Assessing the Incidence of Snakebites in Rural Gabon-A Community-Based, Cross-Sectional Pilot Survey.

Snakebite envenoming (SBE) is a neglected tropical disease (NTD). Community-based studies from sub-Saharan Africa are urgently required as data on the incidence are scarce. This study aimed to determine the lifetime prevalence of snakebites in rural Gabon by preparing the conduct of a larger regional survey. A cross-sectional community-based epidemiological survey in Sindara, Ngounie province, was conducted. Households were interviewed about the history of snakebites of household members to calculate lifetime prevalence. In addition, the average annual incidence rate per 100,000 over the last 5 years was calculated. A total of 771 inhabitants were enrolled, of which 5 (0.65%; 95% confidence interval (95% CI: 0.2-1.5%)) were victims of snakebites. Over the past 5 years, annual incidence was 77 bites per 100,000 (95% CI: 0-620). This study provides a first rough estimate of the incidence of SBE from rural central Gabon, demonstrating the importance of this NTD. Key Contribution: The estimated annual incidence of snakebites found was 77 per 100,000. Snakebites occurred mainly during agricultural activities.

A randomized assessors-blind clinical trial to evaluate the safety and the efficacy of albendazole alone and in combination with mebendazole or pyrantel for the treatment of Trichuris trichiura infection in school-aged children in Lambaréné and surroundings.

Helminthiasis remains a public health issue in endemic areas. Various drugs have been proposed to improve efficacy against helminths. The study aimed to assess the safety and efficacy of three different anthelmintic combinations to treat Trichuris trichiura infections. We conducted a randomized assessors-blind clinical trial involving children aged 2-17 years with T. trichiura. Participants were randomly assigned to one of three treatment arms. On the first and third days, all participants got albendazole 400 mg, and on the second day, albendazole (arm A), mebendazole 500 mg (arm B), or pyrantel 125 mg/kg (arm C). We assessed treatment efficacy using the cure rate (CR) and egg reduction rate (ERR) at 3 and 6 weeks post-treatment. At 3 weeks post-treatment, ERR and CR were highest in study arm A [ERR = 94%, 95% confidence interval (CI): 92-95; CR = 71%; 95% CI: 58-81] compared to the B and C arms. Decrease in ERR was significant only for arm B versus arm A (P-value <0.001); decrease in ERR was significant for arms B and C (P-value <0.001). No statistical difference was observed in CR when comparing arms A and B (P-value =1.00) and C (P-value =0.27). At 6 weeks, a decrease in ERR was observed in three arms, significant only for arm C, 81% (95% CI: 78-83). A significant increase in egg counts was observed between 3 and 6 weeks post-treatment. All treatments were safe with mild adverse events. Albendazole 400 mg/day (arm A) showed the highest efficacy against trichuriasis. Nonetheless, this treatment regimen was able to cure half of the treated individuals highlighting concerns about controlling the transmission of T. trichiura.CLINICAL TRIALRegistered at ClinicalTrials.gov (NCT04326868).

Dynamics of Plasmodium species and genotype diversity in adults with asymptomatic infection in Gabon.

OBJECTIVES: We investigated the diversity and dynamics of Plasmodium infection in serially collected samples from asymptomatic participants of a clinical trial assessing the efficacy and safety of ivermectin in Gabon. We checked whether the baseline sample reflected the P. falciparum genotype and Plasmodium species diversity seen over 7 days of follow-up. METHODS: Blood samples were collected at inclusion, every 8 hours until hour 72, daily until day 7, and on day 14. Plasmodium species was determined by qPCR and pfmsp1 length polymorphism was assessed for P. falciparum genotyping. RESULTS: In 17/48 (35%) individuals, all pfmsp1 genotypes identified during the assessed period were detected at baseline; in 31/48 (65%), new genotypes were found during follow-up. Additional sampling at hour 24 allowed the identification of all genotypes seen over 7 days in 50% of the individuals. Ivermectin did not impact the genotype dynamics. Mixed Plasmodium spp. infections were detected in 28/49 (57%) individuals at baseline, and detection of non-falciparum infections during follow-up varied. CONCLUSIONS: Our results reveal complex intra-host dynamics of P. falciparum genotypes and Plasmodium species and underscore the importance of serial sampling in clinical trials for antimalarial drugs with asymptomatically P. falciparum-infected individuals. This might allow a more accurate identification of genotypes in multiple infections, impacting the assessment of drug efficacy.

Analysis of diagnostic test outcomes in a large loiasis cohort from an endemic region: Serological tests are often false negative in hyper-microfilaremic infections.

BACKGROUND: The parasitic disease loiasis is associated with significant morbidity and mortality. Individuals with hyper-microfilaremia (greater than 20,000 microfilariae per mL of blood) may suffer from serious treatment-related or spontaneous adverse events. Diagnosing loiasis remains complex and primarily relies on direct parasite detection. In this study, we analyzed the performance of various diagnostic tests and the influence of parasitological and clinical factors on test outcomes in samples from individuals living in an endemic region. METHODS: Data and samples were collected from rural Gabon. Loiasis was defined as either detectable microfilaremia, or a positive history of eyeworm as assessed by the RAPLOA questionnaire. Diagnostic testing included a quantitative PCR (qPCR) for detection of Loa loa DNA in blood samples, an in-house crude L. loa antigen IgG ELISA, and a rapid test for antibodies against the Ll-SXP-1 antigen (RDT). Sensitivity and specificity were determined for each test and factors potentially influencing outcomes were evaluated in an exploratory analysis. RESULTS: ELISA, RDT and qPCR results were available for 99.8%, 78.5%, and 100% of the 1,232 participants, respectively. The ELISA and RDT had only modest diagnostic accuracy. qPCR was specific for L. loa microfilaremia and Cycle threshold values correlated with microfilarial density. Anti-L. loa IgG levels were highest in occult loiasis, and antibody levels correlated inversely with L. loa microfilarial density as did RDT line intensities. Only 84.6% and 16.7% of hyper-microfilaremic individuals tested positive by ELISA (11/13) and RDT (2/12), respectively. CONCLUSION: None of the tests demonstrated high sensitivity and specificity for loiasis. Indirect diagnostic assays were characterized by low specificity. Additionally, hyper-microfilaremic individuals often tested negative by RDT and ELISA, indicating that these tests are not suitable for individual case management in endemic populations.

Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study.

BACKGROUND: Children are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine-artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM). METHODS: An integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum, body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population). PA was administered once daily for 3 days; two trials included the comparator artemether-lumefantrine (AL). PCR-adjusted day 28 adequate clinical and parasitological response (ACPR) was evaluated. Real-world PA granules safety and effectiveness was also considered. RESULTS: In the integrated safety analysis, 63.9% (95% CI 60.2, 67.4; 426/667) of patients had adverse events following PA and 62.0% (95% CI 56.9, 66.9; 222/358) with AL. Vomiting was more common with PA (7.8% [95% CI 6.0, 10.1; 52/667]) than AL (3.4% [95% CI 1.9, 5.8; 12/358]), relative risk 2.3 (95% CI 1.3, 4.3; P = 0.004), occurring mainly following the first PA dose (6.7%, 45/667), without affecting re-dosing or adherence. Prolonged QT interval occurred less frequently with PA (3.1% [95% CI 2.1, 4.8; 21/667]) than AL (8.1% [95% CI 5.7, 11.4; 29/358]), relative risk 0.39 (95% CI 0.22, 0.67; P = 0.0007). In CANTAM, adverse events were reported for 17.7% (95% CI 16.3, 19.2; 460/2599) of patients, most commonly vomiting (5.4% [95% CI 4.6, 6.4; 141/2599]), mainly following the first dose, (4.5% [117/2599]), with all patients successfully re-dosed, and pyrexia (5.4% [95% CI 4.6, 6.3; 140/2599]). In the two comparative clinical trials, Day 28 ACPR in the per-protocol population for PA was 97.1% (95% CI 94.6, 98.6; 329/339) and 100% (95% CI 99.3, 100; 514/514) versus 98.8% (95% CI 95.7, 99.9; 165/167) and 98.4% (95% CI 95.5, 99.7; 188/191) for AL, respectively. In CANTAM, PA clinical effectiveness was 98.0% (95% CI 97.3, 98.5; 2273/2320). CONCLUSIONS: Anti-malarial treatment with PA paediatric granules administered once daily for 3 days was well tolerated in children and displayed good clinical efficacy in clinical trials, with effectiveness confirmed in a real-world study. Trial registration Clinicaltrials.gov: SP-C-003-05: identifier NCT00331136; SP-C-007-07: identifier NCT0541385; SP-C-021-15: identifier NCT03201770. Pan African Clinical Trials Registry: SP-C-013-11: identifier PACTR201105000286876.

Safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnant women with HIV from Gabon and Mozambique: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin-piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. METHODS: For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin-piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2-10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16-27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. FINDINGS: From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03-0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27-0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. INTERPRETATION: In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin-piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.

The African eye worm: current understanding of the epidemiology, clinical disease, and treatment of loiasis.

Loa loa, the African eye worm, is a filarial pathogen transmitted by blood-sucking flies of the genus Chrysops. Loiasis primarily affects rural populations residing in the forest and adjacent savannah regions of central and west Africa, where more than 20 million patients are chronically infected in medium and high transmission regions. For a long time, loiasis has been regarded as a relatively benign condition. However, morbidity as measured by disability-adjusted life-years lost might be as high as 400 per 100 000 residents, and the population attributable fraction of death is estimated at 14·5% in highly endemic regions, providing unequivocal evidence for the substantial disease burden that loiasis exerts on affected communities. The clinical penetrance of loiasis is variable and might present with the classic signs of eye worm migration or transient Calabar swellings, but might include common, unspecific symptoms or rare but potentially life-threatening complications. Although adult worm migration seems most closely linked to symptomatic disease, high levels of microfilaraemia are associated with clinically important complications and death. Loiasis remains difficult to diagnose, treat, and control due to an absence of reliable point-of-care diagnostic assays, safe and efficacious drugs, and cost-effective prevention strategies. This Review summarises the major advances in our understanding of loiasis made over the past decade and highlights the many gaps that await to be addressed urgently.

Efficacy and safety of ivermectin for the treatment of Plasmodium falciparum infections in asymptomatic male and female Gabonese adults - a pilot randomized, double-blind, placebo-controlled single-centre phase Ib/IIa clinical trial.

BACKGROUND: Ivermectin's mosquitocidal effect and in vitro activity against Plasmodium falciparum asexual stages are known. Its in vivo blood-schizonticidal efficacy is unknown. Ivermectin's tolerability and efficacy against P. falciparum infections in Gabonese adults were assessed. METHODS: The study consisted of a multiple dose stage and a randomized, double-blind, placebo-controlled stage. Adults with asymptomatic P. falciparum parasitaemia (200-5000 parasites/µl) were enrolled. First, three groups of five participants received 200 µg/kg ivermectin once daily for one, two, and three days, respectively, and then 34 participants were randomized to 300 µg/kg ivermectin or placebo once daily for 3 days. Primary efficacy outcome was time to 90% parasite reduction. Primary safety outcomes were drug-related serious and severe adverse events (Trial registration: PACTR201908520097051). FINDINGS: Between June 2019 and October 2020, 49 participants were enrolled. Out of the 34 randomized participants, 29 (85%) completed the trial as per protocol. No severe or serious adverse events were observed. The median time to 90% parasite reduction was 24.1 vs. 32.0 h in the ivermectin and placebo groups, respectively (HR 1.38 [95% CI 0.64 to 2.97]). INTERPRETATION: Ivermectin was well tolerated in doses up to 300 µg/kg once daily for three days and asymptomatic P. falciparum asexual parasitaemia was reduced similarly with this dose of ivermectin compared to placebo. Further studies are needed to evaluate plasmodicidal effect of ivermectin at higher doses and in larger samples. FUNDING: This study was funded by the Centre de Recherches Médicales de Lambaréné and the Centre for Tropical Medicine of the Bernhard Nocht Institute for Tropical Medicine.

Community health workers in clinical research at the example of a phase IIIb/ IV antimalarial drug trial conducted in five African countries.

Global health, particularly in underserved settings can benefit immensely from well-trained community health workers (CHWs) supporting primary healthcare interventions. They can reduce morbidity and mortality of infectious diseases like malaria. Disease control programs can particularly benefit from a tight link between CHWs and communities and several studies have shown the benefit of the participation of non-facility-based CHWs in malaria control program activities for reducing malaria-related mortality in children. Because CHWs are often part of and trusted by served communities, they can also be an important resource to address challenges faced by their communities. Where post-marketing surveillance systems are underserved, they can relay important information about suspected safety signals and factors affecting therapeutic effectiveness in their communities. The CANTAM-Pyramax® trial was a phase IIIb/ IV cohort event monitoring study conducted at six centers in five African countries. To assess real-world effectiveness and safety of the anti-malarial pyronaridine-artesunate in 8560 malaria episodes, follow-up was not primarily conducted by medical staff but by specifically trained CHWs. This perspective paper discusses how the participation of a CHW workforce can be of benefit for effectiveness trials in limited-resource settings, using the example of the CANTAM-Pyramax trial.

Efficacy, safety, and tolerability of albendazole and ivermectin based regimens for the treatment of microfilaraemic loiasis in adult patients in Gabon: A randomized controlled assessor blinded clinical trial.

BACKGROUND: There is a lack of systematic evidence for strategies to control loiasis transmission in highly endemic regions. Here we assessed albendazole and ivermectin based treatment regimens to reduce Loa loa microfilaraemia in Gabon. METHODS: Eligible adult patients with L. loa microfilaraemia between 5,000 and 50,000 microfilariae/ml were randomized to either a control or one of three intervention groups (1:2:2:2 allocation ratio) consisting of three-week twice daily 400mg oral albendazole followed by 1) no treatment, 2) two further weeks of twice daily 400mg albendazole, or 3) a single dose of ivermectin in this open label randomized assessor blinded controlled clinical trial. The primary outcome was the proportion of participants with L. loa microfilaraemia ≤ 100 mf/ml at Day 168. RESULTS: In the efficacy-population of 42 patients 0 (0%; control group), 1 (9%; 3-week albendazole), 5 (39%; 5-weeks albendazole) and 2 (22%; 3-week albendazole plus single dose ivermectin) participants met the primary outcome of microfilaraemia below 100/ml at day 168. A 80-90% reduction of microfilaraemia was observed in the active treatment groups. CONCLUSION: The 5-week regimen of albendazole or a 3-week regimen of albendazole followed by ivermectin were most efficacious to reduce microfilaraemia. All therapeutic regimens were well tolerated and safe. TRIAL REGISTRATION: Trial registered at the Pan-African Clinical Trials Registry: PACTR201807197019027.

Epidemiology of co-infections in pregnant women living with human immunodeficiency virus 1 in rural Gabon: a cross-sectional study.

BACKGROUND: There is no recent epidemiological data on HIV infection in Gabon, particularly in pregnant women. To close this gap, an HIV-prevalence survey was conducted among Gabonese pregnant women, followed by a cross-sectional case-control study in which the prevalence of various co-infections was compared between HIV-positive and HIV-negative pregnant women. METHODS: Between 2018 and 2019, data for the HIV-prevalence survey were collected retrospectively in 21 Gabonese antenatal care centres (ANCs). Subsequently, for the prospective co-infection study, all HIV-positive pregnant women were recruited who frequented the ANC in Lambaréné and a comparator sub-sample of HIV-negative pregnant women was recruited; these activities were performed from February 2019 to February 2020. The mean number of co-infections was ascertained and compared between HIV-positive and HIV-negative women. Additionally, the odds for being co-infected with at least one co-infection was evaluated and compared between HIV-positive and HIV-negative women. RESULTS: HIV-positivity was 3.9% (646/16,417) among pregnant women. 183 pregnant women were recruited in the co-infection study. 63% of HIV-positive and 75% of HIV-negative pregnant women had at least one co-infection. There was a trend indicating that HIV-negative women were more often co-infected with sexually transmitted infections (STIs) than HIV-positive women [mean (standard deviation, SD): 2.59 (1.04) vs 2.16 (1.35), respectively; P = 0.056]; this was not the case for vector-borne infections [mean (SD): 0.47 (0.72) vs 0.43 (0.63), respectively; P = 0.59]. CONCLUSIONS: Counterintuitively, the crude odds for concomitant STIs was lower in HIV-positive than in HIV-negative women. The change of magnitude from the crude to adjusted OR is indicative for a differential sexual risk factor profile among HIV-positive and HIV-negative women in this population. This might potentially be explained by the availability of sexual health care counselling for HIV-positive women within the framework of the national HIV control programme, while no such similar overall service exists for HIV-negative women. This highlights the importance of easy access to sexual healthcare education programmes for all pregnant women irrespective of HIV status.

Real-life effectiveness of anti-malarial treatment regimens: what are we aiming for?

Three-day artemisinin-based combination therapy (ACT) is the current standard of care for the treatment of malaria. However, specific drug resistance associated with reduced efficacy of ACT has been observed, therefore necessitating the clinical development of new anti-malarial drugs and drug combinations. Previously, Single Encounter Radical Cure and Prophylaxis (SERCAP) has been proposed as ideal target-product-profile for any new anti-malarial drug regimen as this would improve treatment adherence besides ensuring complete cure and prevention of early reinfection. Arguably, this concept may not be ideal as it (1) necessitates administration of an excessively high dose of drug to achieve plasmodicidal plasma levels for a sufficient time span, (2) increases the risk for drug related adverse drug reactions, and (3) leaves the patient with a one-time opportunity to achieve-or not-cure by a single drug intake. Over the past years, SERCAP has led to the halt of promising drug development programmes, leading to potentially unnecessary attrition in the anti-malarial development pipeline. One proposition could be the concept of single-day multi-dose regimens as a potentially better alternative, as this allows to (1) administer a lower dose of the drug at each time-point leading to better tolerability and safety, (2) increase treatment adherence based on the intake of the anti-malarial drug within 24 h when malaria-related symptoms are still present, and (3) have more than one opportunity for adequate intake of the drug in case of early vomiting or other factors causing reduced bioavailability. In line with a recently published critical viewpoint on the concept of SERCAP, an alternative proposition is-in contrast to the current World Health Organization (WHO) treatment guidelines-to aim for less than three days, but still multiple-dose anti-malarial treatment regimens. This may help to strike the optimal balance between improving treatment adherence, maximizing treatment effectiveness, while keeping attrition of new drugs and drug regimens as low as possible.

Prevalence and impact of SARS-CoV-2 infection on maternal and infant health in African populations: protocol of a multicentre prospective cohort study (MA-CoV project).

INTRODUCTION: Pregnant women are currently considered a vulnerable population to SARS-CoV-2 infection, with increased risk of severe COVID-19, preterm birth and maternal mortality. There is, however, a paucity of data on the burden of maternal SARS-CoV-2 infection in sub-Saharan countries. The objective of this study is to determine the prevalence and health effects of maternal SARS-CoV-2 infection in selected sites from Gabon and Mozambique. METHODS AND ANALYSIS: MA-CoV (MAternal CoVid) is an observational, multicentre prospective cohort study where 1000 pregnant women (500 per country) will be enrolled at the antenatal clinic visits. Participants will undergo monthly follow-up at each antenatal care visit, delivery and postpartum visit. The primary study outcome is the prevalence of SARS-CoV-2 infection during pregnancy. The clinical presentation of COVID-19 in pregnancy will also be characterised, and incidence of infection during pregnancy will be evaluated, as well as the risk factors of maternal and neonatal morbidity and mortality associated with SARS-CoV-2 infection and the risk of mother to child transmission of SARS-CoV-2. SARS-CoV-2 infection screening will be performed through PCR diagnosis. ETHICS AND DISSEMINATION: The protocol was reviewed and approved by the Comité National d'Éthique pour la Recherche au Gabon, Comité Nacional de Bioética para Saúde de Moçambique and the Ethics Committee of the Hospital Clinic of Barcelona (Spain). Project results will be presented to all stakeholders and published in open access journals. TRIAL REGISTRATION NUMBER: NCT05303168.

Focussed Assessment with Sonography in acute Lassa Fever (FASLa): Development of a point-of-care protocol and description of common ultrasound findings.

BACKGROUND: Managing Lassa fever (LF) patients is challenging because of the complexity of this life-threatening infectious disease, the necessary isolation measures, and the limited resources in countries where it is endemic. Point-of-care ultrasonography (POCUS) is a promising low-cost imaging technique that may help in guiding the management of patients. METHODS: We conducted this observational study at the Irrua Specialist Teaching Hospital in Nigeria. We developed a POCUS protocol, trained local physicians who applied the protocol to LF patients and recorded and interpreted the clips. These were then independently re-evaluated by an external expert, and associations with clinical, laboratory and virological data were analyzed. FINDINGS: We developed the POCUS protocol based on existing literature and expert opinion and trained two clinicians, who then used POCUS to examine 46 patients. We observed at least one pathological finding in 29 (63%) patients. Ascites was found in 14 (30%), pericardial effusion in 10 (22%), pleural effusion in 5 (11%), and polyserositis in 7 (15%) patients, respectively. Eight patients (17%) showed hyperechoic kidneys. Seven patients succumbed to the disease while 39 patients survived, resulting in a fatality rate of 15%. Pleural effusions and hyper-echoic kidneys were associated with increased mortality. INTERPRETATION: In acute LF, a newly established POCUS protocol readily identified a high prevalence of clinically relevant pathological findings. The assessment by POCUS required minimal resources and training; the detected pathologies such as pleural effusions and kidney injury may help to guide the clinical management of the most at-risk LF patients.

Rabies post-exposure prophylaxis of international travellers - Results from two major German travel clinics.

BACKGROUND: Travel to regions with rabies risk has increased. However, data on adequate rabies post exposure prophylaxis (PEP) abroad is scarce. The aim of this study was to assess the appropriateness of medical management following suspected rabies exposure (SRE) in international travellers. METHOD: A cross-sectional questionnaire-based study in returning travellers with reported SRE who sought post-exposure medical care was conducted in two large German travel clinics. RESULTS: The 75 included SRE cases had a median age of 34 years (range 26-43) and showed a female predominance (59%, 44/75). Most participants returned from Asia (47%, 34/72). About 28% had received pre-exposure prophylaxis (PrEP, ≥2 vaccine doses) (20/71). In 51% the animal was actively approached (34/67). All patients had category II/III exposure according to the World Health Organization (65% category III, 49/75). With 78% (52/67), most patients cleaned the wound after SRE; 36% (24/67) used water and soap. Only 57% (41/72) of participants sought medical care during their trip. Overall, 45% (33/74) received rabies vaccination abroad which corresponds to 80% out of those who sought healthcare (33/41). CONCLUSIONS: Awareness for appropriate first aid and the urgency of seeking timely professional treatment including PEP after an SRE seems to be insufficient in German travellers. Travel practitioners need to educate travellers about rabies risk, prevention measures and the correct behaviour after SRE including adequate wound treatment and seeking immediate medical help for PEP. PrEP should be offered generously especially to travellers with high rabies-exposure risk and those visiting areas with limited healthcare access.

Symptoms of illness during travel and risk factors for non-adherence to malaria prophylaxis-a cross-sectional study in travellers from Germany.

BACKGROUND: Perceived adverse effects of antimalarial chemoprophylaxis can be difficult to distinguish from travel-related illness and are often cited as important reasons for non-adherence or refusal of antimalarial chemoprophylaxis. We aimed to investigate the occurrence of symptoms of illness in travellers with and without chemoprophylaxis in a cross-sectional study after travel and to identify risk factors for non-adherence to prophylaxis. METHODS: We enrolled 458 travellers to Africa and South America during their pre-travel medical consultation at the travel clinic of the University Medical Centre Hamburg-Eppendorf and conducted post-travel interviews on symptoms of illness and intake of malaria prophylaxis. RESULTS: Eleven percent (49/437) of the participants reported symptoms of illness during travel. In total, 36% (160/448) of the participants reported prescription of chemoprophylaxis, the vast majority of these travelled to Africa (98%) and received atovaquone/proguanil (93%). Frequency of symptoms did not differ significantly between participants without prophylaxis and those taking atovaquone/proguanil. Non-adherence to prophylaxis was frequent (20%), but only 3% (4/149) of the participants stopped the medication early because of perceived side effects. Risk factors associated with non-adherence to prophylaxis included age under 30 years, travel to West or Central Africa and travel duration greater than 14 days. CONCLUSIONS: Symptoms of illness during travel occurred at similar frequencies irrespective of intake of chemoprophylaxis. Travellers should be informed about chemoprophylaxis in a balanced way, without raising fear of side effects, especially among groups at higher risk for incorrect use of prophylaxis.

Alveolar echinococcosis in immunocompromised hosts.

BACKGROUND: Alveolar echinococcosis (AE) results of an infection with the larval stage of Echinococcus multilocularis. It has been increasingly described in individuals with impaired immune responsiveness. OBJECTIVES: This narrative review aims at describing the presentation of AE according to the type of immune impairment, based on retrospective cohorts and case reports. Implications for patient management and future research are proposed accordingly. SOURCES: Targeted search was conducted in PubMed using ((alveolar echinococcosis) OR (multilocularis)) AND ((immunosuppressive) OR (immunodeficiency) OR (AIDS) OR (solid organ transplant) OR (autoimmunity) OR (immune deficiency)). Only publications in English were considered. CONTENT: Seventeen publications were found, including 13 reports of 55 AE in immunocompromised patients (AE/IS) and 4 retrospective studies of 755 AE immunocompetent patients and 115 AE/IS (13%). The cohorts included 9 (1%) solid organ transplantation (SOT) recipients, 2 (0.2%) HIV patients, 41 (4.7%) with chronic inflammatory/autoimmune diseases (I/AID) and 72 (8.3%) with malignancies. SOT, I/AID and malignancies, but not HIV infection, were significantly associated with AE (odds ratios of 10.8, 1.6, 5.9, and 1.3, respectively). Compared to AE immunocompetent patients, AE/IS was associated with earlier diagnosis (PNM stages I-II: 49/85 (58%) vs. 137/348 (39%), p < 0.001), high rate of atypical imaging (24/50 (48%) vs. 106/375 (28%), p < 0.01), and low sensitivity of serology (19/77 (25%) vs. 265/329 (81%), p < 0.001). Unusually extensive or disseminated infections were described in SOT and I/AID patients. IMPLICATIONS: Patients who live in endemic areas should benefit from serology before onset of a long-term immunosuppressive therapy, even if the cost-benefit ratio has to be evaluated. Physicians should explain AE to immunocompromised patients and think about AE when finding a liver lesion. Further research should address gaps in knowledge of AE/IS. Especially, extensive and accurate records of AE cases have to be collected by multinational registries.

Pharmacokinetics of Ribavirin in the Treatment of Lassa Fever: An Observational Clinical Study at the Irrua Specialist Teaching Hospital, Edo State, Nigeria.

BACKGROUND: Lassa fever is endemic in large parts of West Africa. The recommended antiviral treatment is ribavirin. Two treatment regimens are currently endorsed in Nigeria: the "McCormick regimen" based on a study published in 1986 and the "Irrua regimen" constituting a simplified schedule developed at the Irrua Specialist Teaching Hospital, Nigeria. Evidence for the safety and efficacy of ribavirin in Lassa fever patients is poor and pharmacokinetic data for both regimens are lacking. METHODS: Polymerase chain reaction-confirmed Lassa fever patients with mild to moderate disease severity were invited to participate in this prospective, observational pharmacokinetic study. Pharmacokinetics of ribavirin, clinical, virologic, and clinical laboratory parameters were assessed. RESULTS: Using a population pharmacokinetic approach, plasma concentrations of ribavirin were best described by a 3-compartment model. Drug exposure was remarkably consistent between participants. Overall, drug clearance was 28.5% lower in female compared with male participants. Median (5th-95th percentile) time above half maximal inhibitory concentration (IC50) was 37.3% (16.9%-73.1%), 16.7% (8.2%-58.5%), and 9.6% (4.9%-38.4%) on days 1, 7, and 8, respectively. Clinical laboratory parameters indicated reduction of cell damage and development of hemolytic anemia in the course of the treatment period. CONCLUSIONS: This observational study characterizes the pharmacokinetics of ribavirin in the treatment of Lassa fever indicating consistent exposure across patients. Whereas only a short time interval of concentrations above the IC50 implies rather low antiviral efficacy in vivo, the prominent reduction of cell damage markers might point to indirect-potentially anti-inflammatory-effects of ribavirin. The role of ribavirin in the treatment of Lassa fever requires further scrutiny.