Interrupting the febrile neutropenia series to write about Zika virus, which has been in the global news for some months but very recently became a hot topic in the local mainstream news because of the explosive nature of its spread in South America, the new association of this South American strain with microcephaly (in children born to infected pregnant women) and Guillain-Barre syndrome, and the fact that Singapore seems to be very vulnerable to the virus. Before I go on, here is the link to a remarkably comprehensive set of resources and links about the current Zika virus outbreak, assembled and updated regularly by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota. It is well worth a visit.

The Zika virus is a member of the Flavivirus family (technically genus) along with dengue, West Nile, yellow fever and other encephalitis viruses. The virus was named for the Zika forest in Uganda where it was found in 1947 by accident in a “sentinel monkey” put up by scientists hoping to study the yellow fever virus. Attempts to find the virus animal reservoir in Uganda in the 1960s failed, although it is likely (see below) that the virus is maintained in its sylvatic cycle in primates. The Zika virus – like other flaviviruses – is transmitted by mosquitoes, in this case, a variety of Aedes mosquitoes. Investigators at the Environmental Health Institute in Singapore have shown that the Zika virus can potentially be spread by the two major strains of Aedes mosquitoes in Singapore – Aedes aegypti and Aedes albopictus. I have tried to find evidence as to whether transovarial transmission of Zika virus is possible (i.e. from mother mosquito to offspring), but there appears to be a knowledge gap here.

The virus is also present in Asia, in particular Malaysia and Indonesia. For example, here is a link to an article showing that Zika virus could be found in up to 13% of free-ranging orangutans in Sabah between 1996-1998 (although as a caution, the serologic tests used may not have been that specific for the virus, but the results corroborate the findings of a separate group using more specific serological tests), and here is a case report published in 2013 of an Australian contracting Zika virus infection after a 9-day trip to Jakarta, Indonesia. The first outbreak of Zika in humans outside Asia and Africa (and in fact, the very first large outbreak of Zika virus in humans), occurred on Yap island in Micronesia in 2007. How the virus was imported to the island remains unknown. Unlike the current epidemic in South America, the Micronesian outbreak was not associated with pregnancy-related or neurological sequelae.

Like dengue, up to 80% of patients with Zika virus infection exhibit no symptoms of infection (i.e. asymptomatic). As in the case of dengue again, it is likely that people who are asymptomatic are still able to transmit their virus to mosquitoes, making the control of this disease difficult if one were to only target the patients that presented with symptoms (like dengue as well!). The clinical presentation of patients that are symptomatic are so similar to dengue (fever, headache, muscle and joint pains, and rash) that Zika had previously been described as “mild dengue”. The key difference is that non-purulent conjunctivitis is more common with Zika virus infections. There is no definitive treatment, as with most other viral infections.

The Ministry of Health Singapore has put up a webpage with a list of countries with ongoing Zika virus transmission, and has issued an advisory against traveling to these countries for women who are pregnant. It has separately emailed doctors with a list of sensible actions in the case that a patient with suspect or confirmed Zika virus infection is encountered. There is no serological testing available in Singapore yet, unlike dengue or Chikungunya, but PCR tests (which can only be used to diagnose infections when patients are symptomatic and not afterwards) can be performed at the National Public Health Laboratory (NPHL).  The World Health Organization (WHO) is set to meet on 1st February to discuss the Zika epidemic, and there is little reason for the WHO to not list this as a “Public Health Emergency of International Concern”. Although there appears to be a race to develop a Zika virus vaccine, one will not be commercially available in the short-to-medium term. After all, for decades, hardly anyone (other than dedicated researchers) cared about this “wimpy dengue-like” virus.

To summarise then:

1. The Zika virus is a flavivirus that is spread via Aedes mosquitoes, and therefore it has the same potential to take root and spread in Singapore like dengue.
2. Its clinical presentation resembles a milder form of dengue, with the exception that more patients will present with non-purulent conjunctivitis.
3. Up to 80% of infected persons are asymptomatic, but are presumably still able to pass the virus to a mosquito.
4. The link between Zika virus and microcephaly in newborns of infected mothers is epidemiologically very strong, but not conclusively proven. It appears to only be associated with the South American Zika virus, and not the Asian, African or Polynesian strains of Zika viruses.
5. There is no definitive treatment and no vaccine. Currently, diagnosis can only be confirmed in the acute phase via a blood test performed at the NPHL in Singapore. However, serological testing is available if blood samples are sent out to the Centers for Disease Prevention and Control (CDC) in Atlanta, and also at other international laboratories.
6. Given the common vector for this virus and dengue, it seems incredibly tempting to target control of Aedes mosquitoes in general, rather than focus on human cases. Do we need mosquitoes? That is an incredibly complex question to answer. Tests of genetic and other modifications of mosquitoes (i.e. with Wolbachia) are underway.

Updated 31st January 2016

A point I had failed to mention earlier. Current commercial tests for dengue antibodies (i.e. dengue IgM and IgG assays based on ELISA methodology) will likely be positive (a false positive result) if performed on the blood of a patient with recent or ongoing Zika virus infection. This is because of the high degree of cross-reactivity between the various flavivirus ELISA tests. A test for neutralising antibodies to Zika virus is far more specific but is not available commercially (and not available in Singapore currently, as far as I know). The dengue NS1 (non-structural protein 1) antigen test which is widely available in Singapore is specific for dengue, however. If this test is negative within the 3rd to 9th day of illness whereas dengue antibody tests are positive, the patient does not have acute dengue but some other flavivirus infection (or past dengue infection).