CHIKUNGUNYA VIRUS INFECTION: WHAT DOESN’T KILL US DOES NOT ALWAYS MAKE US STRONGER

By: Ni Luh Putu Ariastuti, Adhella Menur

CHIKV: The neglected bending virus

Chikungunya virus (CHIKV) infection might not be as famous as dengue virus (DENV) or Zika virus (ZIKV) infection due to the low mortality rate compared to other infections. But don’t let that fool you; its high morbidity rate and long-lasting health issues create significant economic and social burdens. The virus was first identified in human serum back in 1952 on Tanzania’s Ma-konde Plateau, which is also how it got its name. “Chikungunya” comes from the Makonde word for “that which bends up,” describing the stooped posture and severe joint pain sufferers endure. Transmitted by Aedes mosquitoes (Ae. albopictus and Ae. aegypti), CHIKV is a public health threat based on several records of CHIKV outbreaks across Africa, Asia, Europe, and the Americas and sporadic non-outbreak cases. Numerous CHIKV re-emergences have been documented with irregular intervals of 2–20 years between outbreaks. In 2000, a massive outbreak of CHIKV infection resurged in Congo, followed by global emergence in 2004. By 2005-2006, the outbreak had reached the Indian Ocean Island of La Réunion, part of France, affecting an estimated 300,000 people and causing 237 deaths. In Sri Lanka and India, CHIKV infected more than 100,000 and 1.3 million persons, respectively, then subsequently spread to Southeast Asia, including Indonesia. In 2007, a localized outbreak occurred in Italy, traced back to a traveler from India. The virus spread further through international travelers. By 2015, CHIKV was officially recognized as a notifiable disease by the US-CDC. During the past 20 years, over 10 million cases of chikungunya have been reported in more than 125 countries. The latest outbreak was reported in the Malé and Hulhu-malé regions of the Maldives during March-May 2024.

In Indonesia, the first recognized CHIKV outbreak occurred in Samarinda, East Kalimantan, in 1973, and the first virologically confirmed cases were detected in Jambi in 1982. Since then, isolated outbreaks have been reported more frequently, peaking during a nationwide epidemic in 2009-2010 with 137,655 cases and a smaller outbreak in 2013 with 15,324 cases. Thence, annual CHIKV cases have returned to pre-epidemic levels (<10,000). A recent suspected local outbreak occurred in Nagasepaha Village, Buleleng, North Bali, from December 2015 to January 2016. Moreover, Indonesia has been identified as a potential source of CHIKV transmission abroad, with studies highlighting infected travelers returning from Indonesia to Taiwan (2006-2009) and Japan (2006-2016) as common sources of imported cases. Unfortunately, CHIKV infection often goes neglected and is sometimes thought of as the “nicer” sibling of DENV infection. This edition aims to shed light on CHIKV infection and its implications for public health.

Getting to know CHIKV

CHIKV belongs to the Togaviridae family – the Alphavirus genus, and it’s part of the Semliki Forest virus antigenic complex, which also includes O’Nyong Nyong, Mayaro, and Ross River viruses. This virus is an enveloped positive-strand RNA virus with the genome encoding four nonstructural proteins (nsP1 to nsP4) and five structural proteins (C-E3-E2-6k-E1). Genetic analysis based on the E1 envelope glycoprotein sequences showed three distinct lineages: West African, Asian, and East/Central/South Africa (ECSA). The Indian Ocean lineage (IOL) is a sub-lineage evolved from the ECSA lineage. In Indonesia, sequencing and evolutionary studies have primarily identified Asian genotypes, with some isolates matching the ECSA genotypes. Notably, the ECSA isolates first identified in Indonesia in 2008 were closely related to the viruses causing significant outbreaks in Southeast Asia around that time.

CHIKV transmission occurs through both urban and sylvatic cycles. In the sylvatic cycle, primarily observed in Africa, CHIKV is transmitted among arboreal forest Aedes mosquitoes and diverse amplifying hosts (mammals including primates, sheep, rodents, bats; as well as birds). Humans are incidental hosts in this cycle, typically infected when they venture into forested areas or are bitten by infected vectors. In the urban cycle, transmission involves humans and urban mosquitoes like Ae. aegypti and Ae. albopictus. CHIKV can be transmitted horizontally in Aedes mosquitoes, aiding in maintaining the infection cycle. Additionally, vertical transmission from mosquitoes to their offspring has been noted, potentially allowing the virus to persist under harsh environmental conditions. Once a mosquito carrying CHIKV bites a human, the virus replicates at the bite site, with skin fibroblasts serving as the primary amplification points. The virus then spreads to other peripheral organs via the bloodstream. The incubation period varies from one to twelve days, and individuals can exhibit viremia for up to ten days. CHIKV infects various cell types, including myoblasts, skeletal and synovial fibroblasts, and joint macrophages. It also has been detected in epithelial and endothelial layers of lymphoid organs, the liver, and the brain. However, monocytes, B cells, T cells and monocyte-derived dendritic cells may not be susceptible to CHIKV infection. Maternal-fetal transmission has been observed, although there’s no evidence of transmission through breast milk. While CHIKV RNA has been detected in semen up to 30 days post-symptom onset, suggesting potential sexual transmission, direct human-to-human transmission has not been documented.

Humans serve as the primary host of the virus during epidemics. Anyone with suspected chikungunya infection should avoid mosquito exposure for at least 7 days after the onset of illness to reduce the possibility of transmitting the virus to mosquitoes, which could then transmit to other humans. The complete transmission cycle from human to mosquito and back to another human can take place in less than a week. Once a mosquito is infectious, it may be capable of transmitting the virus for the remainder of its lifespan (about 2 weeks). Infection with chikungunya virus confers long-lasting, possibly lifelong, immunity.

Acute CHIKV infection

CHIKV disease in humans is typically marked by two phases, an acute phase and a chronic phase. The acute phase of CHIKV disease lasts typically <21 days after the onset of infection. It is divided into two different stages, the viraemic stage (5-10 days), marked by abrupt high fever (>38.9°C) and polyarthralgia/arthritis (usually sym-metrical and primarily involves peripheral joints), myalgia, headaches and skin rashes; and the post-viraemic stage (6-21 days), characterised by a lack of fever, polyarthralgia/arthritis and, to a lesser extent, myalgia, fatigue and anorexia. Preliminary diagnosis relies on the individual’s clinical presentation and a thorough travel history. However, CHIKV manifestations overlap with those of other endemic infections such as dengue virus (DENV) and Zika virus (ZIKV). Confirming the diagnosis requires laboratory testing. The more widely available tests include polymerase chain reaction (PCR) to detect viral RNA in the first 8 days of illness, or acute-phase serology to detect IgM, IgG, and neutralizing antibodies toward the end of the first week of illness (>4 days post-onset) paired with a conva-lescent-phase serology; although possible, viral cultures in the first 3 days of illness are less frequently used. Unfortunately, cross-reaction with another arbovirus can happen on antigen-based test thus make some test less sensitive in detecting CHIKV. Additionally due to limited resources, this laboratory test might not be available in certain countries.

In the INA-RESPOND AFIRE study (2013-2016), CHIKV emerged as a significant cause of fever among hospitalized patients, yet it often went unrecognized by clinicians. Out of 40 cases of acute CHIKV infection, none were correctly di-agnosed by the attending clinicians at the study sites. Eleven patients were misdiagnosed with DENV, eight with typhoid fever, and one with leptospirosis. The other 20 cases were misdiag-nosed to various other conditions: unspecified fever (6), respiratory infections (5), nonspecific viral infections (4), fever with rash (2), enteritis (2), and endocarditis (1). Currently CHIKV IgM rapid diagnostics are plagued by low sensitivity.

Performance is better for the ECSA genotype, but suboptimal for the Asian genotype circulat-ing in Indonesia. And since IgM is usually de-tectable 5 days after fever onset, utility of IgM in acute specimens is minimal. Additionally, persistence of IgM for CHIKV more than a year after infection may confound interpretation of positive results. These challenges highlight the need for CHIKV RNA, or antigen based rapid diagnostic testing to guide clinical decision making.

Surviving the acute phase: weakening in the chronic

For many individuals with chikungunya, the disease is benign and self-limiting. However, after the acute phase of the illness, some patients develop long-term symptoms, known as the chronic phase, that can last from several weeks to months or years (>1 year). Studies vary widely in terms of the percentage (14-43%) of patients that experience the chronic disease and the disease longevity. The primary symptoms for chronic disease in patients with chikungunya are arthralgia and/or arthritis. CHIKV-induced arthritis resembles rheumatoid arthritis (RA), but, unlike RA, there is no evidence that CHIKV-associated arthropathies are caused by autoim-munity. Rather, it is thought that the persistence of viral antigens could be a contributing factor to the development of chronic CHIKV induced arthritis. Chronic arthralgia generally involves the same joints affected during the acute phase and the arthropathy is not usually overtly erosive. Fatigue, depression, mood and sleep disorders, neurological disorders, and alopecia were also common chronic symptoms. Factors predisposing to chronic disease included comorbidities (such as osteoarthritis and diabetes), older age (>35 years), and high viraemia and severe disease during the acute stage.

A recent study from Brazil investigated the mor-tality risk between individuals exposed to CHIKV and those not exposed, examining both the tim-ing and causes of death. The findings are con-cerning. CHIKV disease is associated with an increased risk of all-cause natural mortality, as well as an increased risk of death from cerebro-vascular disease, ischaemic heart disease, diabe-tes, and kidney disease within 84 days of symp-tom onset. Notably, the study also highlights that CHIKV diseases can exacerbate underlying diseases, further elevating the risk of severe out-comes. A greater understanding of both the acute and chronic phases of CHIKV disease and the role of host immune responses in the pathobiology of the disease is required to de-velop therapeutic approaches to enhance early viral clearance and limit the development of chronic disease.

Chikungunya – outbreak and non-outbreak, and public health efforts

As previously mentioned, chikungunya can pre-sent in outbreak and non-outbreak settings. Often, non-outbreak cases go unnoticed, while those occurring during outbreaks tend to exhib-it more severe symptoms. This observed differ-ence in symptom severity could be due to in-creased awareness during outbreaks or may re-flect actual variations in clinical presentation. A thorough analysis comparing viral, vector, host, and environmental factors between outbreak and non-outbreak cases would provide valuable in-sights into these dynamics. Moreover, outbreak recurrences are often preceded by long periods spanning several years or decades with minimal or no cases. Several factors contribute to these recur-rences. For instance, the emergence of new virus variants can play a significant role; the ECSA geno-type with the A226V mutation of the E1 protein, for example, enhances vector competence in Ae. albopictus but not in Ae. aegypti. Additionally, the absence of pre-existing immunity, particularly in younger populations who have not been exposed during silent epidemiological periods, can facilitate the spread of the virus. Environmental and host-vector interactions might also trigger outbreaks, as demonstrated by the 2010 outbreak in North Kayong, West Kalimantan, where farming activities in forested areas combined with poor vector control were significant risk factors.

The expanding geographical range of chikungunya is attributed to factors such as increased urbanization, international travel, and global warming, which contribute to the proliferation and migration of mosquito vector populations. While the disease itself is rarely lethal, its acute phase can be intensely painful and debilitating. Moreover, the long-term effects of chikungunya can severely restrict daily activities and significantly reduce the quality of life, impacting them both psychosocially and economically. Therefore, public health efforts are crucial to control CHIKV infection.

In addressing CHIKV infection, promising new or repurposed antiviral compounds have been developed. Yet, most require validation through in vivo studies and clinical trials, and they face potential issues with antiviral resistance. Antibody-based therapies, only effective in the acute phase and are costly. Treatment primarily focuses on supportive care—rest, hydration, and pain relief. For chronic cases, treatment strategies emphasize pain management, anti-inflammatory medications, and supportive physical and rehabilitation therapies. After decades, a single-shot chikungunya vaccine, VLA1553/ IXCHIQ®, manufactured by Valneva, was approved in the U.S. in November 2023 and recommended for adults: travellers at high risk, laboratory workers, and those at increased risk of severe disease. However, its distribution remains limited, particularly in endemic regions where it is most needed.

Effective prevention of chikungunya hinges on robust vector control, which is challenged by rampant urbanization, inadequate sanitation, and increasing insecticide resistance in mosquitoes. An integrated approach to virus control is essential, combining epidemiological surveillance, environmental management to eliminate mosquito breeding sites, chemical control using repellents and insecticides, and biological controls targeting mosquito eggs, larvae, and adults.

To effectively combat CHIKV, a virus that can significantly bend and weaken us, it’s essential to maintain strong public health awareness, engage in comprehensive research for new treatments and vaccine development, and conduct thorough serological and genomic surveillance to predict and prepare for future outbreaks. Keep being strong and proactive in these efforts!

References

• Arif, M., et al. (2020). Chikungunya in Indonesia: Epide-miology and diagnostic challenges. PLoS Neglected Tropical Diseases.
• Bartholomeeusen, K., et al. (2023). Chikungunya fever. Nature Reviews Disease Primers.
• Cerqueira-Silva, T., et al. (2024). Risk of death following chikungunya virus disease in the 100 Million Brazilian Cohort, 2015–18: A matched cohort study and self-controlled case series. The Lancet Infectious Diseases.
• Hapuarachchi, H., et al. (2021). Transient transmission of Chikungunya virus in Singapore exemplifies successful mitigation of severe epidemics in a vulnerable popula-tion. International Journal of Infectious Diseases.
• Harapan, H., et al. (2019). Chikungunya virus infection in Indonesia: A systematic review and evolutionary analysis. BMC Infectious Diseases.
• Henderson Sousa, F., et al. (2023). Evolution and immunopathology of chikungunya virus informs therapeutic development. Disease Models & Mechanisms.
• Huang, Y.S., et al. (2017). Biological control strategies for mosquito vectors of arboviruses. Insects.
• Khongwichit, S., et al. (2021). Chikungunya virus infection: Molecular biology, clinical characteristics, and epidemiology in Asian countries. Journal of Biomedical Science.
• Mourad, O., et al. (2022). Chikungunya: An emerging public health concern. Current Infectious Disease Re-ports.
• PAHO. (2017). Tool for the Diagnosis and Care of Patients with Suspected Arboviral Diseases. Retrieved from https://iris.paho.org/bitstream/handle/10665.2/33895/9789275119365_eng.pdf
• Panning, M., et al. (2009). No evidence of chikungunya virus and antibodies shortly before the outbreak on Sri Lanka. Medical Microbiology and Immunology.
• Sari, K., et al. (2017). Chikungunya fever outbreak identi-fied in North Bali, Indonesia. Transactions of the Royal Society of Tropical Medicine and Hygiene.
• Schwartz, O., & Albert, M.L. (2010). Biology and pathogenesis of chikungunya virus. Nature Reviews Microbiology.
• Silva, T., et al. (2018). A scoping review of chikungunya virus infection: Epidemiology, clinical characteristics, viral co-circulation complications, and control. Acta Tropica.
• Sitepu, F.Y., et al. (2020). Epidemiological investigation of chikungunya outbreak, West Kalimantan, Indonesia. Clinical Epidemiology and Global Health.
• Stubbs, S. C. B., et al. (2020). An investigation into the epidemiology of chikungunya virus across neglected regions of Indonesia. PLoS Neglected Tropical Diseases.
• Suhrbier, A. (2019). Rheumatic manifestations of chikungunya: Emerging concepts and interventions. Nature Reviews Rheumatology.
• WHO. Regional Office for South-East Asia. (2009). Guidelines for prevention and control of chikungunya fever. World Health Organization.
• WHO. (2016). Monitoring and Managing Insecticide Resistance in Aedes mosquito Populations-Interim Guid-ance for Entomologists.
• WHO. (2018). Chikungunya. Retrieved from https://www.who.int/news-room/fact-sheets/detail/chikungunya