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Background Up to 45% of febrile returning travellers remain undiagnosed after a thorough diagnostic work-up, even at referral centres. Although metagenomic next-generation sequencing (mNGS) has emerged as a promising tool, evidence of its usefulness in imported fever is very limited. Methods Travellers returning with fever were prospectively recruited in three referral clinics from November 2017 to November 2019. Unbiased mNGS optimised for virus detection was performed on serum samples of participants with acute undifferentiated febrile illness (AUFI), and results were compared to those obtained by reference diagnostic methods (RDM). Results Among 507 returned febrile travellers, 433(85.4%) presented with AUFI. Dengue virus (n  = 86) and Plasmodium spp. (n  = 83) were the most common causes of fever. 103/433(23.8%) AUFI remained undiagnosed at the end of the follow-up. Metagenomic next-generation sequencing unveiled potentially pathogenic microorganisms in 196/433(38.7%) AUFI. mNGS identifications were more common in patients with a shorter duration of fever (42.3% in ≤5 days vs 28.7% in >5 days, P  = 0.005). Potential causes of fever were revealed in 25/103(24.2%) undiagnosed AUFI and 5/23(21.7%) travellers with severe undiagnosed AUFI. Missed severe aetiologies included eight bacterial identifications and one co-infection of B19 parvovirus and Aspergillus spp. Additional identifications indicating possible co-infections occurred in 29/316(9.2%) travellers with AUFI, and in 11/128(8.6%) travellers with severe AUFI, who had received a diagnosis through RDM. The most common co-infections detected in severe AUFI were caused by Gram-negative bacteria. Serum mNGS was unable to detect >50% of infectious diagnoses achieved by RDM and also yielded 607 non-pathogenic identifications. Discussion mNGS of serum can be a valuable diagnostic tool for selected travellers with undiagnosed AUFI or severe disease in addition to reference diagnostic techniques, especially during the first days of symptoms. Nevertheless, mNGS results interpretation presents a great challenge. Further studies evaluating the performance of mNGS using different sample types and protocols tailored to non-viral agents are needed. [ABSTRACT FROM AUTHOR]

Background Failure of artemisinin-based combination therapy is increasingly reported in patients with Plasmodium falciparum malaria in sub-Saharan Africa. We aimed to describe the clinical and genomic characteristics of recent cases of P. falciparum malaria failing artemether-lumefantrine in Belgium. Methods Travel-related cases of malaria confirmed at the national reference laboratory of the Institute of Tropical Medicine, Antwerp, Belgium, were reviewed. All cases for which attending clinicians reported persistence (beyond Day 3 post-treatment initiation, i.e. early failure) or recrudescence (from Day 7 to 42, i.e. late failure) of P. falciparum parasites despite adequate drug intake were analysed. Both initial and persistent/recurrent samples were submitted to next generation sequencing to investigate resistance-conferring mutations. Results From July 2022 to June 2023, eight P. falciparum cases of failure with artemether-lumefantrine therapy were reported (early failure = 1; late failure = 7). All travellers were returning from sub-Saharan Africa, most (6/8) after a trip to visit friends and relatives. PfKelch13 (PF3D7_1343700) mutations associated with resistance to artemisinin were found in two travellers returning from East Africa, including the validated marker R561H in the patient with early failure and the candidate marker A675V in a patient with late failure. Additional mutations were detected that could contribute to decreased susceptibility to artemisinin in another three cases, lumefantrine in six cases and proguanil in all eight participants. Various regimens were used to treat the persistent/recrudescent cases, with favourable outcome. Conclusion Within a 12-month period, we investigated eight travellers returning from sub-Saharan Africa with P. falciparum malaria and in whom artemether-lumefantrine failure was documented. Mutations conferring resistance to antimalarials were found in all analysed blood samples, especially against lumefantrine and proguanil, but also artemisinin. There is a pressing need for systematic genomic surveillance of resistance to antimalarials in international travellers with P. falciparum malaria, especially those experiencing treatment failure. [ABSTRACT FROM AUTHOR]

The risk of infection after exposure to clade IIb mpox virus (MPXV) is unknown, and potential presymptomatic shedding of MPXV remains to be demonstrated. High‐risk contacts of mpox patients were followed‐up in a prospective longitudinal cohort study. Individuals reporting sexual contact, >15 min skin‐to‐skin contact, or living in the same household with an mpox patient were recruited in a sexual health clinic in Antwerp, Belgium. Participants kept a symptom diary, performed daily self‐sampling (anorectal, genital, and saliva), and presented for weekly clinic visits for physical examination and sampling (blood and oropharyngeal). Samples were tested for MPXV by PCR. Between June 24 and July 31, 2022, 25 contacts were included, of which 12/18 (66.0%) sexual and 1/7 (14.0%) nonsexual contacts showed evidence of infection by MPXV‐PCR. Six cases had typical mpox symptoms. Viral DNA was detected as early as 4 days before symptom onset in 5 of them. In 3 of these cases, replication‐competent virus was demonstrated in the presymptomatic phase. These findings confirm the existence of presymptomatic shedding of replication‐competent MPXV and emphasize the high risk of transmission during sexual contact. Sexual contacts of mpox cases should abstain from sex during the incubation period, irrespective of symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Infection with Mansonella perstans is a neglected filariasis, widely distributed in sub-Saharan Africa, characterized by an elusive clinical picture; treatment for mansonellosis is not standardized. This retrospective study aimed to describe the clinical features, treatment schemes and evolution, of a large cohort of imported cases of M. perstans infection seen in four European centres for tropical diseases.Methods: Mansonella perstans infections, diagnosed by identification of blood microfilariae in migrants, expatriates and travellers, collected between 1994 and 2018, were retrospectively analysed. Data concerning demographics, clinical history and laboratory examinations at diagnosis and at follow-up time points were retrieved.Results: A total of 392 patients were included in the study. Of the 281 patients for whom information on symptoms could be retrieved, 150 (53.4%) reported symptoms, abdominal pain and itching being the most frequent. Positive serology and eosinophilia were present in 84.4% and 66.1%, respectively, of those patients for whom these data were available. Concomitant parasitic infections were reported in 23.5% of patients. Treatment, administered to 325 patients (82.9%), was extremely heterogeneous between and within centres; the most commonly used regimen was mebendazole 100 mg twice a day for 1 month. A total of 256 (65.3%) patients attended a first follow-up, median 3 months (interquartile range 2-12) after the first visit; 83.1% of patients having received treatment based on mebendazole and/or doxycycline, targeting Wolbachia, became amicrofilaremic, 41.1-78.4% of whom within 12 months from single treatment.Conclusions: Lack of specific symptoms, together with the inconstant positivity of parasitological and antibody-based assays in the infected population, makes the clinical suspicion and screening for mansonellosis particularly difficult. Prospective studies evaluating prevalence of infection in migrants from endemic areas, infection-specific morbidity, presence of Wolbachia endosymbionts in M. perstans populations from different geographical areas and efficacy of treatment regimens are absolutely needed to optimize the clinical management of infection. [ABSTRACT FROM AUTHOR]

Background In low-resource settings, inflammatory biomarkers can help identify patients with acute febrile illness who do not require antibiotics. Their use has not been studied in persistent fever (defined as fever lasting for ≥7 days at presentation). Methods C-reactive protein (CRP) and procalcitonin (PCT) levels were measured in stored serum samples of patients with persistent fever prospectively enrolled in Cambodia, the Democratic Republic of Congo, Nepal, and Sudan. Diagnostic accuracy was assessed for identifying all bacterial infections and the subcategory of severe infections judged to require immediate antibiotics. Results Among 1838 participants, CRP and PCT levels were determined in 1777 (96.7%) and 1711 (93.1%) samples, respectively, while white blood cell (WBC) count was available for 1762 (95.9%). Areas under the receiver operating characteristic curve for bacterial infections were higher for CRP (0.669) and WBC count (0.651) as compared with PCT (0.600; P <.001). Sensitivity for overall and severe bacterial infections was 76.3% (469/615) and 88.2% (194/220) for CRP >10 mg/L, 62.4% (380/609) and 76.8% (169/220) for PCT >0.1 µg/L, and 30.5% (184/604) and 43.7% (94/215) for WBC >11 000/µL, respectively. Initial CRP level was <10 mg/L in 45% of the participants who received antibiotics at first presentation. Conclusions In patients with persistent fever, CRP and PCT showed higher sensitivity for bacterial infections than WBC count, applying commonly used cutoffs for normal values. A normal CRP value excluded the vast majority of severe infections and could therefore assist in deciding whether to withhold empiric antibiotics after cautious clinical assessment. [ABSTRACT FROM AUTHOR]

Background: Benznidazole is an effective drug in the trypanocidal treatment of acute and chronic indeterminate Chagas' disease (CD). However, adverse drug reactions (ADR) are common and frequently cause patients to discontinue treatment.Objectives: We hypothesized that antioxidant supplementation could mitigate benznidazole-induced toxicity.Methods: We co-supplemented an adult traveller with chronic indeterminate CD who experienced benznidazole ADR with ascorbic acid (AA), 1000 mg/day. We measured selected serum biomarkers of oxidative stress [total antioxidant status (TAS), total oxidative status (TOS), nuclear factor erythroid 2-related factor 2 (Nrf2), malondialdehyde (MDA), extracellular glutathione peroxidase (GPX3), catalase (CAT) and total superoxide dismutase (T-SOD)] at timepoints before and throughout benznidazole treatment and after AA co-supplementation.Results: AA co-supplementation effectively mitigated benznidazole-induced ADR during the aetiological treatment of chronic indeterminate CD. The kinetics of serum biomarkers of oxidative stress suggested significantly decreased oxidative insult in our patient.Conclusions: We hypothesize that the key pathophysiological mechanism of benznidazole-associated toxicity is oxidative stress, rather than hypersensitivity. AA co-supplementation may improve adherence to benznidazole treatment of chronic indeterminate (or acute) CD. Oxidative stress biomarkers have the potential to guide the clinical management of CD. Prospective studies are needed to establish the benefit of antioxidant co-supplementation to benznidazole treatment of CD in reducing benznidazole toxicity, parasite clearance and the prevention of end-organ damage. [ABSTRACT FROM AUTHOR]

Background Information on human filariasis in international travelers is scarce. We describe the epidemiology, clinical presentation, and outcome of these infections in a reference travel clinic over the past decades. Methods We reviewed all cases of filariasis diagnosed at the Institute of Tropical Medicine, Antwerp, Belgium, from 1994 to 2018. Diagnosis was obtained by either parasitological methods (confirmed) or strict clinical case definitions (probable). We assessed the characteristics of cases at diagnosis and response to therapy within 3–12 months. Results A total of 320 patients (median age: 41 years; 71% males) were diagnosed with 327 filarial infections (Wuchereria bancrofti = 6, Onchocerca volvulus = 33, Loa loa = 150, Mansonella perstans = 130, unspecified species = 8). Diagnosis was confirmed in 213/320 (67%) patients. European long-term travelers accounted for 166 patients (52%) and visitors/migrants from tropical countries for another 110 (34%). Central Africa was the likely region of acquisition for 294 (92%) patients. The number of filariasis cases decreased from 21.5/year on average in the 1990s to 6.3/year in the past decade, when loiasis became predominant. Cases reported symptoms in >80% of all filarial infections but mansonellosis (45/123 single infections; 37%). Lymphatic filariasis and onchocerciasis cases responded well to conventional therapy. However, 30% of patients with loiasis and mansonellosis experienced treatment failure (with diethylcarbamazine and levamisole-mebendazole, respectively). Conclusions The burden and species distribution of filariasis in travelers evolved in the past decades. Most presentations were symptomatic. Case management would benefit from more effective therapies for loiasis and mansonellosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Giardiasis failing nitroimidazole first-line treatment is an emerging problem in returning European travelers. We present data on the efficacy and tolerability of 2 second-line treatment regimens. Methods This prospective, open-label, multicenter study assessed the efficacy and tolerability of quinacrine monotherapy (100 mg 3 times per day for 5 days) and albendazole plus chloroquine combination therapy (400 mg twice daily plus 155 mg twice daily for 5 days) in nitroimidazole-refractory giardiasis. The defined end points were the clinical outcome, assessed at week 5 after treatment and the parasitological outcome, assessed using microscopy of 2 stool samples, ≥2 to ≤5 weeks after treatment. Results A total of 106 patients were included in the study. Quinacrine achieved clinical and parasitological cure in 81% (59/73) and 100% (56/56), respectively. Albendazole plus chloroquine achieved clinical and parasitological cure in 36% (12/33) and 48% (12/25), respectively. All patients (9/9) who clinically and parasitologically failed albendazole plus chloroquine treatment and opted for retreatment with quinacrine achieved clinical cure. Mild to moderate treatment-related adverse events were reported by 45% and 30% of patients treated with quinacrine and albendazole plus chloroquine, respectively. One patient treated with quinacrine developed severe neuropsychiatric side effects. The majority of nitroimidazole-refractory Giardia infections (57%) were acquired in India. Conclusions Quinacrine was a highly effective treatment in nitroimidazole-refractory giardiasis, but patients should be cautioned on the low risk of severe neuropsychiatric adverse event. Albendazole plus chloroquine had a low cure rate in nitroimidazole-refractory giardiasis. Nitroimidazole-refractory giardiasis was primarily seen in travelers returning from India. [ABSTRACT FROM AUTHOR]

Background Diagnosis of schistosomiasis remains elusive soon after infection. We evaluated several diagnostic methods in a cluster of travelers with simultaneous freshwater exposure in South Africa. Methods Eosinophil count, schistosome antibody tests, stool and urine microscopy, and serum Dra1 PCR assays were performed at weeks 4–5 (early symptomatic phase), 7–8 (praziquantel treatment), and 13–14 (after treatment). Sequencing was done on serum samples from 3 patients to identify the species. Results Of the 34 travelers (16 adults and 18 children), 32 developed symptoms 2–6 weeks after exposure. A raised eosinophil count (>750/µL) was seen in 12 of 33 at weeks 4–5, and in 22 of 34 at weeks 7–8. Schistosoma antibodies were detected in 3 of 33 at weeks 4–5 and in 12 of 34 at weeks 7–8 and weeks 13–14. The Dra1 PCR result was positive in 24 of 33 travelers at weeks 4–5, in 31 of 34 at weeks 7–8, in 25 of 34 at weeks 13–14, and at least once in all. Ova were absent in all urine and stool samples obtained. Sequencing identified Schistosoma mattheei nuclear and Schistosoma haematobium mitochondrial DNA, indicative of a hybrid species. Conclusions The Dra1 PCR confirmed the diagnosis in all exposed travelers at a much earlier stage than conventional tests. The causative species is probably an S. mattheei × S. haematobium hybrid. [ABSTRACT FROM AUTHOR]

Keywords: Fasciola; Fasciola gigantica; ectopic migration; liver lesions; skin emergence EN Fasciola Fasciola gigantica ectopic migration liver lesions skin emergence 1 2 2 11/08/23 20230801 NES 230801 Case presentation An asymptomatic 73-year-old Belgian woman, with a history of cholecystectomy and colon cancer in remission 6 years earlier, was found with a high eosinophil count (3890/ l; 40% of the total leucocytes) during a check-up, 3 months after resettlement in Belgium. Fascioliasis should be suspected whenever liver lesions are associated with eosinophilia.[6] In this scenario, a positive serology justifies empirical treatment with triclabendazole, without parasitological confirmation by liver biopsy and/or coprological exams. During the subsequent workup, liver imaging (Figure 1) showed multiple hypermetabolic nodular liver lesions predominantly in the right liver lobe and a hypermetabolic structure between the liver and abdominal wall. [Extracted from the article]

Yellow fever (YF) causes high fever, liver dysfunction, renal failure, hypercoagulopathy and platelet dysfunction and can lead to shock and death with a case-fatality ratio of 20-50%. YF vaccination results in long-lasting protective immunity. Serious adverse events (SAEs), such as YF vaccine-associated neurotropic disease (YEL-AND) are rare. We present a case of a 56-year-old Caucasian man with fever, headache, cognitive problems at the emergency department. He received a primary YF vaccination 4 weeks prior to symptom onset. Cerebrospinal fluid tested positive (POS) for YF virus by reverse transcriptase polymerase chain reaction and confirmed diagnosis of YEL-AND. The patient recovered with symptomatic treatment. We reviewed published clinical reports on YEL-AND indexed for MEDLINE. We identified and analyzed 53 case reports. Forty-five patients were male and eight were female. Twenty-nine cases met criteria for definite YEL-AND and twenty-four for suspected YEL-AND according to YF Vaccine Safety Working Group. We applied the Brighton Collaboration diagnostic criteria to assess the diagnostic accuracy of the clinical diagnoses and found meningoencephalitis in 38 reported YEL-AND cases, Guillain Barré Syndrome (GBS) in seven, Acute Disseminated Encephalomyelitis (ADEM) in six and myelitis in five. Thirty-five patients recovered or improved; however, not all cases had a complete follow-up. The prognosis of YEL-AND presenting with GBS, ADEM or myelitis was poor. Fourteen patients received therapy (corticosteroids, intravenous immunoglobulins and/or plasmapheresis). In conclusion, YF vaccine-associated neurotropic disease is a very rare but SAE after YF vaccination. We described a case of YEL-AND and propose a standardized clinical workup of this condition based on a review of the literature. Centralized registration of complications of YF vaccination is encouraged. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 45-year-old Belgian woman who was admitted to the hospital with a flu-like syndrome, during a trip to Southern Germany. Topics include diagnosis of meningoencephalitis and completion of a 10-day course of intravenous ceftriaxone, diagnosis of TBE based on specific antibody detection, and no change in tick-borne encephalitis virus (TBEV) immunofluorescence and neutralization assay results.

A letter to the editor is presented related to emergence of arthropod-borne West Nile virus (WNV) in Greece.