Madhukar Pai

Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD

Tuberculosis (TB), smoking, HIV and chronic obstructive pulmonary disease (COPD) are burgeoning epidemics in developing countries. The link between TB and HIV is well established. Less well recognised is the strong relationship between tobacco smoking and the development and natural history of TB. These associations are of considerable relevance to public health and disease outcomes in individuals with TB. Moreover, tobacco smoking, a modifiable risk factor, is associated with poorer outcomes in HIV-associated opportunistic infections, of which TB is the commonest in developing countries. It is now also becoming clear that TB, like tobacco smoke, besides its known consequences of bronchiectasis and other pulmonary morbidity, is also a significant risk factor for the development of COPD. Thus, there is a deleterious and synergistic interaction between TB, HIV, tobacco smoking and COPD in a large proportion of the world’s population. Further work, specifically mechanistic and epidemiological studies, is required to clarify the role of tobacco smoke on the progression of TB and HIV infection, and to assess the impact of smoking cessation interventions. These interactions deserve urgent attention and have major implications for coordinated public health planning and policy recommendations in the developing world.

Novel tests for diagnosing tuberculous pleural effusion: what works and what does not?

Tuberculous pleuritis is a common manifestation of extrapulmonary tuberculosis and is the most common cause of pleural effusion in many countries. Conventional diagnostic tests, such as microscopic examination of the pleural fluid, biochemical tests, culture of pleural fluid, sputum or pleural tissue, and histopathological examination of pleural tissue, have known limitations. Due to these limitations, newer and more rapid diagnostic tests have been evaluated. In this review, the authors provide an overview of the performance of new diagnostic tests, including markers of specific and nonspecific immune response, nucleic acid amplification and detection, and predictive models based on combinations of markers. Directions for future development and evaluation of novel assays and biomarkers for pleural tuberculosis are also suggested.

Bacteriophage- based tests for the detection of Mycobacterium tuberculosis in clinical specimens: a systematic review and meta- analysis

BackgroundSputum microscopy, the most important conventional test for tuberculosis, is specific in settings with high burden of tuberculosis and low prevalence of non tuberculous mycobacteria. However, the test lacks sensitivity. Although bacteriophage-based tests for tuberculosis have shown promising results, their overall accuracy has not been systematically evaluated.MethodsWe did a systematic review and meta-analysis of published studies to evaluate the accuracy of phage-based tests for the direct detection of M. tuberculosis in clinical specimens. To identify studies, we searched Medline, EMBASE, Web of science and BIOSIS, and contacted authors, experts and test manufacturers. Thirteen studies, all based on phage amplification method, met our inclusion criteria. Overall accuracy was evaluated using forest plots, summary receiver operating (SROC) curves, and subgroup analyses.ResultsThe data suggest that phage-based assays have high specificity (range 0.83 to 1.00), but modest and variable sensitivity (range 0.21 to 0.88). The sensitivity ranged between 0.29 and 0.87 among smear-positive, and 0.13 to 0.78 among smear-negative specimens. The specificity ranged between 0.60 and 0.88 among smear-positive and 0.89 to 0.99 among smear-negative specimens. SROC analyses suggest that overall accuracy of phage-based assays is slightly higher than smear microscopy in direct head-to-head comparisons.ConclusionPhage-based assays have high specificity but lower and variable sensitivity. Their performance characteristics are similar to sputum microscopy. Phage assays cannot replace conventional diagnostic tests such as microscopy and culture at this time. Further research is required to identify methods that can enhance the sensitivity of phage-based assays without compromising the high specificity.

Are interferon-γ release assays useful for diagnosing active tuberculosis in a high-burden setting?

Although interferon-&ggr; release assays (IGRAs) are intended for diagnosing latent tuberculosis (TB), we hypothesised that in a high-burden setting: 1) the magnitude of the response when using IGRAs can distinguish active TB from other diagnoses; 2) IGRAs may aid in the diagnosis of smear-negative TB; and 3) IGRAs could be useful as rule-out tests for active TB. We evaluated the accuracy of two IGRAs (QuantiFERON®-TB Gold In-tube (QFT-GIT) and T-SPOT®.TB) in 395 patients (27% HIV-infected) with suspected TB in Cape Town, South Africa. IGRA sensitivity and specificity (95% CI) were 76% (68–83%) and 42% (36–49%) for QFT-GIT and 84% (77–90%) and 47% (40–53%) for T-SPOT®.TB, respectively. Although interferon-&ggr; responses were significantly higher in the TB versus non-TB groups (p<0.0001), varying the cut-offs did not improve discriminatory ability. In culture-negative patients, depending on whether those with clinically diagnosed TB were included or excluded from the analysis, the negative predictive value (NPV) of QFT-GIT, T-SPOT®.TB and chest radiograph in smear-negative patients varied between 85 and 89, 87 and 92, and 98% (for chest radiograph), respectively. Overall accuracy was independent of HIV status and CD4 count. In a high-burden setting, IGRAs alone do not have value as rule-in or -out tests for active TB. In smear-negative patients, chest radiography had better NPV even in HIV-infected patients.

High prevalence of smoking among patients with suspected tuberculosis in South Africa

There is growing evidence that tobacco smoking is an important risk factor for tuberculosis (TB). There are no data validating the accuracy of self-reported smoking in TB patients and limited data about the prevalence of smoking in TB patients from high-burden settings. We performed a cross-sectional analysis of 500 patients with suspected TB in Cape Town, South Africa. All underwent comprehensive diagnostic testing. The accuracy of their self-reported smoking status was determined against serum cotinine levels. Of the 424 patients included in the study, 56 and 60% of those with active and latent TB infection (LTBI), respectively, were current smokers. Using plasma cotinine as a reference standard, the sensitivity of self-reported smoking was 89%. No statistically significant association could be found between smoking and active TB or LTBI. In Cape Town, the prevalence of smoking among patients with suspected and confirmed TB was much higher than in the general South African population. Self-reporting is an accurate measure of smoking status. These results suggest the need to actively incorporate tobacco cessation programmes into TB services in South Africa.

Comparative cost and performance of light-emitting diode microscopy in HIV–tuberculosis-co-infected patients

Light-emitting diode (LED) microscopy has recently been endorsed by the World Health Organization (WHO). However, it is unclear whether LED is as accurate and cost-effective as Ziehl–Neelsen (ZN) microscopy or mercury vapour fluorescence microscopy (MVFM) in tuberculosis (TB)–HIV-co-infected subjects. Direct and concentrated sputum smears from TB suspects were evaluated using combinations of LED microscopy, ZN microscopy and MVFM. Median reading time per slide was recorded and a cost analysis performed. Mycobacterial culture served as the reference standard. 647 sputum samples were obtained from 354 patients (88 (29.8%) were HIV-infected and 161 (26%) were culture-positive for Mycobacterium tuberculosis). Although overall sensitivity of LED compared with ZN microscopy or MVFM was similar, sensitivity of all three modalities was lower in HIV-infected patients. In the HIV-infected group, the sensitivity of LED microscopy was higher than ZN microscopy using samples that were not concentrated (46 versus 39%; p=0.25), and better than MVFM using concentrated samples (56 versus 44; p=0.5). A similar trend was seen in the CD4 count <200 cells·mL−1 subgroup. Median (interquartile range) reading time was quicker with LED compared with ZN microscopy (1.8 (1.7–1.9) versus 2.5 (2.2–2.7) min; p≤0.001). Average cost per slide read was less for LED microscopy (US

Chloroquine or amodiaquine combined with sulfadoxine–pyrimethamine for uncomplicated malaria: a systematic review

1.63) compared with ZN microscopy (US

Predictive value of latent tuberculosis tests in Indian healthcare workers: a cohort study

2.10). Among HIV–TB-co-infected patients, LED microscopy was cheaper and performed as well as ZN microscopy or MVFM independent of the staining (ZN or auramine O) or processing methods used.

Profile of adults seeking voluntary HIV testing and counseling in rural Central India: results from a hospital-based study.

Objective  To compare the efficacies against uncomplicated falciparum malaria of chloroquine (CQ), amodiaquine (AQ), sulfadoxine–pyrimethamine (SP) and combinations of these inexpensive drugs.

Accuracy of perception and touch for detecting fever in adults: a hospital‐based study from a rural, tertiary hospital in Central India

To the Editors: Healthcare workers (HCWs) in high tuberculosis (TB)-burden countries are known to have a substantially higher risk of latent TB infection (LTBI) and TB disease [1], and this has been demonstrated repeatedly in India [2, 3]. Several studies have evaluated interferon-γ release assays (IGRAs) in HCWs [4], but no study has reported the predictive value of IGRAs in this population of HCWs at risk for TB exposure. Between January and June 2004, we had performed a cross-sectional comparison of the tuberculin skin test (TST) (1 tuberculin unit of purified protein derivation RT23) and QuantiFERON®-TB Gold In-Tube (QFT; Cellestis Ltd, Melbourne, Australia) in a cohort of 726 HCWs (719 had valid test results for both tests) at the Mahatma Gandhi Institute of Medical Sciences (Sevagram, India), with young trainees making up half the cohort [5]. A total of 360 (50%) HCWs were found to be positive using either the TST or QFT assay at baseline, and 226 (31%) were found to be positive using both tests. The prevalence estimates of TST and QFT positivity were comparable, with high concordance between test results [5]. Although isoniazid preventive therapy (IPT) was offered to HCWs with positive baseline TST or QFT results, only a small proportion had completed INH therapy. In 2010, ∼6 yrs after …