Cytokines profiling in patients infected with Chikungunya virus in Northeast BrazilAbstract
Chikungunya is an arbovirus transmitted to humans through the bite of an infected arthropod, specifically Aedes mosquitoes. In Brazil, the first autochthonous cases were reported in 2014, and the disease has since become endemic in several regions of the country. The aim of this study was to evaluate serum cytokine levels in patients with Chikungunya fever (CHIKF) attended in public hospitals in a state in the Northeast region of Brazil. A total of 744 serum samples from patients were analyzed, and 547 were diagnosed with CHIK by ELISA (IgM-positive). Among these, 409 samples were from female patients and 138 from male patients, comprising 377 adults, 82 elderly individuals, and 88 children and adolescents. Most of the patients resided in urban areas (n= 490; 89.4%). Cytokine quantification was performed on a random subset of 240 samples using flow cytometry with the CBA Human Th1/Th2/Th17 cytokine kit. Interleukin-6 (IL-6) was identified as the most prevalent cytokine, particularly during the second week following symptom onset. Given that elevated IL-6 levels contribute to a positive feedback loop that exacerbates arthralgia, the detection and quantification of IL-6 may serve as a valuable biomarker for CHIKV diagnosis, prognosis, and severity assessment, as well as guiding clinical management.
Keywords:
Chikungunya; cytokines; inflammation
Resumo
Chikungunya é um arbovírus transmitido aos seres humanos através da picada de um artrópode infectado, especificamente mosquitos do gênero Aedes. No Brasil, os primeiros casos autóctones foram relatados em 2014, e a doença tornou-se endêmica em várias regiões do país. O objetivo deste estudo foi avaliar os níveis séricos de citocinas em pacientes com febre chikungunya (CHIKF) atendidos em hospitais públicos de um estado da região Nordeste do Brasil. Um total de 744 amostras de soro de pacientes foram analisadas e 547 foram diagnosticadas com CHIK por ELISA (IgM-positivo). Destes, 409 amostras foram de pacientes do sexo feminino e 138 de pacientes do sexo masculino, compreendendo 377 adultos, 82 idosos e 88 crianças e adolescentes. A maioria dos pacientes residia em área urbana (n= 490; 89,4%). A quantificação de citocinas foi realizada por citometria de fluxo em um subconjunto aleatório de 240 amostras utilizando o kit de citocinas Cytometric Bead Array (CBA) Human Th1/Th2/Th17. A interleucina-6 (IL-6) foi identificada como a citocina mais prevalente, particularmente durante a segunda semana após o início dos sintomas. Dado que níveis elevados de IL-6 contribuem para um ciclo de feedback positivo que exacerba a artralgia, a detecção e quantificação de IL-6 podem servir como um biomarcador valioso para o diagnóstico, prognóstico e avaliação da gravidade do CHIKV, além de orientar o manejo clínico.
Palavras-chave:
Chikungunya; citocinas; inflamação
1. Introduction
Chikungunya Fever (CHIKF) is a disease caused by the Chikungunya virus (CHIKV), which is transmitted by Aedes aegypti and Aedes albopictus mosquitoes infected with the virus (Tsetsarkin et al., 2007). CHIKV is an enveloped alphavirus belonging to the Togaviridae family and has a single-stranded, positive-sense RNA genome (Fox and Diamond, 2016).
The term chikungunya originates from the Makonde language, spoken in southeastern Tanzania and northern Mozambique. It means “that which bends up”, referring to the stooped posture of patients suffering from severe arthralgia, a hallmark symptom of the disease (Kucharz and Cebula-Byrska, 2012).
In 2004, a major outbreak in Africa facilitated the rapid spread of the virus to Asia, Europe, and the Americas, establishing CHIKV as a global public health threat (Zhang et al., 2019). In the Americas alone, more than one million cases were reported in 2017. Brazil accounted for over 150,000 of these cases, with the state of Rio de Janeiro becoming a major hub of transmission partly due to the increased influx of tourists and international travelers during the 2016 Olympic Games (Xavier et al., 2019).
Following the bite of an infected mosquito, symptomatic disease typically develops after an incubation period of approximately 10 days. However, not all infected individuals present clinical symptoms. Serological studies suggest that between 3% and 28% of individuals with anti-CHIKV antibodies may have asymptomatic infections. Nonetheless, both symptomatic and asymptomatic individuals in the acute phase can contribute to disease transmission if competent vectors are present in the environment (Moya et al., 2014)
Clinically, patients with CHIKF commonly present fever, myalgia, severe arthralgia, headache, nausea, fatigue, and cutaneous rash (Fox and Diamond, 2016; Amdekar et al., 2017). Following the acute phase, which typically lasts from 3 to 10 days, some individuals progress to two subsequent stages: a subacute phase, characterized by persistent joint pain lasting up to three months, and a chronic phase, in which chronic arthritis may persist for months or even years after initial infection (Fox and Diamond, 2016; Borgherini et al., 2008; Pialoux et al., 2007; Renault et al., 2007; Kennedy et al., 1980).
Although CHIKF is generally not associated with high mortality, it exhibits a strong epidemic potential and is marked by significant morbidity, particularly due to prolonged joint involvement. This results in decreased productivity, social functioning, and overall quality of life (Horcada et al., 2015).
Recent advances in the understanding of arboviral pathophysiology have highlighted the role of the host immune response, particularly the presence of elevated pro-inflammatory cytokines in both acute and chronic manifestations of diseases such as dengue, chikungunya, and Zika virus infections (Fox and Diamond, 2016; Tanabe et al., 2019; Ninla-Aesong et al., 2019; Backonja et al., 2008). The correlation between heightened serum cytokine levels and persistent symptoms underscores the potential for novel therapeutic strategies aimed at modulating the inflammatory response. Targeting these cytokines could offer relief from chronic pain and inflammation, which are often refractory to conventional treatment.
In this context, the present study aimed to evaluate the serum levels of pro- and anti-inflammatory cytokines in patients infected with Chikungunya virus, in order to explore their association with disease severity and potential prognostic value.
2. Material and Methods
2.1. Ethics statement
The study was approved by the Research Ethics Committee of Ceuma University (process number 1.570.391/2016) and conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants or from parents/legal guardians in the case of minors.
2.2. Participants
This study population consisted of patients diagnosed with CHIKV infection, treated in public health units across 37 municipalities in the state of Maranhão, Brazil, during the 2016–2017 outbreak.
A total of 744 serum samples were collected by venipuncture into EDTA-containing tubes and stored at -80 ºC until further analysis. The presence of CHIKV-specific IgM antibodies was confirmed by enzyme-linked immunosorbent assay (ELISA).
2.3. Demographic data
Epidemiological and clinical data were collected from patients at the time of sample acquisition. The variables assessed included sex, age, region of origin (classified as rural, peri-urban, or urban), and time since onset of symptoms (1-7, 8-14, 15-21, and 22-28 days). For analytical purposes, patients were grouped into three age categories: children and adolescents (0-18 years), adults (19 to 59 years), and elderly individuals (60-85 years).
2.4. Serum cytokine evaluation
From the total sample pool, 240 serum samples were randomly selected for cytokine quantification. The following cytokines were measured: IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, TNF-α, and INF-α. Quantification was performed using flow cytometry with the Cytometric Bead Array (CBA) Human Th1/Th2/Th17 cytokine kit (Becton Dickinson Biosciences, San Jose, CA, USA), following the manufacturer’s instructions.
2.5. Statistical analysis
Statistical analyses were performed using the GraphPad Prism software, version 8.01. Results were expressed as mean ± standard deviation (SD). The normality test was performed through the D’Agostino and Pearson test. Comparisons between groups were made using the Kruskal-Wallis test.
3. Results
3.1. Serological analysis and geographic distribution
A total of 744 serum samples were analyzed, of which 547 (73.5%) tested positive for CHIKV-specific IgM antibodies by ELISA. The virus was detected in samples from 37 municipalities across the state. The highest number of cases was recorded in São Luis, the state capital, with 253 cases (46.25%), followed by Caxias (16.64%), Paço do Lumiar (5.30%), Santa Inês (4.94%), and others (Table 1).
Geographical origin of patients with Chikungunya fever treated in public hospitals in Northeast Brazil during the outbreak from February 2016 to October 2017.
To date, only one study has specifically addressed CHIKV epidemiology in Maranhão (Nunes et al., 2019). Most of the existing data come from public health bulletins, which reported a significant increase in suspected CHIKF cases between 2016 and 2017, totaling approximately 13,392 probable cases statewide during the period.
3.2. Demographic characteristics
CHIKV infection was more prevalent among females, with 409 cases (74.8%), compared to 138 (25.2%) in males (Table 2). The adult population accounted for the largest proportion of the cases (n = 387 / 70.7%) (mean ± S.D.: 35.3 ± 10.9). Elderly individuals comprised 82 cases (15.0%; 68.6 ± 7.4 years), while children and adolescents represented 78 cases (14.3%; 12.6 ± 4.6 years).
Epidemiological data of patients with Chikungunya fever treated in public hospitals in Northeast Brazil during the outbreak from February 2016 to October 2017.
Most patients (n = 489; 89.4%) resided in urban areas. Regarding skin color, the majority identified as brown (n = 327; 59.8%), followed by white (n = 197; 36.0%) and black (n = 23; 4.2%) (Table 2).
3.3. Cytokine profile
From the total pool of CHIKV-positive sera, 240 samples were randomly selected for cytokine quantification. Of the cytokines analyzed (IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, INF-α, and IL-17A), only IL-6 and IL-10 were detected at measurable levels. The remaining cytokines were either undetectable or present in negligible concentrations using the flow cytometry-based assay.
IL-6 levels were significantly higher than IL-10 (Figure 1A), with peak levels for both cytokines observed during the first week after symptom onset (Figures 11C). When stratified by age, adults exhibited the highest levels of IL-6 and IL-10 (Figures 22B). In children and adolescents, cytokine production was mostly concentrated within the first two weeks of symptoms onset (Figures 22D). Among adults, cytokine levels remained elevated throughout the four-week period, with a statistically significant peak in the second week (Figures 22F). In the elderly patients, IL-6 and IL-10 levels also peaked in the second week, although the differences were not statistically significant (Figures 22H).
Cytokine production in patients Chikungunya fever (CHIKF) according to symptoms onset. Serum samples from CHIKF patients were analyzed for cytokine (IL-6, IL-10, TNF-α, IFN-γ and IL-12) and chemokine (MCP-1) levels using a Cytometric Bead Array (CBA) kit via flow cytometry. (A) Quantification of IL-6 and IL-10 in serum samples; (B) IL-6 levels according to days since symptom onset; (C) IL-10 levels according to days since symptom onset. Results are expressed as mean ± S.D. Statistical analysis was performed using the Kruskal-Wallis test. ****p< 0.0001; *p <0.01.
Cytokines production according to patient age groups and time since symptoms onset. (A) Total IL-6 by age groups; (B) Total IL-10 by age groups; (C) IL-6 levels in serum from children/adolescents; (D) IL-10 levels in serum from children/adolescents; (E) IL-6 levels in serum from adults; (F) IL-10 levels in serum from adults; (G) IL-6 levels in serum from elderly individuals; (H) IL-10 levels in serum from elderly individuals. Results are expressed as mean ± S.D. Statistical analysis was performed using the Kruskal-Wallis test. *p <0.001.
4. Discussion
In this work, we analyzed the epidemiological profile of patients diagnosed with CHIKF treated in public hospitals across the state of Maranhão, Brazil. The highest number of CHIKF cases was recorded in São Luís, the state capital, followed by Caxias and Paço do Lumiar, two other major urban centers. This distribution aligns with the known behavior of the primary vectors, A. aegypti and A. albopictus, which have adapted well to urban environments. Their widespread presence facilitates the intercity transmission of arboviruses such as CHIKV (Weaver and Forrester, 2015).
Our findings indicate that while both sexes were affected, there was a notable predominance in female patients (74.8%). This pattern has been observed in other regions as well. For example, a study conducted in Africa reported that most individuals seeking care for CHIKF were women (Van Genderen et al., 2016). Sociocultural and behavioral factors may explain this trend. Women are generally more proactive in seeking care and are often more present in domestic environments, potentially increasing their exposure to vector mosquitoes (Levorato et al., 2014).
In terms of age distribution, adults accounted for over 70% of the cases, which is consistent with findings from other Brazilian regions, such as Roraima in the Amazon (Hayd et al., 2020). Adults may be more likely to seek medical care due to their awareness of health issues, the impact of symptoms on occupational activities, and concerns related to social security (Levorato et al., 2014). Furthermore, some studies have identified age as a risk factor for CHIKF, particularly for the development of more severe prolonged symptoms (Galatas et al., 2016; Sissoko et al., 2008).
Innate immunity constitutes the first line of defense against invading microorganisms and plays a crucial role in limiting viral replication through both cytolytic and non-cytolytic mechanisms (Chan et al., 2019; Caglioti et al., 2013). In the present study, only IL-6, a key pro-inflammatory mediator, and IL-10, an anti-inflammatory cytokine, were detected at measurable levels, whereas the remaining cytokines were below the assay’s detection limits. Importantly, this finding is consistent with the known immunological profile of CHIKV infection, in which IL-6 and IL-10 are among the predominant circulating cytokines, while others may be present at low or transient levels depending on the timing of sample collection.
Notably, we observed a clear temporal pattern: lower or undetectable cytokine levels were more frequent in samples collected at later time points after symptom onset, whereas higher levels of IL-6 and IL-10 were predominantly observed during the first weeks of infection. This behavior is consistent with the well-established window of cytokine detection, in which cytokine production is transient and peaks during the acute phase before declining rapidly, often to levels near or below assay detection limits.
Both IL-6 and IL-10 are known to participate in the innate immune response and are likely upregulated in response to recognition of viral components by host immune cells. The concomitant elevation of IL-10 may represent a compensatory mechanism by the host to modulate the inflammatory process and mitigate potential tissue damage associated with the excessive immune activation, a hallmark of CHIKV infection (Goupil and Mores, 2016). This dynamic interplay between pro- and anti-inflammatory cytokines reflects the host’s attempt to balance effective viral clearance with the prevention of immune-mediated pathology.
Burt et al. (2017) correlated the elevated levels of the cytokines IL-6 and IL-10 with high viral load, viral persistence in tissues, and more severe clinical manifestations. In contrast, a study by Kulkarni et al. (2017), which analyzed Indian patients during the acute phase, with chronic CHIKV arthritis, and those recovered from the disease, found that IL-10 levels were lower in patients during the acute phase compared to those who had recovered. Furthermore, during a Chikungunya outbreak in the Réunion Islands (France), it was observed that in environments with high viral circulation, the number of cases was directly associated with greater symptom intensity (Renault et al., 2007).
Our analysis revealed an increase in IL-6 levels at the onset of the acute phase, followed by a clear decline as the disease progressed and the convalescent phase began. Cronstein (2007) highlighted IL-6 as a key cytokine in the acute phase of CHIKF, acting as a critical mediator of fever by stimulating cellular metabolism to raise core body temperature. Given that fever is a hallmark symptom in the acute phase of CHIKV infection, it is highly likely that elevated IL-6 levels contribute significantly to its onset.
Evidence suggests that IL-6 plays a critical role in the persistence of symptoms caused by CHIKV, particularly the characteristic arthralgia. This cytokine recruits CD14+ monocytes to the site of infection and promotes their differentiation into osteoblasts (Phuklia et al., 2013). Moreover, IL-6 stimulates the release of receptor activator of nuclear factor kappa-β ligand (RANKL) and inhibits the expression of osteoprotegerin (OPG) by osteoblasts. This imbalance in the RANKL/OPG ratio, mediated by IL-6 in CHIKV-infected individuals, may contribute to bone loss and the development of arthritis and arthralgia (Noret et al., 2012).
In some patients, sustained high levels of IL-6 create a positive feedback loop that drives the progression and persistence of arthralgia, often accompanied by polyarticular pain (Phuklia et al., 2013; Chow et al., 2011). While acute symptoms of the disease may resolve rapidly, joint pain can persist for years particularly in individuals over the age of 40, who are at higher risk for developing chronic symptoms (Cronstein, 2007).
Despite the relevance of the findings presented in our study, we acknowledge that ELISA-based assays could provide higher sensitivity for the quantification of cytokines. The cytokine measurements in this study were performed using a flow cytometry assay, a widely used and well-established approach that allows the simultaneous detection of multiple analytes with high specificity and a broad dynamic range. While single-analyte ELISA assays may offer higher sensitivity for specific targets, multiplex platforms are particularly suitable for exploratory immunological profiling, as proposed here.
In addition, the absence of longitudinal follow-up prevented us from assessing the temporal evolution of cytokines and their relationship with symptom persistence, an aspect already highlighted in cohort studies. A study conducted by Ninla-Aesong et al. (2019) in southern Thailand reported that individuals affected by the 2008–2009 outbreak continued to experience chronic CHIKV-induced arthritis symptoms years later.
A study conducted by Ninla-Aesong et al. (2019) in southern Thailand reported that individuals affected by the 2008–2009 outbreak continued to experience chronic CHIKV-induced arthritis symptoms years later.
Chang et al. (2018) conducted a nested case-control study comparing serum cytokine concentrations during acute CHIKV infection in patients who developed chronic joint pain versus age- and gender-matched controls who recovered 20 months post-infection. The findings suggested that a strong cytokine response during the acute phase is essential for effective viral clearance. Notably, TNF-α and cytokines associated with immune tolerance during acute infection may play a protective role against the development of chronic arthritis.
Regarding pediatric patients, no significant increases in IL-6 and IL-10 levels were observed at the onset of the acute phase compared to the later stages. This group was largely composed of newborns and infants, whose immune responses rely heavily on the adaptive immune system. However, in neonates, T cell-mediated responses are underdeveloped compared to those of older children and adults. Neonatal T cells reflect the immunological environment of fetal life, where exposure to foreign antigens is mostly limited to maternal alloantigens (Simon et al., 2015; Maródi, 2006). This developmental immaturity likely accounts for the lower cytokine responses observed in newborns.
On the other hand, a study by Simarmata et al. (2016), which analyzed clinical and immunological responses, focusing on cytokine and chemokine profiles, in a CHIKV-infected pediatric cohort from Malaysia, demonstrated that children exhibited higher levels of several immune mediators (including TNF-β, TRAIL, IL-5, GRO-α, IL-18, IFN-α, IL-2Ra) than adults. These findings highlight the variability of immune responses across different pediatric age groups.
5. Conclusion
Taken together, our results suggest that acute CHIKV infection induces a significant increase in IL-6 levels, a cytokine that plays a central role in the innate immune response. This elevation is likely associated with the host's recognition of viral components and the early activation of pro-inflammatory pathways. The predominance of IL-6 during the first and second weeks after symptom onset, especially in adult patients, highlights its importance in the acute phase of the disease. Additionally, the sustained elevation of IL-6 in some individuals may contribute to the persistence of symptoms, particularly arthralgia, which is a hallmark of CHIKV infection. Therefore, the detection and quantification of IL-6 may serve not only as a valuable biomarker for diagnosis and disease monitoring, but also as a predictor of severity and progression, supporting clinical decision-making and patient management.
Data Availability Statement
The entire data set that supports the results of this study was published in the article itself.
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Editor:
Marcelo A.M. Esquisatto
