The possibly neglected victims: Re‐examining the involvement of children in the chikungunya epidemic

GLOBAL RE‐EMERGENCE OF CHIKUNGUNYA VIRUS AND ESCALATING RISKS FOR CHILDREN

According to a World Health Organization briefing in July 2025, chikungunya has been reported in 119 countries, placing an estimated 5.5 million people at risk of infection. ¹ Recent outbreaks have rapidly expanded across Southeast Asia, the Indian Ocean islands, East Africa, South Asia, and southern China, with locally acquired cases even reported in parts of southern Europe. As vectors such as Aedes albopictus continue to spread globally, the geographic reach of the chikungunya virus (CHIKV) is expected to further expand. In July 2025, a chikungunya outbreak was reported in Foshan, Guangdong Province, China, ² with a rapid spread that echoed patterns previously seen in the Indian Ocean islands and parts of sub‐Saharan Africa. While CHIKV infections in children were first described in India and South Asia as early as the 1960s, ³ the true impact of the virus on pediatric health has been underestimated. Also, within the global child health agenda, attention to this resurging arboviral threat remains limited.

CHIKV, a member of the Togaviridae family and Alphavirus genus, is primarily transmitted by Aedes aegypti and Aedes albopictus mosquitoes. ⁴ Currently, three major genotypes have been identified: West African, East/Central/South African (ECSA), and Asian. ⁵ Of note, a key mutation (A226V in the E1 envelope protein) emerged within the ECSA genotype in 2005, enhancing the virus's replication efficiency in Aedes albopictus and thereby expanding its potential for transmission into subtropical and even temperate regions. ⁶ CHIKV is predominantly transmitted via a human–mosquito–human cycle, with humans serving as the principal reservoir. ⁷ In addition to vector‐borne transmission, vertical transmission, blood transfusion, and organ transplantation have also been documented. However, there is currently no evidence supporting transmission via breastfeeding or sexual contact. ⁸ , ⁹

The term chikungunya originates from the Makonde language in southern Tanzania, meaning “to become contorted” or “to bend up,” vividly describing the posture of patients who are forced to hunch over due to severe joint pain. ¹⁰ This symptom serves as a key clinical differentiator from other arboviral infections, such as dengue fever. Clinically, chikungunya fever is characterized by sudden‐onset high fever, intense arthralgia, and skin rash. ¹¹ In the early decades (1960s to early 2000s), infections in children were typically mild and dengue‐like, manifesting mainly as fever, rash, and mild arthralgia. ³ Since the 2005 outbreaks, perinatal infections and vertical transmission have become increasingly recognized, particularly in regions such as La Réunion Island, India, Sri Lanka, and parts of South America. ¹² Severe pediatric outcomes such as seizures, encephalopathy, congenital heart defects, necrotic skin lesions, and preterm birth have been reported with growing frequency. ³

Currently, there is no specific antiviral treatment for chikungunya, and clinical management relies mainly on supportive care. ¹³ Although vaccine development has made progress, only two vaccines, VLA1553 (a live attenuated vaccine) and PXVX0317 (a virus‐like particle vaccine), have been approved to date, ¹⁴ and widespread deployment remains limited. Of note, beyond the acute febrile and inflammatory phase, a subset of patients may go on to develop chronic arthritis, leading to long‐term impairment in quality of life. Thus, reintegrating children into the global chikungunya public health response is an urgently needed corrective measure in the current control framework.

MULTISYSTEM MANIFESTATIONS AND HEALTH THREATS OF CHIKV INFECTION IN CHILDREN

The recognition and diagnosis of chikungunya fever in children present significant challenges. Due to the high degree of clinical similarity to dengue virus (DENV) and Zika virus infections, especially in symptoms such as fever, rash, myalgia, arthralgia, and thrombocytopenia, pediatric CHIKV infections are often misdiagnosed as dengue. ³ Studies have suggested that fever accompanied by rash and thrombocytopenia without significant bleeding may indicate CHIKV infection, ¹⁵ and the clinical pattern in pediatric patients tends to be more multisymptomatic compared to that in adults. ¹⁶ In a study of hospitalized children initially diagnosed with severe dengue, laboratory testing revealed that only 5.8% had isolated DENV infection, while more than 75% had CHIKV alone or CHIKV‐DENV co‐infection. ¹⁷ Notably, only 11.1% of children with CHIKV or mixed infections tested positive for immunoglobulin M antibodies, ¹⁷ indicating very low diagnostic sensitivity of serological methods in children. This is particularly true during the fourth day of fever, a period of high viremia, when antibody levels have not yet reached a sufficient threshold. This initial misdiagnosis may lead to inappropriate treatment strategies. For instance, nonsteroidal anti‐inflammatory drugs recommended for CHIKV are contraindicated in dengue, potentially affecting clinical decision‐making and outcomes.

Infants under 2 years of age are considered among the most susceptible and vulnerable populations, with higher rates of hospitalization and mortality compared to other age groups. ¹⁸ In this population, factors such as immature immune development, insufficient type I interferon responses, and enhanced viral replication contribute to increased disease severity. During the acute phase, children have higher viral loads than adults, reaching up to 10⁹ RNA copies per milliliter, compared to 10⁶ in adults. ¹⁹ Higher viral load is positively correlated with disease severity. ²⁰ In IFN‐α/βR^−/− mouse models, CHIKV infection more readily spreads to the central nervous system, suggesting that impaired innate immune responses, such as immature type I interferon activity in children, may play a central role in the development of severe disease. ²¹ Background factors such as malnutrition, low birth weight, and immunosuppressive states are also associated with severe pediatric CHIKV infection. ³ , ¹⁵ , ²² Children, especially neonates, face increased risk during perinatal CHIKV infection, typically occurring around the period of maternal viremia before or after delivery. ²³ , ²⁴ Although CHIKV antigens and inflammatory responses have occasionally been detected in placental tissues, such as Hofbauer cells, ²⁵ viral transmission across an intact placental barrier is rare. Most perinatal transmission is believed to result from structural damage to the placenta or maternal blood contamination during labor. ²⁶ A meta‐analysis estimated an overall perinatal transmission risk of 15.5% by pooled analysis, with 15.3% of neonates developing symptoms. Some infants may present with encephalitis, sepsis‐like manifestations, and neurological delays, leading to death. ²⁷ Central nervous system injuries caused by perinatal CHIKV infection may result in lifelong disabilities. During the 2005–2006 outbreak in Réunion Island, the cumulative incidence of CHIKV‐associated encephalitis reached 187 per 100 000 children under 1 year of age, higher than that in other age groups. Three years after infection, 30%–45% of affected children continued to exhibit neurological sequelae, including cerebral palsy, visual impairment, and delayed language development. ²⁸ In another study of 38 full‐term neonates with perinatal CHIKV infection, approximately 45% developed severe neurological complications, including seizures, cerebral edema, and diffuse hemorrhage, with some presenting with myocarditis or hemorrhagic syndrome. ²⁹ By 10 years of age, 57.9% of these children displayed impairments in cognitive and executive functions requiring special education support. Neuroimaging revealed widespread damage to white matter in the frontal lobes and corpus callosum, suggesting long‐term negative effects on brain development in infants. ²⁹ A prospective cohort study from Curaçao further confirmed that among severely affected infants, up to 72.2% exhibited abnormal cognitive or socio‐emotional development within 2 years after infection. Among them, 41.2% had mild to moderate cognitive delay, and 61.1% showed socio‐emotional developmental abnormalities. ³⁰

Although most pediatric CHIKV infections are self‐limited, not all affected children experience mild illness, and the characteristics of infection differ from those in adults (Table 1). CHIKV infection in children often involves multiple organ systems. Cardiac involvement is particularly prominent and may present as arrhythmias, myocarditis, and heart failure. Cases of myocardial hypertrophy, ventricular dysfunction, and cardiac‐related deaths have also been reported in perinatal infections. ³¹ Unlike adults, whose severe cardiac events often arise in the context of underlying comorbidities, most pediatric cases occur in previously healthy children, suggesting that the virus may directly mediate myocardial damage.

TABLE 1.

Comparison of chikungunya virus infection characteristics between children and adults

Characteristics	Children	Adults
Transmission	Mosquito‐borne and possible perinatal transmission	Mosquito‐borne
Sex distribution	Slight female predominance	Relatively equal between sexes
Viral load	Higher during the acute phase (up to 109 copies/mL)	Lower (∼106 copies/mL)
Immune response	Immature immunity, low seroconversion, and weaker humoral response	Mature immunity and higher seroconversion
Pathogenesis	Related to an immature immune system; direct viral neuroinvasion and neuronal apoptosis may play major roles	Some neurological complications may involve autoimmune mechanisms and occur after a latent period.
Clinical manifestations	Prominent fever, rash, and neurological symptoms; less joint involvement	Typical fever, rash, joint pain, symmetric arthritis
Severe manifestations	Higher risk of encephalopathy, hemophagocytic lymphohistiocytosis, and multi‐organ failure in young children	Often linked to underlying conditions (e.g., myocarditis and hypertension)
Chronic sequelae	Lower overall risk; increases with age (esp. adolescents)	Chronic joint pain is common and long‐lasting
Vaccine data	Limited trial data; early pediatric results are promising, but not approved	Approved vaccines available (e.g., Ixchiq and Vimkunya)
Hospitalization/mortality rate	Higher in infants and young children	Influenced by comorbidities
Research attention	Often underrepresented in studies; limited follow‐up	Greater focus on clinical research and vaccine trials

Children are also vulnerable to neurological complications following CHIKV infection. ³² Multiple studies have shown that CHIKV can cause severe complications in children, including encephalopathy, seizures, encephalitis, and even death. ¹⁸ , ³³ , ³⁴ Notably, severe neurological complications such as acute necrotizing encephalopathy remain underrecognized in children. A characteristic imaging feature of this condition is bilateral thalamic necrosis with a trilaminar pattern on apparent diffusion coefficient imaging. ³⁵ Recognizing this distinct radiological signature may aid in early diagnosis and differentiation from other causes of encephalopathy.

Pediatric CHIKV infection may also present with skin manifestations, including bullous rashes, necrotic lesions, and purpura. ³² In contrast, arthralgia is less frequently observed in children than in adults. ³⁶ Nevertheless, predictive model studies indicate that joint pain remains one of the most important diagnostic variables for CHIKV infection. ³⁷ In clinical settings, the combination of fever, joint pain, and rash, especially in patients who test negative for dengue, should raise a strong suspicion for CHIKV.

Beyond acute manifestations, the risk of chronic sequelae following pediatric CHIKV infection also deserves attention. While the incidence of chronic arthritis in adults can reach 60% and persist for months or years, ³⁸ , ³⁹ the overall rate in children is lower, with about 12% experiencing prolonged joint symptoms. ⁴⁰ However, this apparent protection is not equally distributed. Studies have shown that the risk of chronic disease increases with age. In a prospective cohort in Colombia, 24.1% of children under 10 years old experienced chronic joint pain, compared to 35.5% among adolescents aged 15–19 years. ⁴¹ Older children, particularly those nearing puberty, often develop persistent arthritis, skin lesions, and functional impairments similar to adults, with some cases showing no recovery even after 1 year of follow‐up. In children, joint pain most commonly affects the lower limbs, followed by the hands and trunk, while in adults, there is no significant difference in distribution across body regions. ⁴¹ Intermittent joint pain has been identified as a key predictor of chronic progression in children, a pattern not observed in adults. ⁴¹

In summary, children, particularly neonates and young infants, show high susceptibility and a greater tendency toward severe disease following CHIKV infection. Adolescents represent a critical transition stage from self‐limiting to chronic disease. Identifying and protecting these high‐risk pediatric groups should be a key priority in CHIKV prevention and vaccine policy development.

THE ABSENCE OF CHILDREN IN CHIKV PUBLIC HEALTH RESPONSES AND THE NEED FOR A STRATEGIC SHIFT

Despite the growing global threat posed by CHIKV, children have not received adequate attention in mainstream public health response frameworks. In comparison with other arboviruses such as dengue and Zika, CHIKV interventions have shown a clear lack of coverage for children in terms of vaccination, surveillance systems, and targeted strategies. This is evident in epidemiological studies, where children are often not analyzed as a distinct subgroup. ⁴² In resource‐limited settings, pediatric CHIKV incidence may be underestimated due to limited diagnostic capacity. ¹⁹ This phenomenon of “data absence” indirectly affects the allocation of public health resources and the establishment of strategic priorities.

In the field of vaccine development, most CHIKV vaccines that are licensed or in late‐stage clinical trials lack systematic evaluation in pediatric populations. The proportion of children enrolled in clinical trials remains low, and knowledge of immunogenicity, safety, and appropriate dosing in children is still limited. Studies have shown that approximately 16% of real‐time polymerase chain reaction–positive children fail to seroconvert following natural infection, with the majority of these cases occurring in children under 6 years of age. ⁴⁰ This finding suggests a possible developmental immaturity in humoral immune responses in younger children, making it difficult to establish protective immunity through natural exposure. In contrast, vaccine studies in adults have demonstrated higher seroconversion rates and stronger neutralizing antibody responses, compared to children, further impairing effective immune protection.

Although progress has been made in the development of CHIKV vaccines for children in recent years, the overall effort is limited, and current achievements are insufficient to establish an effective population‐level protective barrier. For example, the live attenuated vaccine Valneva VLA1553 (Ixchiq) reported Phase II clinical trial results in 2025 involving 304 children aged 1–11 years. The study showed a 96.5% seroresponse rate in the full‐dose group, with sustained antibody levels at 180 days and no serious adverse events observed. ⁴³ These results laid the groundwork for a planned Phase III pediatric trial, expected to begin in 2026. Another virus‐like particle vaccine, PXVX0317 (VIMKUNYA), was approved in 2025 by the U.S. Food and Drug Administration, European Medicines Agency, and U.K. Medicines and Healthcare products Regulatory Agency for use in individuals aged 12 years and older. To expand its indication, a global Phase III clinical trial was initiated in 2025, aiming to enroll approximately 720 children aged 2–11 years, with a 2‐year follow‐up period. Primary outcomes are expected in the first half of 2028. ⁴⁴ Although these data are encouraging, only two vaccines are currently being evaluated in pediatric trials, and neither has received formal approval for use in younger children. However, this effort does not yet meet the global immunization needs of children, particularly in low‐ and middle‐income countries where CHIKV is endemic.

In the context of global climate change, urbanization, and the continued expansion of mosquito habitats, the risk of CHIKV transmission is increasing, and the exposure environment for children is becoming more complex. ⁴⁵ Following the COVID‐19 pandemic, routine vaccination rates have declined in many regions, further elevating susceptibility to viral diseases among children. In high‐density exposure settings such as schools, daycare centers, and maternity wards, preventive measures and resources remain inadequate, and public health emergency responses often lack systematic consideration of children.

To effectively address the historical underrepresentation of children in CHIKV prevention and control efforts, it is necessary to place greater emphasis on children across research, diagnostics, surveillance, and policy domains. Children should be prioritized in global CHIKV vaccine clinical trial frameworks, with age‐specific standards established for immunogenicity and safety evaluation. Long‐term follow‐up studies are also needed to identify the risk of chronic disease progression. Epidemiological research should strengthen subgroup analysis in children and focus on unique clinical manifestations, such as a higher frequency of lower limb arthralgia and neurological symptoms. A priority should focus on children with symptoms lasting more than 10 days, as they may be at increased risk of chronicity.

In terms of surveillance and intervention, it is recommended to establish sentinel networks for pediatric CHIKV and integrate these into existing arbovirus monitoring systems, including dengue and Zika. Perinatal transmission prevention must also be strengthened through maternal screening during pregnancy, maternal–infant viral testing at delivery, neonatal follow‐up, and early intervention. Additional research on fetal immune status is needed to optimize perinatal management strategies. Technically, international organizations such as the World Health Organization should include pediatric CHIKV as a priority topic in the global neglected tropical disease agenda. In low‐resource settings, molecular diagnostic platforms that are automated, require small sample volumes, and support multiplex pathogen detection should be promoted to address diagnostic challenges and surveillance gaps, especially in children with atypical symptoms or difficult sampling conditions. In children presenting with neurological symptoms, the integration of advanced neuroimaging techniques, where available, may also aid in early detection of central nervous system involvement and support clinical decision‐making. Furthermore, countries should be encouraged to develop tropical disease treatment guidelines tailored for pediatric patients. Until vaccines become widely available, children should be prioritized for mosquito bite prevention and active case detection. This includes the promotion of picaridin‐based repellents, maternal and child hygiene measures, and community‐level health education to enhance protective capacity.

CONCLUSION

As CHIKV continues to spread globally, children are facing an underrecognized health threat. From infection detection and clinical diagnosis to vaccine development and public health response, children have largely been absent from existing systems. Current prevention and control strategies require a fundamental shift that places children at the center of monitoring networks, clinical trials, and policy agendas. Addressing this critical gap will help to provide a comprehensive CHIKV response system to enhance the effectiveness of global arbovirus control efforts.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Wang R, Kain KC, Xie Z. The possibly neglected victims: Re‐examining the involvement of children in the chikungunya epidemic. Pediatr Investig. 2025;234–240. 10.1002/ped4.70022