The new england journal of medicine

Review Article

Dan L. Longo, M.D., Editor Approach to in the Returning Traveler

Guy E. Thwaites, F.R.C.P., and Nicholas P.J. Day, F.Med.Sci., F.R.C.P.​​

From the Centre for Tropical Medicine ever in the returning traveler is a common clinical scenario and Global Health, Nuffield Department that often leads to hospitalization and may be the only symptom of a serious of Medicine, University of Oxford, Oxford, 1 United Kingdom (G.E.T., N.P.J.D.); Ox- or life-threatening illness. Three percent of 784 Americans who traveled ford University Clinical Research Unit, F 2 abroad for short periods reported an episode of febrile illness, and fever was the Ho Chi Minh City, Vietnam (G.E.T.); and chief symptom in 28% of 24,920 ill travelers who presented to travel clinics on the Mahidol–Oxford Tropical Medicine 3 Research Unit, Faculty of Tropical Medi- their return home. The absolute number of travelers is large and rising, with the cine, Mahidol University, Bangkok, Thai- International Tourism Organization reporting 1.2 billion trips in 2015, an increase land (N.P.J.D.). Address reprint requests of 4.4% from the previous year.4 The challenge presented by returning travelers with to Prof. Thwaites at Oxford University Clinical Research Unit, 764 Vo Van Kiet, febrile illnesses is changing for two reasons. First, increasing numbers of travelers Quan 5, Ho Chi Minh City, Vietnam, or at are older than 60 years of age or are seeking health care elsewhere (“medical tour- ­gthwaites@​­oucru​.­org. ists”), and these travelers are more likely than others to have clinically significant N Engl J Med 2017;376:548-60. coexisting conditions and consequently increased morbidity from infections. Sec- DOI: 10.1056/NEJMra1508435 ond, the likelihood of multidrug resistance in the infecting organisms is increas- Copyright © 2017 Massachusetts Medical Society. ing.5-7 The recent Ebola epidemic in West Africa, the emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV), and the reemergence of Zika and chikungunya have highlighted the importance of being alert to the possi- bility that an emerging pathogen is causing a febrile episode. Fever in the returning traveler is an evolving clinical challenge, with respect to both the infections responsible for the fever and the sources and quality of informa- tion available to assist the physician. We review available sources of global informa- tion on outbreaks and the epidemiologic features of infectious and offer a practical approach to emerging or transmissible infectious diseases that may pose a life-threatening risk to patients, as well as clinicians and laboratory workers.

Surveillance and Sources of Information A detailed travel history is central to the assessment of the febrile returning traveler. Its value, however, depends on accurate, up-to-date, and rapidly accessible informa- tion about the possible infections acquired in the places visited. There are a bewil- dering number of sources of information concerning the geographic risk of various infectious agents; an overview is provided in Table S1 in the Supplementary Ap- pendix, available with the full text of this article at NEJM.org. The Centers for Dis- ease Control and Prevention (CDC) website summarizes the global epidemiologic features of the key travel-related infections and provides essential information on the geographic risks of malaria. surveillance among travelers provides an important source of informa- tion that can inform advice before travel and clinical management after travel.8 Furthermore, surveillance among travelers can identify sentinels for outbreaks of new diseases and can be used to track the global movement of infectious diseases.9 Collaborative networks of travel clinics have been developed as a powerful surveil- lance tool; GeoSentinel is the preeminent example. Established in 1995 by the Inter-

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national Society of Travel Medicine and the CDC, pendent evaluations of the program’s performance GeoSentinel consists of 63 travel clinics on six suggest that it provides a reasonably accurate dif- continents that contribute Web-based, real-time ferential diagnosis that may alert inexperienced data on ill travelers to a central database.10 Ongoing physicians, in particular, to unconsidered infec- trends are tracked on a month-to-month basis for tions.20-23 60 key diagnoses, with additional syndromic sur- veillance. Quarterly reports are generated centrally Clinical Approach for participating sites, and published scientific articles report longer-term trends.11 Linked sur- The possible causes of fever in the returning trav- veillance networks exist in Canada (CanTravNet)12 eler are legion, and a specific diagnosis is often and Europe (EuroTravNet).13 All these networks difficult to establish because diagnostic tests for share the same limitations of sampling and selec- many diseases either perform poorly or are not tion bias, since they typically include information available locally. Even at referral centers with di- on travelers seen at an institution with a linked agnostic expertise, approximately 25% of patients participating clinic, and many of the clinics are in never receive a diagnosis (though they generally specialized academic centers. Incidence rates and do well clinically).3 For this reason, a risk-based absolute risks cannot be calculated without esti- approach is advisable, with initial priority given mates of denominators and missing cases. to identifying and treating life-threatening causes Novel surveillance methods provide a valuable of fever and those posing a high risk of trans- additional source of information. Automated news- mission to health care workers, laboratory staff, scanning software can enable early detection of and the wider population (Fig. 1). outbreaks.14 For example, HealthMap successfully tracked the 2009 H1N1 global influenza outbreak Recognizing Life-Threatening Causes of Fever using multilingual data from news wires, media Among 82,825 cases of illness in travelers that websites, RSS (Really Simple Syndication) feeds, were reported to GeoSentinel between 1996 and mailing lists such as ProMED, and authoritative 2011, a total of 3655 cases (4%) involved acute sources such as the World Health Organization and potentially life-threatening tropical diseases, (WHO), the CDC, and the European Centre for and fever was a symptom in 91% of these cases11 Disease Prevention and Control.15 (Table 1). Falciparum malaria accounted for 77% Advanced clinical decision-making tools are of the 3655 cases, and enteric fever for 18%. Thir- also available to assist physicians. Swiss guidelines teen patients (0.4%) died: 10 with falciparum ma- for primary care physicians on the management of laria, 2 with , and 1 with severe den- febrile illness in travelers are available through a gue. Falciparum malaria was acquired mainly in Web-based diagnostic algorithm (www.fevertravel West Africa, and enteric fever was contracted .ch).16 A recent evaluation involving 539 physician– largely on the Indian subcontinent. Travelers in patient pairs showed approximately 40% adher- this study had predominantly visited developing ence to the provided guidance per case and good countries and were seen at travel clinics, charac- clinical outcomes.17 KABISA, developed by the teristics that skewed the results. For the examin- Institute of Tropical Medicine of Antwerp, Bel- ing clinician, more widely distributed “cosmopoli- gium, is another clinical decision-making sup- tan” infections that cause severe febrile illness port system that is available free of charge for should not be overlooked, including respiratory the diagnosis of febrile illnesses after tropical and urinary tract infections, meningococcal dis- travel. In a study involving 205 patients, KABISA ease, and tuberculosis. Even among travelers re- performed as well as expert travel physicians in turning from the tropics, “nontropical” causes of diagnosing febrile illnesses, often providing un- fever are common, with a rate of 34% reported considered diagnoses.18 The Global Infectious Dis- in one European case series.25 eases and Epidemiology Network (GIDEON) offers Morbidity, including rates of hospitalization a commercial computer software program that with febrile illness, and mortality are greater uses a Bayesian matrix to generate a differential among elderly travelers than among those who diagnosis on the basis of a patient’s travel history, are younger.5,25 In most case series involving fever the clinical and laboratory findings, and the in- in returning travelers, deaths have been uncom- cubation periods for possible infections.19 Inde- mon, with overall mortality ranging from 0.2 to

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The new england journal of medicine (without Diarrhea) Fever with Jaundice Fever with Diarrhea Severe, Prolonged or Bloody Diarrhea Fever with Abdominal Pain or Tenderness tract infection, cholecystitis, pancreatitis) treat with tinidazole or metronidazole blood cultures, stool examination) ultrasound, serologic tests) spirosis, severe malaria, viral hemorrhage , yellow fever, severe dengue, Carrión’s disease) CMV, EBV (serologic tests) (ultrasound, blood cultures, stool examination) Travelers’ diarrhea (ETEC, norovirus) Giardiasis Cryptosporidiosis Campylobacter infection Nontyphoidal Intestinal amebiasis biotics may reduce symptom duration cultures, stool PCR or Ag detection; sigmoidoscopy with biopsy to rule out inflammatory bowel disease or fluoroquinolones (tinidazole metronidazole, if amebiasis or giardiasis suspected) Cosmopolitan causes (e.g., appendicitis, urinary Enteric fever (blood culture) Giardiasis (stool microscopy, Ag detection, PCR); Acute cholangitis — stones, flukes (ultrasound, Liver — pyogenic or amebic (blood cultures, Rule out possible life-threatening infections (lepto- Consider acute viral hepatitis (hepatitis A, B, C, E), Consider acute cholangitis — stones, liver flukes Common causes Diarrhea is usually self-limiting, though empirical anti- Investigate with stool microscopy and culture, blood Rehydration and empirical treatment with macrolides Consider: Within 4 Days after Return from Country Where an Outbreak of Influenza or a Pandemic Was Occurring Test for influenza with rapid test or PCR Treat with neuraminidase inhibitor Isolate at home (or in hospital, if avian influenza suspected) Consolidation (Clinically or on Chest Film) Fever Symptoms urinary tract infection, EBV, viral URTI, , ) causes (e.g., dengue, rickett- sial infections, , chikungunya, Zika [all diagnosed on serologic tests, Ag detection, or PCR] and enteric fever [blood cultures]) Katayama fever, scrub , melioidosis) tuberculosis, , Prolonged Fever (>7 Days) ( or azithromycin) to cover rickettsia and leptospirosis Cosmopolitan causes (e.g., Common tropical or subtropical If bacterial suspected, treat as community-acquired Consider highly transmissible infections (influenza, tuberculosis, MERS-CoV, ) Consider unusual infections with pulmonary involvement (, psittacosis, leptospirosis, If eosinophilia consider filariasis, strongyloidiasis, fungal infections abscess, noninfective causes treatment with IV ceftriaxone), visceral leishmaniasis, Q fever, Undifferentiated Nonmalarial endocarditis (echocardiogram), Fever with Respiratory Consider enteric fever (empirical Consider empirical antibiotics Consider: Rash Present Eschar Present or group rickettsial infection tests or PCR doxycycline chikungunya, Zika virus and rickettsial infections, acute HIV infection, measles, Katayama fever doxycycline for rickettsia, once dengue ruled out Consider Diagnosis: serologic Empirical treatment: Consider dengue, Consider empirical P. ovale , or RDT Malaria Malaria Possible primaquine P. malariae , or Treat with ACT with or without or chloroquine, thin blood films P. vivax , Nonfalciparum Uncomplicated Obtain thick and P. knowlesi malaria Isolate patient as appropriate C-reactive protein, blood cultures, chest film, urine microscopy and culture, baseline serologic tests, whole-blood EDTA sample for PCR, saving of serum for later testing, and specific investigations focal disease; RDTs for diseases endemic in the visited areas (e.g., dengue, leptospirosis, and rickettsioses for Southeast Asia) abdominal tenderness, pulmonary consolidation, eschar, , genital sores, eye signs Suspected life-threatening tropical infection? Suspected highly transmissible infection? Investigations: CBC, biochemical studies (e.g., LFTs and creatinine), History: travel, fever onset, symptoms, possible exposures Examination: rash, jaundice, altered mentation, neck stiffness, cellulitis, Risk assessment: Uncomplicated Disease (qSOFA Score <2 and No Signs of Severe Disease) malaria Malaria Initial Risk Assessment talization for 24 hr Falciparum P. falciparum Fever in a Returning Traveler Treat with ACT Consider hospi- Uncomplicated Threatening Suspected Life- Tropical Infection by ACT Severe Falciparum artesunate, followed Treat with parenteral or Knowlesi Malaria Assess qSOFA score (altered mentation, tachypnea, hypotension) Assess for signs of severe disease (cyanosis, meningism, peritonism, digital ) Possible highly transmissible infection? If yes, isolate patient as appropriate or Other Clinical Concern) care suspected, isolate patient as appropriate severe malaria with parenteral artesunate, followed by ACT into account possible pathogens and likely AMR patterns qSOFA score <2) infections, as well cosmopolitan causes of sepsis Possible Severe Disease (qSOFA Score ≥2 Urgent Hospital Admission If qSOFA score ≥2, consider ICU If highly transmissible disease Resuscitate if patient in shock Perform blood cultures Obtain malaria films or RDT, if appropriate; treat Consider empirical antibiotic treatment, taking History, examination, and investigations (as for Consider causes of life-threatening tropical Assess risk of highly transmissible infection

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Figure 1 (facing page). A Risk-based Approach to Fever and urgent empirical treatment with antibiotics in the Returning Traveler. (i.e., patients meeting two or more of the follow- A positive result of a rapid diagnostic test (RDT) for ing criteria: altered mentation, respiratory rate malaria should always be confirmed by assessing thick ≥22 breaths per minute, and systolic blood pres- and thin blood films. After glucose-6-phosphate dehy- sure ≤100 mm Hg).27 An eschar should be specifi- drogenase (G6PD) testing to rule out G6PD deficiency, cally sought; for travelers returning from south- give primaquine for a radical cure if Plasmodium vivax or P. ovale infection is confirmed. The Quick Sepsis- ern Africa, one or more eschars may point to the related Organ Failure Assessment (qSOFA) score relatively benign African tick typhus (caused by ranges from 0 to 3, with 1 point for each of the follow- ), but for those returning from ing findings: low blood pressure (systolic pressure South or Southeast Asia, an eschar suggests scrub ≤100 mm Hg), high respiratory rate (≥22 breaths per typhus ( infection), a poten- minute), and altered mentation (a score of <15 on the 28 Glasgow Coma Scale, which ranges from 3 to 15, with tially fatal disease. The eschar of scrub typhus lower scores indicating reduced levels of conscious- is often missed, because the mite vector frequent- ness). ACT denotes artemisinin-based combination ly bites in moist areas of the body that are usually therapy, Ag antigen, AMR antimicrobial drug resis- covered, such as the genitalia, the perineum, and tance, CBC complete blood count, CMV cytomegalovi- the area beneath the breasts.29 rus, EBV Epstein–Barr virus, ETEC enterotoxigenic , ICU intensive care unit, IV intrave- As a priority, malaria should be actively ruled nous, LFT liver-function tests, MERS-CoV Middle East out in all travelers returning from regions where respiratory syndrome coronavirus, PCR polymerase it is endemic, regardless of whether they have been chain reaction, and URTI upper respiratory tract infec- receiving chemoprophylaxis (Fig. 1). Thick and 24 tion. Adapted from Gherardin and Sisson. thin blood smears should be tested, with testing repeated twice if the results are negative. Malaria can be diagnosed within minutes when rapid di- 0.5%.3,25,26 Falciparum malaria is the most com- agnostic tests are performed either at the bedside mon serious infection seen in returning travelers or in the laboratory. These tests are particularly and remains the main cause of death. In areas useful in areas where local expertise in micro- where falciparum malaria is not endemic, a delay scopic examination for malaria is in short supply, in diagnosis is common and may have fatal con- though the result should be confirmed by assess- sequences. During the recent Ebola epidemic in ment of a blood smear. Patients with malaria who West Africa, falciparum malaria was the most are prostrate or comatose; those who have shock, common diagnosis in patients returning from the acidosis, severe anemia, hypoglycemia, evidence affected area.12 Other reported causes of death in- of vital organ dysfunction, or a high parasitemia clude melioidosis, severe dengue, scrub typhus, level (>10%); and those who are unable to take oral enteric fever, encephalitis, and nontropical infec- reliably should be treated for severe tions, including influenza, bacterial pneumonia, malaria. In adults, children, and pregnant women, and septicemia.5 severe malaria should be treated promptly with Initial assessment of the patient should be the parenteral artesunate, which has been shown to same as that for any ill patient suspected of having reduce mortality substantially as compared with an infection. A full history should be obtained, quinine (and by extension quinidine).30,31 This is with a view to determining exposure risks, risks followed by a course of oral artemisinin-based associated with particular geographic areas, and combination therapy (ACT) when oral likely incubation periods (Table 2). A thorough can be taken reliably. The Food and Drug Admin- physical examination should be performed, with istration has not approved the use of artesunate particular attention to signs of severity, a rash, in the United States, but it is available through and an infectious focus such as a chest infection the CDC Malaria Hotline.32 or jaundice indicating hepatitis. The Quick Sepsis- Empirical treatment of patients with suspected related Organ Failure Assessment (qSOFA), recom- life-threatening infections should be driven by the mended recently on the basis of the Third Interna- clinical picture and likely exposure. If severe sepsis tional Consensus Definitions for Sepsis and Septic is suspected, local and national guidelines should Shock (Sepsis 3), can be used as part of a rapid be followed, with modifications for any differences clinical assessment to identify patients at risk for in the prevalence of antimicrobial resistance in the severe sepsis and in need of high levels of care geographic location visited. For example, Entero-

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Vector or Exposure gion); exposure to blood to gion); exposure animals infected from camels animals products animal infected humans or animals or humans infected in mosquitoes sabethes and cycle jungle the squirrel flying humanus ), some possibly ectoparasites, ticks Poultry re - by vary (species Mosquitoes bite Animal Contact with infected humans or humans infected with Contact or humans infected with Contact mosquitoes Culex or animals infected with Contact Fecal–oral transmission Fecal–oral Aedes mosquitoes Ixodid (hard) ticks; contact with contact ticks; (hard) Ixodid haemagogus Aedes mosquitoes; ( Pediculus lice Human body South and Southeast Asia, Southeast and South Central and South Caribbean, America, Africa East, Africa, northwestern Africa, East, China South North, and America; usually outbreak- associated Geographic Regions Affected East and Southeast Asia Southeast and East peninsula Arabian Africa, Widespread Arabian peninsula Arabian Africa Pacific western Asia, Asia and Africa in Enzootic South and Southeast Asia Southeast and South Widespread, particularly Widespread, Southern Europe, Middle Europe, Southern Africa America, South Central, Asia; Africa; Central 2–8 days 2–8 days 2–6 4–7 days 4–7 3–8 days 3–8 <22 days <22 2–14 days 2–14 days 5–15 6–30 days 6–30 7–14 days 7–14 ger than 4 weeks but weeks 4 than ger occa - shorter; be can or months sionally years) thrax, 1–7 days for days 1–7 thrax, anthrax pulmonary 3–13 days for infec - for days 3–13 contact tive 20–60 days (usually lon - (usually days 20–60 1 day for cutaneous an - cutaneous for day 1 1–9 days for tick bite, tick for days 1–9

serovar enterica S. other lyssaviruses) other za A virus) A za serovar Typhi serovar enterica and ver, and Marburg hemor - Marburg and ver, rhagic fever Paratyphi A and C) and A Paratyphi fever prowazekii ) Life-Threatening Tropical Infections Characterized by Fever.* by Characterized Infections Tropical Life-Threatening 1. Table Rabies (rabies virus and virus (rabies Rabies Disease (pathogen) Viral infections Viral influen - (H5N1 influenza Avian fever Valley Rift MERS-CoV encephalitis Japanese infections Bacterial ) anthracis ( Bacillus Anthrax ( Salmonella fever Enteric Ebola virus disease, Lassa fe - Lassa disease, virus Ebola Crimean–Congo hemorrhagic Crimean–Congo dengue Severe ( Rickettsia typhus Epidemic Yellow fever Yellow

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Bacterial culture Bacterial Bacterial culture Bacterial culture Bacterial blood smear, IgM and IgG and IgM smear, blood PCR ELISAs, blood, lymph node fluid, node lymph blood, or -tissue biopsy or specimen thick and thin blood thin and thick diagnostic rapid smears; detection) (antigen tests thick and thin blood thin and thick smears IgM and IgG ELISAs, PCR ELISAs, IgG and IgM IgM and IgG ELISAs, PCR ELISAs, and IgG IgM PCR ELISAs, and IgG IgM IgM and IgG ELISAs, PCR ELISAs, and IgG IgM Microscopic examination of examination Microscopic Microscopic examination of examination Microscopic Microscopic examination of examination Microscopic Microscopic examination of examination Microscopic ACT denotes artemisinin-based combination therapy, ELISA enzyme-linked immu - 11 animals (many domestic (many animals including animals, wild and rodents) or surface water surface or Contact with urine from infected from urine with Contact ) humanus ( P. lice body Human Contact with contaminated soil contaminated with Contact Rodent Rodent sandflies Phlebotomine Mostly ticks fleas Rodent Larval mites (chiggers) mites Larval Tsetse flies Tsetse Anopheles mosquitoes Anopheles Anopheles mosquitoes Anopheles South and Southeast Asia Southeast and South America South and northern Australia; isolat - Australia; northern and Africa from reports ed America South Southeast Asia Southeast Peru America South and highest risk of infection in infection of highest risk Africa sub-Saharan Borneo Widespread, particularly Widespread, Ethiopia, Eritrea, and Sudan and Eritrea, Ethiopia, South and Southeast Asia, Southeast and South Widespread, particularly Widespread, particularly America, South Widespread Asia, Africa, of areas Remote Asia and northern Australia and northern Asia Eastern and southern Africa southern and Eastern Africa, Asia, South America; South Asia, Africa, Southeast Asia, particularly Asia, Southeast 4–14 days 4–14 2–29 days 2–29 7–14 days 7–14 days 2–14 6–20 days 6–20 days 7–21 10–14 days 10–14 10–210 days 10–210 months or years) or months , 1–3 days for plague, 1–3 days plague pneumonic ger) 1–21 days (but can be can (but days 1–21 2–6 days for bubonic for days 2–6 7–30 days (can be lon - be (can days 7–30

, and rochalimae , B. Borrelia recurrentis ) ( Borrelia pseudomallei ) R. typhi ) ( R. bacillifor - ( Bartonella ease mis , B. ancashensis ) B. gamushi ) rhode - brucei ( Trypanosoma siense ) Plasmodium falciparum ) ( Plasmodium Louseborne relapsing fever relapsing Louseborne Leptospirosis Melioidosis ( Burkholderia Melioidosis Murine or endemic typhus endemic or Murine dis - Carrión’s or fever, Oroya rickettsioses group fever Spotted ) pestis ( Yersinia Plague Orientia tsutsu - ( Orientia typhus Scrub infections Protozoal sickness sleeping African East Falciparum malaria Falciparum ) knowlesi ( P. malaria Knowlesi nosorbent assay, ICU intensive care unit, MERS-CoV Middle East respiratory syndrome coronavirus, RFFIT rapid fluorescent focus inhibition test, and RT-PCR real-time polymerase chain reaction. The listed diseases are those with an incubation period of less than 4 weeks and at least a 5% risk death within aft er symptom onset in the absence treatment. Only dis - eases largely confined to tropical or subtropical regions are included. Data from Jensenius et al. * 

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Streptobacillus moniliformis Streptobacillus Implications or Associated Diseases infection, hepatitis A and E, amebic , brucellosis, brucellosis, dysentery, amebic E, and A hepatitis infection, rhea; Zika virus infection; viral hemorrhagic fevers hemorrhagic viral infection; virus Zika rhea; infection B herpesvirus simian infection), fever, West Nile virus infection, filarial fever filarial virus infection, Nile West fever, fever, hemorrhagic Crimean–Congo quintana ) ectoparasites animal from diseases Provides geographic disease associations disease geographic Provides malaria or diseases vaccine-preventable out rule not do but diagnosis differential the Narrow malaria) (e.g., presentation disease alter or delay may infection of treatment Partial infection CMV infections, fungal tuberculosis, listeriosis, Melioidosis, campylobacter shigellosis, fever, enteric salmonellosis, nontyphoidal giardiasis, diarrhea, Travelers’ Leptospirosis, acute schistosomiasis acute Leptospirosis, melioidosis Strongyloidiasis, babesiosis malaria, infection, CMV infection, HIV acute infection, virus C or B Hepatitis gonor - ; infection; virus C or B, A, hepatitis infection; HIV acute infection; herpesvirus Primary Tuberculosis, other infections transmitted by exposure to ill persons ill to exposure by transmitted infections other Tuberculosis, Valley Rift fever, yellow encephalitis, Japanese infection, virus Zika chikungunya, fever, dengue Malaria, babesiosis, encephalitis, tickborne disease, Lyme fever, relapsing tickborne fever, Q Rickettsioses, akari ) ( R. typhus, Scrub plague typhus, Murine ( Bartonella fever trench ), prowazekii ( R. typhus epidemic recurrentis ), ( B. fever relapsing Louseborne fever (sandfly) phlebotomus , sickness, sleeping African Leishmaniasis, disease Chagas’ or minus ( Spirillum fever rat-bite henselae ), ( B. fever cat-scratch Rabies, psittacosis, plague, virus, Hendra virus, Nipah infection, hantavirus fever, Q anthrax, Toxoplasmosis, Psittacosis, avian influenza avian Psittacosis, diseases associated with immune deficit) immune with associated diseases food raw and blood-product transfusions) blood-product and partners multiple or workers, Mosquitoes Ticks Mites Fleas Lice Flies bugs Triatomine Obtaining a History of the Returning Traveler with Fever.* with Traveler Returning the of History a Obtaining 2. Table History itinerary Day-by-day prophylaxis malaria and Vaccinations traveling since or while taken Other drugs splenectomy, failure, renal treatment, glucocorticoid (diabetes, status Immune or cooked improperly or milk, unpasteurized water, unclean of Consumption Exposure to fresh water (rafting, kayaking, swimming in rivers or lakes, floods) lakes, or rivers in swimming kayaking, (rafting, water fresh to Exposure barefoot) walking (e.g., soil with contact Skin injections (e.g., procedures medical or use, drug intravenous piercings, Tattoos, sex commercial partner, new a with sex unprotected specifically contact, Sexual Visits with relatives or friends while abroad (Was anyone ill?) anyone (Was abroad while friends or relatives with Visits bites Insect bites Animal animals with contact Close Close contact with wild or pet birds pet or wild with contact Close CMV denotes cytomegalovirus, and HIV human immunodeficiency virus. * 

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bacteriaceae that produce extended-spectrum beta- are listed in Table S1 in the Supplementary Ap- lactamase (ESBL) are highly prevalent in many de- pendix. The level of risk is defined according to veloping countries, and travelers to such countries the exposure history, but direct contact with body are at risk for colonization with these resistant fluids from people or animals known or suspected bacteria, particularly if the travelers were hospi- to have a viral hemorrhagic fever constitutes high talized or received antibiotic treatment for trav- risk. Sexual contact with an infected person and eler’s diarrhea.33 If local guidelines for the treat- funeral attendance may also increase exposure and ment of community-acquired sepsis do not include the risk of infection from Ebola, Lassa, and Mar- a carbapenem, this should be given if the patient burg viruses.39-41 has traveled to an area where ESBL is highly preva- Malaria remains the most likely diagnosis in lent, such as South or Southeast Asia. Similarly, patients with suspected viral hemorrhagic fever,12 melioidosis (caused by the environmental bacte- and blood films and other essential tests (blood rium Burkholderia pseudomallei) is a common cause cultures, a complete blood count, and tests of kid- of sepsis in parts of Southeast Asia, and suspected ney and liver function) should not be delayed infection should be treated with a carbapenem or pending the results of tests for viral hemorrhagic ceftazidime, since the bacteria are intrinsically fever, which are usually performed by specialist resistant to most beta-lactam antibiotics and to reference laboratories. Any laboratory should be aminoglycosides.34 If severe scrub typhus (or an- informed, however, of specimens submitted from other rickettsial infection) is suspected, doxycy- patients with possible viral hemorrhagic fever. cline should be added to the empirical regimen, Public Health England recommends that these since O. tsutsugamushi and rickettsia species are specimens be analyzed with the use of biosafety intrinsically resistant to beta-lactams.35 level 2 laboratory procedures and autoanalyzers; standard precautions should also be taken. Recognizing Highly Transmissible Causes Outbreaks of severe respiratory viral infections of Fever during the past decade, such as those involving A risk assessment for highly transmissible patho- influenza viruses (H5N1, H7N9, and H1N1) and gens is a critical first step in the approach to the MERS-CoV, as well as the severe acute respiratory febrile traveler (Table 3 and Fig. 1). Categorizing syndrome,42 have exemplified the role of travelers risk allows for appropriate precautions to be taken as sentinels, carriers, and transmitters of these that are aimed at protecting health care and labo- infections and the need for continued vigilance ratory workers, other patients, visitors, and the for novel respiratory pathogens. Knowledge of cur- wider community from acquiring life-threatening rent outbreaks is essential for identifying cases infections. Viral hemorrhagic fevers such as Ebola, early and reducing transmission risks. More famil- Crimean–Congo hemorrhagic fever, Marburg hem- iar and potentially highly transmissible infections, orrhagic fever, and Lassa fever must be considered such as measles, chicken pox, and tuberculosis, because of the high associated mortality and po- also require prompt consideration, especially in tential for human-to-human transmission with hospitals because of the proximity of potentially nosocomial outbreaks.36 But infections transmit- vulnerable patients. ted by droplets or aerosols, such as influenza, Colonization or infection with antibiotic-resis- MERS-CoV infection, measles, and tuberculosis, tant bacteria may complicate treatment and spread should also be considered, as should coloniza- to others. Travel to tropical regions is associated tion or infection with antibiotic-resistant organ- with the transient acquisition of antibiotic-resis- isms such as methicillin-resistant Staphylococcus au- tant commensal bacteria in the gastrointestinal reus or carbapenem-resistant . tract, lasting around 3 months,43 and the global- Risk-assessment algorithms published by Public ization of health care, including the development Health England and the CDC note that viral hem- of medical tourism, has created new risks for pa- orrhagic fever should be suspected in patients who tients and hospitals. Planned or emergency in- have fever (temperature, ≥37.5°C) or a history of hospital care in one country, followed by the trans- fever in the previous 24 hours and who have trav- fer of care to another country, has the potential eled within 21 days to an area where viral hem- to fuel the rapid global dissemination of highly orrhagic fever is endemic or epidemic.37,38 Sources antibiotic-resistant organisms.44 of information on affected countries and regions Patients should be isolated in a single room

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Immediate Precautions for Suspected Infection* nursing techniques; hospital workers hospital techniques; nursing in infected been frequently have outbreaks Ebola techniques nursing techniques nursing nursing techniques nursing should staff techniques; nursing masks N95 FFP3 or wear should staff techniques; nursing masks N95 FFP3 or wear nursing techniques; staff should staff techniques; nursing prophylac - masks; N95 FFP3 or wear doxycycline or ciprofloxacin oral tic health a if administered be should exposed is worker care Isolate patient and use strict barrier strict use and patient Isolate barrier strict use and patient Isolate barrier strict use and patient Isolate Isolate patient and use strict barrier strict use and patient Isolate barrier strict use and patient Isolate barrier strict use and patient Isolate Isolate patient and use strict barrier strict use and patient Isolate 1–4 days 1–4 2–21 days 2–21 days 3–10 days 5–21 2–14 days 2–14 bite, 5–13 days 5–13 bite, con - direct for tact quired through quired inhalation Incubation Period 1–9 days for tick for days 1–9 1–3 days, if ac - if days, 1–3 Mode of Transmission gans, or other body fluids of infected of fluids body other or gans, (e.g., objects with contact persons; contaminated clothing) or needles secretions infected with rousettus by inhabited caves or mines transmission person-to-person bats; or blood with contact direct requires infected an from fluids other body or saliva, urine, vomit, person (feces, secretions) respiratory excreta rodent infected with contact per - water; or food in or surfaces on occurs transmission son-to-person body infected with contact through se - or urine, saliva, blood, (e.g., fluids men) di - through humans to transmission infect - of fluids body with contact rect animals or humans ed or airborne transmission of large of transmission airborne or droplets septice - in lungs to spread togenous plague bubonic or mic Direct contact with blood, secretions, or - secretions, blood, with contact Direct in exposure through infection Initial indirect or direct through infection Initial possible but transmission, Tickborne Direct or airborne transmission airborne or Direct secretions respiratory with contact Direct hema - or droplets infective of Inhalation Geographic Regions Affected Coast, Sudan, Uganda, Kenya, Uganda, Sudan, Coast, Congo, of Republic Democratic Gabon, Congo, the of Republic Zimbabwe Angola, Congo, of Republic Democratic Gabon, Congo, the of Republic Zimbabwe Angola, East, Asia, Eastern Europe; outbreaks Kazakhstan, Iran, Turkey, Russia, in Albania, Kosovo, Mauritania, Pakistan influenza in Southeast Asia and Asia Southeast in influenza China Arabia America Guinea, Sierra Leone, Liberia, Ivory Liberia, Leone, Sierra Guinea, Kenya, Uganda, Sudan, Coast, Ivory Nigeria Liberia, Leone, Sierra Guinea, Middle Africa, endemicity: of area Broad Global distribution; outbreaks of avian of outbreaks distribution; Global Saudi particularly Peninsula, Arabian South and Asia, Africa, of areas Remote Serious Transmissible Infections in Febrile Returning Travelers. Returning Febrile in Infections Transmissible Serious 3. Table Infection fevers hemorrhagic Viral disease virus Ebola fever hemorrhagic Marburg fever Lassa fever hemorrhagic Crimean–Congo Severe acute respiratory infections respiratory acute Severe A Influenza MERS-CoV plague Pneumonic

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immediately if they might have a life-threatening and potentially transmissible infection. Patients transferred from a health care facility in another country may also need to be isolated before it has been established whether they are colonized or infected with drug-resistant bacteria. Health care workers in direct contact with patients at high risk for a viral hemorrhagic fever or severe airborne infections can reduce their risk of ex- posure by increasing levels of personal protec- tions and previous infections in con - in infections previous and tions pa - other and (staff hospital in tacts tients) tions and previous infections in con - in infections previous and tions pa - other and (staff hospital in tacts tients) multidrug-resistant tuberculosis, multidrug-resistant negative-pressure in patient isolate available if room, tion, including meticulous hand hygiene, double Isolate patient; check status of vaccina - of status check patient; Isolate Isolate patient; check status of vaccina - of status check patient; Isolate Isolate patient; for suspected case of case suspected for patient; Isolate gloves, fluid-repellent disposable gowns and foot- wear, a full face shield or goggles, and a fluid- repellent respirator (FFP3 [filtering facepiece, class 3] or N95) for splash and respiratory pro- tection. Negative-pressure isolation reduces the 7–21 days 7–21 10–21 days 10–21 risk of airborne pathogen transmission to other Months to years to Months patients and staff. Finally, those responsible for hospital infection control and public health must be informed about all patients with a suspected or confirmed life-threatening infection with the potential for person-to-person transmission.

Approach to Lower-Risk Travelers with Fever Once the life-threatening and transmissible causes of fever in a returning traveler have been ruled out, there is a long list of other possible causes of fever, not all of which are related to travel in tropical regions or to an infectious disease (Fig. 1, and Direct or airborne transmission airborne or Direct transmission airborne or Direct Airborne transmission Airborne Table S2 in the Supplementary Appendix).45 How- ever, the number of possible travel-related infec- tious causes can be reduced substantially by iden- tifying possible exposures and applying knowledge of the incubation periods for various infections. A detailed travel and activity history is essential.46 Different geographic regions are associated with different presentations; systemic febrile illness without localizing findings is common among travelers returning from sub-Saharan Africa or Southeast Asia, acute diarrhea is common among breaks and Asia and those returning from South Asia and Central Asia, Global distribution with regional out - regional with distribution Global distribution Global Global distribution; common in Africa common distribution; Global and dermatologic problems are common among those returning from the Caribbean, Central America, or South America.47 Travel in temperate regions may also be associated with specific tick- borne infections, such as , tulare- mia, babesiosis, and spotted fevers in parts of the United States and other diseases in eastern Eu- rope and Russia. Each country visited, with dates, must be determined and activity-based risks iden- tified, including types of accommodation; food Other serious infections serious Other Measles Chickenpox Pulmonary tuberculosis Pulmonary Strict barrier nursing techniques include the use of masks, gloves, and gowns. FFP3 denotes filtering facepiece, class 3.

*  eaten; exposure to animals, fresh water, and

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bloodborne diseases (e.g., through tattoos or den- are influenza, enteric fever, and viral hepatitis.53 In tal work); insect bites; and sexual activity. Con- the GeoSentinel database, vaccine-preventable dis- tact with ill persons, including those visited in a eases are relatively uncommon (accounting for hospital, may provide important links to disease approximately 3% of cases) but are associated with outbreaks. high rates of hospitalization (60%), a finding The reasons for travel, together with the trav- that supports the effectiveness of pretravel vac- eler’s age, sex, and immune status, may influence cination in reducing the morbidity and mortality the risks and possible causes of fever. Travelers from these diseases.10 who visit friends or relatives are at greater risk for The recent epidemics of Zika virus infection malaria, enteric fever, nondiarrheal intestinal para- in Latin America, the Caribbean, and the Pacific sitic infections, respiratory syndromes, tuberculo- Islands have caused considerable alarm, particu- sis, and sexually transmitted diseases than other larly because of increasingly strong associations travelers.48,49 Expatriates are at disproportionately with the Guillain–Barré syndrome and birth de- greater risk for chronic infections, including fects, such as microcephaly.54,55 The presentation malaria, filariasis, schistosomiasis, strongyloidia- of symptomatic acute Zika virus infection is simi- sis, giardiasis, brucellosis, and tuberculosis than lar to that of a number of other common causes are short-term travelers.50 Travelers older than of fever, including dengue and chikungunya (also 60 years of age have proportionally more life- transmitted by various species of aedes mosqui- threatening illnesses, especially severe malaria toes and often sympatric), rickettsial infections, and lower respiratory tract infections,5 than chil- and leptospirosis. Patients with these infections dren, in whom diarrheal, skin, and upper respi- commonly present with fever, headache, arthral- ratory tract infections account for the majority of gia, and a maculopapular rash (although the rash reported diagnoses.51 How sex influences infec- is rarely associated with leptospirosis). Zika virus tion susceptibility and reporting patterns is un- infection can cause conjunctivitis, as can chi- certain, but women appear to be proportionally kungunya, and conjunctival suffusion and sub- more likely than men to report acute or chronic conjunctival hemorrhage are common in pa- diarrhea and upper respiratory tract infection tients with leptospirosis. and less likely to report vectorborne diseases, Initial investigations should include a com- such as malaria or rickettsioses.52 Opportunistic plete blood count; biochemical studies, including infections in travelers who are immunocompro- tests of liver and renal function; blood culture; mised further complicate the clinical assessment. rapid diagnostic tests for malaria and dengue; Travelers taking immunosuppressive drugs or polymerase-chain-reaction (PCR) testing of a plas- glucocorticoids and travelers with poorly con- ma sample (e.g., for rickettsia); serologic tests; a trolled human immunodeficiency virus infection chest film; blood-smear examination; and urine are at increased risk for infections (e.g., talaro- tests, including a dipstick test, microscopic ex- mycosis in Southeast Asia and leishmaniasis in amination, culture, and possibly PCR testing southern Europe, South Asia, and South America). (e.g., for Zika virus or leptospira) (Fig. 1, and The majority of febrile illnesses related to Table S2 in the Supplementary Appendix). Clini- exposures during travel develop within a month.3 cal suspicion may call for more specific investi- Knowledge of the incubation periods of the sus- gations, such as stool-sample examination for ova pected infectious diseases can be used to narrow and parasites, intracranial imaging and lumbar the . For example, if fever puncture in cases of reduced consciousness (in- begins more than 21 days after a traveler’s return, cluding cases of confirmed cerebral malaria), then dengue, rickettsial infections, Zika virus in- and abdominal or renal tract ultrasonography or fection, and viral hemorrhagic fevers are unlikely, computed tomography in cases of jaundice or regardless of the traveler’s exposure history. Infec- acute kidney injury. Point-of-care rapid diagnos- tious causes may be further narrowed by pretravel tic tests for several tropical infections are in- vaccinations and chemoprophylaxis, although nei- creasingly available, have been well validated, and ther approach is 100% effective. The most com- are particularly widely used for the diagnosis of mon vaccine-preventable causes of fever in travelers malaria and dengue.

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Future Developments likely to improve with the increasing connectivity and Conclusions associated with these initiatives. Future integra- tion of clinical data from electronic medical re- The evidence base to inform the physician in cords would further enhance real-time surveillance making a rapid diagnosis and instituting appro- and potentially provide early signals of changes priate treatment of fever in the returning traveler in disease or patterns of antimicrobial drug resis- is growing rapidly, thanks to surveillance net- tance and early warnings of developing epidemics. works based in travel clinics (e.g., GeoSentinel) There will be new challenges as well. The rise and international surveillance networks, many in popularity of medical tourism will provide in- of which report up-to-date information in digital creased opportunities for hospital-associated mul- form (e.g., HealthMap). With the spotlight on tidrug-resistant pathogens to spread to hospitals antimicrobial drug resistance as a global health and communities in the traveler’s home country, threat, funding for antimicrobial-resistance net- and the continuing rise in travel in general, par- works, such as the WHO Global Antimicrobial ticularly among the elderly, will increase the Resistance Surveillance System (GLASS) and the cross-border movement of infections. We can ex- recent Fleming Fund initiative (https:/​­/​­wellcome​ pect continued expansion in resources to aid .ac­ .​ uk/­ press-release/​­ fleming-fund-launched​­ physicians in the treatment of returning travelers, -tackle-global-problem-drug-resistant-infection), allowing for further improvements in evidence- is increasing and should lead to higher-quality based diagnosis and management. geographic information on the prevalent antibi- No potential conflict of interest relevant to this article was reported. otic-resistance patterns in countries visited. The Disclosure forms provided by the authors are available with collection, processing, and analysis of data are the full text of this article at NEJM.org.

References 1. Wilson ME, Freedman DO. Etiology health surveillance and travelers’ health. et al. Information technology and global of travel-related fever. Curr Opin Infect Curr Opin Infect Dis 2009;​22:​423-9. surveillance of cases of 2009 H1N1 influ- Dis 2007;​20:​449-53. 9. Leder K. Travelers as a sentinel popu- enza. N Engl J Med 2010;​362:​1731-5. 2. Hill DR. Health problems in a large lation: use of sentinel networks to inform 16. Ambresin AE, D’Acremont V, Mueller cohort of Americans traveling to develop- pretravel and posttravel evaluation. Curr Y, Martin O, Burnand B, Genton B. www. ing countries. J Travel Med 2000;​7:​259-66. Infect Dis Rep 2009;​11:​51-8. fevertravel.ch: an online study prototype 3. Wilson ME, Weld LH, Boggild A, et al. 10. Torresi J, Leder K. Defining infections to evaluate the safety and feasibility of Fever in returned travelers: results from in international travellers through the computerized guidelines for fever in re- the GeoSentinel Surveillance Network. GeoSentinel surveillance network. Nat turning travellers and migrants. Comput Clin Infect Dis 2007;​44:​1560-8. Rev Microbiol 2009;​7:​895-901. Methods Programs Biomed 2007;​85:​19- 4. International tourist arrivals up 4% 11. Jensenius M, Han PV, Schlagenhauf P, 31. reach a record 1.2 billion in 2015. Press et al. Acute and potentially life-threaten- 17. Mueller Y, D’Acremont V, Ambresin release of the United Nations World Tour- ing tropical diseases in western travelers AE, et al. Feasibility and clinical out- ism Organization, January 18, 2016 — a GeoSentinel multicenter study, 1996- comes when using practice guidelines for (http://media.unwto​ .org/​ press-release/​ ​ 2011. Am J Trop Med Hyg 2013;​88:​397-404. evaluation of fever in returning travelers 2016-01-18/​international-tourist-arrivals- 12. Boggild AK, Esposito DH, Kozarsky and migrants: a validation study. J Travel 4-reach-record-12-billion-2015). PE, et al. Differential diagnosis of illness Med 2014;​21:​169-82. 5. Gautret P, Gaudart J, Leder K, et al. in travelers arriving from Sierra Leone, 18. Demeester RP, Bottieau E, Pini A, et Travel-associated illness in older adults Liberia, or Guinea: a cross-sectional study al. Prospective multicenter evaluation of (>60 y). J Travel Med 2012;​19:​169-77. from the GeoSentinel Surveillance Net- the expert system “KABISA TRAVEL” in 6. Molton JS, Tambyah PA, Ang BS, Ling work. Ann Intern Med 2015;​162:​757-64. diagnosing febrile illnesses occurring af- ML, Fisher DA. The global spread of 13. Schlagenhauf P, Weld L, Goorhuis A, ter a stay in the tropics. J Travel Med 2011;​ healthcare-associated multidrug-resis- et al. Travel-associated infection present- 18:386-94.​ tant bacteria: a perspective from Asia. ing in Europe (2008-12): an analysis of 19. Edberg SC. Global Infectious Diseas- Clin Infect Dis 2013;​56:​1310-8. EuroTravNet longitudinal, surveillance es and Epidemiology Network (GIDEON): 7. Nüesch-Inderbinen M, Abgottspon H, data, and evaluation of the effect of the a World Wide Web-based program for di- Sägesser G, Cernela N, Stephan R. Anti- pre-travel consultation. Lancet Infect Dis agnosis and informatics in infectious dis- microbial susceptibility of travel-related 2015;15:​ 55-64.​ eases. Clin Infect Dis 2005;​40:​123-6. serovar Typhi isolates 14. Brownstein JS, Freifeld CC, Reis BY, 20. Ross JJ, Shapiro DS. Evaluation of the detected in Switzerland (2002-2013) and Mandl KD. Surveillance Sans Frontières: computer program GIDEON (Global In- molecular characterization of quinolone Internet-based emerging infectious dis- fectious Disease and Epidemiology Net- resistant isolates. BMC Infect Dis 2015;​ ease intelligence and the HealthMap proj- work) for the diagnosis of fever in pa- 15:212.​ ect. PLoS Med 2008;​5(7):​e151. tients admitted to a medical service. Clin 8. Marano C, Freedman DO. Global 15. Brownstein JS, Freifeld CC, Chan EH, Infect Dis 1998;​26:​766-7.

n engl j med 376;6 nejm.org February 9, 2017 559 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on March 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Approach to Fever in the Returning Traveler

21. Luo RF, Bartlett JG. Use of the com- 33. Kantele A, Lääveri T, Mero S, et al. An- 44. van der Bij AK, Pitout JD. The role of puter program GIDEON at an inpatient timicrobials increase travelers’ risk of international travel in the worldwide infectious diseases consultation service. colonization by extended-spectrum beta- spread of multiresistant Enterobacteria- Clin Infect Dis 2006;​42:​157-8. lactamase-producing Enterobacteriaceae. ceae. J Antimicrob Chemother 2012;​67:​ 22. Kimura M, Sakamoto M, Adachi T, Clin Infect Dis 2015;​60:​837-46. 2090-100. Sagara H. Diagnosis of febrile illnesses in 34. Pitman MC, Luck T, Marshall CS, An- 45. Ryan ET, Wilson ME, Kain KC. Illness returned travelers using the PC software stey NM, Ward L, Currie BJ. Intravenous after international travel. N Engl J Med GIDEON. Travel Med Infect Dis 2005;​3:​ therapy duration and outcomes in melioi- 2002;347:​ 505-16.​ 157-60. dosis: a new treatment paradigm. PLoS 46. Johnston V, Stockley JM, Dockrell D, 23. Bottieau E, Moreira J, Clerinx J, Cole- Negl Trop Dis 2015;​9(3):​e0003586. et al. Fever in returned travellers present- bunders R, Van Gompel A, Van den Ende 35. Rahi M, Gupte MD, Bhargava A, Var- ing in the United Kingdom: recommenda- J. Evaluation of the GIDEON expert com- ghese GM, Arora R. DHR-ICMR guide- tions for investigation and initial man- puter program for the diagnosis of im- lines for diagnosis & management of rick- agement. J Infect 2009;​59:​1-18. ported febrile illnesses. Med Decis Mak- ettsial diseases in India. Indian J Med Res 47. Freedman DO, Weld LH, Kozarsky PE, ing 2008;28:​ 435-42.​ 2015;​141:​417-22. et al. Spectrum of disease and relation to 24. Gherardin A, Sisson J. Assessing fever 36. Ftika L, Maltezou HC. Viral haemor- place of exposure among ill returned trav- in the returned traveller. Aust Prescr rhagic fevers in healthcare settings. J Hosp elers. N Engl J Med 2006;​354:​119-30. 2012;​35:​10-4. Infect 2013;83:​ 185-92.​ 48. Leder K, Tong S, Weld L, et al. Illness 25. Bottieau E, Clerinx J, Schrooten W, et 37. Ebola (Ebola virus disease): epidemio- in travelers visiting friends and relatives: al. Etiology and outcome of fever after a logic risk factors to consider when evalu- a review of the GeoSentinel Surveillance stay in the tropics. Arch Intern Med 2006;​ ating a person for exposure to Ebola vi- Network. Clin Infect Dis 2006;​43:​1185-93. 166:1642-8.​ rus. Atlanta:​ Centers for Disease Control 49. Matteelli A, Schlagenhauf P, Carvalho 26. O’Brien DP, Leder K, Matchett E, and Prevention, May 28, 2015 (https:/​/​ AC, et al. Travel-associated sexually trans- Brown GV, Torresi J. Illness in returned www.cdc​ .gov/​ vhf/​ ebola/​ exposure/​ risk​ mitted infections: an observational cross- travelers and immigrants/refugees: the -factors-when-evaluating-person-for sectional study of the GeoSentinel sur- 6-year experience of two Australian infec- -exposure.html).​ veillance database. Lancet Infect Dis tious diseases units. J Travel Med 2006;​ 38. Public Health England. Risk assess- 2013;​13:​205-13. 13:​145-52. ment of the Ebola virus disease outbreak 50. Lim PL, Han P, Chen LH, et al. Expa- 27. Singer M, Deutschman CS, Seymour in West Africa: updated 24 June 2015 triates ill after travel: results from the CW, et al. The third international consen- (https://​ www​ .gov​ .uk/​ government/​ ​ Geosentinel Surveillance Network. BMC sus definitions for sepsis and septic uploads/​system/​uploads/​attachment Infect Dis 2012;​12:​386. shock (Sepsis-3). JAMA 2016;​315:​801-10. _data/file/​ 437990/​ PHE_Risk_Assessment​ 51. Hagmann S, Neugebauer R, Schwartz 28. Taylor AJ, Paris DH, Newton PN. A _Update_7_FINAL.pdf).​ E, et al. Illness in children after interna- Systematic Review of Mortality from Un- 39. Rogstad KE, Tunbridge A. Ebola virus tional travel: analysis from the GeoSenti- treated Scrub Typhus (Orientia tsutsuga- as a sexually transmitted infection. Curr nel Surveillance Network. Pediatrics mushi). PLoS Negl Trop Dis 2015;​9(8):​ Opin Infect Dis 2015;​28:​83-5. 2010;125(5):​ e1072-e1080.​ e0003971. 40. Nielsen CF, Kidd S, Sillah AR, Davis 52. Schlagenhauf P, Chen LH, Wilson ME, 29. Kundavaram AP, Jonathan AJ, Na- E, Mermin J, Kilmarx PH. Improving buri- et al. Sex and gender differences in travel- thaniel SD, Varghese GM. Eschar in scrub al practices and cemetery management associated disease. Clin Infect Dis 2010;​ typhus: a valuable clue to the diagnosis. during an Ebola virus disease epidemic 50:826-32.​ J Postgrad Med 2013;​59:​177-8. — Sierra Leone, 2014. MMWR Morb Mor- 53. Boggild AK, Castelli F, Gautret P, et 30. Dondorp A, Nosten F, Stepniewska K, tal Wkly Rep 2015;​64:​20-7. al. Vaccine preventable diseases in re- Day N, White N. Artesunate versus qui- 41. Public Health England. Viral haemor- turned international travelers: results nine for treatment of severe falciparum rhagic fever: ACDP algorithm and guidance from the GeoSentinel Surveillance Net- malaria: a randomised trial. Lancet 2005;​ on management of patients. November work. Vaccine 2010;​28:​7389-95. 366:717-25.​ 19, 2015 (https:/​/​www​.gov​.uk/​government/ 54. Moulin E, Selby K, Cherpillod P, Kai- 31. Dondorp AM, Fanello CI, Hendriksen ​publications/viral-haemorrhagic-fever​ ser L, Boillat-Blanco N. Simultaneous out- IC, et al. Artesunate versus quinine in the -algorithm-and-guidance-on-management breaks of dengue, chikungunya and Zika treatment of severe falciparum malaria in -of-patients). virus infections: diagnosis challenge in a African children (AQUAMAT): an open- 42. Hui DS, Zumla A. Emerging respira- returning traveller with nonspecific fe- label, randomised trial. Lancet 2010;​376:​ tory tract viral infections. Curr Opin Pulm brile illness. New Microbes New Infect 1647-57. Med 2015;​21:​284-92. 2016;11:​ 6-7.​ 32. Artesunate is available to treat severe 43. Ruppé E, Armand-Lefèvre L, Estellat 55. Wikan N, Smith DR. Zika virus: his- malaria in the United States. Atlanta:​ C, et al. High rate of acquisition but short tory of a newly emerging arbovirus. Lan- Centers for Disease Control and Preven- duration of carriage of multidrug-resis- cet Infect Dis 2016;​16(7):​e119-e126. tion, 2010 (www​.cdc​.gov/​malaria/​diagno- tant Enterobacteriaceae after travel to the Copyright © 2017 Massachusetts Medical Society. sis_treatment/​artesunate​.html). tropics. Clin Infect Dis 2015;​61:​593-600.

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