Zika: The Expanding and Deepening Threat

Marc Gozlan, MD

Disclosures

November 14, 2016

May 2016

Early May 2016. A study[55] was published that investigated temporal correlations and time lags between outbreaks of acute exanthematous illness attributed to Zika virus, GBS, and microcephaly occurring in 2015 in Salvador, the largest city in northeastern Brazil and one of the main epicenters of the Zika epidemics.

This Brazilian report showed a clear temporal relationship between the peak of Zika virus infection and a peak of GBS incidence 5-9 weeks later, consistent with an autoimmune-mediated pathologic mechanism rather than a direct neuropathic viral effect. This peak was followed by a spike in microcephaly 30-33 weeks later,[55] which corresponded to potential infection during the first trimester of pregnancy.

To investigate the mechanisms by which Zika virus induced microcephaly and other neurologic disorders, US researchers used mouse neurospheres and human embryonic stem cell (hESC)-derived cerebral organoids to recapitulate early-stage fetal brain development. They revealed another piece of the puzzle by showing that Zika virus infects neural progenitor cells. Indeed, cerebral organoids generated from hESCs mimic the developing fetal brain and develop malformations and severely inhibit growth after inoculation with Zika virus.[56]

May 13, 2016. Another study, published 10 days later on May 13, 2016, also showed that Zika virus targets human brain cells, reducing the viability and growth of neurospheres and brain organoids.[57] Collectively, these results suggested that Zika virus abrogates neurogenesis during human brain development.

At the same time, two research teams reported animal data, reinforcing the growing body of evidence linking the Zika outbreak to the alarming number of cases of congenital brain malformations. In the first study, published in Nature,[58] results in mice showed that Zika virus infects fetuses, causing intrauterine growth restriction, including signs of microcephaly. The researchers also reported that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicated that Zika virus crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death and impairing neurodevelopment.[58]

In the second study, published in Cell,[59] more evidence from experiments on Zika virus-infected pregnant mice suggested that Zika virus infection can cause injury of the fetal brain as well as placental damage and fetal demise.

Mid- to late May 2016. Sexual transmission of Zika virus had been reported in 10 countries (United States, France, Italy, Argentina, Chile, Peru, Portugal, New Zealand, Canada, and Germany) and occurred mainly from vaginal intercourse.[60] All of the male travelers had symptoms consistent with Zika virus infection and could have transmitted infections to their sex partners a few days before or after as well as during the time in which symptoms appeared.[19,61,62]

At that time, the message delivered was that such cases presented valuable opportunities to learn about this emerging mode of transmission and highlighted the need for clinicians to remain vigilant for any suspected Zika infections in symptomatic persons without travel history but who reported unprotected sexual contact with a person who traveled to an area with active Zika virus transmission.[2]

Very soon after, a case report raised suspicion of Zika virus transmission through oral sex. A woman living in Paris had sexual contact with a man who had stayed in Brazil and who presented with symptoms of Zika virus infection. Transmission through oral sex was suspected because the sexual activity involved vaginal intercourse with no condom and no ejaculation, and oral sex with ejaculation.[63]

Very soon after, a case report raised suspicion of Zika virus transmission through oral sex.

On May 20, 2016, WHO reported that the sequencing of the virus in Cape Verde confirmed that the Zika virus currently circulating in the island was the same as the one circulating in the Americas—the Asian type—and was most likely imported from Brazil.[64] This was the first time that the Zika strain responsible for the outbreaks linked to neurologic disorders and microcephaly had been detected in Africa.[64]

As of May 25, 2016, 60 countries and territories reported continuing mosquito-borne transmission of Zika virus. Of these, 46 countries were experiencing a first outbreak of Zika virus since 2015, with no previous evidence of circulation and with ongoing transmission by mosquitos.[65]

At the same time, a mathematical estimate of the microcephaly risk, based on reports from the Brazilian state of Bahia, concluded that a fetus infected with the Zika virus during the first trimester of pregnancy had 0.88%-13.2% risk of developing microcephaly.[66]

Furthermore, a study[67] indicated that a contemporary strain of Zika virus, isolated from villous tissue of full-term placentae and closely related to the strains currently circulating in Brazil, infects and replicates in human placental macrophages (Hofbauer cells) and to a lesser extent in cytotrophoblasts. These experimental findings suggested a mechanism for intrauterine transmission in which Zika virus gains access to the fetus by directly infecting placental cells and disrupting the placental barrier.[67]

These results added more evidence to the body of literature showing the possibility that Zika virus could cross the placenta. A previous report[14] had identified by immunohistochemistry the presence of viral antigen in placental tissue (chorionic villi from a miscarriage) from a mother with Zika virus infection.

As knowledge of the clinical sequelae of congenital Zika virus infection advanced, it became apparent that microcephaly was only one possible adverse outcome among a range of disorders that might be part of congenital Zika virus syndrome. Indeed, infants without microcephaly could still have been infected by Zika virus during gestation. The case of an infant with a diagnosis of congenital Zika virus infection, who did not have microcephaly but did have ocular findings, was published online in the Lancet[68] on June 7, 2016. This case highlighted that ocular findings might be underdiagnosed if microcephaly is the only criterion in the screening of this group of infants.

Moreover, during the first half of 2016, several studies reported the prolonged presence of Zika virus in semen, detected by RT-PCR. One of these studies[69] documented that the Zika virus RNA viral load in the semen was roughly 100,000 times that in the patient's blood or urine more than 2 weeks after symptom onset. In another report,[70] published in May 2016, researchers reported the case of a 68-year-old man returning to the United Kingdom from the Cook Islands. His semen was positive for Zika virus 62 days after his symptoms began, and the RT-PCR signals were stronger than those obtained in tests of the original serum sample.

Since then, reports of viral permanence detected by RT-PCR, with even longer duration of shedding of the Zika virus in semen, were documented in several letters and articles, quickly published online, from France (80[71] and 93 days[72]) and Italy (181 days[73]). However, the infectious Zika virus itself, isolated by culture from semen samples, was recovered from semen up to 24 days after the onset of symptoms.[63]

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