Smear-negative Tuberculosis Cases Research Articles

A Diagnostic Accuracy Study of Xpert®MTB/RIF in HIV-Positive Patients with High Clinical Suspicion of Pulmonary Tuberculosis in Lima, Peru

BackgroundDiagnosis of pulmonary tuberculosis (TB) among human immunodeficiency virus (HIV) patients remains complex and demands easy to perform and accurate tests. Xpert®MTB/RIF (MTB/RIF) is a molecular TB diagnostic test which is rapid and convenient; the test requires minimal human resources and reports results within two hours. The majority of performance studies of MTB/RIF have been performed in high HIV burden settings, thus TB diagnostic studies among HIV patients in low HIV prevalence settings such as Peru are still needed.Methodology/Principal FindingsFrom April 2010 to May 2011, HIV-positive patients with high clinical suspicion of TB were enrolled from two tertiary hospitals in Lima, Peru. Detection of TB by MTB/RIF was compared to a composite reference standard Löwenstein-Jensen (LJ) and liquid culture. Detection of rifampicin resistance was compared to the LJ proportion method. We included 131 patients, the median CD4 cell count was 154.5 cells/mm3 and 45 (34.4%) had TB. For TB detection among HIV patients, sensitivity of MTB/RIF was 97.8% (95% CI 88.4–99.6) (44/45); specificity was 97.7% (95% CI 91.9–99.4) (84/86); the positive predictive value was 95.7% (95% CI 85.5–98.8) (44/46); and the negative predictive value, 98.8% (95% CI 93.6–99.8) (84/85). MTB/RIF detected 13/14 smear-negative TB cases, outperforming smear microscopy [97.8% (44/45) vs. 68.9% (31/45); p = 0.0002]. For rifampicin resistance detection, sensitivity of MTB/RIF was 100% (95% CI 61.0–100.0) (6/6); specificity was 91.0% (95% CI 76.4–96.9) (30/33); the positive predictive value was 66.7% (95% CI 35.4–87.9) (6/9); and the negative predictive value was 100% (95% CI 88.7 –100.0) (30/30).Conclusions/SignificanceIn HIV patients in our population with a high clinical suspicion of TB, MTB/RIF performed well for TB diagnosis and outperformed smear microscopy.

Mortality among tuberculosis patients in the Democratic Republic of Congo

Kinshasa, Democratic Republic of Congo. To identify programmatic interventions for improved survival in patients receiving treatment for tuberculosis (TB) at primary care clinics. Retrospective cohort of adult patients initiating anti-tuberculosis treatment between January 2006 and May 2007. Among 5685 patients, 390 deaths occurred during anti-tuberculosis treatment, of which half (52%) did so during the first 2 months. Patients with smear-negative pulmonary TB were at greater risk of death in the first 2 months of treatment (human immunodeficiency virus [HIV] positive HR 1.49, 95%CI 0.89-2.49; HIV-negative HR 1.77 95%CI 1.06-2.95), but not thereafter. Patients with extra-pulmonary TB were at increased risk of death in the first 2 months of anti-tuberculosis treatment if they were non-HIV-infected (HR 2.42, 95%CI 1.52-3.85), and were half as likely to die during the remainder of treatment (HIV-positive HR 0.46, 95%CI 0.22-0.97; HIV-negative HR 0.47, 95%CI 0.23-0.94). Antiretroviral therapy (ART) reduced the risk of death by an estimated 36% (HR 0.64, 95%CI 0.37-1.11). High mortality in the first months of anti-tuberculosis treatment could be reduced by addressing diagnostic delays, particularly for extra-pulmonary and smear-negative TB cases and, in HIV-infected patients, by initiation of ART soon after starting anti-tuberculosis treatment.

Epidemiology of smear-negative pulmonary tuberculosis in the United States, 1993–2008

Smear-negative tuberculosis (TB) is difficult to diagnose and has been associated with poor treatment outcomes and excessive mortality, particularly in high human immunodeficiency virus (HIV) prevalent settings. However, few studies have used mycobacterial culture to rigorously confirm all smear-negative TB cases in a population-based cohort. We included all culture-confirmed, pulmonary TB cases reported to the US National TB Surveillance System from 1993 to 2008. We analyzed smear-negative TB risk factors and survival, as compared to smear-positive TB. We calculated prevalence ratios (PRs) and adjusted for confounders (aPR). From 1993 to 2008, 159,121 cases of culture-confirmed pulmonary TB were reported in the United States, of which 58,786 (37%) were sputum smear-negative. Smear-negative TB cases were more likely to be foreign-born (aPR 1.10, 95%CI 1.08-1.12), incarcerated (aPR 1.52, 95%CI 1.48-1.56) or HIV-infected (aPR 1.27, 95%CI 1.24-1.30). Hispanics and non-Hispanic Blacks were less likely to have smear-negative TB (respectively aPR 0.87, 95%CI 0.85-0.89 and aPR 0.90, 95%CI 0.89-0.92). Smear-negative TB cases had lower mortality (aRR 0.78, 95%CI 0.74-0.81), independent of HIV status. Smear-negative TB represents a large proportion of TB cases in the United States, and occurs more often among persons in groups more likely to undergo TB screening. The lower mortality may indicate earlier TB detection, and underscores the need for continued vigilance in screening of high-risk persons.

Evaluation of the diagnostic value of measuring IgG, IgM, and IgA antibodies to mycobacterial A60 antigen in active tuberculosis

The purpose of the present study was to evaluate the clinical usefulness of detection of serum immunoglobulin A (IgA), IgG, and IgM antibodies raised against the mycobacterial A60 antigen for the diagnosis and discrimination of active tuberculosis (TB) from other pulmonary diseases. Three commercially available ELISA kits (IgA, IgG, and IgM) (ANDA Biologicals, Strasbourg, France) were evaluated simultaneously in 246 serum samples from 3 groups of patients: group I, 171 patients with active TB (128 pulmonary TB and 43 extrapulmonary TB); group II, 73 patients with pulmonary non-TB diseases; and group III, 2 leprosies patients. The sensitivities of tests ranged from 31.3% (IgA) to 94% (IgG) in pulmonary TB patients and from 21% (IgA) to 84% (IgG) in extrapulmonary TB patients. The specificities of assays varied from 92% (IgG) to 96% (IgA) in the pulmonary non-TB group. Combination of IgG with IgA and/or IgM does not improve its sensitivity. Clinical use of the A60-based serodiagnostic IgG assay is of great value for the rapid diagnosis and discrimination between active TB and pulmonary non-TB diseases. Moreover, this test could be used to increase diagnostic accuracy, especially for smear-negative TB cases, which are difficult to diagnose.

Clinical Evaluation of a Homemade Enzyme-Linked Immunospot Assay for the Diagnosis of Active Tuberculosis in China

The rapid diagnosis of smear-negative pulmonary tuberculosis (TB) and extrapulmonary TB is a significant problem in clinical practice. We evaluated the usefulness of a homemade enzyme-linked immunospot (ELISPOT) assay for the diagnosis of active TB in China. Seventy-eight healthy volunteers, 60 patients with active TB, and 32 patients with non-TB diseases were evaluated by tuberculin skin test (TST), an ELISPOT assay using a recombinant CFP-10/ESAT-6 fusion protein (rCFP-10/ESAT-6) as a stimulant, and T-SPOT-TB assay. The spot-forming cells (SFC) from 78 healthy subjects containing both PPD-positive and -negative persons was 3.7 ± 6.5. Among 31 diagnosed TB patients, the ELISPOT assay had a sensitivity of 67.7%, compared to a sensitivity of 77.4% for the T-SPOT-TB assay. The ELISPOT assay was more sensitive in smear-positive TB cases (76.9%) than in smear-negative TB cases (61.1%), while T-SPOT-TB had roughly similar sensitivities in smear-positive (76.9%) and smear-negative TB cases (77.8%). The specificity was 90.6% for ELISPOT and 78.1% for T-SPOT-TB among 32 subjects with non-TB diseases. The SFC of TB cases was significantly higher than that of non-TB disease cases, and the SFC of smear-positive TB cases was significantly higher than that of smear-negative TB cases (P < 0.01). We confirmed that the homemade ELISPOT assay appears more specific for the diagnosis of active TB than T-SPOT-TB. ELISPOT assay may be a useful method for the rapid diagnosis of active TB, especially for cases of smear-negative TB.

Pulmonary Tuberculosis and Drug Resistance in Dhaka Central Jail, the Largest Prison in Bangladesh

BackgroundThere are limited data on TB among prison inmates in Bangladesh. The aim of the study was to determine the prevalence of pulmonary tuberculosis (TB), its drug resistance and risk factors in Dhaka Central Jail, the largest prison in Bangladesh.MethodsCross sectional survey with, active screening of a total number of 11,001 inmates over a period of 2 years. Sputum samples from TB suspects were taken for acid- fast bacilli (AFB) microscopy, culture and drug susceptibility testing.ResultsAmong 1,781 TB suspects 245 (13.8%) were positive for AFB on microscopy and/or culture. The prevalence rate of sputum- positive pulmonary TB was 2,227/100,000. Fifty three cases (21.6% of 245 cases) were AFB- negative on microscopy but were found positive on culture. Resistance to isoniazid, rifampicin, streptomycin and ethambutol was 11.4%, 0.8%, 22.4% and 6.5% respectively. No multidrug resistance was observed. The main risk factors of TB in prison were exposure to TB patients (adjusted odds ratio 3.16, 95% CI 2.36–4.21), previous imprisonment (1.86, 1.38–2.50), longer duration of stay in prison (17.5 months for TB cases; 1.004, 1.001–1.006) and low body mass index which is less than 18.5 kg/m2 (5.37, 4.02–7.16).ConclusionsThe study results revealed a very high prevalence of TB in the prison population in Dhaka Central Jail. Entry examinations and active symptom screening among inmates are important to control TB transmission inside the prison. Identifying undiagnosed smear-negative TB cases remains a challenge to combat this deadly disease in this difficult setting.

Study on factors affecting TB/HIV co-infection in four counties of China

The factors affecting case detection of tuberculosis (TB)/human immunodeficiency virus (HIV) co-infection cases were explored in order to provide evidence-based formulation of a TB/HIV co-infection control strategy in China. Four counties with different modes of HIV transmission and varying cooperation mechanisms between TB and HIV institutions were selected. HIV test among TB patients and TB examination among people living with HIV/acquired immunodeficiency syndrome (AIDS) were conducted. Patients also completed questionnaires on potential factors affecting TB/HIV co-infection. The results showed that 19 (1.7%) were HIV-positive among 1089 cases of people living with active TB who received HIV testing. Conversely, there were 126 (10%) cases of active TB among 1255 cases of people living with HIV/AIDS. Among the newly discovered 145 cases of TB/HIV co-infection, AIDS institutions found 86.9% of these co-infections and 14.1% came from TB institutes. In different registration categories, there were 31 (21.4%) cases of smear positive TB, 104 (71.7%) cases of smear negative TB, and extrapulmonary cases accounted for 10 (6.9%). Gender, occupation, marital status, ethnic group, education, HIV transmission route, CD4 level, and type of TB susceptible symptoms had significant effects on whether HIV/AIDS patients were co-infected with TB disease (P < 0.01). Sex, age, ethnic group, occupation, and type of tuberculosis had no significant influence on whether TB patients had HIV infection. AIDS institutions could find more TB/HIV co-infection patients in comparison with TB institutions, particularly in patients with smear negative pulmonary tuberculosis and extrapulmonary tuberculosis. Therefore, a cooperation mechanism should be built up between TB and HIV control systems, and routine TB checks should be conducted for HIV/AIDS patients. In areas where sex or drug use is the major transmission mode of HIV infection, antiretroviral therapy should be expanded, treatment adherence should be improved and patients’ immunity level should be increased in order to decrease TB incidence. Cough and expectoration of more than two weeks, bloody sputum, and recurrent fevers could be revealing symptoms in TB screening of HIV/AIDS patients.

Clinical guidelines to diagnose smear‐negative pulmonary tuberculosis in Pakistan, a country with low‐HIV prevalence

To develop and validate clinical guidelines for diagnosis of smear-negative pulmonary tuberculosis (TB) in developing countries with low-HIV prevalence. We developed diagnostic guidelines for smear-negative TB. Clinical diagnoses based on these guidelines were compared with sputum culture, chest X-rays and reports of an expert panel. The guidelines achieved a sensitivity of 0.59 [confidence interval (CI) 0.46-0.66] and a specificity of 0.86 (CI 0.84-0.88) in diagnosing smear-negative TB. A total of 6.8% of patients who initially improved after a course of antibiotics were later confirmed to have TB. Clinicians detected an abnormal chest X-ray in 92% (CI 88-96%) and radiological signs of pulmonary TB in 98% (CI 94-100%) of cases. Our experience highlights a number of dilemmas faced in developing, testing and implementing diagnostic guidelines in poorly resourced conditions. Using radiological criteria for TB and appropriate training can help in improving the diagnostic skills of primary care clinicians working in low-HIV settings with access to X-ray facilities. But a significant number of apparently smear-negative TB cases may in fact be smear positive and TB programmes should focus on improving the quality of direct acid-fast bacilli microscopy. The value of an antibiotic trial is questionable due to the relatively large number of false negatives generated by this approach.

The first-three year report of the Tuberculosis Control Project, Lumbini, Rupandehi

The Tuberculosis Control Project, Lumbini, Rupandehi (TCPLR) is a bilateral cooperative venture between two NGO's, the Nepal Anti-Tuberculosis Association (NATA) and the Japan Anti-Tuberculosis Association (JATA), which consists of planning and implementing pilot tuberculosis control activities in Lumbini, Rupandehi district in Nepal, aiming at achieving high cure rate of newly detected smear-positive pulmonary tuberculosis patients before introducing DOTS strategies. Between December 1993 and July 1996, 349 tuberculosis (TB) cases were enrolled in the TCPLR. The categories of cases were as follows: 138 cases (40%) of new smear-positive pulmonary TB [new Sm(+) PTB], and 54 cases (15%) of smear positive pulmonary TB other than new Sm(+) PTB [other Sm(+) PTB] including such cases as continued treatment and relapse, 106 cases (30%) of new smear-negative TB [new Sm(-) TB], and 51 cases (15%) of other smear-negative TB other than New Sm(-) PTB [other Sm(-) TB]. The number and proportion of new Sm(+) PTB cases enrolled in the project have been increasing [6 cases (23%) for the first year, 102 cases (54%) for the third year] although the proportion is still low (40% overall). The regimens of chemotherapy in the initial intensive and the continuation phases of treatment according to the categories of TB were as follows: New Sm(+) PTB; 2HRZE(S)/6HE, other Sm(+) PTB; 2HRZES/1HRZE/5HRE, and Sm(-) TB; 2HRZ/6HE. The proportion of cases treated by the appropriate regimen of chemotherapy has increased. The cohort analysis of the treatment outcome of the cases enrolled in the project showed the following. The proportion of cured cases plus smear-unconfirmed cases completing treatment among new Sm(+) PTB was 74% overall, however, the proportion of defaulters increased in the third year. The proportion of cured cases plus smear-unconfirmed cases completing treatment among other Sm(+) PTB cases was 66% overall, which is slightly lower than that of new Sm(+) PTB cases, however, the difference was not so marked. The proportion of treatment completed cases among smear-negative pulmonary TB cases was 77% overall, however, proportion of defaulters increased in the third year. The treatment outcome in this report was obtained before the adoption of DOTS strategies: However, it showed that cure and treatment completion rates were comparable to those obtained in the SEARO countries which adopt DOTS strategies. The treatment outcome could be improved after the introduction of DOTS strategies in 1997.