Download Emergency Department Evaluation of Fever in the Returning Traveler

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