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T R O P I C A L D I S E A S EMALARIA, DENGUE,

C H I K U N G U N YA , A N D Z I K A

E V E B . H O OV E R , M S PA S , PA - CT H A N K YO U , A S A PA !

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OBJECTIVES:

Investigate how travel affects exposure to tropical diseases

Develop a recognition of Malaria, Dengue, Chikungunya, and Zika

Symptoms

Signs

Pathophysiology

Diagnosis

Treatment

Prevention

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OUR PATIENTS ARE ON THE MOVE!!

• International students on the rise to and from USA

Figure 1. International students at U.S. Colleges and Universities in 2013/2014 (Institute of International Education, 2013, para. 1) 4

STUDY ABROAD CONTINUES TO INCREASE AND EXPAND

Historically, most study abroad students travel to Europe; however, recently destinations are expanding

According to Rhodes et al. (2014) research, travel to Africa, Asia and the Middle East is increasing while travel to Europe is decreasing

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OUR PATIENTS ARE ON THE MOVE!!

Travel is steadily increasing for work, education and pleasure (US Travel Assn)

*73.9 MILLION international arrivals to US in 2014 * 2.1 BILLION trips taken by Americans in 2014

A tropical medicine zebra may need to be considered in the appropriate patient population You will never know if you don’t ASK!! Thorough patient history is ESSENTIAL

“People, as well as pathogens, travel from all around the world in all directions” (Piyaphanee et al., 2012, p. 337).

6*Retrieved from https://www.ustravel.org/sites/default/files/page/2013/08/US_Travel_AnswerSheet.pdf

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WHERE HAVE YOU TRAVELLED INTERNATIONALLY IN LAST YEAR?

• What countries have you visited outside of the United States in the last year?

• Prior to travel, did you or your family have a pre-travel medicine consult?

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PRE-TRAVEL CONSULT IS OFTEN OVERLOOKED

According to Leder et al (2013) research

< 40% of febrile travelers going to risky destinations (such as Africa, Asia, India) sought any form of pre-travel consult.

Keys to increase Pre-Travel Consults

Deliver prevention messages

Develop Health Communication Strategies

8Cullen & Arguin, 2014, p. 17.

EXPOSURE TO TROPICAL ILLNESS IS A REAL CONCERN

A 19-year-old, previously healthy male, lay on the examination table. He was covered with a blanket and shaking uncontrollably with intense rigors that correlated with his 103 degree fever.

Although he was hesitant to answer questions due to feeling so ill, he reported having returned from India 2 weeks prior and his Sx’s (fever, rigors, ache, fatigue, HA, and nausea), began abruptly, hours before arriving to the clinic.

The waiting room was packed on this January morning…9

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EXPOSURE TO TROPICAL ILLNESS IS A REAL CONCERN

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High index of suspicion in appropriate patient population is paramount

PATIENT PRESENTATION, CONTINUED…

Pt was diaphoretic and taking rapid, shallow inspirations.

BP: 148/86 R: 24 T: 103 HR: 112

HEENT: Dry mucous membranes, but no other abnormality. Neck was supple with no LA and no nuchal rigidity.

Heart rate tachycardic with no murmur or rub.

Lungs clear to auscultation.

Abdomen was soft, nontender, BS x 4. No CVA tenderness.

Skin was warm, clammy, without rash.

No focal neurologic deficits.11

TO SOLVE THIS MYSTERY, LET’S EXAMINE FOUR CAUSES OF TROPICAL MEDICINE MOSQUITO-BORNE ILLNESS

MALARIA

DENGUE

CHIKUNGUNYA

ZIKA12

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MALARIA: EPIDEMIOLOGY 198 million clinical episodes of malaria worldwide in 2013 (WHO)

Caused over 500,000 deaths

In 2011, CDC reported 1,925 cases of malaria in US

Infection with the following protozoal parasites:

Plasmodium falciparum

Plasmodium vivax

Plasmodium ovale

Plasmodium malariae

Occasionally other Plasmodium species

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Most Severe!

**Falciparum and Vivax Are the 2 Most Common Causes of Malaria

MALARIA: PATHOPHYSIOLOGY AND DIAGNOSIS

7-30 days Following an anopheles mosquito bite, parasites develop in patient’s RBCs causing toxins to develop.

Diagnosis Thick and thin blood film Gold Standard

Rapid diagnostic test (RDT) Polymerase chain reaction (PCR)**Consider screening for malaria in all febrile travelerswho traveled to tropical destinations w/i previous 12 months**

14CDC, 2015, retrieved from http://www.cdc.gov/dpdx/malaria/gallery.html#pfalringformtrophs

MALARIA: SIGNS AND SYMPTOMS

No symptomsFever Headache, back pain, chills, sweating, myalgia, nausea,

vomiting, and cough

Atypical symptoms Respiratory distressConvulsionsRenal failure

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MALARIA: TREATMENT

Based on severity AND probability of resistance (resistance )

Falciparum vs. non-falciparum Ex. of anti-malaria drugs: sulphate, atovaquone-proguanil, artemether-lumefantrine,

doxycycline, clindamycin, sulphadoxine-pyrimethamine, chloroquine, and primaquine.

Combination regimens are often needed due to resistance

Most common Tx of non-falciparum: Chloraquine + Primaquine Primaquine covers dormant liver malaria

Severe malaria: Quinine + Artesunate IV

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MALARIA: PREVENTION

Avoid mosquito bites

Long pants, shirts

Close windows

Avoid standing water

Bed nets

Spray for mosquitos, mosquito repellant

Chemoprophylaxis

Ex. Doxycycline

Not 100% protective (even if taken perfectly)

If taken inadequately, can delay Sx onset and cause initial blood film to be falsely negative. Repeat test if suspicious

Resistance to chemoprophylaxis is increasing

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MALARIA: WHO 1.5 MINUTE VIDEO CLIP

18World Health Organization https://www.youtube.com/watch?v=gwYIyjwYluc

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WHICH OF THE FOLLOWING CAUSES OF MALARIA HAS THE WORST PROGNOSIS?

A. Plasmodium ovale

B. Plasmodium vivax

C. Plasmodium falciparum

D. Plasmodium malariae

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LET’S MOVE ON TO DENGUE

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DENGUE: PATHOPHYSIOLOGY

The most common arbovirus in humans

Mosquito-borne disease (transmitted by an infected Aedesmosquito)

Caused by four types of Flaviviruses

Outbreaks have increased by 30x in last 50 years.

Outbreaks present in over 100 countries including US

FL, TX, Hawaii

21Tomashek & Margolis, 2014

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DENGUE: SIGNS AND SYMPTOMS

75% of infected patients with DF are asymptomatic

If Sx’s, occur 4-7 days after bite

Shorter incubation period than malaria

Fever, myalgia, headache, rash, arthralgia, abdominal pain, and nausea

Atypical symptoms

ARDS, DIC, conduction cardiac defects, renal failure

22Tomashek & Margolis, 2014

“Bone Break Pain”

DENGUE CATEGORIES

PRIOR TO 2009

• Dengue Fever

• Dengue Hemorrhagic Fever

• Dengue Shock Syndrome

2009-PRESENT

• Dengue

• Dengue with Warning Signs

• Severe Dengue

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TOURNIQUET TEST FOR DENGUE

Marker for microvascular fragility

Inflate BP cuff ½ way between systolic and diastolic BP

Maintain pressure for 5 minutes

+ Test: >10 petechiae found in one square inch

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WHICH OF THE FOLLOWING IS NOT A SIGN OF SEVERE WORSENING DENGUE?

A. Epistaxis

B. Bloody stool

C. Headache

D. Menorrhagia

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DENGUE: DIAGNOSIS

Often a clinical diagnosis based on signs and symptoms

Laboratory diagnosis confirmation:

Detection of dengue viruses (DENV) through

Polymerase chain reaction (PCR)

Nonstructural protein 1 (NS1) antigen by immunoassay

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DENGUE: TREATMENT AND PREVENTION

Self-limiting febrile illness Typically resolves after 4-7 days Supportive care (rest, acetaminophen, fluids)NO NSAIDS

If severe case, admission requiredPreventionAVOID MOSQUITO BITES! (See next Slide)No available vaccine, antiviral or chemoprophylaxis

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An ill traveler can spread disease if sustains a mosquito bite while ill The mosquito can carry on the virus to other locals

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http://www.cdc.gov/zika/images/local_transmission_chikv_denv_zika.jpg

DENGUE: 1 MINUTE VIDEO CLIP

29https://www.youtube.com/watch?v=uTjNX3mYvjQ

LET’S MOVE ON TO CHIKUNGUNYA

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CHIKUNGUNYA (CHIKV): PATHOPHYSIOLOGY AND EPIDEMIOLOGY

Swahili and Makonde language

“The one that is folded”

Arbovirus

Transmitted by Aedes mosquitoes

> One million cases of CHIKV were reported in the Americas since October 2013

Most cases occur in travelers, but local transmission is possible

31Vega-Rua, 2015

CHIKUNGUNYA: SIGNS AND SX’S

Abrupt development fever, HA, polyarthralgia (usually small joints: hands, ankles, wrists) and myalgia

Hunched over gait

Back pain

Joint involvement can become chronic

Continued arthralgia in 60% even after 36mos.

Rash common (maculopapular or bullous)

Atypical symptoms: Encephalomyelitis, Hearing loss, Guillian Barre, Meningoencephalitis

32HRNJAKOVIC CVJETKOVIC, 2015

CHIKUNGUNYA: DIAGNOSIS

Chikungunya should not be a clinical diagnosis as it is difficult to differentiate from Dengue and other viral illnesses

Confirm Dx detection of CHIKV:

Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)

Enzyme linked Immunosorbent Assay (ELISA)

Access to testing is limited

CDC, 1 commercial lab, few health departments

CHIKV only recently has become issue in US

33Lindsey et al., 2015

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CHIKUNGUNYA TREATMENT AND PREVENTION

Supportive care Rest, hydration, acetaminophen, ice packs

Prevention

No available vaccine, antiviral, or chemoprophylaxis

AVOID MOSQUITO BITES Lets touch on mosquito avoidance with the following question...

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A 50-YEAR-OLD MALE PRESENTS FOR A PRE-TRAVEL CONSULT BEFORE HIS TRIP TO INDIA . HE INQUIRES ABOUT MOSQUITO AVOIDANCE.

Which of the following would you advise for this patient?A. If possible, move bedding into cool, dark areas (like a bathroom or closet) as mosquitos tend to avoid these areasB. If using insect repellent, long sleeves and long pants are unnecessary to avoid mosquito bitesC. Avoid standing water (such as flower pots), which can encourage mosquito breedingD. Open windows during cool evenings to allow for adequate ventilation

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CHIKUNGUNYA

36https://www.youtube.com/watch?v=wx-VXmY-yQY

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MOVING ON TO OUR LAST TOPIC… ZIKA

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ZIKA: PATHOPHYSIOLOGY

Flavivirus transmitted primarily by the bite of an infected Aedesmosquito (similar to Dengue and Chikungunya)Has been detected in: Blood (10 wks), urine (91 days), semen (188 days), vaginal secretions

(11 days), saliva (91 days), CSF, amniotic fluid, and breast milk Viral load in semen is 100,000 x stronger than in urine or serum

Other modes of Transmission:Maternal-fetal Sexual transmission (vaginal, anal, oral) Blood/Tissue Donation Occupational Exposure (1 documented lab exposure) 38

ZIKA: EPIDEMIOLOGY 1947: First isolated in Rhesus monkey from Zika Forest in Uganda 1st major outbreak in Yap Islands of Micronesia in 2007 (70% of population age 3+

infected) Outbreak in Brazil May 2015 (1.5 million cases and 4,000 cases of microcephaly)

1st case of Zika related microcephaly in US was dx in Hawaii Jan. 2016 (Mom lived in Brazil during pregnancy)

Territories with Active Zika Transmission:

Anguilla, Antigua, Argentina, Aruba, Barbados, Barbuda, Belize, Bolivia, Bonaire, Brazil, Cape Verde, Cayman Islands, Colombia, Common Wealth of Puerto Rico, Costa, Rica, Cuba, Curacao, Dominica, Dominican Republic, Ecuador, El Salvador, Fiji, French Guiana, Grenada, Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Jamaica, Marshall Islands, Martinique, Mexico, Micronesia, New Caledonia, Nicaragua, Panama, Papua New Guinea, Paraguay, Peru, Saba, Saint Lucia, Saint Martin, Samoa, Suriname, Trinidad and Tobago, Tonga, Turks and Caicos, US Virgin Islands, United States, Venezuela, Oceania, Pacific Islands American Samoa

Feb. 2016: WHO declared ZIKA an international health emergency

39UpToDate: Zika Virus Infection, http://www.cdc.gov/zika/geo/active-countries.htmlhttps://qzprod.files.wordpress.com/2016/01/microce1.jpg?quality=80&strip=all&w=640

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ZIKA CASES REPORTED IN THE US (CDC SEPT. 2016)

40http://www.cdc.gov/zika/intheus/maps-zika-us.html

ZIKA: EPIDEMIOLOGY

Imported Zika in travelers returning to US (3,132)

Travel Assoc. Cases of Zika: AZ: 29, CA:224, NY: 685

Sexually transmitted cases of Zika (26 cases in US)

Locally acquired Zika 1st identified in Florida

43 locally acquired Zika infections in FL (CDC, late Sept)

Just to give a comparison…Puerto Rico: 7855 locally acquired infections

41https://qzprod.files.wordpress.com/2016/01/microce1.jpg?quality=80&strip=all&w=640

ACTIVE ZIKA VIRUS LOCAL TRANSMISSION IN FLORIDA (CDC)

W Y N W O O D N E I G H B O R H O O D A N D S E C T I O N O F M I A M I B E A C H

42http://www.cdc.gov/zika/intheus/maps-zika-us.html

Pregnant Women advised to avoid

travel to Wynwood neighborhood and an area of Miami

Beach

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ZIKA: SIGNS/SX’S No Sx’s (80%)

Sx start 2-14 days after bite (20%):

2 or more of the following:

Low-grade fever (100-101.3)

Maculopapular rash

Arthralgia

Conjunctivitis

Other Sx’s: Myalgia, HA, pain behind eyes common

Occasionally, abd pain, nausea, diarrhea, itching

Sx’s resolve within 2-7 days

Complications: Congenital microcephaly, fetal loss, Guillian-Barre (8 cases of Zika assoc. GB in US) 43

http://www.diseasezika.com, http://www.cdc.gov/zika/symptoms/symptoms.html

ZIKA: WHEN SHOULD WE SUSPECT IN NON-PREGNANT PT? If relevant exposure

Travel to or residence in endemic area within 2 weeks

Unprotected intercourse with person who meets above criteria

AND

2 or More of the Following Sx’s:

LG fever

Rash

Arthralgia

Conjunctivitis 44

Zika???

ZIKA: DIAGNOSTIC TESTS Preferred test for dx of acute Zika: Real-Time Reverse-transcription

polymerase chain reaction (rRT-PCR) for Zika RNA in serum and urine Test when viral load is highest (serum w/i 7 days Sx’s, urine may be + for 14d) Neg test does not exclude infection

Zika virus serology Draw lab 4 or more days after Sx onset Caution: Cross-reactivity with other flavivirus (West Nile, Dengue) limits

specificity If + IgM, check Zika Virus Plaque-Reduction Neutralization test (PRNT) PRNT is used to rule out false positive IgM

Commercial assays recently developed: PCR-based assay and a serologic assay Contact state health departments/CDC if testing needed

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http://www.medscape.com/viewarticle/865985_2, http://www.uptodate.com/contents/zika-virus-infection-an-overview?source=search_result&search=zika+virus&selectedTitle=1%7E59#H4142744963

*When testing for Zika, also test for Dengue and

Chikungunya*

1-800-CDC-INFO or [email protected]

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ZIKA: TREATMENT IN NONPREGNANT PT

No FDA approved treatment Rest, Fluids, Acetaminophen No ASA or NSAIDS until Dengue ruled out

Avoid mosquito bites while ill to decrease local spread How long to wait before unprotected sexual activity (CDC)? Symptomatic men with Zika: Wait > 6mos Symptomatic women with Zika: Wait >8 weeks Asymptomatic men or women with Zika exposure: Wait >8 weeksWHO: Recommends waiting >6mos for both men and women

who travel to areas with active transmission regardless of Sx’s46

ZIKA: PREVENTION

No vaccine…Yet… (Presently under development)

Avoid mosquito bites Both in Zika area and upon return to non-Zika area

Personal protective Measures: Long sleeves and pants, insect repellant, staying indoors

Avoid standing water

Universal testing of donated blood products in the U.S. and its territories (Aug 2016)

47http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM518213.pdf

ZIKA: PREVENTION IN PREGNANCY

In Jan. 2016, CDC advised that pregnant women postpone travel to endemic area

Men with Zika who have pregnant partner

Abstain from intercourse (vaginal, anal, oral) for duration of pregnancy or use barrier protection

In areas with active Zika transmission, CDC recommends abstinence or barrier method for all individuals while transmission persists

Breast feeding- CDC encourages continued breast feeding

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ZIKA: WORKUP IN PREGNANCY

Ask about relevant exposure in patient and partner at EACHprenatal visit Exposure: Residence or recent travel to Zika area or unprotected

intercourse with partner who traveled to or lived in Zika area

Workup for Pregnant Pt (see algorithm next slide)

No exposure: Zika labs not indicated

Exposure (w/i 2 wks) WITH OR WITHOUT Sx’s: Lab indicated (rRT-PCR serum and urine). If neg, serum testing

Exposure (2 wks -12 weeks) WITH OR WITHOUT: Zika IgM and Dengue IgM. rRT-PCR, PRNT

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50http://www.uptodate.com/contents/image?imageKey=OBGYN%2F109190&topicKey=ID%2F107211&rank=2%7E59&source=see_link&search=zika+virus&utdPopup=true

ZIKA: WORKUP IN PREGNANCY

If + Zika labs, get US US is the major tool used to screen for congenital Zika

If negative Zika labs in pt with exposure, get Ultrasound (US) If normal US, consider one or more f/u US Abnormal US Fetal Microcephaly (difficult to dx before 3rd trimester) Intracranial Calcifications (seen in 2nd or 3rd trimester) If + US, recheck maternal serology/rRT-PCR and consider

amniocentesis

51http://www.uptodate.com/contents/zika-virus-infection-pregnancy-and-congenital-infection?source=search_result&search=zika+virus&selectedTitle=2%7E59

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Pregnant pt with Exposure

Zika Sx’s (w/i 2 wks)

No Zika Sx’s (w/i 2 wks)

Zika Labs

Labs + or inconclusive

Fetal US and offer amniocentesis

Zika Labs -

Fetal US

US +

Consider Amnio

US -

Fetal US looking for microcephaly,

calcifications

US + US -

Serial US

Zika labs, consider amnio

If +52

Adapted from Peterson et al. (2016)

53http://www.nejm.org/doi/full/10.1056/NEJMoa1600651

Numerous Calcifications

In Brain

Numerous Calcifications in Placenta

ZIKA: WORKUP IN PREGNANCY, CONT. If positive/inconclusive labs in mother Consider Amniocentesis and Serial US (q 3-4 weeks) Zika rRT-PCR in Amniotic fluid is diagnostic of exposure (sensitivity

and specificity unknown) + Amnio does not mean fetal abnormality is present If negative Amnio and abnormal US, consider other cause of

microcephaly All infants with possible Zika exposure obtain thorough evaluation w/i 24

hours after delivery Thorough Physical Exam and Head circumference Zika labs Consider histopathology of placenta and umbilical cord

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Cranial Ultrasound (even if prenatal US was normal)

Hearing Test

Ophthalmologic Evaluation

Comprehensive Physical Exam

If Microcephaly…Geneticist, Neurologist, ID, endocrinologist…

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Malaria Dengue Fever Chikungunya Zika

WBC count (If elevated, Consider leptospirosis)

Normal or mildly increased

Platelet count (<150,000) 3-6 days into illness

Usually normal, occasionally

Usually normal

Hemoglobin (frequently <10 g/dL)

Normal Normal Normal

ESR

CRP or (may remain elevated for wks)

Other Total bilirubin can be

Rising Hct can indicate shock, worsening DF.

AST, ALT. Nl bili

RF may be positive

Elevated LDH

Confirmatory Labs for Diagnosis

Thick and Thin blood film gold standardRDT, PCR

DENV (PCR or immunoassay)(<5d after fever onsetELISA IgM(>4d after fever onset)

Detection of IgM antibodies or rising IgG antibodiesIsolation of virus

ELISA IgM and IgGViral RNA by RT-PCR

Table Adapted from: Hoover, E. (2016)

College health may be full of surprises:

International Travelers and Tropical Diseases.

Clinician Reviews. 42-50.

FUTURE ZIKA IMPLICATIONS… Zika Funding

CDC estimates that 41* states are in the potential range of Aedes aegypti or Aedes albopictus mosquitoes

Aug. 24, 2016: Director at NIH states that Zika virus could extend its reach across the U.S. Gulf Coast (Louisiana and Texas)

Record flooding in Louisiana in Aug. 2016 increases risk of Zika

“Diffuse, broad outbreak” unlikely but CDC recommends preparation for that possibility

State-level strategies for improving access to contraceptives to decrease unintended pregnancies

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http://www.medscape.com/viewarticle/867701?nlid=109062_1981&src=WNL_mdplsnews_160826_mscpedit_fmed&uac=251395CJ&spon=34&impID=1186096&faf=1, http://www.medscape.com/viewarticle/867131?src=wnl_edit_tpal&uac=251395CJ*Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Minnesota, Mississippi, Missouri, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Utah, Vermont, Virginia, West Virginia, and Wisconsin.

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REMEMBER OUR PREVIOUS PATIENT?

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OUR FEBRILE PATIENT, CONT.Laboratory Workup

CBC, CMP, and UA were without abnormality.

Thick and thin blood smear revealed multiple infected red blood cells and the appearance of the classic head phone form within the red blood cell.

WHAT DID OUR PATIENT HAVE?

And how did we treat him?59CDC 2015

THAT IS RIGHT!! OUR PATIENT HAD MALARIA (CAUSED BY PLASMODIUM VIVAX) The 19-year-old febrile traveler was diagnosed with malaria very

quickly based on the in-office laboratory results of the thick and thin blood smear.

He did not take malaria chemoprophylaxis prior to his trip

No pre-travel consult prior to travel

Consider Leder et al’s research: Talk to your patients and encourage pre-travel consults

Short hospital admission for hydration, observation, treatment, and consultation with ID yielded rapid improvement

Pt back to the rigorous demands of college life

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TAKE HOME MESSAGE

Early detection and appropriate supportive care of patients with Malaria, dengue, Chikungunya and Zika can make the difference between life and death.

Remember to consider these conditions in the febrile returning traveler.

Encourage patients to consider pre-travel medical consults

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THANK YOU ALL!W I S H I N G Y O U A L L S A F E T R A V E L S !

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REFERENCESCDC: Choosing a drug to prevent malaria. (2012). Retrieved from http ://www.cdc.gov/malaria/travelers/drugs.html

CDC: Laboratory identification of parasites of public health concern (n.d.). Retrieved from http://www.cdc.gov/dpdx/resources/pdf/benchAids/malaria/Pfalciparum_benchaidV2.pdf

CDC: Malaria Facts (2015). Retrieved from http://www.cdc.gove/malaria/about/facts.html

http://www.cdc.gov/zika/geo/active-countries.html

Cullen, K. A., & Arguin, P. M. (2014). Malaria Surveillance — United States, 2012. MMWR Surveillance Summaries, 63(12), 1-22.

Das, S., Sarkar, N., Majumder, J., Chatterjee, K., & Aich, B. (2014). Acute disseminated encephalomyelitis in a child with Chikungunya virus infection. Journal Of Pediatric Infectious Diseases, 9(1), 37-41. doi:10.3233/JPI-140414

Hearn, P., & Johnston, V. (2014). Syndromic presentations: Assessment of returning travelers with fever. Medicine, 42(Tropical Infections), 66-72. doi:10.1016/j.mpmed.2013.11.009

HRNJAKOVIĆ CVJETKOVIĆ, I. B., CVJETKOVIĆ, D., PATIĆ, A., NIKOLIĆ, N., STEFAN MIKIĆ, S., & MILOŠEVIĆ, V. (2015). CHIKUNGUNYA -- ASERIOUS THREAT FOR PUBLIC HEALTH. Medicinski Pregled / Medical Review, 68(3/4), 122-125. doi:10.2298/MPNS1504122H

Hoover, E. (2016) College health may be full of surprises: International Travelers and Tropical Diseases. Clinician Reviews. 42-50.

Institute of International Education. (2013).Open Doors Report on International Educational Exchange. Retrieved from http://www.iie.org/opendoors

Joshi, H. A., & Shah, S. S. (2013). Platelet Count - A Diagnostic Aid in Fever. National Journal of Integrated Research in Medicine, 4(3), 128-132.

Leder, K., Torresi, J., Libman, M. D., Cramer, J. P., Castelli, F., Schlagenhauf, P., & ... Freedman, D. O. (2013). GeoSentinel Surveillance of Illness in Returned Travelers, 2007-2011. Annals of Internal Medicine, 158(6), 456-468.

Lindsey, N. P., Prince, H. E., Kosoy, O., Laven, J., Messenger, S., Staples, J. E., & Fischer, M. (2015). Chikungunya virus infections among travelers-United States, 2010-2013. The American Journal Of Tropical Medicine And Hygiene, 92(1), 82-87. doi:10.4269/ajtmh.14-0442

Mayxay, M., Phetsouvanh, R., Moore, C. E., Chansamouth, V., Vongsouvath, M., Sisouphone, S., & ... Newton, P. N. (2011). Predictive diagnostic value of the tourniquet test for the diagnosis of dengue infection in adults. Tropical Medicine & International Health, 16(1), 127-133. doi:10.1111/j.1365-3156.2010.02641.x

Nimmagadda, S. S., Mahabala, C., Boloor, A., Raghuram, P. M., & Akshatha, Nayak, U. (2014). Atypical manifestations of dengue fever (DF) - Where do we stand today? Journal of Clinical & Diagnostic Research, 8(1), 71-73.

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REFERENCES, CONTINUEDPalecek, D. (2012). UNWTO says int'l tourism to hit 1B in 2012. Travel Weekly, 71(4), 13

Petersen, E., Staples, E., Meaney-Delman, D., Fischer, M., Ellington, S., Callaghan, W., Jamieson, D. (2016). Interim guidelinesfor pregnant women during a zika virus outbreak- United States, 2016. Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report. Vol 65.

Piyaphanee, W., Steffen, R., Shlim, D. R., Gherardin, T., & Chatterjee, S. (2012). Travel medicine for Asian travelers--do we need new approaches?. Journal Of Travel Medicine, 19(6), 335-337. doi:10.1111/j.1708-8305.2012.00661.x

Rhodes, G., DeRomana, I., Ebner, J. (2014). Study abroad & other international student travel. Retrieved from http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-8-advising-travelers-with-specific-needs.aspx

Schwartz, K. L., Giga, A., & Boggild, A. K. (2014). Chikungunya fever in Canada: fever and polyarthritis in a returned traveller. CMAJ: Canadian Medical Association Journal = Journal De L'association Medicale Canadienne, 186(10), 772-774. doi:10.1503/cmaj.130680

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