DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial.

BACKGROUND: Despite treatment with highly effective antimalarial drugs, malaria annually claims the lives of over half a million children under 5-years of age in sub-Saharan Africa. Cerebral malaria (CM), defined as Plasmodium falciparum infection with coma, is the severe malaria syndrome with the highest mortality. Studies in the CM mouse model suggest that a T cell-mediated response underlies CM pathology, opening a new target for therapy in humans. This trial aims to establish the preliminary safety of one such novel therapy, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). METHODS: In this phase I/IIa dose-escalation clinical trial, a single dose of intravenous (IV) DON is administered to three participants groups-healthy adults and adults with uncomplicated malaria, then pediatric participants with CM-to primarily assess safety. The secondary objective of this trial is to assess pharmacokinetics of DON over a range of doses. The open-label adult portion of the trial enrolls 40 healthy adults concurrently with 40 adults with uncomplicated malaria. Cohorts of 10 participants receive a single IV dose of DON with doses escalating between cohorts from 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, to 10 mg/kg. Following subsequent safety review, a randomized, double-blind, and placebo-controlled pediatric study enrolls 72 participants aged 6 months to 14 years with CM. The pediatric portion of the study minimally spans three malaria seasons including a planned interim analysis after 50% of pediatric enrollments. The first half of pediatric participants receive DON 0.1 mg/kg, 1.0 mg/kg, or placebo. Dosing for the second half of pediatric participants is informed by the safety and preliminary efficacy results of those previously enrolled. The pediatric portion of the study has an exploratory outcome evaluating the preliminary efficacy of DON. Efficacy is assessed by diagnostics predictive of CM outcome: electroencephalography (EEG), magnetic resonance imaging (MRI), and transcranial doppler (TCD), measured before and after DON administration. All participants with malaria receive standard of care antimalarials in accordance with local guidelines, regardless of study drug dose group. DISCUSSION: This preliminary safety and efficacy study evaluates DON, a candidate adjunctive therapy for pediatric CM. If results support DON preliminary safety and efficacy, follow-up phase II and III clinical trials will be indicated. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 28 July 2022 (NCT05478720).

Individual and population level costs and health-related quality of life outcomes of third-generation cephalosporin resistant bloodstream infection in Blantyre, Malawi.

Data which accurately enumerate the economic costs of antimicrobial resistance (AMR) in low- and middle- income countries are essential. This study aimed to quantify the impact of third-generation cephalosporin resistant (3GC-R) bloodstream infection (BSI) on economic and health related quality of life outcomes for adult patients in Blantyre, Malawi. Participants were recruited from a prospective, longitudinal cohort study of hospitalised patients with bloodstream infection caused by Enterobacterales at Queen Elizabeth Central Hospital (QECH). Primary costing studies were used to estimate the direct medical costs associated with the inpatient stay. Recruited participants were asked about direct non-medical and indirect costs associated with their admission and their health-related quality of life was measured using the EuroQol EQ-5D questionnaire. Multiple imputation was undertaken to account for missing data. Costs were adjusted to 2019 US Dollars. Cost and microbiology surveillance data from QECH, Blantyre was used to model the annual cost of, and quality-adjusted life years lost to, 3GC-R and 3GC-Susceptible BSI from 1998 to 2030 in Malawi. The mean health provider cost per participant with 3GC-R BSI was US$110.27 (95%CR; 22.60-197.95), higher than for those with 3GC-S infection. Patients with resistant BSI incurred an additional indirect cost of US$155.48 (95%CR; -67.80, 378.78) and an additional direct non-medical cost of US$20.98 (95%CR; -36.47, 78.42). Health related quality of life outcomes were poor for all participants, but participants with resistant infections had an EQ-5D utility score that was 0.167 (95% CR: -0.035, 0.300) lower than those with sensitive infections. Population level burden estimates suggest that in 2016, 3GC-R accounted for 84% of annual societal costs from admission with bloodstream infection and 82% of QALYs lost. 3GC-R bloodstream infection was associated with higher health provider and patient level costs than 3GC-S infection, as well as poorer HRQoL outcomes. We demonstrate a substantial current and future economic burden to society as a result of 3GC-R E. coli and Klebsiella spp. BSI, data urgently needed by policy makers to provide impetus for implementing strategies to reduce AMR.

A comparison of four epidemic waves of COVID-19 in Malawi; an observational cohort study.

BACKGROUND: Compared to the abundance of clinical and genomic information available on patients hospitalised with COVID-19 disease from high-income countries, there is a paucity of data from low-income countries. Our aim was to explore the relationship between viral lineage and patient outcome. METHODS: We enrolled a prospective observational cohort of adult patients hospitalised with PCR-confirmed COVID-19 disease between July 2020 and March 2022 from Blantyre, Malawi, covering four waves of SARS-CoV-2 infections. Clinical and diagnostic data were collected using an adapted ISARIC clinical characterization protocol for COVID-19. SARS-CoV-2 isolates were sequenced using the MinION™ in Blantyre. RESULTS: We enrolled 314 patients, good quality sequencing data was available for 55 patients. The sequencing data showed that 8 of 11 participants recruited in wave one had B.1 infections, 6/6 in wave two had Beta, 25/26 in wave three had Delta and 11/12 in wave four had Omicron. Patients infected during the Delta and Omicron waves reported fewer underlying chronic conditions and a shorter time to presentation. Significantly fewer patients required oxygen (22.7% [17/75] vs. 58.6% [140/239], p < 0.001) and steroids (38.7% [29/75] vs. 70.3% [167/239], p < 0.001) in the Omicron wave compared with the other waves. Multivariable logistic-regression demonstrated a trend toward increased mortality in the Delta wave (OR 4.99 [95% CI 1.0-25.0 p = 0.05) compared to the first wave of infection. CONCLUSIONS: Our data show that each wave of patients hospitalised with SARS-CoV-2 was infected with a distinct viral variant. The clinical data suggests that patients with severe COVID-19 disease were more likely to die during the Delta wave.

Artemether-lumefantrine efficacy among adults on antiretroviral therapy in Malawi.

BACKGROUND: When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response. METHODS: Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ) or no prophylaxis. After diagnosis of uncomplicated Plasmodium falciparum malaria, a therapeutic efficacy monitoring was conducted with PCR-correction according to WHO guidelines. The plasma lumefantrine levels on day 7 in 100 episodes of uncomplicated malaria was measured. A frailty proportional hazards model with random effects models to account for clustering examined the relationship between participant characteristics and malaria treatment failure within 28 days. Pearson's Chi-squared test was used to compare lumefantrine concentrations among patients with treatment failure and adequate clinical and parasitological response (ACPR). RESULTS: 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008). CONCLUSION: Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.

Effect of resistance to third-generation cephalosporins on morbidity and mortality from bloodstream infections in Blantyre, Malawi: a prospective cohort study.

BACKGROUND: The burden of antimicrobial resistance is a major threat to global health; however, prospective clinical outcome data from Africa are scarce. In Malawi, third-generation cephalosporins are the antibiotics of choice in patients admitted to hospital despite a rapid proliferation of resistance to these drugs. We aimed to quantify the effect of resistance to third-generation cephalosporins on mortality and length of hospital stay among patients with bloodstream infections. METHODS: We did a prospective cohort study of patients admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Patients of all ages who had positive blood cultures for Enterobacterales were included, with the exception of those from the genus Salmonella, and were followed up for 180 days. We characterised blood culture isolates using whole-genome sequencing and used Cox regression models to estimate the effect of resistance to third-generation cephalosporins on length of hospital stay, in-hospital mortality, and survival. FINDINGS: Between Jan 31, 2018, and Jan 13, 2020, we recruited 326 patients, from whom 220 (68%) of 326 isolates were resistant to third-generation cephalosporins. The case fatality proportion was 45% (99 of 220) in patients with bloodstream infections that were resistant to third-generation cephalosporins, and 34% (36 of 106) in patients with bloodstream infections that were sensitive to third-generation cephalosporins. Resistance to third-generation cephalosporins was associated with an increased probability of in-hospital mortality (hazard ratio [HR] 1·44, 95% CI 1·02-2·04), longer hospital stays (1·5 days, 1·0-2·0) and decreased probability of discharge alive (HR 0·31, 0·22-0·45). Whole-genome sequencing showed a high diversity of sequence types of both Escherichia coli and Klebsiella pneumoniae. Although isolates associated with death were distributed across clades, we identified three E coli clades (ST410, ST617, and ST648) that were isolated from 14 patients who all died. INTERPRETATION: Resistance to third-generation cephalosporins is associated with increased mortality and longer hospital stays in patients with bloodstream infections in Malawi. These data show the urgent need for allocation of resources towards antimicrobial resistance mitigation strategies in Africa. FUNDING: Wellcome Trust and Wellcome Asia and Africa Programme.

Isoniazid preventive therapy-related adverse events among Malawian adults on antiretroviral therapy: A cohort study.

Adverse events may be a cause of observed poor completion of isoniazid preventive therapy (IPT) among people living with HIV in high tuberculosis burden areas. Data on IPT-related adverse events (AE) from sub-Saharan Africa are scarce. We report IPT-related AEs, associated clinical characteristics, and IPT discontinuations in adults who were stable on antiretroviral therapy (ART) when they initiated IPT. Cohort study nested within a randomized, controlled, clinical trial of cotrimoxazole and chloroquine prophylaxis in Malawians aged ≥ 18 years and virologically suppressed on ART. Eight hundred sixty-nine patients were followed for a median of 6 months after IPT initiation. IPT relatedness of AEs was determined retrospectively with the World Health Organization case-causality tool. Frailty survival regression modeling identified factors associated with time to first probably IPT-related AE. The overall IPT-related AE incidence rate was 1.1/person year of observation. IPT relatedness was mostly uncertain and few AEs were severe. Most common were liver and hematological toxicities. Higher age increased risk of a probably IPT-related AE (aHR = 1.02; 95% CI 1.00-1.06; P = .06) and higher weight reduced this risk (aHR = 0.98; 95% CI 0.96-1.00; P = .03). Of 869 patients, 114 (13%) discontinued IPT and 94/114 (82%) discontinuations occurred at the time of a possibly or probably IPT-related AE. We observed a high incidence of mostly mild IPT-related AEs among individuals who were stable on ART. More than 1 in 8 persons discontinued IPT. These findings inform strategies to improve implementation of IPT in adults on ART, including close monitoring of groups at higher risk of IPT-related AEs.

Colonization dynamics of extended-spectrum beta-lactamase-producing Enterobacterales in the gut of Malawian adults.

Drug-resistant bacteria of the order Enterobacterales which produce extended-spectrum beta-lactamase enzymes (ESBL-Enterobacterales, ESBL-E) are global priority pathogens. Antimicrobial stewardship interventions proposed to curb their spread include shorter courses of antimicrobials to reduce selection pressure but individual-level acquisition and selection dynamics are poorly understood. We sampled stool of 425 adults (aged 16-76 years) in Blantyre, Malawi, over 6 months and used multistate modelling and whole-genome sequencing to understand colonization dynamics of ESBL-E. Models suggest a prolonged effect of antimicrobials such that truncating an antimicrobial course at 2 days has a limited effect in reducing colonization. Genomic analysis shows largely indistinguishable diversity of healthcare-associated and community-acquired isolates, hence some apparent acquisition of ESBL-E during hospitalization may instead represent selection from a patient's microbiota by antimicrobial exposure. Our approach could help guide stewardship protocols; interventions that aim to review and truncate courses of unneeded antimicrobials may be of limited use in preventing ESBL-E colonization.

Acute Malaria in Malawian Children and Adults is Characterized by Thrombocytopenia That Normalizes in Convalescence.

Background: Plasmodium falciparum malaria has been linked with significant perturbations of the peripheral cell-mediated immune system during acute phase. Some of these changes include lower than normal platelet counts. Although the exact mechanisms that drive thrombocytopenia in P. falciparum malaria are not fully known, a number of hypotheses have been proposed. We conducted two sets of studies with one aimed at determining platelet counts in Malawian children, and the other in adults during acute P. falciparum malaria and a month post treatment. Materials and Methods: We recruited a total of 113 HIV-uninfected children with acute malaria [n=54 with uncomplicated malaria (UCM), n=30 with severe malarial anemia (SMA), n=29 presenting with cerebral malaria (CM)]. We also recruited 42 HIV-uninfected healthy controls. Out of the 113 participants with malaria, 73 (65%) [n=34 (63%) UCM, n=21 (70%) SMA and n=18 (62%) CM] were successfully followed-up one month after treatment. A 5mL peripheral blood sample was collected for platelet count using HMX Haematological Analyzer analysis both at baseline (acute malaria) and at follow-up a month later. Platelet counts were also determined in blood samples of 106 HIV-uninfected adults, 47 of whom presented with UCM and 29 with severe malaria (SM) and these counts were compared to those of 30 healthy controls. Of the malaria cases, platelet counts for 44 UCM and 21 SM were determined again during follow-up a month after treatment. Results: In both children and adults, platelet counts were significantly lower during acute disease compared to the levels in the healthy controls with the lowest levels observed in CM (children) or SM (adults). These lower than normal levels increased close to normal levels a month post treatment. Conclusion: P. falciparum malaria in Malawian children and adults was characterized by profound thrombocytopenia which recovered during convalescence.

High burden of malaria among Malawian adults on antiretroviral therapy after discontinuing prophylaxis.

OBJECTIVE: Many individuals living with the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapy (ART) reside in areas at high risk for malaria but how malaria affects clinical outcomes is not well described in this population. We evaluated the burden of malaria infection and clinical malaria, and impact on HIV viral load and CD4 + cell count among adults on ART. DESIGN: We recruited Malawian adults on ART who had an undetectable viral load and ≥250 CD4 +  cells/µl to participate in this randomized trial to continue daily trimethoprim-sulfamethoxazole (TS), discontinue daily co-trimoxazole, or switch to weekly chloroquine (CQ). METHODS: We defined clinical malaria as symptoms consistent with malaria and positive blood smear, and malaria infection as Plasmodium falciparum DNA detected from dried blood spots (collected every 4-12 weeks). CD4 + cell count and viral load were measured every 24 weeks. We used Poisson regression and survival analysis to compare the incidence of malaria infection and clinical malaria. Clinicaltrials.gov NCT01650558. RESULTS: Among 1499 participants enrolled, clinical malaria incidence was 21.4/100 person-years of observation (PYO), 2.4/100 PYO and 1.9/100 PYO in the no prophylaxis, TS, and CQ arms, respectively. We identified twelve cases of malaria that led to hospitalization and all individuals recovered. The preventive effect of staying on prophylaxis was approximately 90% compared to no prophylaxis (TS: incidence rate ratio [IRR] 0.11, 95% confidence interval [CI] 0.08, 0.15 and CQ: IRR 0.09, 95% CI 0.06, 0.13). P. falciparum infection prevalence among all visits was 187/1475 (12.7%), 48/1563 (3.1%), and 29/1561 (1.9%) in the no prophylaxis, TS, and CQ arms, respectively. Malaria infection and clinical malaria were not associated with changes in CD4 + cell count or viral load. CONCLUSION: In clinically stable adults living with HIV on ART, clinical malaria was common after chemoprophylaxis stopped. However, neither malaria infection nor clinical illness appeared to affect HIV disease progression.

A comparison of four epidemic waves of COVID-19 in Malawi; an observational cohort study.

Background: Compared to the abundance of clinical and genomic information available on patients hospitalised with COVID-19 disease from high-income countries, there is a paucity of data from low-income countries. Our aim was to explore the relationship between viral lineage and patient outcome. Methods: We enrolled a prospective observational cohort of adult patients hospitalised with PCR-confirmed COVID-19 disease between July 2020 and March 2022 from Blantyre, Malawi, covering four waves of SARS-CoV-2 infections. Clinical and diagnostic data were collected using an adapted ISARIC clinical characterization protocol for COVID-19. SARS-CoV-2 isolates were sequenced using the MinIONâ"¢ in Blantyre. Results: We enrolled 314 patients, good quality sequencing data was available for 55 patients. The sequencing data showed that 8 of 11 participants recruited in wave one had B.1 infections, 6/6 in wave two had Beta, 25/26 in wave three had Delta and 11/12 in wave four had Omicron. Patients infected during the Delta and Omicron waves reported fewer underlying chronic conditions and a shorter time to presentation. Significantly fewer patients required oxygen (22.7% [17/75] vs. 58.6% [140/239], p<0.001) and steroids (38.7% [29/75] vs. 70.3% [167/239], p<0.001) in the Omicron wave compared with the other waves. Multivariable logistic-regression demonstrated a trend toward increased mortality in the Delta wave (OR 4.99 [95% CI 1.0-25.0 p=0.05) compared to the first wave of infection. Conclusions: Our data show that each wave of patients hospitalised with SARS-CoV-2 was infected with a distinct viral variant. The clinical data suggests that patients with severe COVID-19 disease were more likely to die during the Delta wave. Summary: We used genome sequencing to identify the variants of SARS-CoV-2 causing disease in Malawi, and found that each of the four waves was caused by a distinct variant. Clinical investigation suggested that the Delta wave had the highest mortality.

High Intrapulmonary Rifampicin and Isoniazid Concentrations Are Associated With Rapid Sputum Bacillary Clearance in Patients With Pulmonary Tuberculosis.

BACKGROUND: Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. METHODS: Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0-8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. RESULTS: Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. CONCLUSIONS: Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.

Genomic and antigenic diversity of colonizing Klebsiella pneumoniae isolates mirrors that of invasive isolates in Blantyre, Malawi.

Members of the Klebsiella pneumoniae species complex, particularly K. pneumoniae subsp. pneumoniae are antimicrobial resistance (AMR) associated pathogens of global importance, and polyvalent vaccines targeting Klebsiella O-antigens are in development. Whole-genome sequencing has provided insight into O-antigen distribution in the K. pneumoniae species complex, as well as population structure and virulence determinants, but genomes from sub-Saharan Africa are underrepresented in global sequencing efforts. We therefore carried out a genomic analysis of extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae species complex isolates colonizing adults in Blantyre, Malawi. We placed these isolates in a global genomic context, and compared colonizing to invasive isolates from the main public hospital in Blantyre. In total, 203 isolates from stool and rectal swabs from adults were whole-genome sequenced and compared to a publicly available multicounty collection and previously sequenced Malawian and Kenyan isolates from blood or sterile sites. We inferred phylogenetic relationships and analysed the diversity of genetic loci linked to AMR, virulence, capsule and LPS O-antigen (O-types). We find that the diversity of Malawian K. pneumoniae subsp. pneumoniae isolates represents the species' population structure, but shows distinct local signatures concerning clonal expansions. Siderophore and hypermucoidy genes were more frequent in invasive versus colonizing isolates (present in 13 % vs 1 %) but still generally lacking in most invasive isolates. O-antigen population structure and distribution was similar in invasive and colonizing isolates, with O4 more common (14%) than in previously published studies (2-5 %). We conclude that host factors, pathogen opportunity or alternate virulence loci not linked to invasive disease elsewhere are likely to be the major determinants of invasive disease in Malawi. Distinct ST and O-type distributions in Malawi highlight the need to sample locations where the burden of invasive Klebsiella disease is greatest to robustly define secular trends in Klebsiella diversity to assist in the development of a useful vaccine. Colonizing and invasive isolates in Blantyre are similar, hence O-typing of colonizing Klebsiella isolates may be a rapid and cost-effective approach to describe global diversity and guide vaccine development.

A Longitudinal, Observational Study of Etiology and Long-Term Outcomes of Sepsis in Malawi Revealing the Key Role of Disseminated Tuberculosis.

BACKGROUND: Sepsis protocols in sub-Saharan Africa are typically extrapolated from high-income settings, yet sepsis in sub-Saharan Africa is likely caused by distinct pathogens and may require novel treatment strategies. Data to guide such strategies are lacking. We aimed to define causes and modifiable factors associated with sepsis outcomes in Blantyre, Malawi, in order to inform the design of treatment strategies tailored to sub-Saharan Africa. METHODS: We recruited 225 adults who met a sepsis case definition defined by fever and organ dysfunction in an observational cohort study at a single tertiary center. Etiology was defined using culture, antigen detection, serology, and polymerase chain reaction. The effect of treatment on 28-day outcomes was assessed using Bayesian logistic regression. RESULTS: There were 143 of 213 (67%) participants living with human immunodeficiency virus (HIV). We identified a diagnosis in 145 of 225 (64%) participants, most commonly tuberculosis (TB; 34%) followed by invasive bacterial infections (17%), arboviral infections (13%), and malaria (9%). TB was associated with HIV infection, whereas malaria and arboviruses with the absence of HIV infection. Antituberculous chemotherapy was associated with survival (adjusted odds ratio for 28-day death, 0.17; 95% credible interval, 0.05-0.49 for receipt of antituberculous therapy). Of those with confirmed etiology, 83% received the broad-spectrum antibacterial ceftriaxone, but it would be expected to be active in only 24%. CONCLUSIONS: Sepsis in Blantyre, Malawi, is caused by a range of pathogens; the majority are not susceptible to the broad-spectrum antibacterials that most patients receive. HIV status is a key determinant of etiology. Novel antimicrobial strategies for sepsis tailored to sub-Saharan Africa, including consideration of empiric antituberculous therapy in individuals living with HIV, should be developed and trialed.

Spatial and Genomic Data to Characterize Endemic Typhoid Transmission.

BACKGROUND: Diverse environmental exposures and risk factors have been implicated in the transmission of Salmonella Typhi, but the dominant transmission pathways through the environment to susceptible humans remain unknown. Here, we use spatial, bacterial genomic, and hydrological data to refine our view of typhoid transmission in an endemic setting. METHODS: A total of 546 patients presenting to Queen Elizabeth Central Hospital in Blantyre, Malawi, with blood culture-confirmed typhoid fever between April 2015 and January 2017 were recruited to a cohort study. The households of a subset of these patients were geolocated, and 256 S. Typhi isolates were whole-genome sequenced. Pairwise single-nucleotide variant distances were incorporated into a geostatistical modeling framework using multidimensional scaling. RESULTS: Typhoid fever was not evenly distributed across Blantyre, with estimated minimum incidence ranging across the city from <15 to >100 cases per 100 000 population per year. Pairwise single-nucleotide variant distance and physical household distances were significantly correlated (P = .001). We evaluated the ability of river catchment to explain the spatial patterns of genomics observed, finding that it significantly improved the fit of the model (P = .003). We also found spatial correlation at a smaller spatial scale, of households living <192 m apart. CONCLUSIONS: These findings reinforce the emerging view that hydrological systems play a key role in the transmission of typhoid fever. By combining genomic and spatial data, we show how multifaceted data can be used to identify high incidence areas, explain the connections between them, and inform targeted environmental surveillance, all of which will be critical to shape local and regional typhoid control strategies.

Inflammatory pathways amongst people living with HIV in Malawi differ according to socioeconomic status.

BACKGROUND: Non-communicable diseases (NCDs) are increased amongst people living with HIV (PLWH) and are driven by persistent immune activation. The role of socioeconomic status (SES) in immune activation amongst PLWH is unknown, especially in low-income sub-Saharan Africa (SSA), where such impacts may be particularly severe. METHODS: We recruited Malawian adults with CD4<100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031), as well as volunteers without HIV infection. Clinical assessment, socioeconomic evaluation, blood draw for immune activation markers and carotid femoral pulse wave velocity (cfPWV) were carried out at 2- and 42-weeks post-ART initiation. Socioeconomic risk factors for immune activation and arterial stiffness were assessed using linear regression models. RESULTS: Of 279 PLWH, the median (IQR) age was 36 (31-43) years and 122 (44%) were female. Activated CD8 T-cells increased from 70% amongst those with no education to 88% amongst those with a tertiary education (p = 0.002); and from 71% amongst those earning less than 10 USD/month to 87% amongst those earning between 100-150 USD/month (p = 0.0001). Arterial stiffness was also associated with higher SES (car ownership p = 0.003, television ownership p = 0.012 and electricity access p = 0.029). Conversely, intermediate monocytes were higher amongst those with no education compared to a tertiary education (12.6% versus 7.3%; p = 0.01) and trended towards being higher amongst those earning less than 10 USD/month compared to 100-150 USD/month (10.5% versus 8.0%; p = 0.08). Water kiosk use showed a protective association against T cell activation (p = 0.007), as well as endothelial damage (MIP1ß, sICAM1 and sVCAM1 p = 0.047, 0.026 and 0.031 respectively). CONCLUSIONS: Socioeconomic risk factors for persistent inflammation amongst PLWH in SSA differ depending on the type of inflammatory pathway. Understanding these pathways and their socioeconomic drivers will help identify those at risk and target interventions for NCDs. Future studies assessing drivers of inflammation in HIV should include an SES assessment.

Incidence of HIV-positive admission and inpatient mortality in Malawi (2012-2019).

OBJECTIVE: To investigate trends in population incidence of HIV-positive hospital admission and risk of in-hospital death among adults living with HIV between 2012 and 2019 in Blantyre, Malawi. DESIGN: Population cohort study using an existing electronic health information system ('SPINE') at Queen Elizabeth Central Hospital and Blantyre census data. METHODS: We used multiple imputation and negative binomial regression to estimate population age-specific and sex-specific admission rates over time. We used a log-binomial model to investigate trends in risk of in-hospital death. RESULTS: Of 32 814 adult medical admissions during Q4 2012--Q3 2019, HIV status was recorded for 75.6%. HIV-positive admissions decreased substantially between 2012 and 2019. After imputation for missing data, HIV-positive admissions were highest in Q3 2013 (173 per 100 000 adult Blantyre residents) and lowest in Q3 2019 (53 per 100 000 residents). An estimated 10 818 fewer than expected people with HIV (PWH) [95% confidence interval (CI) 10 068-11 568] were admitted during 2012-2019 compared with the counterfactual situation where admission rates stayed the same throughout this period. Absolute reductions were greatest for women aged 25-34 years (2264 fewer HIV-positive admissions, 95% CI 2002-2526). In-hospital mortality for PWH was 23.5%, with no significant change over time in any age-sex group, and no association with antiretroviral therapy (ART) use at admission. CONCLUSION: Rates of admission for adult PWH decreased substantially, likely because of large increases in community provision of HIV diagnosis, treatment and care. However, HIV-positive in-hospital deaths remain unacceptably high, despite improvements in ART coverage. A concerted research and implementation agenda is urgently needed to reduce inpatient deaths among PWH.

Impact and effectiveness of 13-valent pneumococcal conjugate vaccine on population incidence of vaccine and non-vaccine serotype invasive pneumococcal disease in Blantyre, Malawi, 2006-18: prospective observational time-series and case-control studies.

BACKGROUND: The population impact of pneumococcal conjugate vaccines (PCVs) depends on direct and indirect protection. Following Malawi's introduction of the 13-valent PCV (PCV13) in 2011, we examined its impact on vaccine and non-vaccine serotype invasive pneumococcal disease among vaccine-eligible-age and vaccine-ineligible-age children and adults. METHODS: We did a prospective observational time-series analysis and a case-control study. We used data from between Jan 1, 2006, and Dec 31, 2018, from laboratory-based surveillance at a government hospital in Malawi. This period included 6 years before and 7 years after introduction of PCV13. By use of negative-binomial regression, we evaluated secular trend-adjusted incidence rate ratio (IRR) in vaccine serotype and non-vaccine serotype invasive pneumococcal disease before and after introduction of PCV. We compared predicted counterfactual incidence in hypothetical absence of vaccine with empirically observed incidence following vaccine introduction. The case-control study assessed vaccine effectiveness, comparing PCV uptake among cases of vaccine-eligible-age invasive pneumococcal disease versus matched community controls. FINDINGS: Surveillance covered 10 281 476 person-years of observation, with 140 498 blood and 63 291 cerebrospinal fluid cultures. A reduction in total (vaccine serotype plus non-vaccine serotype) invasive pneumococcal disease incidence preceded introduction of PCV: 19% (IRR 0·81, 95% CI 0·74 to 0·88, p<0·0001) among infants (<1 year old), 14% (0·86, 0·80 to 0·93, p<0·0001) among children aged 1-4 years, and 8% (0·92, 0·83 to 1·01, p=0·084) among adolescents and adults (≥15 years old). Among children aged 5-14 years there was a 2% increase in total invasive pneumococcal disease (1·02, 0·93 to 1·11, p=0·72). Compared with the counterfactually predicted incidence, incidence of post-PCV13 vaccine serotype invasive pneumococcal disease was 74% (95% CI 70 to 78) lower among children aged 1-4 years and 79% (76 to 83) lower among children aged 5-14 years, but only 38% (37 to 40) lower among infants and 47% (44 to 51) lower among adolescents and adults. Although non-vaccine serotype invasive pneumococcal disease has increased in incidence since 2015, observed incidence remains low. The case-control study (19 cases and 76 controls) showed vaccine effectiveness against vaccine serotype invasive pneumococcal disease of 80·7% (-73·7 to 97·9). INTERPRETATION: In a high-mortality, high-HIV-prevalence setting in Africa, there were significant pre-vaccine reductions in the incidence of invasive pneumococcal disease. 7 years after PCV introduction, although vaccine-attributable impact among vaccine-eligible-age children was significant, indirect effects benefitting unvaccinated infants and adults were not. Policy decisions should consider multiple alternative strategies for reducing disease burden, including targeted vaccination outside infant Expanded Programme of Immunization to benefit vulnerable populations. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, and National Institute for Health Research.