Dick Menzies

Systematic Review: T-Cell–based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update

Context Tuberculin skin tests (TSTs) and new interferon-release assays (IGRAs) are alternative tests for detecting latent tuberculosis. Contribution This updated meta-analysis of 38 studies found that sensitivity of IGRAs and TST was not consistent across tests and populations, but TSPOT.TB seemed to be more sensitive than QuantiFERON tests and TST. Both the TST and IGRAs had high specificity (>95%) for tuberculosis in populations not vaccinated with bacille CalmetteGurin (BCG). The specificity of IGRAs was also high in populations vaccinated with BCG, whereas TST specificity was low and highly variable. Caution The studies had many limitations, including small sample sizes and no reference standard test for diagnosing latent tuberculosis. Implication The specificity of IGRAs for detecting latent tuberculosis is good and seems unaffected by BCG vaccination status. The Editors The tuberculin skin test (TST) was formerly the only test for detecting latent tuberculosis infection; however, interferon-release assays (IGRAs) have emerged as attractive alternatives. Two IGRAs, QuantiFERON-TB Gold (Cellestis, Carnegie, Australia) and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom), are now commercially available, and their use is expanding. Although IGRAs are intended for diagnosing latent tuberculosis infection, active tuberculosis is used as a surrogate standard to estimate accuracy in the absence of a gold standard for latent tuberculosis infection. In a recent meta-analysis (1), Menzies and colleagues showed that IGRAs have high specificity, especially in populations who have received bacille Calmette-Gurin (BCG) vaccination. However, the sensitivity of both TST and IGRAs was suboptimal, and none of these tests could distinguish between latent tuberculosis and active disease. Since the publication of this meta-analysis, the evidence base for IGRAs has rapidly grown with publication of several guidelines and statements (26). We present an updated meta-analysis that will provide helpful information for clinicians and for agencies developing updated guidelines. Methods Study Selection and Eligibility Using the same search strategy as that published elsewhere (1), we searched PubMed for new studies through 31 March 2008 that reported data on the sensitivity and specificity of commercial IGRAs. We reviewed citations of all original articles, guidelines, and reviews for studies published in English. The inclusion criteria for this update were narrower than for the original meta-analysis, which included research, in-house, or commercial versions of QuantiFERON or enzyme-linked immunospot (ELISpot) tests that used early-secreted antigenic target 6, with or without culture filtrate protein 10 and with or without TB7.7 antigens. For the update, we restricted the studies to QuantiFERON-TB Gold (also known as QFT-2G), QuantiFERON-TB Gold In-Tube (also known as QFT-3G) (both from Cellestis, Victoria, Australia), and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom) or its precommercial ELISpot version, when data on the commercial version were lacking. Unlike the original meta-analysis, we excluded studies with fewer than 10 participants, studies that included only immunocompromised populations, and studies that used only early-secreted antigenic target 6. For studies assessing sensitivity, the study sample had to comprise participants with microbiologically confirmed active tuberculosis, but not include only immunocompromised participants. For studies assessing specificity, the sample had to comprise healthy, low-risk individuals without known exposure to tuberculosis who were from countries with a low tuberculosis incidence rate. Two independent reviewers performed searches and selected articles meeting the inclusion criteria. One reviewer abstracted data on participant characteristics and test characteristics and performance, and a second reviewer double-checked these data. When necessary, we contacted the original investigators for additional information. Data Synthesis For each study, we calculated sensitivity or specificity and 95% CIs and summarized the results in forest plots. To pool estimates across the studies, we did a fixed-effects meta-analysis with correction for overdispersion to account for between-study variability by using MetaDiSc software, version 1.4 (Hospital Ramn y Cajal, Madrid, Spain; www.hrc.es/investigacion/metadisc_en.htm). We evaluated heterogeneity by using the chi-square and I 2 tests. Because we found heterogeneity, we performed subgroup analyses; we analyzed each commercial test (and test version, in the case of QuantiFERON) separately and evaluated BCG-vaccinated and nonvaccinated groups separately for specificity studies. When data on the sensitivity and specificity of concurrently done TSTs were reported, we extracted and summarized the data in tables and forest plots. Role of the Funding Source The Canadian Institutes of Health Research and the Fonds de la recherche en sant du Qubec had no role in the design, conduct, and analysis of the study or the decision to submit the manuscript for publication. Results A total of 38 articles (744) met our inclusion criteria, 20 of which (comprising 1879 participants) were new articles not included in our previous meta-analysis. Of these, 15 included QuantiFERON-TB Gold or QuantiFERON-TB Gold In-Tube and 9 included T-SPOT.TB. Eight articles in the original meta-analysis (1) were excluded from this update because they included noncommercial assays (4548), had fewer than 10 participants (49, 50), included only immunocompromised populations (51), or used only early-secreted antigenic target 6 as the antigen (45). Appendix Tables 1, 2, 3, and 4 provide details on the included studies. All studies were cross-sectional. Of the 38 studies, 21 (55%) had some sort of industry involvement or support, such as sponsorship, donation of test kits, participation in advisory boards, involvement of test developers, or ownership of patents. Appendix Table 1. Sensitivity of QuantiFERON-TB Gold (QFT) among Patients with Active Tuberculosis (TB) Appendix Table 2. Sensitivity of T-SPOT.TB among Patients with Active Tuberculosis (TB) Appenix Table 3. Specificity of QuantiFERON-TB Gold (QFT) in Bacille CalmetteGurin (BCG)Vaccinated and NonBCG-Vaccinated Patients with an Expected Low Prevalence of Tuberculous Infection* Appendix Table 4. Specificity of Enzyme-Linked Immunospot (ELISpot) and T-SPOT.TB in Bacille CalmetteGurin (BCG)Vaccinated and NonBCG-Vaccinated Participants with an Expected Low Prevalence of Tuberculous Infection* Sensitivity of Interferon-Release Assays We identified 22 studies of QuantiFERON tests, comprising 1369 participants (Appendix Table 1), and 13 studies of T-SPOT.TB, comprising 726 participants (Appendix Table 2). Active tuberculosis was confirmed by culture in most cases, and most studies included participants without HIV infection. Three of the QuantiFERON studies were from countries with a high rate of tuberculosis incidence, whereas none of the T-SPOT.TB studies was from a high-incidence country. Almost all of the sensitivity studies included only adults. Figure 1 shows the forest plot and pooled sensitivity estimates. The pooled sensitivity of all 22 QuantiFERON studies was 76% (95% CI, 72% to 80%) (plot not shown). Pooled sensitivity was 78% (CI, 73% to 82%) for QuantiFERON-TB Gold, 70% (CI, 63% to 78%) for QuantiFERON-TB Gold In-Tube, and 90% (CI, 86% to 93%) for T-SPOT.TB (Figure 1). Although we found no obvious differences in sensitivity between QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube, the nonoverlapping CIs suggest that the pooled sensitivity of T-SPOT.TB was higher than that of either QuantiFERON-TB test. Figure 1. Forest plot of studies estimating sensitivity of interferon-release assays in patients with active tuberculosis as a surrogate for latent tuberculous infection. Point estimates for sensitivity and 95% CIs are shown along with pooled estimates. Top. QuantiFERON-TB Gold (16 studies). Middle. QuantiFERON-TB Gold In-Tube (6 studies). Bottom. T-SPOT.TB (13 studies). Seven studies (Appendix Table 5) reported head-to-head comparisons of T-SPOT.TB and QuantiFERON sensitivity. In 6 of those studies, T-SPOT.TB had a higher sensitivity than QuantiFERON-TB Gold, with difference ranging from 3% to 25%. One study reported identical sensitivity estimates for both assays. Studies that used QuantiFERON-TB Gold showed lower sensitivity relative to T-SPOT.TB than did studies that used QuantiFERON-TB Gold In-Tube. Appendix Table 5. Head-to-Head Comparisons of Sensitivity of QuantiFERON-TB (QFT) Gold versus T-SPOT.TB among Patients with Active Tuberculosis (TB) Specificity of Interferon-Release Assays We identified 16 studies of QuantiFERON tests, 8 of BCG-vaccinated and 8 of nonBCG-vaccinated samples, comprising 1624 participants (Appendix Table 3). None of the specificity studies was from a country with a high rate of tuberculosis incidence. Almost all of the specificity studies included only adults. The BCG vaccination policies in the study countries varied; for example, Japan and South Korea have a policy of repeated BCG vaccinations, whereas the United States and the Netherlands do not recommend BCG vaccination. We identified 2 studies that used the commercial T-SPOT.TB assay and 4 studies that used the precommercial ELISpot version, with a combined total of 290 participants. Appendix Table 4 summarizes these 6 studies. Figure 2 presents the forest plot and pooled estimates. The pooled specificity was 98% (CI, 96% to 99%) for all QuantiFERON studies, 99% (CI, 98% to 100%) for QuantiFERON among nonBCG-vaccinated populations, and 96% (CI, 94% to 98%) for QuantiFERON among BCG-vaccinated populations (Figure 2). The pooled specificity of T-SPOT.TB/ELISpot was 93% (CI, 86% to 100%) (Figure 2). All but 1 T-SPOT.TB study included BCG-vaccinated participants. When only the 2 commercial T-SPOT.TB studies were pooled, the specificit

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57–72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45–66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36–60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27–53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4–16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4–26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6–9.0 months duration and the total duration of treatment 20.1–25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens.

Adverse reactions to first-line antituberculosis drugs

Introduction: Tuberculosis continues to be a major cause of morbidity and mortality worldwide. Currently available drugs are effective for treatment of the disease or latent infection, but may cause serious adverse effects. Methods: The authors reviewed the literature for side effects of five first-line antituberculous medications (isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin). Incidence of the major side effects were compiled with particular attention to the incidence of isoniazid hepatotoxicity. Results: Hepatotoxicity to isoniazid is a serious problem. Although overall incidence may be decreasing, incidence averaged 9.2 per 1000 patients who were compliant, in multiple studies, with a case fatality rate of 4.7%. The incidence is higher with increasing age. Other serious adverse effects include dermatological, gastrointestinal, hypersensitivity, neurological, haematological and renal reactions. They can lead to drug discontinuation (in up to 10% of patients) or even more serious morbidity or mortality. Conclusions: Side effects to antituberculosis drugs are common, and include hepatitis, cutaneous reactions, gastrointestinal intolerance, haematological reactions and renal failure. These adverse effects must be recognised early, to reduce associated morbidity and mortality.

Fixed-dose combination antituberculosis therapy: a systematic review and meta-analysis

Fixed-dose combination (FDC) formulations are currently recommended for the treatment of active tuberculosis (TB). We have conducted a systematic review to evaluate the risk of treatment failure or disease relapse, acquired drug resistance, bacterial conversion after 2 months of treatment, adverse events, adherence and treatment satisfaction associated with treatment of active TB using FDC or separate drug formulations. We searched four electronic databases for randomised controlled trials and cohort studies. Results from trials that directly compared FDC to separate drug formulations were pooled. Results from other studies were reported separately. We identified 2450 citations from which 15 controlled trials and four additional relevant studies were included. In the 15 trials there were no differences in acquired drug resistance, bacterial conversion after 2 months of treatment or adverse drug reactions with FDC or separate drug formulations. There was a trend toward higher risk of failure or relapse with FDC (pooled relative risk 1.28 (95% CI 0.99–1.7)). Based on individual study results, only one of two trials that assessed treatment satisfaction, and none of five that assessed patient adherence, favoured FDCs. Although FDC formulations simplify TB therapy, the current evidence does not indicate that these formulations improve treatment outcomes among patients with active TB. Current evidence does not indicate that fixed-dose combinations of first-line TB drugs improve treatment outcomes http://ow.ly/la48v

Tuberculosis in association with travel

Throughout history, tuberculosis has been spread by the movement of human populations. Modern travel continues to be associated with risk of tuberculosis infection and disease. TB transmission has been documented on commercial aircraft, from personnel or passengers to other personnel and passengers, but the risk of transmission is low. As in other settings, the likelihood of transmission is proportional to duration and proximity of contact. Travellers from low incidence to high incidence countries have an appreciable risk of acquiring TB infection similar to that of the general populations in the countries they visit, but the risk is higher if they work in health care. Two-step tuberculin skin testing prior to departure, followed by single-step tuberculin testing after return, is recommended for all such travellers. For travellers from high incidence to low incidence countries the risk of acquiring new TB infection is low. Tuberculin screening is not beneficial and not recommended. Chest X-ray screening is expensive and complex but may be beneficial for long-term migrants. For short-term travellers, such as the pilgrims to Mecca in Saudi Arabia, there is no practical or feasible intervention to detect or prevent TB. Emphasis should be placed on public awareness and education campaigns to facilitate passive diagnosis of symptomatic cases. Mycobacterium tuberculosis (MTB) continues to be a common concern for the global traveller.

Treatment of latent TB: first do no harm.

Treatment of latent TB infection (LTBI) prevents active disease and is an essential component of TB control in low-incidence countries. Because only a minority of latently infected individuals go on to develop active disease, the decision to treat latent TB requires careful consideration of the long-term benefits of prevention versus the immediate risk of therapy-associated adverse events. This article will summarize the current state of latent TB management, highlighting recent advances and future directions. Treatment of LTBI can reduce morbidity, mortality and healthcare costs [1,2]. People with LTBI are neither symptomatic nor contagious, and the majority will never develop active disease. Recommended treatment is lengthy and has the potential for serious adverse effects. Hence, the risk should be weighed carefully against the potential benefit of preventing active disease. Current guidelines recommend treating people with LTBI that are at increased risk of development of active disease [1,3,101]. Risk factors for reactivation include recent TB infection, comorbid conditions and medications that impair host immune responses (e.g., HIV infection, solid organ transplant, diabetes mellitus, chronic hemodialysis, certain cancers, smoking, glucocorticoids and TNF-a inhibitors), low bodyweight (BMI ≤20) and radiographic abnormalities typical of prior TB infection [1,3,101]. Among latently infected persons that are at low risk of adverse events from treatment, if they have any risk factor that confers an increased risk of reactivation, then treatment is warranted. The decision to treat is more difficult when patients with LTBI possess risk factors for reactivation and also for therapy-associated adverse events. A thorough understanding of LTBI treatment options and their sideeffect profiles will guide clinicians in the management of such cases.

Serum lipids as biomarkers for therapeutic monitoring of latent tuberculosis infection.

To the Editor: The World Health Organization has estimated that more than two billion persons in the world carry latent tuberculosis infection (LTBI). The diagnosis and treatment of LTBI could have an important impact in preventing the development of active tuberculosis (TB), a disease that causes 1.4 million deaths annually [1]. The current standard treatment of LTBI is nine months of isoniazid (INH) [2]. To improve adherence, a shorter regimen of 4 months rifampicin (RIF) is being evaluated in a multicentre randomised trial (CIHR MCT-94831, registered at www.controlled-trials.com/ISRCTN05675547). This ongoing trial offers an opportunity to study potential biomarkers as surrogates of successful prevention of active disease [3]. Several changes in lipid metabolism could potentially be utilised as biomarkers of effectiveness of LTBI treatment with RIF or INH. RIF is an important stimulator of the pregnane X receptor (PXR), which has been hypothesised to increase the blood levels of high density lipoprotein cholesterol (HDLC) and its protein component apolipoprotein A-1 (apoA) [4, 5]. This hypothesis was supported by observational studies that demonstrated an increased plasma level of HDLC among epileptic patients who were taking anticonvulsant medications which activate the PXR [6]. By contrast, treatment with INH was associated with lower cholesterol blood levels in one small study [7]. ApoA and apolipoprotein B (apoB), a protein component of low density lipoprotein cholesterol (LDLC), have stable serum blood levels without post-prandial changes and low within-individual variability [8]. Total cholesterol and HDLC are inexpensive to measure, reliably …

Global survey of national tuberculosis drug policies

SETTING National tuberculosis (TB) programmes (NTPs) in 100 countries. OBJECTIVES To evaluate the relationship between the estimated prevalence of multidrug resistance in previously untreated TB cases and policies regarding sales and distribution of TB drugs, particularly rifampicin (RMP). DESIGN Questionnaire survey of national TB drug control policies, completed by NTP managers. Results were correlated with recent World Health Organization estimates of prevalence of drug resistance in new cases of TB. RESULTS Questionnaires were received from 100 countries, including 88 low- and middle-income countries (LMICs) and 17 of the 22 high-burden countries. Current policies were considered adequate in only 40 of the 88 LMICs (45%). A higher prevalence of multidrug resistance was associated with fewer years of free availability of TB drugs from the NTP (P = 0.02) and more years of availability of RMP from providers or pharmacies outside the NTP (P = 0.02). Eleven of the 20 countries with the highest prevalence of multidrug resistance had inadequate policies governing sales and distribution of TB drugs. CONCLUSIONS These findings suggest that policies regarding sales and distribution of TB drugs should receive more emphasis as part of the global strategy to control drug resistance.

Bacillus Calmette-Guérin (BCG) vaccination patterns in the province of Québec, Canada, 1956–1974

BACKGROUND In the province of Québec, Canada, the Bacillus Calmette-Guérin (BCG) vaccine was offered to newborns and school-age children from the 1950s to mid-1970s in an organized tuberculosis prevention program. OBJECTIVE We aimed to describe the annual rates of skin test administration, proportion of skin tests that were positive, and rates of BCG vaccination from 1956 to 1974 according to age, sex, and administrative region. METHODS For rates, numerators were extracted from the Québec BCG Vaccination Registry whereas population denominators were obtained from the Canadian Census and governmental publications. Time trends were assessed with linear regression. RESULTS A total of 2,755,336 skin tests and 2,531,366 BCG vaccinations were administered. Yearly rates of skin tests, routinely administered before vaccination among all except newborns, were highest among children aged 5-9 (9.3 per 100) and 10-14years (7.9 per 100). The proportion of positive skin tests varied greatly by age, ranging from 10.2% among children <1year to 67.2% among adults ≥20years. The vast majority of individuals who had a negative skin test were subsequently vaccinated, whereas those with a positive result were not, as per recommended guidelines. The average annual vaccination rate was highest among children aged <1year (43.8 per 100) and 5-9year-olds (6.9 per 100). There were salient differences in immunization rates, including positive skin tests and vaccinations, across administrative regions but no difference by sex. CONCLUSION This is the first comprehensive description of the tuberculosis prevention program in Québec which offered free, non-mandatory BCG vaccination. Our results confirm that the targeted groups, newborns and school-age children, were preferentially reached. Socioeconomic, demographic, and organizational factors may explain regional differences in immunization rates. Beyond presenting a historical context for this vaccination campaign, our findings are relevant to contemporary uses of the Québec BCG Vaccination Registry in epidemiological research.

Occupation-Related Respiratory Infections Revisited

Occupational pulmonary infectious diseases include tuberculosis (TB) and many viral pathogens, including influenza, coronavirus (severe acute respiratory syndrome or SARS), varicella, respiratory syncytial virus, and hantavirus. This review focuses on TB, influenza, and SARS, because the published literature is extensive for these 3 infections. The lessons from these 3 are relevant for all nosocomial pulmonary infectious diseases.