Clinical Review & Education

JAMA OtolaryngologyHead & Neck Surgery | Review

Zika VirusWhat the Otolaryngologist Should Know

A Review
Demetri Arnaoutakis, MD; Tapan Padhya, MD
Invited Commentary
IMPORTANCE Initially discovered in 1947, Zika virus infection received little notoriety as a

tropical disease until 2015 when an outbreak of microcephaly cases was reported in Brazil.
Zika is a single-stranded RNA arbovirus of the Flaviviridae family. The primary source of
infection in humans stems from Aedes aegypti mosquito bites but can also occur through
sexual, blood, and perinatal transmission. With expectations that 3 to 4 million people across
the Americas will be infected over the next year, the World Health Organization has declared
this event a Public Health Emergency of International Concern.
OBSERVATIONS Although acute Zika virus infection is typically mild and self-limited,
researchers have demonstrated serious neurologic complications associated with it such as
microcephaly and Guillain-Barre syndrome. Otolaryngologists should be aware of head and
neck manifestations which include conjunctivitis, retro-orbital pain, cephalgia, and
odynophagia. The Centers for Disease Control and Prevention have developed specific
molecular and serologic testing protocols and algorithms for follow-up care of suspected
cases. Currently, the mainstay of management is conservative care while researchers attempt
to develop a vaccine. Strategies to contain the Zika virus include vector control, travel
restriction for women who are pregnant or trying to become pregnant, and avoidance of
mosquito bites in endemic regions of the world.
CONCLUSIONS AND REVELANCE The future outlook regarding the current Zika virus outbreak
in the Americas remains uncertain. What is certain is our need to promptly and efficiently
address research gaps in our understanding of clinical outcomes from infection and
environmental factors that influence emergence meanwhile improving diagnostic,
therapeutic, and preventive measures against the disease.
JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2016.3427
Published online November 17, 2016.

ika virus is a mosquito-borne flavivirus originally discovered in the Zika Forest of Uganda in 1947 and belonging to
the same viral genus as the dengue and West Nile viruses.1
The single-stranded RNA virus circulated predominantly in wild primates and arboreal mosquitoes confined to limited areas in Africa
and Asia, rarely leading to spillover infections in humans.2 It received little coverage until a significant series of microcephaly cases
born to infected pregnant women was reported during a 2015 outbreak in Brazil.3
In light of recent cases now appearing in Puerto Rico and Florida
caused by bites of local Aedes aegypti mosquitoes, Zika poses a serious public health issue in the United States with respect to infection control and prevention. We review here the pathogenesis of Zika
infection, the clinical course and diagnosis with particular insight provided to the otolaryngologist, and outline subsequent management and prevention tactics.
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Author Affiliations: Department of

OtolaryngologyHead and Neck
Surgery, University of Texas
Southwestern Medical Center, Dallas
(Arnaoutakis); Department of
OtolaryngologyHead and Neck
Surgery, University of South Florida
College of Medicine, Tampa (Padhya).
Corresponding Author: Demetri
Arnaoutakis, MD, Department of
OtolaryngologyHead and Neck
Surgery, University of Texas
Southwestern Medical Center, 5323
Harry Hines Blvd, Dallas, TX 753909035 (takis.demetri@gmail.com).

Pathogenesis
The primary source of Zika virus infection in humans comes from
bites of infected mosquitoes,4 although there have also been cases
of sexual,5 perinatal,6 and blood transfusion transmission.7 There
are 2 ways in which Zika virus can persist in a region: through continued transmission in animals with occasional crossover into humans or through sustained transmission in humans.8,9 The virus can
be detected in the blood for an average of 10 days after infection,
although nearly 99% of patients will clear the virus by 24 days. Antibodies become detectable about 9 days following infection.10 Duration of immunity against Zika remains unknown, yet evidence from
other flaviviruses suggests it can be lifelong.11
There is a possibility that immunological interaction with other
flaviviruses may facilitate the spread of Zika. In the dengue virus,

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Clinical Review & Education Review

Zika VirusWhat the Otolaryngologist Should Know

preexisting antibodies to 1 serotype can enhance subsequent infections with another serotype.12 This is known as antibody dependence enhancement, and several in vitro experiments have
demonstrated increased Zika virus replication in the presence of antibodies to other flaviviruses.13 Studies that measure preexisting dengue and Zika antibodies and track clinical outcomes may help illuminate this point of contention.

Clinical Presentation
Fortunately, the majority of Zika virus infections are asymptomatic.14
A suspected case is a person with a rash (maculopapular) and/or fever (37.8 to 38.5C) with at least 1 of the following symptoms (not
explained by other medical conditions): arthralgia, muscle pain arthritis, and/or headache. The otolaryngologist should also monitor
for head-specific and neck-specific manifestations such as conjunctivitis (nonpurulent/hyperemic), retro-orbital pain, cephalgia, and
odynophagia.15 Usually the viral illnesses are mild, lasting for several days to a week and have not been noted to cause hemorrhagic
fever or death.
Much of the concern surrounding the virus has focused on the
link between infection during pregnancy and microcephaly.16 In fact,
public health authorities in Brazil reported a 20-fold increase in the
incidence of newborn microcephaly, largely concurrent with Zika virus circulation in the northeastern area of the country.17 The primary etiological cause of microcephaly stems from mutations in a
number of well-defined microcephaly genes, which encode centrosomal proteins but can also ensue following in utero insults.18 No
other flavivirus is known to have these teratogenic effects.
Beyond microcephaly, there is emerging evidence that Zika
can lead to serious neurologic sequelae. Data from French Polynesia documented an epidemic of 42 cases of Guillain-Barre
syndrome.19 A case-control study performed not only confirmed
the link between Zika virus infection and Guillain-Barre syndrome,
but it also shed light on useful findings regarding clinical
characteristics.20 Most patients had electrophysiological findings
compatible with acute motor axonal neuropathy type of the syndrome and had rapid evolution of the disease. The clinical outcome
of these patients was generally favorable, despite a rapid onset and
short plateau phase, as can be seen in other patient groups suffering from the acute motor axonal neuropathy type of Guillain-Barre
syndrome.
The otolaryngologist should be aware there has been a case report of hearing loss associated with gestational Zika infection.21 A
newborn from a twin pregnancy in northeastern Brazil was delivered via caesarian section birth at the 37th week of gestation, and
the only apparent anomaly at birth was microcephaly. Transient otoacoustic emissions were absent. Frequency-specific auditory brainstem response with tone bursts was completed and confirmed bilateral profound hearing loss. Polymerase chain reaction (PCR)
testing for other TORCH infections (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus, and
herpes infections) was negative, as was other causes of microcephaly such as alcoholism and genetic disorders. Interestingly, the
other twin was complication free. There remains a lot to be learned
regarding the frequency and spectrum of associated conditions developed during pregnancy.
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Diagnosis
In the setting of a pure Zika epidemic, the diagnosis can reliably be
made on clinical terms. A suspected case should have relevant epidemiologic exposure (residence in or travel to an area where mosquito-borne transmission of Zika virus infection has been reported
or unprotected sexual contact with a person who meets these criteria), even though epidemiologic exposure is currently not included in the World Health Organization (WHO) categorization of a
suspected case. Clinicians should be vigilant in questioning suspected patients about recent travel to endemic areas.
However, the clinical picture can be confounded by other arboviruses (arthropod-borne viruses) such as dengue and chikungunya that have been epidemic in the Americas before. Specific tests
for these other viruses are not always available while a commercial
test for Zika has not yet been developed. A specific, easily administered antibody test would be extremely helpful to patient care and
surveillance. Such a test would enable researchers to estimate the
true incidence of Zika, confirm infection and test for immunity in
pregnant women.
Laboratory testing can confirm Zika virus infection. Molecular
(reverse transcription PCR) techniques are used to detect it in
serum, saliva, and urine.22 As mentioned previously, timing of
sample collection is critical because viral RNA is only detectable in
the serum for 3 to 5 days after symptom onset. Serologic detection of immunoglobulin M (IgM) antibodies and IgM-capture,
enzyme-linked immunosorbent assay (MAC-ELISA) can also be
performed. A probable case of Zika infection is suspected when
epidemiologic exposure exists and the IgM antibody against Zika
virus is positive. A case is confirmed either by detection of viral
RNA or antigen in serum or other samples or by detection of Zika
IgM antibody and a positive Zika virus plaque-reduction neutralization test (PRNT). A PRNT is necessary to find out if a positive
IgM antibody reflects a recent Zika infection or is a false-positive
result.
According to the Centers for Disease Control and Prevention, a
PRNT titer greater than 10 is evidence of infection with a specific flavivirus when the PRNT to the other flaviviruses tested is less than
10.23 This differs from the WHO criteria that requires testing for IgM
antibodies against Zika virus to be positive and PRNT titer greater
than or equal to 20 and PRNT titer ratio to be greater than or equal
to 4 compared with other flaviviruses.24 Congenital infection has
been observed with detection of viral RNA in placental tissue, amniotic fluid and fetal brain tissues, and anti-Zika virus IgM in the cerebrospinal fluid of neonates with microcephaly.25

Treatment & Prevention

No specific antiviral treatment is available for the Zika virus disease. The mainstay of management is supportive care and includes
bed rest, fluids, and use of analgesics. Owing to its similarity in geographic distribution and clinical presentation, patients with suspected Zika virus infection should also be evaluated for possible dengue fever. Aspirin and other nonsteroidal anti-inflammatory drugs
should be avoided until that delineation can be made to avoid the
risk of serious hemorrhage.

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Zika VirusWhat the Otolaryngologist Should Know

Review Clinical Review & Education

Pregnant women or those desiring to become pregnant should

avoid travel to Zika endemic areas. Because the virus can be transmitted through intercourse, clinicians should educate patients to use
sexual barriers such as condoms during vaginal, anal, and oral sex,
even if the infected sex partner remains asymptomatic. The Centers for Disease Control and Prevention have recently updated recommendations that men should consider using condoms or not having sex for at least 6 months after symptoms begin, and women
should consider using condoms or not having sex for at least 8 weeks
after symptoms begin.3
A vaccine would likely serve as the best method to protect an
at-risk population over the long term. Epidemics appear sporadically and unpredictably, leaving health care personnel with the same
moral dilemma as in the past. Preemptively vaccinating large populations in anticipation of outbreaks may be prohibitively expensive
and not cost-effective. Although there are at least 18 active research projects pursuing vaccine development, phase 1 clinical trials
are not expected to begin till the end of 2016.26 Thus, a vaccine is
unlikely to be offered in time to alter the course of the current outbreak in the Americas.
Without a vaccine, the best preventive measure for patients residing in areas infested with Aedes aegypti is to eliminate the places
ARTICLE INFORMATION
Accepted for Publication: September 6, 2016.
Published Online: November 17, 2016.
doi:10.1001/jamaoto.2016.3427
Author Contributions: Dr Arnaoutakis had full
access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: All Authors.
Acquisition, analysis, or interpretation of data:
Arnaoutakis.
Drafting of the manuscript: Arnaoutakis.
Critical revision of the manuscript for important
intellectual content: All Authors.
Administrative, technical, or material support:
Arnaoutakis.
Study supervision: All Authors.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.

where the mosquito lays eggs, primarily artificial containers that hold
water.27,28 Items that collect rainwater or store water should be covered. This action will eradicate the mosquito eggs and larvae and limit
the number of mosquitoes present in these areas.29 Using air conditioning or window and door screens can help reduce the risk of
mosquitoes entering indoors. Topical insect repellents and other personal protective measures do reduce mosquito biting and should
help curb the risk of Zika infection.30

Conclusions
The rise of Zika virus after decades of apparent little importance
underscores how little we truly know about the global spread of
vector borne diseases. Although the world community has impressively garnered and published epidemiologic and clinical information on Zika in a short period of time, therapeutic information significantly lags behind. Preventing epidemic disease mandates a
coordinated community effort to increase education and awareness about Zika, how to recognize its presentation, and how
to control the mosquito vector that is largely responsible for
transmitting it.

virusTexas, January 2016. MMWR Morb Mortal

Wkly Rep. 2016;65(14):372-374.
6. Besnard M, Lastere S, Teissier A, Cao-Lormeau V,
Musso D. Evidence of perinatal transmission of Zika
virus, French Polynesia, December 2013 and
February 2014. Euro Surveill. 2014;19(13):2075.
7. Musso D, Nhan T, Robin E, et al. Potential for Zika
virus transmission through blood transfusion
demonstrated during an outbreak in French
Polynesia, November 2013 to February 2014. Euro
Surveill. 2014;19(14):2076.

17. Pan American Health Organization.

Epidemiological update: neurological syndrome,
congenital anomalies, and Zika virus infection. http:
//www.paho.org/hq/index.php?option=com
_docman&task=doc_view&Itemid=270&gid
=32878&lang=en. Published January 17, 2016.
Accessed October 17, 2016.

8. Lloyd-Smith JO, George D, Pepin KM, et al.

Epidemic dynamics at the human-animal interface.
Science. 2009;326(5958):1362-1367.

18. Tang BL. Molecular genetic determinants of

human brain size. Biochem Biophys Res Commun.
2006;345(3):911-916.

9. Althouse BM, Hanley KA, Diallo M, et al. Impact

of climate and mosquito vector abundance on
sylvatic arbovirus circulation dynamics in Senegal.
Am J Trop Med Hyg. 2015;92(1):88-97.

19. Rapid risk assessment: Zika virus infection

outbreak, French Polynesia. Stockholm: European
Centre for Disease Prevention and Control,
February 14, 2014 (http://ecdc.europa.eu/en
/publications/Publications/Zika-virus-French
-Polynesia-rapid-risk-assessment.pdf)

REFERENCES

10. Lessler J, Ott CT, Carcelen AC, et al. Times to

key events in the course of Zika infection and their
implications for surveillance: a systematic review
and pooled analysis [published online March 2,
2016]. bioRxiv. doi:10.1101/041913

1. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I.

Isolations and serological specificity. Trans R Soc
Trop Med Hyg. 1952;46(5):509-520.

11. Murphy BR, Whitehead SS. Immune response to

dengue virus and prospects for a vaccine. Annu Rev
Immunol. 2011;29:587-619.

2. Pierson TC, Diamond MS. Flaviviruses. In: Knipe

DM, Howley PM, Cohen IC, et al, eds. Fields virology.
Vol 1. 6th ed. Philadelphia, Pennsylvania: Wolters
Kluwer; 2014:746-794.

12. Halstead SB. In vivo enhancement of dengue

virus infection in rhesus monkeys by passively
transferred antibody. J Infect Dis. 1979;140(4):527533.

3. U.S Centers for Disease Control and Prevention.

Zika Virus. http://www.cdc.gov/zika. Published
online February 26, 2016. Accessed October 17,
2016.

13. Paul LM, Carlin ER, Jenkins MM, et al. Dengue

virus antibodies enhance Zika virus infection
[published online April 25, 2016]. bioRxiv. doi:10
.1101/050112

4. Chan JF, Choi GK, Yip CC, Cheng VC, Yuen KY.
Zika fever and congenital Zika syndrome: An
unexpected emerging arboviral disease. J Infect.
2016;72(5):507-524.

14. Duffy MR, Chen TH, Hancock WT, et al. Zika

virus outbreak on Yap Island, Federated States of
Micronesia. N Engl J Med. 2009;360(24):2536-2543.

5. Deckard DT, Chung WM, Brooks JT, et al.

Male-to-male sexual transmission of Zika

jamaotolaryngology.com

16. Rasmussen SA, Jamieson DJ, Honein MA,

Petersen LR. Zika virus and birth defects-reviewing
the evidence of causality. N Engl J Med. 2016;374
(20):1981-1987.

15. Petersen LR, Jamieson DJ, Powers AM, Honein

MA. Zika Virus. N Engl J Med. 2016;374(16):1552-1563.

20. Cao-Lormeau VM, Blake A, Mons S, et al.

Guillain-Barr Syndrome outbreak associated with
Zika virus infection in French Polynesia:
a case-control study. Lancet. 2016;387(10027):
1531-1539.
21. Leal MC, Muniz LF, Caldas Neto SD, van der
Linden V, Ramos RC. Sensorineural hearing loss in a
case of congenital Zika virus. Braz J Otorhinolaryngol.
2016;S1808-8694(16)30127-6.
22. Musso D, Roche C, Nhan TX, Robin E, Teissier A,
Cao-Lormeau VM. Detection of Zika virus in saliva.
J Clin Virol. 2015;68:53-55.
23. Rabe IB, Staples JE, Villanueva J, et al; MTS.
Interim Guidance for Interpretation of Zika Virus
Antibody Test Results. MMWR Morb Mortal Wkly Rep.
2016;65(21):543-546.
24. World Health Organization. Emergencies
preparedness, response: Zika virus disease. http:
//www.who.int/csr/disease/zika/case-definition/en/
25. Cordeiro MT, Pena LJ, Brito CA, Gil LH, Marques
ET. Positive IgM for Zika virus in the cerebrospinal

(Reprinted) JAMA OtolaryngologyHead & Neck Surgery Published online November 17, 2016

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/ on 11/22/2016

E3

Clinical Review & Education Review

Zika VirusWhat the Otolaryngologist Should Know

fluid of 30 neonates with microcephaly in Brazil.

Lancet. 2016;387(10030):1811-1812.
26. World Health Organization. Current Zika
Product Pipeline. http://who.int/csr/research-and
-development/zika-rd-pipeline.pdf. Accessed
October 17, 2016.
27. PanAmerican Health Organization. Dengue and
dengue haemorrhagic fever in the Americas:

E4

guidelines for prevention and control. Washington,

DC: WHO/PAHO; 1994. (Scientific publication; no.
548).
28. Halstead SB. Selective primary health care:
strategies for control of disease in the developing
world. XI. Dengue. Rev Infect Dis. 1984;6(2):251-264.

Geneva, Switzerland: WHO; 1982. (Offset

publication; no.66).
30. Fradin MS, Day JF. Comparative efficacy of
insect repellents against mosquito bites. N Engl J Med.
2002;347(1):13-18.

29. World Health Organization. Manual on

environmental management of mosquito central.

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