Neurologic sequelae of severe chikungunya infection in the first 6 months of life: a prospective cohort study 24-months post-infection

Chikungunya virus is a mosquito-borne alphavirus, known for causing acute emerging public health problems. A small group of patients presents with severe disease. Infants, immunocompromised patients and the elderly are at higher risk for severe disease, with neuro-invasive manifestations and multi-organ involvement. Recent studies have described an association between chikungunya and neurological sequelae [1‐3].

Since 2000, large outbreaks of the virus have spread to previously non-endemic regions. In addition the chikungunya virus, which is normally transmitted by Aedes aegypti has adapted genetically to Aedes albopictus, posing a threat for a more global distribution of the virus [4‐7]. In 2013, the first cases of an outbreak in the Western hemisphere of the Asian genotype of the virus were identified. From there, more than a million confirmed or suspected cases were identified in 48 countries or territories in the Caribbean and the Americas [4]. On the island of Curaçao, part of the Dutch Antilles, 835 laboratory proven cases of chikungunya virus infections, of the Asian genotype were reported. It is estimated that 50.000–75.000 inhabitants were infected, corresponding to 30–50% of the total population [2, 8].

Patients with chikungunya infections generally present with high fever, arthralgia, and an erythematous, maculopapular rash, and irritability in infants specifically. Severe infection can present with encephalitis, myocarditis, hepatitis, and multi-organ failure [4, 9]. Convulsions, encephalopathy and intracranial haemorrhage, in some cases leading to death, have been reported [1, 10‐14]. Infections occur either through vertical transmission from infected women to newborns peri-partum or through mosquito bites [1, 13]. Information about long-term cognitive effects among infected infants is scarce. Available data show suggest significant global cognitive delay in 51% of mother-to-child vertical infected neonates at 2 years of age [3].

During the chikungunya epidemic in Curaçao in 2014–2015, infants under the age of 6 months with suspected chikungunya infection were admitted to hospital for clinical observation and analysis according to local protocol. We observed severe disease in perinatal and postnatal infected infants [10, 15]. We hypothesized that young infants who had been postnatally infected in the first 6 months of life, could be prone to global developmental delay as well. The objective of this study was to evaluate whether these chikungunya infected neonates and infants presenting with severe disease were prone to developmental deficits.

A prospective cohort study was conducted between January 2017 and April 2017. Participants in this study were selected from our previously described cohorts [10, 15]. Baseline data was collected retrospectively. The follow-up study was developed prospectively. The research protocol was developed according to the RECORD guidelines (Reporting of studies Conducted using Observational Routinely-collected health Data) and the ICMJE recommendations (Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals) [16, 17].

The study was approved by the Medical Ethical Board of the Saint Elisabeth Hospital in Curaçao (reference number 2016–002). All parents of the children who entered this study signed a written informed consent. Documents and informed consent were provided in both official languages, Dutch and Papiamentu.

This is the first study to describe long-term neurological outcomes in a highly selected cohort of infants with a severe chikungunya infection in their first 6 months of life. Using an uncontrolled design, we identified delayed cognitive development in up to 41.2% of the infants, and an abnormal social emotional development score (ITSEA) in 61% of the infants presenting with a severe chikungunya infection. In as much as 72% of the children we found an abnormal score on either BSID-III or ITSEA. The delayed cognitive development was not attributable to the included perinatally infected children. We did not observe other sequelae like epilepsy or abnormal muscle tone. There was a mix of socio-emotional problems.

Recent evidence describes long-term sequelae associated with chikungunya virus infections in vulnerable patients. A systematic review of long-term sequelae described three studies focussing on mother-to-child transmission [3, 13, 28], of which the CHIMERE cohort study of Gérardin et al. (2014) was the only one that addressed development after perinatal chikungunya infection. Our study is the first to investigate child development after a postnatal chikungunya infection [3]. In the CHIMERE cohort, severe illness was seen in 52.6% of the vertically infected neonates, of which nine developed encephalopathy and two intracranial haemorrhage [1, 13]. The CHIMERE cohort study (N = 33) showed that 51% of the vertically infected infants had moderate or severe global developmental delay at 2 years of age, as assessed by the Revised Brunet-Lézine (RBL) scale, compared to a control group of 135 uninfected children, wherein 16% had moderate global developmental delay (p < 0.001). When these authors also included subscores, 73.9% of the infected infants had a developmental deficit. The non-controlled design and inclusion of a different population limits detailed comparison with our infants. Nevertheless, these figures are in the same range as our results with cognitive delay in 41.2% and any abnormal score in up to 72.2%, but there were no children with severe delays (cognitive score < 70) in our case series. The CHIMERE cohort study combined children with encephalitis and ‘mild prostration’ (defined as neonates unable to be breastfed or bottle-fed), and even in this ‘mild prostration’ group, up to 38.1% had a global developmental deficit, underlining the seriousness of the neuroinvasive effects of chikungunya to the young brain [1, 3]. Although arthritis and chronic arthralgia are the most frequent long-term sequelae in adults, in our cohort, similarly to the CHIMERE cohort, the developmental delay was mainly cognitive and the motor development was less affected [1, 3].

A systematic review of neuroinvasive chikungunya showed a bimodal patient age distribution, with complications more frequently seen in the youngest and the elderly [29]. Among neonates, infants and elderly with comorbidities, neurologic complications, mainly encephalitis and acute encephalopathy, are assumed to be directly related to the acute infection. In contrast, for otherwise healthy adults there is a symptom-free interval between the infection and neurologic disorders (such as acute disseminated encephalomyelitis, optic neuropathy and Guillain–Barré syndrome) suggesting that these neurologic complications are due to an underlying autoimmune process [29]. The neuroinvasive potential of the chikungunya virus is supported by in vitro studies that demonstrate that the virus is capable of infecting mouse brain neurons, astrocytes and oligodendrocytes. The infection induces apoptosis in neurons and astrocytes, together with initializing the production of pro-apoptotic factors [29‐31]. This supports our hypothesis that young infants who lack a fully developed, mature innate and adaptive immune response as well as perinatally infected neonates are at risk for developmental disorders, although the exact pathogenesis in humans remains to be determined [3, 29]. Since the chikungunya virus does not cross the placenta [13], we presume that the developmental delay among perinatally infected neonates is induced after birth analogous to postnatally infected young infants. Future research will have to determine up to what age and which infants are at risk for developmental delay.

Although the 2 years outcomes were comparable, the genotype of the chikungunya virus in the CHIMERE cohort on La Réunion was different from that in Curaçao. In Curaçao the Asian genotype was identified whereas the one in the CHIMERE cohort was the East Central South Africa genotype (ECSA) [3, 8]. The neurovirulence of the Asian genotype was recognized with increasing reports of neurologic complications in cases infected in the Americas after the 2014 epidemic. Although in vivo mice studies performed with the ECSA and the Asian genotype demonstrated neurovirulence with both strains. The Asian genotype showed higher mortality and higher apoptosis gene expression [29, 32].

Although prospective recruitment is a strength of our study, we acknowledge several major limitations. This is a small sample of a highly selected group of severely ill children. The diagnosis of chikungunya infection was made by immunoglobulin assay because PCR was not available in our laboratory at the time when patients were enrolled in the study. Consequently, some patients may have had co-infection with other viruses. Bacterial cultures were performed on all patients. Although other arboviruses may present with sepsis-like illness and encephalitis with overlapping clinical cases, no long-term cognitive delay of this level has been described for locally circulating arboviruses, mainly dengue and Zika [33, 34]. Of importance, Zika was not identified on Curaçao until 2016 [35]. Therefore it is possible that the cognitive delay that we observed was not the results of chikungunya infection alone. Another important limitation was the lack of a control group. There are no normative studies for the BSID-III and the ITSEA for the Dutch Antilles, nor did we include a control group. Therefore over estimation, but also underestimation of the describes outcomes cannot be excluded. Finally, since the investigators who performed the neurologic and developmental assessments were not blinded, they may have been biased.

Our data contribute to the scarce existing knowledge regarding the impact on development of chikungunya virus infection in young infants. Although causality and the extent to which chikungunya contributes to cognitive delay and the development in late childhood is still to be determined, we believe that these data will be helpful to policy makers and paediatricians caring for infants up to 6 months of age who had chikungunya infection. Future studies are needed to determine the attributable effect of chikungunya on cognitive delay and development in these infants. When causality of chikungunya and developmental deficits are proven, structured interventions can be implemented, which is of importance for participation in society later in life. We hope that these data will inspire researchers to continue investigating the impact of chikungunya infection on suspected vulnerable groups, as well as to encourage the development and implementation of public health measures and therapeutic options, like vaccines and neutralizing antibodies. Advances such as maternal antenatal vaccination could limit the burden of disease in this vulnerable population [29, 30, 36].

In the first study to describe the effect of chikungunya infections in early infancy, nearly three quarters of the children had mild cognitive delay or social emotional problems at 24 month follow-up. Although there are important limitations to our study, the association of neurologic sequelae with chikungunya infection in infants is worrisome. Further studies are needed to determine causality. In the meantime preventive measures during outbreaks should also include young infants and those who have been infected in early infancy should receive follow up.