Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

Mosquito-transmitted alphaviruses causing human rheumatic disease are globally distributed and include chikungunya virus, Ross River virus, Barmah Forest virus, Sindbis virus, o'nyong-nyong virus and Mayaro virus. These viruses cause endemic disease and, occasionally, large epidemics; for instance, the 2004-2011 chikungunya epidemic resulted in 1.4-6.5 million cases, with imported cases reported in nearly 40 countries. The disease is usually self-limiting and characterized by acute and chronic symmetrical peripheral polyarthralgia-polyarthritis, with acute disease usually including fever, myalgia and/or rash. Arthropathy can be debilitating, usually lasts weeks to months and can be protracted; although adequate attention to differential diagnoses is recommended. The latest chikungunya virus epidemic was also associated with some severe disease manifestations and mortality, primarily in elderly patients with comorbidities and the young. Chronic alphaviral rheumatic disease probably arises from inflammatory responses stimulated by the virus persisting in joint tissues, despite robust antiviral immune responses. Serodiagnosis by ELISA is the standard; although international standardization is often lacking. Treatment usually involves simple analgesics and/or NSAIDs, which can provide relief, but better drug treatments are clearly needed. However, the small market size and/or the unpredictable and rapid nature of epidemics present major hurdles for development and deployment of new alphavirus-specific interventions.

BackgroundLittle is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection.MethodsThe CHIMERE ambispective cohort study compared the neurocognitive function of 33 p-CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ≤85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms.ResultsThe mean DQ score was 86.3 (95%CI: 81.0–91.5) in infected children compared to 100.2 (95%CI: 98.0–102.5) in uninfected peers (P<0.001). Fifty-one percent (n = 17) of infected children had a GND compared to 15% (n = 21) of uninfected children (P<0.001). Specific neurocognitive delays in p-CHIKV-infected children were as follows: coordination and language (57%), sociability (36%), movement/posture (27%). After adjustment for maternal social situation, small for gestational age, and head circumference, p-CHIKV infection was found associated with GND (incidence rate ratio: 2.79, 95%CI: 1.45–5.34). Further adjustments on gestational age or breastfeeding did not change the independent effect of CHIKV infection on neurocognitive outcome. The mean DQ of p-CHIKV-infected children was lower in severe encephalopathic children than in non-severe children (77.6 versus 91.2, P<0.001). Of the 12 cases of CHIKV neonatal encephalopathy, five developed a microcephaly (head circumference <−2 standard deviations) and four matched the definition of cerebral palsy. MRI scans showed severe restrictions of white matter areas, predominant in the frontal lobes in these children.ConclusionsThe neurocognitive outcome of children exposed to perinatal mother-to-child CHIKV infection is poor. Severe CHIKV neonatal encephalopathy is associated with an even poorer outcome.

Chikungunya virus, a mosquito-borne arbovirus, was responsible for a massive epidemic in La Réunion Island during 2005 to 2006. The disease is usually benign, but neurologic involvement, with sometimes fatal outcome, has been described. We report a retrospective hospital-based pediatric series of 30 children (23 boys and 7 girls) who presented neurologic manifestations of chikungunya such as encephalitis (n = 12), febrile seizures (n = 10), meningeal syndrome (n = 4), and acute encephalopathy (n = 4). Cerebrospinal fluid biological and cytological analyses (n = 23) were unremarkable except for 1 case of acute disseminated encephalomyelitis. The presence of viral genome in cerebrospinal fluid was inconstantly positive. Brain magnetic resonance imaging (MRI) scans (n = 14) were abnormal in 5 cases. Electroencephalography was nonspecific. Two patients died. At discharge and 6 months later, 5 children had neurologic sequelae. Patients with initial severe neurologic presentation and having pathological brain MRI had more sequelae or fatal disease.

Chikungunya virus (CHIKV) surprised medical workers by a massive outbreak in the Indian Ocean region, reaching Europe in 2007, with exceptional pathologies in infants and elderly patients. Although CHIKV was recently shown to persist in myoblasts, monocytes, and macrophages, we argued that robust antiviral mechanisms, including apoptosis, are essential to ward off the virus. Herein, we tested the capacity of CHIKV to mobilize the apoptotic machinery in HeLa cells as well as primary fibroblasts, making use of several inhibitors of caspases, cell blebbing, and engulfment of the apoptotic blebs by neighboring cells. CHIKV triggered apoptosis through intrinsic and extrinsic pathways. Bystander apoptosis was also evidenced in neighboring cells in a caspase-8-dependent manner. Remarkably, by hiding in apoptotic blebs, CHIKV was able to infect neighboring cells. In HeLa cells, these events were inhibited specifically by zVAD-fmk and DEVD-cho (caspase inhibitors), blebbistatin, Y-27632 (ROCK inhibitor), and genistein, annexin V, and cytochalasin B (inhibitors of blebbing and engulfment). These CHIKV-apoptotic blebs were also capable of infecting macrophages (primary cultures, MM6- and THP1-PMA differentiated cells) otherwise refractory to infection by CHIKV alone. Remarkably, viral replication in macrophages did not yield a proinflammatory response. We describe a novel infectious mechanism by which CHIKV invades host cells and escapes the host response.