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Prolonged Zika Virus Viremia During Pregnancy - NEJM

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Anna Suy, M.D., Ph.D.
Hospital Vall d’Hebron, Barcelona, Spain 

Elena Sulleiro, M.D.
Carlota Rodó, M.D.
Universitat Autònoma de Barcelona, Barcelona, Spain

Élida Vázquez, M.D.
Cristina Bocanegra, M.D.
Israel Molina, M.D., Ph.D.
Juliana Esperalba, M.D.
Hospital Vall d’Hebron, Barcelona, Spain

María P. Sánchez-Seco, M.D., Ph.D.
Centro Nacional de Microbiología, Madrid, Spain

Hector Boix, M.D.
Tomás Pumarola, M.D., Ph.D.
Elena Carreras, M.D., Ph.D.
Hospital Vall d’Hebron, Barcelona, Spain

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

Drs. Suy, Sulleiro, and Rodó contributed equally to this letter.

This letter was published on December 7, 2016, at NEJM.org.

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To the Editor:

We describe a case of Zika virus (ZIKV) infection during pregnancy in a Colombian woman. She was infected in December 2015 while she was visiting her home country. At 9 weeks’ gestation, she had a self-limited maculopapular, nonconfluent rash for 3 days that affected her trunk, arms, and legs; she had no fever or other concurrent symptoms. She was screened for ZIKV and other flaviviruses.

A reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay (RealStar Zika Virus RT-PCR Kit 1.0, Altona Diagnostics) of a serum sample was positive for ZIKV, and testing remained positive for 89 days (or 107 days after the onset of symptoms, until 29 weeks’ gestation), in six consecutive blood samples. Testing for ZIKV in the urine, vagina, and endocervix was negative. No fetal brain abnormalities were observed on scans obtained at 12 and 15 weeks’ gestation. Neurosonography performed at 20, 24, and 29 weeks’ gestation revealed bilateral mild ventriculomegaly and a shortened corpus callosum. The posterior fossa was normal. The brain parenchyma had calcifications and severe atrophy. Similar findings were seen on magnetic resonance imaging (MRI). No other anomalies were found in the fetus or the placenta. An RT-PCR assay of the amniotic fluid was positive for ZIKV, and screening was negative for dengue virus, chikungunya virus, cytomegalovirus, varicella–zoster virus, parvovirus B19, Toxoplasma gondii, and sexually transmitted infectious agents (Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis, Ureaplasma parvum, M. genitalium, U. urealiticum, and Trichomonas vaginalis). The ZIKV viral load in the amniotic fluid was higher than that in the maternal serum (cycle threshold values, 28 vs. 35; RT-PCR cycle threshold values were used as an indirect marker of viral load). Results of targeted genetic testing of the amniotic fluid by means of microarray-based comparative genomic hybridization (SurePrint G3 Unrestricted CGH ISCA v2 Microarray Kit, 8x60K, Agilent Technologies) were normal.

The baby was delivered at 37 weeks’ gestation because of suspected growth restriction. At this time, RT-PCR assays of the maternal serum, urine, amniotic fluid, placenta, membranes, and umbilical cord were negative for ZIKV. RT-PCR assays of the neonatal serum, urine, and cerebrospinal fluid were also negative. Postnatal ultrasonography and MRI studies confirmed the presence of microcephaly with a thinned corpus callosum and brain atrophy with parenchymal calcifications. (Table 1TABLE 1nejmc1607580_t1.gifPatient Data. shows the evolution of laboratory and ultrasonographic findings in the mother and the baby.)

ZIKV has been documented to be detectable in maternal blood by means of molecular techniques during the acute phase of the infection (the first 5 days after the onset of clinical symptoms).1 Driggers et al. (June 2 issue)2detected ZIKV RNA in maternal serum 8 weeks after the onset of clinical symptoms. They suggested that persistent viremia may occur as a consequence of viral replication in the fetus or placenta. In our case, certain findings would support this hypothesis. First, the viral load in the amniotic fluid was higher than that in the maternal serum. Second, the viral load in the maternal serum remained stable (cycle threshold value, approximately 35) for 14 weeks and then became negative, instead of decreasing progressively, as would be expected. Third, neutralizing antibodies and ZIKV RNA were present in the maternal serum. In addition, RT-PCR assays of the maternal urine were negative, while testing of the maternal serum was positive. According to previous studies,3 ZIKV RNA would be detectable in urine longer than in serum, so an RT-PCR assay of the maternal urine would be expected to be positive in the presence of maternal viremia. For all these reasons, we would hypothesize that the persistent viremia that was detected in the mother could be the result of viral replication in the fetus or placenta, which thus acts as a reservoir.

We presume that the RT-PCR testing of neonatal samples was negative because the clinical infection occurred during prenatal life; hence, it is possible that ZIKV antibodies developed in the baby’s immune system before birth. In summary, persistent ZIKV RNA in maternal serum could be a sign of fetal infection, and thus the fetus may play a role in persistent maternal viremia.

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  1. 1

    Petersen EE, Polen KN, Meaney-Delman D, et al. Update: interim guidance for health care providers caring for women of reproductive age with possible Zika virus exposure — United States, 2016. MMWR Morb Mortal Wkly Rep 2016;65:315-322
    CrossRef | Web of Science | Medline

  2. 2

    Driggers RW, Ho C-Y, Korhonen EM, et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med 2016;374:2142-2151
    Free Full Text | Web of Science | Medline

  3. 3

    Martínez de Salazar P, Suy A, Sánchez-Montalvá A, Rodó C, Salvador F, Molina I. Zika fever. Enferm Infecc Microbiol Clin 2016;34:247-252
    CrossRef | Web of Science | Medline

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