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Ill returning traveler Brian S. Schwartz, MD

UCSF, Division of Infectious Diseases

• I have no disclosures

International travel in 2010

• 940 million travelers crossed international boarders

• 60 million traveled from the US internationally

– Almost half traveled to a developing country

UNWTO World Tourism Barometer. World Tourism Organization; 2011.Office of Travel and Tourism Industries 2010 Outbound Analysis, US Dept of Commerce 2011

Travelers crossing international borders

Keystone. Travel Medicine. 2008

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What is the magnitude of travel related morbidity/mortality

• 20‐70% report some illness

• 1‐5% seek medical attention

• 3% report fevers

• 0.1‐0.01% require medical evacuation

• 1/100,000 – deathHill DR. CID. 2006

Cardiovascular Disease49%

Injury22%

Infection1%

Other/Unknown6%

Cancer6%

Suicide/Homicide3%

Medical14%

Exacerbation of comorbidities is the predominant cause of death in US Travelers:

Hargarten SW. Annals of Emergency Medicine.1991

Preventable causes of death in US travelers 2008‐2010

Air accident, 82

Disaster, 131

Drowning, 329

Drug‐related, 67

Execution, 13

Homicide, 533

Maritime accident, 31

Accident other, 332

Suicide, 357

Terrorist, 52

Vehicle accident, 735

http://travel.state.gov/law/family_issues/death accessed 01.10.2012

Illness in returned travelers: 2007‐2011

GI37%

Febrile25%

Derm21%

Resp12%

GU/STI3%

Neuro2%

Leder K. Ann Intern Med. 2013

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Top 5 complaints in returning travelers leading to MD visit

• Fever without localizing findings

• Acute diarrhea

• Dermatological disorders

• Chronic diarrhea

• Nondiarrheal gastrointestinal disorders

Freedman DO. NEJM. 2006.

Fever

• 2‐3% of American/European travelers to developing countries

– 39% fever when abroad

– 37% fevers abroad and home

– 24% fevers at home only

• Medical emergency

Hill DR. J Trav Med. 2000

How to determine etiology of fever in returned traveler?

• Destination

• Incubation period

• Exposures

• Exam findings/labs

• Prophylaxis/immunizations

0

100

200

300

400

500

600

700

800

900

1000

Carribean C. America S. America Sub‐SaharanAfrica

SouthCentral Asia

SE Asia

Cases

Freedm

an DO

. NE

JM. 2006.

Destination: Etiology of fever according to region traveled

Dengue

Unknown

EBV/CMV

Malaria

Rickettsia

Typhoid

Dengue

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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0‐7 7‐14 14‐21 21‐28 28‐35 35‐42 >42

Proportion of Diagn

oses

Days post‐travel

7

Incubation period: Etiology of fever according to interval after travel

Wilson ME. CID. 2007.

Rickettsia

P. falciparum

P. vivax

CMV/EBV

DengueTyphoid

Other

Malaria Other

7 14 21 28 35 42 490

Exposures?

• Insect or animal exposures?

• Fresh water exposure?

• What did they eat/drink?

• Other ill travelers?

• Sexual activity?

Specific symptoms or exam findings?

• Symptoms

– Abdominal pain

– Arthralgias

• Exam findings

– Rash

– Jaundice

– Ocular changes

What kind of prevention measures were used?

• Vaccinations?

– Which ones?

– Timing of vaccinations?

• Malaria prophylaxis?

– Appropriate agents?

– Taken appropriately?

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Case 1

29 year‐old paleontologist returned 3 days ago from a 3 week research trip to southern Bangladesh complaining of fever. 

He complains of high fevers and now diffuse myalgias.

Initial testing?

Initial testing?

• Complete blood count

• Liver function tests

• Blood cultures 

• Thick and thin blood smears (malaria)

• Urinalysis

• Chest x‐ray

• Additional testing based on history/exam

Skin and Labs• 2.1>37<67

• Cr: 0.8

• AST: 78

• ALT: 93

• AP: 88

• Bili: 0.7

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Your DDx? Dengue fever

• 50‐100 million infections/year

• Mosquito vector (daytime)

• Urban and rural

Dengue fever: worldwide distribution

http://www.healthmap.org/dengue/index.php

Dengue fever: clinical disease

• Incubation: 4‐7 days

• Clinical Manifestations:– Severe headache, joint and muscle aches

– Nausea and vomiting

– Rash

• Dengue Hemorrhagic Fever/Shock Syndrome– Occurs 3‐7 days into illness, often w/ end of fever

• Labs: leukopenia, thrombocytopenia,  LFTs

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Dengue rash1‐2 days post onset of symptoms

Flushing erythema 

3‐5 days

Morbilliform eruptionw/ petechiae and islands of sparing

Pincus LB. J Am Acad Dermatol. 2008

Dengue diagnostics

Guzman MG. Nature Reviews Micro.2010

Dengue fever: treatment and prevention

• Treatment: supportive

• Prevention of mosquito exposure 

– Avoid endemic areas

– DEET 

– Permethrin

Dengue in Hawaii!! 

• In 2001‐2002 > 1,000 infected on 3 islands

• No Aedes aegypti were found

• Aedes albopictus was able to transmit dengue

• Returning traveler to Hawaii infected with dengue after visiting French Polynesia

Dengue Fever Hawaii 2001-2002. Emerging Infect Dis.2005

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Chikungunya fever

http://www.cdc.gov/chikungunya/

Chikungunya in the Caribbean!

476

116

3643

Chikungunya fever

• Incubation period 2‐4 days (1‐14)

• Clinical manifestations

– Fever

– Polyarthralgias 2‐4 days later: Hands/ankles

– Rash ~ 50%, maculopapular, hyperpigmentation

• Labs: Lymphopenia, thrombocytopenia,  LFTs

• Severe complications/deaths in elderly

Chikungunya: diagnostic testing

• Serological testing (IgM/IgG) available via CDC and Quest Diagnostics (via Focus Labs)

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Case 2

• 63 year‐old male with no PMH returned from a 10 day vacation to South Africa with complaints of fever, myalgias, and rash.

History cont.

July0 2110 122 13 19

To South Africa

In South Africa

Return to USA

15

Noticed lesion on right waist‐band area, non‐tender

Fevers (Tm‐101), myalgias, fatigue

Developed “red spots” on chest, arms

UCSF ED

Physical Exam

• VS: 38.5, 76, 128/70, 16, 99% RA

• Lymph:

– 1 cm R inguinal LAD, mild tenderness

• Skin:

– right waistband region, 1.5 x 1 cm ulcer w/ mild surrounding erythema non‐painful

– ~20, 0.2‐0.3 cm papulo‐vesicular lesions on trunk, flank, back, forehead, extremities

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Labs and Microbiology

Hematology

\ /5.4 ‐‐‐‐‐‐‐‐ 214

/ 47 \

DiffPoly ‐ 31%Lymph ‐ 51%Mono ‐ 15%Eos ‐ 2%Baso ‐ 1%

Chemistry

Chem 7 ‐ wnl

LFTS – wnl;  UA ‐ wnl

Micro

7/18 ‐ Bld Cx X 2 – NGTD

7/18 – thin/thick ‐ neg

Your DDx?

African Tick Bite Fever

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African Tick Bite Fever

• Rickettsia africae

Jensenius, Lancet ID 2003

Clinical Presentation

• Fever

• Headache

• Muscle aches

• Inoculation eschar, often multiple

• Regional lymph node swelling

• Rash

Jensenius M. African Tick Bite Fever. Lancet Infect Dis 2003; 3: 557–64. Rauolt D. Rickettsia Africae, A Tick-borne Pathogen In Travelers To Sub-Saharan Africa. N Engl J Med 2001, 344 (20)

African tick‐bite fever

“Tache noire”

Treatment

• Doxycycline 100 mg BID x 7 days or until 48h after defervescence

• Symptoms often improve 24‐48h after initiation of treatment

Rolain JM. In Vitro Susceptibilities of 27 Rickettsiae to 13 Antimicrobials. Antimicrobial Agents and Chemotherapy. 1998. 1537–41

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Case 3• 28 year‐old male returned 3 weeks ago from a trip to Kenya

• Last week developed fever (up to 103), occasional hives, and occasional cough/wheezing

Physical Exam

• T‐101, VSS

• HEENT: oropharynx clear

• CHEST: clear

• CV: RRR no M

• ABD: soft, no HSM

• EXT: WWP

• DERM: faint diffuse maculopapular rash

Labs

• CXR ‐ clear• 8>40<320

• Eos: 6.0

• AST‐55, ALT‐63, AP & Bili‐wnl

• Cr‐0.9

Exposures

• Swam in a fresh water lake 

– After swimming in lake he developed an “itchy rash” which resolved in a few days

• No uncooked food/unfiltered water

• Denies exposure to sick contacts

• Sexually active with girlfriend

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Fever and Eosinophilia?

• Strongyloides

• Acute schistosomiasis (Katayama fever)

• Visceral larva migrans (toxocariasis)

• Hookworm

• Ascariasis

• Cutaneous larva migrans

• Filariasis

• Trichinosis

Eosinophilia in returning travelers

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

SE Asia Ind.subcont.

Mid East Asiaother

S. & C.America

Sub‐sah.Africa

Oceania

% of cases

Non‐schisto eos Schistosomiasis

Meltzer E. AJTMH. 08.

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Diagnostics

• Bld cx x 2 – NGTD

• Thick/thin smear – negative

• Schisto IgG ‐ positive

Schistosomiasis

Gryseels B. Lancet ‘06

“Swimmer’s itch”(12-24 hrs)

Katayama Fever(2-6 wks)Chronic Infx

-Gut-Urine-Liver-Other (months-yrs)

Diagnosis

• Micro

– Stool O&P

– Urine O&P

• Serology

• Histology

Gryseels B. Lancet ‘06

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Treatment

• Praziquantil is the treatment of choice

– Not active against immature forms

– Katayama fever, repeat 6‐8 weeks later (+/‐steroids)

Case 4

• 45 year‐old Russian business man presents to urgent care with fever and rash for several days. He also complains of cough, nasal congestion, and itchy eyes

• He has been in San Francisco for 1 week for a conference.  He otherwise has no past medical history

http://children.webmd.com/

Morbilliform eruption and fever in returning traveler

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Measles cases in US 2001‐2013

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6236a2.htm

Case 5

• 34 y/o M presents with fever

• Returned 2 wks ago from a 3 wk trip to Ghana

• Received hep A, typhoid, yellow fever vaccines•

• Drank bottled water, cooked his food paying close attention to preparation

• Used treated bed net, no malaria prophylaxis

Exam

• T‐102.3, 110, 123/67, 20, 99% RA

• HEENT: oropharynx clear

• CHEST: clear

• CV: RRR no M

• ABD: soft, no HSM

• EXT: WWP

• DERM: clear

Labs

• WBC: 8

• HCT: 35

• PLT: 90

• AST‐33, ALT‐36, Alk Phos 67, TBili: 1.9

• Cr‐0.9

• CXR ‐ clear

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http://www.cdc.gov/dpdx/malaria/gallery.html#pfalmaurerclefts http://www.cdc.gov/dpdx/malaria/gallery.html#pfalmaurerclefts

Malaria

Freeman DO. NEJM 2008

Malaria in the US ‐ 2011

0

500

1000

1500

2000

2500

2008 2009 2010 2011

Malaria Cases

Undetermined

Mixed

Other species

P. vivax

P. falciparum

CDC. Malaria Surveillance — United States, 2011. 2013

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Clinical signs and symptoms

• Fever/Chills/Sweats

• Headaches

• Nausea/vomiting

• Body aches

• General malaise

• Enlarged spleen/Mild jaundice

• Enlargement of the liver

Severe malaria

• Impaired consciousness/coma/seizure

• Severe normocytic anemia

• Renal failure

• Pulmonary edema/ARDS

• Hemaglobinuria

• Jaundice

• Parasitemia of > 5%

Treatment of uncomplicated P. falciparum

• Atovaquone‐proguanil (Malarone™)

– 4 adult tabs po qd x 3 days 

• Artemether‐lumefantrine (Coartem™)

– 3‐day (total of 6 oral doses): initial dose, second dose 8 hrs later, 1 dose po bid x 2 days

• Quinine + (Doxy or Tetra or Clinda) x 7 days

• Mefloquine (Lariam™)

– 750 mg salt, then 500 mg salt 6‐12 hours later

http://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf

Treatment of complicated P. falciparum

• Artesunate (plus second agent)

– Malaria Hotline: 770‐488‐7788 (M‐F, 8am‐4:30pm, eastern time) or after hours, 770‐488‐7100

• Quinidine plus (doxy, tetra, or clinda)

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Malaria prevention

• Low risk: Insect avoidance, consider chemoprophylaxis in certain travelers

– vulnerable travelers– immigrants visiting friends/relatives– prolonged travel (> 1 mo)– unreliable access to medical care

• Moderate‐high risk: Chemoprophylaxis

sporozoites

schizont

schizont

trophozoite

merozoites

merozoites

LIVERRBC

Hepatocyte

Lifecycle of P. falciparum

7-14d after infection

MefloquineDoxycyclineChloroquine

Atovaquone/proguanil

Malaria chemoprophylaxisDrug Areas of use Directions Pro/cons

Atovaquone/ proguanil

AllDaily; 1 wk post

Pro: Minimal SEsCon: $

ChloroquineChloroquine‐susceptible

Weekly; 4 wks post

Pro: WeeklyCon: GI upset

Doxycycline AllDaily; 4 wks post

Pro: $Con: Photos; GI

Mefloquine Mefloquine‐susceptible

Weekly;4 wks post

Pro: $, ok in preg, kidsCon: Dreams, avoid psych/Seiz.

Top 5 complaints in returning travelers leading to MD visit

• Fever without localizing findings

• Acute diarrhea

• Dermatological disorders

• Chronic diarrhea

• Nondiarrheal gastrointestinal disorders

Freedman DO. NEJM. 2006.

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Travelers’ diarrhea (TD)

• #1 travel‐related illness: 30‐70% of travelers

• Pathogens: 

– Bacteria 80‐90%: ETEC, campy, shigella, salmonella

– Viruses 10%: Norovirus, rotavirus

• Course: 

– Bacterial and viral diarrhea lasts 3‐5 days

– Longer durations suggests other diseases

Prevention of TD

• Prevention

–Avoidance of contaminated food/water

• Prophylaxis

–Bismuth subsalicylate 2 tabs QID

–Rifaximin 200 mg PO QD‐BID (vs. placebo)

• TD: 15% vs. 54% in Mexican travelers

DuPont HL. Annals of Internal Medicine. 2005

Self‐treatment of TD

• Ciprofloxacin: 

– 500 mg PO BID for 1‐3 days

• Azithromycin: SE Asia, children, pregnancy

– 500 mg PO QD x 3 days or 1000 mg PO x 1

• Rifaximin: not for invasive infections

– 200 mg PO TID x 3 days

• Loperamide: not for invasive infections

– Added benefit, use in “emergency”

Top 5 complaints in returning travelers leading to MD visit

• Fever without localizing findings

• Acute diarrhea

• Dermatological disorders

• Chronic diarrhea

• Nondiarrheal gastrointestinal disorders

Freedman DO. NEJM. 2006.

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10 top dermatological conditions in returning travelers

1. Cutaneous larva migrans

2. Bacterial SSTIs

3. Arthropod bites

4. Allergic reaction/urticaria

5. Myiasis

6. Superficial fungal infx

7. Injuries/animal bites

8. Scabies

9. Cutaneous leishmaniasis

10. Tungiasis

Cutaneous larva migrans Cutaneous larva migrans

• Treatment:

– Albendazole 400 BID x 3‐7d OR

– Ivermectin 200 mcg/kg QD x 1‐2d

• Prevention: wear shoes in risk areas

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Returning traveler from Panama Returning traveler from Costa Rica

Returning traveler from Portugal Returning traveler from Israel

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Returning traveler from Brazil

Cutaneous leishmaniais

Protozoa(single‐celled eukaryotes)

GI/GUBlood

TissueEntamoebaGiardiaCryptosporidiumTrichomonas

PlasmodiumBabesia

TrypanosomaLeishmaniaToxoplasma

Leishmaniasis: Clinical disease

Cutaneous MucosalVisceral

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Distribution of species by clinical disease

Cutaneous

Mucosal

Visceral

L major

L aethiopica

L mexicana

L panamensisL braziliensis

L infantum

L donovani

L tropica

Distribution of species by geography

Old WorldNew World

L major

L aethiopica

L mexicana

L panamensis

L braziliensis

L infantum

L donovani

L tropica

Where do you get it? Cutaneous How do you get it?

Sand fly

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Clinical manifestations

• Incubation period: 1‐4 weeks

• Morphology: 

– Small raised bump  ulcer (months)

– May grow as large as 5 cm

• Not painful in most cases

• Often self‐resolves within 6 months 

Mucocutaneous disease

• Caused by only a few species

– L. braziliensis

– L. panamensis

• Weeks to years 

• Ulcerations that eventuate in mutilating destruction of the oropharynx  Schwartz E. Lancet Infect Dis 2006.

Diagnosis• Skin biopsy: sterile, full‐thickness punch‐biopsy specimens at the active border of the lesion

• Aspiration for culture and PCR testing

• Coordinate testing swith CDC

– Frank Steurer (tele: 404‐718‐4175; email: fsteurer@cdc.gov; fax: 404‐718‐4195) 

http://www.cdc.gov/parasites/leishmaniasis/resources/pdf/cdc_diagnosis_guide_leishmaniasis.pdf.pdf

Treatment

• Key factors

1. species 

2. extent of disease

3. comorbidities

• Options: 

– No treatment

– Topical: Paromomycin

– Intralesional injections: Antimony

– Systemic: Antimony; Ampho B; Miltefosine; Azoles

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L guyanensis‐ Ambisome

L panamensis– miltefosine (FDA IND)

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L infantum – posaconazole then topical amphotericin (study)

L major – topical paromomycin

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Other skin lesions that might “bug” your patients

McGraw TA. J Am Acad Dermatol. 2008

Returning traveler after an Amazonian trek

Botfly

Returning researcher from Ethiopia

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Tungiasis Top 5 complaints in returning travelers leading to MD visit

• Fever without localizing findings

• Acute diarrhea

• Dermatological disorders

• Chronic diarrhea

• Nondiarrheal gastrointestinal disorders

Freedman DO. NEJM. 2006.

Chronic diarrhea

• Protozoal infections

– Giardia

– Cryptosporidium

– Entamoeba histolytica

– Other: Cyclospora, isospora, etc…

• Other infections

– C. difficile colitis

• Non‐infectious etiologies

Evaluation of chronic diarrhea

• Bacterial culture

• Stool O&P x 3

• Other tests

– Giardia antigen

– Stool AFB stain (cryptosporidium, isospora, etc.)

– Stool Cryptosporidium antigen

– Stool Entamoeba histolytica antigen

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Top 5 complaints in returning travelers leading to MD visit

• Fever without localizing findings

• Acute diarrhea

• Dermatological disorders

• Chronic diarrhea

• Nondiarrheal gastrointestinal disorders

Freedman DO. NEJM. 2006.

Nondiarrheal gastrointestinal disorders

• Intestinal nematode infection

– Strongyloides, schistosomiasis, ascaris

• Gastritis/PUD

• Acute hepatitis

– Hepatitis A, E, B

• Constipation

Evaluation of nondiarrhealgastrointestinal disorders

• Check LFTs

• CBC w/ differential (eos?)

• Stool O&P x 3

• Serology: Strongyloides and schistosoma IgG

• GI referral for other diagnoses

Post‐infectious irritable bowel syndrome

• 3‐10% of travelers after episode of TD

• Diagnosis of exclusion

• Last months ‐ years

Connor BA. Clin Inf Dis. 2005

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Summary

• Fever (with rash) and cutaneous diseases are very common in returning travelers

• A systematic approach to diagnosis includes a detailed travel history and for febrile patients laboratory testing is often indicated