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

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

3. 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)

4. Travelers get sick ….
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)

5. 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

6. 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)

7. 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)

8. 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)

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

10. 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

11. 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

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

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

14. 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

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

16. 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

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

18. 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:

19. 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:

20. 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: Suh, K, et al. Medical Clinics of North America 1999:83(4)

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

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

23. Fever Associated Signs and Symptoms

24. 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

25. 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

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

27. 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

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

29. 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

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

31. 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

32. Lymphadenopathy
EBV
HIV
Dengue
NOT in malaria

33. Typhoid Fever
Salmonella typhi

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

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

36. Typhoid Fever

37. Typhoid Fever

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

39. 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%

40. 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

41. 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

43. 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)

44. 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%

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

46. Hepatitis A

47. Hepatitis A
From:

48. 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

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

50. Dengue Fever

51. 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

52. 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)

53. Aedes aegypti
Bite during day
Urban dwellers

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

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

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

58. 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

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

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

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

62. 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

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

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

65. Merozoite of p. falciparum
Malaria
Merozoite of p. falciparum

66. 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

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

68. Malaria life-cycle

69. 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

70. 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)

71. Malaria in Canada 1994 – 430 cases reported 1995 – 621 cases reported
Per capita rate 10x as high as USA
– 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)

72. Malaria

73. 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

74. 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

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

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

77. 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

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

79. 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

80. 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):

81. “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

82. 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

83. 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

84. 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

85. 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?

86. 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.)

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

88. 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

89. 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

90. When in doubt ….

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

92. 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

93. 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

94. 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

95. 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

96. 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

97. 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

98. 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

99. 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)

100. 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