Evaluation of Fever in the Returning Traveler Aric Storck October 23, 2003

Objectives  Approach to the febrile traveler –History  Travel history  Immunization history  Chemoprophylaxis –Investigations –Treatment  Brief overview of the most commonly 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)

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

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)

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:S / 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)

After the holiday …  Swiss study –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:  5% of travelers consult MD upon return Thanassi M, Thanassi W. EMR 1998;9(22)

Many of the returning ill will present to the Emergency Department

ED evaluation of the febrile traveler 1. What infections are possible given the patient’s travel history 2. What infections are probable given the patient’s medical history and presentation 3. What infections are life-threatening or contagious or both

 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 General Medical History

 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 VaccineEfficacyDuration Cholera50%3-6 months Typhoid Vi CPS43-96%2-3 years Typhoid Ty21A years Yellow Fever100%10 years Japanese encephalitis85%3 years Meningococcus85-95%3 years HAV Immune Globulin70-80%3-5 months Hepatitis A>90%>10 years Hepatitis B>90%>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 –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:

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:

Commonest causes of fever (%) diagnosisMacLean et al (n=587) Doherty et al (n=195) O’Brien et al (n=232) Malaria Hepatitis6113 (Hep A) Respiratory infection Urinary tract infection42.62 Dysentery (gastroenteritis) Dengue fever26.28 Enteric fever21.53 Tuberculosis120.4 Rickettsial infection10.52 Acute HIV infection Amebiasis101 Other infections Non-infectious causes 613 Undiagnosed sources: O’Brien D, et al. Clinical Infectious Diseases 2001;33: Suh, K, et al. Medical Clinics of North America 1999:83(4)

Incubation Periods  Short (<1 week) –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

Case 1  35 y.o. oilfield worker in rural Sudan –Returned 5 days ago after 6 months abroad –Fever, chills, cough started yesterday –What else do you need to know?

 PMHx –Healthy  Pre-departure consultation by GP –Vaccinated against HAV/HBV, Typhoid –Prescribed mefloquine for malaria prophylaxis. –Stopped taking it because of concerns of long term side-effects

 Physical – / –Diaphoretic –Otherwise normal examination  CXR –Normal  Laboratory –Hb 110 –WBC 8 –Platelets 65 –Lytes normal –Malaria smear negative

 What is your differential diagnosis?  What is the most dangerous likely pathogen?  How would you manage this patient?

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 – million people get malaria – million people die from malaria  90% in rural, sub-Saharan Africa  Disproportionately in children <5

 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) Malaria, not hard to get …..

Malaria in Canada  1994 – 430 cases reported  1995 – 621 cases reported  1997 – 1036 cases reported  Per capita rate 10x as high as USA  – tenfold increase in severe malaria requiring admission to ICU  Calgary has among the highest per capita rate in Canada (oil & gas industry) Kain K, et al. Malaria deaths in visitors to Canada and in Canadian travellers; a case series. CMAJ 2001;164(5)

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) IntervalP. vivaxP. falciparumP. malaria P. ovaleTotal (months)(%) < > N Adapted from MMWR 44:1-14, 1995

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)  40% of malaria mortality in US is due to missed diagnosis Stanley J. Malaria. Emergency Medicine Clinics of North America 1997;15(1)

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):

“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

Back to our case…  You correctly have malaria on the top of your differential diagnosis –What investigations rule in or out malaria

Malaria Diagnosis  Current Standard of Care –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

 Our patient’s thin smear shows malaria of undetermined species? –Is this a severe or uncomplicated infection? –What are you going to treat it with?  What if the initial smear is negative? –Are you going to treat?

Malaria Treatment  Choice of treatment based on –Species of malaria –Level of parasitemia –Likelihood of drug resistance –Severity of infection

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

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

Criteria for severe P.falciparum Either 1. History of recent possible exposure and no other recognized pathology Or 2. 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

 Your patient is getting progressively more obtunded. His BP is now 85/50. Repeat CBC shows Hb of 85.  Now how would you treat him?

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

Rewind …  The pathologist calls back. The species has been definitively identified as Plasmodium Vivax.  Does this change your management?

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

 You treated your patient with chloroquine as recommended.  Three months she returns with a fever. She has not travelled recently  What’s going on?

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 1.Doxycycline 100mg po bid x 7 days 2.Fansidar – single dose of 3 tabs 3.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

Case 2  25 y.o. waitress from Canmore –Returned 15 days ago from 6 months in Southern Thailand –Religiously took her malarone –Ate pad thai from street vendors every day –Malaise x 2 days –Today fever & “gassy” abdominal discomfort

 PMHx –Healthy –Vaccinated  HAV/HBC  Typhoid  Meds –Finished malarone last week –OCP  O/E – / –Very slightly tender abdomen –Otherwise normal exam  Lab –CBC, lytes normal –LFTs very slightly elevated –Urine clear –Malaria smear negative

 What is your differential diagnosis?  What investigations would you like?  Where are you going to send this patient?

Typhoid Fever Salmonella typhi

Typhoid Fever  Gram negative bacilli –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

 Early –Fever –Malaise  Intermediate –Abdominal pain –Rose spots  Blanching, erythematous, maculopapular spots 2-4mm –Relative bradycardia –Diarrhea or constipation –Hepatosplenomegaly Classical Presentation

Late Complications Bowel perforation (1- 3%) GI bleed –erosion of necrotic Peyer’s patch into vessel (10%)  Encephalopathy

diagnosis  Laboratory –Nonspecific  Anemia  Leukocytosis / leukopenia  Abnormal LFTs –specific  Blood culture – sensitivity 40-80% –Higher in first week and with large blood volumes (>15ml); lower with prior Abx  Bone marrow – sensitivity ~ 98%  Stool culture – sensitivity 30-40%

Back to our case …  Malaria smears remain negative x 3  Blood culture grows gram negative bacilli, final ID pending  What do you think she’s got?  How will you treat her?

The bottom line …. Typhoid should be considered in any febrile patient recently in an endemic area in whom malaria has been excluded

Global Distribution of Resistance to Salmonella Typhi, 1990 through NEJM 2002; 347(22)

Treatment - summary  Fluoroquinolone –Ciprofloxacin 500 mg bid –Ofloxacin 400 mg bid  If from a known area or resistance add  3 rd generation cephalosporin –Ceftriaxone 2-3 g od –Continue while sensitivities pending

 Your patient asks if she can go back to waiting tables on Monday?  You are doing extenders with the public health department. What do you tell her?

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

Treatment of chronic carriers  Lots of antibiotics –Ampicillin + Probenecid x 90 days –Septra x 3 months –Cipro 750 bid x 28 days  Cholecystecomy if gallstones  Treatment of schistosomiasis (praziquantel) for chronic urinary carriers

Case 3  25 y.o. male –Returned 2 days ago from Guyana –worked with orphans in the slums of Georgetown –Now fever, headache, and severe bony pains –+nausea, no vomiting, no real abdominal pain

 PMHx –Healthy –Vaccinated for HAV/HBV, typhoid  Meds –Still taking mefloquine for malaria prophylaxis  O/E – / –Diaphoretic, looks uncomfortable –Normal cardiovascular, resp, and abdo exam –You notice petechiae on his arm after taking his BP  Lab –HB 137 WBC 8.3 Plt 120 –Normal lytes, LFT’s –Malaria smear neg x 1

Dengue Fever  Flavivirus composed of single-stranded RNA  No vaccination  No chemoprophylaxis  No specific treatment

Dengue virus  Arbovirus transmitted Aedes aegypti mosquito –Urban dwellers –Bite during the day

Dengue Virus  Causes both –Dengue Fever  benign self limited illness –Dengue Hemorrhagic Fever (DHF)  life threatening

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

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 –Travel to endemic area within past 2 weeks  Clinical –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 –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

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

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