A Smartphone App for Real-Time Assessment of Malaria Prophylaxis Adverse Events.

Background: Growth of international travel to malarial areas over the last decades has contributed to more travelers taking malaria prophylaxis. Travel-related symptoms may be wrongly attributed to malaria prophylaxis and hinder compliance. Here, we aimed to assess the frequency of real-time reporting of symptoms by travelers following malaria prophylaxis using a smartphone app. Method: Adult international travelers included in this single-center study (Barcelona, Spain) used the smartphone Trip Doctor® app developed by our group for real-time tracking of symptoms and adherence to prophylaxis. Results: Six hundred four (n = 604) international travelers were included in the study; 74.3% (449) used the app daily, and for one-quarter of travelers, malaria prophylaxis was prescribed. Participants from the prophylaxis group traveled more to Africa (86.7% vs. 4.3%; p < 0.01) and to high travel medical risk countries (60.8% vs. 18%; p < 0.01) and reported more immunosuppression (30.8% vs. 23.1% p < 0.01). Regarding symptoms, no significant intergroup differences were observed, and no relationship was found between the total number of malarial pills taken and reported symptoms. Conclusions: In our cohort, the number of symptoms due to malaria prophylaxis was not significantly higher than in participants for whom prophylaxis was not prescribed, and the overall proportion of symptoms is higher compared with other studies.

Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement.

BACKGROUND: Trypanosoma cruzi causes Chagas disease (CD), a potentially fatal disease characterized by cardiac disorders and digestive, neurological or mixed alterations. T. cruzi is transmitted to humans by the bite of triatomine vectors; both the parasite and disease are endemic in Latin America and the United States. In the last decades, population migration has changed the classic epidemiology of T. cruzi, contributing to its global spread to traditionally non-endemic countries. Screening is recommended for Latin American populations residing in non-endemic countries. METHODS: The present study analyzes the epidemiological characteristics of 2,820 Latin American individuals who attended the International Health Service (IHS) of the Hospital Clinic de Barcelona between 2002 and 2019. The initial assessment of organ damage among positive cases of T. cruzi infection was analyzed, including the results of electrocardiogram (ECG), echocardiogram, barium enema and esophagogram. RESULTS: Among all the screened individuals attending the clinic, 2,441 (86.6%) were born in Bolivia and 1,993 (70.7%) were female. Of individuals, 1,517 (81.5%) reported previous exposure to the vector, which is a strong risk factor associated with T. cruzi infection; 1,382 individuals were positive for T. cruzi infection. The first evaluation of individuals with confirmed T. cruzi infection, showed 148 (17.1%) individuals with Chagasic cardiomyopathy, the main diagnostic method being an ECG and the right bundle branch block (RBBB) for the most frequent disorder; 16 (10.8%) individuals had a normal ECG and were diagnosed of Chagasic cardiomyopathy by echocardiogram. CONCLUSIONS: We still observe many Latin American individuals who were at risk of T. cruzi infection in highly endemic areas in their countries of origin, and who have not been previously tested for T. cruzi infection. In fact, even in Spain, a country with one of the highest proportion of diagnosis of Latin American populations, T. cruzi infection remains underdiagnosed. The screening of Latin American populations presenting with a similar profile as reported here should be promoted. ECG is considered necessary to assess Chagasic cardiomyopathy in positive individuals, but echocardiograms should also be considered as a diagnostic approach given that it can detect cardiac abnormalities when the ECG is normal.

Clinical evaluation of BioFire® multiplex-PCR panel for acute undifferentiated febrile illnesses in travellers: a prospective multicentre study.

BACKGROUND: Identifying the causes of Acute Undifferentiated Febrile Illness (AUFI) is key to improve the management of returning travellers with fever. We evaluated a BioFire®FilmArray® prototype panel of multiplex nucleic acid amplification tests (NAAT) targeting different relevant pathogens in travellers returning with fever. METHODS: Prospective, multicentre study to evaluate a prototype panel in whole blood samples of adult international travellers presenting with AUFI in three European travel Clinics/Hospitals (November 2017-November 2019). We evaluated 15 target analytes: Plasmodium spp., Plasmodium falciparum, Plasmodium knowlesi, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, chikungunya virus, dengue virus, Zika virus, Anaplasma phagocytophilum, Borrelia spp., Leptospira spp., Orientia tsutsugamushi, Rickettsia spp. and Salmonella spp. Results were compared with composite reference standards (CRSs) for each target infection, including direct methods [smear microscopy, rapid diagnostic test (RDT), reference NAAT and blood cultures] and indirect methods (paired serology). FINDINGS: Among 455 travellers with AUFI, 229 target infections were diagnosed; the prototype panel detected 143 (overall sensitivity and specificity of 62.5 and 99.8%, respectively). The panel identified all Plasmodium infections (n = 82). Sensitivity for dengue (n = 71) was 92.9, 80.8 and 68.5% compared with RDT, NAAT and CRS, respectively. Compared with direct methods and CRS, respectively, the prototype panel detected 4/4 and 4/6 chikungunya, 2/2 and 4/29 Leptospira spp., 1/1 and 1/6 O. tsutsugamushi and 2/2 and 2/55 Rickettsia spp., but 0/2 and 0/10 Zika, 0/1 and 0/11 A. phagocytophylum and 0/3 Borrelia spp. diagnosed by serology and only 1/7 Salmonella spp. diagnosed by blood cultures. 77/86 (89.5%) infections not detected by the panel were diagnosed by serology. INTERPRETATION: The prototype panel allowed rapid and reliable diagnosis for malaria, dengue and chikungunya. Further improvements are needed to improve its sensitivity for Zika and important travel-related bacterial infections.

Doxycycline responding illnesses in returning travellers with undifferentiated non-malaria fever: a European multicentre prospective cohort study.

BACKGROUND: Diagnosis of undifferentiated non-malaria fevers (NMF) in returning travellers is a great challenge. Currently, there is no consensus about the use of empirical antibiotics in returning travellers with undifferentiated NMF. Although studies in endemic areas showed that a wide range of pathogens implicated in undifferentiated NMF are treatable with doxycycline, the role of doxycycline in returning travellers with fever still has to be explored. METHODS: Prospective European multicentre cohort study of febrile international travellers (November 2017-November 2019). Immunological and molecular diagnostic techniques for doxycycline responding illnesses (DRI) agents such as Anaplasma phagocytophilum, spotted fever group Rickettsia spp., typhus group Rickettsia spp., Coxiella burnetii, Bartonella spp., Orientia tsutsugamushi, Borrelia miyamotoi, Borrelia recurrentis and Leptospira spp. were systematically performed in all patients with undifferentiated NMF. We estimated the prevalence and predictive factors of DRI in returning travellers with undifferentiated NMF. RESULTS: Among 347 travellers with undifferentiated NMF, 106 (30·5%) were finally diagnosed with DRI. Only 57 (53·8%) of the 106 DRI infections were diagnosed by the standard of care. The main causes of DRI were: 55 (51·9%) Rickettsia spp., 16 (15·1%) C. burnetii; 15 (14·2%) Bartonella spp.; 13 (12·3%) Leptospira spp. and 10 (9·5%) A. phagocytophilum. The only predictive factor associated with DRI was presenting an eschar (aOR 39·52, 95%CI 4·85-322·18). Features of dengue such as retro-orbital pain (aOR 0·40, 95%CI 0·21-0·76) and neutropenia (aOR 0·41, 95%CI 0·21-0·79) were negatively associated with DRI. CONCLUSIONS: Although DRI are responsible for 30% of undifferentiated NMF cases in travellers, those are seldom recognized during the first clinical encounter. Empirical treatment with doxycycline should be considered in returning travellers with undifferentiated fever and negative tests for malaria and dengue, particularly when presenting severe illness, predictive factors for rickettsiosis or no features of dengue.

Causes of fever in returning travelers: a European multicenter prospective cohort study.

BACKGROUND: Etiological diagnosis of febrile illnesses in returning travelers is a great challenge, particularly when presenting with no focal symptoms [acute undifferentiated febrile illnesses (AUFI)], but is crucial to guide clinical decisions and public health policies. In this study, we describe the frequencies and predictors of the main causes of fever in travelers. METHODS: Prospective European multicenter cohort study of febrile international travelers (November 2017-November 2019). A predefined diagnostic algorithm was used ensuring a systematic evaluation of all participants. After ruling out malaria, PCRs and serologies for dengue, chikungunya and Zika viruses were performed in all patients presenting with AUFI ≤ 14 days after return. Clinical suspicion guided further microbiological investigations. RESULTS: Among 765 enrolled participants, 310/765 (40.5%) had a clear source of infection (mainly traveler's diarrhea or respiratory infections), and 455/765 (59.5%) were categorized as AUFI. AUFI presented longer duration of fever (p < 0.001), higher hospitalization (p < 0.001) and ICU admission rates (p < 0.001). Among travelers with AUFI, 132/455 (29.0%) had viral infections, including 108 arboviruses, 96/455 (21.1%) malaria and 82/455 (18.0%) bacterial infections. The majority of arboviral cases (80/108, 74.1%) was diagnosed between May and November. Dengue was the most frequent arbovirosis (92/108, 85.2%). After 1 month of follow-up, 136/455 (29.9%) patients with AUFI remained undiagnosed using standard diagnostic methods. No relevant differences in laboratory presentation were observed between undiagnosed and bacterial AUFI. CONCLUSIONS: Over 40% of returning travelers with AUFI were diagnosed with malaria or dengue, infections that can be easily diagnosed by rapid diagnostic tests. Arboviruses were the most common cause of AUFI (above malaria) and most cases were diagnosed during Aedes spp. high season. This is particularly relevant for those areas at risk of introduction of these pathogens. Empirical antibiotic regimens including doxycycline or azithromycin should be considered in patients with AUFI, after ruling out malaria and arboviruses.

Relevance of screening for Chagas and viral hepatitis in Bolivian migrants

Objectives: Given the scarcity of data regarding prevalence of various infectious diseases in Latin-American countries, our study aims to assess the burden of T. cruzi, S. stercoralis, HIV and viral hepatitis in Latin-American migrants, with a focus on Bolivian migrants.MethodsWe performed a retrospective observational study of 565 screening evaluations in adults (≥18 years) carried out at our International Healthcare referral service in Barcelona. We reviewed structured clinical records and microbiological results of patients attended between February 2012 and April 2015.ResultsThe median age was 35 years and 74% were women. Of the population screened, 87% were of Bolivian origin. We found a 48% prevalence of T. cruzi, 16% of S. stercoralis, 0.2% of HIV, 0.2% HBV and 0.2% HCV.ConclusionsThese results support the relevance of screening for T. cruzi and S. stercoralis in Bolivian migrants but challenge the pertinence of systematic screening for HBV in this population. (AU)

Objetivos: Dada la escasez de datos con relación a la prevalencia de diversas enfermedades infecciosas en los países iberoamericanos, el objetivo de nuestro estudio fue evaluar la carga de T. cruzi, S. stercoralis, VIH y hepatitis vírica en los emigrantes iberoamericanos, con especial atención en los emigrantes bolivianos.MétodosEstudio observacional retrospectivo de 565 cribados en adultos (≥ 18 años) realizado en nuestro servicio de Servicio de Salud Internacional en Barcelona. Revisamos los registros clínicos estructurados y los resultados microbiológicos de los pacientes asistidos entre febrero de 2012 y abril de 2015.ResultadosLa edad media fue de 35 años y el 74% fueron mujeres. El origen boliviano representó el 87% de la población cribada. Encontramos una prevalencia de 48% de T. cruzi, 16% de S. stercoralis, 0,2% de VIH, 0,2% de VHB y 0,2% de VHC.ConclusionesEstos resultados respaldan la relevancia del cribado de T. cruzi y S. stercoralis en migrantes bolivianos, aunque cuestiona la pertinencia del cribado sistemático de VHB en esta población. (AU)

Incidence of human granulocytic anaplasmosis in returning travellers with fever.

BACKGROUND: Although tick-borne pathogens have been reported as an important cause of imported fever, the incidence of Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis (HGA), in travellers is unknown. METHODS: We conducted a prospective cohort study to investigate the aetiologies of fever in returning travellers (November 2017-July 2019). Polymerase chain reaction for msp2 gene amplification and indirect immunofluorescence assay for A. phagocitophilum were performed in all returning travellers with undifferentiated non-malarial fever. RESULTS: Among 141 travellers included, 8 patients were diagnosed with probable or confirmed HGA. The overall incidence rate of HGA was 19.9 cases/1000 person-week of travel. The main destination of travel was Asia, accounting for 62.5% patients with HGA. Co-infections were found in 37.5% of patients with HGA. CONCLUSIONS: Diagnosis of HGA and empirical treatment with doxycycline should be considered in travellers with fever.

Zika virus infection in pregnant travellers and impact on childhood neurodevelopment in the first two years of life: A prospective observational study.

BACKGROUND: The emergence of Zika virus (ZIKV) represents a threat with consequences on maternal and children's health. We aimed to assess the clinical and epidemiological characteristics of pregnant women returning from ZIKV affected areas, and the effects of maternal ZIKV infection on birth outcomes and children's health. METHODS: This was a hospital-based prospective observational study conducted at the Hospital Clínic of Barcelona and Hospital Sant Joan de Déu, Barcelona, Spain, from January 2016 to February 2020. RESULTS: One hundred and ninety-five pregnant women who had travelled to ZIKV affected areas during pregnancy were recruited. Four women (2.1%) had a confirmed ZIKV infection, 40 women (20.5%) a probable infection, and 151 (77.4%) were negative for ZIKV. Among the ZIKV confirmed cases, a pregnant woman suffered a miscarriage, highly plausible to be associated with ZIKV infection. Brain cysts and microcalcifications were detected in 7% of fetuses or infants from women with confirmed or probable ZIKV infection. Neurodevelopmental delay in the language function was found in 33.3% out of the 21 children evaluated. CONCLUSIONS: These findings contribute to the understanding of ZIKV prevalence estimates, and the impact of maternal ZIKV infection on pregnancy outcomes and children's health. Results highlight the importance of long-term surveillance in pregnant travellers and their children.

Relevance of screening for Chagas and viral hepatitis in Bolivian migrants.

OBJECTIVES: Given the scarcity of data regarding prevalence of various infectious diseases in Latin-American countries, our study aims to assess the burden of T. cruzi, S. stercoralis, HIV and viral hepatitis in Latin-American migrants, with a focus on Bolivian migrants. METHODS: We performed a retrospective observational study of 565 screening evaluations in adults (≥18 years) carried out at our International Healthcare referral service in Barcelona. We reviewed structured clinical records and microbiological results of patients attended between February 2012 and April 2015. RESULTS: The median age was 35 years and 74% were women. Of the population screened, 87% were of Bolivian origin. We found a 48% prevalence of T. cruzi, 16% of S. stercoralis, 0.2% of HIV, 0.2% HBV and 0.2% HCV. CONCLUSIONS: These results support the relevance of screening for T. cruzi and S. stercoralis in Bolivian migrants but challenge the pertinence of systematic screening for HBV in this population.

Positive direct antiglobulin test in post-artesunate delayed haemolysis: more than a coincidence?

BACKGROUND: Delayed haemolysis is a frequent adverse event after treatment with artesunate (AS). Removing once-infected "pitted" erythrocytes by the spleen is the most accepted mechanism of haemolysis in these cases. However, an increasing number of cases with positive direct antiglobulin test (DAT) haemolysis after AS have been reported. METHODS: All malaria cases seen at Hospital Clinic of Barcelona between 2015 and 2017 were retrospectively reviewed. Clinical, parasitological and laboratory data from patients treated with intravenous artesunate-specifically looking for delayed haemolysis and DAT-was collected. RESULTS: Among the 36 severe malaria patients treated with artesunate at the hospital, 10 (27.8%) developed post-artesunate delayed haemolysis. Out of these, DAT was performed in six, being positive in four of them (at least 40%). DAT was positive only for complement-without IgG-suggesting drug-dependent immune-haemolytic anaemia of the immune-complex type. Three of the four patients were treated with corticosteroids and two also received blood transfusion, with a complete recovery. CONCLUSIONS: Drug-induced auto-immune phenomena in post-artesunate delayed haemolysis may be underreported and must be considered. The role of corticosteroids should be reassessed.

Prospective comparative multi-centre study on imported Plasmodium ovale wallikeri and Plasmodium ovale curtisi infections.

BACKGROUND: Few previous retrospective studies suggest that Plasmodium ovale wallikeri seems to have a longer latency period and produces deeper thrombocytopaenia than Plasmodium ovale curtisi. Prospective studies were warranted to better assess interspecies differences. METHODS: Patients with imported P. ovale spp. infection diagnosed by thick or thin film, rapid diagnostic test (RDT) or polymerase chain reaction (PCR) were recruited between March 2014 and May 2017. All were confirmed by DNA isolation and classified as P. o. curtisi or P. o. wallikeri using partial sequencing of the ssrRNA gene. Epidemiological, analytical and clinical differences were analysed by statistical methods. RESULTS: A total of 79 samples (35 P. o. curtisi and 44 P. o. wallikeri) were correctly genotyped. Males predominate in wallikeri group (72.7%), whereas were 48.6% in curtisi group. Conversely, 74.3% of curtisi group were from patients of African ethnicity, whilst 52.3% of Caucasians were infected by P. o. wallikeri. After performing a multivariate analysis, more thrombocytopaenic patients (p = 0.022), a lower number of platelets (p = 0.015), a higher INR value (p = 0.041), and shorter latency in Caucasians (p = 0.034) were significantly seen in P. o. wallikeri. RDT sensitivity was 26.1% in P. o. curtisi and 42.4% in P. o. wallikeri. Nearly 20% of both species were diagnosed only by PCR. Total bilirubin over 3 mg/dL was found in three wallikeri cases. Two patients with curtisi infection had haemoglobin under 7 g/dL, one of them also with icterus. A wallikeri patient suffered from haemophagocytosis. Chemoprophylaxis failed in 14.8% and 35% of curtisi and wallikeri patients, respectively. All treated patients with various anti-malarials which included artesunate recovered. Diabetes mellitus was described in 5 patients (6.32%), 4 patients of wallikeri group and 1 curtisi. CONCLUSIONS: Imported P. o. wallikeri infection may be more frequent in males and Caucasians. Malaria caused by P. o. wallikeri produces more thrombocytopaenia, a higher INR and shorter latency in Caucasians and suggests a more pathogenic species. Severe cases can be seen in both species. Chemoprophylaxis seems less effective in P. ovale spp. infection than in P. falciparum, but any anti-malarial drug is effective as initial treatment. Diabetes mellitus could be a risk factor for P. ovale spp. infection.