8 September 2016
Ahead of the addition of an important new section on the Zika virus in the Health Needs Assessment Toolkit for Congenital Disorders, PHG Foundation fellow, Lavinia Schuler Faccini, brings us up to date on what is known about the disease and its spread. Co-authors on the article are Maria Teresa V Sanseverino, André A da Silva, Silvani Herber, Ian M Feitosa, Fernanda S L Vianna, Luis Nacul.
September 2016 marks one year after the observation of an unexpected increase in babies born with microcephaly in Brazil.
Two months after the first reports, the Brazilian government recognised the strong possibility this could be related to prenatal infection by a previously almost unimportant virus – Zika. Zika Virus (ZIKV) was accidentally identified in Uganda in 1947 as a virus infecting Rhesus monkeys and transmitted by the mosquito Aedes Africanus; it soon proved to be also infective to humans in Nigeria in 1954. During the following 50 years it spread to other areas of Africa and Oceania with significant outbreaks in the Pacific islands in 2007 (Yap Islands) and 2014 (French Polynesia), by which time the virus had fully adapted to infect humans. However, ZIKV was thought to only cause a self-limited infection – one that resolves itself without treatment - and which was either asymptomatic or presented with mild symptoms such as low grade fever, cutaneous rash and arthralgia. In early 2015, the first outbreak in the Americas region was documented in Northeast Brazil, where its main vector, the yellow fever mosquito (Aedes egyptii)is abundant.
A significant rise in the birth of babies with microcephaly in Pernambuco, Northeast Brazil in the second half of the same year marked a dramatic change in the previously quiet history of ZIKV. Although initially contested, this increase was confirmed and it was also detected in other parts of Brazil. Geographic and temporal links of microcephaly and ZIKV infection in pregnancy were soon observed. Moreover, maternal history compatible with ZIKV infection, mostly during the first half of pregnancy, and brain images suggestive of congenital infection (periventricular and cortical calcifications, ventricular enlargement, cortical abnormalities) were reported in a great majority of cases. The association between prenatal exposure to ZIKV and brain disruption was recognized by February 2016, when the WHO World Health Organization declared Zika a global public health emergency. The fast spread of ZIKV to the majority of the countries in the Americas, including the USA, led to major global concern and the mobilization of scientists and health agencies.
At present there is no effective vaccine or specific treatment available for ZIKV, and the battle to control its major vector, the mosquito, has been largely ineffective so far. Moreover, new evidence of sexual and other forms of transmission have been raising further concerns over the global spread of the infection. Although a cause-effect relationship between ZI KV prenatal infection and brain damage seems certain, the number of unanswered questions has multiplied. One of the main questions relates to the exact pathological mechanisms through which the virus affects the developing nervous system. Experimental studies, both in vivo and in vitro, are helping to elucidate and to propose mechanisms by which the virus infects and disrupts progenitor neural cells. Major mechanisms may involve direct damage by the virus to the progenitor cells, or the inflammatory response could play a key role in cell damage and death. Recent investigations show that neural progenitor cells in the adult mouse can also be infected and show altered proliferation. Clinical and epidemiological research is posing newer questions. There is now strong evidence that fetal brain damage is not restricted to first trimester infections, but may also result from later exposures in pregnancy, even as late as the third trimester. Some babies with confirmed prenatal ZIKV infection but born with head circumferences within the range of normality are now also showing brain calcifications and possibly developmental abnormalities.
The central nervous system (CNS) may not be the only affected organ. Arthrogryposis, which is frequently observed in these babies, may be a consequence of CNS injury, but it may also result from direct damage to the peripheral nervous system. More information about other factors that might contribute to the susceptibility and outcome of the infected babies, for example, variations in genes involved in CNS development or in inflammatory response pathways, is also critical. environmental risk or protective factors such as nutrition, previous flavivirus infections or vaccinations, use of anti-inflammatory drugs, among others, might also play a role.
In 2010 the PHG Foundation launched the Health Needs Assessment Toolkit for Congenital Disorders as a comprehensive tool to help countries assess their health needs , prioritise actions and produce strategies to address them which reflect their local circumstances. The toolkit is now looked after by a team based in Brazil. In October 2016 they will be adding a new chapter on Zika virus congenital infection to the toolkit, representing an important additional tool to help control this urgent global health problem.