Madhukar Pai

McGill University, Montréal, Quebec, Canada

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Publications (244)1502.16 Total impact

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    ABSTRACT: Rationale: Interferon-gamma release assays for latent tuberculosis infection result in a larger than expected number of conversions and reversions in occupational screening programs and reproducibility of test results is a concern. Objectives: Knowledge of the relative contribution and extent of the individual sources of variability (immunological, pre-analytical, or analytical) could help optimize testing protocols. Methods: We performed a systematic review of studies published by October 2013 on all potential sources of variability of commercial Interferon-gamma release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB). The included studies assessed test variability under identical conditions and under different conditions (the latter both overall and stratified by individual sources of variability). Linear mixed effects models were used to estimate within-subject standard deviation. Measurements and Main Results: We identified a total of 26 articles, including 7 studies analyzing variability under the same conditions, 10 studies analyzing variability with repeat testing over time under different conditions and 19 studies reporting individual sources of variability. Most data were on QuantiFERON (only 3 studies on T-SPOT.TB). A considerable number of conversions and reversions were seen around the manufacturer-recommended cut-point. The estimated range of variability of interferon-gamma response in QuantiFERON under identical conditions was +/-0.47 IU/mL (coefficient of variation 13%) and +/- 0.26 IU/mL (30%) for individuals with an initial interferon-gamma response in the borderline range (0.25-0.80 IU/mL). The estimated range of variability in non-controlled settings was substantially larger (+/- 1.4 IU/mL; 60%). Blood volume inoculated into QuantiFERON tubes and pre-analytic delay were identified as other key sources of variability. Conclusion: This systematic review shows substantial variability with repeat Interferon-gamma release assays testing even under identical conditions suggesting that reversions and conversions around the existing cut-point should be interpreted with caution.
    Annals of the American Thoracic Society. 09/2014;
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    ABSTRACT: India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited.
    PLoS Medicine 07/2014; 11(7):e1001674. · 15.25 Impact Factor
  • Claudia M Denkinger, Madhukar Pai
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 05/2014;
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    ABSTRACT: The absence of a gold standard, i.e., a diagnostic reference standard having perfect sensitivity and specificity, is a common problem in clinical practice and in diagnostic research studies. There is a need for methods to estimate the incremental value of a new, imperfect test in this context.
    BMC Medical Research Methodology 05/2014; 14(1):67. · 2.21 Impact Factor
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    ABSTRACT: To the Editor:Globally, a third of all tuberculosis (TB) cases are not notified and many patients do not receive drug susceptibility testing (DST) (1). New diagnostics can contribute to increased case detection, shorter diagnostic delay and reduced TB transmission. While the Xpert MTB/RIF assay (Cepheid Inc., Sunnyvale, CA, USA) is a much needed breakthrough (2), it may not reach lower tiers of the healthcare system (3) and doesn't meet all needs (e.g. cannot detect resistance against multiple drugs).Several promising diagnostics are under development and companies are showing interest in TB products, inspired by the success of Xpert MTB/RIF (4). But which new TB diagnostics should they invest in, and what is the potential market size for these products? Stakeholders have expressed a need for different products, including a test for childhood TB (5), a simple point-of-care-test for active pulmonary TB (6), a molecular smear replacement test (7), DST for expected new drug regimens (8), predictive biomarkers for latent TB infection (LTBI) (9), and treatment monitoring (10).Given the variety of these needs, it is important for product developers to have access to: 1) a clearly identified list of diagnostics that are considered high priority by the TB community; 2) well developed, detailed.
    European Respiratory Journal 04/2014; · 6.36 Impact Factor
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    ABSTRACT: Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is endorsed for the detection of pulmonary tuberculosis (TB). We performed a systematic review and meta-analysis to assess the accuracy of Xpert for the detection of extrapulmonary TB.We searched multiple databases to October 15, 2013. We determined the accuracy of Xpert compared with culture and a composite reference standard (CRS). We grouped data by sample type and performed meta-analyses using a bivariate random-effects model. We assessed sources of heterogeneity using meta-regression for predefined covariates.We identified 18 studies involving 4461 samples. Sample processing varied greatly among the studies. Xpert sensitivity differed substantially between sample types. In lymph node tissues or aspirates, Xpert pooled sensitivity was 83.1% (95% CI 71.4-90.7%) versus culture and 81.2% (95% CI 72.4-87.7%) versus CRS. In cerebrospinal fluid, Xpert pooled sensitivity was 80.5% (95% CI 59.0-92.2%) against culture and 62.8% (95% CI 47.7-75.8%) against CRS. In pleural fluid, pooled sensitivity was 46.4% (95% CI 26.3-67.8%) against culture and 21.4% (95% CI 8.8-33.9%) against CRS. Xpert pooled specificity was consistently >98.7% against CRS across different sample types.Based on this systematic review, the World Health Organization now recommends Xpert over conventional tests for diagnosis of TB in lymph nodes and other tissues, and as the preferred initial test for diagnosis of TB meningitis.
    European Respiratory Journal 04/2014; · 6.36 Impact Factor
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    ABSTRACT: To the Editor:We have previously shown that Indian healthcare workers have higher prevalence of latent tuberculosis infection (LTBI) and are at increased risk for new infection (1-4). Interferon-γ release assays (IGRAs) have been introduced as an alternative to the tuberculin skin test (TST) for diagnosing LTBI in healthcare workers and other high-risk groups. They have logistical advantages over the TST and will not cross-react with the bacille Calmette Guérin vaccine. IGRAs are now being widely used for screening healthcare workers (5), yet recent reports indicate that switching from TST to IGRAs for the serial testing of healthcare workers may result in increased rates of test conversions and reversions (3, 6-8). Most of these studies are from low tuberculosis (TB) incidence settings, with limited opportunity for nosocomial TB exposure; as a result, the increased conversion rates are considered false-positive test conversions, making it difficult for clinicians to interpret IGRA test conversions in these settings (9). It remains unclear whether IGRA conversions are associated with TB exposure in high TB incidence settings where unprotected exposure to infectious TB patients is more common among healthcare workers.To evaluate whether IGRA conversions may represent new cases of LTBI, in a high TB incidence setting, in the.
    European Respiratory Journal 04/2014; · 6.36 Impact Factor
  • Madhukar Pai, Sandra V Kik, Niaz Banaei
    Annals of the American Thoracic Society. 03/2014; 11(3):399-401.
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    ABSTRACT: To the Editor:Sputum smear microscopy (SSM) has been the cornerstone of tuberculosis (TB) diagnosis, and is mainly performed in peripheral microscopy centres attached to primary health centres where TB therapy can be administered. Although SSM is inexpensive and easy to perform with a limited infrastructure, the shortcomings are its relatively low sensitivity and its inability to detect drug-resistance. Thus, there is a need for a more sensitive technology that can replace microscopy (1, 2).Several next-generation molecular diagnostics are under development with the specific intention of use in microscopy centres (3-5). In a recent survey of 22 high-burden countries (HBCs), we showed that the conditions, equipment and expertise present in microscopy centres are challenging and need to be considered by product developers (6). While the Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) assay is accurate, endorsed by the World Health Organization and is being implemented in many countries, it was not designed for use in peripheral microscopy centres (7, 8). To assist product developers working on tests for use in microscopy centres, we have outlined the desirable test characteristics (1).For companies to take on the challenge and invest in new diagnostics, an understanding of the potential market size is paramount (9). A.
    European Respiratory Journal 02/2014; · 6.36 Impact Factor
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    ABSTRACT: Background. Xpert® MTB/RIF, the first automated molecular test for tuberculosis, is transforming the diagnostic landscape in low-income countries. However, little information is available on its performance in low-incidence, high-resource countries. Methods. We evaluated the accuracy of Xpert in a university hospital TB clinic in Montreal, Canada, for the detection of pulmonary TB on induced sputum samples, using mycobacterial cultures as the reference standard. We also assessed the potential reduction in time-to-diagnosis and treatment initiation. Results. We enrolled 502 consecutive patients who presented for evaluation of possible active TB (most with abnormal chest radiographs, only 18% symptomatic). Twenty-five subjects were identified to have active TB by culture. Xpert had a sensitivity of 46% (95% confidence interval (CI): 26-67) and specificity of 100% (CI: 99-100) for detection of Mycobacterium tuberculosis. Sensitivity was 86% (CI: 42-100) in the 7 smear-positive subjects, and 28% (CI: 10-56) in the remaining smear-negative, culture-positive subjects; in this latter group positive Xpert results were obtained a median 12 days before culture results. Subjects with positive cultures but negative Xpert results had minimal disease: 11 of 13 had no symptoms on presentation, and mean time to positive liquid culture results was 28 days (CI: 25-47 days; compared to 14 days, CI: 8-21days in Xpert/culture-positive cases). Conclusion. Our findings suggest limited potential impact of Xpert testing in high-resource, low-incidence ambulatory settings due to lower sensitivity in the context of less extensive disease, and limited potential to expedite diagnosis beyond what is achieved with the existing, well-performing diagnostic algorithm.
    Clinical Infectious Diseases 01/2014; · 9.37 Impact Factor
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    ABSTRACT: SUMMARY Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.
    Clinical microbiology reviews 01/2014; 27(1):3-20. · 14.69 Impact Factor
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    ABSTRACT: In India, the quality of care that tuberculosis (TB) patients receive varies considerably and is often not in accordance with the national and international standards. In this article, we provide an overview of the third (latest) edition of the International Standards of Tuberculosis Care (ISTC). These standards are supported by the existing World Health Organization guidelines and policy statements pertaining to TB care and have been endorsed by a number of international organizations. We call upon all health care providers in the country to practice TB care that is consistent with these standards, as well as the upcoming Standards for TB Care in India (STCI).
    The Indian journal of tuberculosis 01/2014; 61(1):12-8.
  • Madhukar Pai
    Journal of Epidemiology and Global Health. 01/2014;
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    Madhukar Pai, Prashant Yadav, Ravi Anupindi
    The Lancet Global Health. 01/2014; 2(4):e189–e190.
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    Madhukar Pai, Prashant Yadav, Ravi Anupindi
    The Lancet Global Health. 01/2014; 2(7):e389.
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    ABSTRACT: Multidrug-resistant tuberculosis (MDR-TB) is resistant to both rifampicin (RIF) and isoniazid (INH). Whereas many TB diagnostics detect RIF-resistance, few detect INH-monoresistance, which is common and may increase risk of acquired MDR-TB. Whether inclusion of INH-resistance in a first-line rapid test for TB would have an important impact on MDR-TB rates remains uncertain. WE DEVELOPED A TRANSMISSION MODEL TO EVALUATE THREE TESTS IN A POPULATION SIMILAR TO THAT OF INDIA: a rapid molecular test for TB, the same test plus RIF-resistance detection ("TB+RIF"), and detection of RIF and INH-resistance ("TB+RIF/INH"). Our primary outcome was the prevalence of INH-resistant and MDR-TB at ten years. Compared to the TB test alone and assuming treatment of all diagnosed MDR cases, the TB+RIF test reduced the prevalence of MDR-TB among all TB cases from 5.5% to 3.8% (30.6% reduction, 95% uncertainty range, UR: 17-54%). Despite using liberal assumptions about the impact of INH-monoresistance on treatment outcomes and MDR-TB acquisition, expansion from TB+RIF to TB+RIF/INH lowered this prevalence only from 3.8% to 3.6% further (4% reduction, 95% UR: 3-7%) and INH-monoresistant TB from 15.8% to 15.1% (4% reduction, 95% UR: (-8)-19%). When added to a rapid test for TB plus RIF-resistance, detection of INH-resistance has minimal impact on transmission of TB, MDR-TB, and INH-monoresistant TB.
    PLoS ONE 01/2014; 9(1):e84197. · 3.73 Impact Factor
  • Madhukar Pai, David Dowdy
    The lancet. Respiratory medicine. 01/2014; 2(1):25-7.
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    Expert Review of Molecular Diagnostics 11/2013; 13(8):763-7. · 4.09 Impact Factor
  • Richard N van Zyl-Smit, Madhukar Pai
    The International Journal of Tuberculosis and Lung Disease 11/2013; 17(11):1375-1376. · 2.76 Impact Factor
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    ABSTRACT: Background The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical eff ect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical eff ect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. Methods In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from fi ve primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials. gov, number NCT01554384. Findings Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not diff er between groups at 2 months (2 [IQR 0–3] in the smear microscopy group vs 2 [0·25–3] in the MTB/RIF group; p=0·85) or 6 months (1 [0–3] vs 1 [0–3]; p=0·35), nor did median KPS at 2 months (80 [70–90] vs 90 [80–90]; p=0·23) or 6 months (100 [90–100] vs 100 [90–100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specifi city (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specifi city (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0·0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408). Interpretation Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefi ts did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients.
    The Lancet 10/2013; · 39.06 Impact Factor

Publication Stats

8k Citations
1,502.16 Total Impact Points


  • 2006–2014
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
  • 2013
    • Himalayan Institute of Medical Sciences
      Dehra, Uttarakhand, India
    • Stanford Medicine
      • Department of Pathology
      Stanford, CA, United States
  • 2012–2013
    • Maastricht University
      • Department of Health, Ethics & Society
      Maastricht, Provincie Limburg, Netherlands
    • Institute of Bioinformatics and Applied Biotechnology
      Bengalūru, Karnātaka, India
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
    • University of Washington Seattle
      • Department of Health Services
      Seattle, WA, United States
  • 2011–2013
    • Beth Israel Deaconess Medical Center
      • • Division of Infectious Diseases
      • • Department of Medicine
      Boston, Massachusetts, United States
    • Groote Schuur Hospital
      Kaapstad, Western Cape, South Africa
    • University of Alberta
      • Department of Medical Microbiology and Immunology
      Edmonton, Alberta, Canada
  • 2009–2013
    • University of Cape Town
      • Department of Medicine
      Kaapstad, Western Cape, South Africa
  • 2007–2013
    • Christian Medical College Vellore
      • Department of Medicine
      Velluru, Tamil Nādu, India
  • 2011–2012
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, MD, United States
  • 2010–2011
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Division of HIV/AIDS
      San Francisco, CA, United States
    • King Saud medical city
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
    • Foundation for Innovative New Diagnostics
      Genève, Geneva, Switzerland
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2007–2011
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2002–2009
    • University of California, Berkeley
      • Division of Epidemiology
      Berkeley, California, United States
  • 2008
    • Universidade Gama Filho
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2003–2008
    • Mahatma Gandhi Institute of Medical Sciences
      • • Department of Biochemistry
      • • Department of Medicine
      Wardha, State of Maharashtra, India
  • 2005–2007
    • Francis J. Curry National Tuberculosis Center
      San Francisco, California, United States
    • CSU Mentor
      Long Beach, California, United States