirmed tuberculosis. A total of 100 (11.1%) isolates of M. tuberculosis were resistant to at least one first line antituberculosis agent. Resistance to at least H and R (defined as multi-drug resistance – MDR) was detected in 22 (2.4%) M. tuberculosis isolates. Of the 22 MDR-TB isolates, 17 were from the respiratory tract (sputum n=11, bronchoscopy n=5, nasogastric lavage n=1), 3 from lymph node, one from a sacral mass, and one sterile site fluid. Smear-positive specimens from the MDR-TB cases were found in sputum (n=6), lymph node (n=2), and one each of bronchoscopy and nasogastric aspirate specimens. The country of birth was known for all 100 cases with a drug-resistant isolate; 10 of whom were born in Australia, The 90 overseas born cases with drug resistant disease were from 27 countries. Two Australian born cases had MDR-TB; one had worked extensively in the Philippines; the other was a contact of a known MDR-TB case. No cases of XDR-TB were identified in 2006. However, an on-going review of laboratory data identified one case of XDR-TB in 2004.
Comment: The rate of MDR-TB has now nearly doubled. This might be expected given our migration program from high incidence countries. The authors don’t tell us whether the two cases with bovine TB were born overseas. It is to be hoped that this disease has been eliminated from Australia.
JT

World News

Measuring tuberculosis burden, trends, and the impact control programmes.

Dye et al Geneva Switzerland

Lancet Infect Dis 2008; 8: 233

Summary: The targets for tuberculosis control, framed within the United Nations Millennium Development Goals, are to ensure that the incidence per head of tuberculosis is falling by 2015, and that the 1990 prevalence and mortality per head are halved by 2015. In monitoring progress in tuberculosis control, the ultimate aim for all countries is to count tuberculosis cases (incidence) accurately through routine surveillance. Disease prevalence studies are costly and laborious, but give unbiased measures of tuberculosis burden and trends, and are justified in high-burden countries where many cases and deaths are missed by surveillance systems. Most countries in which tuberculosis is highly endemic do not yet have reliable death registration systems. Verbal autopsy, used in cause-of-death surveys, is an alternative, interim method of assessing tuberculosis mortality, but needs further validation. Although several new assays for Mycobacterium tuberculosis infection have recently been devised, the tuberculin skin test remains the only practical method of measuring infections in populations. However, this test typically has low specificity and is therefore best used comparatively to assess geographical and temporal variation in risk of infection. By 2015, every country should be able to assess progress in tuberculosis control by estimating the time trend in incidence, and the magnitude of reductions in either prevalence or deaths.
Comment: All current tests for tuberculosis infection sacrifice specificity for sensitivity and vice versa.
JT

Population studies

Prevalence of tuberculous infection and incidence of tuberculosis: a re-assess-ment of the Styblo rule.

Van Leth et al The Hague Netherlands

Bull World Health Organ 2008; 86: 20

Objective: To evaluate the validity of the fixed mathematical relationship between the annual risk of tuberculous infection (ARTI), the prevalence of smear- positive tuberculosis (TB) and the incidence of smear-positive TB specified as the Styblo rule, which TB control programmes use to estimate the incidence of TB disease at a population level and the case detection rate.
Methods: Population-based tuberculin surveys and surveys on prevalence of smear-positive TB since 1975 were identified through a literature search. For these surveys, the ratio between the number of tuberculous infections (based on ARTI estimates) and the number of smear-positive TB cases was calculated and compared to the ratio of 8-12 tuberculous infections per prevalent smear-positive TB case as part of the Styblo rule.
Findings: Three countries had national population –based data on both ARTI and prevalence of smear-positive TB for more than one point in time. In China, the ratio ranged from 3.4 to 5.8, in the Philippines from 2.6 to 4.4, and in the Republic of Korea, from 3.2 to 4.7. All ratios were markedly lower than the ratio that is part of the Styblo rule.
Conclusion: According to recent country data, there are typically fewer than 8 to 12 tuberculous infections per prevalent TB case, and it remains unclear whether this ratio varies significantly among countries. The decrease in the ratio compared to the Styblo rule probably to improvements in the prompt treatment of TB disease (by national TB programmes). A change in the number of tuberculous infections per prevalent smear-positive TB case in population based surveys suggests the assumed fixed mathematical relationship between ARTI and incidence of smear-positive TB is no longer valid.
Comment: Could it be that in China the case detection rate is better than is currently assumed?
JT

Treatment

Long term efficacy of DOTS regimens for tuberculosis: systematic review.

Cox et al Melbourne Vic Australia

BMJ 2008; 336: 484

Objective: To identify published studies assessing tuberculosis recurrence after successful treatment with standard short course regimens for six months to determine the strength and sufficiency of evidence to support current guidelines.
Design: Systematic review.
Data Sources: Medline, Embase, Cochrane clinical trials register, specialist tuberculosis journals and reference lists. Only English language publications were eligible.
Review methods: Studies were included irrespective of methodology or quality. Abstracted information included inclusion and exclusion criteria for participants, duration of follow-up, and definitions of treatment success and disease recurrence. The primary outcome was the proportion of successfully treated patients recorded with recurrent tuberculosis during the follow-up period.
Results: 17 study arms from 16 studies met the inclusion criteria: 10 were controlled clinical trials and six were either studies done under programmatic conditions or observational studies from functioning tuberculosis programmes. Although several clinical trials supported the use of daily treatment regimens, studies reporting tuberculosis recurrence after intermittent regimens were limited. Few studies carried out under routine programmatic conditions reported disease recurrence. Overall there was wide variation in recurrence after successful treatment, ranging from 0% to 14 %. Considerable heterogenicity across studies precluded the systematic assessment of factors contributing to tuberculosis recurrence.
Conclusions: Despite DOTS (directly observed treatment, short course) being implemented for more than 10 years and millions of patients treated for tuberculosis, few studies have assessed the ability of standard DOTS regimens to result in lasting cure for patients treated under routine programmatic conditions.
Comment: So we thought we were practicing evidence based medicine when we prescribed “standard” short course regimens for our patients.
JT

Fluoroquinolones for treating tuberculosis

Ziganshina et al Kazan Russia

Cochrane Database Syst Rev 2008 Jan 23; (1): CD 004795

Background: Fluoroquinolones are sometimes used to treat multiple drug-resistant and drug-sensitive tuberculosis. The effects of fluoroquinolones in tuberculosis regimens need to be assessed.
Objectives : To assess fluoroquinolones as additional or substitute components to antituberculous drug regimens for drug-sensitive and drug-resistant tuberculosis.
Search Strategy: In July 2007, we searched the Cochrane Infectious Diseases Group Specialized Register. CENTRAL (The Cochrane Library 2007, issue3), Medline, Embase, Lilacs, Science Citation Index, Database of Russian Publications, and metaRegister of Controlled Trials. We also scanned reference lists of all identified studies and contacted researchers.
Selection Criteria: Randomized controlled trials of antituberculous regimens containing fluoroquinolones in people diagnosed with bacteriologically positive (sputum smear or culture) pulmonary tuberculosis.
Data Collection and Analysis: Two authors independently applied inclusion criteria, assessed methodological quality, and extracted data. We used relative risk (RR) for dichotomous data, weighted mean difference (WMD) for continuous data (both with 95% confidence intervals (CI)), and the random effects model if we detected heterogeneity and it was appropriate to combine data.
Main Results: Eleven trials (1514 participants) met the inclusion criteria. No statistically significant difference was found in trials substituting ciprofloxacin, ofloxacin or moxifloxacin for first line drugs in relation to cure (416 participants, 3 trials) , treatment failure (388 participants, 3 trials), or clinical or radiological improvement (216 participants, 2 trials). Substituting ciprofloxacin into first-line regimens in drug-sensitive tuberculosis led to a higher incidence of relapse (RR 7.17, 95% CI 1.33 to 38.85; 384 participants, 3 trials) and longer time to sputum culture conversion (WMD 0.50 months, 95% CI 0.18 to 0.82; 168 participants, 1 trial), although this was confined to HIV-positive participants. Substituting for ethambutol in first-line regimens led to a higher incidence of total number of adverse events (RR 1.34, 95% CI v 1.05 to 1.72; 492 participants, 2 trials). Adding or substituting levofloxacin to basic regimens in drug-resistant areas had no effect. A comparison of sparfloxacin versus ofloxacin added to regimens showed no statistically significantly difference in cure (184 participants, 2 trials), treatment failure (149 participants, 2 trials), or the total number of adverse events (253 participants, 3 trials).
Authors’ Conclusions: Only ciprofloxacin, levofloxacin, sparfloxacin and moxifloxacin have been tested in randomized controlled trials in treating tuberculosis. We cannot recommend ciprofloxacin in treating tuberculosis. Trials of newer fluoroquinolones for treating tuberculosis are needed and are on-going. No difference has been demonstrated between sparfloxacin and ofloxacin in drug –resistant tuberculosis.
Comment: Then there’s the question of dose and frequency of administration.
JT

Immunity

The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis.

Caws et al Ho Chi Minh City Vietnam

PLoS Pathog 2008; 4: e1000034

Summary: The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M.tuberculosis) are more capable of causing disseminated disease and may be associated with polymorphisms in host genes responsible for the innate response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M.tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis. (OR for causing TBM 0.395, 95% CI 0.193-0.806, P=0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR= 1.57 [95% CI 1.15-2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis.
Comment: There will be much more to come on this topic.
JT

IL-23 and IL-17 in tuberculosis

Khader et al Saranac Lake NY USA

Cytokine 2008; 41: 709

Summary: Tuberculosis is a chronic disease requiring the constant expression of cellular immunity to limit bacterial growth. The constant expression of immunity also results in inflammation, which requires regulation. While IFN-gamma-producing CD4+ T helper cells (Th1) are required for control of bacterial growth they also initiate and maintain a mononuclear inflammatory response. Other T cell subsets are induced by Mycobacterium tuberculosis (Mtb) infection including those able to produce IL-17 (Th17). IL-17 is a potent inflammatory cytokine capable of inducing chemokine expression and recruitment of cells to parenchymal tissue. Both the IL-17 and the Th17 response to Mtb are largely dependant on IL-23. Although both Th17 and Th1 cells are induced following primary infection with Mtb, the protective response is significantly altered in the absence of Th1 cells, but not in the absence of Th17. In contrast, in vaccinated animals the absence of memory Th17 cells results in loss of both the accelerated memory Th1 response and protection. Th1 and Th17 responses cross regulate each other during mycobacterial infection and this may be important for immunopathologic consequences not only in tuberculosis but also other mycobacterial infections.
Comment: It would be nice if someone could publish a simple flow chart showing how all the interleukin cytokines interact in response to M. tuberculosis.
JT

Risk Factors

The incidence of tuberculosis after a measles outbreak.

Lee et al Seoul Korea

Clin Infect Dis 2008; 46: 902

Summary: Among 53,974 cases of measles that occurred during the 200-2001 outbreak in Korea, the incidence of tuberculosis following measles was 47 cases per 214,949.6 person-years, which was significantly lower than in the general population (standardized incidence ratio, 0.73; 95% confidence interval, 0.54-0.96). In conclusion, we did not find a positive relationship between measles and tuberculosis.
Comment: Either measles is no longer a risk factor for tuberculosis or the widespread BCG vaccination of Korean children is remarkably effective.
JT

Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis

Nnoaham et al Oxford UK

Int J Epidemiol 2008; 37: 113

Objective: To explore the association between low serum vitamin D and risk of active tuberculosis in humans.
Design: Systematic review and meta-analysis.
Data Sources: Observational studies published between 1980 and July 2006 (identified through Medline) that examined the association between low serum vitamin D and risk of active tuberculosis.
Results: For the review, seven papers were eligible from 151 identified in the search. The pooled effect size in random effects meta-analysis was 0.68 with 95 % CI 0.43-0.93. This ‘medium to large’ effect represents a probability of 70% that a healthy individual would have a higher serum vitamin D level than an individual with tuberculosis if they were both chosen at random from a population. There was little heterogenicity between the studies.
Conclusions: Low serum vitamin D levels are associated with higher risk of active tuberculosis. Although more prospectively designed studies are needed to firmly establish the direction of this association, it is more likely that low body vitamin D levels increase the risk of active tuberculosis. In view of this, the potential role of vitamin D supplementation in people with tuberculosis and hypovitaminosis D-associated conditions like chronic kidney disease should be evaluated.
Comment: The life style factors associated with low vitamin D levels are many. The possibility of confounding makes a true association difficult to assess.
JT

Transplantation-transmitted tuberculosis
Oklahoma and Texas, 2007

CDC Atlanta GA USA

MMWR Morb Mortal Wkly Rep 2008; 57: 333

Summary: Approximately 28,000 organ transplants were performed in the United States in 2007. When infections are transmitted from donors, the implications can be serious for multiple recipients. Tuberculosis (TB), a known infectious disease complication associated with organ transplantation, occurs in an estimated 0.35%-6.5% of organ recipients in the United States and Europe transplantation. In 2007, the Oklahoma State Department of Health identified Mycobacterium tuberculosis in an organ donor 3 weeks after the donor’s death. This report summarizes results of the subsequent investigation, which determined that disseminated TB in two of three transplant recipients
from this donor, and one recipient died. Genotypes of the donor and recipient TB isolates were identical, consistent with transmission of TB by organ transplantation. To reduce the risk for TB transmission associated with organ transplantation, organ recovery personnel should consider risk factors for TB when assessing all potential donors. In addition, clinicians should recognize transplant recipients with TB might have unusual signs or symptoms. When transmission is suspected, investigation of potential donor-transmitted TB requires rapid communication among physicians, transplant centers, organ procurement organizations and public Health authorities.
Comment: The donor was a severe and long standing alcoholic, who should never have been selected as a donor.
JT
Imaging

Ultrasonographic diagnosis and typing of renal tuberculosis

Rui et al Hangzhou China

Int J Urol 2008; 15: 135

Aim: To evaluate the clinical value of sonography in the diagnosis and typing of renal tuberculosis.
Methods: A total of 258 cases of renal tuberculosis with complete sonographic data were reviewed. The distinguishing features of the ultrasound images of these cases were reviewed.
Results: The coincidence rate of ultrasonography in the diagnosis of renal tuberculosis was 58.9 % (152/258). According to the distinguishing features of the ultrasound images, renal tuberculosis could be described under six types. Type 1: nephrectasia type, 23 cases; type 11 ; hydrops type; 21 cases; type 111: empyema type, 13 cases; type IV: inflammatory and atrophy type, 15 cases; type V : calcification, 34 cases; type VI: mixed type 46 cases.
Conclusion: Ultrasonographic examination has convenient , low-priced and non-invasive advant-ages. The typing of renal tuberculosis based on the distinguishing features of the ultrasound provides important and reliable information for the clinical diagnosis, differential diagnosis and treatment of renal tuberculosis.
Comment: Ultrasound may be less specific than contrast CT scanning, it has a place in less wealthy countries.
JT

Tracheal bronchus misdiagnosed as tuberculosis

Saad et al Brisbane Qld Australia

Australas Radiol 2007; 51: Suppl: B238

Summary: We present an uncommon case of a congenital tracheal bronchus, diagnosed on a CT scan of the chest, which was performed on a patient with long standing right upper lobe reticulonodular lung changes, assumed to be due to tuberculosis.
Comment: The presence of right upper lobe infiltrates in this case was due to long standing obstruction in this bronchus.
JT

Non tuberculous Mycobacteria

Glassroth Chicago IL USA

Chest 2008; 133: 243

Summary: Non Tuberculous mycobacteria (NTM) are increasingly associated with pulmonary disease. This is a worldwide phenomenon and one that is not related just to better diagnostic techniques or HIV infection. The mode of transmission of NTM is not well defined, but environmental exposure may be the major factor. While most exposed and infected individuals never acquire NTM disease, some ostensibly immunocompetent persons will. Although our understanding of the pathogenesis of NTM disease is incomplete, we believe that both host and mycobacterial factors are involved. Among the former, interferon-gamma “ trafficking” may well play a central role. When disease occurs, it is likely to present in one of three prototypical forms: a tuberculosis-like pattern often affecting older male smokers with COPD; nodular bronchiectasis classically occurring in middle-aged or older women who never smoked and present with cough; and hypersensitivity pneumonitis following environmental exposure. While Mycobacterium avium complex has been described with all three forms, many other NTM can produce one or another of them; variants of these prototypes also exist. Diagnosis of NTM disease relies on microbiology and chest CT scanning and criteria to aid diagnosis are available.. Treatment of disease depends on the species involved, extent and form of the disease, and overall condition of the patient. Surgery for localised disease may be useful for those species expected to be refractory to medical therapy. Observation without treatment may be appropriate for some patients with slowly progressive disease that is expected to be particularly difficult to treat.
Comment: Remember that for some diseases due to NTM, a single isolate is not enough to make a diagnosis, yet for others it may be more than enough.
JT

Lady Windermere syndrome: an inappropriate eponym for an increasingly important condition.

Kasthoori et al Kuala Lumpur Malaysia

Singapore Med J 2008; 49: e 47

Summary: Non-tuberculous mycobacterial infection (NMI) occurs in elderly women with no pre-existing lung disease, and this has been termed the Lady Windermere syndrome. NMIs are increasing in prevalence and an increasing number of pulmonary mycobacterial infections is due to non-tuberculous mycobacteria.. The diagnosis is often difficult because the organism is not readily isolated or cultured, and the condition may not be considered by the radiologist. We report NMI in a 64 year old woman, based on clinical and radiological findings. Although termed the Lady Windermere syndrome, the name does not correspond to the character in the Oscar Wilde play; hence the eponym is not widely used.
Comment: It may be tempting to attribute cough in elderly women who have middle lobe or lingular bronchiectasis to mycobacterial disease, but response to a trial of therapy that might include rifampicin, a macrolide or a quinolone, by no means clinches the diagnosis. If Lady Windermere could resist temptation so should we.
JT

Visualization of Mycobacterium avium in Crohn’s tissue by oil-immersion microscopy.

Jeyanathan et al Montreal Canada

Microbes Infect 2007; 9: 1567

Summary: Studies seeking Mycobacterium avium subsp. paratuberculosis in Crohn’s disease by PCR have generated inconsistent findings. As an alternative, microscopy offers a number of advantages, including direct visualisation of organisms in tissue. Experimental infections have demonstrated that M. avium organisms can be seen by both acid-fast staining and species specific in situ hybridisation, but because they are smaller than M. tuberculosis, oil immersion microscopy (* 1,000 magnification) is needed. We performed a blinded search for M. avium in paraffin-embedded specimens surgical sections from Crohn’s and control subjects at two centres.. Specimens were coded and subjected to acid-fast staining and ribosomal RNA in situ hybridisation for M. avium rRNA. Agreement between these two methods was good (42/52 patients), kappa=0.60) and similar results were observed for patients from two centres. Together, both methods provided positive results in 10 of 17 Crohn’s subjects (59%, 95% CI: 36-78), contrasting with only 5 of 35 control subjects (odds ratio for Crohn’s vs. controls =8.6, p=0.002). M. avium organisms had an intracellular localisation within inflammatory lesions, but were often observed as lone organisms outside of granulomas. Using two assays in two settings, presence of M. avium organisms was strongly associated with Crohn’s disease.
Comment: Are the investigators entitled to regard acid fast bacilli as M.avium paratuberculosis in the absence of a positive hybridisation test?
JT

Diagnosis

Improved diagnosis of pleural tuberculosis using the microscopic –observation drug-susceptibility technique.

Tovar et al Lima Peru

Clin Infect Dis 2008; 46: 909

Summary: Tests for pleural tuberculosis are insensitive and expensive. We compare non-proprietary microscopic drug-susceptibility (MODS) culture with Lowenstein-Jensen culture for evaluation of pleural specimens. MODS culture was associated with greatly increased diagnostic sensitivity and shorter time to diagnosis, compared to Lowenstein-Jensen culture (sensitivity of culture of biopsy specimens, 81% vs 51%; time to diagnosis, 11 days vs 24 days; P< 0.001). The MODS technique is inexpensive, allows drug-susceptibility testing , and is a considerably improved diagnostic method for pleural tuberculosis.
Comment: We have many such studies emanate from Lima, Peru in the last eight years. In poor countries the technique seems appealing, but I am unaware of any comparisons with the automated radiometric broth methods, which at present remain the gold standard.
JT

Fluoroquinolones in community acquired pneumonia when tuberculosis is around: an instructive case.

Grupper et al Haifa Israel

Am J Med Sci 2008; 335: 141

Summary: Fluoroquinolones are increasingly used for the treatment of community acquired pneumonia. However, their use has been associated with a delay in the diagnosis and treatment of pulmonary tuberculosis. We describe the clinical and insightful bacteriological course of a 39 year old patient with pulmonary tuberculosis who had presented as having community acquired pneumonia and was treated empirically with levofloxacin. The case highlights a major problem associated with the indiscriminate use of fluoroquinolones.
Comment: It seems that those countries with the most tuberculosis have the least controls over the use of fluoroquinolones, macrolides and indeed any antituberculosis drug: a potent source of extensive drug resistance.
JT

History

History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story

Herr et al New York USA

J Urol 2008; 179: 53

Purpose: We review how the bacillus Calmette-Guerin vaccine evolved to become standard therapy for superficial bladder cancer.
Materials and Methods: We reviewed the historical literature describing the origin of the bacillus Calmette-Guerin vaccine as an anticancer agent and its singular success as the most effective immunotherapy used against a human neoplasm.
Results: The association between tuberculosis and cancer, and the demonstration that bacillus Calmette-Guerin invoked immunological activity, inhibiting tumor growth in experimental animal models, led to clinical trials showing that intravesical bacillus Calmette-Guerin eradicated and prevented recurrence of superficial bladder cancers.
Conclusions: For the last 3 decades bacillus Calmette-Guerin therapy has remained the most effective local therapy for superficial bladder cancer, an outstanding example of successful translational medicine in urology.
Comment: We need to hear some good news about BCG every so often, despite a long list of disseminated BCG disease that has followed the procedure.
JT

Experimental therapeutics

Selective killing of nonreplicating mycobacteria

Bryk et al New York USA

Cell Host Microbe 2008; 3: 137

Summary: Antibiotics are typically more effective against replicating rather than nonreplicating bacteria. However, a major need in global health is to eradicate persistent or nonreplicating subpopulations
Of bacteria such as Mycobacterium tuberculosis (Mtb). Hence, identifying chemical inhibitors that selectively kill bacteria that are not replicating is of practical importance. To address this, we screened for inhibitors of dihydrolipoamide acyltransferase (DiaT), an enzyme required by Mtb to cause tuberculosis in guinea pigs and used by the bacterium to resist nitric oxide-derived reactive nitrogen intermediates, a stress encountered in the host. Chemical screening for inhibitors of Mtb DiaT identified select rhodanines as compounds that almost exclusively kill nonreplicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and are effective on bacteria within macrophages, a cellular reservoir for latent Mtb. Compounds that kill nonreplicating pathogens in cooperation with host immunity could complement the conventional chemotherapy of infectious disease.
Comment: Overcoming the Mtb’s lipid coat seems to be the key.
JT

Nursing

Transmission network analysis in tuberculosis contact investigations.

Cook et al Vancouver BC Canada

J Infect Dis 2007; 196: 1517

Background: Social network analysis (SNA) is an innovative approach to the collection and analysis of infectious disease transmission data. We studied whether this approach can detect patterns of Mycobacterium tuberculosis transmission and play a helpful role in the complex process of prioritizing tuberculosis (TB) contact investigations.
Methods: We abstracted routine demographic and clinical variables from patient medical records and contact interview forms. We also administered a structured questionnaire about places of social aggregation to TB patients and their contacts. All case-contact, contact-contact, case-place, and contact-place dyads (pairs and links) were considered in order to analyze the structure of a social network of TB transmission. Molecular genotyping was used to confirm SNA-detected clusters of TB.
Results: TB patients not linked through conventional contact-investigation data were connected through mutual contacts or places of social aggregation, using SNA methods. In some instances, SNA detected connected groups prior to the availability of genotyping results. A positive correlation between positive results of contacts’ tuberculin skin test (TST) and location in denser portions of the person-place network was observed ( P<0.01).
Conclusions: Correlation between TST-positive status and dense subgroup occurrence supports the value of collecting place data to help prioritise TB contact investigations. TB controllers should consider developing social network analysis capacity to facilitate the systematic collection, analysis and interpretation of contact- investigation data.
Comment: This was what I thought good TB public health nurses had been doing for years. They will be pleased to know that they now have a new name for the process- SNA.
JT

Prevention:

Safety of upper-room ultraviolet germicidal air disinfection for room occupants: results from the Tuberculosis Ultraviolet Shelter Study.

Nardell et al Boston MA USA

Public Health Rep 2008; 123: 52

Objectives: We evaluated the safety of room occupants in the Tuberculosis Ultraviolet Shelter Study (TUSS), a double-blind, placebo-controlled field trial of upper-room ultraviolet germicidal irradiation (UVGI) at 14 homeless shelters in six US cities from 1997 to 2004.
Methods: Data collection involved administering questionnaires regarding eye and skin irritation to a total of 3,611 staff and homeless study subjects.
Results: Among these subjects, there were 223 reports of eye or skin symptoms. During the active UV period, 95 questionnaires (6%) noted such symptoms, and during the placebo period, 92 questionnaires (6%) did so . In the 36 remaining cases, either the UV period when symptoms took place was unknown or the symptoms spanned both periods. There was no statistically significant difference in the reports of symptoms between the active and the placebo periods. One definite instance of UV-related keratoconjunctivitis occurred , resulting from a placement of a bunk bed in a dormitory where a single had been used when the UV fixtures were first installed.
Conclusions: These findings demonstrate that careful application of upper-room UVGI can be achieved without an apparent increase in the incidence of the most common side-effects of accidental UV overexposure.
Comment: Unless you sleep in the top bunk!
JT

Children

Underuse of effective measures to prevent and manage pediatric tuberculosis in the United States.

Lobato et al Atlanta GA USA

Arch Pediatr Adolesc Med 2008; 162: 426

Objective: To characterize problems with prevention and management of pediatric tuberculosis (TB) and latent TB infection (LTBI).
Design: A multisite, cross-sectional study using data from medical records and public health logs to categorize and define use of routine prevention practices in managing pediatric TB and LTBI.
Setting: Four areas of the United States
Participants: Children younger than 5 years diagnosed with TB from January 1, 2002 through December 31, 2004, and children with LTBI reported during a continuous 12-month period in 2003 and 2004.
Main Exposure: Mycobacterium tuberculosis
Main Outcome Measures: Underuse or nonuse of standard medical and public health interventions.
Results: Almost 40% of children had a TB risk factor related to their country of birth, parental origin or travel to a country with a high incidence of TB. Children having LTBI were less likely than those having TB to complete treatment (53.7% vs 88,6%, respectively). Almost half (46.3%) of children with TB came to medical attention late in their course when they already had symptoms. Among 63 adult source patients, 19 (30.2%) previously had LTBI but were not treated, and none of the foreign-born source patients were known to have been evaluated for TB before entry into the United States,
Conclusions: Preventions efforts are unsatisfactory to prevent TB in children. Effective interventions such as treatment of LTBI and TB evaluation of adult immigrants remain less than optimal.
Comment: I hope we are doing better in Australia
JT

Social Issues

Ethical challenges in TB control in the era of XDR-TB

Selgelid et al Canberra ACT Australia

Int J Tuberc Lung Dis 2008; 12: 231

Summary: Tuberculosis (TB) is the second leading cause of preventible illness worldwide and arguably the most important neglected topic in bioethics. This papoer 1) explains the ethic importance of TB, 2) documents its neglect in bioethics discourse, 3) maps the terrain of ethical issues associated with TB, and 4) calls for ethicists, activists and socially concerned health professionals to raise and debate the full range of ethical issues associated with TB.
Comment: In the past ethicists and some activists have made uneasy bedfellows. It would be well to remember that the weight given to individual human rights over communal rights will vary across the world.
JT

An ethnographic study of barriers to and enabling factors for tuberculosis treatment adherence in Timor Leste.

Martins et al Canberra ACT, Darwin NT Australia, Dili Timor Leste

Int J Tuberc Lung Dis 2008; 12: 532

Background: Tuberculosis (TB) is a major public health problem in Timor Leste; treatment adherence was identified by the National TB Control Programme (NTP) as an impediment to TB control.
Objective: To identify barriers to and enabling factors for the successful implementation of DOTS strategy in Timor Leste.
Method: Quantitative research was carried out in the two districts (one rural and one urban) with the lowest treatment completion rates. Semi-structured interviews and focus group discussions were conducted with patients, health workers and community members in eight villages.
Result: Good knowledge of TB, including a correct understanding of how it is cured, together with the provision of incentives, were important factors contributing to treatment completion. Defaulting patients and community members had less knowledge of TB. TB nurses had a good understanding of, and a high level of commitment to implementing the DOTS strategy. Obstacles to treatment completion included preference for traditional medicine, economic difficulties and geographic remoteness.
Conclusion: Local cultural practices and knowledge as well as socio-economic factors contribute to less than optimal adherence to TB treatment.. This study has assisted Timor Leste’s NTP in modifying its DOTS expansion strategies to overcome barriers to treatment completion.
Comment: As ever, money seems to talk here.
JT

Active pulmonary tuberculosis

Extra pulmonary Tuberculosis

Tuberculous meningitis: does lowering the treatment threshold result in many more treated patients?

Moreira et al Antwerp Belgium

Trop Med Int Health 2008; 13: 68

Objective: To determine how many more patients would be treated when lowering the treatment threshold for tuberculous meningitis.
Methods: From 1989 to 2004 findings of patients with symptoms lasting more than 1 week and inflammatory changes of cerebrospinal fluid (CSF) were collected. Several models of latent class analysis were tested. Cumulative numbers of cases were plotted against different cut-offs for post-test probability.
Results: In a cohort of 232 patients the prevalence of tuberculous meningitis (TBM) was estimated at 79.8 % (95% CI 67, 0-88,1); probabilities above 80% were reached in 73% of patients. Lowering this threshold from 80% to 20% would add 14% more patients to be treated for a total of 87%. A further lowering of the threshold to 5% would imply 5% more patients to be treated, bringing the cumulative number to 92%. The difference of lowering the threshold from 80% to 5% was 19%.
Conclusion: In this setting, at least 75% of patients showing suggestive symptoms for more than a week and CSF changes very probably had TBM. The number of patients that should be treated does not increase linearly when lowering the threshold.
Comment: This sort of analysis is only useful if the incidence of TBM in those presenting to the institution is known.
JT

TB and HIV

Immune reconstitution and“unmasking” of tuberculosis during antiretroviral therapy.

Lawn et al Cape Town South Africa

Am J Resp Crit Care Med 2008; 177: 680

Summary: Tuberculosis (TB) is the most common opportunistic disease in HIV-infected patients during the initial months of antiretroviral therapy (ART) and presents a great challenge to ART programs in resource-limited settings. The mechanisms underlying development of TB in this period are complex. Some cases may represent progression of undiagnosed subclinical disease present before starting ART, emphasizing the importance of careful screening strategies for TB. It has been suggested that progression in such cases is due to immune constitution disease- a phenomenon in which dysregulated restoration of pathogen-specific immune responses triggers the presentation of subclinical disease. However, whereas some cases have exaggerated or overtly inflammatory manifestations consistent with existing case definitions for IRD, many others do not. Moreover, since ART-induced immune recovery is a time dependent process, active TB may develop as a consequence of persisting immunodeficiency. All these mechanisms are likely to be important, representing a spectrum of complex interactions between mycobacterial burden and changing host immune response. We propose that the potential range of effects of ART includes (1) shortening of the time for subclinical TB to become symptomatic (a phenomenon often referred to as “unmasking”), (2) increased rapidity of initial onset of TB symptoms, and (3) heightened intensity of clinical manifestations. We suggest that the term “ART-associated TB” be used to refer collectively to all cases of TB presenting during ART and that “immune reconstitution disease” be used to refer to the subset of ART-associated TB cases in which the effect on disease severity results in exaggerated and overtly inflammatory disease.
Comment: As HIV and TB becomes more common in our neighbouring countries we need to be clear about the difference between the two entities.
JT

Contact Detection by RFLP

Contact detection by RFLP

February 2008 No 1

Contents

Editorial

Education – BCG and HIV – TB and HIV

Population Studies – Children – Diagnosis of Infection

Risk Factors – Health Care Workers – Immunity Issues

Prevention and Control – Imaging – Zoonoses

Non TB Mycobacteria – Social Issues – Nursing

Editorial Group:

Drs John Thompson Canberra

Email: jtjnj@actewagl.net.au

http://tbreview.wordpress.com

Forthcoming Conferences

12 th IUATLD North America Region

San Diego USA 28 Feb-1 March 2008

Email: biagtan@bc.lung.ca

39th Union World Conference on Lung

Health Paris France 16-20 Oct 08

Email: paris2008@iuatld.org

Editorial

It is now five years since Australia’s livestock has been officially declared free of bovine tuberculosis (TB). In 2000 the disease had been eliminated from cattle and two years later from buffaloes. This is a remarkable achievement in view of Australia’s vast spaces, where so called scrub cattle and buffaloes could hide, avoid mustering and hence testing for TB.
Small wonder that the scrub bull catcher has pride of place in the National Museum of Australia in Canberra.
Although human cases of bovine TB do occur among migrants to this country, we can be happy that the steady trickle of this disease among Australian meat workers has been stopped.
Our neighbours in New Zealand are not so fortunate as the study from Massey University tells us in this edition (P13). There, bovine TB in cattle has been perpetuated by their contact with tuberculous possums.
Ironically these are descendants of possums sent to New Zealand from Australia 150 or more years ago. Yet TB has remained rare in our brushtail possums, rare enough not to be a reservoir of infection for our cattle or even wild deer, whose numbers in this country are slowly increasing. We don’t know the reason for this nor why wild pigs have not played a similar role. We do know that wild pigs can be heavily infected with atypical mycobacteria, particularly in tropical Australia. Perhaps this gives them immunity to TB. Is the same true for Australian possums? Meantime we can be encouraged that bovine TB is declining in New Zealand.

Education

Background
The ability of medical residents training at U.S. urban medical centers to diagnose and manage tuberculosis cases has important public health implications. We assessed medical resident knowledge about tuberculosis diagnosis and early management based on American Thoracic Society guidelines.

Methods
A 20-question tuberculosis knowledge survey was administered to 131 medical residents during a single routinely scheduled teaching conference at four different urban medical centers in Baltimore and Philadelphia. Survey questions were divided into 5 different subject categories. Data was collected pertaining to institution, year of residency training, and self-reported number of patients managed for tuberculosis within the previous year. The Kruskal-Wallis test was used to detect differences in median percent of questions answered correctly based on these variables.

Results
The median percent of survey questions answered correctly for all participating residents was 55%. Medical resident knowledge about tuberculosis did not improve with increasing post-graduate year of training or greater number of patients managed for tuberculosis within the previous year. Common areas of knowledge deficiency included the diagnosis and management of latent tuberculosis infection (median percent correct, 40.7%), as well as the interpretation of negative acid-fast sputum smear samples.

Conclusion
Many medical residents lack adequate knowledge of recommended guidelines for the management of tuberculosis. Since experience during training influences future practice patterns, education of medical residents on guidelines for detection and early management of tuberculosis may be important for future improvements in national tuberculosis control strategies.

The questions and correct answers based on the ATS guidelines follow (Ed)

For each of the following case scenarios, please circle the most appropriate answer (circle only one)
1. A 32 year-old asymptomatic woman who recently emigrated from Vietnam has a 12 mm indurated reaction 72 hours after a tuberculin skin test was placed for employment purposes. Her chest X-ray is unremarkable. She has normal liver function tests. She states she received the BCG vaccine at birth and again at age 20. The next course of action is:

a. Four-drug therapy with isoniazid, rifampin, ethambutol, and pyrazinamide for 2 months, followed by 4 months of isoniazid and rifampin

b. Isoniazid with vitamin B6 for 9 months

c. Sputum sample for acid-fast bacilli and cultures

d. No treatment; the positive tuberculin skin test may be explained by the history of BCG vaccination

2. A 29 year-old homeless man presents to your clinic with a 2-month history of fevers, night sweats, and weight loss. He denies cough or hemoptysis. On physical examination you detect cervical lymphadenopathy, and a chest X-ray reveals normal lung fields but enlarged mediastinal lymph nodes. You suspect extrapulmonary tuberculosis. You place a tuberculin skin test. The next course of action is:

a. Sputum sample for acid-fast bacilli and cultures

b. Cervical lymph node biopsy for acid-fast staining and mycobacterial cultures

c. Blood cultures for mycobacteria

d. Serum early secreted antigen-6 (ESAT-6)

3. One of your co-workers is being relocated to Mali for 2 years. He inquires about tuberculosis prophylaxis. You recommend:

a. BCG vaccination

b. Daily isoniazid during his stay

c. Weekly rifampin during his stay

d. The use of N-95 respiratory masks while in crowded public places

e. No specific prophylaxis

4. A 26 year-old asymptomatic man who recently immigrated from El Salvador is found to have a positive tuberculin skin test. The following are acceptable treatments for latent tuberculosis infection EXCEPT:

a. Daily isoniazid for nine months

b. Daily rifampin for 4 months

c. Daily rifampin and pyrazinamide for 2 months.

5 A 5-mm reaction after tuberculin skin test placement is considered positive for all of the following cases EXCEPT:

a. 38 year-old woman with HIV

b. 24 year-old husband of a known TB case

c. 67 year-old man with fibrotic changes in the right upper lobe on chest X-ray

d. 52 year-old woman on immunosuppression for renal transplant

e. 32 year-old nurse working at university student health clinic

6. The lifetime risk of developing active disease in non-HIV-infected patients with latent tuberculosis infection is:

a. 0.1–0.5%

b. 1–2%

c. 5–10%

d. 25–35%

e. 50–75%

7. The annual risk of developing active disease in patients with HIV and latent tuberculosis infection is approximately:

a. 0.1%

b. 1%

c. 10%

d. 25%

e. 50%.

8 You have diagnosed a 30 year-old man with pulmonary tuberculosis and have started therapy with a four-drug combination including isoniazid, rifampin, pyrazinamide, and ethambutol. You should advise your patient of the following EXCEPT:

a. To avoid the use of contact lenses

b. To limit the consumption of green leafy vegetables

c. To avoid alcohol consumption

d. To report changes in color vision

e. To report numbness or tingling of the extremities

9. A patient with no prior medical history is diagnosed with pulmonary tuberculosis and you prescribe a daily combination regimen containing isoniazid, rifampin, pyrazinamide, and ethambutol. The patient sees his primary care doctor 3 weeks later for a scheduled office visit, at which time routine chemistry tests reveal a 2-fold elevation of the aspartate aminotransferase (AST) above a normal baseline value. At this point, the patient should:

a. Discontinue isoniazid only

b. Discontinue rifampin only

c. Discontinue rifampin and pyrazinamide

d. Discontinue all anti-TB drugs until AST returns to baseline

e. Continue current regimen and monitor symptoms and transaminases

10. Pyridoxine supplementation (25 mg/day) during treatment of latent tuberculosis infection is recommended for the following patients EXCEPT:

a. 31 year-old pregnant woman

b. 28 year-old man with HIV

c. 74 year-old man with peripheral neuropathy

d. 21 year-old woman with anemia

11. A 67 year-old woman with rheumatoid arthritis and chronic obstructive pulmonary disease presents with a right upper lobe cavitary lesion. Her greatest risk factor for tuberculosis is:

a. Age

b. History of rheumatoid arthritis

c. Prior use of methotrexate

d. Smoking history

e. Prior use of infliximab

The following are TRUE or FALSE statements. Please check the most appropriate answer (check only one)
12. 1Patients who are AFB smear-negative cannot transmit Mycobacterium tuberculosis.

□ True □ False

13. Patients with extrapulmonary disease are less likely to transmit Mycobacterium tuberculosis than those with pulmonary involvement.

□ True □ False

14. The diagnosis of pulmonary tuberculosis can be reliably excluded on the basis of a negative tuberculin skin test.

□ True □ False

15. The diagnosis of pulmonary tuberculosis can be reliably excluded after 3 sequential sputum samples are negative for acid-fast bacilli (AFB).

□ True □ False

16. The diagnosis of pulmonary tuberculosis can be reliably excluded after a single bronchoscopic alveolar lavage sample is negative for acid-fast bacilli (AFB).

□ True □ False

17. A positive sputum sample using a nucleic acid amplification technique (e.g., the MTB direct test) indicates the diagnosis of tuberculosis.

□ True □ False

18. A negative nucleic acid amplification test (e.g., the MTB direct test) performed on an AFB-negative sputum sample can reliably exclude the diagnosis of tuberculosis.

□ True □ False

19. Of first-line anti-TB agents, rifampin has the greatest potential for drug-drug interactions in patients receiving highly active antiretroviral therapy (HAART).

□ True □ False

20. In HIV-infected patients with CD4 < 100, HAART should be withheld until active tuberculosis has been completely treated.

□ True □ False

Answers

1 (b), 2 (b), 3 (e), 4 (c), 5 (e),

6 (c), 7 (c), 8 (b), 9 (e),

10 (d), 11 (e), 12 (f), 13 (T),

14 (F), 15 (F), 16 (F), 17 (T),

18 (F), 19 (T), 20 (F).

Editorial comment: While the answers to 17 questions are universally accepted, I doubt if TB experts in some countries would agree with those for with Q1, Q3,and Q 10. JT

BCG and HIV

The risk of disseminated bacille Calmette Guerin (BCG) disease in HIV-infected children

Vaccine 2007; 25: 14

Objectives: Bacille Calmette Guerin (BCG), a live attenuated Mycobacterium bovis vaccine, poses a risk to human immunodeficiency virus (HIV)-infected children; this risk has not been well quantified. We estimate the risk of disseminated BCG disease in HIV-infected children in a setting highly endemic for tuberculosis and HIV.

Design and Methods: We conducted a prospective hospital-based prospective study in the Western Cape Province, South Africa. Clinical and laboratory confirmed cases of disseminated BCG disease in children <1 year of age from January 2002 to December 2004 at a referral hospital were used as numeratory data. Denominator data for calculations of disseminated BCG risk were obtained through estimating the total number of HIV- infected infants receiving BCG based on the known vaccination coverage in the study setting, combined with population data on the total number of children <1 year of age, the known HIV prevalence amongst women attending public antenatal care facilities and different scenarios (5-15 %) for the rate of vertical HIV transmission.

Results: Nine cases of disseminated BCG disease were identified over the study period, seven of these were in HIV-infected infants. The estimated risk for HIV-infected infants to develop disseminated BCG disease, given a 95% BCG coverage and an HIV prevalence of 12.4 -15.4 % amongst women, were as follows for different scenarios of vertical HIV transmission: 329-417 /100000 vaccinees (assuming 15% vertical HIV transmission), 164-208 /100,000 (assuming 10% vertical transmission) and 110-139 /100,000 vaccinees (assuming 15 % vertical transmission .

Conclusions: The risk of disseminated BCG disease is increased several hundred fold in HIV-infected infants compared to the documented risk in HIV-uninfected infants. Data on the protective effect of BCG in HIV-exposed and infected children is lacking. Population –and hospital –based surveillance is vitally important to more accurately estimate the safety and benefits of BCG in HIV-exposed and infected infants.

Assessment of bacille Calmette Guerin vaccine reaction in HIV-exposed Thai infants

Summary: We evaluated local reactions at 1, 2, and 4 months of age to bacille Calmette Guerin vaccine given at birth to 1058 infants who were exposed to human immunodeficiency disease (HIV). No scar was discernable in 12 (12.4%) of 97 HIV-infected infants and 20 (2.1%) of 961 uninfected infants (relative risk, 5.9; 95% confidence interval, 2.0 -11.8). This difference may reflect poorer immunogenicity in HIV-infected infants.

Editorial comment: These studies do nothing to nothing to reassure us that we are not doing harm by vaccinating infants with BCG in high HIV and TB prevalent regions.

John Thompson

HIV infection and multidrug-resistant tuberculosis: the perfect storm.

J Infect Dis 2007; 196 Suppl1: S86-107

Summary: Knowing the human immunodeficiency virus (HIV) status of tuberculosis (TB) patients is essential to optimal patient management. TB is an acquired immunodeficiency syndrome (AIDS) –defining opportunistic condition. Patients with both TB and HIV infection are five times more likely to die during anti-TB treatment than patients who are not HIV infected (CDC, unpublished data, 2003). HIV infection is the greatest known risk factor for progression from latent TB infection to TB disease. In the United States, after TB exposure and infection, HIV-infection persons who do not receive appropriate treatment progress to TB disease over 5 years at a rate 10 times greater than that for persons not infected with HIV. In 1989, CDC recommended that all TB patients be offered HIV testing and in 2006, called for routine HIV screening of all TB patients after the patient is notified that testing will be performed, unless the patient declines (opt-out screening). In addition to enabling optimal patient management, knowing the HIV status (i.e. positive or negative) of TB patients helps public health agencies to identify HIV-infected contacts of TB patients. Highly active antiretroviral therapy (HAART) can reduce progression to TB disease, TB relapse and death. To assess reported HIV status of TB patients and selected characteristics of TB patients with HIV infection, CDC analyzed data from the US National TB Surveillance System for the period 1993-2005. This report summarizes the results of that analysis, which indicated that 1) reporting of HIV status among TB patients increased from 35% in 1993 to 68% in 2003, 2) HIV status of 31% of TB patients was unknown in 2005, 3) 9% of TB patients were HIV positive in 2005, and 4) groups of TB patients at greater risk for HIV infection included injection-drug users(IDUs), noninjection –drug users (NIDUs), homeless persons, nonHispanic blacks, correctional facility inmates, and alcohol abusers. Increased promotion of routine HIV testing and rapid HIV tests might increase acceptability of testing, which would allow health-care providers to know the HIV status of a greater percentage of TB patients and enable them to provide optimal care.

Background: Multidrug-resistant(MDR-TB) tuberculosis has emerged as a global epidemic, with ~ 425,000 new cases estimated to occur annually. The global human immunodeficiency virus (HIV) infection epidemic has caused explosive increases in TB incidence and may be contributing to increases in MDR-TB prevalence.

Methods: We reviewed published studies and available surveillance data evaluating links between HIV infection and MDR-TB to quantify convergence of these 2 epidemics, evaluate the consequences, and determine essential steps to address these epidemics.

Results: Institutional outbreaks of MDR-TB have primarily affected HIV-infected persons. Delayed diagnosis, inadequate initial treatment, and prolonged infectiousness led to extraordinary attack rates among HIV-infected persons. Whether this sequence occurs in communities is less clear. MDR-TB appears not to cause infection or disease more readily than drug-susceptible TB in HIV-infected persons. HIV infection may lead to malabsorption of anti-TB drugs and acquired rifamycin resistance. HIV-infected patients with MDR-TB have unacceptably high mortality; both antiretroviral and antimycobacterial treatment are necessary. Simultaneous treatment requires 6-10 different drugs. In HIV-prevalent countries, TB programs struggle with increased caseloads, which increase the risk of acquired MDR-TB. Surveillance data suggest that HIV infection and MDR-TB may converge in several countries.

Conclusions: Institutional outbreaks, overwhelmed public health programs, and complex clinical management issues may contribute to the convergence of the MDR-TB and HIV infection epidemics. To forestall disastrous consequences, infection control, rapid case detection, effective treatment, and expanded program capacity are needed urgently.

Editorial comment: The situation was not helped when World Bank and IMF “rescue “ packages to struggling countries stipulated that State controlled health services be dismantled or wound down.

JT

Population Studies

Background: Pediatric tuberculosis (TB) is important medically and indicative of a public health problem. An understanding of the epidemiology and case characteristics of pediatric TB, in a province that accepts a large numbers of immigrants, can inform TB elimination strategy.

Methods: All cases of pediatric TB notified in Alberta between 1990 and 2004 were identified in the TB Registry. Individual diagnostic criteria were reviewed and case patients were related to a population grid derived from Statistics Canada censuses and population estimates of Status Indians from the Department of Indian and Northern Affairs, Canada. Incidence rates were determined by ethnic group and gender. Clinical/mycobacteriologic case characteristics were compared by ethnic group and birth country.

Results: Among 124 notified cases, 95 (96 episodes) met strict diagnostic criteria: 45 status Indians, 30 Canadian-born ‘other’ and 21 foreign-born. Incidence rates were much higher in Status Indians and the foreign-born compared to Canadian-born ‘other’; 10.7, 5.4 and 0.4 per 100,000 person-years, respectively. Among Canadian-born ‘other’ cases, 12 were Metis and 11 were Canadian-born children of foreign-born parents. Compared to foreign-born cases, Canadian-born cases were more likely to have a source case in Alberta, to be detected through contact tracing, to have primary pulmonary TB and to have a rural address.

Conclusion: Pediatric TB in Alberta is mainly the result of ongoing transmission in Aboriginal peoples and immigration to Canada of persons to Canada with latent TB infection. The elimination of pediatric TB will require interruption of transmission in Aboriginal peoples and prevention of disease in immigrants.

Editorial Comment: If cases among Status Indians are added to those among the Metis, the rate among those of indigenous origin becomes even greater; even greater than among Indigenous Australians in North Australia.

· JT

Prevalence of Mantoux positivity and annual risk of infection for tuberculosis in New South Wales prisoners, 1996 and 2001.

Objectives: This study compares the prevalence of Mantoux positivity among prisoners in NSW in 1996 and 2001 and examines factors associated with Mycobacterium tuberculosis infection.

Design : Cross-sectional random samples of prisoners, including a longitudinal cohort of prisoners screened in both 1996 and 2001.

Setting: 29 correctional centers

Participants: 747 men and 167 women participated in the 2001 NSW Inmate Health Surveys.

Results: The prevalence of Mantoux positivity remained stable between 1996 and 2001 (12% and 14%, p=0.2), and increased among prisoners from Asian backgrounds (21% and 47%, p=0.02). The annual risk of infection in the cohort was among those detained continuously between 1996 and 2001 was 3.1%, and among recidivists it was 2.7% (p=0.6).

Conclusion: The risk of M. tuberculosis infection for Australian prisoners is assessed to be approximately four times higher than that for the community, however there is no attributable risk to the prison environment itself.

Editorial comment: It can be confusing when Mantoux results are not expressed as continuous variables. In this case the “cutpoint” was 10mm.

JT

Children

Background: isoniazid (INH) therapy for tuberculosis carries a known risk for hepatoxicity and leads to in a small subset of patients. This incidence has been described in adults, but is uncertain in children. Our aim was to estimate the incidence of pediatric referrals for INH-related liver failure, and to describe the characteristics and outcomes of these patients.

Methods: The 84 US centers performing liver transplants between 1987 and 1997 were surveyed regarding patients with INH-induced liver failure. Additional transplant statistics were obtained from the United Network for Organ Sharing. Estimates of the number of children taking preventive INH were derived from a nationwide public health database.

Results: Twenty cases of INH-related liver failure were found during a 10 year period. Four patients (20%) recovered spontaneously; 10 (50%) underwent orthoptic liver transplantation (OLT), while six died awaiting OLT. Mean age at presentation was 9.8years(range 1.3-17). Mean length of INH therapy was 3.3 months (range 0.5-9). Notably, five patients seen for symptoms of hepatitis were initially told not to stop treatment. INH –associated liver failure accounted for 0.2 % (8 of 4679) of all pediatric OLTs, and 14% (8/56) of transplants for drug hepatotoxicity. The estimated incidence of liver failure was up to 3.2 /100,000 for children on prophylactic INH.

Conclusions: While INH-associated liver failure in children is rare, discontinuation at the onset of symptoms does not ensure recovery. This indicates a need for increased awareness of hepatotoxicity risk, expanded biochemical monitoring for children receiving INH , and prompt withdrawal in symptomatic patients.

Editorial comment: However there is no convincing evidence that biochemical monitoring will do more than reassure the attending health care staff.

JT

Predictors of Mycobacterium tuberculosis infection in international adoptees

Objective: The objective of this study was to measure the factors that are associated with Mycobacterium tuberculosis infection in international adoptees.

Methods: A retrospective chart review was conducted on 880 international adoptees who presented to the International Adoption Clinic at the University of Minnesota between 1986 and 2001. Five tuberculin units of purified protein derivative were placed intradermally on the left forearm. The largest diameter of induration was measured in millimeters between 48 and 72 hours. Nutritional status was assessed using anthropometric measures at initial screening. Data on age, birth country, and year of adoption were assessed.

Results: Adoptees (mean age: 26 months; range 1-200 months; 62% female) came from 33 birth countries. Twenty eight percent and 5 % had evidence of chronic and acute malnutrition, respectively. Twelve percent had evidence of M. tuberculosis infection. The odds of M.tuberculosis infection increased 7% for each subsequent year during the period studied, increased 142% with each additional year of age for children 24 months of age at the time of evaluation. Tuberculin skin test induration response was not associated with nutritional status or birth region.

Conclusions: Our study demonstrated a high prevalence of M.tuberculosis infection and malnutrition in internationally adopted children, placing them at considerable risk for progression to tuberculosis disease. These findings also support current guidelines recommending completion of tuberculin screening immediately after adoption.

Editorial comment: One wonders if the over 100 infected children had received a CT scan of the chest, how many would show signs of TB disease.

JT

Diagnosis of Infection

Setting: A rural population in Tiruvallur district, south India.

Objective: To study the variability of skin test reaction sizes between 48 and 72 hours.

Methods: A tuberculin test survey was conducted among children ages less than 10 years. The reaction sizes were read by the same reader at 48 hours and 72 hours independently. The results of the tuberculin test were compared.

Results: 957 children aged below 10 years were included in the study; the male to female ratio was 1: 1.1. There no significant differences between the readings of reaction size at 48 and 72 hours.

Conclusion: The tuberculin test results can be read either at 48 hours or 72 hours without compromising their validity.

Editorial comment: As the original studies on this were done half a century ago, it doesn’t hurt to have modern confirmation.

JT

Detection of Mycobacterium tuberculosis infection in United States Navy recruits using the tuberculin skin test or whole-blood interferon-gamma release assays.

Background: Military personnel are at risk for acquiring Mycobacterium tuberculosis infection because of activities in close quarters and in regions with a high prevalence of tuberculosis (TB). Accurate tests are needed to avoid unnecessary treatment because of false-positive results and to avoid TB because of false-negative results and failure to diagnose and treat M. tuberculosis Infection. We sought to estimate the specificity of the tuberculin skin test (TST) and 2 whole-blood interferon-gamma release assays (QuantiFERON-TB assay [QFT])and QuantiFERON-TB Gold assay [QFT-G]). And to identify factors associated with test discordance.

Methods: A cross-sectional comparison study was performed in which 865 US Navy recruits were tested for M. tuberculosis infection using the TST, QFT and QFT-G.

Results: Among the study subjects, 5.1% of TSTs resulted in an induration > or = 10 mm, and 2.9% of TSTs resulted in an induration > or = 15 mm. Eleven percent of QFT results and 0.6 $% of QFT-G results were positive. Assuming recruits at low risk for M. tuberculosis exposure were not infected, estimates of TST specificity were 99.1% (95 % confidence interval [CI], 98.3-99.9 ) when a 15- mm cutoff value was used and 98.4% (95% CI 97.3-99.4) when a 10mm cutoff value was used . The estimated QFT specificity was 92.3% (95% CI 90.0-94.5), and the estimated QFT-G specificity was 99.8% (95% CI 99.5-100). Recruits who were born in countries with a high prevalence of TB were 26-40 times more likely to have discordant results involving a positive TST result and a negative QFT-G result than were recruits born in countries with a low prevalence of TB. Nineteen (50%) of 38 recruits with this type of discordant result had a TST induration>or= 15mm

Conclusions: The QFT-G and TST are more specific that the QFT. No statistically significant difference in specificity between the QFT-G and TST was found using the 15-mm induration cutoff value. The discordant results observed among recruits with increased risk of M. tuberculosis infection may have been because of lower TST specificity or lower QFT-sensitivity. Negative QFT-G results for recruits born in countries where TB is highly prevalent and who TST induration was . or=15 mm suggest that the QFT-G may be less sensitive than the TST. Additional studies are needed to determine the risk of TB when TST and QFT-G results are discordant.

Editorial comment: I suspect that previous BCG vaccination in those born outside the USA may have influenced the results more than the authors admit. JT

Prospective comparison of the tuberculin skin test and 2 whole-blood interferon-gamma release assays in persons with suspected tuberculosis.

Background: Interferon-gamma release assays (IGRAs) are attractive alternative to the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis. However, the inability to definitively confirm the presence of most M. tuberculosis infect ions hampers assessment of IGRA accuracy. Although IGRAs are primarily indicated for the detection of latent tuberculosis infection , we sought to determine the sensitivity of the TST and 2 whole-blood IFGRs (QuantiFERON TB assay[QFT] and QuantiFERON-TB Gold assay[QFT-G]) in situations in which infection is confirmed by recovery of M. tuberculosis by culture.

Methods: We conducted a prospective, multicenter, cross-sectional comparison study in which 148 persons suspected as having tuberculosis were tested simultaneously with the TST, QFT and QFT-G.

Results: M. tuberculosis was cultured from samples from 69 (47%) of 148 persons suspected to have tuberculosis; the TST induration was >/= 5 mm for 51 (73.9%) of the 69 subjects (95% confidence interval [CI], 62.5%-82.8%). The QFT indicated tuberculosis infection for 48 (69.6%) of the 69 subjects (95% CI, 57.9%- 79.2%) and was indeterminate for 7 (10.1%). The QFT-G yielded positive results for 46 (66.7%) of the 69 subjects (96% CI, 54.9%-76.7%) and indeterminate results for 9 subjects (13.0%). If subjects with indeterminate QFT-G results were excluded, 46 (76.7%) of 60 subjects (95% CI, 64.6%-85.6%) had positive TST results, and the same number of subjects had positive QFT-G results. HIV infection was associated with false-negative TST results but not with false-negative QFT-G results.

Conclusions: The TST, QFT, QFT-G have similar sensitivity in persons with culture-confirmed infection. As with the TST, negative QFT and QFT-G results should not be used to exclude the diagnosis of tuberculosis in persons with suggestive signs or symptoms.

Editorial comment: An excellent idea to use bacteriological status as gold standard, but the study is diminished by taking TST of >/= 5 mm as the cutpoint. This contradicts the previous study where specificity is examined. We already know the low specificity of an TST induration of <10)mm.
JT

Health Care Workers

Background: In 2003 the NIH perceived a need to strengthen teaching about tuberculosis (TB) to health professions students. The National Tuberculosis Curriculum Consortium (NTCC( was funded to meet this need. The purpose of this study was to survey students enrolled in NTCC schools prior to NTCC-developed educational materials being made available to faculty.
Methods: A self-administered survey for students in NTCC schools to establish a baseline level of knowledge, attitudes and confidence about tuberculosis.
Results: 1480/2965 (50%) students in 28 programs in 20 NTCC schools completed the survey. If public health students are eliminated from totals (only 61 respondents of 765 public health students), the overall response proportion for the seven clinically=related disciplines was 64.5%. The majority (74%) were in schools of medicine(MD/DO), undergraduate nursing (BSN), and pharmacy (PharmD); others were in programs for physician assistants (PA), advanced practice nursing (NP/APN), respiratory therapy (RT), clinical laboratory sciences (MT/CLS), and public health (MPH). Almost 90% had attended at least one lecture about TB. Although 91.4% knew TB was transmitted by aerosols, about one-third did not know the method for administering tuberculin, or that Bacillus Calmette-Guerin (BCG) vaccine was not a contraindication to TB skin testing. Fewer than two thirds knew that about 10% of people in the USA who have latent tuberculosis infection (LTBI) and a normal immune system will develop TB disease, or that BCG is not part of the routine vaccination program in the USA because it complicates surveillance for new TB infection .
Conclusion: There is room for improvement in knowledge, attitudes and confidence about TB by health professions students surveyed. The NTCC-developed educational products may be used by faculty to improve student performance to be assessed with future surveys.
Editorial comment: Would we do any better in Australia? JT

Immunity Issues

Summary: Neutrophils contain antimicrobial peptides with antituberculous activity, but their contribution to immune resistance to tuberculosis (TB) infection has not been previously investigated to our knowledge. We determined differential white cell counts in peripheral blood of 189 adults who had come in contact with patients diagnosed with active TB in London, United Kingdom, and evaluated them for evidence of TB infection and capacity to restrict mycobacterial growth in whole-blood assays. Risk of TB infection was inversely and independently associated with peripheral blood neutrophil count in contacts of patients diagnosed with pulmonary TB. The ability of whole blood to restrict growth of Mycobacterium bovis bacilli Calmette Guerin and Mycobacterium tuberculosis was impaired 7.3 and 3.1 fold, respectively, by neutrophil depletion. In microbiological media, human neutrophil peptides (HNPs) 1-3 killed M. tuberculosis. The neutrophil peptides cathelicidin LL-37 and lipocalin 2 restricted growth of the organism, the latter in an iron-dependant manner. Black African participants had lower neutrophil counts and lower circulating concentrations of HNP 1-3 and lipocalin 2 than south Asian and white participants. Neutrophils contribute substantially to innate resistance to TB infection, an activity associated with their antimicrobial peptides. Elucidation of the regulation of neutrophil antimicrobial peptides could facilitate prevention and treatment of TB.
Editorial comment: Are the authors implying that those racial groups with the longest exposure to TB have developed genes that code for these peptides in their neutrophils

Mycobacterium tuberculosis induced gamma interferon production by natural killer cells requires cross talk with antigen-presenting cells involving Toll-like receptors 2 and 4 and the mannose receptor in tuberculous pleurisy.

Summary: Tuberculous pleurisy allows the study of human cells at the site of active Mycobacterium tuberculosis infection. In this study, we found that among pleural fluid (PF) lymphocytes, natural killer (NK) cells are a major source of early gamma interferon (IFN-gamma) upon N. tuberculosis, leading us to investigate the mechanisms and molecules involved in this process. We show that the whole bacterium is the best inducer of IFN-gamma, although a high molecular-weight fraction of culture filtrate proteins from M. tuberculosis H37Rvand the whole cell lysate also induce its expression. The mannose receptor seems to mediate the inhibitory effect of mannosylated lipoarab-inomannan, and Toll-like receptor 2 and 4 activate NK cells but do not induce IFN-gamma like M. tuberculosis does. Antigen presenting cells (APC) and NK cells bind M. tuberculosis, and although interleukin -12 is required, it is not sufficient to induce IFN-gamma expression, indicating that NK cell-APC contact takes place. Indeed, major histocompatibility complex class 1, adhesion, and co-stimulatory molecules as well as NK receptors regulate IFN-gamma induction. The signaling pathway is partially inhibited by dexamethasone and sensitive to Ca2+flux and cyclosporine. Inhibition of p38 and extracellular-regulated kinase mitogen-activated protein kinase pathways reduces the number of IFN-gamma + NK cells. Phosphorylated p38 (p-p38) is detected in ex vivo PF-NK cells at the same time that binding between NK and M. tuberculosis reaches its maximum value. Thus, interplay between M. tuberculosis and NKcells/APC triggering IFN-gamma would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a type 1 profile.
Editorial Comment: Does this explain why some recover spontaneously from their tuberculous pleurisy?
JT

Risk Factors:

Background: Tuberculosis (TB) remains a major cause of mortality in developing countries, and in these countries diabetes prevalence is increasing rapidly. Diabetes increases the risk of TB. Our aim was to assess the potential impact of diabetes as a risk factor for incident pulmonary tuberculosis, using India as an example.
Methods: We constructed an epidemiological model using data on tuberculosis incidence, diabetes prevalence, population structure, and relative risk of tuberculosis associated with diabetes. We evaluated the contribution made by diabetes to both tuberculosis incidence and to the difference between tuberculosis incidence in urban and rural areas.
Results: In India in 2000 there were an estimated 20.7 million adults with diabetes, and 900,000 incident adult cases of pulmonary tuberculosis. Our calculations suggest that diabetes accounts for 14.8% (uncertainty range 7.1% to 23..8%) of pulmonary tuberculosis and 20.2 % (8.3% to 41.9%) of smear-positive (i.e. infectious) tuberculosis. We estimate that the increased diabetes prevalence in urban areas is associated with a 15.2% greater smear-positive tuberculosis incidence in urban than rural areas-over one fifth of the estimated total difference.
Conclusion: Diabetes makes a substantial contribution to the burden of incident tuberculosis in India and the association is particularly strong for the infectious form of tuberculosis. The current diabetes epidemic may lead to a resurgence of tuberculosis in endemic regions, especially in urban areas. This potentially caries a risk of global spread with serious implications for tuberculosis control and the achievement of the United Nations Millennium Development Goals.
Editorial comment: Does this mean that the urban population are eating more, gaining weight, developing more diabetes and becoming tuberculous? On the other the absence of starvation may lead to less TB. JT

Lower risk of tuberculosis in obesity

Leung et al Hong Kong China

Background: Obesity is increasingly prevalent in both developed and developing areas. Although undernutrition is well associated with tuberculosis, few studies have systematically examined the association with obesity.
Method: A cohort of 42,116 individuals 65 years or older enrolled at 18 health centers for elderly patients in Hong Kong, China(which has a tuberculosis incidence of approximately 90 per 100,000 population), in 2000 were followed up prospectively through the territory-wide tuberculosis registry for the development of active tuberculosis from 3 months after enrollment until December 31, 2005, using the identity card number as the unique identifier. The association with body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), as categorized by the Asian standards, was assessed with the control of other baseline characteristics.
Results: Obese (BMI > or=30) and overweight)BMI, 25-<30) individuals were at significantly lower risks of developing active tuberculosis than normal weight individuals (BMI 18.5 to < 25), with hazard ratios (95% confidence intervals) of 0.36 (0.20-0.66) and 0.55 (0.44-0.70), respectively, after adjustment for baseline demographic, social and clinical values. An inverse linear association was observed predominantly for pulmonary but not for extrapulmonary tuberculosis. This association persisted after controlling for potential confounders or excluding individuals with known tuberculosis risk factors.
Conclusions: Obesity is associated with a lower risk of older pulmonary tuberculosis in the older population of Hong Kong. The presence of such a strong but selective association across the whole spectrum of BMI could have major biological, clinical and/or epidemiological implications. Further studies are indicated to explore the underlying mechanisms, potential clinical utilities, and possible epidemiological implications

Editorial comment: We know that there is a socioecomic gradient for TB and that in developing countries obesity has a similar gradient between rich and poor running in the opposite direction. Only further studies will tell us if they have dealt with this confounder.
JT

Brief communication: characteristics of spontaneous cases of tuberculosis associated with infliximab

Background: A warning for tuberculosis was added to the approved labeling for infliximab in October 2001.
Objective: To describe adverse event reports of tuberculosis during infliximab therapy after labeling changes.
Design: Case series.
Setting: Spontaneous adverse events reports maintained in the Adverse Event Reporting System database in the United States.
Patients: 130 patients with infliximab-associated tuberculosis.
Measurements: Clinical and laboratory data.
Results: The US Food and Drug Administration received 130 domestic, spontaneous reports of tuberculosis in patients treated with infliximab between 1 November 2001 and 30 May 2006, including 59 (45%) with extrapulmonary disease. The most commonly reported risk factors included concomitant immunosuppressant use (n=89), history of latent or active tuberculosis (n=33), and being born into or having spent extensive time in an area where tuberculosis is endemic (n=25). In the subset of 67 cases with documented initiation of infliximab therapy after the drug labeling change, 34 patients with a negative tuberculin skin test result before initiation of infliximab therapy developed tuberculosis after receiving infliximab,
Limitation: Conclusions from spontaneous case reports may not be generalizable to the entire infliximab-receiving population.
Conclusion: Clinicians should be vigilant in screening and monitoring for tuberculosis in patients receiving infliximab.
Editorial comment: Yet 26% of those who subsequently developed TB would have not detected at screening. Would IFN-gamma releasing assays have done any better?
JT

Imaging
Diagnostic accuracy of MR. imaging in tuberculous spondylitis.

Objective: To systemically evaluate MR. imaging features of tuberculous spondylitis and to find features that may help differentiating tuberculosis from other spinal diseases.

Material and Method: Retrospective review of 65 MR. imaging of two groups of patients between January 2002 and December 2005. Thirty one patients were diagnosed with tuberculous spondylitis and the rest were a randomly selected group of 34 patients with other spinal diseases. All images were reviewed by two neuroradiologists blinded to clinical data. Sensitivity and specificity of each MR. imaging features were calculated.

Results: Three most useful MR. imaging features with high sensitivity and specificity (>80%) were endplate disruption (100%, 81.4%), paravertebral soft tissue (96.8%, 85.3%), and high signal intensity of intervertebral disc of T2W (80.6%, 82.43%). High sensitivity but low specificity signs in MRI included bone marrow edema (100%, 42.4%), posterior element involvement (93.5%, 76.5%), canal stenosis (87.1%, 26.5%), and spinal cord or nerve root compression (80.6%, 38.2%). Low sensitivity but high specificity features in MRI were intervertebral disc enhancement (63.3%, 84.2%), vertebral collapse (58.1%,85.3%), and kyphosis deformity (67.7%, 82.4%). Overall , the sensitivity and specificity of MRI for spinal tuberculosis were 100% and 88.2% respectively.

Conclusion: The authors presented three good to excellent sensitivity and specificity MR. imaging features for spinal tuberculosis, end plate disruption, paravertebral soft tissue formation and high signal of intervertebral disc on T2W. In contrast to a previous study, most of the presented cases still presented classic radiological pictures of “ two vertebral disease with the destruction of the intervertebral disc”. Only a small portion of the patients revealed sparing intervening disc or isolated single vertebral body involvement, which possibly reflected the early stages of the disease process.

Editorial comment: But would this specificity be enough to forego biopsy ?

JT

Radiographic predictors of subsequent reactivation of tuberculosis.

Setting: A cohort of migrants to Australia (n =7265) selected to be at increased risk of tuberculosis (TB) were assessed at the Liverpool Chest Clinic, Sydney, between 1984 and 2003.

Objective: To assess the reproducibility and predictive value of various radiographic criteria for predicting the subsequent development of TB.

Methods: A nested case control study was conducted. Cases were those who had a confirmed diagnosis of TB during follow up (n=60). A random sample of 107 controls was selected. Initial chest X-rays were read independently blinded to case vs. control status by two readers according to two classification systems. Agreement was quantified by weighted kappa (kappaw). Sensitivity and specificity for subsequent TB were estimated.

Results: There was moderate agreement between readers for both classification systems (kappaw o.67 and 0.60, respectively). The presence of calcified nodular densities or fibrosis together with non-calcified densities in mid and/or upper lung zones or the presence or the presence of a pulmonary infiltrate typical of TB had a sensitivity of 66% for subsequent pulmonary TB and a specificity of 82% . Minor abnormalities or findings consistent with past primary TB infection alone were not predictive of subsequent TB.

Conclusions: Radiographic screening can be helpful in identifying individuals at increased risk of subsequent TB.

Editorial comment: These predictors seem good enough to know who to offer treatment to, but not who to follow up or not.

JT

Zoonoses

Vet Res 2007; 38: 465

Summary: We describe the temporal and geographical distribution of confirmed cases of bovine tuberculosis (TB) in a population of cattle in the south-east of the North Island of New Zealand. Data were derived from routine TB testing conducted between 1980 and 2003 and included details for 69 farms. Four six year periods were defined to coincide with changes in depopulation strategies against the wildlife TB reservoir , the brushtail possum Trichosuris vulpecula. For the periods 1980 to 1985 and 1986 to 1991 the median annual incidence rate of TB was 0.4 and 4.7 cases per 1000 cattle years at risk , respectively. For the period 1992 to 2003 the median annual incidence rate of TB decreased to 1.8 cases per 1000 cattle years at risk, coincident with the use of poisoning to control possums in the surrounding forest park ( a major possum habitat area). We identified clusters of TB cases adjacent to the forest park and found no evidence of spatio-temporal interaction of TB risk among farms. Our findings support the hypothesis that possums living in the forest park are a source of bovine TB in this area and that farm to farm spread of disease was not an important infection mechanism.

Editorial Comment: So it is thought that possum eradication is the key to eliminating bovine TB in New Zealand.

JT

Nontuberculous Mycobacteria

Background: Comparative genomics has greatly improved our understanding of the evolution of pathogenic mycobacteria such as Mycobacterium tuberculosis. Here we have used data from a genome microarray analysis to explore insertion-deletion (InDel) polymorphism among a diverse strain collection of Mycobacterium ulcerans, the causative agent of the devastating skin disease, Buruli ulcer. Detailed analysis of large sequence polymorphisms in twelve regions of difference (RDs), comprising irreversible genetic markers, enabled us to refine the phylogenetic succession within M. ulcerans, to define features of a hypothetical M. ulcerans most recent common ancestor and to confirm its origin from Mycobacterium marinum.

Results: M. ulcerans has evolved into five InDel haplotypes that separate into two distinct lineages: (1) the “classical” lineage including the most pathogenic genotypes _ those that come from Africa, Australia and South East Asia; and (2) an “ancestral” M. ulcerans lineage comprising strains from Asia (China/Japan), South America and Mexico. The ancestral lineage is genetically closer to the progenitor M. marinum in both RD composition and DNA sequence identity, whereas the classical lineage has undergone major genomic rearrangements.

Conclusion: Results of the InDel analysis are in complete accord with recent multilocus sequence analysis and indicate that M. ulcerans has passed through at least two major evolutionary bottlenecks since divergence from M. marinum. The classical lineage shows more pronounced reductive evolution than the ancestral lineage, suggesting that there may be differences in the ecology between the two lineages. These findings improve the understanding of the adaptive evolution and virulence of M. ulcerans and pathogenic mycobacteria in general and will facilitate the development of new tools for improved diagnostics and molecular epidemiology.

Editorial Comment: The ability of the classical lineage to survive in two very distinct climactic and circumscribed areas of Australia raises even more questions about the adaptive evolution of this Mycobacterium.

JT

Social Issues

Summary: This paper describes the key factors and remaining challenges for tuberculosis (TB) control programmes in complex emergencies. A complex emergency is “a humanitarian crisis in a country, region or society where there is a total or considerable breakdown of authority resulting from internal or external conflict and which requires an international response that goes beyond the mandate or capacity of any single agency and/or the ongoing United Nations country programme”. Some 200 million people are believed to live in countries affected by complex emergencies; almost all of these are developing countries that also bear the main burden of TB. The effects of complex emergencies impact on TB control programmes interfering with the goals of identifying and curing TB patients and possibly leading to the emergence of MDR-TB. There are are many detailed descriptions of aid interventions during complex emergencies; yet TB control programmes are absent from most of these reports. If TB is neglected, it may quickly result in increased morbidity and mortality, as was demonstrated in Bosnia and Herzegovina and in Somalia. TB is a major disease in complex emergencies and requires an appropriate public health response. While there is no manual to cover complex emergencies, the interagency manual for TB control in refugee and displaced populations provides valuable guidance. These programmes contribute to the body of knowledge needed to compile such a manual, and should ensure that the experiences of TB control in complex emergencies lead to the establishment of evidence-based programmes.

Editorial comment: Not an easy task JT

Nursing

Background: The efficacy of a nurse case-managed intervention was evaluated in subsamples of participants with one of the following characteristics: female gender, African American ethnicity, recruited from a homeless shelter, lifetime injection drug use,daily alcohol and drug use, a history of military service, poor physical health and a history of poor mental health.

Objective: To determine whether a validated nurse case-managed intervention with incentives and tracking would improve adherance to latent tuberculosis infection treatment in subsamples of homeless people with characteristics previously identified in the literature as predictive of nonadherence.

Methods: A prospective two-group site-randomized design was conducted with 520 homeless adults residing in 12 homeless shelters and residential recovery sites in the Skid Row region of Los Angeles from 1998 to 2003.

Results: Daily drug users, participants with a history of injection drug use, daily alcohol users, and persons who were not of African American race or ethnicity had particularly poor completion rates, even in the nurse case-managed intervention program (48%, 55%, 54% and 50%, respectively). However, the intervention achieved a 91% completion rate for homeless shelter residents and significantly improved latent tuberculosis infection treatment adherence in 9 of 12 subgroups tested (odds ratio = 2.51- 10.41), including daily alcohol and drug users, when potential confounders were controlledusing logistic regression analysis.

Discussion: Nurse case management with incentives appears to be a good foundation for increasing adherance to 6-month isoniazid treatment in a variety of homeless subgroups and, in particular, for sheltered homeless populations. However, additional social-structural and environmental strategies are needed to address those at greatest risk of nonadherance.

Editorial comment: The excellent results in homeless shelters can be achieved by persuading the management not to admit the residents until they had swallowed their isoniazid.

Ritchie et al Auckland New Zealand

Eur Respir J 2007; 30: 501

Summary: it was hypothesized that the time to detect Mycobacterium tuberculosis in liquid culture of sputum from patients with pulmonary tuberculosis may be a better indicator for the duration of respiratory isolation than sputum smear status. Pre-treatment and during-treatment sputum acid-fast bacilli (AFB) smear and culture results were reviewed in 284 patients with pulmonary tuberculosis. The time to detect M.tuberculosis in liquid culture (TTD-TB) was the number of days from inoculation of the Mycobacterial Growth Indicator Tube (MGIT) to culture detection and visualization of AFB. The median (interquartile range) TTD-TB for smear group 0 (no bacilli seen) was 14 (12-20 days). This value was used as the standard at which release from isolation could be permitted. In smear group 4 (> 9 AFB per high-power field (hpf) in sputum specimens before treatment) patients, the TTD-TB exceeded 14 days after a median of 25 days of treatment. The current authors recommend that patients in smear groups 1 and 2 (1-9 AFB per 100 hpf and 1-9 AFB per high-power field (hpf) in sputum specimens before treatment) patients, the TTD-TB exceeded 14 days after a median of 25 days of treatment. The current authors recommend that patients in smear groups 1 and 2 (1-9 AFB per 100 hpf and 1-9 AFB per 10 hpf in sputum specimens before treatment, respectively) receive treatment in respiratory isolation for 7 days , provided the risk of drug resistance is low. Smear group 3 (1-9 AFB per hpf) and 4 patients should receive treatment in respiratory isolation for 14 and 25 days, respectively. These criteria would have reduced the duration of respiratory isolation by 1,516 days in the 143 study participants with sputum smear pulmonary tuberculosis. Provided clinical and radiographical criteria are satisfactory, use of the time to detect Mycobacterium tuberculosis in liquid culture could enable the duration of respiratory isolation to be predicted from the pre-treatment sputum smear grade. The recommendations enable isolation to end well before sputum becomes smear negative, with considerable benefits to patients and healthcare providers.

Editorial comment: An ingenious attempt to rationalize the isolation period for TB patients.