Emergency Department Evaluation of Fever in the Returning Traveler Dr. Aric Storck October 31, 2002

Objectives Approach to the febrile traveler History Travel history Vaccinations Chemoprophylaxis Laboratory studies Treatment overview of common imported diseases

Background >500,000,000 people cross international boundaries each year >12,000,000 North Americans travel to developing countries each year  international travel =  importation of exotic infectious diseases Suh, K, et al. Evaluation of Fever in the Returned Traveler. Medical Clinics of North America 1999:83(4)997-1018.

Travelers get sick …. 20-70% of travelers report health problems while traveling 1-5% seek medical attention abroad 0.01-0.1% require emergency medical evacuation 1 in 100,000 dies Kain K, Ryan E. Health Advice and Immunization for Travelers. NEJM 2000;342(23)1716-1725.

Low awareness of traveler’s health issues Many travelers do not seek predeparture medical consultation Poor understanding of risks Not covered by health insurance Shortage of physicians with travel medicine expertise

For example … Study of 353 North American passengers boarding international flights to regions where Hepatitis A is endemic 72% did not obtain immunizations 78% did not know the route of transmission of hepatitis A 95% unable to identify fever, abdominal pain, jaundice as symptoms 88% of flight crew were not immunized Quoted in: Thanassi M, Thanassi W. EMR 1998;9(22)239-246

The result …. 1-2% of unimmunized travelers visiting a developing country for >1 month will develop hepatitis A Steffen R. Risk of hepatitis A in travelers: the European experience. Journal of Infectious Disease 1995;171:S24-28. 300 / 100,000 travelers / month in tourist areas of developing countries 5-7 x increased risk for “backpackers” Quoted in:Kain K, Ryan E. Health Advice and Immunization for Travelers. NEJM 2000;342(23)1716-1725.

After the holiday … Swiss study 5% of travelers consult MD upon return 4% of travelers to developing countries for >3 weeks develop fever 61-71% remained febrile upon return Steffen R, et al. Health problems after travel to developing countries. J Infect Dis 1987;156:84-91. 5% of travelers consult MD upon return Thanassi M, Thanassi W. EMR 1998;9(22)239-246

Many of the returning ill will present to the Emergency Department!

ED evaluation of the febrile traveler What infections are possible given the patient’s travel history What infections are probable given the patient’s medical history and presentation What infections are life-threatening or contagious or both

General Medical History Immunocompromise Increased risk of all infectious diseases Decreased gastric acidity (achlorhydria, H2 blockers, PPI) Increased risk of enteric illness (eg: cholera, typhoid) Chronic respiratory disease Increased risk of respiratory infections

Sickle Cell Trait / G6PD deficiency Asplenia Encapsulated organisms Sickle Cell Trait / G6PD deficiency Confer protection against malaria

Pre-travel History ? pre-departure medical consultation Vaccination status Which vaccines When Chemoprophylaxis Which specific medication Dosing schedule Patient compliance

Travel Immunizations Vaccine Efficacy Duration Cholera 50% 3-6 months Typhoid Vi CPS 43-96% 2-3 years Typhoid Ty21A 60-72 5-7 years Yellow Fever 100% 10 years Japanese encephalitis 85% 3 years Meningococcus 85-95% HAV Immune Globulin 70-80% 3-5 months Hepatitis A >90% >10 years Hepatitis B >7 years

Vaccination against the following makes diagnosis unlikely: Yellow fever Hepatitis A Hepatitis B Vaccinations for following are not very effective Typhoid Cholera

Travel History Precise dates of travel Countries and regions visited Arrival & departure from endemic regions Countries and regions visited Urban Rural Type of accommodation  hotel Bamboo hut

Infection prophylaxis Insect repellants Mosquito nets Bottled water Activities Freshwater exposure (rafting, swimming...) Trekking Contact with animals Drug use

Sexual contacts 66% of 213 Australians going to Thailand reported plans to have sex 25% of Swedish women on charter holidays reported a sexual encounter with an unknown partner 18.6% of 757 patients at Hospital for Tropical Diseases in London reported new sexual partner during last trip Only 36% regularly used condoms Quoted in: Matteelli A, Carosi G. Sexually Transmitted Diseases in Travelers. Clinical Infectious Diseases 2001;32:1063-1067.

Sex and the long-term traveler 60% of 1080 Peace Corps had sexual encounter with new partner 40% with local partner 1/3 used condoms 50% of Belgian expatriates in Central Africa reported extramarital sex 1/3 with commercial sex workers Quoted in: Matteelli A, Carosi G. Sexually Transmitted Diseases in Travelers. Clinical Infectious Diseases 2001;32:1063-1067.

Commonest causes of fever (%) diagnosis MacLean et al (n=587) Doherty et al (n=195) O’Brien et al (n=232) Malaria 32 42 27 Hepatitis 6 11 3 (Hep A) Respiratory infection 2.6 24 Urinary tract infection 4 2 Dysentery 4.5 5.1 14 (gastroenteritis) Dengue fever 6.2 8 Enteric fever 1.5 3 Tuberculosis 1 0.4 Rickettsial infection 0.5 Acute HIV infection 0.3 1.0 Amebiasis Other infections 4.3 9.2 Non-infectious causes Undiagnosed 25 24.6 9 sources: O’Brien D, et al. Clinical Infectious Diseases 2001;33:603-9. Suh, K, et al. Medical Clinics of North America 1999:83(4)997-1018.

Incubation Periods Short (<1 week) Medium (1-2 weeks) GI bacterial pathogens Dengue Fever Yellow Fever Medium (1-2 weeks) Malaria Typhoid Trypanosomiasis

Incubation Periods Long (>3 weeks) Viral hepatitis Malaria Schistosomiasis Tuberculosis Amoebic liver abscess Rabies

Fever Associated Signs and Symptoms

Frequency of presenting symptoms in febrile returned travelers % of patients (N=232) Fever 100 Headache 63 Myalgia 40 Cough 32 Diarrhea 31 Nausea 27 Abdominal pain 24 Vomiting 22 Arthralgia 17 Rash 13 Skin lesion 5 Dyspnea hemoptysis 1 O’Brien D, et al. Fever in Returned Travelers. Clinical Infectious Diseases 2001;33:603-9

Diarrhea Traveler’s Diarrhea (e. coli) Dysentery (bloody diarrhea) Most common travel related illness Only 15% febrile Dysentery (bloody diarrhea) Campylobacter, Salmonella, Shigella Typhoid 30-50% c/o diarrhea Viral, protozoal, helminth Malaria

Jaundice Hepatitis A Yellow fever Hemorrhagic fevers Leptosporosis Most common cause Yellow fever Hemorrhagic fevers Leptosporosis Malaria 20% jaundiced secondary to hemolysis

Respiratory complaints The usual suspects CAP, influenza Tuberculosis Usually due to reactivation Suspect in immigrants, not in travelers P.falciparum ARDS (often fatal) Helminths Strongyloides, schistosoma, ascaris Protozoa Entamoeba histolytica, trypanosoma

Dermatologic complaints Rose spots - Typhoid faint pink macules/papules on trunk Maculopapular exanthem Dengue fever Viral hemorrhagic fevers Petechiae / ecchymotic lesions Meningococcemia Dengue

Neurologic complaints Meningitis Meningococcal Aseptic (enterovirus, rickettsiae, typhoid...) Encephalitis Arbovirus (eg: Japanese encephalitis) Cerebral malaria (P.falciparum) Looks like toxic coma Consider empiric antimalarial therapy if neurologic SSx and diagnosis uncertain

Splenomegaly Common and non-specific Malaria Trypanosomiasis Dengue OR 7.9; 95% CI 2.4-27.3; P<0.001 O’Brien D, et al. Fever in Returned Travelers. Clinical Infectious Diseases 2001;33:603-9 Trypanosomiasis Dengue

Hepatomegaly Malaria OR 4.0; 95%CI 1.3-12.5; P=0.006 O’Brien D, et al. Fever in Returned Travelers. Clinical Infectious Diseases 2001;33:603-9

Lymphadenopathy EBV HIV Dengue NOT in malaria

Typhoid Fever Salmonella typhi

Typhoid Fever Gram negative bacilli Fecal-oral route Salmonella typhi Salmonella paratyphi Fecal-oral route Contaminated food or water Incubation period 5-21 days

Typhoid Fever Endemic in almost all developing countries 16,000,000 clinically significant cases annually (WHO) Many more subclinical cases 600,000 deaths annually

Typhoid Fever

Typhoid Fever

Classical Presentation Week 1 Fever Bacteremia Week 2 Abdominal pain Rash (Rose spots) Week 3 Hepatosplenomegaly Intestinal perforation / hemorrhage

diagnosis Laboratory Isolation of bacteria Anemia Leukocytosis / leukopenia Abnormal LFTs Isolation of bacteria Blood culture – positive in 40-80% Stool culture – positive in 30-40% Bone marrow – positive in 98%

Treatment Fluoroquinolone Plus 3rd generation cephalosporin Ciprofloxacin 500 mg bid Ofloxacin 400 mg bid Plus 3rd generation cephalosporin High levels of resistance in some strains Continue while sensitivities pending Ceftriaxone 2-3 g od

Typhoid Mary … 2-5% of hosts become asymptomatic carriers Very high risk of transmitting disease to others if involved in food preparation Mary Mallon – responsible for 54 cases of typhoid and 3 deaths in New York

Hepatitis A Most common vaccine-preventable illness in travelers Fecal-oral transmission via food and water Risk as high as 2 cases / 100 travellers / 4 week stay 10-100x more common than typhoid 1000x more common than cholera Thanassi M, Thanassi W. EMR 1998;9(22)239-246

Hepatitis A Incubation period 15 – 30 days Fever in pre-icteric phase Often asymptomatic in children Jaundice by age group <6 = <10% 6-14 = 40-50% >14 = 70-80%

Hepatitis A Complications Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis No chronic sequelae Overall mortality 1:1000 cases (varies widely according to age)

Hepatitis A

Hepatitis A From:http://www.worldwidevaccines.com/public/diseas/hepa23.asp

Age Specific Mortality Age group (years) Fatalities / 1000 <5 3.0 5-14 1.6 15-29 30-49 3.8 >49 17.5 overall 4.1 Source: CDC

Diagnosis & Treatment Clinical Laboratory Treatment Fever Jaundice RUQ pain Laboratory Transaminitis Cholestatis Hepatitis serology Treatment Supportive

Dengue Fever

Dengue virus Causes both Dengue Fever – benign self limited illness Dengue Hemorrhagic Fever (DHF) – life threatening Flavivirus composed of single-stranded RNA Arbovirus transmitted by the Aedes aegypti mosquito No vaccination, no chemoprophylaxis, no specific treatment

Incubation period 4-7 days Four serotypes (DEN 1,2,3,4) No cross immunity Prior infection with different serotype, co-infection with >1 serotype increases risk of DHF Incubation period 4-7 days Do not include in DDx if >14 days from exposure Symptoms persist 3-10 days (avg =5)

Aedes aegypti Bite during day Urban dwellers

Distribution of Aedes aegypti in 1970 (end of mosquito eradication program), and in 1997 Source: CDC

American countries with laboratory-confirmed hemorrhagic fever (red shaded areas), prior to 1981 and from 1981 to 1997 Source: CDC

The epidemic… Declining vector control Poor water supply systems Increasing use of non-biodegradable containers Increased air travel Increased urban population density

Dengue Fever Clinical Features High Fever Severe headache – retro-ocular Bony pains (aka. break-bone fever) Nausea and vomiting Blanching macular rash Hemorrhagic manifestations Altered LOC

Hemorrhagic Manifestations Mild Petechiae, ecchymosis Gingival bleeding Epistaxis GI bleed Severe Hemorrhagic shock

Diagnosis History Clinical Travel to endemic area within past 2 weeks Evidence of increased vascular permeability (pleural effusions, ascites) Hemorrhage Tourniquet test

Tourniquet Test Inflate BP cuff to MAP x 5 minutes. >20 petechiae / square inch suggests dengue

Diagnosis Laboratory Diagnosis Routine Blood Work Generally neutropenic and thrombocytopenic Dengue serology (definitive) Viral culture – only within 5 days of onset of symptoms IgM ELISA – after 5 days of symptoms

Treatment Outpatient Outpatient observation Hospitalization Well hydrated No hemorrhagic manifestations Outpatient observation Mild hemorrhagic manifestations Dehydration Hospitalization Severe hemorrhage Shock

Treatment Supportive Educate outpatients about danger signs Close follow-up needed HPTP Odyssey Travel Clinic

Merozoite of p. falciparum Malaria Merozoite of p. falciparum

Malaria, what is it? Protozoal infection caused by Plasmodium falciparum Africa, East Asia, Oceania, Haiti 50% of all cases 95% of all deaths Plasmodium vivax Central America, Middle East, India, SE Asia Plasmodium ovale Plasmodium malariae NB: Mixed infections common

Malaria the vector Anopheles mosquito Also maternal-fetal, blood transfusions, dirty needles, etc.

Malaria life-cycle

Malaria Epidemiology >2 billion people (41% of the world population) live in malaria-risk areas Endemic to >100 countries Every year 300-500 million people get malaria 1.5-2.7 million people die from malaria 90% in rural, sub-Saharan Africa Disproportionately in children <5

Malaria, not hard to get ….. Studies of European / North American travelers to Kenya and Peace Corps volunteers in Africa Malarial attack rate of 15/1000 per month 2-4% mortality in those infected Quoted in: Stanley J. Malaria. Emergency Medicine Clinics of North America 1997;15(1)113-155.

Malaria in Canada 1994 – 430 cases reported 1995 – 621 cases reported Per capita rate 10x as high as USA 1994-1997 – tenfold increase in severe malaria requiring admission to ICU Severe malaria increase – thought to be secondary to increased drug resistance Kain K, et al. Malaria deaths in visitors to Canada and in Canadian travellers; a case series. CMAJ 2001;164(5)656-659

Malaria

Malaria Symptoms Headache Muscle aches Diarrhea Fever Chills Vomiting Coughing Abdominal pain Malaria symptoms usually appear within 7 to 21 days of the mosquito bite, but may not appear until later

Interval between date of entry and onset of illness by plasmodium species for imported malaria cases in the United States (1992) Interval P. vivax P. falciparum P. malaria P. ovale Total (months) (%) <1 31.6 88.4 50.0 5.0 51.6 1-2 18.4 6.6 15.0 30.0 14.4 3-5 23.4 3.5 10.0 15.5 6-12 22.8 1.0 20.0 40.0 >12 3.8 0.5 0.0 2.9 N 316 198 20 554 Adapted from MMWR 44:1-14, 1995

Nobody should die of malaria! Malaria is …. Usually preventable Almost always curable Nobody should die of malaria!

Early diagnosis and treatment of malaria is crucial to preventing morbidity and mortality

Case in point … Vietnam War Mortality of US soldiers from malaria 40 times greater when treated by civilian MD vs. military MD Stanley J. Malaria. Emergency Medicine Clinics of North America 1997;15(1)113-155. 40% of malaria mortality in US is due to missed diagnosis

Plasmodium Falciparum Two merozoites of Plasmodium falciparum (blue and pink) in red blood cell

Plasmodium Falciparum Potentially fatal due to: Expression of membrane proteins causing adherence of red cells to endothelial walls End organ microcirculatory occlusion and tissue ischemia Death usually due to brain or lung injury Other species rarely fatal as they do not induce cytoadherence

Plasmodium Falciparum Malaria Renal failure Hepatic failure Pulmonary Edema Seizures Coma Death (up to 7% of North American and European travelers) Lobel HO, Kozansky PE. Update on prevention of malaria for travelers. JAMA. 1997; 278(21): 1767-1771.

“FEVER OCCURRING IN A TRAVELLER WITHIN 3 MONTHS OF DEPARTURE FROM A MALARIA-ENDEMIC AREA IS A MEDICAL EMERGENCY …” Canadian recommendations for the prevention and treatment of malaria among international travellers. CATMAT, Laboratory for Disease Control. Canadian Communicable Disease Report 2000;26(Supp 2):I-vi, 1-42

Malaria Diagnosis Current Standard of Care Gold Standard The Future Thick film – screen for malaria Thin film – species identification Gold Standard PCR detect low levels of parasitemia and mixed infections The Future Dipsticks – presently being investigated

Malaria Diagnosis Thick/Thin films often negative with low levels of parasitemia A high index of suspicion requires repeat films q12h x 3 to rule out malaria NB: malaria is a reportable disease in every province

Malaria laboratory investigations All of the following are necessary to determine severity of disease CBC LFTs, bilirubin INR, aPTT BUN, Creatinine Glucose Urinalysis G6PD prior to initiating treatment with primaquine for non-falciparum malaria

The three essential questions … Is this infection caused by P. falciparum? Is this a severe or complicated infection? Was this infection acquired in an area of known drug resistance?

Malaria Treatment Choice of treatment based on Species of malaria Level of parasitemia Likelihood of drug resistance Severity of infection Patient specific factors (age, immunocompromise, etc.)

Malaria drug resistance Kain, K et al. Malaria deaths in visitors to Canada and in Canadian travellers. CMAJ (2001);164(5)654-9

Criteria for severe P.falciparum Either History of recent possible exposure and no other recognized pathology Or Asexual forms of Plasmodium falciparum on blood smear

And 1 or more of: Decreased LOC Severe normocytic anemia Renal failure Pulmonary edema Hypoglycemia Shock Spontaneous bleeding / DIC Seizures Acidosis Hemaglobinuria >5% parasitemia in non-immune individuals

When in doubt ….

Treat all infections as severe, drug-resistant, Plasmodium Falciparum

Treatment of uncomplicated falciparum malaria Malarone 4 tabs po od x 3 days OR Quinine sulfate 350mg po tid x 7 days AND Doxycycline 100mg po bid x 7 days

Uncomplicated P. falciparum Can treat as outpatient if: First dose of medication given in ER and tolerated Patient has reliable supply of medication Patient has reliable supervision Patient has close follow-up Malaria smears od/bid until negative Odyssey clinic

Treatment of severe Falciparum Malaria Immediate hospitalization Mortality rate >20% IV quinine Available 24 hours a day through pharmacy at Alberta Children’s Hospital Comes with detailed instructions IV quinidine equally effications but more cardiotoxic Requires cardiac monitoring

Treatment Non-Falciparum Malaria Chloroquine 1.5g po over 3 days 300 mg po bid on days 1-2 300 mg po od on day 3 80% chloroquine resistance of P.vivax in Papua New Guinea and Irian Jaya Reports of resistance in Indonesia, Myanmar, Guyana, Solomon Islands

Prevention of Relapse in Non-Falciparum Malaria Primaquine 15mg po od x 14 days Absolute contraindication: G6PD deficiency MUST CHECK G6PD LEVEL FIRST! Plus one of Doxycycline 100mg po bid x 7 days Fansidar – single dose of 3 tabs Clindamycin 10mg/kg iv loading dose followed by 5mg/kg iv q8h until blood is clear of parasites (only if unable to tolerate 1 or 2) Canadian recommendations for the prevention and treatment of malaria among international travellers. CATMAT, Laboratory for Disease Control. Canadian Communicable Disease Report 2000;26(Supp 2):I-vi, 1-42

Non-falciparum Malaria Can treat as outpatient if: First dose of medication given in ER and tolerated Patient has reliable supply of medication Patient has reliable supervision Patient has close follow-up Malaria smears od/bid until negative Odyssey Clinic

The most important factors that determine the survival of patients with falciparum malaria are early diagnosis and prompt initiation of appropriate treatment. Canadian recommendations for the prevention and treatment of malaria among international travellers. CATMAT, Laboratory for Disease Control. Canadian Communicable Disease Report 2000;26(Supp 2):I-vi, 1-42

Where do I send my patients for follow-up? Dr. Susan Kuhn Odyssey Travel & Tropical Medicine Clinic 208 2004 14th Street NW Calgary, AB T2M 3N3 Tel: (403) 210-4770

Summary Tropical infectious diseases are coming to an Emergency Department near you Many potentially lethal diseases are easily diagnosed and treated The first step to making a diagnosis is to think about it