Level of understanding of co-trimoxazole use among HIV infected, recurrent pulmonary tuberculosis suspects at a national referral tuberculosis clinic in Kampala, Uganda: a qualitative analysis.

Background: Co-trimoxazole use is the standard of care for preventing Pneumocystis jirovecii pneumonia in sub-Saharan Africa but implementation remains slow. Co-trimoxazole is self- administered with uncertain adherence. Knowledge of co-trimoxazole use among HIV infected persons is unknown.Objectives: To assess knowledge, attitudes and practices of co-trimoxazole use among HIV infected adults evaluated for recurrent PTB in Kampala, Uganda.Methods: A qualitative study utilizing 5 focus group discussions among 30 HIV infected PTB suspects at the national referral tuberculosis treatment centre in Kampala.Results: Males and females had similar median ages. 80% were currently on co-trimoxazole and 50% of participants were on HAART. Majority of participants defined co-trimoxazole as an analgesic. Few noted co-trimoxazole was a drug to treat cough and chest pain. However, few responses revealed that co-trimoxazole prevents opportunistic diseases among PLHIV. Most of participants believed HAART and anti-TB drugs work as co-trimoxazole thus it should not be taken together with them. This belief may lead to increased risk of opportunistic infections, morbidity and mortality.Conclusions: We revealed gaps in understanding of co-trimoxazole use among study participants. We therefore recommend that more facts about co-trimoxazle as prophylaxis against P. jirovecii, bacterial and diarrheal pathogens should be incorporated in VCT fact sheets.Key words: Recurrent tuberculosis; HIV; Co-trimoxazole use; Chemoprophylaxis; Adherenc

Immunology in Africa.

Africa is a continent with a large burden of both infectious and non-communicable diseases. If we are to move forward as a continent, we need to equip our growing cadre of exceptional young scientists with the skills needed to tackle the diseases endemic to this continent. For this, immunology is among the key disciplines. Africans should be empowered to study and understand the diseases that affect them, and to perform their cutting-edge research in their country of origin. This requires a multifaceted approach, with buy-in from funders, overseas partners and perhaps, most important of all, African governments themselves

Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study.

BACKGROUND: With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis. METHODS: Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months' follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months. RESULTS: Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95% confidence interval (CI), p-value) -1488.6 pg/ml ((-2682.5, -294.8), p = 0.01), and IL- 2 (-213.1 pg/ml (-419.2, -7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95% CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6. CONCLUSIONS: IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries. TRIAL REGISTRATION: ISRCTN registry, ISRCTN15705625. Registered on 30(th) September 2015

Sputum microbiota profiles of treatment-naïve TB patients in Uganda before and during first-line therapy

Information on microbiota dynamics in pulmonary tuberculosis (TB) in Africa is scarce. Here, we sequenced sputa from 120 treatment-naïve TB patients in Uganda, and investigated changes in microbiota of 30 patients with treatment-response follow-up samples. Overall, HIV-status and anti-TB treatment were associated with microbial structural and abundance changes. The predominant phyla were Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria and Actinobacteria, accounting for nearly 95% of the sputum microbiota composition; the predominant genera across time were Prevotella, Streptococcus, Veillonella, Haemophilus, Neisseria, Alloprevotella, Porphyromonas, Fusobacterium, Gemella, and Rothia. Treatment-response follow-up at month 2 was characterized by a reduction in abundance of Mycobacterium and Fretibacterium, and an increase in Ruminococcus and Peptococcus; month 5 was characterized by a reduction in Tannerella and Fusobacterium, and an increase in members of the family Neisseriaceae. The microbiota core comprised of 44 genera that were stable during treatment. Hierarchical clustering of this core’s abundance distinctly separated baseline (month 0) samples from treatment follow-up samples (months 2/5). We also observed a reduction in microbial diversity with 9.1% (CI 6–14%) of the structural variation attributed to HIV-status and anti-TB treatment. Our findings show discernible microbiota signals associated with treatment with potential to inform anti-TB treatment response monitoring

Developing digital contact tracing tailored to haulage in East Africa to support COVID-19 surveillance: a protocol

International audienceIntroduction At the peak of Uganda’s first wave of SARS-CoV-2 in May 2020, one in three COVID-19 cases was linked to the haulage sector. This triggered a mandatory requirement for a negative PCR test result at all ports of entry and exit, resulting in significant delays as haulage drivers had to wait for 24–48 hours for results, which severely crippled the regional supply chain. To support public health and economic recovery, we aim to develop and test a mobile phone-based digital contact tracing (DCT) tool that both augments conventional contact tracing and also increases its speed and efficiency. Methods and analysis To test the DCT tool, we will use a stratified sample of haulage driver journeys, stratified by route type (regional and local journeys). We will include at least 65% of the haulage driver journeys ~83 200 on the network through Uganda. This allows us to capture variations in user demographics and socioeconomic characteristics that could influence the use and adoption of the DCT tool. The developed DCT tool will include a mobile application and web interface to collate and intelligently process data, whose output will support decision-making, resource allocation and feed mathematical models that predict epidemic waves. The main expected result will be an open source-tested DCT tool tailored to haulage use in developing countries. This study will inform the safe deployment of DCT technologies needed for combatting pandemics in low-income countries. Ethics and dissemination This work has received ethics approval from the School of Public Health Higher Degrees, Research and Ethics Committee at Makerere University and The Uganda National Council for Science and Technology. This work will be disseminated through peer-reviewed publications, our websites https://project-thea.org/ and Github for the open source code https://github.com/project-thea/

Feasibility of a streamlined tuberculosis diagnosis and treatment initiation strategy.

OBJECTIVE: To assess the feasibility of a streamlined strategy for improving tuberculosis (TB) diagnostic evaluation and treatment initiation among patients with presumed TB. DESIGN: Single-arm interventional pilot study at five primary care health centers of a streamlined, SIngle-saMPLE (SIMPLE) TB diagnostic evaluation strategy: 1) examination of two smear results from a single spot sputum specimen using light-emitting diode fluorescence microscopy, and 2) daily transportation of smear-negative sputum samples to Xpert® MTB/RIF testing sites. RESULTS: Of 1212 adults who underwent sputum testing for TB, 99.6% had two smears examined from the spot sputum specimen. Sputum was transported for Xpert testing within 1 clinic day for 83% (907/1091) of the smear-negative patients. Of 157 (13%) patients with bacteriologically positive TB, 116 (74%) were identified using sputum smear microscopy and 41 (26%) using Xpert testing of smear-negative samples. Anti-tuberculosis treatment was initiated in 142 (90%) patients with bacteriologically positive TB, with a median time to treatment of 1 day for smear-positive patients and 6 days for smear-negative, Xpert-positive patients. CONCLUSION: The SIMPLE TB strategy led to successful incorporation of Xpert testing and rapid treatment initiation in the majority of patients with bacteriologically confirmed TB in a resource-limited setting

Accuracy of Xpert Ultra in the diagnosis of pulmonary tuberculosis among children in Uganda: a sub-study from the SHINE trial

Background: Childhood tuberculosis presents significant diagnostic challenges associated with paucibacillary disease, and requires a more sensitive test. We evaluated the diagnostic accuracy of XpertMTB/Rif Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial.Design/Methods: SHINE is a randomized trial evaluating shorter treatment in 1204 children with minimal TB disease in Africa/India. Among 352 samples and one cervical lymph node fine needle aspirate, one sample was randomly selected per patient and tested with Xpert MTB/Rif (Xpert), Lowenstein Jensen (LJ) and liquid (MGIT) cultures. We selected only uncontaminated stored sample pellet for Ultra testing. We estimated sensitivity of Xpert and Ultra against culture and a composite microbiological reference standard (any positive result).Results: Of 398 children, 353 (89%) had culture, Xpert and Ultra results. Median age was 2.8-years (IQR 1.3-5.3); 8.5% (30/353) HIV-infected, 54.4% (192/353) male. 31/353 (9%) were positive by LJ and/or MGIT; 36 (10%) by Ultra and 16 (5%) by Xpert. Sensitivities were (%; 95% CI), 58% (39-65% (18/31)) for Ultra and 45% (27-64% (14/31)) for Xpert against any culture-positive, with false-positives of <1% and 5.5% for Xpert and Ultra. Against a composite microbiological reference, sensitives were 72% (58-84% (36/50) for Ultra, and 32% (20-47% (16/50)) for Xpert. However, there were 17 samples that are positive only on Ultra (majority trace).Conclusions: Among children screened for minimal TB in Uganda, Ultra has higher sensitivity than Xpert. This represents an important advance for a condition which has posed a diagnostic challenge for decades

Cellular immune activation in cerebrospinal fluid from ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome.

BACKGROUND: Human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is characterized by high fungal burden and limited leukocyte trafficking to cerebrospinal fluid (CSF). The immunopathogenesis of CM immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy at the site of infection is poorly understood. METHODS: We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10). RESULTS: At diagnosis, highly activated CD8(+) T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4(+) T cells (increased from 2.2% to 23%; P = .06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P = .03). CSF cellular responses were distinct from responses in peripheral blood. CONCLUSIONS: After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4(+) T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS

Effect of Schistosoma mansoni Infection on Innate and HIV-1-Specific T-Cell Immune Responses in HIV-1-Infected Ugandan Fisher Folk.

In Uganda, fisher folk have HIV prevalence rates, about four times higher than the national average, and are often coinfected with Schistosoma mansoni. We hypothesized that innate immune responses and HIV-specific Th1 immune responses might be downmodulated in HIV/S. mansoni-coinfected individuals compared with HIV+/S. mansoni-negative individuals. We stimulated whole blood with innate receptor agonists and analyzed supernatant cytokines by Luminex. We evaluated HIV-specific responses by intracellular cytokine staining for IFN-γ, IL-2, and TNF-α. We found that the plasma viral load and CD4 count were similar between the HIV+SM+ and HIV+SM- individuals. In addition, the TNF-α response to the imidazoquinoline compound CL097 and β-1, 3-glucan (curdlan), was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. The frequency of HIV-specific IFN-γ+IL-2-TNF-α- CD8 T cells and IFN-γ+IL-2-TNF-α+ CD4 T cells was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. These findings do not support the hypothesis that S. mansoni downmodulates innate or HIV-specific Th1 responses in HIV/S. mansoni-coinfected individuals