Tracing Makerere University's 100 years' contribution to lung science/medicine.

Dear Editor, African Health Sciences Journal, This year, 2022, Makerere University will be celebrating 100 years of existence. As current lung science/medicine experts, we felt it as important to trace the University's contribution to lung science and medicine. In this letter, we trace and describe some of the early work done by Makerere University/Mulago Hospital affiliated scientists, identify prominent players in lung science over the 100 years, and present the university's scholarly contribution to this field, as available in online databases. We include both Makerere University and Mulago Hospital affiliated scientists, because for many years, staff of these two institutions have worked together in teaching, research and patient care.

Treatment Outcome of MDR/RR TB in a Resource-Constrained Setup: A Four-Year Retrospective Analysis.

Introduction: The emergence of drug resistance in TB treatment is a major public health threat. However, there are limited studies which are directed towards identifying factors that explain the gap in achieving treatment targets. Objective: : This study aimed to assess the treatment outcome and its associated factors among patients with MDR/RR-TB in Dilchora Hospital Treatment Initiation Center from January 2014 to December 2018. Method: : A retrospective cross-sectional study was conducted on patients with MDR/RR TB who initiated treatment between January 2014 and December 2018. Data were extracted from patient medical charts using a structured questionnaire. SPSS version 26 was used for analysis. Reports are presented using percentages and frequency. Independently associated factors for unfavorable outcome were identified using binary logistic regression model. Adjusted and crude odds ratio with 95% CI was used. P-value less than 0.05 was used to declare statistical significance. Result: : A total of 146 patients were included in this study. The overall prevalence of unfavorable outcomes in this study for those with known outcomes was 8.6%. People living with HIV had a 6.47 times (95% CI: 1.14-36.68) increased odds of death as compared to those who are HIV negative. For every 1kg/m2 increment in BMI, there was a 35.3% (AOR = 0.647; CI: 0.44-0.95) reduction in the odds of death as compared to those who had a 1kg/m2 lower BMI. Each additional month without culture conversion also increased the odds of death 2.24 times (95%CI: 1.08-4.66). Conclusion & Recommendation: : The findings of our study showed an appreciably low poor treatment outcome for this outpatient program. HIV screening and early initiation of HAART, early identification and treatment of those who are underweight and a critical follow-up to the time of sputum culture conversion could help in further improving the outcomes.

Patient perceptions of infectious illnesses preceding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

OBJECTIVES: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often reported to be caused by an infectious agent. However, it is unclear whether one infectious agent might be the cause or whether there might be many different infectious agents. The objective of this study was to identify self-reported infectious illnesses associated with the onset of ME/CFS. METHODS: The present study involved data from multiple sites in several countries. 1773 individuals diagnosed with either ME, CFS or ME/CFS provided qualitative data concerning infectious triggers which were coded and classified for analysis. RESULTS: 60.3% of patients report a variety of infectious illnesses some time before onset of ME/CFS. The most frequently reported infectious illness was Mononucleosis, which occurred in 30% of infections. However, over 100 other infectious illnesses were mentioned. DISCUSSION: The findings suggest that many infectious agents might be associated with the onset of ME/CFS.

Physical activity levels, exercise preferences, and exercise barriers in Korean children and adolescents after cancer treatment.

PURPOSE: The purpose of the current study was to explore physical activity (PA) levels, exercise preferences, and perceived barriers to PA in childhood cancer survivors. METHODS: This cross-sectional study surveyed 120 childhood cancer survivors aged 8-18 years from the pediatric oncology center in South Korea between March and August 2017. The modified Exercise & Quality of Life questionnaire, Korea Youth Risk Behavior Web-based Survey, and Godin Leisure-Time Questionnaire were used to assess PA levels, preferences, and exercise barriers. RESULTS: Among 120 participants (72 boys, 48 girls) whose average age at the time of the survey was 14.57 ± 3.00 years and the average age at diagnosis was 8.22 years, the three most common diagnoses were acute leukemia (43.3%), brain tumor (13.3%), and malignant lymphoma (10.8%). Only 16 participants (5%) met the PA recommendations for children (at least 60 min of moderate PA per day). The most preferred sporting activities included soccer, basketball, strengthening exercises, badminton, dance, and taekwondo. They generally had positive attitudes toward exercise, and more than 63% of participants intended to exercise the following month. The five most prevalent perceived barriers to exercise were lack of time, poor health, reluctance to sweat, lack of exercise skills, and no exercise partners. CONCLUSIONS: While most childhood cancer survivors did not meet the PA recommendation, most of them agreed that exercise was beneficial, and they intended to participate in the exercise. Exercise and PA programs should be tailored to the personal health and preferences of childhood cancer survivors.

Exercise participation, barriers, and preferences in Korean prostate cancer survivors.

Objective: To identify patterns of physical activity (PA) participation, exercise preference, and barriers of stage 2-3 prostate cancer survivors across cancer trajectories based on selected demographic and medical variables.Design: The current study is a descriptive cross-sectional study which included data from a total of 111 prostate cancer survivors, at Shinchon Severance Hospital, Seoul, Korea. The survey includes PA levels before and after prostate cancer diagnosis, exercise barriers, and preferences.Results: Moderate- to vigorous-intensity PA levels were significantly lower after cancer diagnosis (vigorous PA:41.9 ± 123.1 min/week vs. 4.6 ± 29.8 min/week, p < 0.001; moderate PA: 159.9 ± 240.0 min/week vs. 56.8 ± 129.7 min/week, p < .001) compared to their PA level before cancer diagnosis. Perceived exercise barriers were distinctly different according to participants' age and time since surgery. The two most prevalent exercise barriers among prostate cancer survivors <65 years were lack of time (28.6%) and poor health (26.5%), whereas the exercise barriers for prostate cancer survivors aged ≥65 years were lack of exercise facilities (21.4%) and lack of exercise information (17.9%). Furthermore, within 6 months after surgery, prostate cancer survivors perceived poor health (29.5%) and pain at the surgery site (29.5%) to be the two most prevalent exercise barriers. 6 months after surgery, prostate cancer survivors perceived lack of time (21.3%) and poor health (14.8%) to be the two most prevalent exercise barriers. Walking, pelvic floor and Kegel exercises were three most preferred exercises among prostate cancer survivors in our study, which uniquely differ according to time since surgery.Conclusion: This study showed significant reduction in PA levels among prostate cancer survivors and their perceived exercise barriers were distinct according to their age and time since surgery. Therefore, PA and exercise recommendation should be specific to their personal characteristics such as age and time since surgery.

Mortality and its predictors among patients treated for acute exacerbations of chronic obstructive respiratory diseases in Jimma Medical Center; Jimma, Ethiopia: Prospective observational study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma exacerbations are associated with ill health, increased mortality, and health care costs. However, there is limited evidence regarding mortality and its predictors among patients treated for COPD and asthma exacerbations in low-income nations, particularly in Ethiopia. METHODS: A-6 month prospective observational study was conducted from April 20-September 20, 2019. Data were collected on socio-demographic, baseline clinical characteristics and outcomes of asthma and COPD exacerbations. Data were entered into Epi-Data version 4.02.01 for cleaning and exported to STATA 14.0 for analysis. Kaplan-Meier (Log-rank test) was used to compare the baseline survival experience of the study participants and Cox proportional hazard regression analysis was conducted to determine the predictors of mortality. Adjusted hazard ratios (AHRs) with two-sided p-value <0.05 were considered statistically significant. RESULTS: A total of 130 patients (60% males) were included. The median (interquartile range (IQR)) age of the study participants was 59(50-70) years. The median (IQR) survival time to death was 17.5 (10-26) days. The total proportion of in-hospital mortality was 10.78% (14/130), and the incidence rate of mortality was 2.56 per 1000 person-years. The duration of oxygen therapy ≥16hours/day (AHR = 6.330, 95% CI [1.092-36.679], and old age (AHR = 1.066, 95% CI [1.0001-1.136] were the independent predictors of in-hospital mortality. CONCLUSION: In this study, the in-hospital mortality rate was very high. Moreover, prolonged oxygen therapy (≥16hours/day) and old age were independently associated with in-hospital mortality. Therefore, special attention should be given to recipients of prolonged oxygen therapy and the elderly during hospital stay.

Disseminated Coccidioidomycosis in Africa.

BACKGROUND: Coccidioidomycosis is an endemic disease in the Americas. No cases have been reported in Africa. PATIENT: A 23-year-old HIV seronegative Ugandan man was referred to Mulago National Referral Hospital in Kampala, Uganda with a 10-month history of haemoptysis and difficulty breathing, and a 6-month history of localized swellings on the extremities. He had associated weight loss and drenching sweats, but no fevers. He had taken anti-tuberculosis medicine for 2 months with no improvement. He had never travelled out of Uganda. On physical examination, he had cystic swellings and ulcerated lesions on the extremities. He had tachypnoea, crackles in the chest and mild hepatomegaly. Bronchoscopic examination showed two masses occluding the right main bronchus. Bronchoscopic biopsy showed findings consistent with coccidioidomycosis. The patient improved with antifungal treatment and was discharged. CONCLUSION: We report the first case of disseminated coccidioidomycosis with pulmonary and cutaneous manifestations in Africa. LEARNING POINTS: Coccidioidomycosis is an endemic disease in the Americas and may now be present in Africa.The patient had taken anti-tuberculosis medicine for 2 months with no improvement.Coccidioidomycosis should be considered in the differential diagnosis of tuberculosis.

Predictors and short-term outcomes of recurrent pulmonary tuberculosis, Uganda: a cohort study.

INTRODUCTION: Recurrent tuberculosis (TB) occurring >2 years after completing treatment for a prior TB episode is most often due to reinfection with a new strain of M. tuberculosis. OBJECTIVES: We determined the prevalence and outcome of late recurrent TB among hospitalized patients in Kampala, Uganda. METHODS: We conducted a retrospective analysis of patients admitted to Mulago Hospital who had cough of >2 weeks' duration and completed TB treatment >2 years prior to admission. All patients had mycobacterial culture performed on two sputum specimens and vital status ascertained 2-months post-enrollment. We performed modeling to identify predictors of recurrent TB and of survival. RESULTS: Among 234 patients, 84 (36%) had recurrent TB. Independent predictors included younger age (aOR=0.64, 95% CI=0.42-0.97, p=0.04), chest pain >2 weeks (aOR=3.32, 95% CI=1.38-8.02, p=0.007), severe weight loss ≥5 kilograms (aOR=4.88, 95% CI=1.66-14.29, p=0.004) and presence of ≥1 WHO danger sign of severe illness (aOR=3.55, 95% CI=1.36-9.29, p=0.01). Two-month mortality was 17.8% (95% CI=10.5-29.2%), and was higher among patients not initiated on TB treatment (aHR=16.67, 95% CI=1.18-200, p=0.04), not on ART if HIV-positive (aHR=16.99, 95% CI=1.17-246.47, p=0.04) and with a history of smoking (aHR=1.20, 95% CI=1.03-1.40, p=0.02). CONCLUSION: The high prevalence of late recurrent TB likely reflects high levels of TB transmission in Kampala. Increased use of empiric TB treatment and early ART treatment initiation if HIV-positive should be considered in patients with a prior history of TB, particularly if young, with weight loss ≥5kgs, chest pain >2 weeks or ≥1 WHO danger sign of severe illness.

The lung microbiome of Ugandan HIV-infected pneumonia patients is compositionally and functionally distinct from that of San Franciscan patients.

Sub-Saharan Africa represents 69% of the total number of individuals living with HIV infection worldwide and 72% of AIDS deaths globally. Pulmonary infection is a common and frequently fatal complication, though little is known regarding the lower airway microbiome composition of this population. Our objectives were to characterize the lower airway microbiome of Ugandan HIV-infected patients with pneumonia, to determine relationships with demographic, clinical, immunological, and microbiological variables and to compare the composition and predicted metagenome of these communities to a comparable cohort of patients in the US (San Francisco). Bronchoalveolar lavage samples from a cohort of 60 Ugandan HIV-infected patients with acute pneumonia were collected. Amplified 16S ribosomal RNA was profiled and aforementioned relationships examined. Ugandan airway microbiome composition and predicted metagenomic function were compared to US HIV-infected pneumonia patients. Among the most common bacterial pulmonary pathogens, Pseudomonas aeruginosa was most prevalent in the Ugandan cohort. Patients with a richer and more diverse airway microbiome exhibited lower bacterial burden, enrichment of members of the Lachnospiraceae and sulfur-reducing bacteria and reduced expression of TNF-alpha and matrix metalloproteinase-9. Compared to San Franciscan patients, Ugandan airway microbiome was significantly richer, and compositionally distinct with predicted metagenomes that encoded a multitude of distinct pathogenic pathways e.g secretion systems. Ugandan pneumonia-associated airway microbiome is compositionally and functionally distinct from those detected in comparable patients in developed countries, a feature which may contribute to adverse outcomes in this population.

Prevalence and outcomes of cryptococcal antigenemia in HIV-seropositive patients hospitalized for suspected tuberculosis in Uganda.

BACKGROUND: Cryptococcal infection occurs in HIV-seropositive patients and is associated with high mortality. However, limited information is available on the prevalence and outcomes of cryptococcal antigenemia among hospitalized HIV-seropositive patients in sub-Saharan Africa. OBJECTIVES: To determine the prevalence of and risk factors for cryptococcal antigenemia among HIV-seropositive patients presenting to Mulago Hospital (Kampala, Uganda) with unexplained cough ≥2 weeks and suspected tuberculosis (TB) and also to determine if antigenemia is associated with an increased mortality. METHODS: Between September 2009 and September 2010, we enrolled consecutive HIV-seropositive adults hospitalized at Mulago Hospital with cough ≥2 weeks and suspected TB. Banked serum was tested for cryptococcal antigen. We compared demographic and clinical characteristics, and 2-month mortality in patients with and without cryptococcal antigenemia. RESULTS: Of 563 HIV-seropositive patients, 32 (5.7%) were cryptococcal antigen (CrAg) positive. None had Cryptococcus neoformans detected on fungal culture of bronchoalveolar lavage fluid (n = 116). CrAg-positive patients had a lower median CD4 count compared with CrAg-negative patients (25 vs. 55 cells/µL, P = 0.02), and a substantial proportion of CrAg-positive patients also had concurrent TB (31%). A positive CrAg test was not associated with increased mortality during the 2-month follow-up period (hazard ratio: 0.99, 95% confidence interval: 0.63 to 1.54, P = 0.95) after adjusting for CD4 count and antiretroviral therapy use at enrollment and/or follow-up. CONCLUSIONS: Occult cryptococcal antigenemia occurs commonly among hospitalized HIV-seropositive patients with suspected TB. CrAg testing should be considered in hospitalized HIV-seropositive patients with CD4 count <50 cells/µL, coupled with longer follow-up to evaluate the diagnostic value of CrAg and therapeutic interventions in patients with asymptomatic cryptococcal antigenemia.

Low prevalence of Pneumocystis pneumonia (PCP) but high prevalence of pneumocystis dihydropteroate synthase (dhps) gene mutations in HIV-infected persons in Uganda.

Pneumocystis jirovecii pneumonia (PCP) is an important opportunistic infection in patients infected with HIV, but its burden is incompletely characterized in those areas of sub-Saharan Africa where HIV is prevalent. We explored the prevalence of both PCP in HIV-infected adults admitted with pneumonia to a tertiary-care hospital in Uganda and of putative P. jirovecii drug resistance by mutations in fungal dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr). In 129 consecutive patients with sputum smears negative for mycobacteria, 5 (3.9%) were diagnosed with PCP by microscopic examination of Giemsa-stained bronchoalveolar lavage fluid. Concordance was 100% between Giemsa stain and PCR (dhps and dhfr). PCP was more prevalent in patients newly-diagnosed with HIV (11.4%) than in patients with known HIV (1.1%; p = 0.007). Mortality at 2 months after discharge was 29% overall: 28% among PCP-negative patients, and 60% (3 of 5) among PCP-positive patients. In these 5 fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation. No non-synonymous dhfr mutations were detected. PCP is an important cause of pneumonia in patients newly-diagnosed with HIV in Uganda, is associated with high mortality, and putative molecular evidence of drug resistance is prevalent. Given the reliability of field diagnosis in our cohort, future studies in sub-Saharan Africa can investigate the clinical impact of these genotypes.

Bronchoalveolar lavage enzyme-linked immunospot for diagnosis of smear-negative tuberculosis in HIV-infected patients.

BACKGROUND: Peripheral blood interferon-gamma release assays (IGRAs) have sub-optimal sensitivity and specificity for diagnosis of active pulmonary tuberculosis (TB). However, assessment of local immune responses has been reported to improve the accuracy of TB diagnosis. METHODS: We enrolled HIV-infected adults with cough ≥2 weeks' duration admitted to Mulago Hospital in Kampala, Uganda and referred for bronchoscopy following two negative sputum acid-fast bacillus smears. We performed an ELISPOT-based IGRA (T-SPOT.TB®, Oxford Immunotec, Oxford, UK) using peripheral blood and bronchoalveolar lavage (BAL) fluid mononuclear cells, and determined the accuracy of IGRAs using mycobacterial culture results as a reference standard. RESULTS: 94 HIV-infected patients with paired peripheral blood and BAL IGRA results were included. The study population was young (median age 34 years [IQR 28-40 years]) and had advanced HIV/AIDS (median CD4+ T-lymphocyte count 60 cells/µl [IQR 22-200 cells/µl]). The proportion of indeterminate IGRA results was higher in BAL fluid than in peripheral blood specimens (34% vs. 14%, difference 20%, 95% CI 7-33%, p = 0.002). BAL IGRA had moderate sensitivity (73%, 95% CI 50-89%) but poor specificity (48%, 95% CI 32-64%) for TB diagnosis. Sensitivity was similar (75%, 95% CI 57-89%) and specificity was higher (78%, 95% CI 63-88%) when IGRA was performed on peripheral blood. CONCLUSIONS: BAL IGRA performed poorly for the diagnosis of smear-negative TB in a high HIV/TB burden setting. Further studies are needed to examine reasons for the large proportion of indeterminate results and low specificity of BAL IGRA for active TB in high HIV/TB burden settings.

Acute hypoglycemia causes depressive-like behaviors in mice.

Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia. Mice were fasted for 12 hours and then administered intraperitoneal insulin to induce a blood glucose nadir of 50 mg/dL at 0.75 hour after injection that by 2 hours postinjection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference, and novel object recognition were subsequently examined. Mice made hypoglycemic showed depressive-like behaviors 24 hours after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 hours after its resolution. By 48 hours posthypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST, as did the antiadrenergic agents phentolamine, metoprolol, and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 hours postadministration that subsequently resolved by 48 hours. These data indicate that, in mice, acute hypoglycemia through adrenergic pathways caused depressive-like behaviors that exist well beyond the resolution of hypoglycemia.

Low prevalence of Pneumocystis jirovecii lung colonization in Ugandan HIV-infected patients hospitalized with non-Pneumocystis pneumonia.

Pneumocystis jirovecii is an important opportunistic infection in human immunodeficiency virus (HIV)-infected patients. In the developed world, P. jirovecii epidemiology is marked by frequent colonization in immunosuppressed patients, but data on the prevalence of colonization are very limited in sub-Saharan Africa, where the majority of persons living with HIV reside. Our objective was to describe the epidemiology of P. jirovecii colonization among HIV-positive patients in a cross-sectional, hospital-based study of patients admitted with suspected pneumonia in Kampala, Uganda. P. jirovecii was detectable in bronchoalveolar lavage fluid from 7 (6%) of 124 consecutive patients with non-Pneumocystis pneumonia. Colonization was not associated with patient demographic or clinical information. This prevalence is substantially lower than in published studies in the developed world and suggests that there is a limited reservoir of organisms for clinical infections in this Ugandan population. These findings may partially explain the low incidence of Pneumocystis pneumonia in Uganda and other sub-Saharan African countries.

The role of speciation in positive Lowenstein-Jensen culture isolates from a high tuberculosis burden country.

OBJECTIVE: To determine the need for routine speciation of positive Lowenstein-Jensen mycobacterial cultures in HIV-infected patients suspected of having pulmonary tuberculosis at Mulago Hospital in Kampala, Uganda. METHODS: Sputum and bronchoalveolar lavage Lowenstein-Jensen mycobacterial culture isolates from consecutive, HIV-infected patients admitted to Mulago Hospital with 2 weeks or more of cough were subjected to IS6110 PCR and rpoB genetic analysis to determine the presence of Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM). RESULTS: Eighty (100%) mycobacterial cultures from 65 patients were confirmed to be members of MTBC. Subsequent analysis of the cultures from 54 patients by PCR and sequence analyses to identify co-infection with NTM confirmed the presence of MTBC as well as the presence of Micrococcus luteus (n = 4), Janibacter spp. (n = 1) and six cultures had organisms that could not be identified. CONCLUSIONS: Presumptive diagnosis of tuberculosis on the basis of a positive Lowenstein-Jensen culture is sufficient in HIV-infected Ugandans suspected of having tuberculosis. Routine molecular confirmation of positive Lowenstein-Jensen cultures is unnecessary in this low resource setting.

Clinical significance of normal chest radiographs among HIV-seropositive patients with suspected tuberculosis in Uganda.

BACKGROUND AND OBJECTIVE: The frequency, aetiologies and outcomes of normal chest radiographs (CXRs) among HIV-seropositive patients with suspected pulmonary tuberculosis (TB) have been infrequently described. METHODS: Consecutive HIV-seropositive adults hospitalized for cough of ≥2 weeks duration at Mulago Hospital (Kampala, Uganda), between September 2007 and July 2008, were enrolled. Baseline CXRs were obtained on admission. Patients with sputum smears that were negative for acid-fast bacilli (AFB) were referred for bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid was examined for mycobacteria, Pneumocystis jirovecii and other fungi. Patients were followed for 2 months after enrolment. RESULTS: Of the 334 patients, 54 (16%) had normal CXRs. These patients were younger (median age 30 vs 34 years, P = 0.002), had lower counts of CD4+ T lymphocytes (median 13 vs 57 cells/µL, P < 0.001), and were less likely to be smear positive for AFB (17% vs 39%, P = 0.002) than those with abnormal CXRs. Pulmonary TB was the most frequent diagnosis (44%) among those with normal CXRs, followed by unknown diagnoses, pulmonary aspergillosis and pulmonary cryptococcosis. The frequency of normal CXRs was 12% among pulmonary TB patients. There was a trend towards increased 2-month mortality among patients with normal CXRs compared to those with abnormal CXRs (40% vs 29%, P = 0.15). CONCLUSIONS: Normal CXR findings were common among HIV-seropositive patients with suspected TB, especially those who were young, those with low CD4+ T cell counts and those with sputum smears that were negative for AFB. Mortality was high among those with normal CXRs. Normal CXR findings should not preclude further diagnostic evaluation in this population.

Integrated strategies to optimize sputum smear microscopy: a prospective observational study.

RATIONALE: Smear-positive tuberculosis (TB) case detection rates are far below targets in most low-income countries. The standard approach to smear microscopy involves sputum collection over multiple days and examination of sputum smears by light microscopy (LM), an insensitive and time-consuming technique. OBJECTIVE: To determine whether two alternative approaches can increase smear-positive case detection by increasing the efficiency (single-specimen microscopy) or sensitivity (light-emitting diode [LED] fluorescence microscopy [FM]) of TB suspect evaluation. METHODS: We enrolled patients with cough of 2 weeks or more admitted to Mulago Hospital in Kampala, Uganda and collected spot and early morning sputum specimens. We compared the diagnostic accuracy of four prespecified strategies based on the number of sputum specimens collected (one specimen versus two specimens) and the type of microscopy (LM versus LED FM) using mycobacterial culture as a reference standard. MEASUREMENTS AND MAIN RESULTS: Two hundred thirty-three of 464 (50%) patients had culture-positive TB. There was no difference in sensitivity between single-specimen and two-specimen strategies when smears were examined with LM (55 vs. 56%; difference, -1%; 95% confidence interval [CI], -5 to +2%) or LED FM (61 vs. 64%; difference, -3%; 95% CI, -7 to +1%). LED FM was more sensitive than LM with both the single-specimen (61 vs. 55%; difference, 6%; 95% CI, 2-10%) and two-specimen strategies (64 vs. 56%; difference, 8%; 95% CI, 3-12%). Findings were similar among the HIV-infected patient subset (n = 321 patients). CONCLUSIONS: In low-income, high TB burden settings, single-specimen microscopy and LED FM, either alone or in combination, could considerably increase identification of smear-positive TB cases.

Causes of early mortality in HIV-infected TB suspects in an East African referral hospital.

BACKGROUND: Respiratory infections are a leading cause of death in Africa, especially among HIV-infected patients. Data on the etiology of fatal respiratory diseases are largely based on autopsy studies. We evaluated causes of pneumonia associated with early mortality among hospitalized HIV-infected patients in Kampala, Uganda. METHODS: Prospective cohort study of HIV-infected patients admitted to Mulago Hospital, Kampala, with at least 2 weeks of cough. Consecutively enrolled patients with negative Ziehl Neelsen sputum smears for acid-fast bacilli underwent bronchoscopy with bronchoalveolar lavage and examination for mycobacteria (smear, solid culture), Pneumocystis jirovecii (Giemsa stain), and fungi (KOH mount, India ink stain, Sabouraud culture). Early mortality was defined as death before the 2-month follow-up visit. RESULTS: Follow-up data were available for 353 (87%) of 407 patients enrolled. Of participants with follow-up data, 112 (32%) died within 2 months. Among patients with early mortality, a diagnosis was confirmed in 74 (66%), including tuberculosis (TB) (56%), cryptococcal pneumonia (1%), Pneumocystis pneumonia (3%), pulmonary Kaposi sarcoma (4%), and pneumonia caused by 2 or more disease processes (3%). CONCLUSIONS: Mortality in HIV-infected TB suspects is high, with TB associated with the largest proportion of deaths. A significant proportion of patients die without a confirmed diagnosis.

Clinical and radiographic factors do not accurately diagnose smear-negative tuberculosis in HIV-infected inpatients in Uganda: a cross-sectional study.

BACKGROUND: Although World Health Organization guidelines recommend clinical judgment and chest radiography for diagnosing tuberculosis in HIV-infected adults with unexplained cough and negative sputum smears for acid-fast bacilli, the diagnostic performance of this approach is unknown. Therefore, we sought to assess the accuracy of symptoms, physical signs, and radiographic findings for diagnosing tuberculosis in this population in a low-income country with a high incidence of tuberculosis. METHODOLOGY: We performed a cross-sectional study enrolling consecutive HIV-infected inpatients with unexplained cough and negative sputum smears for acid-fast bacilli at Mulago Hospital in Kampala, Uganda. Trained medical officers prospectively collected data on standard symptoms and signs of systemic respiratory illness, and two radiologists interpreted chest radiographs in a standardized fashion. We calculated positive- and negative-likelihood ratios of these factors for diagnosing pulmonary tuberculosis (defined when mycobacterial cultures of sputum or bronchoalveolar lavage fluid were positive). We used both conventional and novel regression techniques to develop multivariable prediction models for pulmonary tuberculosis. PRINCIPAL FINDINGS: Among 202 enrolled HIV-infected adults with negative sputum smears for acid-fast bacilli, 72 (36%) had culture-positive pulmonary tuberculosis. No single factor, including respiratory symptoms, physical findings, CD4+ T-cell count, or chest radiographic abnormalities, substantially increased or decreased the likelihood of pulmonary tuberculosis. After exhaustive testing, we were also unable to identify any combination of factors which reliably predicted bacteriologically confirmed tuberculosis. CONCLUSIONS AND SIGNIFICANCE: Clinical and radiographic criteria did not help diagnose smear-negative pulmonary tuberculosis among HIV-infected patients with unexplained cough in a low-income setting. Enhanced diagnostic methods for smear-negative tuberculosis are urgently needed.

Role of interferon-gamma release assays in the diagnosis of pulmonary tuberculosis in patients with advanced HIV infection.

BACKGROUND: T-cell interferon-gamma release assays (IGRAs) may have a role in the diagnosis of active tuberculosis when evaluating patients for whom standard microbiology has limited sensitivity. Our objective was to examine the accuracy of a commercial IGRA for diagnosis of active tuberculosis in HIV-infected persons. METHODS: We enrolled HIV-infected patients admitted to Mulago Hospital in Kampala, Uganda with cough > or = 2 weeks. All patients underwent standard medical evaluation. We collected peripheral blood specimens at enrollment and performed a commercial, ELISPOT-based IGRA according to the manufacturer's recommendations. IGRA sensitivity and specificity were determined using mycobacterial culture results as the reference standard. RESULTS: Overall, 236 patients were enrolled. The median CD4+ T-lymphocyte count was 49 cells/microl and 126 (53%) patients were diagnosed with active pulmonary tuberculosis. IGRAs were not performed in 24 (10%) patients due to insufficient mononuclear cell counts. In the remaining 212 patients, results were indeterminate in 54 (25%). IGRAs were positive in 95 of 158 (60%) patients with interpretable results. The proportion of positive test results was similar across CD4+ count strata. IGRA sensitivity was 73% and specificity 54%. IGRA results did not meaningfully alter the probability of active tuberculosis in patients with negative sputum smears. CONCLUSIONS: An ELISPOT-based IGRA detected a high prevalence of latent tuberculosis infection in a hospitalized population of tuberculosis suspects with advanced HIV/AIDS but had limited utility for diagnosis of active tuberculosis in a high prevalence setting. Further research is needed to identify stronger and more specific immune responses in patients with active tuberculosis.