Intestinal protozoa in returning travellers: a GeoSentinel analysis from 2007 to 2019.

BACKGROUND: Prolonged diarrhoea is common among returning travellers and is often caused by intestinal protozoa. However, the epidemiology of travel-associated illness caused by protozoal pathogens is not well described. METHODS: We analysed records of returning international travellers with illness caused by Giardia duodenalis, Cryptosporidium spp., Cyclospora cayetanensis, or Cystoisospora belli, reported to the GeoSentinel Network during January 2007-December 2019. We excluded records of travellers migrating, with an unascertainable exposure country, or from GeoSentinel sites that were not located in high-income countries. RESULTS: There were 2517 cases, 82.3% giardiasis (n = 2072), 11.4% cryptosporidiosis (n = 287), 6.0% cyclosporiasis (n = 150), and 0.3% cystoisosporiasis (n = 8). Overall, most travellers were tourists (64.4%) on long trips (median durations: 18-30 days). Cryptosporidiosis more frequently affected people < 18 years (13.9%) and cyclosporiasis affected people ≥40 years (59.4%). Giardiasis was most frequently acquired in South-Central Asia (45.8%) and Sub-Saharan Africa (22.6%), cryptosporidiosis in Sub-Saharan Africa (24.7%) and South-Central Asia (19.5%), and cyclosporiasis in South East Asia (31.3%) and Central America (27.3%). and cystoisosporiasis in Sub-Saharan Africa (62.5%). Cyclosporiasis cases were reported from countries of uncertain endemicity (e.g. Cambodia) or in countries with no previous evidence of this parasite (e.g. French Guiana). The time from symptom onset to presentation at a GeoSentinel site was the longest among travellers with giardiasis (median: 30 days). Over 14% of travellers with cryptosporidiosis were hospitalized. CONCLUSIONS: This analysis provides new insights into the epidemiology and clinical significance of 4 intestinal protozoa that can cause morbidity in international travellers. These data might help optimize pretravel advice and post-travel management of patients with travel-associated prolonged gastrointestinal illnesses. This analysis reinforces the importance of international travel-related surveillance to identify sentinel cases and areas where protozoal infections might be undetected or underreported.

Chikungunya infection in returned travellers: results from the geosentinel network, 2005-2020.

BACKGROUND: Chikungunya is an important travel-related disease because of its rapid geographical expansion and potential for prolonged morbidity. Improved understanding of the epidemiology of travel-related chikungunya infections may influence prevention strategies including education and vaccination. METHODS: We analysed data from travellers with confirmed or probable chikungunya reported to GeoSentinel sites from 2005 to 2020. Confirmed chikungunya was defined as a compatible clinical history plus either virus isolation, positive nucleic acid test or seroconversion/rising titre in paired sera. Probable chikungunya was defined as a compatible clinical history with a single positive serology result. RESULTS: 1202 travellers (896 confirmed and 306 probable) with chikungunya were included. The median age was 43 years (range 0-91; interquartile range [IQR]: 31-55); 707 (58.8%) travellers were female. Most infections were acquired in the Caribbean (28.8%), Southeast Asia (22.8%), South Central Asia (14.2%) and South America (14.2%). The highest numbers of chikungunya cases reported to GeoSentinel were in 2014 (28.3%), 2015 (14.3%) and 2019 (11.9%). The most frequent reasons for travel were tourism (n = 592; 49.3%) and visiting friends or relatives (n = 334; 27.7%). The median time to presentation to a GeoSentinel site was 23 days (IQR: 7-52) after symptom onset. In travellers with confirmed chikungunya and no other reported illnesses, the most frequently reported symptoms included musculoskeletal symptoms (98.8%), fever/chills/sweats (68.7%) and dermatologic symptoms (35.5%). Among 917 travellers with information available, 296 (32.3%) had a pretravel consultation. CONCLUSIONS: Chikungunya was acquired by international travellers in almost 100 destinations globally. Vector precautions and vaccination where recommended should be integrated into pretravel visits for travellers going to areas with chikungunya or areas with the potential for transmission. Continued surveillance of travel-related chikungunya may help public health officials and clinicians limit the transmission of this potentially debilitating disease by defining regions where protective measures (e.g. pretravel vaccination) should be strongly considered.

Dengue Types 1 and 3 Identified in Travelers Returning from Kathmandu, Nepal, during the October 2022 Outbreak Are Related to Strains Recently Identified in India.

Phylogenetic analysis of dengue serotypes 1 and 3, which were diagnosed in travelers and Nepalese infected in Kathmandu during the October 2022 outbreak, revealed that both serotypes were clustered closest to the sequences sampled in India. This suggests both serotypes may have originated in India.

Comparison of clinical and laboratory parameters of primary vs secondary dengue fever in travellers.

BACKGROUND: Dengue fever (DF), caused by the dengue virus (DENV), is the most common arboviral disease in travellers worldwide. It is hypothesized that compared with primary DF, secondary DF may result in antibody-dependent enhancement of the immune response, resulting in more severe disease. We aimed to compare clinical and laboratory parameters in travellers with primary and secondary DF to determine whether secondary DF is associated with markers of severe disease. METHODS: We conducted a retrospective cohort study, which included all patients diagnosed with DF at the Central Virology Laboratory of the Israeli Ministry of Health during 2008-19. Clinical, laboratory and virological data were extracted from laboratory and patient records. A diagnosis of DENV infection was based on a positive nonstructural protein 1 (NS1) test, polymerase chain reaction or serology testing for immunoglobulin M (IgM) and immunoglobulin G (IgG). Primary and secondary infections were classified based on travel history, NS1 result and IgM/IgG ratio. Severe DF was defined according to WHO classification. RESULTS: We identified 245 DF cases: 210 (86%) primary and 35 (14%) secondary. Whilst fever duration was significantly longer in secondary compared with primary infections (6.4 vs 5.3 days, P = 0.027), mean Aspartate aminotransferase levels were significantly higher in primary compared with secondary cases (146 vs 65 U/L, P < 0.001), and no other clinical or laboratory parameter differed significantly between the groups. Of note, only four patients had severe DF, all had primary infections and none died. CONCLUSIONS: In a cohort of returning travellers with DF, secondary infection, compared with primary infection, was not associated with a consistent trend towards greater severity of the clinical and laboratory markers examined in this study.

Emergence of artemisinin-based combination treatment failure in patients returning from sub-Saharan Africa with P. falciparum malaria.

BACKGROUND: Artemisinin-based combination therapies (ACTs) are recommended as first-line treatment against uncomplicated Plasmodium falciparum infection. Mutations in the PfKelch13 (PF3D7_1343700) gene led to resistance to artemisinin in Southeast Asia. Mutations in the Pfcoronin (PF3D7_1251200) gene confer reduced artemisinin susceptibility in vitro to an African Plasmodium strain, but their role in clinical resistance has not been established. METHODS: We conducted a retrospective observational study of Israeli travellers returning from sub-Saharan Africa with P. falciparum malaria, including patients with artemether-lumefantrine (AL) failure. Blood samples from all malaria-positive patients are delivered to the national Parasitology Reference Laboratory along with personal information. Confirmation of malaria, species identification and comparative parasite load analysis were performed using real-time PCR. DNA extractions from stored leftover samples were analysed for the presence of mutations in Pfkelch13 and Pfcoronin. Age, weight, initial parasitaemia level and Pfcoronin status were compared in patients who failed treatment vs responders. RESULTS: During 2009-2020, 338 patients had P. falciparum malaria acquired in Africa. Of those, 15 (24-69 years old, 14 males) failed treatment with AL. Four were still parasitemic at the end of treatment, and 11 had malaria recrudescence. Treatment failure rates were 0% during 2009-2012, 9.1% during 2013-2016 and 17.4% during 2017-2020. In all patients, the Pfkelch13 propeller domain had a wild-type sequence. We did find the P76S mutation in the propeller domain of Pfcoronin in 4/15 (28.6%) of the treatment-failure cases compared to only 3/56 (5.5%) in the successfully treated patients (P = 0.027). CONCLUSION: AL treatment failure emergence was not associated with mutations in Pfkelch13. However, P76S mutation in the Pfcoronin gene was more frequently present in the treatment-failure group and merits further investigation. The increase of malaria incidence in sub-Saharan-Africa partly attributed to the COVID-19 pandemic might also reflect a wider spread of ACT resistance.

Zika virus infection in European travellers returning from Thailand in 2022: A GeoSentinel case series.

Zika virus is a mosquito-borne flavivirus which caused major epidemics in the Pacific and the Americas between 2013 and 2015. International travellers have previously acted as a sentinel population for Zika virus transmission in endemic areas, where local transmission may be incompletely captured by local surveillance systems. We report five recent European travellers returning from Thailand with Zika virus infection, highlighting the risk of ongoing endemic transmission in this popular tourist destination.

Morbidity of Returning Travelers Seen in Community Urgent Care Centers throughout Israel.

Information regarding post-travel morbidity is usually reported via dedicated post-travel clinics and mainly relates to travelers returning from low-middle-income countries (LMIC), however, the spectrum of morbidity seen within the community setting is scarcely reported. This prospective observational study among visitors to 17 community Urgent Care Centers (UCC) was designed to evaluate the reasons for post-travel community clinic visits and to compare travelers returning from LMIC to high-income countries (HIC). All visitors within one-month post-travel to all destinations were included. A total of 1580 post-travel visits were analyzed during 25 months. Travelers to LMICs were younger (mean 36.8 years old vs. 41.4 in the HIC group) and stayed longer periods abroad (30.1 ± 41.2 vs. 10.0 ± 10.6 in the HIC group) but more of them had pre-travel vaccines (35.5% vs. 6.6%). Travel-related morbidity was significantly more common in the LMIC group 58.3% (253/434) vs. 34.1% (391/1146) in the HIC group, (p < 0.001). Acute diarrhea was the leading cause of morbidity after visiting LMIC (28.8%) and was significantly more common than in the HIC (6.6%, p < 0.001). Other common morbidities in the LMIC cohort were respiratory (23.3%), cutaneous (15.8%), and injuries (9.9%). In the HIC group, the common morbidities were respiratory (37.3%), and diarrhea composed only 6.6% of the complaints. Our study group represents a less biased sample of travelers to LMIC as well as HIC, therefore, data from the UCC setting and at the specialized travel clinics complete each other in understanding the true extent of morbidity in travelers.

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.

Cutaneous Leishmaniasis Caused by Leishmania infantum, Israel, 2018-2021.

Cutaneous leishmaniasis (CL) is endemic to Israel. Previously, CL caused by Leishmania infantum had been reported in Israel only once (in 2016). We report 8 L. infantum CL cases; 7 occurred during 2020-2021. None of the patients had systemic disease. L. infantum CL may be an emerging infection in Israel.

[POST-ARTEMISININ DELAYED HEMOLYSIS AFTER TREATMENT OF MALARIA].

INTRODUCTION: Falciparum malaria is highly endemic in sub-Saharan Africa. The disease is caused by the intra-cellular parasite Plasmodium within erythrocytes. The recommended treatment is artemisinin-based combination which is efficient and safe. In some patients, artemisinin can cause hemolysis weeks after treatment, presenting with severe anemia. Most of the published cases were following intravenous treatment. We present a case of a falciparum malaria patient with hemolysis and severe anemia two weeks after oral treatment with artemisinin-based combination therapy.

The Role of NS1 Protein in the Diagnosis of Flavivirus Infections.

Nonstructural protein 1 (NS1) is a glycoprotein among the flavivirus genus. It is found in both membrane-associated and soluble secreted forms, has an essential role in viral replication, and modulates the host immune response. NS1 is secreted from infected cells within hours after viral infection, and thus immunodetection of NS1 can be used for early serum diagnosis of dengue fever infections instead of real-time (RT)-PCR. This method is fast, simple, and affordable, and its availability could provide an easy point-of-care testing solution for developing countries. Early studies show that detecting NS1 in cerebrospinal fluid (CSF) samples is possible and can improve the surveillance of patients with dengue-associated neurological diseases. NS1 can be detected postmortem in tissue specimens. It can also be identified using noninvasive methods in urine, saliva, and dried blood spots, extending the availability and effective detection period. Recently, an enzyme-linked immunosorbent assay (ELISA) assay for detecting antibodies directed against Zika virus NS1 has been developed and used for diagnosing Zika infection. This NS1-based assay was significantly more specific than envelope protein-based assays, suggesting that similar assays might be more specific for other flaviviruses as well. This review summarizes the knowledge on flaviviruses' NS1's potential role in antigen and antibody diagnosis.

Epidemiological and clinical characteristics of patients with monkeypox in the GeoSentinel Network: a cross-sectional study.

BACKGROUND: The early epidemiology of the 2022 monkeypox epidemic in non-endemic countries differs substantially from the epidemiology previously reported from endemic countries. We aimed to describe the epidemiological and clinical characteristics among individuals with confirmed cases of monkeypox infection. METHODS: We descriptively analysed data for patients with confirmed monkeypox who were included in the GeoSentinel global clinical-care-based surveillance system between May 1 and July 1 2022, across 71 clinical sites in 29 countries. Data collected included demographics, travel history including mass gathering attendance, smallpox vaccination history, social history, sexual history, monkeypox exposure history, medical history, clinical presentation, physical examination, testing results, treatment, and outcomes. We did descriptive analyses of epidemiology and subanalyses of patients with and without HIV, patients with CD4 counts of less than 500 cells per mm3 or 500 cells per mm3 and higher, patients with one sexual partner or ten or more sexual partners, and patients with or without a previous smallpox vaccination. FINDINGS: 226 cases were reported at 18 sites in 15 countries. Of 211 men for whom data were available, 208 (99%) were gay, bisexual, or men who have sex with men (MSM) with a median age of 37 years (range 18-68; IQR 32-43). Of 209 patients for whom HIV status was known, 92 (44%) men had HIV infection with a median CD4 count of 713 cells per mm3 (range 36-1659; IQR 500-885). Of 219 patients for whom data were available, 216 (99%) reported sexual or close intimate contact in the 21 days before symptom onset; MSM reported a median of three partners (IQR 1-8). Of 195 patients for whom data were available, 78 (40%) reported close contact with someone who had confirmed monkeypox. Overall, 30 (13%) of 226 patients were admitted to hospital; 16 (53%) of whom had severe illness, defined as hospital admission for clinical care rather than infection control. No deaths were reported. Compared with patients without HIV, patients with HIV were more likely to have diarrhoea (p=0·002), perianal rash or lesions (p=0·03), and a higher rash burden (median rash burden score 9 [IQR 6-21] for patients with HIV vs median rash burden score 6 [IQR 3-14] for patients without HIV; p<0·0001), but no differences were identified in the proportion of men who had severe illness by HIV status. INTERPRETATION: Clinical manifestations of monkeypox infection differed by HIV status. Recommendations should be expanded to include pre-exposure monkeypox vaccination of groups at high risk of infection who plan to engage in sexual or close intimate contact. FUNDING: US Centers for Disease Control and Prevention, International Society of Travel Medicine.

Failure to Detect Leishmania in the Blood of Patients with Old-World Cutaneous Leishmaniasis: Implications for Blood Donation.

Cutaneous leishmaniasis (CL) is endemic in Israel, caused mainly by Leishmania major (L. major) and L. tropica. In addition, returning travelers import another leishmanial species such as L. braziliensis. Although we are dealing with a skin disease, the blood bank in Israel does not accept blood donations from people infected with CL in cases of multiple lesions due to the possibility of transfusion. Our purpose was to investigate the prevalence of Leishmania in the blood of patients with active or previous CL. This pilot study screened patients with active or previous CL for parasites in their blood. All patients were infected in Israel or were returning travelers with leishmaniasis acquired in Latin America. Patients were seen at the Sheba Medical Center. In addition, patients were seen at their homes in L. tropica and L. major endemic regions in Israel. Blood samples were taken from each patient for culture and polymerase chain reaction (PCR). Altogether 62 blood samples were examined (L. tropica = 26, L. major = 33, and L. braziliensis = 3). Twenty-seven patients had an active disease and 35 were recovered. All blood cultures and PCR were negative for parasites except one blood sample that was PCR positive for L. braziliensis. The findings of our study, although a small sample, suggest that people with active or recent CL caused by L. major and L. tropica, do not harbor parasites in their blood. Thus, their exclusion from blood donation should be revisited. Further studies are needed with larger sample size and highly sensitive tests.

Can Biomarkers of Oxidative Stress in Serum Predict Disease Severity in West Nile Virus Infection? A Pilot Study.

West Nile virus (WNV) can cause asymptomatic infection in humans, result in self-limiting febrile illness, or lead to severe West Nile Neuroinvasive disease (WNND). We conducted a pilot study to compare selected biomarkers of oxidative stress in sera of viremic West Nile virus patients and asymptomatic infected blood donors to investigate their potential as predictors of disease severity. We found that total oxidant status was elevated in WNND and in uncomplicated WNV infections (median 9.05 (IQR 8.37 to 9.74) and 7.14 (7.03 to 7.25) µmol H2O2 equiv./L, respectively) compared to asymptomatic infections (0.11 (0.07 to 0.19) µmol H2O2 equiv./L) (p = 0.048). MDA levels showed a similar trend to TOS, but differences were not significant at α = 0.05. Total antioxidant status did not differ significantly between different disease severity groups. Oxidative stress appears to be associated with more severe disease in WNV-infected patients. Our preliminary findings warrant prospective studies to investigate the correlation of oxidative stress with clinical outcomes and severity of WNV infection.

Unusual and Severe Complications of Acute Schistosomiasis in Travelers.

Acute schistosomiasis (ASC) is a hypersensitivity reaction seen mostly in nonimmune travelers and manifests mainly with fever, urticaria, and respiratory symptoms. We describe unusual severe presentations of ASC in 3 patients, including hip-monoarthritis, peri-myocarditis, and optic neuritis. In all 3 patients, clinical symptoms appeared or worsened after praziquantel administration.

Gender and Cutaneous Leishmaniasis in Israel.

Leishmaniasis is estimated to be more common in males than in females. Our purpose was to evaluate differences in preponderance in relation to sex and gender across cutaneous and mucocutaneous leishmaniasis in Israel. An observational study was performed, including cases of endemic CL (cutaneous leishmaniasis) in Israel, and imported MCL (mucocutaneous leishmaniasis). CL is a notifiable disease and is supposed to be reported to the Ministry of Health (MOH). The MOH database shows that males as more likely to be infected by leishmania, with an incidence of 5/100,000 in males vs. 3.5/100,000 in females. However, while conducting a demographic house-to-house survey in several locations in Israel where CL is highly endemic, among 608 people who were screened only 49% were males in Leishmania major (L. major) endemic regions and 41% were males in Leishmania tropica (L. tropica) endemic regions, while among 165 cases of imported New-World cutaneous leishmaniasis in Israeli travelers freturning from abroad, 142 (86%) were males. It may be postulated that there is no real gender difference in leishmanial infection, but, perhaps, infections are more commonly seen in men because of referral/reported bias, due to more risk-taking behaviors by men or, perhaps, men are less likely to strictly adhere to recommended preventive measures and thus increase their risk of contracting the disease.

Corrigendum to "Does ivermectin have a place in the treatment of mild Covid-19?" [New Microbes New Infect 46 (C) (2022 Mar) 100985].

[This corrects the article DOI: 10.1016/j.nmni.2022.100985.].