Discussion: Developing a Culture of Evidence-Based Practice

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Travel Medicine and Infectious Disease

journal homepage: www.elsevier.com/locate/tmaid

International travelers with infectious diseases determined by pathology results, Centers for Disease Control and Prevention — United States, 1995–2015

Kristina M. Angeloa,∗, Kira Barbrea, Wun-Ju Shiehb, Phyllis E. Kozarskya,c, Dianna M. Blaub, Mark J. Sotira, Sherif R. Zakib

a Travelers' Health Branch, Division of Global Migration and Quarantine, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, USA b Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, USA c Department of Medicine, Emory University, Atlanta, USA

A R T I C L E I N F O

Keywords: Pathology Autopsy International Travel Biopsy

A B S T R A C T

Background: The failure to consider travel-related diagnoses, the lack of diagnostic capacity for specialized la- boratory testing, and the declining number of autopsies may affect the diagnosis and management of travel- related infections. Pre- and post-mortem pathology can help determine causes of illness and death in interna- tional travelers. Methods: We conducted a retrospective review of biopsy and autopsy specimens sent to the Infectious Diseases Pathology Branch laboratory (IDPBL) at the Centers for Disease Control and Prevention (CDC) for diagnostic testing from 1995 through 2015. Cases were included if the specimen submitted for diagnosis was from a tra- veler with prior international travel during the disease incubation period and the cause of illness or death was unknown at the time of specimen submission. Results: Twenty-one travelers, six (29%) with biopsy specimens and 15 (71%) with autopsy specimens, met the inclusion criteria. Among the 15 travelers who underwent autopsies, the most common diagnoses were protozoal infections (7 travelers; 47%), including five malaria cases, followed by viral infections (6 travelers; 40%). Conclusions: Biopsy or autopsy specimens can assist in diagnosing infectious diseases in travelers, especially from pathogens not endemic in the U.S. CDC's IDPBL provides a useful resource for clinicians considering in- fectious diseases in returned travelers.

1. Introduction

International travel has expanded over the past 50 years. In 2012, annual worldwide international tourist arrivals exceeded one billion, and arrivals will likely reach 1.8 billion by 2030 [1]. Travel destina- tions continue to diversify, with emerging economies accounting for approximately 533 million tourist arrivals in 2015 [1]. These trends bring more travelers into contact with infectious pathogens, which can have serious individual and public health consequences and can con- tribute to infectious disease spread [2].

Travelers often acquire infections while abroad, most commonly a gastrointestinal or systemic febrile illness [3]. However, an etiology to explain the travelers' symptoms may not always be determined in the clinical setting. Ill travelers may require non-routine laboratory or

pathology services, including special serologies or biopsies, to confirm a diagnosis and guide effective treatment and public health interventions. In addition, healthcare providers in non-endemic countries may fail to consider travel-related diagnoses such as malaria, leading to delays in treatment, or death. Healthcare providers should take detailed travel histories and have increased suspicion for travel-related infections, using available diagnostic tests as appropriate. Specialized pathological biopsy and autopsy specimen testing provide useful information about causes of undetermined illness and death in travelers [4] and can ex- pedite appropriate treatment. Published data on the total number of deaths due to infectious diseases acquired while traveling abroad is lacking.

We present clinical vignettes and final infectious diseases diagnoses of 21 international travelers with either biopsy or autopsy specimens

http://dx.doi.org/10.1016/j.tmaid.2017.10.003 Received 1 August 2017; Received in revised form 2 October 2017; Accepted 5 October 2017

∗ Corresponding author. Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop E-28, Atlanta, GA 30329, USA. E-mail address: [email protected] (K.M. Angelo).

Travel Medicine and Infectious Disease 19 (2017) 8–15

Available online 07 October 2017 1477-8939/ Published by Elsevier Ltd.

T

sent to the Infectious Diseases Pathology Branch Laboratory (IDPBL) at the Centers for Disease Control and Prevention (CDC) for diagnostic assistance of unexplained illnesses and deaths. The IDPBL applies his- tological, immunohistochemical, molecular, microbiologic, and ultra- structural methodologies to uncover infectious disease diagnoses on tissue specimens or cultures and is available to domestic and interna- tional clinicians, hospital systems, and health departments [5].

2. Methods

We conducted a retrospective review of autopsy and biopsy speci- mens sent to CDC's IDPBL for diagnostic testing from 1995 through 2015. Cases were included if the specimen was from an international traveler, the cause of illness or death was unknown at the time of specimen submission, and travel was during the disease incubation period. Clinicians and pathologists submitted assorted information ex- tracted from the travelers' medical record. We reviewed all available information and recorded traveler demographics, travel destination, travel purpose, reported exposures or behaviors during travel, pre- sumptive clinical diagnoses, and clinical course details, including out- come.

3. Results

Twenty-one travelers met the inclusion criteria (Table 1). Median age was 38 years (range 2–73), 43% were female, and 15 (71%) were U.S. residents. Twelve (57%) contracted their illness in Sub-Saharan Africa; other exposure regions included Central America (two tra- velers), South America (two travelers), Asia (one traveler), the Car- ibbean (one traveler), the Middle East (one traveler), North America (one traveler), and Oceania (one traveler). Six (29%) had biopsy spe- cimens and 15 (71%) had autopsy specimens sent to the IDPBL.

3.1. Travelers with biopsies

Among the six travelers with biopsy specimens, five had cutaneous specimens and one had an open lung biopsy specimen; none died (Table 1).

Traveler 1 (2008): A 58-year-old female had a scalp lesion biopsied after returning to the United States from Belize. Gross examination confirmed myiasis with the botfly Dermatobia hominis (Fig. 1A).

Traveler 2 (2011): U.S. immigration officials detained a 62-year-old female with extensive face and upper-extremity skin lesions after re- turning from an 8-week missionary trip to rural Ghana. Tissue Gram stain on skin biopsy specimens sent to the IDPBL yielded Gram-positive cocci, and immunohistochemistry (IHC) demonstrated group A strep- tococci among diffuse neutrophilic infiltrates with epithelial necrosis, consistent with impetigo (Fig. 1B and C).

Traveler 3 (2011): A 59-year-old male developed fever, myalgia, arthralgia, non-productive cough, hemoptysis, and dyspnea on exertion after returning from a 1-week trip constructing homes in rural Panama. A chest radiograph and computed tomography scan of the chest re- vealed pulmonary lesions with mediastinal and hilar lymphadenopathy; he underwent an open lung biopsy. Tissue staining revealed multiple small budding yeasts; in conjunction with IHC and polymerase chain reaction (PCR), the IDPBL confirmed acute Histoplasma capsulatum pneumonia (Fig. 1D).

Traveler 4 (2012): A 31-year-old male developed a painful, ul- cerated leg lesion and fever while traveling in rural Papua New Guinea. An infectious diseases consultant suspected a Buruli ulcer caused by Mycobacterium ulcerans. A biopsy sent to IDPBL revealed a tropical phagedenic ulcer with necrotizing dermatitis, hemorrhage, edema and thrombosis, including a polymicrobial infection with Fusobacterium nucleatum and Treponema vincentii. The traveler underwent debridement and took cephalexin for 1 week, with lesion improvement.

Traveler 5 (2014): A 39-year-old male sustained an insect bite on his

leg that ulcerated a few months after returning from Peru. The lesion was biopsied and IHC revealed intra- and extracellular basophilic structures at the IDPBL, consistent with New World cutaneous leish- maniasis (Fig. 1E and F).

Traveler 6 (2015): A 65-year-old female complained of headache, fevers, chills, myalgias, and an eschar on her left calf, where she re- called a tick bite. She recently returned from a 2-week trip to South Africa. Her physician prescribed doxycycline and submitted skin biopsy specimens to the IDPBL. IHC demonstrated epidermal ulceration with lymphohistiocytic inflammation, and PCR yielded Rickettsia africae, the causal agent of African tick bite fever (Fig. 1G and H).

3.2. Travelers with autopsies

Among the 15 travelers who underwent autopsies, the most common diagnoses were protozoal (7; 47%) and viral (6; 40%) infec- tions. Ten (67%) traveled to Sub-Saharan Africa during their illness incubation periods.

3.2.1. Protozoal infections: malaria Upon histological examination of multiple organs and identification

of intraerythrocytic Plasmodium falciparum trophozoite and schizont staining patterns by IHC, the IDPBL diagnosed travelers 7–11 with fatal P. falciparum malaria.

Travelers 7 and 8 (1996): Two male (unknown ages) Romanian cargo ship workers in Sub-Saharan Africa died aboard their ship. They had recent port calls in Gabon, Guinea, and South Africa. Authorities suspected Ebola due to a concurrent outbreak in Gabon [6].

Traveler 9 (2004): A 36-year-old male cargo ship worker became ill with fever, chills, headache, myalgias, sore throat, nausea, vomiting, jaundice, and bloody urine. Clinicians suspected Lassa fever due to multiple recent port calls in West Africa (Nigeria, Sierra Leone, and Côte d’Ivoire). The traveler died while aboard; authorities detained the ship and crew offshore until autopsy results became available [6].

Traveler 10 (2005): A 43-year-old male complained of fever, cough, myalgias, arthralgias, and “dark urine” after returning from a 2-week missionary trip to the Central African Republic and Côte d’Ivoire. His clinician suspected yellow fever or dengue infection. He did not take malaria chemoprophylaxis. He died upon arrival to the hospital [6].

Traveler 11 (2011): A 4-year-old female complained of fever, cough, diarrhea, and vomiting while visiting friends and relatives in Uganda. She did not take malaria chemoprophylaxis. A physician in Uganda treated her for a bacterial infection and tested her for malaria, but she did not receive a confirmed diagnosis or malaria treatment. Her con- dition worsened and she died shortly after arrival in the United States [7]. (Fig. 2A).

3.2.2. Protozoal infections: other Traveler 12 (2009): A 30-year-old female Sudanese refugee became

ill with acute leukemia after arriving in the United States from Kenya. She developed severe cardiac failure 2 months after receiving a bone marrow transplant and died. Cardiac tissue sent to the IDPBL indicated myocarditis with protozoal organisms consistent with Sarcocystis spp, confirmed by PCR (Fig. 2B).

Traveler 13 (2011): A 2-year-old male became ill with cough, rhi- norrhea, and left hemiparesis after returning to the United States from Mexico. Brain imaging suggested neurocysticercosis; he received ster- oids and albendazole, without improvement. He developed seizures and died. Microscopic examination of brain biopsy specimens sent to the IDPBL revealed granulomatous inflammation with necrosis and amebic organisms highlighted with IHC (Fig. 2C and D). PCR confirmed in- fection with Balamuthia mandrillaris, a free-living ameba causing gran- ulomatous amebic encephalitis.

3.2.3. Viral infections Traveler 14 (1999): A 45-year-old male became ill after returning to

K.M. Angelo et al. Travel Medicine and Infectious Disease 19 (2017) 8–15

9

Ta bl e 1

In te rn at io na

l tr av

el er s w it h a bi op

sy or

au to ps y sp ec im

en su bm

it te d to

th e C en

te rs

fo r D is ea se

C on

tr ol

an d Pr ev

en ti on

's In fe ct io us

D is ea se s Pa

th ol og

y la bo

ra to ry ,1

99 5–

20 15

(n =

21 ).

Tr av

el er

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C ou

nt ry

of R es id en

ce Ex

po su re

C ou

nt ry

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el R ea so n

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or te d

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su re s/ Be

ha vi or s

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ic al

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at io n

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th ol og

ic Fi nd

in gs

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is m (s )

Fi na

l D ia gn

os is

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m e

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el er s w it h a B io ps

y Sp

ec im

en 1

20 08

45 F

U ni te d

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e U nk

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ol og

ic al

fe at ur es

co m pa

ti bl e w it h di pt er a

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2 20

11 62

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na M is si on

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Q ue

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bl e ex po

su re

to an

im al

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an d ar m

le si on

s w it h ul ce ra ti on

s C ut an

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in fi lt ra te s in

th e ep

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an d up

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w it h

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11 59

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m at io n

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12 31

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no t ta ke

m al ar ia

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op ro ph

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ve r,

co ug

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lg ia s,

ar th ra lg ia s,

“d ar k ur in e”

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fe ve

r, D en

gu e

M ul ti pl e or ga

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in tr ae ry th ro cy ti c pa

ra si te s

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d ve

ss el s

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iu m

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(c on

tin ue d on

ne xt

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K.M. Angelo et al. Travel Medicine and Infectious Disease 19 (2017) 8–15

10

Ta bl e 1 (c on

tin ue d)

Tr av

el er

Y ea r

A ge

Se x

C ou

nt ry

of R es id en

ce Ex

po su re

C ou

nt ry

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el R ea so n

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or te d

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su re s/ Be

ha vi or s

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ic al

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at io n

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os is

H is to pa

th ol og

ic Fi nd

in gs

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is m (s )

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l D ia gn

os is

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m e

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s an

d re la ti ve

s

pa ra si te s in

bl oo

d ve

ss el s

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A )

12 20

10 30

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da n

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n or

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ya R ef ug

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no w n

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fa ilu

re N on

e M yo

ca rd it is

w it h pr ot oz

oa l

or ga

ni sm

s (F ig .2

B) Sa

rc oc ys tis

sp p.

Sa rc oc

ys to si s

D ea th

13 20

11 2

M U ni te d

St at es

M ex ic o

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no w n

Sw am

in a ho

te l po

ol C ou

gh ,r

hi no

rr he

a, le ft

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N eu

ro cy st ic er co

si s

G ra nu

lo m as

w it h am

eb ic

or ga

ni sm

s (F ig .2

C an

d D )

Ba la m ut hi a

m an

dr ill ar is

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lo m at ou

s am

eb ic

en ce ph

al it is

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14 19

99 45

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sw am

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ne cr os is

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fe ve

r D ea th

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04 38

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sy nd

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fe ve

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E an

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ic fe ve

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17 20

10 12

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se iz ur es ,

al te re d m en

ta l st at us

Ba ct er ia l m en

in gi ti s

M en

in go

en ce ph

al it is

w it h

ne ur on

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cr os is ,

ne ur on

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an d gl ia l

no du

le s

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ne se

en ce ph

al it is

vi ru s

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ne se

En ce ph

al it is

D ea th

18 20

11 24

M U ni te d

St at es

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ni st an

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Bi tt en

by a do

g on

th e

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t ha

nd Se

ve re

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pa in

an d ri gh

t ha

nd pa

re st he

si as ,

di ffi cu

lt y sw

al lo w in g,

vo m it in g,

at ax

ia

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on it is , G as tr it is

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rk in je

ce lls

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G an

d H )

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19 20

11 73

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s an

d re la ti ve

s

Bi tt en

by a do

g R ig ht

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sh or tn es s of

br ea th ,m

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ha llu

ci na

ti on

s, di ffi cu

lt y

m ai nt ai ni ng

ba la nc

e

N on

e M en

in go

en ce ph

al it is

w it h

vi ra l in cl us io ns

in Pu

rk in je

ce lls

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ie s vi ru s

R ab

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D ea th

20 19

95 38

F Sw

it ze rl an

d Bu

ru nd

i Bu

si ne

ss C ar ed

fo r ill

pr is on

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w it h

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r, ch

ill s,

m ya

lg ia s,

se ve

re th ro m bo

cy to pe

ni a

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ic fe ve

r, ty ph

oi d fe ve

r V as cu

lit is

in m ul ti pl e

or ga

ns R ic ke tts ia

pr ow

az ek ii

Ep id em

ic (l ou

se -

bo rn e)

ty ph

us D ea th

21 19

99 39

F U ni te d

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ya M is si on

ar y

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d in

a ru ra l ar ea ,

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d in

th e fo re st

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ss

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ar ,f ev

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the United States from a 10-day trip to Venezuela, where he swam in fresh water and visited the rainforest. He developed fulminant renal and liver failure and disseminated intravascular coagulation, compli- cated by an intracerebral hemorrhage, and died a few days after ad- mission. Autopsy specimens sent to the IDPBL showed histopathologic changes with massive hepatocellular necrosis, and IHC confirmed the etiologic agent as yellow fever virus.

Traveler 15 (2004): A 38-year-old male Liberian-born U.S. resident became ill with fever, chills, sore throat, diarrhea, and back pain while visiting farms in Liberia and Sierra Leone. After returning to the United States, he clinically deteriorated with acute respiratory distress syn- drome despite treatment for malaria and typhoid fever. IHC on liver biopsy specimens performed by the IDPBL were positive for Lassa virus. The result was further confirmed by serum antigen detection, virus isolation in cell culture, and virus identification by PCR on blood, liver, and skin specimens [8] (Fig. 2E and F).

Traveler 16 (2008): A 33-year-old Zambian male paramedic cared for a 36-year-old woman on a medical evacuation flight from Zambia to South Africa. The woman had a rash, facial swelling, and myalgia and

received mechanical ventilation during the flight. The paramedic de- veloped headache, myalgia, and fever six days after the flight and died. Blood, liver, and skin specimens underwent IHC testing, demonstrating scattered hepatocellular necrosis, and PCR revealed a novel Old World arenavirus, Lujo virus. The paramedic's infection was one of three secondary cases from nosocomial contact with the ill woman [9].

Traveler 17 (2010): A 12-year-old female became ill with headache, fever, nausea, vomiting, seizures, and altered mental status after re- turning to the United States from a 2-week trip to Manila, Philippines. She did not improve with treatment for bacterial meningitis and died. Brain biopsy specimens tested at both the state lab and IDPBL demon- strated meningoencephalitis with neuronal necrosis, neuronophagia, and glial nodules; PCR indicated infection with Japanese encephalitis virus.

Traveler 18 (2011): A 24-year-old male soldier deployed to Afghanistan sustained a dog bite to the right hand. He did not receive rabies post-exposure prophylaxis. He developed severe arm pain and right hand paresthesia while en-route to the United States, followed by progressive meningoencephalitis and death. Nuchal biopsy specimens,

Fig. 1. Histopathologic findings of biopsy and autopsy specimens from international travelers submitted to the Centers for Disease Control and Prevention's Infectious Diseases Pathology Branch la- boratory, 1995–2015. A) Traveler 1: Dermatobia hominis myiasis. Microscopic examination demonstrating the cuticle, striated mus- cles, and spiracles of the larva; H & E staining, original magnifica- tion: ×200. B–C) Traveler 2: Group A Streptococcus impetigo. B) Skin biopsy demonstrates epidermal ulceration and neutrophilic infiltrate in dermis; H & E staining, original magnification: ×200. C) Numerous gram-positive cocci in the dermis admixed with neutrophils; Lillie-Twort Gram staining, original magnification: ×400. D) Traveler 3: Acute pulmonary histoplasmosis. Lung biopsy demonstrating necrotizing inflammation with multiple yeast or- ganisms, some with budding feature; Grocott's methenamine-silver staining, original magnification: ×400. E–F) Traveler 5: Cutaneous leishmaniasis. E) Skin biopsy demonstrates lymphohistiocytic in- filtrates in dermis with abundant intra- and extracellular round basophilic structures; H & E staining, original magnification: ×400. F) Immunostaining of Leishmania species in dermis; immunoalka- line phosphate staining, naphthol fast red substrate with light he- matoxylin counterstain, original magnification: ×400. G–H) Traveler 6: African tick-bite fever. G) Skin biopsy demonstrates leukocytoclastic vasculitis and perivascular lymphohistiocytic in- filtrate; H & E staining, original magnification: ×200. H) Immunostaining of spotted fever group rickettsiae in the vascular wall and perivascular infiltrates; immunoalkaline phosphate staining, naphthol fast red substrate with light hematoxylin coun- terstain, original magnification: ×400.

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saliva, CSF, and autopsy brain samples underwent testing. Microscopic examination of the autopsy brain samples demonstrated Negri bodies, and IHC showed rabies viral antigens (Fig. 2 G–H). PCR confirmed ra- bies [10].

Traveler 19 (2011): A 73-year-old Haitian female developed right shoulder pain, headaches, and difficulty swallowing while visiting friends and relatives in the United States; she developed encephalitis and died. A nuchal skin biopsy sent to the CDC rabies laboratory de- monstrated rabies antigens by direct fluorescent antibody testing, and a saliva specimen tested positive by PCR for rabies virus. Autopsy brain samples submitted to IDPBL showed Negri bodies, and IHC was positive for rabies virus. A dog bit the traveler in Haiti and she did not receive post-exposure prophylaxis [11].

3.2.4. Rickettsial infections Traveler 20 (1995): A 38-year-old Swiss female nurse caring for ill

prison inmates in Burundi developed fever, chills, and myalgias asso- ciated with severe thrombocytopenia. She received ciprofloxacin for presumed typhoid fever. Despite treatment, she died. Histopathologic examination of autopsy specimens sent to the IDPBL demonstrated

vasculitis in multiple organs, and IHC was positive for typhus group rickettsiae. PCR further identified Rickettsia prowazekii, the causative agent of louse-borne epidemic typhus [12].

Traveler 21 (1999): A 39-year old female developed a furuncle on her left leg associated with fever, chills, myalgias, headache, and a generalized maculopapular rash while on a missionary trip in Kenya. Prior to her illness, her dog had “tick-borne fever” and improved. Despite receiving malaria treatment, her condition worsened. She de- veloped a left leg eschar, in addition to thrombocytopenia (107,000/ mm3), and died. Microscopic examination of autopsy tissues showed vasculitis and microthrombi in multiple organs; IHC was positive for rickettsiae, but did not identify a species [13].

4. Discussion

We describe the pathologic diagnoses of travel-related illnesses using specialized diagnostic capacity from CDC's IDPBL. These findings illustrate the importance of pathology diagnostics in identifying un- diagnosed illness or death from infectious diseases. This is particularly important for the rising numbers of international travelers who may

Fig. 2. Histopathologic findings of biopsy and autopsy specimens from international travelers submitted to the Centers for Disease Control and Prevention's Infectious Diseases Pathology Branch la- boratory, 1995–2015. A) Traveler 11: Plasmodium falciparum ma- laria. Microscopic examination demonstrates intraerythrocytic parasites with hemozoin in blood vessels of multiple organs; H & E staining, original magnification: ×630. B) Traveler 12: Sarcocystosis. Autopsy heart tissue demonstrates numerous Sarcocystis species with inflammation and myocyte necrosis; H & E staining, original magnification: ×400. C–D) Balamuthia man- drillaris granulomatous amebic encephalitis. C) Autopsy brain tissue demonstrates granulomatous inflammation and vascular necrosis with many amebic organisms around the vessel; H & E staining, original magnification: ×400. D) Immunostaining of many Balamuthia mandrillaris in the brain; immunoalkaline phosphate staining, naphthol fast red substrate with light hematoxylin coun- terstain, original magnification: ×400. E-F) Traveler 15: Lassa fever. E) Autopsy liver tissue demonstrates multifocal hepatocel- lular necrosis, H & E staining, original magnification: ×200. F) Immunostaining of abundant Lassa virus antigens in the liver; im- munoalkaline phosphate staining, naphthol fast red substrate with light hematoxylin counterstain, original magnification: ×200. G–H) Traveler 18: Rabies. G) Autopsy brain tissue demonstrates meningoencephalitis with viral inclusions (Negri bodies) in cere- bellar Purkinje cells; H & E staining, original magnification: ×400. H) Immunostaining of rabies virus antigens in the brain; im- munoalkaline phosphate staining, naphthol fast red substrate with light hematoxylin counterstain, original magnification: ×200.

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become ill with infections rare or non-endemic in the United States. It is also important for travel medicine clinicians who provide care to re- turned travelers, to utilize these resources for appropriate diagnosis and treatment.

Obtaining an autopsy from undiagnosed deceased individuals can provide useful information not only about causes of death in travelers, but also on illnesses not recognized clinically prior to death [4,14]. For example, an autopsy was recently instrumental in diagnosing the first measles death in the United States in 12 years [15]. Autopsies may decrease gaps in surveillance, leading to enhanced infectious disease risk estimates, and result in more rapid diagnosis and treatment of contacts, as well as public health response. Despite the autopsy's value for determining cause of death, autopsy rates in the United States have declined significantly since the 1960s [4]. Prior to 1970, 40–60% of all hospital deaths in the United States received autopsies, but in recent years, decreased to approximately 5% [16]. Additionally, infectious diseases accounted for 46% of causes of death determined by autopsy in 2007, down from 79% in 1972 [14]. This may be due to improvement in infectious disease treatment, but also the relative decrease in medical autopsies and the relative increase in autopsies due to external causes (e.g., firearms) [14]. This decline may also be due to cost constraints, clinicians seeking fewer autopsies, and the removal of the minimum autopsy rate mandate for hospitals by the Joint Commission on Ac- creditation for Healthcare Organizations in 1970 [17]. The declining number of medical autopsies has additional effects, such as a decrease in forensic autopsy experience for training pathologists, resulting in a lack of experience to recognize subtle findings, or decreased medical care quality assurance [17].

Among the 15 deaths, more than half were preventable through recommended pre-travel vaccination or chemoprophylaxis. Almost all deaths were potentially preventable through early diagnosis and treatment, including the five in travelers infected with P. falciparum malaria. The focus on alternative diagnoses, despite travel to a malaria- endemic area, resulted in diagnostic and treatment delays. Among the more than 1700 reported malaria infections among U.S. travelers in 2013, Africa was the most common exposure region, P. falciparum comprised the majority of infections, and there were 10 deaths [18]. Malaria must be on the differential diagnosis for febrile travelers with recent travel to a malaria-endemic country, and such travelers should visit a healthcare professional immediately if any malaria symptoms, such as fever, develop during or after travel.

It is imperative to obtain a travel history on all patients, especially those with a fever [3]. Clinicians should also note possible risky ex- posures (e.g., animal, water, or insect exposures) in a travelers' itin- erary. Rash was present in only 26%, and an eschar was present in 55% of U.S. travelers with spotted fever rickettsioses in one report [19], so reliance on the clinical examination and laboratories alone may not always result in a diagnosis.

This report provides details on pathology submissions sent the IDPBL for specialized testing that were shown to be travel-related; however, although only one case each of leishmaniasis and African tick bite fever are presented, the IDPBL received many traveler's skin biopsy specimens from clinicians concerned about these two diseases. The IDPBL identified Leishmania spp. in 370 of these biopsy specimens (CDC data, unpublished). Due to low sensitivity and specificity, serologic testing does not play a role in diagnosis; PCR or specialized tissue di- agnostics are necessary. IDPBL also identified Rickettsia africae in 16 cutaneous biopsy specimens during the same timeframe; African tick bite fever is the most common rickettsiosis identified in travelers re- turning from Africa [19].

One potential limitation is that the clinical data submitted to the IDPBL for each traveler varied. Although we reviewed all available information and recorded traveler demographics, travel destination, travel purpose, reported exposures or behaviors during travel, pre- sumptive clinical diagnoses, and clinical course details, including out- come, this information may not have been available for all travelers.

Efforts are forthcoming to standardize the clinical information sent with submitted specimens. An additional limitation is that clinicians may opt to submit specimens to the IDPBL based upon the lack of availability of diagnostic testing in their institutions or health departments, and the frequency of submission may vary by the type of clinical site (and their specialization) or country.

CDC is committed to promoting pathogen detection through la- boratory-based diagnostics, modern point-of-care testing, and facilita- tion of specimen submission to public health reference laboratories [20]. Access to appropriate diagnostic tests may expedite diagnosis and treatment of travelers with infectious diseases. CDC's IDPBL has the capability to perform specialized diagnostic testing to help diagnose unexplained deaths among international travelers, and providers are encouraged to use this service ([email protected]) when encountering difficult cases.

Declarations

This project was designated nonresearch by a CDC human subjects advisor. None of the authors reported any conflicts of interest.

Author contributions

Kristina M. Angelo: Primary writer, primary contributor to data interpretation.

Kira Barbre: Secondary writer, contributor to data interpretation. Wun-Ju Shieh: Supplied case study information, provided patho-

logic explanations for the images and manuscript, technical editing, contributor to data interpretation.

Phyllis E. Kozarsky: Critical manuscript revision and writing, tech- nical editing, contributor to data interpretation.

Dianna M. Blau: Critical manuscript revision and writing, technical editing, contributor to data interpretation.

Mark J, Sotir: Conception and design, critical manuscript revision and writing, contributor to data interpretation.

Sherif R. Zaki: Conception and design, technical editing, contributor to data interpretation.

Funding

No funding received by the authors.

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the United States Centers for Disease Control and Prevention.

Acknowledgements

We would like to thank the domestic health departments and in- ternational ministries of health that assisted with sending specimens to CDC for testing and the clinicians that provided clinical information on the travelers.

References

[1] World Tourism Organization. UNWTO Tourism Highlights: 2016 Edition. Available at: http://mkt.unwto.org/publication/unwto-tourism-highlights-2016-edition. Accessed 9 November 2016.

[2] Harvey K, Esposito DH, Han P, Freedman DO, Plier DA, Sotir MJ. Surveillance for travel-related disease — GeoSentinel Surveillance System, United States, 1997–2011. MMWR Surveill Summ 2013;62(3):1–23.

[3] Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med 2002;347(7):505–16.

[4] Wilson ML. Infectious diseases and the autopsy. Clin Infect Dis 2006;43(5):602–3. [5] Centers for Disease Control and Prevention. Infectious Disease Pathology Branch

(IDPB): Investigating unexplained Illness and Death. Available from: http://www.

K.M. Angelo et al. Travel Medicine and Infectious Disease 19 (2017) 8–15

14

cdc.gov/ncezid/dhcpp/idpb/unexplained-deaths/index.html. Accessed 4 November 2016.

[6] Genrich GL, Guarner J, Paddock CD, Shieh WJ, Greer PW, Barnwell JW, et al. Fatal malaria infection in travelers: novel immunohistochemical assays for the detection of Plasmodium falciparum in tissues and implications for pathogenesis. Am J Trop Med Hyg 2007;76(2):251–9.

[7] Taylor CA, Blau DM, DiAngelo CR, Shieh WJ, Zaki SR, Arguin PM. Malaria diag- nosed by autopsy in a young traveler returning from Uganda: limitations of sur- veillance. J Travel Med 2013;20(1):47–9.

[8] Centers for Disease Control and Prevention (CDC). Imported Lassa fever — New Jersey, 2004. Morb Mortal Wkly Rep 2004;53(38):894–7.

[9] Paweska JT, Sewlall NJ, Ksiazek TG, Blumberg LH, Hale MJ, Lipkin WI, et al. Nosocomial outbreak of novel arenavirus infection, southern Africa. Emerg Infect Dis 2009;15(10):1598–602.

[10] Centers for Disease Control and Prevention (CDC). Imported human rabies in a U.S. Army soldier — New York, 2011. Morb Mortal Wkly Rep 2012;61(17):302–5.

[11] Centers for Disease Control and Prevention (CDC). Imported human rabies – New Jersey, 2011. Morb Mortal Wkly Rep 2012;60(51):1734–6.

[12] Raoult D, Roux V, Ndihokubwayo JB, Bise G, Baudon D, Marte G, et al. Jail fever

(epidemic typhus) outbreak in Burundi. Emerg Infect Dis 1997;3(3):357–60. [13] Rutherford JS, Macaluso KR, Smith N, Zaki SR, Paddock CD, Davis J, et al. Fatal

spotted fever rickettsiosis, Kenya. Emerg Infect Dis 2004;10(5):910–3. [14] Hoyert DL. The changing profile of autopsied deaths in the United States,

1972–2007. NCHS Data Brief 2011(67):1–8. [15] McCarthy M. US sees first measles death in 12 years. BMJ 2015;351. h3653. [16] Shojania KG, Burton EC. The vanishing nonforensic autopsy. N Engl J Med

2008;358(9):873–5. [17] Reichert CM, Kelly VL. Prognosis for the autopsy. Health Aff 1985;4(2):82–92. [18] Mace KE, Arguin PM. Malaria surveillance — United States, 2014. MMWR Surveill

Summ 2017;66(12):1–24. [19] McQuiston JH, Paddock CD, Singleton JJR, Wheeling JT, Zaki SR, Childs JE.

Imported spotted fever rickettsioses in United States travelers returning from Africa: a summary of cases confirmed by laboratory testing at the Centers for Disease Control and Prevention, 1999–2002. Am J Trop Med Hyg 2004;70(1):98–101.

[20] Centers for Disease Control and Prevention. Global Health Security Agenda: GHSA National Laboratory System Action Package (GHSA Action Package Detect-1). Available at: https://www.cdc.gov/globalhealth/security/actionpackages/ national_laboratory.htm. Accessed 9 November 2016.

K.M. Angelo et al. Travel Medicine and Infectious Disease 19 (2017) 8–15

15