Studies on the global burden of sepsis confirm its major mortality, morbidity, and societal impact, with 85% of cases and deaths occurring in low-income and middle-income countries. Importantly, these analyses have blurred the boundaries between sepsis, defined as a dysregulated host response to infection causing life-threatening organ dysfunction, and endemic and emerging infectious diseases, such as malaria, leptospirosis, tuberculosis, and gastroenteric illnesses, which often follow clinical trajectories distinct from those of so-called standard sepsis. Framing these disease-specific deaths within the broader context of sepsis highlights the unacceptably high mortality from preventable and treatable endemic infectious diseases in resource-limited settings. However, important differences remain. Sepsis management focuses on early diagnosis, timely intervention, organ support, and, increasingly, patient stratification and precision-targeted therapies. In contrast, endemic and emerging infectious diseases often involve lengthy and complex courses before hospital admission and require disease-specific diagnostic and therapeutic approaches. In this Personal View, we discuss how this conceptual overlap affects estimates of disease burden, interpretation of pathophysiological mechanisms, therapeutic decision making, and the development of precision medicine strategies. We propose applying disease-specific stratification to endemic and emerging infectious diseases to distinguish milder cases from life-threatening forms associated with organ dysfunction (sepsis from an endemic and emerging infectious disease [SEEID]). Early recognition and diagnosis of SEEIDs are essential, and expert disease-specific guidance is urgently needed, particularly given the scarcity of randomised clinical trials evaluating treatment strategies for these conditions.
BACKGROUND:Recognition of the 2026 Bundibugyo virus (BDBV) disease outbreak was delayed by adverse political circumstances and logistical constraints. The deployed test was intended for Ebola virus rather than BDBV, a distinct viral species. A virus isolate representing the outbreak strain is unavailable, and regulatory demands on diagnostics have increased. We aimed to provide reference virus material and validate diagnostic tests to aid in regulatory clearance. METHODS:We generated an inactivated, patient-derived BDBV genome reference standard (GRS; 2·4 × 106 copies per mL) from a throat swab of a patient admitted to Charité-Universitätsmedizin Berlin, Berlin, Germany. We distributed the GRS internationally; tested its stability over 90 h at -80°C, 4°C, 20°C, and 37°C; and analytically validated four pilot real-time RT-PCR diagnostic tests. We assessed the sensitivity and run-to-run consistency of the diagnostic tests at the coordinating laboratory and specificity in a network of nine laboratories, using cultured pathogen materials (52-62 samples per test, representing 30 pathogens) and clinical leftover samples (120-172 samples per assay, representing 22 differential diagnostic aetiologies). Detection outcomes from all four tests were pooled in a probit model with assay class as a covariate to estimate the ratio of 95% limits of detection between BDBV-specific and broad-range assays. FINDINGS:Relative to storage at -80°C, GRS viral load after 90 h was reduced 1·15-fold (95% CI 0·96-1·37, p=0·12) at 4°C and at 20°C, and 2·67-fold (2·24-3·19, p<0·0001) at 37°C. 95% limits of detection were 8·4 copies per μL (95% CI 3·2-87·2) for the Altona Diagnostics RealStar Filovirus Screen RT-PCR Kit 1.0, 2·4 copies per μL (1·0-20·6) for the Altona Diagnostics RealStar Bundibugyo RT-PCR Kit 1.0, 11·9 copies per μL (4·7-139·4) for the Roche LightMix Modular Ebola Virus Test Kit, and 2·5 copies per μL (1·2-14·4) for the Roche LightMix Modular Bundibugyo Virus Test Kit. In the pooled probit model, the 95% limits of detection of BDBV-specific assays were 0·24 times (95% CI 0·13-0·47) that of broad-range assays-ie, approximately four times lower. Decentralised evaluation of specificity in nine laboratories was completed within 15 days, and no cross-reactivity occurred in cultured or clinical panels. INTERPRETATION:Decentralised evaluation of diagnostic test kits can facilitate emergency-use decisions, national authorisation, or regulatory review in ongoing outbreaks. This approach defines a course of action for laboratory networks to accelerate the development and assessment of diagnostic medical countermeasures. It bridges the interval between first outbreak recognition and availability of fully certified commercial diagnostic tests, especially for rare, high-consequence pathogens for which virus isolates or clinical materials are scarce. FUNDING:None.
BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir-ritonavir improved long COVID symptoms. METHODS:We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir-100 mg ritonavir twice daily, then 100 mg ritonavir-placebo); 25 days of active intervention (300 mg nirmatrelvir-100 mg ritonavir twice daily); or 25 days of placebo-ritonavir (100 mg ritonavir-placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete. FINDINGS:Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38-59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI -10·4 to 16·8, p=0·65) for the 25-day regimen and -2·2% (-15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were -6·4% (-18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and -0·1% (-12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were -7·8% (-19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (-11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study. INTERPRETATION:Nirmatrelvir-ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed. FUNDING:National Institutes of Health.
BACKGROUND:Cost-effective, socially acceptable, and sustainable strategies for dengue vector control are urgently needed, particularly in settings with low resources for prevention measures. Following preliminary entomological and safety studies, we evaluated a novel dual-action insecticidal protective coating targeting domestic water containers. METHODS:We conducted a cluster-randomised trial in 20 community clusters (each consisting of about 2000 households) in metropolitan Cúcuta, Colombia. Ten matched pairs of clusters were defined on the basis of sociodemographic, environmental, and epidemiological characteristics; within each pair, clusters were randomly assigned (1:1) to intervention or control by simple lottery. The control group received no study-specific treatment, but households in both study groups remained subject to standard routine municipal vector control activities. Entomological and sociodemographic surveys were conducted at baseline in 250 households per cluster. The intervention consisted of applying the protective coating (containing microencapsulated pyriproxyfen and alpha-cypermethrin) to indoor ground-level water containers (used for cleaning and washing) with support from trained community health volunteers. Follow-up over 12 months included two interim entomological surveys (40 households per cluster) and a final survey (250 households per cluster). Dengue incidence was obtained from the national surveillance system (SIVIGILA). Intervention effects were estimated using a difference-in-differences approach with Poisson regression accounting for clustering. The primary outcome was the change in annual dengue incidence across all clusters. Secondary outcomes included Aedes infestation indices. Direct intervention costs were also estimated. This study is registered with ClinicalTrials.gov (NCT06268691) and is complete. FINDINGS:Between Dec 3, 2019, and Feb 27, 2020, 20 clusters (ten matched pairs) were enrolled and randomly assigned to the study groups. Ten clusters were allocated to the control group (18 410 households) and ten to the intervention group (20 029 households). In the intervention group, 15 580 households were eligible for treatment, of which 13 803 (88·6%) received the protective coating on water tanks. In the control group, 15 594 households were eligible and received no treatment. At follow-up in 2022, pooled annual dengue incidence was 337·1 cases per 100 000 population (95% CI 299·3-378·4) in the intervention clusters and 528·5 cases per 100 000 population (478·9-581·9) in the control clusters. The incidence rate ratio comparing changes between 2022 and 2021 for intervention versus control clusters was 0·55 (95% CI 0·45-0·68; p<0·0001). The absolute difference-in-differences was 352·7 cases per 100 000 population (95% CI 31·0-674·4; p=0·033). Aedes infestation indices decreased significantly, including the house index (difference-in-differences effect 31·7 percentage points, 95% CI 28·4-35·0; p<0·0001) and the pupae per person index (0·8 pupae per person, 95% CI 0·2-1·4; p=0·0090). The estimated direct cost of the intervention was US$2 per household per year. INTERPRETATION:The intervention reduced dengue incidence and Aedes aegypti infestation over 12 months. A single application of a dual-action insecticidal coating to domestic water containers represents a scalable and affordable complementary strategy for dengue control in endemic urban settings. FUNDING:Colombian Ministry of Science, Technology and Innovation (Minciencias), Government of Norte de Santander, Colombia, and the Centre for Planetary Health, University of Freiburg. TRANSLATION:For the Spanish translation of the abstract see Supplementary Materials section.
BACKGROUND:Shigella is the leading cause of morbidity and mortality in children younger than 5 years in low- and middle-income countries and is a major actor in antimicrobial resistance. An effective vaccine is urgently needed. SF2a-TT15, a conjugate featuring a synthetic 15-mer oligosaccharide surrogate of the O-antigen component of Shigella flexneri 2a (SF2a) lipopolysaccharide, was previously shown to be safe and immunogenic in a first-in-human study. We aimed to assess its safety and immunogenicity in infants from an endemic setting, the target population for a Shigella vaccine. METHODS:We conducted a phase 2a, age-descending, dose-escalating, double-blind, randomised, placebo-controlled study at the Clinical Research Center, Kenya Medical Research Institute/Walter Reed Army Institute of Research (Kericho, Kenya). Healthy adults aged 18-50 years and healthy children aged 2-5 years with a weight-for-age Z score of -2 or more were randomly assigned (3:1) to receive a 10 μg oligosaccharide dose of SF2a-TT15 adjuvanted with aluminium hydroxide (alum) or matching placebo. Healthy infants aged 9 months plus or minus 1 month with a weight-for-age Z score of -2 or more were randomly assigned (3:3:3:3:1:1) in a stepwise manner to receive a 2 μg oligosaccharide dose of non-alum-adjuvanted SF2a-TT15, a 2 μg oligosaccharide dose of alum-adjuvanted SF2a-TT15, a 10 μg oligosaccharide dose of non-alum-adjuvanted SF2a-TT15, a 10 μg oligosaccharide dose of alum-adjuvanted SF2a-TT15, non-alum-adjuvanted placebo, or alum-adjuvanted placebo, concomitantly with routine measles-rubella vaccination. Study products were administered intramuscularly on day 0, 90, and 270, with a 6-month follow-up after the last injection. The randomisation sequence was computer-generated and randomisation was stratified by cohort and treatment group. Syringes were over-labelled before injection to maintain masking; all clinical site teams were masked except the pharmacist team, including the pharmacy data quality monitoring team, and one person in the Institut Pasteur team. All participants were also masked. Progression between cohorts and dose levels was overseen by an independent data monitoring committee. The primary outcomes were the incidence of adverse events in all cohorts and immunogenicity in the infant cohort, as measured at days 14 and 28 after each injection and at the end of the study by serum IgG antibodies to SF2a lipopolysaccharide and proportion of responders. Safety endpoints were analysed in all participants receiving at least one injection and immunogenicity endpoints were analysed in the full analysis set and in the per-protocol analysis set. This study is registered with ClinicalTrials.gov, NCT04602975, and is completed. FINDINGS:Enrolment was between Oct 26, 2020, and Jan 5, 2022. 54 adults were screened for eligibility, 16 of whom were enrolled and randomly assigned to the adjuvanted 10 μg oligosaccharide dose (n=12) or adjuvanted placebo (n=4). 30 children were screened for eligibility, 16 of whom were enrolled and randomly assigned to the adjuvanted 10 μg oligosaccharide dose (n=12) or adjuvanted placebo (n=4). 413 infants were screened for eligibility, 216 of whom were enrolled and randomly assigned to the non-adjuvanted 2 μg oligosaccharide dose (n=46), the adjuvanted 2 μg oligosaccharide dose (n=44), the non-adjuvanted 10 μg oligosaccharide dose (n=41), the adjuvanted 10 μg oligosaccharide dose (n=43), non-adjuvanted placebo (n=22), or adjuvanted placebo (n=20). 112 (52%) of 215 infants in the safety analysis set were female and 103 (48%) were male. The SF2a-TT15 glycoconjugate was well tolerated and induced high serum IgG geometric mean titres (GMTs) to SF2a lipopolysaccharide in adults and children. In infants, SF2a-TT15 was well tolerated at both doses, adjuvanted or non-adjuvanted, with no vaccine-related serious adverse events. 202 (94%) of 216 infants had at least one unsolicited adverse event. 182 (90%) of these infants had adverse events considered not related to study products. No significant differences in the frequency of unsolicited adverse events were reported between any treatment groups (p>0·05 for all comparisons). 1235 adverse events were recorded in the infant cohort, most being unrelated to the study product (1226 [99%]) and of mild (744 [60%]) or moderate (435 [35%]) grading. At 28 days after each injection and for both doses, adjuvanted or non-adjuvanted, SF2a-TT15 induced significantly higher serum IgG GMTs to SF2a lipopolysaccharide compared with corresponding GMTs in placebo recipients (p=0·047 for the non-adjuvanted 2 μg oligosaccharide dose 28 days after the first injection and p<0·001 for all the other comparisons). The highest GMTs were elicited in the adjuvanted 10 μg oligosaccharide dose group (11 240·0 [95% CI 6187·6-20 418·0]), corresponding to a geometric mean ratio (GMR) of 55·0 (95% CI 30·3-99·7) with 93·8% (95% CI 79·2-99·2) of responders at 14 days after the first injection, and increased to 28 528·3 (18 805·1-43 279·0), corresponding to a GMR of 139·6 (79·5-245·2) with 100% (89·1-100·0) of responders at 14 days after the second injection, with no further increase after the boost vaccine. The adjuvanted 2 μg oligosaccharide dose group had significantly higher serum IgG GMTs to SF2a lipopolysaccharide than the non-adjuvanted 2 μg oligosaccharide dose group (p<0·001 at day 28 after the two first injections, p=0·022 at 28 days after the boost vaccine), but GMT were not significantly different between the adjuvanted and non-adjuvanted 10 μg oligosaccharide dose SF2a-TT15 groups (p>0·5 for all timepoints). At the end of the study, for both doses, adjuvanted or not, GMTs were decreased but were still significantly elevated compared with the placebo group (p<0·001). INTERPRETATION:SF2a-TT15 is well tolerated and strongly immunogenic in Kenyan infants, showing potential for further development. Available data support advancing a multivalent synthetic glycan-based Shigella vaccine. FUNDING:Gates Foundation, The Wellcome Trust, The European Union Seventh Framework Programme, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases, and Institut Pasteur. TRANSLATION:For the Kiswahili translation of the abstract see Supplementary Materials section.
