Prolonged Shedding of Zika Virus Associated with Congenital Infection

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
gain occurs during national holidays. Although Brian Wansink, Ph.D.
this population sample may be wealthier, better Cornell University
NY
educated, and more motivated toward weight Ithaca,
fblsubmissions@​­cornell​.­edu
loss than average, it still provides insights for
Angela Chieh, M.S.
practice. Advising a patient to have better self- Withings
3,4
control over the holidays is one approach.
Paris, France
Yet given the weight-loss patterns shown in
Disclosure forms provided by the authors are available with
Figure 1, it might be better to advise patients the full text of this letter at NEJM.org.
that although up to half of holiday weight gain 1. Roberts SB, Mayer J. Holiday weight gain: fact or fiction?
is lost shortly after the holidays, half the weight Nutr Rev 2000;​58:​378-9.
gain appears to remain until the summer 2. Yanovski JA, Yanovski SZ, Sovik KN, Nguyen TT, O’Neil PM,
Sebring NG. A prospective study of holiday weight gain. N Engl
months or beyond. Of course, the less one gains, J Med 2000;​342:​861-7.
the less one then has to worry about trying to 3. Hull HR, Radley D, Dinger MK, Fields DA. The effect of the
Thanksgiving holiday on weight gain. Nutr J 2006;​5:​29.
lose it.
4. Phelan S, Wing RR, Raynor HA, Dibello J, Nedeau K, Peng W.
Elina E. Helander, Ph.D.
Holiday weight management by successful weight losers and normal weight individuals. J Consult Clin Psychol 2008;​76:​442-8.
Tampere University of Technology
Tampere, Finland
DOI: 10.1056/NEJMc1602012
Prolonged Shedding of Zika Virus Associated with Congenital
Infection
To the Editor: The presence of Zika virus
(ZIKV) infection has been associated with microcephaly in multiple studies,1-3 although little is
known about ZIKV shedding in congenitally infected infants. We report a case of a newborn
who had continued viremia with ZIKV for at
least 67 days after birth.
On January 2, 2016, a male child was born with
microcephaly in São Paulo, Brazil, at 40 weeks of
gestation to a mother who had reported having
symptoms associated with ZIKV infection during
the 26th week of pregnancy. At birth, the weight
was 3095 g, the length 48 cm, and the head
circumference 32.5 cm. The neurologic abnormality was not detected during an initial physical examination.
An analysis of cerebrospinal fluid and ophthalmologic and otoacoustic evaluations were normal. Magnetic resonance imaging (MRI) showed
a reduced brain parenchyma, notably in the
frontal and parietal lobes, foci of calcification in
the subcortical area, and compensatory dilatation of the infratentorial supraventricular system
(Fig. 1). At day 54, serum, saliva, and urine were
tested for ZIKV on quantitative real-time polymerase-chain-reaction (qRT-PCR) assay. All three
assays were positive for ZIKV RNA, with 1.4×105
copies per milliliter in the serum, 4.1×104 in the
saliva, and 5.4×103 in the urine. (Details of all
analyses are provided in the Methods section in
the Supplementary Appendix, available with the
full text of this letter at NEJM.org.)
RNA sequencing of a urine sample obtained
from the infant showed a high degree of similarity with samples isolated in the Americas with
98.5% bootstrap support (Fig. S3 in the Supplementary Appendix). ZIKV-specific IgM and IgG
were positive as well. On day 67, ZIKV RNA in
the serum continued to be detected on qRT-PCR,
with 2.8×104 copies per milliliter. On day 216,
ZIKV RNA was no longer detected in the serum
on qRT-PCR; the ZIKV-specific IgG titer was
high (>320) in comparison with the first and
second samples (average titer, <99).
When the infant was examined on day 54,
he had no obvious illness or evidence of any
immunocompromising condition. However, by
6 months of age, he showed neuropsychomotor
developmental delay, with global hypertonia and
spastic hemiplegia, with the right dominant side
more severely affected.
During the third trimester of pregnancy, the
infant’s mother had presented with fever, pruritic maculopapular rash, headache, conjunctival
hyperemia, and swelling and pain in the joints
of the hands and feet at 26 weeks of gestation;
n engl j med 375;12 nejm.org September 22, 2016
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Correspondence
A
Mother
Father
CSF: normal results
and VDRL–
Newborn
Newborn
delivery
Day Day
0
1
Toxoplasma/
rubella/CMV:
IgM– and IgG+
HIV−/VDRL−
Symptoms of
ZIKV infection
at 23 wk of
gestation
of infant
1st trimester
May–July
2nd trimester
Aug–Oct
Normal USG
Apr. 28, 2015
Symptoms of
ZIKV infection
at 26 wk of
gestation
Normal USG
Dec. 28, 2015
3rd trimester
Nov–Jan
Day
4
Toxoplasma/
rubella/
CMV: IgM– and
IgG+
2
3
2015
4
Serum, urine, and saliva:
ZIKV+ on qRT-PCR;
herpes (1-6)–, parvovirus
B19– on PCR;
ZIKV sequenced
Serum: ZIKV– on
(accession no., KX443145)
qRT-PCR; IgM–
IgM+ and IgG+ (low titer)
and IgG+
Day
45
Day
54
Day
59
6
January
2016
17
26
2
February
2016
Serum: ZIKV–
on qRT-PCR;
IgG+ (titer, >320)
Day
67
CSF: normal results
Serum: ZIKV– on
with CMV–, EBV–,
qRT-PCR;
herpes (1-2)–, and
IgM– and IgG+
toxoplasma– on PCR;
serum: toxoplasma– on PCR
5
Serum and semen: ZIKV–
on qRT-PCR; IgG+
Serum: ZIKV+
on qRT-PCR; IgM−
and IgG+ (low titer)
Day
216
Serum: ZIKV–
on qRT-PCR; IgG+
9
March
2016
2
August
2016
B
CT 1
CT 2
MRI 3
MRI 4
MRI 5
Figure 1. Clinical Timeline and Tomographic Findings in an Infant with Congenital ZIKV Infection.
Panel A shows the clinical timeline of pregnancy and delivery events and examinations, indicating the results of testing of serum, urine,
and saliva obtained from the newborn for Zika virus (ZIKV) on quantitative real-time polymerase-chain-reaction (qRT-PCR) assay. Also
outlined are the main ZIKV-related events, as shown in color-coded text with respect to the illnesses of the mother and the father and
the delivery and clinical investigation of the infant. CMV denotes cytomegalovirus, EBV Epstein–Barr virus, USG ultrasonography, and
VDRL Venereal Disease Research Laboratory test for syphilis. Panel B shows the skull tomography of the newborn. Head computed tomographic scans (CT 1 and CT 2) and magnetic resonance imaging scans (MRI 3, MRI 4, and MRI 5) highlight reduced brain parenchyma and multiple calcifications (arrows), notably in the frontal and parietal lobes, with compensatory dilatation of the infratentorial supraventricular system.
all the symptoms had resolved spontaneously.
Although the mother had not left the city of São
Paulo during the pregnancy, it was suspected
that ZIKV could have been sexually transmitted
from the father, who had traveled to the northeast region of Brazil (state of Paraíba) and reported having had the same symptoms as the
mother 3 weeks before the onset of her symptoms. Recently, some cases of sexual transmission of ZIKV have been reported but none in
pregnant women.4,5 Samples obtained from the
mother and father at days 59 and 67 were positive for ZIKV-specific IgG and negative for IgM.
As shown in the timeline of events in this case
in Figure 1, ZIKV infection persisted in a congenitally infected newborn for more than 2
months.
Danielle B.L. Oliveira, Ph.D.
Universidade de São Paulo
São Paulo, Brazil
n engl j med 375;12 nejm.org September 22, 2016
The New England Journal of Medicine
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Copyright © 2016 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
Flávia J. Almeida, M.D., Ph.D.
Irmandade da Santa Casa de Misericórdia de São Paulo
São Paulo, Brazil
Edison L. Durigon, Ph.D.
Érica A. Mendes, Ph.D.
Carla T. Braconi, Ph.D.
Universidade de São Paulo
São Paulo, Brazil
[email protected]
of
m e dic i n e
Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses — Brazil, 2015.
MMWR Morb Mortal Wkly Rep 2016;​65:​159-60.
4. McCarthy M. Zika virus was transmitted by sexual contact in
Texas, health officials report. BMJ 2016;​352:​i720.
5. D’Ortenzio E, Matheron S, de Lamballerie X, et al. Evidence
of sexual transmission of Zika virus. N Engl J Med 2016;​374:​
2195-8.
DOI: 10.1056/NEJMc1607583
Correspondence Copyright © 2016 Massachusetts Medical Society.
Ivan Marchetti, M.D.
Irmandade da Santa Casa de Misericórdia de São Paulo
São Paulo, Brazil
Robert Andreata-Santos, B.Sc.
Marielton P. Cunha, M.Sc.
Rúbens P.S. Alves, M.Sc.
Lennon R. Pereira, M.Sc.
Stella R. Melo, B.M.V.
Daniel F.L. Neto, Ph.D.
Flávio S. Mesquita
Universidade de São Paulo
São Paulo, Brazil
Danielle B. Araujo, M.V., Ph.D.
Silvana R. Favoretto, Ph.D.
Instituto Pasteur de São Paulo
São Paulo, Brazil
Marco A.P. Sáfadi, M.D., Ph.D.
Irmandade da Santa Casa de Misericórdia de São Paulo
São Paulo, Brazil
Luís C.S. Ferreira, Ph.D.
Paolo M.A. Zanotto, Ph.D.
Universidade de São Paulo
São Paulo, Brazil
Viviane F. Botosso, Ph.D.
Instituto Butantan
São Paulo, Brazil
Eitan N. Berezin, M.D., Ph.D.
Irmandade da Santa Casa de Misericórdia de São Paulo
São Paulo, Brazil
Drs. Oliveira and Almeida contributed equally to this letter.
A complete list of authors is available with the full text of this
letter at NEJM.org.
Supported by the Fundação de Amparo à Pesquisa do Estado
de São Paulo.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
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correction
This letter was published on August 24, 2016, at NEJM.org.
1. Mlakar J, Korva M, Tul N, et al. Zika virus associated with
microcephaly. N Engl J Med 2016;​374:​951-8.
2. Sarno M, Sacramento GA, Khouri R, et al. Zika virus infection and stillbirths: a case of hydrops fetalis, hydranencephaly
and fetal demise. PLoS Negl Trop Dis 2016;​10(2):​e0004517.
3. Martines RB, Bhatnagar J, Keating MK, et al. Evidence of
Viral Bronchiolitis in Children (May 5, 2016;374:1791-4). In the
second paragraph of the author’s reply letter (page 1793), the
second sentence should have ended, “. . . the risk of hospitalization for RSV was two to three times higher among preterm
infants than among healthy term infants,” rather than
“. . . was not higher . . . .” The letter is correct at NEJM.org.
n engl j med 375;12 nejm.org September 22, 2016
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