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.

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.

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.

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.

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.

A large outbreak of Salmonella Paratyphi A infection among israeli travelers to Nepal.

BACKGROUND: In Asia, Salmonella Paratyphi A is an emerging infection, and travelers are increasingly at risk. During October 2009-November 2009, an outbreak in S. Paratyphi A infection was noted in Israeli travelers returning from Nepal. METHODS: An outbreak investigation included a standardized exposure questionnaire admitted to all patients and medical chart abstraction. Isolates were tested for antimicrobial susceptibility and pulsed-field gel electrophoresis (PFGE). RESULTS: During 1 October 2009-30 November 2009, 37 Israeli travelers returning from Nepal were diagnosed with S. Paratyphi A bacteremia. All 37 case isolates had an identical pattern on PFGE, and all were nalidixic acid resistant. Only 1 food venue was frequented by all the outbreak cases, with the largest number of exposures occurring around the Jewish New Year. All patients recovered without complications. Time to defervescence in 17 patients treated with ceftriaxone and azithromycin combination was 3.2 days (± 1.7), whereas in 13 cases treated with ceftriaxone monotherapy, the time to defervescence was 6.6 days (± 1.8; P < .001). CONCLUSIONS: A point-source, "Paratyphoid Mary"-like outbreak was identified among Israeli travelers to Nepal. Combination Ceftriaxone-Azithromycin therapy may provide a therapeutic advantage over monotherapy, and merits further clinical trials.

Treatment of giardiasis after nonresponse to nitroimidazole.

During January 2008-October 2013, a total of 12 cases of giardiasis at the Chaim Sheba and Shaare Zedek Medical Centers, Israel, did not respond to nitroimidazole; 83.3% were associated with travel and 33% with immunoglobulin deficiency. Among 110 published cases, the most effective treatment was quinacrine (efficacy 90%-100%), but its availability is limited.

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.

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.

Travel-associated zoonotic bacterial diseases.

PURPOSE OF REVIEW: Bacterial zoonoses are increasingly described in association with travel. Some bacterial zoonoses constitute important causes of post-travel illness. We focus on leptospirosis and rickettsiosis - the most common travel-associated bacterial zoonoses. RECENT FINDINGS: Leptospirosis is regarded to be the most common zoonotic disease worldwide. In industrialized countries recreational exposures, both domestic and overseas, are increasingly becoming a major source of infection. Asymptomatic infection is rare among travelers. Rickettsial diseases account for approximately 1.5-3.5% of febrile travelers. In several series of travel-related rickettsioses, the most common travel-related rickettsial disease is Rickettsia africae. Other rickettsioses including Q fever, scrub typhus and murine typhus are considered rare among travelers. Whereas timely diagnosis of both diseases is still based on exposure history, antigen detection tools to aid the diagnosis during the acute illness are under research and far from being available. Due to these constrains, currently, the true incidence of both diseases is probably underestimated. SUMMARY: Both leptospirosis and spotted fever may be rapidly fatal. Empiric doxycycline in severely ill febrile travelers should be considered. There is an urgent need for widely available antigen detection diagnostic tools to improve the detection of leptospirosis and rickettsial infections during the acute illness.

Protracted rheumatic manifestations in travelers.

BACKGROUND: Travel returnees may complain of protracted rheumatic symptoms, but there are sparse data regarding their causes. We aimed to describe travelers returning with new rheumatic symptoms. METHODS: We conducted a retrospective analysis of Israeli travelers who were referred to the Sheba Medical Center from January 2005 to January 2010 with prolonged (>4 weeks) nontraumatic arthralgia or arthritis. RESULTS: During 5 years, 14 patients (7 men and 7 women) with posttravel arthritis/arthralgia were seen. A total of 5 patients were diagnosed with reactive arthritis, and 9 were diagnosed with rheumatic symptoms related to infection with Alphaviruses: Chikungunya virus or Ross River virus. Some disability remained for several months in most cases, but only 1 case of reactive arthritis eventually evolved to a chronic spondyloarthropathy. CONCLUSIONS: Travel-related arthritis may persist even several months after the exposure. Assessing patients' travel history may help in the evaluation of some cases with rheumatic manifestations. Their prognosis may be better than that of autoimmune arthritides.

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.

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.

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.

Sexually transmitted brucellosis in humans.

Sexual transmission of brucellosis has rarely been reported in humans. We describe 2 cases of probable sexual transmission of Brucella from husband to wife. In 1 case, orchidoepididimitis existed, whereas in the other case, the presence of Brucella in the semen in the absence of genital symptoms was demonstrated by polymerase chain reaction.

Enteric fever: a travel medicine oriented view.

PURPOSE OF REVIEW: Enteric fever continues to be an important infection among populations in endemic countries and among travelers to these areas. This review aims to describe recent epidemiological trends and developments in diagnosis, treatment and prevention. RECENT FINDINGS: Data indicate that the burden of enteric fever is declining in many middle-income countries, whereas the bulk of cases occur in the Indian subcontinent and in south-east Asia. In these regions, Salmonella Paratyphi A is increasingly seen and sometimes surpasses Salmonella Typhi as the main pathogen. Enteric fever caused by S. Paratyphi A is indistinguishable from that caused by S. Typhi. In addition, drug resistance, including nalidixic acid/quinolone resistance now occurs in the majority of clinical isolates of S. Typhi and S. Paratyphi A in Asia. Currently, third generation cephalosporins and azythromycin are the only reasonable therapeutic options for most cases of travel-related enteric fever. SUMMARY: The ongoing emergence of S. Paratyphi A results in partial benefit from current typhoid vaccines in the prevention of enteric fever in travelers. Increasing antimicrobial resistance complicates therapy for travel-related enteric fever. New vaccines, offering protection against both agents of enteric fever, are urgently needed; however, none of the current vaccine candidates is likely to be available for several years.

[Rickettsia africae infection among participants in a women's safari to South Africa].

PREFACE: In recent years infections with Rickettsia africae (African tick bite fever) have become a common and important cause of febrile illness among travelers returning from Sub-Saharan Africa, primarily from South Africa. METHODS: A prospective observational study, involving 671 participants in safaris to South Africa during 2008. RESULTS: Nine participants (1.34%) were diagnosed with African tick bite fever. The symptoms included fever, headache, muscle pain, lymphadenopathy, vesicular rash, and an eschar. Lack of familiarity with the disease led to an incorrect diagnosis and delayed treatment with doxycycline in a number of cases. CONCLUSIONS: African tick bite fever is frequent among Israeli travelers to Sub-Saharan Africa. Travelers should be counseled on tick bite prevention. Increased awareness of the disease among Israeli physicians may prevent diagnostic delays.