Repurposing of anti-malarial drugs for the treatment of tuberculosis: realistic strategy or fanciful dead end?

BACKGROUND: Drug repurposing offers a strategic alternative to the development of novel compounds, leveraging the known safety and pharmacokinetic profiles of medications, such as linezolid and levofloxacin for tuberculosis (TB). Anti-malarial drugs, including quinolones and artemisinins, are already applied to other diseases and infections and could be promising for TB treatment. METHODS: This review included studies on the activity of anti-malarial drugs, specifically quinolones and artemisinins, against Mycobacterium tuberculosis complex (MTC), summarizing results from in vitro, in vivo (animal models) studies, and clinical trials. Studies on drugs not primarily developed for TB (doxycycline, sulfonamides) and any novel developed compounds were excluded. Analysis focused on in vitro activity (minimal inhibitory concentrations), synergistic effects, pre-clinical activity, and clinical trials. RESULTS: Nineteen studies, including one ongoing Phase 1 clinical trial, were analysed: primarily investigating quinolones like mefloquine and chloroquine, and, to a lesser extent, artemisinins. In vitro findings revealed high MIC values for anti-malarials versus standard TB drugs, suggesting a limited activity. Synergistic effects with anti-TB drugs were modest, with some synergy observed in combinations with isoniazid or pyrazinamide. In vivo animal studies showed limited activity of anti-malarials against MTC, except for one study of the combination of chloroquine with isoniazid. CONCLUSIONS: The repurposing of anti-malarials for TB treatment is limited by high MIC values, poor synergy, and minimal in vivo effects. Concerns about potential toxicity at effective dosages and the risk of antimicrobial resistance, especially where TB and malaria overlap, further question their repurposing. These findings suggest that focusing on novel compounds might be both more beneficial and rewarding.

Post-tuberculosis treatment paradoxical reactions.

Paradoxical reactions (PR) to tuberculosis (TB) treatment are common during treatment, but have also been described after treatment. A presentation with recurrent signs or symptoms of TB after cure or completion of prior treatment needs to be differentiated between microbiological relapse and a paradoxical reaction. We searched all published literature on post-treatment PR, and present a synthesis of 30 studies, focusing on the epidemiology, diagnosis and management of this phenomenon. We report an additional case vignette. The majority of studies were of lymph node TB (LN-TB), followed by central nervous system TB (CNS-TB). A total of 112 confirmed and 42 possible post-treatment PR cases were reported. The incidence ranged between 3 and 14% in LN-TB and was more frequent than relapses, and between 0 and 2% in all TB. We found four reports of pulmonary or pleural TB post-treatment PR cases. The incidence did not differ by length of treatment, but was associated with younger age at initial diagnosis, and having had a PR (later) during treatment. Post-treatment PR developed mainly within the first 6 months after the end of TB treatment but has been reported many years later (longest report 10 years). The mainstays of diagnosis and management are negative mycobacterial cultures and anti-inflammatory treatment, respectively. Due to the favourable prognosis in LN-TB recurrent symptoms, a short period of observation is warranted to assess for spontaneous regression. In CNS-TB with recurrent symptoms, immediate investigation and anti-inflammatory treatment with the possibility of TB retreatment should be undertaken.

Performance evaluation of a combination Plasmodium dual-antigen CRP rapid diagnostic test in Lambaréné, Gabon.

PURPOSE: The consequent use of malaria rapid diagnostic tests (RDTs) preceding a treatment decision has improved the global management of malaria. A combination RDT, including an inflammation marker to potentially guide antibiotic prescription, could improve the management of acute febrile illness (AFI). METHODS: We performed a prospective, cross-sectional study in Gabon evaluating the STANDARD Malaria/CRP DUO (S-DUO) RDT. Participants aged 2 to 17 years with fever at presentation and/or a history of fever < 7 days were enrolled. Expert microscopy, SD Bioline Malaria Ag P.f/Pan test for malaria detection, and NycoCard CRP device for CRP were used as comparators. AFI cases were classified on a spectrum encompassing bacterial vs. non-bacterial infection. RESULTS: 415 participants with AFI were enrolled. S-DUO RDT sensitivity and specificity for malaria detection vs. microscopy were 99·1% (95·2-100%) and 72·7% (64·3-80·1%); and for CRP detection (20 mg/L and above) 86·9% (80-92%) and 87% (79·2-92·7%), respectively. The difference in CRP levels between bacterial infection (mean = 41·2 mg/L) and other causes of fever, measured from our study population using the Nycocard device, was statistically significant (p < 0·01); CRP precision-recall AUC to distinguish bacterial infection class vs. non-bacterial classifications was 0·79. CONCLUSION: S-DUO RDT is suitable for malaria detection in moderate-to-high malaria transmission settings such as in Lambaréné; however, a CRP band detection limit > 40 mg/L is more adequate for indication of antibiotic prescription for AFI cases in Gabon.

Drug-induced hepatotoxicity and association with slow acetylation variants NAT2*5 and NAT2*6 in Cameroonian patients with tuberculosis and HIV co-infection.

BACKGROUND: Human immunodeficiency virus (HIV) and tuberculosis (TB) are major contributors to morbidity and mortality in sub-Saharan Africa including Cameroon. Pharmacogenetic variants could serve as predictors of drug-induced hepatotoxicity (DIH), in patients with TB co-infected with HIV. We evaluated the occurrence of DIH and pharmacogenetic variants in Cameroonian patients. METHODS: Treatment-naïve patients with HIV, TB or TB/HIV co-infection were recruited at three hospitals in Cameroon, between September 2018 and November 2019. Appropriate treatment was initiated, and patients followed up for 12 weeks to assess DIH. Pharmacogenetic variants were assessed by allele discrimination TaqMan SNP assays. RESULTS: Of the 141 treatment naïve patients, the overall incidence of DIH was 38% (53/141). The highest incidence of DIH, 52% (32/61), was observed among HIV patients. Of 32 pharmacogenetic variants, the slow acetylation variants NAT2*5 was associated with a decreased risk of DIH (OR: 0.4; 95%CI: 0.17-0.96; p = 0.038), while NAT2*6 was found to be associated with an increased risk of DIH (OR: 4.2; 95%CI: 1.1-15.2; p = 0.017) among patients treated for TB. Up to 15 SNPs differed in ≥ 5% of allele frequencies among African populations, while 25 SNPs differed in ≥ 5% of the allele frequencies among non-African populations, respectively. CONCLUSIONS: DIH is an important clinical problem in African patients with TB and HIV. The NAT2*5 and NAT2*6 variants were found to be associated with DIH in the Cameroonian population. Prior screening for the slow acetylation variants NAT2*5 and NAT2*6 may prevent DIH in TB and HIV-coinfected patients.

Clinical Characteristics and Outcomes Among Travelers With Severe Dengue : A GeoSentinel Analysis.

BACKGROUND: Dengue virus is a flavivirus transmitted by Aedes mosquitoes and is an important cause of illness worldwide. Data on the severity of travel-associated dengue illness are limited. OBJECTIVE: To describe the epidemiology, clinical characteristics, and outcomes among international travelers with severe dengue or dengue with warning signs as defined by the 2009 World Health Organization classification (that is, complicated dengue). DESIGN: Retrospective chart review and analysis of travelers with complicated dengue reported to GeoSentinel from January 2007 through July 2022. SETTING: 20 of 71 international GeoSentinel sites. PATIENTS: Returning travelers with complicated dengue. MEASUREMENTS: Routinely collected surveillance data plus chart review with abstraction of clinical information using predefined grading criteria to characterize the manifestations of complicated dengue. RESULTS: Of 5958 patients with dengue, 95 (2%) had complicated dengue. Eighty-six (91%) patients had a supplemental questionnaire completed. Eighty-five of 86 (99%) patients had warning signs, and 27 (31%) were classified as severe. Median age was 34 years (range, 8 to 91 years); 48 (56%) were female. Patients acquired dengue most frequently in the Caribbean (n = 27 [31%]) and Southeast Asia (n = 21 [24%]). Frequent reasons for travel were tourism (46%) and visiting friends and relatives (32%). Twenty-one of 84 (25%) patients had comorbidities. Seventy-eight (91%) patients were hospitalized. One patient died of nondengue-related illnesses. Common laboratory findings and signs were thrombocytopenia (78%), elevated aminotransferase (62%), bleeding (52%), and plasma leakage (20%). Among severe cases, ophthalmologic pathology (n = 3), severe liver disease (n = 3), myocarditis (n = 2), and neurologic symptoms (n = 2) were reported. Of 44 patients with serologic data, 32 confirmed cases were classified as primary dengue (IgM+/IgG-) and 12 as secondary (IgM-/IgG+) dengue. LIMITATIONS: Data for some variables could not be retrieved by chart review for some patients. The generalizability of our observations may be limited. CONCLUSION: Complicated dengue is relatively rare in travelers. Clinicians should monitor patients with dengue closely for warning signs that may indicate progression to severe disease. Risk factors for developing complications of dengue in travelers need further prospective study. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention, International Society of Travel Medicine, Public Health Agency of Canada, and GeoSentinel Foundation.

Epidemiology of Pathogens Listed as Potential Bioterrorism Agents, the Netherlands, 2009‒2019.

We provide incidences (cases/10 million persons) in the Netherlands during 2009-2019 for pathogens listed as potential bioterrorism agents. We included pathogens from the highest categories of the European Medicines Agency or the US Centers for Disease Control and Prevention. Notifiable diseases and recently published data were used to calculate the average annual incidence. Coxiella burnetii had the highest incidence because of a Q fever epidemic during 2007-2010. Incidence then decreased to 10.8 cases/. Pathogens with an incidence >1 were Brucella spp. (2.5 cases), Francisella tularensis (1.3 cases), and Burkholderia pseudomallei (1.1 cases). Pathogens with an incidence <1 were hemorrhagic fever viruses (0.3 cases), Clostridium botulinum (0.2 cases), and Bacillus anthracis (0.1 cases). Variola major and Yersinia pestis were absent. The generally low incidences make it unlikely that ill-meaning persons can isolate these pathogens from natural sources in the Netherlands. However, the pathogens are stored in laboratories, underscoring the need for biosecurity measures.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Clinical features, treatment outcomes and mortality risk of tuberculosis sepsis in HIV-negative patients: a systematic review and meta-analysis of case reports.

PURPOSE: Tuberculosis sepsis (TBS) is sepsis due to the Mycobacterium species causing tuberculosis (TB). It seems to be rare in HIV-negative patients and mainly individual case reports have been reported. This systematic review summarizes the epidemiology, clinical features, and treatment outcomes of TBS in HIV-negative patients. METHODS: An electronic search of PubMed, Embase, Web of Science, and Google Scholar was performed to identify published case reports of TBS between January 1991 and September 2022. RESULTS: Twenty-five articles reported 28 cases of TBS in HIV-negative patients, among which 54% (15/28) were women; with 50% (14/28) of patients not having reported predisposing factors. A total of 64% (18/28) of patients died, and the diagnosis was obtained for many of them only post-mortem. Two of the reports mentioned the BCG vaccination status. A higher proportion of deaths occurred in patients with delayed diagnosis of sepsis. The probability of survival of patients diagnosed with tuberculosis sepsis was 68% on day 10; 41% on day 20; and 33% on day 30 after admission. CONCLUSIONS: Our review showed TBS occurred in HIV-negative patients and some of them have no known immunocompromised underlying co-morbidity. TBS might not be rare as clinicians thought but might be prone to be missed. In endemic settings, M. tuberculosis etiology of sepsis should be accounted for early, irrespective of HIV infection status.

Research article network analysis of polymicrobial chronic wound infections in Masanga, Sierra Leone.

BACKGROUND: Chronic wounds are frequently colonized or infected with multiple bacterial or fungal species, which can both promote or inhibit each other. Network analyses are helpful to understand the interplay of these species in polymicrobial infections. Our aim was to analyse the network of bacterial and fungal species in chronic wounds. METHODS: Swabs (n = 163) from chronic wound infections (Masanga, Sierra Leone, 2019-2020) were screened for bacterial and fungal species using non-selective agars. Some of these wounds were suspected but not confirmed Buruli ulcer. Species identification was done with MALDI-TOF mass spectrometry. Network analysis was performed to investigate co-occurrence of different species within one patient. All species with n ≥ 10 isolates were taken into account. RESULTS: Of the 163 patients, 156 had a positive wound culture (median of three different species per patient; range 1-7). Pseudomonas aeruginosa (n = 75) was the dominating species with frequent co-detections of Klebsiella pneumoniae (21 cases; OR = 1.36, 95%CI: 0.63-2.96, p = 0.47), Staphylococcus aureus (14 cases; OR = 1.06, 95%CI: 0.44-2.55, p = 1) and Proteus mirabilis (13 cases; OR = 0.84, 95%CI: 0.35-1.99, p = 0.69). CONCLUSION: The culturome of chronic wounds in Sierra Leonean patients is highly diverse and characterized by the co-occurrence of P. aeruginosa, K. pneumoniae and S. aureus.

Long-term Memory Response After a Single Intramuscular Rabies Booster Vaccination 10-24 Years After Primary Immunization.

BACKGROUND: Published data regarding long-lasting immunological rabies memory after pre-exposure prophylaxis (PrEP) are scarce. We tested the hypothesis that rabies booster immunization elicits rapid anamnestic responses. METHODS: For this observational study, we included participants who had received PrEP 10-24 years before inclusion. We measured rabies antibody titers before, and on days 3, 7, and 14 after a single intramuscular booster. RESULTS: All 28 participants responded adequately regardless of route of administration or 2-dose vs 3-dose PrEP regimen. CONCLUSION: Rabies immunological memory is reactivated within 7 days after a single intramuscular booster immunization, even when administered 10-24 years after PrEP.

Incidence and Predictors of Community-Acquired Pneumonia in Patients With Hematological Cancers Between 2016 and 2019.

BACKGROUND: Patients with hematological cancers (HC) are at high risk of infections, in particular community-acquired pneumonia (CAP). Recent data on incidence and predictors of CAP among patients with HC are scarce. METHODS: We performed a cohort study (2016-2019) in 2 hospitals in the Netherlands among adults with HC to calculate incidence rates (IRs) of CAP. In addition, we performed a nested case-control study to identify predictors of CAP. RESULTS: We identified 275 CAP cases during 6264 patient-years of follow-up. The IR of CAP was 4390/100 000 patient-years of follow-up. Compared with the general population, IR ratios ranged from 5.4 to 55.3 for the different HCs. The case fatality and intensive care unit (ICU) admission rates were 5.5% and 9.8%, respectively. Predictors for CAP in patients with HC were male sex, anemia, lymphocytopenia, chronic kidney disease, cardiovascular disease, autologous and allogeneic stem cell transplantation, treatment with immunosuppressive medication for graft-vs-host disease, treatment with rituximab in the past year, and treatment with immunomodulators (lenalidomide, thalidomide, pomalidomide and/or methotrexate) in the past month. Independent predictors of a severe disease course (death or ICU admission) included neutropenia (odds ratio, 4.14 [95% confidence interval, 1.63-10.2]), pneumococcal pneumonia (10.24 [3.48-30.1]), chronic obstructive pulmonary disease (6.90 [2.07-23.0]), and the use of antibacterial prophylaxis (2.53 [1.05-6.08]). CONCLUSIONS: The burden of CAP in patients with HC is high, with significant morbidity and mortality rates. Therefore, vaccination against respiratory pathogens early in the disease course is recommended, in particular before starting certain immunosuppressive therapies.

Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). METHODS: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. CONCLUSIONS: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03334747).

Immunogenicity of a 5-dose pneumococcal vaccination schedule following allogeneic hematopoietic stem cell transplantation.

The optimal schedule of pneumococcal vaccination after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains controversial. The objective of this study was to investigate the immunogenicity of a 5-dose pneumococcal vaccination schedule in adult allo-HSCT recipients with and without immunosuppressive therapy. In this prospective cohort study, allo-HSCT recipients received four doses of the 13-valent pneumococcal conjugate vaccine (PCV13) and one dose of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) starting 4-6 months after allo-HSCT. PCV13 was administered at T0, T1, T2, and T8 (T = months from enrollment) and PPSV23 at T10. Serum was collected at T0, T4, T8, T10, and T12, and IgG levels were measured for all 24 vaccine serotypes by immunoassay. The primary outcome was overall seroprotection at T12 defined as an IgG concentration ≥1.3 µg/ml for 17/24 vaccine serotypes in allo-HCST recipients with and without immunosuppressive therapy at baseline. Secondary outcomes were serotype-specific seroprotection and dynamics of IgG levels. We included 89 allo-HSCT recipients in the final analysis. Overall seroprotection was 47% (15/32) for patients without immunosuppressive therapy at baseline versus 24% (11/46) for patients with immunosuppressive therapy (p = .03). Seroprotection was higher for PCV13 serotypes (78% and 54% respectively; p = .03) and lower for PPSV23-unique serotypes (28% and 13% respectively; p = .1). IgG concentrations increased significantly over time for all 24 serotypes. Concluding, although immunogenicity of PCV13 serotypes was reasonable, the poor response to PPSV23 serotypes resulted in an insufficient overall response to pneumococcal vaccination for allo-HSCT recipients. Research into vaccination strategies with higher-valent T-cell-dependent pneumococcal vaccines is needed.

Chronic wounds in Sierra Leone: pathogen spectrum and antimicrobial susceptibility.

PURPOSE: Chronic wounds are frequently caused by, or super-infected with, a broad spectrum of bacteria. To guide treatment, healthcare providers need to know the bacterial spectrum and antimicrobial resistance rates to be anticipated. As these data are largely missing for Sierra Leone, we performed a microbiological study on chronic wound infections. METHODS: Wound swabs were analysed for bacteria using culture-based methods. Antimicrobial susceptibility testing was done with Vitek2® automated system and EUCAST clinical breakpoints. Selected resistance phenotypes were confirmed by molecular methods (e.g. mecA/C) and genotyping. RESULTS: Of 163 included patients, 156 (95.7%) had a positive wound culture. Pseudomonas aeruginosa (n = 75), Klebsiella pneumoniae (n = 42), Proteus mirabilis (n = 31), Staphylococcus aureus-related complex (n = 31) were predominant. Among Gram-negative rods, resistance rates were high for piperacillin/tazobactam (3-67%), cefotaxime (19-71%), and ciprofloxacin (13-60%). Among isolates of the S. aureus-related complex, 55% were methicillin resistant (CC8, PVL-negative). CONCLUSION: The high antimicrobial resistance rates in bacteria from chronic wounds strongly speaks against the use of empirical systemic antibiotic therapy if patients do not show signs of systemic infections, and supports the strategy of local wound care.

Creatine kinase-(MB) and hepcidin as candidate biomarkers for early diagnosis of pulmonary tuberculosis: a proof-of-concept study in Lambaréné, Gabon.

BACKGROUND: The present study aimed to evaluate the diagnostic utility of creatine kinase-MB (CK-MB), hepcidin (HEPC), phospholipase A2 group IIA (PLa2G2A), and myosin-binding protein C (MYBPC1) for tuberculosis (TB). These four biomarkers are differentially regulated between quiescent Mycobacterium tuberculosis (Mtb) infected individuals (non-progressors to TB disease) and Mtb-infected TB disease progressors 6 months before the onset of symptoms. METHODS: We enrolled samples from patients experiencing moderate-to-severe pulmonary infections diseases including 23 TB cases confirmed by smear microscopy and culture, and 34 TB-negative cases. For each participant, the serum levels of the four biomarkers were measured using ELISA. RESULTS: The levels of CK-MB and HEPC were significantly reduced in patients with active TB disease. CK-MB median level was 2045 pg/ml (1455-4000 pg/ml) in active TB cases and 3245 pg/ml (1645-4000 pg/ml) in non-TB pulmonary diseases. Using the receiver operating characteristic curve (ROC) analysis, HEPC and CK-MB had the Area Under the Curve (AUC) of 79% (95% CI 67-91%) and 81% (95% CI 69-93%), respectively. Both markers correlated with TB diagnosis as a single marker. PLa2G2A and MYBPC1 with AUCs of 48% (95% CI 36-65%) and 62% (95% CI 48-76%) did not performed well as single biomarkers. The three markers'model (CK-MB-HEPC-PLa2G2A) had the highest diagnostic accuracy at 82% (95% CI 56-82%) after cross-validation. CONCLUSION: CK-MB and HEPC levels were statistically different between confirmed TB cases and non-TB cases. This study yields promising results for the rapid diagnosis of TB disease using a single marker or three biomarkers model.

Point-of-care ultrasound to assess volume status and pulmonary oedema in malaria patients.

PURPOSE: Fluid management is challenging in malaria patients given the risks associated with intravascular fluid depletion and iatrogenic fluid overload leading to pulmonary oedema. Given the limitations of the physical examination in guiding fluid therapy, we evaluated point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) and lungs as a novel tool to assess volume status and detect early oedema in malaria patients. METHODS: To assess the correlation between IVC and lung ultrasound (LUS) indices and clinical signs of hypovolaemia and pulmonary oedema, respectively, concurrent clinical and sonographic examinations were performed in an observational study of 48 malaria patients and 62 healthy participants across age groups in Gabon. RESULTS: IVC collapsibility index (CI) ≥ 50% on enrolment reflecting intravascular fluid depletion was associated with an increased number of clinical signs of hypovolaemia in severe and uncomplicated malaria. With exception of dry mucous membranes, IVC-CI correlated with most clinical signs of hypovolaemia, most notably sunken eyes (r = 0.35, p = 0.0001) and prolonged capillary refill (r = 0.35, p = 0.001). IVC-to-aorta ratio ≤ 0.8 was not associated with any clinical signs of hypovolaemia on enrolment. Among malaria patients, a B-pattern on enrolment reflecting interstitial fluid was associated with dyspnoea (p = 0.0003), crepitations and SpO2 ≤ 94% (both p < 0.0001), but not tachypnoea (p = 0.069). Severe malaria patients had increased IVC-CI (p < 0.0001) and more B-patterns (p = 0.004) on enrolment relative to uncomplicated malaria and controls. CONCLUSION: In malaria patients, POCUS of the IVC and lungs may improve the assessment of volume status and detect early oedema, which could help to manage fluids in these patients.

PREvalence Study on Surgical COnditions (PRESSCO) 2020: A Population-Based Cross-Sectional Countrywide Survey on Surgical Conditions in Post-Ebola Outbreak Sierra Leone.

BACKGROUND: Understanding the burden of diseases requiring surgical care at national levels is essential to advance universal health coverage. The PREvalence Study on Surgical COnditions (PRESSCO) 2020 is a cross-sectional household survey to estimate the prevalence of physical conditions needing surgical consultation, to investigate healthcare-seeking behavior, and to assess changes from before the West African Ebola epidemic. METHODS: This study (ISRCTN: 12353489) was built upon the Surgeons Overseas Surgical Needs Assessment (SOSAS) tool, including expansions. Seventy-five enumeration areas from 9671 nationwide clusters were sampled proportional to population size. In each cluster, 25 households were randomly assigned and visited. Need for surgical consultations was based on verbal responses and physical examination of selected household members. RESULTS: A total of 3,618 individuals from 1,854 households were surveyed. Compared to 2012, the prevalence of individuals reporting one or more relevant physical conditions was reduced from 25 to 6.2% (95% CI 5.4-7.0%) of the population. One-in-five conditions rendered respondents unemployed, disabled, or stigmatized. Adult males were predominantly prone to untreated surgical conditions (9.7 vs. 5.9% women; p < 0.001). Financial constraints were the predominant reason for not seeking care. Among those seeking professional health care, 86.7% underwent surgery. CONCLUSION: PRESSCO 2020 is the first surgical needs household survey which compares against earlier study data. Despite the 2013-2016 Ebola outbreak, which profoundly disrupted the national healthcare system, a substantial reduction in reported surgical conditions was observed. Compared to one-time measurements, repeated household surveys yield finer granular data on the characteristics and situations of populations in need of surgical treatment.

On prioritising global health's triple crisis of sepsis, COVID-19 and antimicrobial resistance: a mixed-methods study from Malawi.

Sepsis causes 20% of global deaths, particularly among children and vulnerable populations living in developing countries. This study investigated how sepsis is prioritised in Malawi's health system to inform health policy. In this mixed-methods study, twenty multisectoral stakeholders were qualitatively interviewed and asked to quantitatively rate the likelihood of sepsis-related medium-term policy outcomes being realised. Respondents indicated that sepsis is not prioritised in Malawi due to a lack of local sepsis-related evidence and policies. However, they highlighted strong linkages between sepsis and maternal health, antimicrobial resistance and COVID-19, which are already existing national priorities, and offers opportunities for sepsis researchers as policy entrepreneurs. To address the burden of sepsis, we recommend that funding should be channelled to the generation of local evidence, evidence uptake, procurement of resources and treatment of sepsis cases, development of appropriate indicators for sepsis, adherence to infection prevention and control measures, and antimicrobial stewardship.

Searching and Finding the Hidden Treasure: A Retrospective Analysis of Rickettsial Disease Among Dutch International Travelers.

BACKGROUND: Rickettsial disease (RD) is a prevalent and underestimated cause of febrile illness worldwide, especially in the absence of an inoculation eschar. We attempted to quantify this underestimation at our clinic, by investigating past cases of febrile illness in travelers who had tested negative for leptospirosis, a disease that can initially present similarly to non-eschar RD, and which we routinely consider when other important causes of unspecified febrile illness have tested negative. METHODS: We performed a retrospective analysis in febrile returned travelers from Asia, Africa, or the Americas between 2010 and 2017, who had tested negative for leptospirosis. Serologic immunofluorescence assays were performed for Orientia tsutsugamushi (scrub typhus), typhus group, and spotted fever group RD. We performed a medical records review of all patients who tested positive. In case of a fitting medical history, cases were deemed either confirmed (based on convalescent serology) or suspected (based on single serology). RESULTS: Among 97 patients, convalescent serology was available in 16 (16.5%) patients, and a single serology in 81 (83.5%) patients. RD was the likely diagnosis in 8 of 16 (50.0%) patients with convalescent serology, and in 8 of 81 (9.9%) with single serology. Of the 16 confirmed/suspected cases, 11 (69%) had been missed and 7 (44%) had not received adequate empiric antibiotic therapy. CONCLUSIONS: This study shows that non-eschar RD is an important and poorly recognized cause of illness in travelers, even in a specialized travel clinic. A lower threshold to test and treat for RD is warranted in returning travelers with febrile illness.

Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.

BACKGROUND: Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. METHODS: In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. FINDINGS: Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [24%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50). INTERPRETATION: Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. FUNDING: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.