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.

Association between Thrombin Generation and Clinical Characteristics in COVID-19 Patients.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) disease is associated with coagulopathy and an increased risk of thrombosis. An association between thrombin generation (TG) capacity, disease severity, and outcomes has not been well described. METHODS: We assessed the correlation of TG with sequential organ failure assessment (SOFA) and sepsis-induced coagulopathy (SIC) scores and clinical outcomes by analysis of plasma samples obtained from hospitalized COVID-19 patients. RESULTS: 32 patients (68.8% male), whose median age was 69 years, were assessed, of whom only 3 patients did not receive anticoagulant therapy. D-dimers were uniformly increased. During hospitalization, 2 patients suffered thrombosis, 3 experienced bleeding, and 12 died. TG parameters from anticoagulated COVID-19 patients did not significantly differ from the values obtained from non-anticoagulated healthy controls. Patients who received higher than prophylactic doses of anticoagulant therapy had increased lag time (p = 0.003), lower endogenous thrombin potential (ETP) (p = 0.037), and a reduced peak height (p = 0.006). ETP correlated with the SIC score (p = 0.038). None of the TG parameters correlated with the SOFA score or were associated with mortality. CONCLUSION: TG was not associated with disease severity among patients hospitalized with COVID-19. However, a correlation between ETP and the SIC score was noted and deserves attention.

Incidence of dengue fever in Israeli travelers 2008-2019.

BACKGROUND: Dengue virus (DENV) is a frequent travel-related infection, but longitudinal data on its incidence is limited. We aimed to study temporal trends of travel-related DENV burden and its geographical sources. METHODS: All cases of laboratory-confirmed DENV infection diagnosed at the Central Virology Laboratory of the Israeli Ministry of Health during 2008-2019 were evaluated. Numbers of Israeli tourist-entries to DENV endemic countries were available from the UN World Tourist Organization (UNWTO) database. DENV attack rates were calculated as cases per 100,000 traveler-entries. In addition, for Thailand and India incidence rates were calculated, using the average duration of stay reported in diagnosed DENV cases. RESULTS: During 2008-2019, 425 Israeli travelers were diagnosed with DENV: 80.3%, 12.8% and 6.9% were acquired in Asia, America and Africa respectively. The average global DENV attack rate increased from 2.5 cases per 100,000 tourist-entries in 2008 to 10.7 cases per 100,000 tourist-entries in 2019. Region-specific DENV attack rates were 4.4, 3.2 and 2.1 cases per 100,000 tourist-entries to Asia, Africa, and America respectively. The highest number of DENV cases were reported from Thailand and India; DENV incidence rates increased from 94.5 to 142.2 cases per 100,000 travel-years, and from 49.3 to 90.4 cases per 100,000 travel-years for Thailand and India respectively. CONCLUSION: Among Israeli travelers, worldwide DENV attack-rates have quadrupled during 2008-2019, reflecting both a growing DENV burden in Asia, but also the emergence of Africa as an important source of DENV. The need to protect travelers through vaccination remains urgent.

Rabies Vaccine Disposition: Trends in Vaccination Among Israeli Travelers.

Travelers are a risk-group for rabies; however, few are protected. We describe changes in pre-travel vaccination rates and post-travel referrals after animal contact. We conducted a nationwide, retrospective study for 2014-2018. The ratio of rabies vaccine courses distributed to travelers and the number of Israeli-tourist-entries to endemic countries was calculated, as was the proportion of travelers referred to a post-travel clinic after animal contact. During the study period, the ratio of pre-travel vaccine courses distributed nationally to outgoing tourism to endemic countries was stable at ≈0.7%; 13% of 256,969 pre-travel consultations included recommendation for rabies vaccination. Backpackers were more likely to be immunized (40.2%) than business travelers (4.4%) or travelers planning organized/high-end travel (2.0%). However, rates of rabies vaccination among backpackers showed a decline during the study period. Post-travel referrals after animal contact were stable at 2% of all referrals; most were exposed in Asia (69.5%) and 51% were bitten by dogs. Only 38% received post-exposure prophylaxis abroad. We conclude that only a minority of Israeli travelers, including backpackers, receive rabies pre-exposure prophylaxis. The proportion of travelers with potentially rabid animal contact is not decreasing; however, many exposed travelers do not receive post-exposure prophylaxis during travel. Because rabies control programs have been compromised in endemic countries during the COVID-19 pandemic, the need to provide rabies protection to travelers has become more urgent. After the ACIP's adoption of the World Health Organization's (WHO) 2-dose regimen, a revision of current vaccine guidelines is required to provide a simplified, more inclusive rabies vaccine policy.

Typhoid and paratyphoid fever: a clinical seminar.

Rationale for review: Enteric fever (EF) caused by Salmonella enterica subspecies enterica serovar Typhi (Salmonella Typhi) and S. Paratyphi (Salmonella Paratyphi) remains an important cause of infectious morbidity and mortality in many low-income countries and, therefore, still poses a major infectious risk for travellers to endemic countries. Main findings: Although the global burden of EF has decreased over the past two decades, prevalence of EF remains high in Asia and Africa, with the highest prevalence reported from the Indian subcontinent. These statistics are mirrored by data on travel-related EF. Widespread and increasing antimicrobial resistance has narrowed treatment options for travel-related EF. Ceftriaxone- and azithromycin-based therapies are commonly used, even with the emergence of extremely drug-resistant typhoid in Pakistan. Preventive measures among locals and travellers include provision of safe food and water and vaccination. Food and water precautions offer limited protection, and the efficacy of Salmonella Typhi vaccines is only moderate signifying the need for travellers to be extra cautious. Recommendations: Improvement in the diagnosis of typhoid with high degree of clinical suspicion, better diagnostic assays, early and accurate detection of resistance, therapy with appropriate drugs, improvements in hygiene and sanitation with provision of safe drinking water in endemic areas and vaccination among travellers as well as in the endemic population are keys to controlling typhoid. While typhoid vaccines are recommended for travellers to high-risk areas, moderate efficacy and inability to protect against Salmonella Paratyphi are limitations to bear in mind. Improved Salmonella Typhi vaccines and vaccines against Salmonella Paratyphi A are required.

Valvular fibroelastomas complicated by Coxiella burnetti endocarditis.

Cardiac papillary fibroelastoma (CPF) is a valvular tumor that may be mistaken for infective endocarditis (IE). We describe a case of CPF complicated by Coxiella burnetti IE. According to Duke's criteria, a diagnosis of IE was repeatedly considered as excluded or established during the clinical course, highlighting the criteria limitations.

Utility of 8-Aminoquinolines in Malaria Prophylaxis in Travelers.

PURPOSE OF REVIEW: To review the current status of 8-aminoquinolines in the prophylaxis of malaria among travelers, in light of the recent approval of tafenoquine. RECENT FINDINGS: Primaquine continues to provide excellent primary prophylaxis against all Plasmodium species. Tafenoquine provides similarly good prophylaxis, with the benefit of weekly dosing. Both agents require glucose-6-phosphate dehydrogenase activity testing before use and are contraindicated in pregnancy. Pharmacodynamic variability relating to CYP2D6 may underlie some cases of primaquine failure; the effects of CYP2D6 on tafenoquine efficacy require further study. Tafenoquine and primaquine are the only current drugs that provide complete malaria prophylaxis, and should be considered the agents of choice in areas where both P. vivax and falciparum are frequent. Monthly tafenoquine is promising and should be further studied in travelers.

Acute Diarrhea in North American Students after Relocation to Israel: A Pilot Study.

BACKGROUND: Travelers' diarrhea (TD) is frequently encountered in people traveling from high-income to low-income countries; however, its epidemiology in those traveling between high-income countries is not known. OBJECTIVES: To evaluate the incidence of diarrhea in North American students relocating to Israel. METHODS: A retrospective cohort study involving medical students from the United States and Canada relocating to Israel was conducted. Students who relocated to Israel during 2010-2016 were contacted by email to participate in an anonymous survey. Data included demographic information as well as occurrence, timing, duration, and outcome of diarrhea after relocation. RESULTS: Ninety-seven students participated in the survey. Most (93.7%) students relocated from the United States or Canada. The period-prevalence of diarrhea was 69.1%. The incidence of diarrhea declined from 34.8 cases per 100 student-months during the first month after relocation to 1.3 cases per 100 student-months after 1 year. The duration of diarrhea was up to 1 week in 72.7%. Students who reported diarrhea were younger than students who did not (mean age 24.0 ± 2.2 and 28.4 ± 1.8 years, respectively, P < 0.001). No other demographic parameter was significantly associated with a higher likelihood of diarrhea. CONCLUSIONS: A high proportion of North American medical students relocating to Israel reported diarrhea with clinical and epidemiological features similar to classic TD. Further studies are needed to elucidate the causative agents of TD in Israel.

[TRAVEL MEDICINE IN ISRAEL: ITS HISTORY AND CONTRIBUTIONS TO THE DISCIPLINE].

INTRODUCTION: The last century in Israel had seen a profound change in the field of travel-related infectious diseases. During the 19th century and throughout the first half of the 20th century, most scientific observations related to the various endemic infections in Palestine, and the risk they posed to the passengers/immigrants. Among the infectious hazards that have characterized the country, malaria, typhoid, cutaneous leishmaniasis, and bilharzia were especially noteworthy. With the establishment of the State of Israel and following the great waves of immigration to Israel, many endemic diseases declined or were completely eradicated, such as malaria. Since the 1980's, the emergence of the Israeli backpacking phenomenon was accompanied by a surge of imported infectious diseases, from Latin America, the Far East and Africa. Israeli travel medicine has documented these developments, with an important contribution to the literature on epidemiology, clinical aspects and the treatment and prevention of many travel-related infections.

D-dimer levels in non-immune travelers with malaria.

BACKGROUND: Elevated serum D-dimer levels may reflect endothelial activation, which in malaria may correlate with parasite biomass and disease severity. METHODS: We performed a retrospective chart review of all non-immune travelers hospitalized with malaria during 01/2000-12/2014 at the Sheba Medical Center, Israel. Admission and peak D-dimer levels were compared among malaria patients, according to Plasmodium species and severity. RESULTS: Complete laboratory data was available for 94/168 travelers hospitalized with malaria, with 68.1% caused by P. falciparum. Admission D-dimer levels were significantly higher in P. falciparum malaria compared to non-falciparum malaria cases (3585 ±â€¯7045 and 802 ±â€¯1248 ng/dL respectively, p = 0.04). Admission D-dimer levels were higher in patients with severe compared to non-severe P. falciparum malaria (4058 ±â€¯3544 & 3490 ±â€¯7549 ng/dL), however the difference was short of statistical significance (P = 0.06). Peak D-dimer levels were also significantly higher in severe and non-severe P. falciparum than in non-falciparum cases. CONCLUSIONS: In most non-immune travelers with malaria, D-dimer levels are elevated, are higher in P. falciparum malaria compared to non-falciparum malaria, and appear to increase with disease severity, probably reflecting the level of endothelial damage.

Zika Virus in Israeli Travelers: Emergence of Asia as a Major Source of Infection.

Zika virus (ZIKV) had emerged as a global arboviral concern since late 2015. In this study, we describe the results of ZIKV testing in returning Israeli travelers from Zika-endemic countries. We conducted a nation-wide prospective observational study, including all ZIKV tests during January 2016-June 2017. Zika virus infection was defined as confirmed, if diagnosed by polymerase chain reaction (PCR) or serology confirmed by neutralization, and as possible if diagnosed by serology alone. During the study period, 1,188 travelers were tested: 66.7%, 30.5%, 1.6%, and 1.2% had returned from the Americas, Asia, Africa, and Oceania, respectively. Thirty persons were diagnosed with ZIKV. Most travelers tested were women of reproductive age; the gender ratio among infected travelers however was 1.0. During 2016, 19/20 (95%) ZIKV cases were acquired in the Americas; in 2017, however, 6/10 (60%) cases were acquired in Asia. Of 248 symptomatic travelers, 28 (11.3%) were diagnosed with ZIKV infection, whereas only 2/940 (0.2%) of asymptomatic travelers were diagnosed with ZIKV infection Odds ratio = 59.7 (95% confidence interval: 14.1-252.5, P < 0.0001). Our findings suggest that although women are more likely to be referred for ZIKV testing, gender does not affect the likelihood of ZIKV infection and that asymptomatic ZIKV infection appears to be rare in travelers. Furthermore, it appears that in 2017, Southeast Asia emerges as the leading source of travel-related ZIKV infection.

Region-Specific, Life-Threatening Diseases among International Travelers from Israel, 2004-2015.

We characterized posttravel hospitalizations of citizens returning to Israel by summarizing the returning traveler hospitalization dataset of the national referral Center for Travel Medicine and Tropical Diseases at Sheba Medical Center in Israel. Of 722 hospitalizations, 181 (25%) infections were life-threatening; most would have been preventable by chemoprophylaxis and pretravel vaccination.

Vivax Malaria Chemoprophylaxis: The Role of Atovaquone-Proguanil Compared to Other Options.

Background: Atovaquone-proguanil is considered causal prophylaxis (inhibition of liver-stage schizonts) for Plasmodium falciparum; however, its causal prophylactic efficacy for Plasmodium vivax is not known. Travelers returning to nonendemic areas provide a unique opportunity to study P. vivax prophylaxis. Methods: In a retrospective observational study, for 11 years, Israeli rafters who had traveled to the Omo River in Ethiopia, a highly malaria-endemic area, were followed for at least 1 year after their return. Malaria prophylaxis used during this period included mefloquine, doxycycline, primaquine, and atovaquone-proguanil. Prophylaxis failure was divided into early (within a month of exposure) and late malaria. Results: Two hundred fifty-two travelers were included in the study. Sixty-two (24.6%) travelers developed malaria, 56 (91.9%) caused by P. vivax, with 54 (87.1%) cases considered as late malaria. Among travelers using atovaquone-proguanil, there were no cases of early P. falciparum or P. vivax malaria. However, 50.0% of atovaquone-proguanil users developed late vivax malaria, as did 46.5% and 43.5% of mefloquine and doxycycline users, respectively; only 2 (1.4%) primaquine users developed late malaria (P < .0001). Conclusions: Short-course atovaquone-proguanil appears to provide causal (liver schizont stage) prophylaxis for P. vivax, but is ineffective against late, hypnozoite reactivation-related attacks. These findings suggest that primaquine should be considered as the chemoprophylactic agent of choice for areas with high co-circulation of P. falciparum and P. vivax.

Travel-Related Tick-Borne Encephalitis, Israel, 2006-2014.

During 2006-2014, four tick-borne encephalitis (TBE) cases occurred among Israeli travelers. We calculated TBE incidence at 321.0, 45.0, 13.2, and 7.5 cases/100,000 travelers/year of travel to Sweden, Switzerland, Austria, and Germany, respectively. TBE incidence among travelers to these destinations appears to justify TBE vaccination in accordance with World Health Organization recommendations.

The Clinical Spectrum of Zika Virus in Returning Travelers.

INTRODUCTION: The clinical spectrum of Zika virus had, to date, been described in small series from endemic/epidemic countries and is not well established. METHODS: We describe the clinical manifestations of laboratory-proven Zika virus infection in Israeli travelers during December 2015-February 2016, and review all published cases of travel-related Zika virus. RESULTS: During the study period, 8 returning Israeli travelers were diagnosed with Zika virus infection. In addition, 41 published cases were included, mostly from Latin America to Europe and North America. Overall, 65.3% were diagnosed by polymerase chain reaction. Rash was the most frequent symptom, present in 95.7% of cases, followed by fever and arthralgia. Conjunctivitis was present in 53.1%; however, only 40.3% presented with a triad of conjunctivitis, fever, and rash. Less frequent symptoms included dysgeusia and nightmares, which, together with arthralgia, persisted for several weeks in some travelers. CONCLUSIONS: Zika virus clinical picture in travelers is diverse. Prolonged symptoms may occur.