Using data from 67 Ugandan HIV clinics (July 2019-January 2022), we report a 40% (1,005/1,662) reduction in the number of people with HIV presenting to care after August 2021 compared to pre-pandemic levels, with a greater proportion presenting with advanced HIV disease (20% vs. 16% in the pre-Covid period).

Background: Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa and is notoriously difficult to diagnose. We describe the impact of improved TBM diagnostics over 6.5 years at two Ugandan referral hospitals. Methods: Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert MTB/Rif (Xpert) on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume centrifuged CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen. We compared rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 HIV-infected adults presenting with suspected meningitis underwent lumbar puncture, of which 33% (558/1672) had negative CSF cryptococcal antigen and 12% (195/1672) were treated for TB meningitis. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in Open Peer Review

Background and Objectives Neuromyelitis optica (NMO) is a CNS inflammatory disease that predominantly affects the optic nerves and the spinal cord. It is more frequent in Asian and African populations than in European ones. Data on epidemiology, clinical presentation, additional investigations, and treatment in the African continent are scarce. We aim to (1) collect and analyze published data on neuromyelitis optica spectrum disorder (NMOSD), (2) indicate challenges in the diagnosis and management, and (3) discuss opportunities for future research, education, and policy making, specifically on the African continent. Methods A systematic review was performed in January 2021 with the search terms “Neuromyelitis optica and Africa,” “Devic Disease and Africa,” and “NMOSD and Africa.” We included all study types except case reports, correspondence, or conference abstracts on NMO or NMOSD. Extracted data included study design, country, study period, demographic and clinical characteristics, results of paraclinical investigations, and outcome. Data analysis was performed with descriptive statistics. Results We retrieved a total of 79 records, of which 19 were included. Ten of 54 African countries reported a total of 410 cases. Almost half of them were from North African countries. The mean age at diagnosis was 33 years (range 7–88 years), and 75% were female. Transverse myelitis followed by optic neuritis were the most frequent symptoms at the time of presentation. One hundred nineteen patients experienced at least 1 previous relapse, and 106 had a relapsing course after diagnosis. Relapses were treated with IV methylprednisolone. Azathioprine and steroids were used most often as maintenance treatments. Outcomes were rarely described. Discussion The majority of studies on NMOSD from the African continent are retrospective, and most countries do not report any data. Our systemic review shows that data derived from patients living in Africa correspond well to what has been previously published in meta-analyses on patients of African ancestry with NMOSD who live outside of Africa, except for a younger age at onset and a lower proportion of females. We advocate for systematic data collection to adequately capture and monitor the burden of NMOSD, for expansion of research efforts and facilities to perform fundamental and clinical research, and for improved access to health care including diagnostics, treatments, and rehabilitation services for people affected by NMOSD in the African continent.

Summary of main point : The Fujifilm SILVAMP TB LAM assay on cerebrospinal fluid performs better than the prior LAM assay at detection of tuberculous meningitis in a Ugandan, predominantly HIV-positive cohort.

Summary: High CSF TB bacillary load, as measured by GeneXpert Ultra CT tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TB meningitis and may be a better predictor of outcome than the reported Xpert Ultra semi-quantitative category. Abstract Background: The World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated PCR assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay‟s PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate TB bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. Methods: We prospectively enrolled 102 HIV-positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between CT and baseline clinical and CSF parameters. Results: Subjects with Ct values in the low tertile (i.e. high bacillary load) had 57% 2-week mortality; worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra-negative (30%) probable TBM cases (p=.01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with medium to low category trending towards worse 2-week survival (42%) compared with very low (28%), trace (26%) and negative (30%) categories (p=.48). Ct tertile was significantly associated with baseline CSF lactate (p=.03). Conclusions: High CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care. curtails bacillary replication through an excessive inflammatory response with ensuing tissue damage or allows unchecked TB replication in the CSF due to a paucity of inflammatory response. CSF cytokine and other studies of host response would be helpful in further understanding these findings. We observed a significant difference in CSF lactate across Ct tertiles, with the highest CSF lactate observed in the low Ct tertile group (i.e. highest bacillary load). Previous studies suggest that lactate levels between 5 – 10 mmol/L support a diagnosis of TBM and high initial lactate levels are associated with death [20]. Further investigation is required into the utility of CSF lactate as a potential diagnostic and prognostic biomarker in TBM. Our data also reveal a non-significant trend towards shorter duration of ART in participants within the intermediate and high Ct tertile groups (intermediate and low bacillary loads). This difference may be explained by unmasking immune reconstitution inflammatory syndrome (IRIS), although formal IRIS case adjudication was not performed. Further work to carefully characterize unmasking TBM-IRIS with correlations to Xpert Ultra results is required.

BACKGROUND:Cryptococcal meningitis accounts for 15% of AIDS-related mortality. Cryptococcal antigen (CrAg) is detected in blood weeks before onset of meningitis, and CrAg positivity is an independent predictor of meningitis and death. CrAg screening for patients with advanced HIV and preemptive treatment is recommended by the World Health Organization, though implementation remains limited. Our objective was to evaluate costs and mortality reduction (lives saved) from a national CrAg screening program across Uganda.METHODS:We created a decision analytic model to evaluate CrAg screening. CrAg screening was considered for those with a CD4<100 cells/μL per national and international guidelines, and in the context of a national HIV test-and-treat program where CD4 testing was not available. Costs (2016 USD) were estimated for screening, preemptive therapy, hospitalization, and maintenance therapy. Parameter assumptions were based on large prospective CrAg screening studies in Uganda, and clinical trials from sub Saharan Africa. CrAg positive (CrAg+) persons could be: (a) asymptomatic and thus eligible for preemptive treatment with fluconazole; or (b) symptomatic with meningitis with hospitalization.RESULTS:In the base case model for 1 million persons with a CD4 test annually, 128,000 with a CD4<100 cells/μL were screened, and 8,233 were asymptomatic CrAg+ and received preemptive therapy. Compared to no screening and treatment, CrAg screening and treatment in the base case cost $3,356,724 compared to doing nothing, and saved 7,320 lives, for a cost of $459 per life saved, with the $3.3 million in cost savings derived from fewer patients developing fulminant meningitis. In the scenario of a national HIV test-and-treat program, of 1 million HIV-infected persons, 800,000 persons were screened, of whom 640,000 returned to clinic, and 8,233 were incident CrAg positive (CrAg prevalence 1.4%). The total cost of a CrAg screening and treatment program was $4.16 million dollars, with 2,180 known deaths. Conversely, without CrAg screening, the cost of treating meningitis was $3.09 million dollars with 3,806 deaths. Thus, despite the very low CrAg prevalence of 1.4% in the general HIV-infected population, and inadequate retention-in-care, CrAg screening averted 43% of deaths from cryptococcal meningitis at a cost of $662 per death averted.CONCLUSION:CrAg screening and treatment programs are cost-saving and lifesaving, assuming preemptive treatment is 77% effective in preventing death, and could be adopted and implemented by ministries of health to reduce mortality in those with advanced HIV disease. Even within HIV test-and-treat programs where CD4 testing is not performed, and CrAg prevalence is only 1.4%, CrAg screening is cost-effective.

for persons with cryptococcal meningitis but without bacteremia was 30% (47/158); 1 patient was lost to follow-up. Thus, the estimated attributable mortality rate for bacteremia was 13% (odds ratio 1.8, 95% CI 0.78–4.0, p = 0.17) compared with patients without bacteremia during their initial hospitalization. Case–control comparisons identified no risk factors for bacteremia (online Technical Appendix, wwwnc. cdc.gov/EID/article/20/4/13-1277Techapp1.pdf). Although 21 (70%) of 30 bacteremia episodes were preceded by phlebitis at a peripheral intravenous site, phlebitis caused by amphotericin was also common in patients without bacteremia (49%), but these percentages did not differ statistically. Accurate data regarding incidence of nosocomial infections in Africa are lacking. A systematic review by WHO in 2011 that assessed published data for 1995–2009 identified only 2 high-quality studies. WHO estimated a prevalence of 2.5%– 14.8% for nosocomial infections and a cumulative incidence of up to 45.8% in some areas (4) and recommended surveillance to estimate the rates of nosocomial infection. WHO acknowledges that health care–associated infections are causes of prolonged hospitalizations, increased antimicrobial drug resistance, financial burdens on health care systems, and causes of excess illness and death (5). Limitations of our study include the retrospective design and inability to identify predictive risk factors for bacteremia. Given the differences in bacteremia incidence between our 2 sites, findings are probably not generalizable to all clinical settings in Africa. However, these findings identify a clinical problem. The incidence of nosocomial bacteremia was 15% in our hospitalized cryptococcal meningitis cohort at a median time of 14 days after hospitalization. The most frequent etiologies were S. aureus and K. pneumonia. Less than 25% of isolates were sensitive to ceftriaxone, a standard empiric drug used throughout Africa. Further prospective studies are needed to determine the prevalence and risk factors for nosocomial infections and prevalence of multidrug resistance among hospitalized persons in resourcelimited areas.

Introduction: Improving HIV outcomes among severely immunocompromised HIV-infected persons who have increased morbidity and mortality remains an important issue in sub-Saharan Africa. We sought to evaluate the impact of targeted clinic-based nurse care on antiretroviral therapy (ART) initiation and retention among severely immunocompromised HIV-infected persons. Methods: The study included ART-naive patients with CD4 counts <100 cells per microliter registered in seven urban clinics in Kampala, Uganda. Data were retrospectively collected on patients enrolled from July to December 2011 (routine care cohort). Between July 2012 and September 2013, 1 additional nurse per clinic was hired (nurse counselor cohort) to identify new patients, expedite ART initiation, and trace those who were lost to follow-up. We compared time to ART initiation and 6-month retention in care between cohorts and used a generalized linear model to estimate the relative risk of retention. Results: The study included 258 patients in the routine care cohort and 593 in the nurse counselor cohort. The proportion of patients who initiated ART increased from 190 (73.6%) in the routine care cohort to 506 (85.3%) in the nurse counselor cohort (P < 0.001). At 6 months, 62% of the routine care cohort were retained in care versus 76% in the nurse counselor cohort (P = 0.001). A 21% increase in the likelihood of retention in the nurse counselor cohort (relative risk: 1.21, 95% CI: 1.09 to 1.34) compared with the routine care cohort was observed. Conclusions: Implementation of targeted nurse-led care of severely immunocompromised HIV-infected patients in public outpatient health care facilities resulted in decreased time to ART initiation and increased retention.

Introduction— TB meningitis (TBM) diagnosis is difficult and novel diagnostic methods are needed. The World Health Organization recommends Xpert MTB/RIF (Xpert) as the initial TBM diagnostic test, based on two studies reporting suboptimal sensitivity (~50–60%). Objective— To study the effect of cerebrospinal fluid (CSF) centrifugation on Xpert performance for TBM detection. Design— 107 predominantly HIV-infected adults with suspected meningitis were screened prospectively in Kampala, Uganda. CSF was tested by 1) microscopy for acid-fast bacilli; 2) Mycobacteria growth indicator tube culture; 3) Xpert of 2mL of unprocessed CSF; 4) Xpert of centrifuged CSF. Diagnostic performance was measured against an a priori composite reference standard of any positive CSF tuberculosis test. Results— 17% (18/107) of participants had definite TBM. When CSF was centrifuged, Xpert had better sensitivity (72%, 13/18) than when using 2mL of unprocessed CSF (28%, 5/18; P=0.008). The median centrifuged CSF volume was 6mL (IQR 4–10mL). Mycobacterial culture yielded 71% (12/17) sensitivity at a median delay of 27 days. Only 39% were positive both by culture and centrifuged Xpert, with additional cases detected by Xpert and culture. Conclusions— Centrifuging of CSF optimizes Xpert diagnostic performance for detection of TBM. A combination of culture and Xpert detected the largest number of cases.

The HIV epidemic in Uganda has highlighted Cryptococcus and Candida infections as important opportunistic fungal infections. However, the burden of other fungal diseases is not well described. We aimed to estimate the burden of fungal infections in Uganda. All epidemiological papers of fungal diseases in Uganda were reviewed. Where there is no Ugandan data, global or East African data were used. Recurrent vaginal candidiasis is estimated to occur in 375 540 Uganda women per year; Candida in pregnant women affects up to 651600 women per year. There are around 45000 HIV-related oral and oesophageal candidosis cases per year. There are up to 3000 cases per year of post-TB chronic pulmonary aspergillosis. There are an estimated 40392 people with asthma-related fungal conditions. An estimated 1300000 cases of tinea capitis occur in school children yearly in Uganda. There are approximately 800 HIV-positive adults with Pneumocystis jirovecii pneumonia (PJP) annually and up to 42 000 children with PJP per year. There are an estimated 4000 cryptococcal cases annually. There are an estimated 2.5 million fungal infections per year in Uganda. Cryptococcus and PJP cause around 28000 deaths in adults and children per year. We propose replicating the model of research around cryptococcal disease to investigate and development management strategies for other fungal diseases in Uganda.

Background: Quantitative cryptococcal cultures provide a measure of disease severity in cryptococcal meningitis, and the rate of fungal clearance by quantitative culture has become a widely accepted surrogate outcome measure in phase II clinical trials. Various quantitative methodologies have been used to quantify CSF fungal burden; however, the reproducibility of between techniques is unknown. Methods & Materials: 213 CSF samples were prospectively collected from 70 individuals with cryptococcal meningitis at Mulago Hospital in Kampala, Uganda during Sept-Nov 2013. Each sample was simultaneously cultured by three different quantitative culturing techniques: 1) “standard” 100mcL input volume of CSF with an additional five 1:10 serial dilutions; 2) a AIDS Clinical Trials Group (ACTG) method using various input volumes (1000,100,10mcL) and two 1:100 dilutions with (100,10 mcL input volume) per dilution; 3) 10mcL calibrated plastic loop of undiluted and 1:100 diluted CSF. Colony forming units (CFU)/mL were quantified on the tenth day of culture. In addition, CSF at time of diagnosis was analyzed by automated cell counter and cryptococcal antigen (CRAG) lateral flow assay (LFA) titers. Results: Mean log10 transformed CFU counts suggested no significant differences between the standard method and either of the two alternative methods by paired t-test (difference=+0.036 ACTG,p=.690;-0.053 log10CFU/mL loop, p=.671), although the ACTG and loop methods differed significantly (difference=+0.55,p=.001). Correlation between tests was high at r=0.82, 0.85, and 0.83 for the standard-ACTG, standard-loop, and ACTG-loop methods, respectively. A weighted kappa statistic allowing for 1 log10 difference between methods showed moderate agreement between all tests, with k=0.50, 0.57, and 0.45 for the standard-ACTG, standard-loop, and ACTG-loop methods, respectively. No significant relationships were identified between culture methods and automated cell counts (diff=-1.13,p<0.001 vs. standard, R2=0.49). Regression analysis showed a significant association between being in the highest tertile of LFA titers and higher CFUs by the standard method (p=.042) Conclusion: Overall, the three methods of quantitative culture produced highly comparable but not identical results. There were significant differences between ACTG and loop techniques. The choice of quantitative method should be made based on lab-specific capacity and reproducibility of each technique.

Toll‐like receptors (TLRs) are transmembrane receptors that activate cells of the innate immune systems upon recognition of pathogen‐associated molecular patterns. The TLR4 is an essential component of the innate immune response to various microorganisms. We investigated the impact of TLR4 polymorphism on development of opportunistic diseases in HIV‐infected patients.