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Positive IgM for Zika virus in the cerebrospinal fluid of 30 neonates with microcephaly in Brazil

2016; Elsevier BV; Volume: 387; Issue: 10030 Linguagem: Inglês

10.1016/s0140-6736(16)30253-7

1474-547X

Marli Tenório Cordeiro, Lindomar Pena, Carlos Alexandre Antunes de Brito, Laura H. V. G. Gil, Ernesto T. A. Marques,

Viral Infections and Vectors

The epidemic of microcephaly in Brazil has been declared a Public Health Emergency of International Concern by WHO.1WHOWHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome.http://www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/Date: Feb 1, 2016Google Scholar The declaration states that a causal relationship between Zika virus infection during pregnancy and microcephaly is strongly suspected, although not yet scientifically proven.1WHOWHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome.http://www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/Date: Feb 1, 2016Google Scholar The hesitancy to accept causation in the presence of much epidemiological circumstantial evidence is due to the paucity of laboratory confirmation of Zika virus in affected neonates. Here, we report the serological confirmation of Zika virus infection in the CNS of 30 neonates with microcephaly. From Oct 21 to Oct 30, 2015, we collected blood and cerebrospinal fluid (CSF) samples from 31 neonates with microcephaly in the state of Pernambuco, Brazil, most of whom were born between Sept 12 and Oct 27, 2015, in public maternity hospitals. The samples were collected on average 9 days after birth (range 1–40 days; 20 of 31 neonates in the first week after birth). The neonates were kept in hospital while results from brain imaging and laboratory tests were awaited. Serum and CSF samples were tested by RT-PCR or real-time RT-PCR, or both, for Zika, dengue, and chikungunya genomes. Viral RNA was not detected, probably because infections in the mother occurred at least 6 months before giving birth. The 31 samples of CSF and serum were tested for IgM specific for Zika virus using capture ELISA based on the US Centers for Disease Control and Prevention (CDC) Emergency Use Authorization protocol with reagents from Robert Lanciotti (CDC Fort Collins, CO, USA). Simultaneous tests were done for dengue virus to investigate cross-reaction between these two flaviviruses. The ratio of patient optical density to negative control value (P/N) was calculated (table).2Lanciotti RS Kosoy OL Janeen J et al.Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007.Emerg Infect Dis. 2008; 14: 1232Crossref PubMed Scopus (1606) Google ScholarTableIgM against Zika virus and dengue virus in the serum and CSF of neonates with microcephaly, Pernambuco State, Brazil, 2015, by age (days) at testingSerum IgMCSF IgMZika virusDengue virus type 1–4 mixtureZika virusDengue virus type 1–4 mixtureInterpretation1 day17·02·712·11·5Positive for Zika virus1 day20·62·916·12·4Positive for Zika virus1 day20·67·814·84·2Zika virus cross-reacting with dengue virus1 day5·20·79·31·0Positive for Zika virus1 day8·21·716·33·4Zika virus cross-reacting with dengue virus2 days6·20·915·01·5Positive for Zika virus2 days6·20·914·52·7Positive for Zika virus2 days7·50·916·12·9Positive for Zika virus2 days4·70·914·21·7Positive for Zika virus2 days12·71·215·92·9Positive for Zika virus2 days10·51·715·82·1Positive for Zika virus3 days10·51·114·82·4Positive for Zika virus3 days15·62·614·82·4Positive for Zika virus3 days16·01·616·41·9Positive for Zika virus4 days3·20·613·51·9Positive for Zika virus5 days3·90·89·30·8Positive for Zika virus5 days11·45·515·54·6Zika virus cross-reacting with dengue virus7 days5·90·713·11·2Positive for Zika virus7 days2·10·915·00·9Positive for Zika virus7 days15·42·213·51·6Positive for Zika virus8 days9·61·815·71·7Positive for Zika virus10 days4·01·514·56·6Zika virus cross-reacting with dengue virus11 days0·91·80·61·9Negative for Zika virus12 days16·16·215·75·0Zika virus cross-reacting with dengue virus13 days15·32·612·11·3Positive for Zika virus17 days6·41·816·11·4Positive for Zika virus17 days16·02·814·83·0Positive for Zika virus22 days4·11·215·52·7Positive for Zika virus23 days3·42·616·15·7Zika virus cross-reacting with dengue virus36 days2·10·915·61·9Positive for Zika virus40 days12·21·113·30·8Positive for Zika virusELISA values are patient optical densities divided by negative control densities (P/N); values less than 2 were considered negative, 2–3 equivocal, and more than 3 positive. CSF=cerebrospinal fluid. Open table in a new tab ELISA values are patient optical densities divided by negative control densities (P/N); values less than 2 were considered negative, 2–3 equivocal, and more than 3 positive. CSF=cerebrospinal fluid. Zika-specific IgM was detected in 30 (97%) of 31 CSF samples and in 28 (90%) of 31 serum samples. One CSF sample tested negative. Monotypic response to Zika virus in the CSF was confirmed by plaque reduction neutralisation test. Since IgM does not cross either the placenta barrier or the blood–brain barrier, the presence of IgM in the CSF indicates that the neonate had the infection in the CNS.3Carrolla ID Toovey SA Dengue fever and pregnancy—a review and comment.Travel Med Infect Dis. 2007; 5: 3183Google Scholar, 4Tunkel AR Glaser CA Bloch KC et al.The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 47: 303-327Crossref PubMed Scopus (709) Google Scholar The finding of Zika-specific IgM in the CSF of those 30 of 31 neonates with brain abnormalities indicates that they had a congenital infection with Zika virus. We believe that this is very strong evidence that the microcephaly was a consequence of Zika virus infection. We declare no competing interests. We thank Laura C Rodrigues and the Microcephaly Epidemic Research Group for their support.