From the Journals

Replicative Zika RNA found in brain and placental tissue



U.S.-based researchers have isolated replicative Zika virus RNA from the brain tissue of infants with microcephaly, and the placenta and fetal tissues from women suspected of being infected with Zika virus during pregnancy.

In a paper published online in Emerging Infectious Diseases, Julu Bhatnagar, PhD, of the Infectious Diseases Pathology Branch at the Center for Emerging and Zoonotic Infectious Diseases in Atlanta, and her coauthors reported a case series in 52 patients – 8 infants with microcephaly who died and 44 women thought to have been infected with Zika virus during pregnancy – using Zika virus reverse transcription PCR and in situ hybridization assay to detect the virus.

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While Zika virus antigens have previously been detected in placentas and in fetal or neonatal brains, this does not necessarily indicate virus replication, the authors wrote (Emerg Infect Dis. 2016 Dec 14. doi: 10.3201/eid2303.161499).

“Nevertheless, localization of replicating Zika virus RNA directly in the tissues of patients with congenital and pregnancy-associated infections is critical for identifying cellular targets of Zika virus infection and virus persistence in various tissues and for further investigating the mechanism of Zika virus intrauterine transmission,” Dr. Bhatnagar said.

Using RT-PCR, the researchers were able to isolate Zika virus RNA from 32 (62%) of the case-patients – all 8 infants with microcephaly who died, and 24 women.

There were no major clinical differences between the women who tested positive for Zika virus with RT-PCR and those who tested negative; the most common symptoms in both groups were rash, fever, arthralgia, headache and conjunctivitis.

Among women who had an adverse pregnancy or birth outcome, 24 (75%) tested positive for Zika virus via RT-PCR, compared to 8 (36%) women with live-born healthy infants (P = .0082).

Symptom onset during the first trimester was associated with a significantly higher risk of adverse pregnancy and birth outcomes. Of the 24 women with positive RT-PCR results and adverse pregnancy outcomes, 23 had symptom onset during the first trimester, while all 8 patients with positive RT-PCR results but healthy infants had symptom onset in the third trimester (P less than .0001).

There were eight cases of infants with microcephaly who died within a few minutes to 2 months after birth, and five women who delivered live infants with microcephaly who survived.

All but one of these tested positive for Zika virus by RT-PCR, either in brain tissue or placental/fetal tissue, and all the women experienced symptom onset during the first trimester. Zika virus was not detected in other tissues from the infants.

Researchers also found that the levels of Zika virus RNA in the brain tissues of the infants who had microcephaly and died were around 1,200-fold higher than the levels observed in second or third trimester or full-term placentas.

Using in situ hybridization assays, researchers found Zika virus RNA in half of the tissues of the 32 case-patients who tested positive with RT-PCR.

“Zika virus replicative RNA, detected by using sense probe, was observed in the neural cells, neurons, and degenerating glial cells within the cerebral cortex of the brain,” the authors wrote.

Zika virus genomic and replicative RNA also was found in the placental chorionic villi – predominantly in the Hofbauer cells – in 9 (75%) of the 12 women with positive RT-PCR results who had experienced an adverse pregnancy outcome during the first or second trimester. The authors said this indicated the possibility that the Hofbauer cells may play a role in disseminating or transferring the virus to the fetal brain.

“This article highlights the value of tissue analysis to expand opportunities to diagnose Zika virus congenital and pregnancy-associated infections and to enhance the understanding of mechanism of Zika virus intrauterine transmission and pathogenesis,” the authors wrote. “In addition, the tissue-based RT-PCRs extend the time frame for Zika virus detection and particularly help to establish a diagnosis retrospectively, enabling pregnant women and their health care providers to identify the cause of severe microcephaly or fetal loss.”

No conflicts of interest were declared.

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