W. Githui

Autopsy study of HIV-1-positive and HIV-1-negative adult medical patients in Nairobi, Kenya

Summary: HIV infection has now been consistently identified as the major cause of death in young Africans in both urban and rural areas. In Africa, several studies have defined the clinical presentation of HIV disease but there have only been a limited number of autopsy studies. Because of the scarcity of autopsy data and the possibility of differing type and frequency of opportunistic infections between different geographic locations we set out to study consecutive new adult medical admissions to a tertiary referral hospital in Nairobi and perform autopsies on a sample of HIV‐1positive and HIV‐1‐negative patients who died in the hospital ward. Basic demographic data were collected on all patients admitted to two acute medical wards over an 11‐month period. Final outcome and final clinical diagnoses were recorded at discharge or death. An autopsy examination was requested if the patient died in the ward. Autopsy examination was performed in 75 HIV‐1‐positive (40 men, 35 women) and 47 HIV‐1‐negative (28 men, 19 women) adults who died in the hospital. This represented 48.4% of all HIV‐1‐positive deaths and 33.3% of all HIV‐1‐negative deaths. Tuberculosis (TB) and bacterial and interstitial bronchopneumonia accounted for 96% of the major pathology in patients found to be HIV‐1‐positive at autopsy. TB was present in half the HIV‐1‐positive autopsy patients and was disseminated in over 80% of cases. Meningeal involvement was present in 26% of those with disseminated TB. By contrast, TB was much less common in the HIV‐1‐negative patients at autopsy in whom bacterial bronchopneumonia and malignancies were the most common pathologies. The type pathology found in the HIV‐1‐positive autopsy patients was not different than that found in other areas in Africa so far studied.

Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: Results of a randomized controlled trial

Objectives: To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV‐1‐infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV‐1‐infected adults. Design and setting: Randomized, double‐blind, placebo‐controlled trial in Nairobi, Kenya. Subjects: Six hundred and eighty‐four HIV‐1‐infected adults. Main outcome measures: Development of tuberculosis and death. Results: Three hundred and forty‐two subjects received isoniazid and 342 received placebo. The median CD4 lymphocyte counts at enrolment were 322 and 346 × 106/l in the isoniazid and placebo groups, respectively. The overall median follow‐up from enrolment was 1.83 years (range, 0–3.4 years). The incidence of tuberculosis in the isoniazid group was 4.29 per 100 person‐years (PY) of observation [95% confidence interval (CI) 2.78–6.33] and 3.86 per 100 PY of observation (95% CI, 2.45–5.79) in the placebo group, giving an adjusted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49–1.71). The adjusted rate ratio for tuberculosis for isoniazid versus placebo for tuberculin skin test (TST)‐positive subjects was 0.60 (95% CI, 0.23–1.60) and for the TST‐negative subjects, 1.23 (95% CI, 0.55–2.76). The overall adjusted mortality rate ratio for isoniazid versus placebo was 1.18 (95% CI, 0.79–1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST‐positive of 0.33 (95% CI, 0.09–1.23) and for TST‐negative subjects, 1.39 (95% CI, 0.90–2.12). Conclusions: Overall there was no statistically significant protective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST‐positive subjects, where reactivation is likely to be the more important pathogenetic mechanism, there was some protection and some reduction in mortality, although this was not statistically significant. The small number of individuals in this subgroup made the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rapid progression to disease or insufficient duration of isoniazid in subjects with relatively advanced immunosuppression. The rate of drug resistance observed in subjects who received isoniazid and subsequently developed tuberculosis was low.

Increased recurrence of tuberculosis in HIV-1-infected patients in Kenya

There is evidence that in human immunodeficiency virus 1 (HIV-1) infected patients with tuberculosis the rate of recurrence of tuberculosis is increased in those patients treated with a standard thiacetazone-containing regimen. To assess the impact of HIV-1 on tuberculosis in Kenya, patients with tuberculosis were studied prospectively. After treatment with either a standard thiacetazone plus isoniazid regimen or a short-course thiacetazone-containing regimen, overall recurrence rate of tuberculosis was 34 times greater in 58 HIV-1-positive patients than in 138 HIV-1-negative patients (adjusted rate ratio 33.8, 95% CI 4.3-264). Recurrence in the HIV-1-positive group was strongly associated with a cutaneous hypersensitivity reaction due to thiacetazone during initial treatment (rate ratio 13.2, 95% CI 3.1-56.2). In all patients with a cutaneous hypersensitivity reaction ethambutol was substituted for thiacetazone. No significant association was found between recurrence among HIV-1-positive patients and initial resistance, initial treatment regimen, a diagnosis of AIDS (WHO definition), or poor compliance. DNA fingerprinting suggested that both relapse and new infection may have produced recurrence of tuberculosis. In patients who had a cutaneous hypersensitivity reaction, increased recurrence rate may have been related to interruption of treatment, subsequent poor compliance, or more advanced immunosuppression. Alternatively, a change to the combination of ethambutol and isoniazid in the continuation phase for 11 months only may not be adequate.

Comparison of PCR with the Routine Procedure for Diagnosis of Tuberculosis in a Population with High Prevalences of Tuberculosis and Human Immunodeficiency Virus

ABSTRACT Direct smear examination with Ziehl-Neelsen (ZN) staining for the diagnosis of tuberculosis (TB) as employed in most low-income countries is cheap and easy to use, but its low sensitivity is a major drawback. The low specificity of chest X-rays, used for the diagnosis of smear-negative TB, risks high levels of overdiagnosis. Major advances in molecular techniques, which rapidly identify mycobacterial DNA in sputa, may overcome these obstacles. In this study, the AMPLICOR PCR system was used to diagnose pulmonary TB in a developing country with high prevalences of both TB and human immunodeficiency virus (HIV). The sensitivity and specificity of this technique were compared to those of the usual diagnostic techniques. Sputum specimens were collected from 1,396 TB suspects attending the Rhodes Chest Clinic, Nairobi, Kenya. The specimens were analyzed for the presence of Mycobacterium tuberculosis by PCR; culture on Löwenstein-Jensen medium was used as the “gold standard.” All culture-positive samples were genotyped to identify the mycobacterial species. The sensitivity and specificity of PCR were 93 and 84%, respectively. HIV status did not affect the sensitivity of PCR. A total of 99.7% of the true smear-positive and 82.1% of the true smear-negative TB patients were correctly identified by PCR. PCR detected M. tuberculosis in 11.7% of the culture-negative suspects, 60% of which had one or two PCR-positive sputum specimens. Of the 490 positive cultures, 486 were identified as M. tuberculosis. The high sensitivity of Amplicor PCR merits usage in a clinical setting with high TB and HIV burdens. Thus, PCR can be considered as an alternative to ZN staining in combination with chest X-ray for diagnosis of TB; however, cost-effectiveness studies and operational studies are required to support an evidence-based decision of introducing PCR for TB control in high-burden environments.

The effect of human immunodeficiency virus type-1 on the infectiousness of tuberculosis

SETTING Developing country tertiary referral hospital plus catchment community. OBJECTIVE To determine the infectiousness of culture-confirmed pulmonary tuberculosis in patients infected with Human Immunodeficiency Virus type-1 (HIV-1). DESIGN Comparison of the incidence of tuberculosis and the prevalence of tuberculin skin test positivity among the household contacts of both HIV-1 positive and negative cases with pulmonary tuberculosis. RESULTS Of 255 contacts of HIV-1 negative index cases, 2 were HIV-1 positive and of 102 contacts of HIV-1 positive index cases, 14 were HIV-1 positive (odds ratio (OR) = 20.0 95% Confidence Interval (CI) 4.4-193). 21 cases of tuberculosis were diagnosed among contacts, of whom 3 were HIV-1 positive. The overall unadjusted OR for tuberculosis among contacts of HIV-1 positive index cases was 1.6 (95% CI 0.6-4.3) compared to contacts of HIV-1 negative index cases. Amongst HIV-1 negative contacts alone the OR was 1.5 (95% CI 0.4-4.4). In this group the best predictors of tuberculosis among contacts were female sex of the index case (OR = 3.4 95% CI 1.1-12), sharing the same bed as the index case (OR = 2.6 95% CI 0.9-7.4), and contacts age less than 5 years (OR = 3.3 95% CI 1.1-9.5). HIV-1 positive contacts were more likely to develop tuberculosis than HIV-1 negative contacts (OR = 4.1 95% CI 0.7-17). Tuberculin skin test positivity rates were the same among the HIV-1 negative contacts of HIV-1 positive and negative index cases (OR = 1.1 CI 0.7-1.6). CONCLUSIONS HIV-1 associated pulmonary tuberculosis is not more infectious than tuberculosis alone. The presence of HIV-1 in a community does not mandate a change in the management of contacts of patients with pulmonary tuberculosis.

Cohort study of HIV-positive and HIV-negative tuberculosis, Nairobi, Kenya: comparison of bacteriological results

We have set up a cohort of human immunodeficiency virus (HIV) positive and negative patients with tuberculosis in order to address the problems associated with HIV-related tuberculosis. We present here the results of sputum smear microscopy, culture, mycobacterial identification tests and drug susceptibility assays from specimens taken at presentation. In this selected population of largely pulmonary tuberculosis cases, HIV infection is not associated with significant differences in sputum smear positivity rate, culture positivity rate or initial drug resistance. No atypical mycobacteria were found. Direct sputum smear examination remains specific for the diagnosis of tuberculosis in Kenya in spite of the presence of HIV. HIV infection was not associated with an increase in the proportion of pulmonary cases still culture-positive at 6 months. However a significant increase in the proportion of cases still culture-positive at 6 months was seen in those with initially resistant strains and also in those treated with standard regimen (streptomycin, thiacetazone and isoniazid for 1 month followed by thiacetazone and isoniazid for 11 months, 1STH/11TH) rather than a short-course, rifampicin-containing regimen (rifampicin, pyrazinamide and isoniazid for 2 months, together with streptomycin for the first month and followed by 6 months of thiacetazone and isoniazid, SHRZ/6TH).

High Prevalence of Pulmonary Tuberculosis and Inadequate Case Finding in Rural Western Kenya

RATIONALE Limited information exists on the prevalence of tuberculosis and adequacy of case finding in African populations with high rates of HIV. OBJECTIVES To estimate the prevalence of bacteriologically confirmed pulmonary tuberculosis (PTB) and the fraction attributable to HIV, and to evaluate case detection. METHODS Residents aged 15 years and older, from 40 randomly sampled clusters, provided two sputum samples for microscopy; those with chest radiograph abnormalities or symptoms suggestive of PTB provided one additional sputum sample for culture. MEASUREMENTS AND MAIN RESULTS PTB was defined by a culture positive for Mycobacterium tuberculosis or two positive smears. Persons with PTB were offered HIV testing and interviewed on care-seeking behavior. We estimated the population-attributable fraction of HIV on prevalent and notified PTB, the patient diagnostic rate, and case detection rate using provincial TB notification data. Among 20,566 participants, 123 had PTB. TB prevalence was 6.0/1,000 (95% confidence interval, 4.6-7.4) for all PTB and 2.5/1,000 (1.6-3.4) for smear-positive PTB. Of 101 prevalent TB cases tested, 52 (51%) were HIV infected, and 58 (64%) of 91 cases who were not on treatment and were interviewed had not sought care. Forty-eight percent of prevalent and 65% of notified PTB cases were attributable to HIV. For smear-positive and smear-negative PTB combined, the patient diagnostic rate was 1.4 cases detected per person-year among HIV-infected persons having PTB and 0.6 for those who were HIV uninfected, corresponding to case detection rates of 56 and 65%, respectively. CONCLUSIONS Undiagnosed PTB is common in this community. TB case finding needs improvement, for instance through intensified case finding with mobile smear microscopy services, rigorous HIV testing, and improved diagnosis of smear-negative TB.

Screening Strategies for Tuberculosis Prevalence Surveys: The Value of Chest Radiography and Symptoms

Background We conducted a tuberculosis (TB) prevalence survey and evaluated the screening methods used in our survey, to assess if screening in TB prevalence surveys could be simplified, and to assess the accuracy of screening algorithms that may be applicable for active case finding. Methods All participants with a positive screen on either a symptom questionnaire, chest radiography (CXR) and/or sputum smear microscopy submitted sputum for culture. HIV status was obtained from prevalent cases. We estimated the accuracy of modified screening strategies with bacteriologically confirmed TB as the gold standard, and compared these with other survey reports. We also assessed whether sequential rather than parallel application of symptom, CXR and HIV screening would substantially reduce the number of participants requiring CXR and/or sputum culture. Results Presence of any abnormality on CXR had 94% (95%CI 88–98) sensitivity (92% in HIV-infected and 100% in HIV-uninfected) and 73% (95%CI 68–77) specificity. Symptom screening combinations had significantly lower sensitivity than CXR except for ‘any TB symptom’ which had 90% (95%CI 84–95) sensitivity (96% in HIV-infected and 82% in HIV-uninfected) and 32% (95%CI 30–34) specificity. Smear microscopy did not yield additional suspects, thus the combined symptom/CXR screen applied in the survey had 100% (95%CI 97–100) sensitivity. Specificity was 65% (95%CI 61–68). Sequential application of first a symptom screen for ‘any symptom’, followed by CXR-evaluation and different suspect criteria depending on HIV status would result in the largest reduction of the need for CXR and sputum culture, approximately 36%, but would underestimate prevalence by 11%. Conclusion CXR screening alone had higher accuracy compared to symptom screening alone. Combined CXR and symptom screening had the highest sensitivity and remains important for suspect identification in TB prevalence surveys in settings where bacteriological sputum examination of all participants is not feasible.

Bleach Sedimentation: An Opportunity to Optimize Smear Microscopy for Tuberculosis Diagnosis in Settings of High Prevalence of HIV

BACKGROUND The purpose of the study was to evaluate the performance and feasibility of tuberculosis diagnosis by sputum microscopy after bleach sedimentation, compared with by conventional direct smear microscopy, in a setting of high prevalence of HIV. METHODS In a community-based study in Kenya (a population in which 50% of individuals with tuberculosis are infected with HIV), individuals with suspected pulmonary tuberculosis submitted 3 sputum specimens during 2 consecutive days, which were examined by blind evaluation. Ziehl-Neelsen-stained smears were made of fresh specimens and of specimens that were processed with 3.5% household bleach followed by overnight sedimentation. Two different cutoffs for acid-fast bacilli (AFB) per 100 high-power fields (HPF) were used to define a positive smear: >10 AFB/100 HPF and 1 AFB/100 HPF. Four smear-positive case definitions, based on 1 or 2 positive smears with the 1 AFB or 10 AFB cutoff, were used. RESULTS Of 1879 specimens from 644 patients, 363 (19.3%) and 460 (24.5%) were positive by bleach sedimentation microscopy, compared with 301 (16.0%) and 374 (19.9%) by direct smear microscopy, with use of the 10 AFB/100 HPF (P < .001) and 1 AFB/100 HPF (P < .001) cutoffs, respectively. Regardless of the case definition used, bleach sedimentation microscopy detected significantly more positive cases than did direct smear microscopy: 26.7% (172 of 644) versus 21.7% (140 of 644), respectively, with the case definition of 1 positive smear and the 1 AFB/100 HPF cutoff (P < .001), and 21.4% (138 of 644) versus 18.6% (120 of 644), respectively, with the case definition of 1 positive smear and the 10 AFB/100 HPF cutoff (P < .001). Inter- and intrareader reproducibility were favorable, with kappa coefficients of 0.83 and 0.91, respectively. Bleach sedimentation was relatively inexpensive and was not time consuming. CONCLUSIONS Bleach sedimentation microscopy is an effective, simple method to improve the yield of smear microscopy in a setting of high prevalence of HIV. Further evaluation of this method, under operational conditions, is urgently needed to determine its potential as a tool for tuberculosis control.

Autopsy findings in HIV-1-infected adults in Kenya.

To determine the major pathology in HIV-1-infected adults dying in hospital in Kenya autopsy examinations were performed on consecutive HIV-1-infected adults who were subjects in an isoniazid preventive therapy study and who died in hospital between January and October 1995. All subjects were confirmed to be HIV-1 infected antemortem on at least two immunoassays. Complete autopsies were performed within 3 days of death on four male and five female subjects of mean age 36 years. The median CD4 count within 6 months of death was 63 with a range of 10-370. Six subjects had received isoniazid 300 mg daily as prophylaxis for 6 months. Tuberculosis (TB) was found in three of the nine patients disseminated in two cases. That TB was difficult to diagnose antemortem points to the need to remain vigilant for TB in the immunosuppressed patient with fever who is not responding to broad spectrum antibiotics. The following major pathology was also observed: bacterial bronchopneumonia PCP CMV pneumonitis Klebsiella pneumoniae septicemia nonspecific interstitial pneumonitis non-typhi Salmonella septicemia pulmonary TB and cryptococcal pneumonitis.