Browsing by Author "Huang, Laurence"
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Item Accuracy of the tuberculosis molecular bacterial load assay to diagnose and monitor response to anti-tuberculosis therapy: a longitudinal comparative study with standard-of-care smear microscopy, Xpert MTB/RIF Ultra, and culture in Uganda(Elsevier Ltd, 2024-03) Musisi, Emmanuel; Wamutu, Samuel; Ssengooba, Willy; Kasiinga, Sharifah; Sessolo, Abdulwahab; Sanyu, Ingvar; Kaswabuli, Sylvia; Zawedde, Josephine; Byanyima, Patrick; Kia, Praiscillia; Muwambi, William; Toskin, Divine Tracy; Kigozi, Edgar; Walbaum, Natasha; Dombay, Evelin; Legrady, Mate Bonifac; Ssemambo, Kizza David-Martin; Joloba, Moses; Kuchaka, Davis; Worodria, William; Huang, Laurence; Gillespie, Stephen H; Sabiiti, WilberAbstract In 2018, the tuberculosis molecular bacterial load assay (TB-MBLA), a ribosomal RNA-based test, was acknowledged by WHO as a molecular assay that could replace smear microscopy and culture for monitoring tuberculosis treatment response. In this study, we evaluated the accuracy of TB-MBLA for diagnosis and monitoring of treatment response in comparison with standard-of-care tests. For this longitudinal prospective study, patients aged 18 years or older with presumptive tuberculosis (coughing for at least 2 weeks, night sweats, and weight loss) were enrolled at China-Uganda Friendship Hospital Naguru (Kampala, Uganda). Participants were evaluated for tuberculosis by TB-MBLA in comparison with Xpert MTB/RIF Ultra (Xpert-Ultra) and smear microscopy, with Mycobacteria Growth Indicator Tube (MGIT) culture as a reference test. Participants who were positive on Xpert-Ultra were enrolled on a standard 6-month anti-tuberculosis regimen, and monitored for treatment response at weeks 2, 8, 17, and 26 after initiation of treatment and then 3 months after treatment. Between Nov 15, 2019, and June 15, 2022, 210 participants (median age 35 years [IQR 27–44]) were enrolled. 135 (64%) participants were male and 72 (34%) were HIV positive. The pretreatment diagnostic sensitivities of TB-MBLA and Xpert-Ultra were similar (both 99% [95% CI 95–100]) but the specificity was higher for TB-MBLA (90% [83–96]) than for Xpert-Ultra (78% [68–86]). Ten participants were Xpert-Ultra trace positive, eight (80%) of whom were negative by TB-MBLA and MGIT culture. Smear microscopy had lower diagnostic sensitivity (75% [65–83]) but higher specificity (98% [93–100]) than TB-MBLA and Xpert-Ultra. Among participants who were smear microscopy negative, the sensitivity of TB-MBLA was 96% (95 CI 80–100) and was 100% (95% CI 86–100) in those who were HIV positive. 129 (61%) participants were identified as tuberculosis positive by Xpert-Ultra and these individuals were enrolled in the treatment group and monitored for treatment response. According to TB-MBLA, 19 of these patients cleared bacillary load to zero by week 2 of treatment and remained negative throughout the 6-month treatment follow-up. Positivity for tuberculosis decreased with treatment as measured by all tests, but the rate was slower with Xpert-Ultra. Consequently, 31 (33%) of 95 participants were still Xpert-Ultra positive at the end of treatment but were clinically well and negative on TB-MBLA and culture at 6 months of treatment. Two patients were still Xpert-Ultra positive with a further 3 months of post-treatment follow-up. The rate of conversion to negative of the DNA-based Xpert-Ultra was 3·3-times slower than that of the rRNA-based TB-MBLA. Consequently for the same patient, it would take 13 weeks and 52 weeks to reach complete tuberculosis negativity by TB-MBLA and Xpert-Ultra, respectively. Participants who were positive on smear microscopy at 8 weeks, who received an extra month of intensive treatment, had a similar TB-MBLA-measured bacillary load at 8 weeks to those who were smear microscopy negative. TB-MBLA has a similar performance to Xpert-Ultra for pretreatment diagnosis of tuberculosis, but is more accurate at detecting and characterising the response to treatment than Xpert-Ultra and standard-of-care smear microscopy. European and Developing Countries Clinical Trials Partnership, Makerere University Research and Innovation Fund, US National Institutes of Health.Item C-Reactive Protein Testing for Active Tuberculosis among Inpatients without HIV in Uganda: a Diagnostic Accuracy Study(Journal of Clinical Microbiology, 2020) Meyer, Amanda J.; Ochom, Emmanuel; Turimumahoro, Patricia; Byanyima, Patrick; Sanyu, Ingvar; Lalitha, Rejani; Kaswabuli, Sylvia; Andama, Alfred; Walter, Nicholas D.; Katamba, Achilles; Cattamanchi, Adithya; Worodria, William; Huang, Laurence; Yoon, Christina; Davis, LucianThe objective of this prospective cross-sectional study, conducted at a national referral hospital in Kampala, Uganda, was to determine diagnostic performance of serum C-reactive protein (CRP) as a triage test for tuberculosis (TB) among HIV-seronegative inpatients. We calculated the sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values to determine the diagnostic performance of a CRP enzyme-linked immunosorbent assay (ELISA) (Eurolyser) in comparison to that of a reference standard of Mycobacterium tuberculosis culture on two sputum samples. We constructed receiver operating curves and reported performance in reference to the manufacturer’s cutoff and also to a threshold chosen to achieve sensitivity of 90%, in accordance with the WHO’s targetproduct profile for a triage test. Among 119 HIV-seronegative inpatients, 46 (39%) had culture-positive pulmonary TB. In reference to M. tuberculosis culture, CRP had a sensitivity of 78% (95% confidence interval [CI], 64 to 89%) and a specificity of 52% (95% CI, 40 to 64%) at the manufacturer’s threshold of 10 mg/liter. At a threshold of 1.5 mg/liter, the sensitivity was 91% (95% CI, 79 to 98%) but the specificity was only 21% (95% CI, 12 to 32%). Performance did not differ when stratified by illness severity at either threshold. In conclusion, among HIV-seronegative inpatients, CRP testing performed substantially below targets for a TB triage test. Additional studies among HIV-seronegative individuals in clinics and community settings are needed to assess the utility of CRP for TB screening.Item Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV(PLoS ONE, 2018) Farr, Katherine; Ravindran, Resmi; Strnad, Luke; Chang, Emily; Chaisson, Lelia H.; Yoon, Christina; Worodria, William; Andama, Alfred; Ayakaka, Irene; Bbosa Nalwanga, Priscilla; Byanyima, Patrick; Kalema, Nelson; Kaswabuli, Sylvia; Katagira, Winceslaus; Denise Aman, Kyomugisha; Musisi, Emmanuel; Tumwine, Nuwagaba Wallen; Sanyu, Ingvar; Ssebunya, Robert; Davis, J. Lucian; Huang, Laurence; Khan, Imran H.; Cattamanchi, AdithyaApproaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy. Methods Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough � 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificity of the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to � 90% as recommended for TB screening. Results The median plasma level of 5 biomarkers (IL-6, INF-γ, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4–49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-γ and IL-6 had the highest specificity (50%; 95% CI 46.7–53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients. Conclusions Direct measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/ chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common.Item Evaluating Tuberculosis Case Detection via Real-Time Monitoring of Tuberculosis Diagnostic Services(American journal of respiratory and critical care medicine, 2011) Davis, J. Lucian; Katamba, Achilles; Vasquez, Josh; Crawford, Erin; Sserwanga, Asadu; Kakeeto, Stella; Kizito, Fred; Dorsey, Grant; Boon, Saskia den; Vittinghoff, Eric; Huang, Laurence; Adatu, Francis; Kamya, Moses R.; Hopewell, Philip C.; Cattamanch, AdithyaTuberculosis case-detection rates are below internationally established targets in high-burden countries. Real-time monitoring and evaluation of adherence to widely endorsed standards of tuberculosis care might facilitate improved case finding. Objectives: To monitor and evaluate the quality of tuberculosis casedetection and management services in a low-income country with a high incidence of tuberculosis. Methods:We prospectively evaluated tuberculosis diagnostic services at five primary health-care facilities in Uganda for 1 year, after introducing a real-time, electronic performance-monitoring system. We collecteddataonevery clinicalencounter,andmeasuredquality using indicatorsderivedfromthe International StandardsofTuberculosisCare. Measurements and Main Results: In 2009, there were 62,909 adult primary-care visits.During the first quarter of 2009, clinicians referred only21%of patients with cough greater than or equal to 2 weeks for sputum smear microscopy and only 71% of patients with a positive sputum examination for tuberculosis treatment. These proportions increased to 53% and 84%, respectively, in the fourth quarter of 2009. The cumulative probability that a smear-positive patient with cough greater than or equal to 2 weeks would be appropriately evaluated and referred for treatment rose from 11% to 34% (P 5 0.005). The quarterly number of tuberculosis cases identified and prescribed treatment also increased four-fold, from 5 to 21. Conclusions: Pooradherence tointernationally acceptedstandards of tuberculosis care improved after introduction of real-time performance monitoring and was associated with increased tuberculosis case detection. Real-time monitoring and evaluation can strengthen health systems in low-income countries and facilitate operational research on the effectiveness and sustainability of interventions to improve tuberculosis case detection.Item Evaluation of in-house PCR for diagnosis of smear-negative pulmonary tuberculosis in Kampala, Uganda(BMC Research Notes, 2012) Nakiyingi, Lydia; Kateete, David P.; Ocama, Ponsiano; Worodria, William; Sempa, Joseph B.; Asiimwe, Benon B.; Katabazi, Fred A.; Katamba, Achilles; Huang, Laurence; Joloba, Moses L.; Mayanja-Kizza, HarrietNucleic acid amplification tests (NAATs) have offered hope for rapid diagnosis of tuberculosis (TB). However, their efficiency with smear-negative samples has not been widely studied in low income settings. Here, we evaluated in-house PCR assay for diagnosis of smear-negative TB using Lowenstein-Jensen (LJ) culture as the baseline test. Two hundred and five pulmonary TB (PTB) suspects with smear-negative sputum samples, admitted on a short stay emergency ward at Mulago Hospital in Kampala, Uganda, were enrolled. Two smear-negative sputum samples were obtained from each PTB suspect and processed simultaneously for identification of MTBC using in-house PCR and LJ culture. Results: Seventy two PTB suspects (35%, 72/205) were LJ culture positive while 128 (62.4%, 128/205) were PCR-positive. The sensitivity and specificity of in-house PCR for diagnosis of smear-negative PTB were 75% (95% CI 62.6-85.0) and 35.9% (95% CI 27.2-45.3), respectively. The positive and negative predictive values were 39% (95% CI 30.4-48.2) and 72.4% (95% CI 59.1-83.3), respectively, while the positive and negative likelihood ratios were 1.17 (95% CI 0.96-1.42) and 0.70 (95% CI 0.43-1.14), respectively. One hundred and seventeen LJ culturenegative suspects (75 PCR-positive and 42 PCR-negative) were enrolled for follow-up at 2 months. Of the PCR-positive suspects, 45 (60%, 45/75) were still alive, of whom 29 (64.4%, 29/45) returned for the follow-up visit; 15 (20%, 15/75) suspects died while another 15 (20%, 15/75) were lost to follow-up. Of the 42 PCR-negative suspects, 22 (52.4%, 22/42) were still alive, of whom 16 (72.7%, 16/22) returned for follow-up; 11 (26.2%, 11/42) died while nine (21.4%, 9/42) were lost to follow-up. Overall, more PCR-positive suspects were diagnosed with PTB during follow-up visits but the difference was not statistically significant (27.6%, 8/29 vs. 25%, 4/16, p = 0.9239). Furthermore, mortality was higher for the PCR-negative suspects but the difference was also not statistically significant (26.2% vs. 20% p = 0.7094). Conclusion: In-house PCR correlates poorly with LJ culture for diagnosis of smear-negative PTB. Therefore, in-house PCR may not be adopted as an alternative to LJ culture.Item Predictors and short-term outcomes of recurrent pulmonary tuberculosis, Uganda: a cohort study(South African respiratory journal, 2017) Kalema, Nelson; Lindan, Christina; Glidden, Dave; Yoo, Samuel D.; atamba, Achilles K; Alfred, Andama; Katagira, Winceslaus; Byanyima, Patrick; Musisi, Emmanuel; Kaswabuli, Sylvia; Ingvar, Sanyu; Zawedde, Josephine; Yoon, Christina; Ayakaka, Irene; Lucian Davis, J.; Huang, Laurence; Worodria, William; Cattamanchi, AdithyaRecurrent 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 logistic regression and Cox proportional hazards modelling to identify predictors of recurrent TB and survival, respectively. 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 who were not initiated on TB treatment (aHR=16.67, 95% CI=1.18-200, p=0.04), those who were HIV-positive and not on antiretroviral treatment (aHR=16.99, 95% CI=1.17-246.47, p=0.04) and those 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 they are young, with weight loss ≥5kgs, chest pain >2 weeks or ≥1 WHO danger sign of severe illness.Item The prevalence and clinical course of HIV-associated pulmonary cryptococcosis in Uganda(Journal of acquired immune deficiency syndromes, 2010) Yoo, Samuel D.; Worodria, William; Davis, J. L.; Cattamanchi, Adithya; Boon, Saskia den; Kyeyune, Rachel; Kisembo, Harriet; Huang, LaurenceThe prevalence and clinical course of pulmonary cryptococcosis in Sub-Saharan Africa are not well-described. Methods—Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between September 2007 and July 2008 with cough ≥ 2 weeks were enrolled. Patients with negative sputum smears for acid-fast bacilli were referred for bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid was examined for mycobacteria, Pneumocystis jirovecii, and fungi. Patients were followed two and six months after hospital discharge. Results—Of 407 patients enrolled, 132 (32%) underwent bronchoscopy. Of 132 BAL fungal cultures, 15 (11%) grew Cryptococcus neoformans. None of the patients were suspected to have pulmonary cryptococcosis on admission. The median CD4 count among those with pulmonary cryptococcosis was 23 cells/μL (IQR 7–51). Of 13 patients who completed six-month follow-up, four died and nine were improved, including five who had started antiretroviral therapy (ART) but had not received antifungal medication. Conclusions—Pulmonary cryptococcosis is common in HIV-infected TB suspects in Uganda. Early initiation of ART in those with isolated pulmonary infection may improve outcomes, even without anti-fungal therapy. This finding suggests that some HIV-infected patients with C. neoformans isolated from respiratory samples may have colonization or localized infection.Item Sex and HIV Differences in Preserved Ratio Impaired Spirometry (PRISm) Among Ugandans Postpneumonia(Oxford University Press, 2024-03) Abelman, Rebecca A; Fitzpatrick, Jessica; Byanova, Katerina L; Zawedde, Josephine; Sanyu, Ingvar; Byanyima, Patrick; Musisi, Emmanuel; Hsieh, Jenny; Zhang, Michelle; Branchini, Jake; Sessolo, Abdul; Hunt, Peter W; Lalitha, Rejani; Davis, J Lucian; Crothers, Kristina; Worodria, William; Huang, LaurencePreserved ratio impaired spirometry (PRISm), defined as a normal ratio of forced expiratory volume in 1 second (FEV ) to forced vital capacity (≥0.70) with low FEV (<80% predicted), has been associated with increased mortality in the general population. Female sex has been associated with increased odds of PRISm in people without HIV. People with HIV (PWH) are at increased risk for lung function abnormalities, but whether HIV modifies the effect of sex on PRISm development is largely unknown. Adults with and without HIV underwent baseline followed by serial spirometry after completing therapy for pneumonia, predominantly tuberculosis (TB), in Kampala, Uganda. Using generalized estimating equations adjusted for age, body mass index, smoking, biomass fuel exposure, HIV, and TB status, we compared individuals with PRISm with those with normal spirometry. These models were stratified by HIV status. Of 339 baseline participants, 153 (45%) were women; 129 (38%) had HIV, of whom 53% were women. Overall, 105/339 participants (31%) had PRISm at baseline. HIV was associated with lower odds of PRISm (adjusted odds ratio [aOR], 0.38; 95% CI, 0.21-0.68; = .001). Female sex trended toward increased odds of PRISm among all participants (aOR, 1.65; 95% CI, 0.99-2.75; = .052). The association between female sex and PRISm tended to be stronger among PWH (aOR, 3.16; 95% CI, 1.14-8.76; = .03) than among those without HIV (aOR, 1.34; 95% CI, 0.73-2.45; = .34); this study was underpowered to detect an HIV-sex interaction of this magnitude ( = .30). Among Ugandan adults who recovered from pneumonia, female sex was associated with increased odds and HIV with decreased odds of PRISm, suggesting independent sex and HIV effects on PRISm pathogenesis.Item Sputum quality and diagnostic performance of GeneXpert MTB/RIF among smear-negative adults with presumed tuberculosis in Uganda(PLoS ONE, 2017) Meyer, Amanda J.; Atuheire, Collins; Worodria, William; Kizito, Samuel; Katamba, Achilles; Sanyu, Ingvar; Andama, Alfred; Ayakaka, Irene; Cattamanchi, Adithya; Bwanga, Freddie; Huang, Laurence; Davis, J. LucianIntroduction of GeneXpert MTB/RIF (Xpert) assay has constituted a major breakthrough for tuberculosis (TB) diagnostics. Several patient factors may influence diagnostic performance of Xpert including sputum quality. Objective We carried out a prospective, observational, cross-sectional study to determine the effect of sputum quality on diagnostic performance of Xpert among presumed TB patients in Uganda. Methods We collected clinical and demographic information and two sputum samples from participants. Staff recorded sputum quality and performed LED fluorescence microscopy and mycobacterial culture on each sample. If both smear examinations were negative, Xpert testing was performed. We calculated diagnostic yield, sensitivity, specificity, and other indicators for Xpert for each stratum of sputum quality in reference to a standard of mycobacterial culture. Results Patients with salivary sputum showed a trend towards a substantially higher proportion of samples that were Xpert-positive (54/286, 19%, 95% CI 15±24) compared with those with all other sputum sample types (221/1496, 15%, 95% CI 13±17). Blood-stained sputum produced the lowest sensitivity (28%; 95% CI 12±49) and salivary sputum the highest (66%; 95% CI 53±77). Specificity didn't vary meaningfully by sample types. Salivary sputum was significantly more sensitive than mucoid sputum (+13%, 95% CI +1 to +26), while bloodstained sputum was significantly less sensitive (-24%, 95% CI -42 to -5). Conclusions Our findings demonstrate the need to exercise caution in collecting sputum for Xpert and in interpreting results because sputum quality may impact test yield and sensitivity. In particular, it may be wise to pursue additional testing should blood-stained sputum test negative while salivary sputum should be readily accepted for Xpert testing given its higher sensitivity and potentially higher yield than other sample types. These findings challenge conventional recommendations against collecting salivary sputum for TB diagnosis and could inform new standards for sputum quality.