A Comprehensive Review on Chikungunya Virus Epidemiology, Pathogenesis, Clinical Manifestations, Treatment and Current Vaccine Development

The alphavirus known as chikungunya virus (CHIKV) is spread via mosquitoes. Chikungunya, which translates to "disease that bends up the joints," is a phrase used by the Makonde people of Tanzania to characterize the illness. Following its initial isolation, CHIKV only sometimes produced outbreaks in Asia and Africa over the next fifty years (about). Despite having a low death rate, CHIKV causes severe morbidity that significantly lowers the quality of life for those who are sick and causes large financial losses, particularly in underdeveloped nations. Additional symptoms, however mild, have also been described; these might include headache, rash, myalgia, and incapacitating polyarthralgia and arthritis. The Zika virus (ZIKV) and dengue fever (DENV) are two well-known arbovirus-induced illnesses that are often misdiagnosed due to the simultaneous circulation of the two viruses in the same area. ^[1],[2] Even while the infection often resolves on its own, some individuals experience chronic joint pain months or years after the acute phase of the illness. More than five hundred years ago, CHIKV was brought to Asia from Africa. The Indian Ocean lineage (IOL) sublineage is another division of the ECSA. ^[3] These genotypes are now widely distributed, with Asian and ECSA genotypes being the most common. Intriguingly, these genotypes showed variations in their cycles of transmission. Assumptions regarding CHIKV infection have suggested that the virus may have developed into a more severe form of the illness, with cases of fulminant hepatitis and involvement of the central nervous system (CNS) being documented. Although CHIKV infection is thought to have a low death rate, there have been theories that it may have developed into a more severe form. ^[5] However, with the infectious mechanisms and related pathologies from the early outbreaks of the twenty-first century being inadequately documented, the gap in CHIKV severe illness may simply be the result of a lack of data. An estimated 775,000 people were infected by CHIKV during this outbreak in 2006, which resulted in 237 fatalities. An alanine to valine mutation at position 226 in the El envelope glycoprotein (E1-A226V) of CHICKV isolates was discovered by further examination of genome microevolution during the 2006 Réunion epidemic. This change, which is present in more than 90% of Réunion Island's viral sequences, was linked to a marginally higher rate of transmission by Ae. albopictus, indicating that the virus has a better capacity to multiply in naturally low-cholesterol insect cells. ^[4] Because of its historical significance, La Réunion Island is red in hue. excludes cases that are imported. Despite Alaska being a blue-colored U.S. territory, no CHIKV transmission was reported there.

The virus was limited to minor outbreaks in Asia and Africa prior to the 2005–2006 Réunion pandemic. These were small outbreaks in Calcutta, India, in 1963; epidemics in Chennai, Pondicherry, and Vellore in 1964; Visakhapatnam, Rajmundry, and Kakinada in 1965; Nagpur in 1965; and Barsi in 1973. The first outbreaks on the African continent were in 2004 in Kenya and in the Comoros Islands, which are situated on the continent's southeast coast. Numerous visitors from developed nations contracted CHIKV during the 2006 Réunion outbreak, and many of them carried the virus back to their home countries. As a result, CHIKV spread to other nations. The first recorded case of CHIKV in Asia occurred in Cambodia in 1961, most likely as a result of the Asian genotype that was then prevalent in the area. The virus was later discovered in 1965 in the Philippines, 1966 and 1967 in Vietnam, and 1972 in Indonesia. After then, CHIKV expanded to several countries, such as Thailand, Malaysia, Sri Lanka, Singapore, and others (for a detailed account of CHIKV transmission, see , where it caused either minor outbreaks or isolated cases. But in 2007, after 40 years, CHIKV made a comeback in Sri Lanka, causing an outbreak that resulted in over 37,000 probable cases.When the French National Reference Centre for Arboviruses confirmed autochthonous cases on Saint Martin Island, an island in the northeast Caribbean Sea, in December 2013, small CHIKV outbreaks started to be reported in the Americas. Afterwards, autochthonous instances were also documented in the British Virgin Islands, Guadeloupe, Saint Barthelemy, and Dominica in January 2014.After a distinct emergence in the Americas, CHIKV became a significant public health concern. By the end of December 2015, approximately one million cases had been reported in the Americas, with 71 fatalities, and more than 50 territories had verified autochthonous transmission. The CHIKV isolated from Saint Martin was shown to be of Asian ancestry by sequence analysis. ^[4] The Pan American Health Organization (PAHO) regional office received 37,480 CHIKV-confirmed cases in the Americas in 2015. A total of 146,914 laboratory-confirmed cases were notified in 2016. Brazil, Bolivia, and Colombia were the American nations that reported the most instances. The simultaneous spread of the two arboviruses, DENV and ZIKV, in Brazil made the CHIKV outbreak worse, with many patients developing a dual infection. Actually, a sizable percentage of patients in Brazil's early surveillance studies of arboviral illnesses in febrile patients had molecular and serological evidence of concurrent arbovirus infection. ^[6] The absence of appropriate treatment and efficient control methods (such as vaccinations and vector control) further exacerbates all of the aforementioned issues. Our goal in this study is to present an update on the pathophysiology, epidemiology, and present state of possible new vaccinations. Even though this subject has already been covered by others, our goal in this review is to present a fresh viewpoint on some of the topics that have not received enough attention. These include the current state of vaccine development, which should be regularly updated, the possibility of neurological complications for CHIKV-infected patients, and the possible pathogenic mechanisms of CHIKV. ^[7]

CLASSIFICATION

All viruses in this family that are animal pathogens and have a global geographic distribution are classified as alphaviruses. Both people and horses can contract encephalitis from the New World alphaviruses, which are found across the Americas. The Venezuelan equine encephalitis virus, the western equine encephalitis virus, and the eastern infectious disease are a few examples. Other members of the group include the Sindbis virus, o'nyong'nyong virus. The majority of alphaviruses are spread by arthropod vectors, which most likely regulate their geographic spread. Several transoceanic exchanges may have taken place.

PATHOGENISIS

After being administered intradermally by infected mosquitoes, CHIKV penetrates subcutaneous capillaries directly and infects vulnerable skin cells, including endothelial cells, fibroblasts, and macrophages, where it replicates to a limited extent. In secondary lymphoid organs, locally generated viruses infect migratory cells, release the viruses into the lymphatic circulation, and then travel to the blood. The virus can enter the bloodstream and spread to the liver, muscles, joints, and brain, among other regions of the body. A significant infiltration of mononuclear cells is linked to the infection in these organs. Strong systemic innate responses are triggered by CHIKV infection, primarily including the generation of the antiviral IFN-a along with many pro-inflammatory cytokines, chemokines, and growth factors. Later phases of the acute phase are characterized by the production of anti-inflammatory proteins IL-1RA and IL-2RA as well as a typical switch to CD4+ T-cell response. Strong inflammation is induced by CHIKV infection, which may be mediated by the production of MIP-1a, IP-10, IL-16, IL-17, and monocyte chemoattractant protein 1 (MCP-1). The development of proinflammatory MIF, MIP-1ß, SDF-1a, IL-6, and IL-8 is indicative of the conclusion of the acute phase. ^[8] All patients had elevated CCL5 (RANTES) levels in the first week following the beginning of symptoms. By directing the deployment of effective antiviral defenses, these chemokines significantly contribute to the recruitment of leukocytes to infection sites. A robust cellular immune response is also induced by CHIKV infection. The participation of cellular responses was suggested by high plasma levels of cytokines that support adaptive immunity, such as IFN-y, IL-4, IL-7, and IL-12p40. Natural killer cells play a crucial part in eliminating contaminated cells and has also been proposed in the development of CHIKV arthralgia. Furthermore, at the conclusion of the acute phase, CD4* T lymphocytes—which are also involved in the promotion of humoral responses—were highly active. After the disease starts, specific IgM lasts for three to four months, whereas IgG lasts for more than six months. It is unclear how they contribute to persistent arthralgia. The incubation period following infection might last anywhere from three to seven days. IgM-capture ELISA and/or reverse-transcription polymerase chain reaction (RI-PCR) tests from blood samples are used in laboratories to make diagnoses. Patients infected with CHIKV had much greater viremia than those infected with the two well-studied arboviruses DENV and ZIKV, with the peak of viremia occurring concurrently with the start of fever. Furthermore, given that hospitalized individuals exhibited greater viremia than non-hospitalized cases, the viral load appears to be a reliable indicator of the severity of the illness. According to estimates, between 30 and 40 percent of those infected go on to have some long-term symptoms, such as arthritis and/or chronic arthralgia, of which around 37 percent have severe pain. ^[9] In the few studies that are currently available, patients who are older than 40, female, and have higher levels of CXCL8 detected during the acute phase of the disease were found to be associated with CHIK persistent arthralgia. However, factors linked to persistence of arthralgia in CHIKV-infected patients have not been thoroughly investigated. CHIKV-associated illness was more severe in a study of newborn mice and adult mice with completely abrogated type-I IN signaling (IFN-a/BR-/-); this severity is correlated with increased virus loads and CNS spread. Overall, our findings clearly show that age and type-I IFN signaling function are at least two host characteristics that significantly influence the severity of CHIKV illness. Even while there has been progress in our knowledge of CHIK infection, it is still unknown exactly what immunopathogenic pathways underlie CHIKV-induced arthralgia. The acute phase of CHIKV viremia is directly correlated with plasma levels of certain cytokines, with maximal values of 10° in adults and 10º RNA copies/mL in children.  As a result, similar to other infectious disorders, viral load may directly affect proinflammatory cytokine and chemokine expression levels, which may then affect how various clinical symptoms manifest. There have been isolated reports of neurological symptoms from several outbreaks, despite the fact that CHIKV is not regarded as a genuine neurotropic virus (one that can infiltrate neural tissue and multiply in neurons). To put it another way, because CHIKV infections seldom cause neurological problems, tiny outbreaks frequently result in few neurological cases that medical experts frequently overlook. Therefore, this component of CHIKV infection just recently began to be described since neurological consequences from CHIKV are rare. According to a prior research, CHIKV neurological consequences were varied, with encephalitis, myelopathy, peripheral neuropathy, myeloneuropathy, and myopathy being the most frequently reported neurological problems. The majority of these patients' cerebrospinal fluid (CSF) samples had CHIKV-specific IgM antibodies, according to laboratory analysis, and at least two of these patients had positive CNS virus detection. ^[4] The human neuroblastoma cell line SH-SY5Y, which is frequently used to simulate neuroinflammation in vitro, has been demonstrated to be vulnerable to CHIKV infection. These cells displayed apoptotic characteristics after infection with a CHIKV virus from east/central/south Africa genotypes isolated from the 2006 Indian epidemic. These included cytochrome-c release, caspase-3 activation, and PARP cleavage, indicating the role of virus-induced apoptosis in disease pathogenesis.  Two days after infection, CHIKV viral antigens and RNA were detected in the cortex of experimentally infected young mice, causing the brain's host proteome to change expressively. Because CHIKV cannot infect neurons or the brain parenchyma, it causes reversible central nervous system symptoms, unlike other well-known encephalitogenic alphaviruses. ^[4]

INDIA

In Kolkata, West Bengal, an epidemic of CHIKV was first documented in India in 1963. During 1964–1965, there were several more outbreaks in Tamil Nadu, Andhra Pradesh, and Maharashtra. After the final outbreak of the virus in the 20th century was recorded in Maharashtra in 1973, the virus all but vanished from India. According to reports, the Asian genotype of the circulating virus was responsible for epidemics in India up until the 1970s. Following a 32-year hiatus, CHIKV returned to the nation and produced a significant outbreak from late 2005 to 2008. The ECSA lineage comprised the causative CHIKV strain. Nearly every Indian state, including Karnataka, Madhya Pradesh, Andhra Pradesh, Tamil Nadu, and Maharashtra, reported more than 1.3 million cases of CHIKV infection. ^{[31,32,33,34,35]} The Indian CHIKV strain found in 2006. Kerala accounted for 55.8% of suspected cases of chikungunya in 2007, making it the state most impacted in the nation. The rapid spread of CHIKV in Kerala may have been greatly aided by the high quantity of A. albopictus in the area known for its rubber plantations. ^[36,37]

CLINICAL MANIFESTATIONS

Following a quiet incubation period of two to six days, the majority of people with CHIKV infection experience persistent viral antigen symptoms that result in joint inflammation (Suhrbier and Mahalingam, 2009; Suhrbier et al., 2012). Some investigations have demonstrated indications of extended symptoms, such as a high fever and severe arthralgia, in cases when the sudden start of CHIKV occurs after a period of time (up to 12 days). The acute stage, also known as the febrile phase, can last up to the chronic phase, which is thought to occur 15 days after the fever first appears. The host immunological response to the infection is what defines this phase (Chang et al., 2018). ^{[13] Forty}-five percent of the patients had periarticular edema, which was more common in the ankles. Just 10.6% of the patients had hemorrhagic symptoms such epistaxis and gin-givorrhagia. ^[15-18] Chikungunya is not normally regarded life threaten-ing; although severe forms can also be present. Patients with severe chikungunya fever needing hospitalization tend to be older and have comorbidities such as cardiovascular, neurologic, and respiratory problems or diabetes, which are independent risk factors for severe illness. ^[19,20] Additionally, neonates are susceptible to serious infections that manifest as neurological symptoms. Neonates of viremic women who were exposed to the virus after delivery may have a 50% infection risk, which can cause severe illness and encephalopathy, which can have long-term neurological effects and lead to a bad prognosis. ^[21]

DIAGNOSIS

Clinical, epidemiological, and laboratory criteria are used to diagnose chikungunya infection. A suspected case of CHIKV is defined as an initial start of fever and severe arthritis or arthralgia that cannot be attributed to other medical conditions. ^[22]

Acute serum specimens (less than eight days) or field-collected mosquitoes can be used for virus isolation. In a reference laboratory, a susceptible cell line or suckling mouse can be infected with serum derived from whole blood taken during the first week of sickness. This can be accomplished if the sample is transferred as quickly as feasible (within 48 hours) and cold (between 2°C and 8°C or dry ice). Because of its higher sensitivity and less chance of contamination, real-time, closed system assays ought to be employed. Whole blood serum is utilized for both viral isolation and PCR testing. Whole blood serum is utilized in the enzyme-linked immunosorbent test (ELISA) for serological diagnostics. The serum (or blood) sample should not be frozen; instead, it should be transported between 2 and 8°C. IgM may be determined using a variety of commercially available methods. It should be noted, nonetheless, that methods that employ the whole virus as antigen have higher sensitivity than those that use recombinant proteins. It is advised that in-house methods for IgM/IgG ELISA be used utilizing the purified viral antigen and according to CDC standards, as the initial commercially available kits produced subpar results. ^[23] It is not advised to utilize fast testing. One to two weeks following the first sample, the second sample should be collected for the serological analysis. An rise in IgG between acute-phase and convalescent-phase blood samples of at least four times is another way to identify seroconversion. ^[24]

TREATMENT

After ruling out more dangerous illnesses such bacterial infections, dengue, and malaria, symptomatic therapy is advised. Treatment for acute infections is supportive and symptomatic, consisting of rest and acetaminophen (less than 4 grams per day) to reduce fever. When dengue infection is ruled out, ibuprofen, naproxen, or another non-steroidal anti-inflammatory drug (NSAID) can be used to treat the arthritic aspect of the illness.^[25]  Patients may be prescribed tramadol or opioids (such as morphine) if they have severe joint pain that is not alleviated by NSAIDs.In order to replace fluids lost from vomiting, perspiration, and other insensible losses, patients should be encouraged to drink a lot of water.^[26] Although convalescence might be delayed and chronic joint discomfort may necessitate pain treatment, including long-term anti-inflammatory medication, healing from CHIK is the anticipated result. A brief course of oral corticotherapy or corticoid injection in the afflicted joint is combined with topical or oral NSAIDs as a specific treatment for diffuse post-CHIKV polyarthralgia in the chronic stage. Tramadol, antiepileptic medications, and tricyclic antidepressants can all be used to treat neuropathic pain. A previous study indicated that hydroxychloroquine phosphate could help with arthritis, however more recent research was unable to validate its effectiveness. ^{[27,28,29,30]} Methotrexate (MTX) is one alternate treatment that might be considered for people with refractory joint problems. In a retrospective research conducted on La Réunion Island, MTX treatment resulted in a good clinical response in 54 of 72 patients. ^[27] Etanercept, ritux-imab, or tocilizumab are examples of immune-modulating biologics that can be utilized in cases when MT is contraindicated or ineffective. Low vitamin D levels have been demonstrated to be negatively correlated with rheumatoid arthritis activity in patients. ^[23] Both acute and chronic stages of the condition may benefit from a regimen of progressive physical therapy in addition to medication for arthralgia and stiff joints. Morning stiffness and soreness are often relieved by movement and little exercise, although intense exercise may make the symptoms worse.

PREVENTION

In many nations and environments, controlling adult and larval mosquito populations has been. comparatively successful and is based on the same principle as dengue. It is necessary to remove, destroy, regularly empty, clean, or apply pesticides to breeding areas. Clothing that reduces skin exposure to day-biting vectors is recommended for protection. Applying repellents to exposed skin or clothes requires careful adherence to the directions on the product label. Insecticide vaporizers, such as mosquito coils, may help lessen indoor biting.

VACCINES

Despite the fact that CHIKV is already common in many areas, there are currently no vaccinations for the virus, and anti-inflammatory medications remain the primary treatment for CHIKV-infected people in order to alleviate their symptoms. In order for impoverished nations to finance a widespread immunization program, it is crucial that a CHIKV vaccine be affordable, manageable, and portable. Currently, a small number of clinical studies are being conducted worldwide, and a number of preclinical vaccines are in development. Some commonly used disease-modifying antirheumatic medications (DMARDs), including methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine, have been used, albeit with limited success, because CHIKV persistent arthralgia disease shares some clinical similarities with rheumatoid arthritis (RA). ^[10] Numerous antivirals have been researched as possible treatments for CHIKV. Several research teams used various strategies to find new possible CHIKV antiviral medications and therapeutic candidates that have been repurposed to prevent CHIKV replication, however none of them are now undergoing clinical testing. A comprehensive and current evaluation of these results is provided by Battisti et al. (2021) and Hucke and Burget (2020). ^[11] CHIKV preclinical candidate vaccines are being developed in a variety of ways, including a live-attenuated vaccine with a longer-lasting and more potent immune response, a whole-virus inactivated vaccine, a VEE/CHIKV chimeric vaccine, a recombinant adenovirus vectored vaccine, a DNA-based CHIKV vaccine, a virus-like particle (VLP) vaccine, and a live-attenuated vaccine. Due to their emergency use permission during the SARS-CoV-2 epidemic, mRNA-based vaccines became available more recently. As a result, pharmaceutical firms are now creating mRNA-based vaccination techniques for CHIKV, and several clinical studies are currently being assessed. We will concentrate on talking about the initial findings of these vaccinations, when they become accessible, and their potential for widespread usage in the general population because they are still in the late stages of research. ^[4]