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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)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:S2428. •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 – 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 1. 2. 3. 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 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 3 years 85-95% HAV Immune Globulin 70-80% 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;32:1063-1067. 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 Doherty et al (n=587) (n=195) O’Brien et al (n=232) Malaria 32 42 27 Hepatitis 6 11 3 (Hep A) Respiratory infection 11 2.6 24 Urinary tract infection 4 2.6 2 4.5 5.1 14 (gastroenteritis) Dengue fever 2 6.2 8 Enteric fever 2 1.5 3 Tuberculosis 1 2 0.4 Rickettsial infection 1 0.5 2 Acute HIV infection 0.3 1.0 0.4 1 0 1 4.3 9.2 8 Non-infectious causes 6 1 3 Undiagnosed 25 24.6 9 Dysentery Amebiasis Other infections 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) – 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 – 105 14 110/75 39.80 – 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 – 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 1997 – 1036 cases reported Per capita rate 10x as high as USA 1994-1997 – 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)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 15.0 10.0 15.5 6-12 22.8 1.0 20.0 40.0 15.5 >12 3.8 0.5 0.0 15.0 2.9 N 316 198 20 20 554 Adapted from MMWR 44:1-14, 1995 Malaria is …. Usually Almost preventable 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 Stanley J. Malaria. Emergency Medicine Clinics of North America 1997;15(1)113-155. 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 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 nonfalciparum malaria Criteria for severe P.falciparum 1. Either 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 – 83 13 110/70 38.60 – Very slightly tender abdomen – Otherwise normal exam HAV/HBC Typhoid Meds – Finished malarone last week – OCP O/E 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 Typhoid Fever Classical Presentation Early – Fever – Malaise Intermediate – Abdominal pain – Rose spots Blanching, erythematous, maculopapular spots 2-4mm – Relative bradycardia – Diarrhea or constipation – Hepatosplenomegaly Late Complications Bowel perforation (13%) 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 marrow – sensitivity ~ 98% Stool culture – sensitivity 30-40% Bone 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 2002. NEJM 2002; 347(22) NEJM 2002; 347(22) NEJM 2002; 347(22) Treatment - summary Fluoroquinolone – Ciprofloxacin 500 mg bid – Ofloxacin 400 mg bid If from a known area or resistance add 3rd 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 – 110 14 120/80 38.40 – Diaphoretic, looks uncomfortable – Normal cardiovascular, resp, and abdo exam – You notice petechiae on his arm after taking his BP – Healthy – Vaccinated for HAV/HBV, typhoid O/E Meds – Still taking mefloquine for malaria prophylaxis 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 3 -10 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 >20 BP cuff to MAP x 5 minutes. petechiae / square inch suggests dengue Diagnosis Laboratory Diagnosis – Routine Blood Work Generally neutropenic and thrombocytopenic – Dengue serology (definitive) culture – only within 5 days of onset of symptoms IgM ELISA – after 5 days of symptoms Viral 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 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