To the Editor:

The first cases of a new illness involving fever and rash that was deemed to have been caused by Zika virus (ZIKV) infection in Brazil were reported in 2014, and the presence of the virus was confirmed in April 2015. In October 2015, an unusual increase in the number of cases of microcephaly among newborn infants was reported in Brazil; this disorder was apparently linked to ZIKV infection. From the first investigations of microcephaly, and from subsequent studies in Brazil and elsewhere, it is now clear that ZIKV is a cause of a range of neurologic disorders, including the Guillain–Barré syndrome (GBS) in adults and abnormalities in fetuses and newborn infants, including microcephaly.1 Here, we use routinely collected surveillance data and medical records to show how the spread of ZIKV in Brazil was associated with an increase in the incidence of GBS and microcephaly during 2015 and 2016. We also highlight the limitations of routinely collected data, which cannot yet explain, for example, why there were many fewer cases of microcephaly than expected in 2016.

To explore the temporal and geographic distribution of ZIKV infection, we used data provided by municipalities and states in each of the five regions of Brazil, as compiled by the Ministry of Health. These data describe the number of suspected and confirmed cases of ZIKV infection and of cases reported as GBS and microcephaly (Sections 1 and 2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

Figure 1. Figure 1. Suspected Cases of Zika Virus (ZIKV) Infection, Guillain–Barré Syndrome, and Microcephaly in Brazil (2015–2016). Panel A shows the suspected cases of ZIKV infection that were reported weekly in clinics and hospitals in the five regions of Brazil during 2015 and 2016. Panel B shows the suspected cases of ZIKV infection, Guillain–Barré syndrome (GBS), and microcephaly in 2015 and 2016, along with the predicted cases of microcephaly in 2015 and 2016. The suspected cases of GBS are reported as excess cases — that is, the numbers of cases that surpass the average number reported each week in the years before the ZIKV epidemic (in 2010 to 2014). In 2015, the incidence of microcephaly followed the identification of ZIKV infection and GBS by an interval of 23 weeks on average. However, there was no predicted resurgence of microcephaly after the apparent seasonal increases in the incidence of ZIKV infection and GBS in 2016. Case series in Panels A and B are plotted as 3-week moving averages. Data were collected by the Ministry of Health in Brazil.

The number of suspected cases of ZIKV infection began to increase in the northeast region of Brazil starting in March 2015 (week 9) (Figure 1A). Cases were subsequently reported in the other four regions, beginning in late 2015 and greatly expanding in 2016. Together with phylogenetic analysis of viral RNA sequences,2 these findings suggest that ZIKV was dispersed widely after a single introduction of infection in the northeast region.

The spread of ZIKV in Brazil has been associated with an increase in the incidence of neurologic disorders, most visibly in cases reported as GBS and microcephaly. Weekly reports of cases from hospitals reveal that the incidence of GBS was markedly higher in the northeast region in 2015 and 2016 and in other areas of Brazil in 2016 than in the years before the ZIKV epidemic (2010 to 2014) (Figure 1B, and Section 3 in the Supplementary Appendix). The rise and fall of suspected cases of ZIKV infection and GBS were approximately synchronous in 2015, although a comparison of the two case series suggests that the incidence of ZIKV infection was underreported in the northeast region early in 2015 (Figure 1B). In Pernambuco state, some of the cases of ZIKV infection were probably misclassified (mainly as dengue) in clinics in 2015, and such misclassification could have been widespread.3

The incidence of microcephaly peaked in late November 2015 (week 47), an average of 23 weeks after the start of the epidemics of ZIKV infection and GBS (Figure 1B). If there was a delay of 3 weeks between the exposure of patients to ZIKV and the development of GBS (i.e., an incubation period plus a typical reporting delay), infections leading to microcephaly would have occurred on average 12 weeks after conception (i.e., with about half the cases occurring during the first trimester and half later in pregnancy) (Section 4 in the Supplementary Appendix).

In view of the apparent resurgence of ZIKV infection and GBS early in 2016, we anticipated a further increase in cases of microcephaly later in the year. But such a resurgence did not happen (Figure 1B), for at least three possible reasons. The first possibility is that in 2016, infections that were attributed to ZIKV and that were linked to an increase in the incidence of GBS were caused by another arbovirus that is also transmitted by Aedes aegypti mosquitoes, since by then there was herd immunity against ZIKV infection after widespread infection in 2015.4 Dengue virus has been identified throughout the Americas (Section 5 in the Supplementary Appendix) but does not appear to be a major cause of GBS. Chikungunya virus was introduced into Brazil in 2014 and caused successively larger epidemics in the northeast region in 2015 and 2016. Chikungunya is a cause of GBS as well, and some chikungunya infections were evidently misclassified as ZIKV infection in Pernambuco in 2016 (Brito C: personal communication). Chikungunya has not been identified as a cause of microcephaly.5

A second possibility is that ZIKV infection during pregnancy is a necessary but not a sufficient condition for the development of microcephaly in newborn infants — in other words, the presence of some other unknown cofactor that is not essential for GBS is required. A third possibility is that fear of the adverse consequences of ZIKV infection led to fewer conceptions or a greater number of pregnancy terminations in 2016. Routinely collected data are not yet complete enough to determine whether birth rates fell or abortion rates increased in 2016 (Section 6 in the Supplementary Appendix). However, since any changes in the number of live births would be small, this hypothesis cannot be the principal reason why few cases of microcephaly were reported in the northeast region in 2016.

Among these hypotheses, the first seems to be the most plausible — that is, both ZIKV and chikungunya viruses are important causes of GBS, but among the arboviruses circulating in Brazil, only ZIKV causes microcephaly and other neurologic disorders after infection during pregnancy. However, the three possibilities are not mutually exclusive, and none can be ruled out with the present data. Further investigations are needed — aided by more sensitive and specific diagnostic tools and the careful interpretation of surveillance data — to clarify the causal links between arbovirus infections, GBS, and microcephaly in Brazil.

Wanderson K. de Oliveira, M.D.

Eduardo H. Carmo, Ph.D.

Ministry of Health, Brasilia, Brazil

Claudio M. Henriques, M.D.

Oswaldo Cruz Foundation, Brasilia, Brazil

Giovanini Coelho, M.D.

Ministry of Health, Brasilia, Brazil

Enrique Vazquez, M.D., Dr.PH.

Juan Cortez-Escalante, Ph.D.

Joaquin Molina, M.D.

Pan American Health Organization, Brasilia, Brazil

Sylvain Aldighieri, M.D.

Marcos A. Espinal, M.D., Dr.PH.

Pan American Health Organization, Washington, DC

Christopher Dye, D.Phil.

World Health Organization, Geneva, Switzerland

[email protected]

Supported by the Ministry of Health in Brazil, the Pan American Health Organization, and the World Health Organization. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on March 29, 2017, and updated on April 6, 2017, at NEJM.org.