Nucleic Acid Amplification Tests for Diagnosis of Smear-Negative TB in a High HIV-Prevalence Setting: A Prospective Cohort Study

Nucleic acid amplification tests are sensitive for identifying Mycobacterium tuberculosis in populations with positive sputum smears for acid-fast bacilli, but less sensitive in sputum-smear-negative populations. Few studies have evaluated the clinical impact of these tests in low-income countries with high burdens of TB and HIV.We prospectively enrolled 211 consecutive adults with cough ≥2 weeks and negative sputum smears at Mulago Hospital in Kampala, Uganda. We tested a single early-morning sputum specimen for Mycobacterium tuberculosis DNA using two nucleic acid amplification tests: a novel in-house polymerase chain reaction targeting the mycobacterial secA1 gene, and the commercial Amplified® Mycobacterium tuberculosis Direct (MTD) test (Gen-Probe Inc, San Diego, CA). We calculated the diagnostic accuracy of these index tests in reference to a primary microbiologic gold standard (positive mycobacterial culture of sputum or bronchoalveolar lavage fluid), and measured their likely clinical impact on additional tuberculosis cases detected among those not prescribed initial TB treatment.Of 211 patients enrolled, 170 (81%) were HIV-seropositive, with median CD4+ T-cell count 78 cells/µL (interquartile range 29-203). Among HIV-seropositive patients, 94 (55%) reported taking co-trimoxazole prophylaxis and 29 (17%) reported taking antiretroviral therapy. Seventy-five patients (36%) had culture-confirmed TB. Sensitivity of MTD was 39% (95% CI 28-51) and that of secA1 was 24% (95% CI 15-35). Both tests had specificities of 95% (95% CI 90-98). The MTD test correctly identified 18 (24%) TB patients not treated at discharge and led to a 72% relative increase in the smear-negative case detection rate.The secA1 and MTD nucleic acid amplification tests had moderate sensitivity and high specificity for TB in a predominantly HIV-seropositive population with negative sputum smears. Although newer, more sensitive nucleic acid assays may enhance detection of Mycobacterium tuberculosis in sputum, even currently available tests can provide substantial clinical impact in smear-negative populations

Communications Biophysics

Contains research objectives and summary of research on nine research projects split into four sections.National Institutes of Health (Grant 5 ROI NS11000-03)National Institutes of Health (Grant 1 P01 NS13126-01)National Institutes of Health (Grant 1 RO1 NS11153-01)National Institutes of Health (Grant 2 R01 NS10916-02)Harvard-M.I.T. Rehabilitation Engineering CenterU. S. Department of Health, Education, and Welfare (Grant 23-P-55854)National Institutes of Health (Grant 1 ROl NS11680-01)National Institutes of Health (Grant 5 ROI NS11080-03)M.I.T. Health Sciences Fund (Grant 76-07)National Institutes of Health (Grant 5 T32 GM07301-02)National Institutes of Health (Grant 5 TO1 GM01555-10

Communications Biophysics

Contains research objectives and reports on six research projects split into three sections.National Institutes of Health (Grant 5 P01 NS13126-07)National Institutes of Health (Training Grant 5 T32 NS07047-05)National Institutes of Health (Training Grant 2 T32 NS07047-06)National Science Foundation (Grant BNS 77-16861)National Institutes of Health (Grant 5 R01 NS1284606)National Institutes of Health (Grant 5 T32 NS07099)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 5 R01 NS14092-04)Gallaudet College SubcontractKarmazin Foundation through the Council for the Arts at M.I.T.National Institutes of Health (Grant 1 R01 NS1691701A1)National Institutes of Health (Grant 5 R01 NS11080-06)National Institutes of Health (Grant GM-21189

Communications Biophysics

Contains reports on ten research projects.National Institutes of Health (Grant 5 P01 NS13126)National Institutes of Health (Training Grant 5 T32 NS0704)National Science Foundation (Grant BNS80-06369)National Institutes of Health (Grant 5 R01 NS11153)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 RO1 NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 P01 NS14092)Karmazin Foundation through the Council for the Arts at MITNational Institutes of Health (Fellowship 5 F32 NS06386)National Science Foundation (Fellowship SP179-14913)National Institutes of Health (Grant 5 RO1 NS11080

Communications Biophysics

Contains reports on four research projects.National Institutes of Health (Grant 5 P01 NS13126-02)National Institutes of Health (Grant 5 K04 NS00113-03)National Institutes of Health (Grant 2 ROI NS11153-02A1)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 RO1 NS10916-03)National Institutes of Health (Fellowship 1 F32 NS05327)National Institutes of Health (Grant 5 ROI NS12846-02)National Institutes of Health (Fellowship 1 F32 NS05266)Edith E. Sturgis FoundationNational Institutes of Health (Grant 1 R01 NS11680-01)National Institutes of Health (Grant 2 RO1 NS11080-04)National Institutes of Health (Grant 5 T32 GIM107301-03)National Institutes of Health (Grant 5 TOI GM01555-10

Communications Biophysics

Contains reports on nine research projects split into four sections.National Institutes of Health (Grant 5 PO1 NS13126)National Institutes of Health (Grant 5 KO4 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Institutes of Health (Training Grant 1 T32 NS07099)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 ROI NS10916)National Institutes of Health (Grant 5 RO1 NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 RO1 NS14092)Edith E. Sturgis FoundationHealth Sciences FundNational Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Fellowship 5 F32 NS05327)National Institutes of Health (Grant 2 ROI NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Communications Biophysics

Contains reports on nine research projects split into four sections.National Institutes of Health (Grant 5 P01 NS13126)National Institutes of Health (Grant 5 K04 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Institutes of Health (Grant 5 ROl NS11153-03)National Institutes of Health (Fellowship 1 T32 NS07099-01)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 ROl NS10916)National Institutes of Health (Grant 5 ROl NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 RO1 NS14092)Health Sciences FundNational Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Grant 2 RO1 NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial.

BACKGROUND: COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HICs), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting. METHODS: LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in Central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years, (2) full-time resident of the study area, (3) daily biomass exposure, (4) post-bronchodilator FEV1/FVC below the 5th percentile of the Global Lung Initiative mixed ethnic reference population, and (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George's Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every 6 months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP), and theophylline levels at baseline, 1 month, and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D. TRIAL REGISTRATION: ClinicalTrials.gov  NCT03984188 . Registered on June 12, 2019 TRIAL ACRONYM: Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD)