The Australian Tuberculosis Review October 2010

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

 

 

 

 

 

 

 

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