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Zika Virus Outbreak on Yap Island, Federated States of Micronesia

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In 2007, physicians on Yap Island reported an outbreak of illness characterized by rash, conjunctivitis, and arthralgia. Although serum from some patients had IgM antibody against dengue virus, the illness seemed clinically distinct from previously detected dengue. Subsequent testing with the use of consensus primers detected Zika virus RNA in the serum of the patients but no dengue virus or other arboviral RNA. No previous outbreaks and only 14 cases of Zika virus disease have been previously documented. We obtained serum samples from patients and interviewed patients for information on clinical signs and symptoms. Zika virus disease was confirmed by a finding of Zika virus RNA or a specific neutralizing antibody response to Zika virus in the serum. Patients with IgM antibody against Zika virus who had a potentially cross-reactive neutralizing-antibody response were classified as having probable Zika virus disease. We conducted a household survey to estimate the proportion of Yap residents with IgM antibody against Zika virus and to identify possible mosquito vectors of Zika virus. We identified 49 confirmed and 59 probable cases of Zika virus disease. The patients resided in 9 of the 10 municipalities on Yap. Rash, fever, arthralgia, and conjunctivitis were common symptoms. No hospitalizations, hemorrhagic manifestations, or deaths due to Zika virus were reported. We estimated that 73% (95% confidence interval, 68 to 77) of Yap residents 3 years of age or older had been recently infected with Zika virus. Aedes hensilli was the predominant mosquito species identified. This outbreak of Zika virus illness in Micronesia represents transmission of Zika virus outside Africa and Asia. Although most patients had mild illness, clinicians and public health officials should be aware of the risk of further expansion of Zika virus transmission.
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original article
The
new england journal
of
me dicine
n engl j med 360;24 nejm.org june 11, 2009
2536
Zika Virus Outbreak on Yap Island,
Federated States of Micronesia
Mark R. Duffy, D.V.M., M.P.H., Tai-Ho Chen, M.D.,
W. Thane Hancock, M.D., M.P.H., Ann M. Powers, Ph.D.,
Jacob L. Kool, M.D., Ph.D., Robert S. Lanciotti, Ph.D., Moses Pretrick, B.S.,
Maria Marfel, B.S., Stacey Holzbauer, D.V.M., M.P.H.,
Christine Dubray, M.D., M.P.H., Laurent Guillaumot, M.S., Anne Griggs, M.P.H.,
Martin Bel, M.D., Amy J. Lambert, M.S., Janeen Laven, B.S., Olga Kosoy, M.S.,
Amanda Panella, M.P.H., Brad J. Biggerstaff, Ph.D., Marc Fischer, M.D., M.P.H.,
and Edward B. Hayes, M.D.
From the Division of Vector-Borne Infec-
tious Diseases, National Center for Zoo -
notic, Vector-Borne, and Enteric Diseases,
Centers for Disease Control and Preven-
tion (CDC ), Fort Collins, CO (M.R.D.,
A.M.P., R.S.L., A.G., A.J.L ., J.L., O.K., A.P.,
B.J.B., M.F., E.B.H.); the Epidemic Intelli-
gence Service Field Assignments Branch,
CDC, Atlanta (T.-H.C., S.H., C.D.); the
Wa’ab Community Health Center (W.T.H.,
M.B.) and the Yap State Department of
Health Service (M.M.) — both in Yap,
Federated States of Micronesia; the Of-
fice for the South Pacific, World Health
Organization, Suva, Fiji ( J.L.K.); the De-
partment of Health, Education, and So-
cial Affairs, Pohnpei, Federated States of
Micronesia (M.P.); and the Pasteur Insti-
tute, Noumea, New Caledonia (L.G.). Ad-
dress reprint requests to Dr. Fischer at
the Arboviral Diseases Branch, Division
of Vector-Borne Infectious Diseases, Cen-
ters for Disease Control and Prevention,
315 0 Ram par t Rd ., Fo rt C olli ns, CO 80 521 ,
or at mfischer@cdc.gov.
N Engl J Med 2009;360:2536-43.
Copyright © 2009 Massachusetts Medical Society.
ABSTR ACT
Bac kgro und
In 2007, physicians on Yap Island reported an outbreak of illness characterized by
rash, conjunctivitis, and arthralgia. Although serum from some patients had IgM
antibody against dengue virus, the illness seemed clinically distinct from previously
detected dengue. Subsequent testing with the use of consensus primers detected
Zika virus R NA i n t he serum of the patients but no dengue vir us or other a rboviral
RNA. No previous outbreaks and on ly 14 cases of Zika vi rus disease h ave been previ-
ously documented.
Methods
We ob t ai ned s e r um sa mples from pat ients a nd i nt e r vie wed pat i e nt s f or i n f o r m ation
on clinical signs and symptoms. Zika virus disease was confirmed by a finding of
Zika virus RNA or a specific neutralizing antibody response to Zika virus in the se-
rum. Patients with IgM antibody against Zika virus who had a potentially cross-reac-
tive neutralizing-antibody response were classif ied as having probable Zika virus
dise ase . We con ducted a house hold sur vey t o e st i m a t e t he pro port ion of Yap r esid e n t s
with IgM antibody against Zika virus and to identify possible mosquito vectors of
Zika virus.
Re sult s
We ident i f ied 49 conf irmed and 59 probable c ases of Zika vi rus disease. The patients
re s ided i n 9 o f t he 10 municip a lit ies on Yap. R a sh, f e ver, art h r alg ia, and c onjunc tiv it is
were common symptoms. No hospitalizations, hemorrhagic manifestations, or deaths
due to Zika virus were reported. We estimated that 73% (95% conf idence interval,
68 to 77) of Yap residents 3 years of age or older had been recently infected with Zika
virus. Aedes hensilli was the predominant mosquito species ident ified.
Conclusions
This outbreak of Zika virus illness in Micronesia represents transmission of Zika
virus outside Africa and Asia. Although most patients had mild illness, clinicians
and public hea lt h off icials should be awa re of the risk of fur ther expansion of Zi ka
virus transmission.
The New England Journal of Medicine
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Zika Virus Outbreak on Yap Island
n engl j med 360;24 nejm.org june 11, 2009
2537
Z
ika virus is a flavivirus (family Flavi-
viridae) related to West Nile, dengue, and
ye llow fever vir uses.
1
Zika vi r us was isol at ed
in 1947 from a rhesus monkey in the Zika forest
near Entebbe, Uganda
2
; it s ge nome w as s equ en ce d
in 2006.
3
There is serologic evidence of human
Zika virus infection in Africa and Asia, and the
virus has been isolated from hu mans in Uganda,
Nigeri a, and Senegal.
2-12
Zika virus is believed to
be transmitted to hu mans by in fected mosquitoe s
and has been isolated from Aedes africanus, Aedes
luteocephalus, and Aede s aegypti.
13-16
No outbreaks
and only 14 cases of human Zika virus disease
have been previously documented.
2,12,17-19
Unti l
this outbreak, no transmission of Zika virus had
been reported outside of Africa and Asia.
In April and May 2007, physicians on Yap Is-
land, Federated States of Micronesia, noted an
outbreak of illness characterized by rash, conjunc-
tivitis, subjective fever, arthralgia, and arthritis.
Although t hree pat ients tested positive wit h a c om-
mercially available dengue IgM kit, the physicians
had the impression that this illness was clinically
distinct from dengue, which had been detected on
Yap in two previous outbreaks.
20,21
In June 2007,
serum from acutely ill patients was sent to the
Centers for Disease Control and Prevention (CDC)
Arbovirus Diagnostic and Reference Laboratory
in Fort Collins, Colorado. Ten of 71 samples (14%)
were found to contain Zika virus RNA according
to reverse-transcriptase–polymerase-chain-reaction
(RT-PCR) assay. RT-PCR assays with the use of
consen sus pr imers for nucleic acid of other a rbo-
viruses, including dengue, chikungunya, o’nyong-
nyong, Ross River, Barmah Forest, and Sindbis
viruses, were all negative. We conducted an inves-
tigation to define the epidemiologic features of t he
outbreak and to describe the clinical manifesta-
tions of Zika virus disease.
Methods
Set ting
The Federated States of Micronesia is an archi-
pelago nation located northeast of Papua New
Guinea. Yap State is the westernmost of the four
states of the country and comprises four closely
groupe d isl a nds a nd se veral o uter isla nds. This i n -
vestigation was conducted on the main group of
four islands, here referred to as Yap. Yap is approx-
imately 6 km wide by 15 km long with a popula-
tion of 7391 persons (2000 census data).
Ca se De finitio n and Find ing
We reviewe d med i c a l records a nd conducted pro-
spective surveillance at the hospital and all four
he alt h cent ers on Yap t o identi f y pat ient s wit h su s-
pected Zika virus dise ase dur ing t he period from
April 1 t hrough July 31, 2007. A patient with sus-
pected disease had acute onset of general ized m ac-
ul ar or papular rash, arthritis or a rthralgia, or no n-
purulent conjunctivitis. Patients with suspected
disease were asked to provide blood specimens
during the acute phase (i.e., within 10 days after
the onset of symptoms) and dur ing t he convales-
cent phase (i.e., 14 days later). We interviewed a
convenience sa mple of these pat ients w it h the use
of a st andard questionnaire to collect information
about demographic features, clinical signs and
symptoms, and the duration and severity of the
illness.
Labor atory Analysis and Case Cl assification
Serum samples were tested by enzyme-linked im-
munosorbent assay (ELISA) for IgM antibodies
against Zika virus and dengue virus.
22,23
Titers of
neutralizing antibody to Zika virus and dengue
virus were determined with the use of plaque-
reduction neutralizat ion tests with a cutoff value
of 90% ( PRNT
90
).
24
Serum sample s f rom patients
in the ac u t e phase we r e t e st e d by RT-PCR f or Zika
vir us and dengue virus RNA.
22,25
We considered a patient to have confirmed Zika
virus disease if Zika virus RNA was detected in
the serum or if all the following f indings were
present: IgM antibody against Zika virus (detected
by ELISA), Zika virus PRNT
90
titer of at least 20,
and a ratio of Zika virus PRNT
90
titer to dengue
virus PRNT
90
titer of at least 4. A patient was cl as-
sif ied as h aving probable Zi ka v i r us d ise ase if IgM
antibody against Zika virus was detected by ELISA,
Zika virus PRNT
90
titer was at least 20, the ratio of
Zika virus PRNT
90
titer to dengue virus PRNT
90
titer was less than 4, and either no Zika virus
RNA was detected by RT-PCR or the serum sam-
ple was inadequate for the performance of RT-PCR
(Fig. 1).
Household Survey
We surveyed the community to define the extent
of the outbreak and determine risk factors for in-
fection. We used simple, random, one-stage cluster
sampling to select 200 (16%) of the 1276 house-
holds on Yap, and we sought to enroll all house-
hold members 3 years of age or older. We used a
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The
new england journal
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n engl j med 360;24 nejm.org june 11, 2009
2538
standard questionnaire to collect dat a from con-
senting household residents regarding age, sex,
bir t hpl ace, pot ential r i sk f actor s for infec t ion, and
il lness since Apr il 1, 2007. We obt ained blood sam-
ples from all eligible consenting household resi-
dents. Participants in whom IgM antibody against
Zika vi r us was detect e d by ELISA we re c onsi d e r e d
to have evidence of recent Zika virus infection.
Entomologic Investigation
Wat er-h oldi ng cont ai ner s and c ont ai ners w it h mo s-
qu i t o l a r vae or pup ae we r e count ed a t t he sur veyed
house holds. L a r vae and pupae we re co l lecte d a nd
identified. Adult mosquitoes were collected by light
traps, gravid traps, and aspiration at representa-
tive point s on Yap and were t h en pooled accor d i n g
to species, trap location, and collect ion date.
26,27
Pools of immature and mature mosquitoes were
tested by viral culture and by RT-PCR for Zika vi-
rus RNA for evidence of infection.
Statistical Analysis
The attack rates of Zika virus infection were cal-
culated with the use of 2000 census data for the
Federated States of Micronesia. Sur vey and surveil-
lance data were analyzed with t he use of SPSS soft-
ware, version 12.0, and S-Plus sof t ware, version 8.
For descriptive results, categorical variables were
gi ven as proport ion s and cont inuous variables were
described by the mean or the median and range.
For population inferences from the household
survey, standard errors, conf idence intervals, and
P values were calculated with the sampling design
taken into account and with the use of a finite
population correction.
28
Categorical variables f rom
the household sur vey were compared with the use
of the Rao and Scott correction to the chi-square
test. Standard calibration-weighted estimators were
used to adjust for nonresponse to the household
survey by calibrat ion to the Yap 2000 census popu-
lation according to 10-year age groups and sex for
the eligible population.
29
Inferences for the ento-
mologic survey were based on a simple random
sample of households, and the score confidence
interval was used for population binomial pro-
portions.
Results
Ca se Finding
We identif ied 185 cases of suspected Zika virus
disease. Of these, 49 (26%) were confirmed and
59 (32 %) were pr obable c a ses ( Fig. 1). Acute-phase
ser u m sample s wer e col lected w it hin 10 day s af t e r
the onset of illness f r om 45 of t he 49 pa t ients wit h
conf irmed dis ease (92%), and Zika virus R NA w as
de tect e d i n 15 of these 45 p at ient s (33%). No den-
gue virus RNA was detected in any of the 137 acute-
phase serum samples tested (45 of these 137 pa-
tients had confirmed Zika virus disease, 51 had
probable disease, and 41 had suspected disease).
The date of symptom onset among patients
39p6
185 Patients sought health care and met the case
definition for suspected Zika virus disease
Presence of Zika virus RNA
or
presence of IgM antibody against
Zika virus and Zika virus
PRNT90 ≥20 and Zika virus
PRNT90 : dengue virus PRNT90
ratio ≥4
No serologic or PCR evidence
of Zika virus infection
with
serum sample collected ≥10 days
after symptom onset
49 Had confirmed Zika
virus disease 5 Did not have Zika virus disease
Absence of Zika virus RNA
and
presence of IgM antibody against
Zika virus and Zika virus
PRNT90 ≥20 and Zika virus
PRNT90 : dengue virus PRNT90
ratio <4
59 Had probable Zika
virus disease
No serologic or PCR evidence
of Zika virus infection
and
no serum sample collected
≥10 days after symptom onset
72 Had suspected Zika
virus disease
AUTHOR:
FIGURE:
JOB: ISSUE:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Duffy (Fischer)
1 of 4
06-11-09
ARTIST: ts
36024
Figure 1. Case Classification of 185 Patients Who Sought Health Care and Met the Case Definition for Suspected Zika Virus Disease
on Yap during the Period from April through July 2007.
The presence of Zika virus RNA was determined by reverse -transcriptase–polymerase-chain-reaction (RT-PCR) assay. PRNT
90
denotes
plaque-reduction neutralization test with a cutoff value of 90%.
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Zika Virus Outbreak on Yap Island
n engl j med 360;24 nejm.org june 11, 2009
2539
wit h conf irmed or probable disease ranged from
April 15 to July 14 (Fig. 2). The number of cases
peaked in late May and subsided in early July. The
median age of patients with confirmed or probable
disease was 36 years (range, 1 to 76); 66 of these
patients (61%) were female.
The overall attack rate for conf irmed and prob-
able Zika virus disease detected among patients
presenting to health care facilities was 14.6 per
1000 Yap residents. The at t ack rates ra nged from
3.6 per 1000 population in both the Kanifay and
the Gilman municipalit ies to 21.5 per 1000 popu-
lation in Tomil municipality (Fig. 3). The sex-spe-
cif ic attack rates were 17.9 per 1000 females and
11.4 per 10 00 m ales. Cases occu rred among all a ge
groups, but the incidence of confirmed and prob-
able Zika virus disease detected by health care
sur vei llance was highest among persons 55 to 59
years of age (Fig. 4).
Of 49 patients with confirmed Zika virus dis-
ease, 31 (63%) provided information regarding
symptoms and exposures. The age and sex distri-
butions of these 31 patients were similar to those
of the remaining 18 patients with confirmed dis-
ease. The most commonly reported symptoms
were rash, fever (measured or repor ted), arthrit is
or arthralgia, and conjunctivitis (
Table 1
). Other
symptoms included myalgia, headache, retro-
orbital pain, edema, and vom iting. Twent y pat ient s
(65%) reported a subjective fever; the body tem-
perature of 12 of t hese pat ients was measured by
a health care provider, and none of the recorded
temperatures were above 37.9°C. The median du-
ration of rash was 6 days (range, 2 to 14), and
that of a r t h ralg ia was 3.5 d ays (range, 1 to 14). No
deaths, hospitalizations, or hemorrhagic compli-
cations were associated with Zika virus illness
during t h is out bre a k. None of t he 31 pat ients who
reported symptoms had traveled outside of Yap
within 2 weeks before the onset of symptoms.
Household Survey
Surveys were completed in 173 of 200 randomly
se lected house hol ds (86%). The 173 enrolled hous e-
holds had 852 residents, and t he med ian number
of re sident s per household wa s 5 (ra nge, 1 t o 18).
Forty-four residents were under 3 years of age and
therefore were not eligible to participate in the
su r ve y.
We obtained blood samples from 557 of the
808 eligible residents (69%). The age and sex dis-
tributions of the participants differed signif icant ly
from those of the eligible Yap population record-
ed in the 2000 census (P<0.001). Children from
3 through 9 years of age were underrepresented,
and adults 40 years of age or older were overrep-
resented in the survey in comparison with the
census population. Overall, males were underrep-
resented and females were overrepresented, al-
though the ratio of male to female participants
varied according to age group.
Among t he 557 household residents who pro-
vided blood samples, 414 (74%) had IgM antibody
against Zika virus, and 156 of these 414 persons
(38%) reported an illness during the outbreak pe-
riod that met the def inition of suspected Zi ka v i r us
disease. However, among the 143 participants who
provided blood samples and had no detectable
IgM antibody against Zika virus, 27 (19%) also
reported an illness that met the definition for sus-
pected Zika virus disease. Thus, among the survey
participants who were positive for IgM antibody
against Zika virus, a total of 19% (38% 19%) re-
ported a clinical illness that was probably attrib-
utable to Zika virus infection.
We used the household survey data to calculate
population estimates after accounting for sam-
pling design and nonresponse; these population
estimates differ slightly from the crude survey re-
sults. We estimated that 5005 of the 6892 Yap
residents who were 3 years of age or older (95%
confidence interval [CI], 4702 to 5308) were in-
fected with Zika virus during the outbreak, an
infection rate of 73% (95% CI, 68 to 77). An esti-
mated 919 residents (95% CI, 480 to 1357), or 18%
22p3
Week of Onset of Illness
No. of Cases
30
35
25
20
10
5
15
0
April 1
April 8
April 15
April 22
April 29
May 6
May 13
May 20
May 27
June 3
June 10
June 17
June 24
July 1
July 8
July 15
July 22
July 29
AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
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Please check carefully.
REG F
Enon
1st
2nd
3rd
Duffy (Fischer)
2 of 4
06-11-09
ARTIST: ts
36024 ISSUE:
Probable cases (N=59) Confirmed cases (N=49)
Figure 2. Confirmed and Probable Cases of Zika Virus Disease on Yap
among Persons Seeking Health Care, According to Week of Onset of Illness
during the Period from April through July 2007.
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of t hose infected (95% CI, 10 to 27), had a clin ical
illness that was probably attributable to Zika vi-
rus. Therefore, the estimated ratio of the number
of residents with illness attributable to Zika virus
to the number of residents who were eit her asy mp-
tomatic or who had illness that could not be at-
tributed to Zika virus was 919:4086, or 1:4.4 (95%
CI, 1:4.3 to 1:4.6).
Male participants were more likely than female
participants to have IgM antibody against Zika
virus (77% [95% CI, 72 to 83] vs. 68% [95% CI,
62 to 74]; relative risk, 1.1 [95% CI, 1.0 to 1.2]).
The seroprevalence of IgM antibody against Zika
virus did not vary significantly across age groups
(P = 0.10). We found no behavioral or environmen-
tal risk factors for Zika virus infect ion. People who
reported an i llness consistent wit h suspected Zika
virus infection were significantly more likely to
have IgM antibody against Zika virus than those
who did not report such illness (P<0.001).
Entomologic Investigation
Of the 1366 water-holding containers identified
during the household survey, 587 (43% [95% CI,
40 to 46]) were infested with mosquito larvae or
pupae; infested containers were found at 148 of
the 170 household s surveye d (87% [95% CI, 81 to
91]). A total of 12 mosquito species belong ing to
four genera were identified; 9 species were iden-
tif ied by examination of larvae, and an additional
3 species were collected as adults. Aedes hensilli
was the predominant species identified and was
present in 489 of the water-holding containers
(36% [95% CI, 33 to 38]). No other species was
present in more than 3% of the containers. No
virus or viral nucleic acid could be detected in
any mosquito pool.
Discussion
In this Zika virus outbreak, approximately three
quar ters of Yap resident s were infected w ith Zi ka
virus, and we est imated that more than 900 peo-
ple had i l lness at t r ibut able t o Zika virus in fect ion.
Zika virus infection was widespread across all geo-
graphic areas of Yap and caused relatively mild
il l ness last i ng several d ays. There were no de aths
or hospitalizations attributed to Zika virus. We
were unable to detect Zika virus in any mosquito
sa m p l e s, a n d t here f ore we c an not d e te r mi ne w it h
ce r t ai nt y t he vector o f t r a n s m i ssio n. On t he b a sis
of the relative abundance of Aedes hensilli and pre-
vious evidence that this species was the most
likely vector of dengue virus transmission on
Yap, it is plausible that Aedes hensilli was a vector
of Zika virus transmission in t his outbreak.
21
The clinical signs and symptoms of Zika virus
infection were consistent with those described in
a previous report of one male patient but differ-
ent from those described in a previous case se-
ries.
2,20
In that case series, rash or conjunctivitis
was not reported and ar t h ralgia was noted in only
one of seven patients. Fever was reported in all
seven pat ients, but the study included only pat ients
who were hospitalized with febrile illness.
19
The detection of Zika virus R NA in the serum
of acutely ill patients and the absence of nucleic
acid of other arboviruses provide convincing evi-
dence t hat the outbreak was caused by Zika virus.
Although the transmission of dengue virus is com-
mon in Micronesia, none of the 137 patients for
whom acute-phase specimens were available had
evidence of dengue virus RNA in their serum.
21,22
Figure 3. Attack Rates for Conf irmed and Probable Zika Virus Disease
per 1000 Population According to Municipality on Yap during the Period
from April through July 2007.
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Zika Virus Outbreak on Yap Island
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2541
All 108 patients with confirmed or probable Zika
virus disease had IgM antibody against Zika virus
and neutralizing antibodies. ELISA for IgM is a
relatively sensit ive and specif ic assay for detecting
arboviral infections.
23
Although the ELISA for IgM
antibody against Zika virus may cross-react with
IgM against other f laviviruses, such as dengue vi-
rus or yellow fever virus, it is not likely to cross-
react with IgM against alphaviruses such as chi-
kungunya or Ross River viruses. PRNTs effectively
discriminate among different primary flavivirus
infections, but patients who have secondary infec-
tions (those who have been previously vacci nated
against or exposed to another flavivirus) may have
indeterminate PRNT results.
30,31
The patients with
confirmed Zika virus disease had titers of neu-
tralizing antibodies against Zika virus that were
at least four times as high as their titers of neu-
tralizing antibodies against dengue virus, a f ind-
ing that provides strong evidence of primar y Zika
virus infection. The patients with probable Zika
virus disease also had neutralizing antibodies
against Zika virus, but the titers were less than
four times as high as the titers of neutralizing
antibodies against dengue virus. Although the re-
sults from these patients do not def initively con-
firm Zika virus infect ion, they are consistent with
Zika virus infection after a previous dengue virus
infection.
The at t ack rates of Zika vir us disease detected
by surveillance were higher among females than
males and among older persons than younger per-
sons. I n cont rast, t he pre valenc e of Ig M ant ibo dy
against Zika virus detected by the survey was
higher in male participants (perhaps because of
the possibility of their greater exposure to mos-
qu itoes) and was r elativel y even ly d istribu t ed across
age groups. These discrepancies may be because
of differences in healt h care–seeking behavior for
this relatively mild illness. The estimated ratio of
symptomatic to asymptomatic patients with Zika
virus infection in this outbreak is similar to that
described for West Nile virus infection.
32,33
We think it unlikely that Zika virus circulated
unrecognized on Yap before this outbreak. The
compact clustering of cases in May and June and
the high seroprevalence of IgM antibody against
Zika virus are consistent with an acute outbreak
of Zika virus illness in a populat ion wit hout pre vi-
ous immunity to Zika virus. Although precise est i-
mates of the persistence of IgM antibody against
Zika virus are not available, IgM antibodies to
dengue virus generally do not persist longer t han
90 days.
33
IgM antibodies to West Nile virus typi-
cally persist for about 5 months.
34-36
There were
no reports of widespread disease outbreaks on Yap
in t he 2 years before this outbreak. These results
support the conclusion that t h is outbreak resulted
from a recent introduction of Zika virus.
Zika virus might have been introduced to Yap
by a viremic nonhuman primate (monkeys live on
nearby Palau but not on Yap), but there were no
reports of any importation or recent arrival of non-
human primates. No other nonprimate vertebrates
or birds a re k nown t o be re ser voirs of Zik a vi r us;
unless ev idence of such a reservoir is discovered,
introduction of Zika virus through an infected
22p3
Attack Rate (per 1000 population)
50
60
40
30
10
20
0
0–4
5–9
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
≥60
AUTHOR:
FIGURE:
JOB:
4-C
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RETAKE
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ICM
CASE
EMail Line
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AUTHOR, PLEASE NOTE:
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Please check carefully.
REG F
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1st
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3rd
Duffy (Fischer)
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ARTIST: ts
36024 ISSUE:
Age (yr)
Probable cases (N=59) Confirmed cases (N=49)
Figure 4. Attack Rates for Conf irmed and Probable Zika Virus Disease
on Yap According to Age Group during the Period from April through
July 2007.
Table 1. Clinical Characteristics of 31 Patients with Confirmed Zika Virus
Disease on Yap Island during the Period from April through July 2007.
Sign or Symptom No. of Patients (%)
Macular or papular rash 28 (90)
Fever* 20 (65)
Arthritis or arthralgia 20 (65)
Nonpurulent conjunctivitis 17 (55)
Myalgia 15 (48)
Headache 14 (45)
Retro-orbital pain 12 (39)
Edema 6 (19)
Vomiting 3 (10)
* Cases of measured and subjective fever are included.
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2542
nonprimate vertebrate seems unlikely. It is more
likely that Zika virus was introduced by an in-
fected mosquito or a viremic human. We did not
find any recently ill residents who had traveled
outside of Yap, but the virus could have been im-
ported by a person with undetected infection. Se-
rolo g ic e v idence of Zi k a virus i n fection in humans
has been reported in the Philippines, and travel
between Yap and the Philippines is common.
The accessibi lit y of ai r travel and the abund a nce
of mosquito vectors of f lavivirus in the Pacif ic re-
gion raise concern for the spread of Zika virus to
other islands in Oceania and even to the Americ as.
The pot ent i a l for such spread i s illust rate d by the
following anecdote. A medical volunteer visited
Yap from June 17 to June 29, 2007, and had onset
of symptoms meeting the case definition of sus-
pected Zika virus disease on July 7, 2007, after her
ret urn to the United States. She had IgM antibody
against Zika virus and neutralizing antibody in
her serum on July 20, indicating she had been in-
fected with Zika virus on Yap and was probably
viremic after arrival in the United States. The
emergence of Zika virus as an important human
pathogen on Yap in 2007 underscores the ease
with which exotic pathogens are transported be-
tween continents and the need for clinical vigi-
lance and strong epidemiologic and laboratory
surveillance systems to detect the spread of infec-
tious diseases.
No potential conflict of interest rele vant to t his article was
reported.
The views e xpressed are those of t he aut hors and do not nec-
essar ily represent the views of the Department of Health and
Human Services.
We t hank the physicians and st af f at t he Wa’ab Communit y
Health Centers, t he Yap State Depa rtment of Healt h Ser vice, the
Federated States of Micronesi a Depar tment of Health, Education,
and Social Affairs, the CDC Arbovira l Diseases Branch Diagnostic
and Reference Laborat ory, and the CDC Global Disease Det ection
Program for thei r support and assistance wit h this investigation.
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... Studies indicate that the majority of individuals infected with ZIKV can be asymptomatic or have mild symptoms, making clinical diagnosis difficult with low sensitivity. In addition, the symptoms can be confounded by other febrile diseases and allergic reactions [7][8][9][10][11] . ...
... In 2014, during the outbreak in French Polynesia, 11.5% of the population sought treatment for symptoms suggestive of ZIKV fever, of the 741 samples sent for PCR analysis, 51% were positive. On Yap Island, Micronesia, in 2017, a population-based study with home visits estimated that a ZIKV outbreak may have affected approximately 75% of the population, but only 19% were symptomatic [8] . Flamand et al. [16] , when studying pregnant women in French Guiana, observed that only 17%-35% were symptomatic, depending on the region studied. ...
Article
Full-text available
Objective: Prenatal infection with the Zika virus (ZIKV) can lead to congenital Zika syndrome (CZS), characterized by microcephaly and brain injury. However, there are questions regarding the prevalence of microcephaly/CZS after the ZIKV outbreak in defined geographic areas. This study aimed to identify adverse outcomes in live births of fetuses exposed in utero to the ZIKV, compared to unexposed births, as well as maternal sociodemographic, delivery, and birth characteristics. Methods: Here, we conducted a cross-sectional observational study to investigate the characteristics of all live births in the city of Tangará da Serra, Mato Grosso, Brazil, in 2016, after the outbreak of ZIKV infection in late 2015. All live births of children to women residing in the municipality of Tangará da Serra between January 1 and December 31, 2016, were evaluated, and head circumference was measured at birth and after 24 hours. Children born with microcephaly or a maternal history of confirmed or suspected prenatal ZIKV infection were evaluated by a multidisciplinary team. The outcomes of the exposed and non-exposed children were compared. Prevalence ratios and their respective 95% confidence intervals were calculated for sociodemographic, delivery, and live birth characteristics. Results: Of 1,441 live births, 106 (7.3%) were from mothers with confirmed or highly probable exposure to ZIKV. The prevalence of severe congenital microcephaly (41.7/10,000) in Tangará da Serra in 2016 was tenfold higher than that in Latin America before 2015. Conclusion: This study may serve as a model to investigate possible outbreaks of infections in a defined geographical space in the future.
... Studies indicate that the majority of individuals infected with ZIKV can be asymptomatic or have mild symptoms, making clinical diagnosis difficult with low sensitivity. In addition, the symptoms can be confounded by other febrile diseases and allergic reactions [7][8][9][10][11] . ...
... In 2014, during the outbreak in French Polynesia, 11.5% of the population sought treatment for symptoms suggestive of ZIKV fever, of the 741 samples sent for PCR analysis, 51% were positive. On Yap Island, Micronesia, in 2017, a population-based study with home visits estimated that a ZIKV outbreak may have affected approximately 75% of the population, but only 19% were symptomatic [8] . Flamand et al. [16] , when studying pregnant women in French Guiana, observed that only 17%-35% were symptomatic, depending on the region studied. ...
Article
Full-text available
Objective: Prenatal infection with the Zika virus (ZIKV) can lead to congenital Zika syndrome (CZS), characterized by microcephaly and brain injury. However, there are questions regarding the prevalence of microcephaly/CZS after the ZIKV outbreak in defined geographic areas. This study aimed to identify adverse outcomes in live births of fetuses exposed in utero to the ZIKV, compared to unexposed births, as well as maternal sociodemographic, delivery, and birth characteristics. Methods: Here, we conducted a cross-sectional observational study to investigate the characteristics of all live births in the city of Tangará da Serra, Mato Grosso, Brazil, in 2016, after the outbreak of ZIKV infection in late 2015. All live births of children to women residing in the municipality of Tangará da Serra between January 1 and December 31, 2016, were evaluated, and head circumference was measured at birth and after 24 hours. Children born with microcephaly or a maternal history of confirmed or suspected prenatal ZIKV infection were evaluated by a multidisciplinary team. The outcomes of the exposed and non-exposed children were compared. Prevalence ratios and their respective 95% confidence intervals were calculated for sociodemographic, delivery, and live birth characteristics. Results: Of 1,441 live births, 106 (7.3%) were from mothers with confirmed or highly probable exposure to ZIKV. The prevalence of severe congenital microcephaly (41.7/10,000) in Tangará da Serra in 2016 was tenfold higher than that in Latin America before 2015. Conclusion: This study may serve as a model to investigate possible outbreaks of infections in a defined geographical space in the future.
... The first human case of ZIKV was reported in 1952 and thereafter, for several decades, sporadic cases of mild illness were reported from Africa and Asia. First major outbreaks were reported from Yap (Micronesia) in 2007and French Polynesia (2013-2014 (Moore et al., 1975;Duffy et al., 2009;Musso et al., 2018). The clinical spectrum of ZVD usually consists of mild illness including fever, myalgia, headache, rash, arthritis, and conjunctival congestion with up to 4/5th of the infected individuals being asymptomatic (Duffy et al., 2009;Calvet et al., 2016). ...
... First major outbreaks were reported from Yap (Micronesia) in 2007and French Polynesia (2013-2014 (Moore et al., 1975;Duffy et al., 2009;Musso et al., 2018). The clinical spectrum of ZVD usually consists of mild illness including fever, myalgia, headache, rash, arthritis, and conjunctival congestion with up to 4/5th of the infected individuals being asymptomatic (Duffy et al., 2009;Calvet et al., 2016). In 2016, a large-scale outbreak of ZVD in Brazil was reported, which was found to be associated with microcephaly and birth defects in newborn babies (Rocha et al., 2019). ...
Article
Full-text available
Background During the second wave of the COVID-19 pandemic, outbreaks of Zika were reported from Kerala, Uttar Pradesh, and Maharashtra, India in 2021. The Dengue and Chikungunya negative samples were retrospectively screened to determine the presence of the Zika virus from different geographical regions of India.Methods During May to October 2021, the clinical samples of 1475 patients, across 13 states and a union territory of India were screened and re-tested for Dengue, Chikungunya and Zika by CDC Trioplex Real time RT-PCR. The Zika rRTPCR positive samples were further screened with anti-Zika IgM and Plaque Reduction Neutralization Test. Next generation sequencing was used for further molecular characterization.ResultsThe positivity was observed for Zika (67), Dengue (121), and Chikungunya (10) amongst screened cases. The co-infections of Dengue/Chikungunya, Dengue/Zika, and Dengue/Chikungunya/Zika were also observed. All Zika cases were symptomatic with fever (84%) and rash (78%) as major presenting symptoms. Of them, four patients had respiratory distress, one presented with seizures, and one with suspected microcephaly at birth. The Asian Lineage of Zika and all four serotypes of Dengue were found in circulation.Conclusion Our study indicates the spread of the Zika virus to several states of India and an urgent need to strengthen its surveillance.
... Une première épidémie de Zika a été détectée à Yap en 2007 (Duffy et al., 2009). En 2013, le virus est réapparu en Polynésie Française, puis a disséminé dans tout le Pacifique (Cao-Lormeau and Musso et al., 2014). ...
... Human ZIKV infection was considered a benign and self-limited exanthematic illness (9). However, identifying neurological complications arising from ZIKV infections, mainly related to Guillain-Barré syndrome (10) and congenital malformations (11) raised new public health concerns. ...
Article
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Introduction Guillain-Barré syndrome (GBS) in association with arboviruses, such as Zika, chikungunya, and dengue, has been previously documented; however, Miller-Fisher Syndrome (MFS) and other GBS subtypes are rarely reported. Methods We identified a series of GBS and MFS cases that were followed during the Zika virus outbreak in Salvador, Brazil (2015–2016). Blood and CSF samples were collected for virus diagnosis. In addition, serological studies to verify previous arboviral infection and electromyography (EMG) were performed. Results Of the 14 patients enrolled, 10 were diagnosed with GBS, including three GBS subtypes (two cases of bifacial weakness with paresthesia and one case of paraparetic GBS), and four as MFS. IgM antibodies against one or more of three arboviruses were present in 11 (78.6%) patients: anti-zika IgM positivity in eight (57%), anti-Chikungunya IgM in three (21%), and anti-Dengue in one (7%) individual. A single case was positive for both anti-Dengue IgM and anti-Chikungunya IgM, suggesting co-infection. EMG revealed an AIDP pattern in all nine patients analyzed. Conclusion The current case series contributes to our knowledge on the clinical presentation of arbovirus-associated GBS and its subtypes, including MFS, and serves as an alert to clinicians and other healthcare professionals in regions affected by arbovirus outbreaks. We highlight the importance of recognizing arboviruses in diagnosing GBS and its subtypes.
... A minority of those who are infected with ZIKV often have mild, non-specific symptoms, such as a low-grade fever, myalgia, or headache [2,68]. In rare cases, patients develop Guillain-Barré syndrome (GBS), a condition that causes damage to the peripheral nervous system [2]. ...
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Zika virus (ZIKV) is mosquito-borne flavivirus that caused a significant public health concern in French Polynesia and South America. The two major complications that gained the most media attention during the ZIKV outbreak were Guillain–Barré syndrome (GBS) and microcephaly in newborn infants. The two modes of ZIKV transmission are the vector-borne and non-vector borne modes of transmission. Aedes aegypti and Aedes albopictus are the most important vectors of ZIKV. ZIKV binds to surface receptors on permissive cells that support infection and replication, such as neural progenitor cells, dendritic cells, dermal fibroblasts, retinal pigment epithelial cells, endothelial cells, macrophages, epidermal keratinocytes, and trophoblasts to cause infection. The innate immune response to ZIKV infection is mediated by interferons and natural killer cells, whereas the adaptive immune response is mediated by CD8+T cells, Th1 cells, and neutralizing antibodies. The non-structural proteins of ZIKV, such as non-structural protein 5, are involved in the evasion of the host’s immune defense mechanisms. Ocular manifestations of ZIKV arise from the virus’ ability to cross both the blood–brain barrier and blood-retinal barrier, as well as the blood-aqueous barrier. Most notably, this results in the development of GBS, a rare neurological complication in acute ZIKV infection. This can yield ocular symptoms and signs. Additionally, infants to whom ZIKV is transmitted congenitally develop congenital Zika syndrome (CZS). The ocular manifestations are widely variable, and include nonpurulent conjunctivitis, anterior uveitis, keratitis, trabeculitis, congenital glaucoma, microphthalmia, hypoplastic optic disc, and optic nerve pallor. There are currently no FDA approved therapeutic agents for treating ZIKV infections and, as such, a meticulous ocular examination is an important aspect of the diagnosis. This review utilized several published articles regarding the ocular findings of ZIKV, antiviral immune responses to ZIKV infection, and the pathogenesis of ocular manifestations in individuals with ZIKV infection. This review summarizes the current knowledge on the viral immunology of ZIKV, interactions between ZIKV and the host’s immune defense mechanism, pathological mechanisms, as well as anterior and posterior segment findings associated with ZIKV infection.
... There were less ZIKV cases since then. The symptoms of ZIKV infection mainly include maculopapular rash, fever, joint pain or arthritis, non-suppurative conjunctivitis, myalgia, headache, eye socket pain, edema, and vomiting [17]. ...
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Background Zika virus (ZIKV) and dengue virus (DENV) cause microcephaly and dengue hemorrhagic fever, respectively, leading to severe problems. No effective antiviral agents are approved against infections of these flaviviruses, calling for the need to develop potent therapeutics. We previously identified gossypol as an effective inhibitor against ZIKV and DENV infections, but this compound is toxic and not suitable for in vivo treatment. Results In this study, we showed that gossypol derivative ST087010 exhibited potent and broad-spectrum in vitro inhibitory activity against infections of at least ten ZIKV strains isolated from different hosts, time periods, and countries, as well as DENV-1-4 serotypes, and significantly reduced cytotoxicity compared to gossypol. It presented broad-spectrum in vivo protective efficacy, protecting ZIKV-infected Ifnar1−/− mice from lethal challenge, with increased survival and reduced weight loss. Ifnar1−/− mice treated with this gossypol derivative decreased viral titers in various tissues, including the brain and testis, after infection with ZIKV at different human isolates. Moreover, ST087010 potently blocked ZIKV vertical transmission in pregnant Ifnar1−/− mice, preventing ZIKV-caused fetal death, and it was safe for pregnant mice and their pups. It also protected DENV-2-challenged Ifnar1−/− mice against viral replication by reducing the viral titers in the brain, kidney, heart, and sera. Conclusions Overall, our data indicate the potential for further development of this gossypol derivative as an effective and safe broad-spectrum therapeutic agent to treat ZIKV and DENV diseases.
Article
The Zika Virus (ZIKV) infection is a serious, public health concern with no vaccines or antiviral treatments. This study aims to identify the differentially expressed long non-coding RNAs (lncRNAs) in ZIKV infected human-induced neuroprogenitor cells (hiNPCs). Though lncRNA is well-known for its role in gene regulation, its role in ZIKV infection remains unclear. Thus, taking advantage of publicly available transcriptome data, BioProject PRJNA551246 was analysed. Performed the gene ontology and pathway analysis of differentially expressed lncRNAs were functionally interpreted based on the neighbouring protein-coding genes (100 kb upstream and downstream of each lncRNAs). The study revealed 19 novels and 237 differentially expressed lncRNAs in ZIKV infected hiNPCs. They are found to be significantly enriched in type I interferon signalling pathway, negative regulation of viral genome replication, defense response to the virus, pathways involved in Influenza A and Herpes simplex infection, tumor necrosis factor signalling pathway, and apoptosis. In ZIKV, associated microcephaly type I interferon act as potential modulating factors. Type-I interferon inhibits ZIKV replication in many human cell types. The results support future studies on understanding the structure and function of the novel lncRNAs and experimental approaches to determine the role of the lncRNAs in ZIKV induced infection.
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Zika virus (ZIKV) and dengue virus (DENV) are two closely related members of the Flaviviridae family, both transmitted by mosquitoes of the genus Aedes, and are among the arboviruses most at risk to human health. Burkina Faso has been facing an upsurge in DENV outbreaks since 2013. Unlike DENV, there is no serological evidence of ZIKV circulation in humans in Burkina Faso. The main objective of our study was to determine the seroprevalence of ZIKV and DENV in blood donors in Burkina Faso. A total of 501 donor samples collected in the two major cities of the country in 2020 were first tested by a competitive enzyme-linked immunosorbent assay to detect flavivirus antibodies. Positive sera were then tested using Luminex to detect ZIKV and DENV antibodies and virus-specific microneutralization tests against ZIKV were performed. The ZIKV seroprevalence was 22.75% in the donor samples and we found seropositivity for all DENV-serotypes ranging from 19.56% for DENV-1 to 48.86% for DENV-2. Molecular analyses performed on samples from febrile patients and Aedes aegypti mosquitoes between 2019 and 2021 were negative. Our study showed the important circulation of ZIKV and DENV detected by serology although molecular evidence of the circulation of ZIKV could not be demonstrated. It is essential to strengthen existing arbovirus surveillance in Burkina Faso and more broadly in West Africa by focusing on fevers of unknown origin and integrating vector surveillance to assess the extent of ZIKV circulation and identify the circulating strain. Further studies are needed to better understand the epidemiology of this virus in order to define appropriate prevention and response methods.
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