Meet dengue’s cousin, Zika

It’s too early to know how alarmed we should be about the spread of Zika virus (ZIKV). The good news is that ZIKV currently presents as a relatively mild and self-limiting illness, with low hospitalization rates. The bad news is that ZIKV is spreading rapidly worldwide, is challenging to diagnose, and may have effects following the illness including autoimmune diseases like Guillain-Barré syndrome (GBS), other neurological disorders and birth defects. The World Health Organization (WHO) has warned its Member States that ZIKV has the potential to place an additional burden on local health systems and recommends development of ZIKV testing capabilities and public education campaigns for prevention of ZIKV.

1. About ZIKV

ZIKV is a mosquito-borne ssRNA flavivirus of the Flaviviridae family that includes dengue virus (DENV), West Nile Virus (WNV), Japanese encephalitis and Yellow Fever. ZIKV’s closest relative is Spondweni virus. Comprehensive genetic comparison has revealed subclades reflecting 2 lineages, one African and one Asian. ZIKV is suspected of having widespread occurrence in Africa and Southeast Asia. Humans and non-human primates are the only known reservoir, but one study did find antibody in rodents.

ZIKV has the ability to infect multiple species of the Aedes genus of mosquito, the same genus that spreads DENV and Chikungunya (CHIK). Perinatal and transfusion transmission of ZIKV are theoretically possible, and sexual transmission has also been reported.

2. History and outbreaks

First identified in a rhesus monkey in the Zika forest of Uganda in 1947, the first human cases were identified in Nigeria in 1954. Although a small cluster of 7 cases was reported in Java, Indonesia, in 1977, no significant human outbreaks had been documented before an outbreak on Yap Island in the Federated States of Micronesia in 2007. Duffy et al. estimate that approximately 900 people were affected, three-fourths of Yap’s population at the time. 2013–2014 had an outbreak in French Polynesia and New Caledonia. In French Polynesia, there were over 8750 suspected cases and 383 cases confirmed, an estimated 11% of the population.

In February 2014, autochthonous transmission was reported on Easter Island, marking ZIKV’s arrival in the Americas. By May 2015, WHO warned of ZIKA in Brazil, and October 2015 brought WHO warnings of ZIKA transmission in Colombia. On November 11, 2015, WHO warned of another country in South America with local ZIKV transmission, Suriname. In 2015, outbreaks in Vanautu, the Solomon Islands and New Caledonia have also been reported.

3. Diagnostic challenges

ZIKV is difficult to diagnose because it shares vectors, geographic distribution and symptoms with DENV and CHIK, making diagnosis by clinical signs and epidemiology unreliable. DENV, ZIKV and CHIK all present clinically with fever, maculopapular rash, conjunctivitis and arthralgia, and are sometimes co-circulating in the same areas or co-infecting patients. Given the potential severity of illness from dengue virus (DENV), it is particularly important to distinguish between the two (see Table 1).

Lab confirmation is recommended for ZIKV diagnosis, but lab confirmation presents its own set of challenges. Although it is unlikely that IgM results will cross-react with an alphavirus like CHIK, cross-reactivity of ZIKV IgM with other flaviruses (especially DENV) has been widely reported.

Current testing recommendations are to obtain RT-PCR by urine or saliva within the first 5 or 6 days of illness, with highest concentrations found in saliva early in the disease course, but possibly remaining detectable for longer in the urine. In the French Polynesia outbreak, some cases had positive ZIKV RT-PCR urine results more than 10 days after symptom onset.

If serology is performed, an acute phase should be drawn from day 6 onward with a convalescent serum drawn 2–3 weeks later. Lanciotti notes that false positives for ZIKV seem more likely if ZIKV is not the first flavivirus that the patient has encountered, but cross-reactivity has also been reported in primary infected patients. If cross-reactivity is suspected, plaque reduction neutralization testing (PRNT) can help to discriminate between cross-reacting antibodies. If an isolated DENV positive titer presents with other negative results, diagnostic suspicion should be raised for other flaviviruses. Pan-flavivirus assays with subsequent sequencing analysis can also be performed.

4. Possible sequelae

There have been reports of an increase in Guillain-Barré syndrome (GBS) and other autoimmune and neurological syndromes in the context of ZIKV outbreaks, but it is not known how many of these patients may have been co-infected or previously infected with DENV, which may increase the risk. In the French Polynesia outbreak, 74 patients presented with neurological or autoimmune illness who had symptoms consistent with ZIKV in the previous days; 42 of these patients were diagnosed with GBS. This was a 20-fold increase over baseline. Oeler et al. speculate that this increase in GBS cases in the presence of ZIKV may reveal the genetic evolution of the virus to a more pathogenic genotype, a particular susceptibility in the Polynesian population, or that previous DENV illness may predispose patients to GBS via sequential arboviral immune stimulation.

Most recently, Brazil has declared a state of emergency because of an alarming increase this year of microcephaly in Pernambuco. The baseline rate for this area of microcephaly is 10 cases per year. As of November 9, 141 cases of microcephaly have been reported in Pernambuco. Although the cause is undetermined at this time, ZIKV was isolated from the amniotic fluid of two of the mothers. On November 24, 2015, health officials in French Polynesia also reported an increase of congenital central nervous system malformations, coinciding with their own outbreak from 2013 to 2014.

5. Vectors and vector control

Prevention of ZIKV is directed at minimizing breeding sites and contact with Aedes mosquitoes. Aedes often live around buildings and in urban areas. They are active during daylight hours, especially near dawn and dusk, and they have a variety of artificial and natural breeding sites. People in endemic areas are encouraged to use insect repellent, wear light-colored long sleeves and pants and inhabit buildings that utilize air conditioning or window and door screens. Bed nets are recommended for residents and travelers who sleep during the day and infants under 3 months old, upon whom insect repellent should not be used.

Concerns exist that other Aedes spp. will become competent vectors for ZIKV. Outbreaks in Yap and other regions have shown that even physically isolated communities can experience rapid ZIKV spread via travel and commerce. The Asian lineage particularly seems to have high epidemic potential.

Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS All rights reserved.