Saturday, 6 February 2016

Zika Virus, Microcephaly and Brazil

As discussed before, Zika Virus (ZIKV) is an emerging arbovirus, spread by Aedes Agypti and Aedes albopictus, which was first isolated in 1947 in Uganda from a Macaca monkey with the first human case being detected in Nigeria (1954). In subsequent decades sporadic cases linked to ZIKV have been reported in Africa and Asia, with a first epidemic reported in 2008 (Yap/Federated States of Micronesia) and a larger one in French Polynesia and Oceania 2013-2014 with the first cases in the Americas were identified in Natal/Brazil in March 2015 in samples from patients displaying dengue-like symptoms.

Table1: Outbreaks of ZIKV 1952-2014

Although most patients experience only a fever or a rash –or even are asymptomatic- following ZIKV infection, during the outbreak in French Polynesia an increase in patients suffering from an otherwise rare neurological disorder, Guillan-Barre Syndrome (GBS), has been reported and associated with a previous ZIKV infection, suggesting that ZIKV might be a neurotropic virus (similar to DENGV or CHIKV), a view supported by studies that suggest that ZIKV can infect and replicate in neuronal cells. If however the infection of ZIKV with neuronal cells is causing GBS has not been established and it might be possible that the immune response –rather than the infection per se- causes the neurological abnormalities reported during the 2013-2014 outbreak.

                                         ZIKV in Brazil

The transmission of ZIKV from the Pacific Islands to Brazil appears to have happened either during the 2014 FIFA World Cup and/or an international canoe-racing event attended exclusively by competitors from the Pacific. Although the first ZIKV were isolated from patients in the city of Natal, patients with symptoms suggesting ZIKV infection were reported in the city of San Salvador from February 15 onwards, and ever since a total of 28 Brazilian states have reported cases of Zika (as of February 06 2016). Following the detection of ZIKV in Brazil, confirmed cases have been reported in throughout Central and South America (with the exception being Chile) as well as the Caribbean. 

Travellers to these countries also lead to the appearance of confirmed cases in Europe, the Near East, Australia, and the US. With the exception of the US, so far however no local transmission has been reported in these countries. In the US, the only cases of transmission occurred horizontally by sexual intercourse and not via mosquitoes. Given the ubiquitous presence of the vector, it is expected that ZIKV being locally transmitted not only in Central and South America (with the exception of Chile) as well as the Caribbean but also in the southern part of the US with expected number of both symptomatic and asymptomatic cases of 3-4 million for 2016 (based on mathematical models).

Following the reports of ZIKV infection in Brazil, the national Ministry of Health (MOH) reported an increase in cases of microcephaly, a normal rare congenital disorder characterised according to Estudio Colaborativo Latino Americano de Malformaciones Congenitas (ECLAMC) initially as a small head defined by a head circumference more than three standard deviations bellow the average in appropriated charts for sex and age, i.e. a head circumference below 33 cm (later changed by the Brazilian MOH to 32 cm).  As of January 30 2016, the Brazilian MOH reported 3670 cases being investigated for microcephaly and 404 cases being confirmed either by clinical signs (congenital infection,intracranial calcification, dilatation of cerebral ventricles or changes in the posterior fossa and other clinical signs) or a linkage to ZIKV infection (maternal and/or fatal).
Figure: Reported cases of microcephaly and confirmed cases
in Brazil May 2015- January 2016

In contrast, the MOH of Colombia (another hotspot of confirmed cases of ZIKV) has not reported any increase in microcephaly cases related to ZIKV despite 2100 pregnant women being infected with ZIKV, raising the possibility that ZIKV is not the causative agent of microcephaly in neonates.

During the epidemic in French Polynesia, an increase in autoimmune diseases (leucopenia and thrombocytopenic purpura) and neurological diseases (GBS and meningoencephalitis) as well as a small increase in microcephaly has been observed, but –as in Brazil- co-infections with both CHIKV and DENGV are possible, suggesting that ZIKV per se is not causing microcephaly.

Several factors may account for the discrepancy between Brazil and Colombia regarding a link between ZIKV and the increase in reported microcephaly cases. First, in Brazil the local SINASC birth database records only 1% of birth defects in live births whereas the expected percentage is 3%, i.e. birth defects in Brazil are underreported and with focusing now on a potential link with ZIKV more cases of microcephaly are reported, fostered not only increased attention of the media but also due to mandatory reporting. Second, cases of microcephaly always have been higher in the northeastern region of Brazil. Third, assuming that the number of pregnant women infected with ZIKV is similar to those infected in the 2007 Yap/Micronesia outbreak, the expected number of microcephaly cases would have been around 360. The key problem might however the reporting system itself, since some states report all cases of microcephaly regardless if any link to ZIKV (either previous infection of the mother or infection of the fetus in utero) has been shown into the registry that originally was set up to report only those cases that may be linked to viral infection either of the mother or the fetus/neonate. Consequently, confirmed cases include also cases without ZIKV.
In the absence of any ZIKV vaccine and clear evidence that ZIKV is causing microcephaly however precautions should be taken. Mass extermination of mosquitoes in Brazil and other countries will not only combat ZIKV but also other arboviruses such as Yellow Fever Virus, CHIKV, and DENGV. The number of diagnostic laboratories needs to be increased and being equipped to detect and distinguish emerging viruses and the public health system needs to be improved. Funds need to be make available to care for children born with microcephaly. Given that ZIKV has been shown to be transmitted by sexual intercourse and blood transfusion, issues like access to birth control need to be addressed in particular if ZIKV can be linked to an increase in microcephaly.
In order to understand ZIKV, we need an animal model – not an easy task since ZIKV only replicates in mice if injected intracelebral. As discussed in a previous post, differences between strains circulating in Asia and in Africa as well as those circulating in monkeys need to be addressed as well. Finally the role of transmission of ZIKV via saliva, urine and sexual intercourse needs to be determined as well, although they might only play  a minor role compared to the transmission of ZIKV by mosquitoes. Finally so far the focus is on pregnant woman, ignoring the prevalence of ZIKV among cohabiting couples. Future epidemiology however will give us hopefully a full picture of the presence of ZIKV among different socioeconomic groups. 

Further reading

SMITHBURN KC, & BUGHER JC (1953). Ultrafiltration of recently isolated neurotropic viruses. Journal of bacteriology, 66 (2), 173-7 PMID: 13084555

Diagne CT, Diallo D, Faye O, Ba Y, Faye O, Gaye A, Dia I, Faye O, Weaver SC, Sall AA, & Diallo M (2015). Potential of selected Senegalese Aedes spp. mosquitoes (Diptera: Culicidae) to transmit Zika virus. BMC infectious diseases, 15 PMID: 26527535 
DICK GW, KITCHEN SF, & HADDOW AJ (1952). Zika virus. I. Isolations and serological specificity. Transactions of the Royal Society of Tropical Medicine and Hygiene, 46 (5), 509-20 PMID: 12995440 
MACNAMARA FN (1954). Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 48 (2), 139-45 PMID: 13157159 

Zanluca C, de Melo VC, Mosimann AL, Dos Santos GI, Dos Santos CN, & Luz K (2015). First report of autochthonous transmission of Zika virus in Brazil. Memorias do Instituto Oswaldo Cruz, 110 (4), 569-72 PMID: 26061233 

Schuler-Faccini L, Ribeiro EM, Feitosa IM, Horovitz DD, Cavalcanti DP, Pessoa A, Doriqui MJ, Neri JI, Neto JM, Wanderley HY, Cernach M, El-Husny AS, Pone MV, Serao CL, Sanseverino MT, & Brazilian Medical Genetics Society–Zika Embryopathy Task Force (2016). Possible Association Between Zika Virus Infection and Microcephaly - Brazil, 2015. MMWR. Morbidity and mortality weekly report, 65 (3), 59-62 PMID: 26820244 

Soares de Araújo JS, Regis CT, Gomes RGS, Tavares TR, Rocha dos Santos C, Assunção PM, et al. 
Microcephaly in Northeast Brazil: a review of 16208 births between 2012 and 2015
[Submitted] Bull World Health Organ, E-pub: 4 Feb 2016. doi: 

ECDC (2015)
Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome [Online]. Stockholm: European Centre for Disease Prevention and Control microcephaly-rapid-risk-assessment.pdf [Accessed 06/02/2016]

ECLAMC (Estudio Colaborativo Latino Americano de Malformaciones Congénitas)

Carneiro LA, & Travassos LH (2016). Autophagy and viral diseases transmitted by Aedes aegypti and Aedes albopictus. Microbes and infection / Institut Pasteur PMID: 26774331 

Musso D, Nhan T, Robin E, Roche C, Bierlaire D, Zisou K, Shan Yan A, Cao-Lormeau VM, & Broult J (2014). Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 19 (14) PMID: 24739982 Aubry M, Richard V, Green J, Broult J, & Musso D (2016). Inactivation of Zika virus in plasma with amotosalen and ultraviolet A illumination. Transfusion, 56 (1), 33-40 PMID: 26283013

Musso D, Roche C, Robin E, Nhan T, Teissier A, & Cao-Lormeau VM (2015). Potential sexual transmission of Zika virus. Emerging infectious diseases, 21 (2), 359-61 PMID: 25625872 

Oster, A., Brooks, J., Stryker, J., Kachur, R., , ., Mead, P., Pesik, N., & Petersen, L. (2016). Interim Guidelines for Prevention of Sexual Transmission of Zika Virus — United States, 2016 MMWR. Morbidity and Mortality Weekly Report, 65 (5), 1-2 DOI: 10.15585/mmwr.mm6505e1er

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