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Chikungunya Fever
Introduction
Chikungunya virus (CHIKV) is an arthropod-borne alphavirus that belongs to the family Togaviridae transmitted by Aedes mosquitoes. The virus is known for causing an acute febrile illness, rash, and arthralgia known as Chikungunya fever followed by potentially chronic and debilitating arthritic symptoms that may last for months or years.[1] Historically, CHIKV was found mainly in Africa and Asia, initially isolated in the Makonde Plateau in Tanzania in 1952.[2] The name Chikungunya is derived from a Makonde phrase meaning, "that which bends up." The worst outbreak reported occurred in the Reunion Island in 2005-2006 affecting nearly 35% of the population.[3] Since 2005, cases of Chikungunya fever have spread mainly in tropical and sub-tropical regions finally reaching the Americas via the Caribbean island of St. Martin in 2013.[4] Today, CHIKV is widespread worldwide and is a global public health concern.
Etiology
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Etiology
The primary vectors for CHIKV are Aedes aegypti and Ae. albopictus (Asian Tiger mosquito). These mosquitoes have biological characteristics that provide effective invasiveness, vector competence, and vectorial capacity that sets the tone for the global manifestation of Chikungunya fever.[5] Invasiveness is highlighted by the species' preference for human blood and its historically-proven ability to establish outside of their native range. Vector competence is determined by the species' physiological characteristics that allow for transmission, such as virus ingestion with blood meal and subsequent infection of the mosquitoes’ salivary glands.[6] Most importantly, vector capacity determines outbreak potential and is mainly influenced by intrinsic (mosquito infection barriers and genetics) and extrinsic (environmental issues) factors. Vector density in relation to the host, the probability that vector feeds on a host in one day, vector survivability, and extrinsic incubation period are all vector competence factors that determine infectivity directly.[7]
Ae. aegypti has been established in the U.S. for more than 300 years while Ae. albopictus has been present since 1985 with different vector characteristics making global expansion of the disease possible. Specifically, CHIKV was found to have adapted to Ae. albopictus fairly recently during the Indian Ocean outbreak in 2005-06 when it acquired a mutation in its E1 membrane protein that allowed it to infest the urban mosquito vector.[8] In general, the threat to public health posed by Ae. aegypti and Ae. albopictus mosquitoes is a function of their focused feeding on and association with humans along with the ability of the human host and mosquito vector to travel.[9]
Epidemiology
CHIKV was first discovered in Tanzania in 1952, has since spread effectively reaching the Americas in 2013, Florida on July 2014, and severely affecting various Caribbean, Central, and South American countries after that.[10] Although the CHIKV virus is considered to be endemic in certain parts of West Africa, global distribution has been facilitated by both human and vector travel. Infected travelers import CHIKV into new areas where local Aedes mosquitoes initiate local transmission.[11] Mosquito larvae and egg transport by ships and air traffic has also been described as dissemination means for mosquitoes into naive and suitable environments.[12] Transmission is mostly via mosquito bites, although maternal-fetal and blood product transmission was also described during the Reunion Island outbreaks.[13]
Ae. aegypti and Ae. albopictus are also the vectors responsible for other notable diseases such as Dengue and Zika, causing coinfection in some cases.[14] Given the similarity in clinical presentation and nearly identical geographic distribution, and differentiation of disease has become an issue.
Pathophysiology
CHIKV is known to transmit in 2 cycles: urban and sylvatic. Urban transmission is from human to mosquito to human and is the main source of the current Western Hemisphere epidemic. Sylvatic transmission can be found in Africa and is based on animal to mosquito to human.[15] As mentioned previously, CHIKV was initially transmitted through the vector Ae. aegypti, but incorporation of Ae. albopictus through a mutation in the E1 envelope protein not only increased the fitness of the virus in this species but improved transmissibility to vertebrates.[16][17]
The route of infection used by CHIKV starts after inoculation and infection of human epithelial and endothelial cells, primary fibroblasts, and monocyte-derived macrophages.[18] After an initial immune response and sheltering in the lymph nodes, CHIKV travels through the lymphatic and circulatory system causing significant viremia.[19] Transportation into target organs (muscles, joints, liver, and brain) has been found to be caused by infected monocyte-derived macrophages.[18] Inflammatory reaction mediated by CD8+ (acute), CD4+ T lymphocytes, and pro-inflammatory cytokines are thought to be responsible for the acute symptoms, while a persistent reservoir of infected monocytes in the joints may be responsible for chronic joint disease.[20]
Histopathology
CHIKV is an arthropod-carried pathogen of the genus alphavirus and the family Togaviridae that possesses 3 known genotypes: Asian, West African, and East Central South African.[21] The virus is described as a positive-sense, single-stranded RNA virus, and sensitive to temperatures greater than 58 C.[17]
History and Physical
Chikungunya fever usually presents with the non-specific findings of high-grade fever and myalgia, following a 3 to 7 day incubation period, and lasting around 3 to 5 days. Bilateral symmetrical polyarthralgia ensues 2 to 5 days after the onset of fevers and preferentially involves distal over proximal joints.[22] The hands have been found to be affected the most with some involvement reported to the axial skeleton, knees, and ankles accompanied by intense pain that lasts between one and three weeks.[23] Another common clinical manifestation is a generalized maculopapular rash that usually involves the extremities first and arises 3 days after the fever symptoms.[24] Although rare, vesiculobullous and mucocutaneous lesions have also been reported.[25][26]
Manifestations such as abdominal pain, diarrhea, vomiting, and generalized lymphadenopathy may also be found. Although it is not considered to be a neurotropic virus, it has long been associated with neurologic symptoms, with encephalitis among newborns infected through mother-to-child transmission being the most common.[27] In a 2018 study in Puerto Rico, red eyes, conjunctivitis, and anterior uveitis were frequently found in patients with Chikungunya fever.[28] Other studies have described recurrent retinitis,[29] congenital ocular symptoms,[30] sepsis/septic shock,[31] and renal manifestations.[32]
Evaluation
Chikungunya fever evaluation consists mainly of the clinical findings of fever and polyarthralgia in a person who recently returned from an affected region with an 84% sensitivity, 71% positive predictive value (PPV), and 83% negative predictive value (NPV).[33] However, overlap of endemic and invaded CHIKV and Dengue virus (DENV) areas makes evaluation and differentiation of disease difficult. CHIKV is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia, while DENV is more likely to cause neutropenia, thrombocytopenia, hemorrhage shock, and death.[34] In light of this, WHO recommends treating everyone for DENV until proven otherwise to improve outcomes.
Diagnosis of CHIKV can be established or confirmed by detection of viral RNA with serology and/or reverse-transcription polymerase chain reaction (RT-PCR) depending on disease timeframe presentation.[35] RT-PCR is mainly used during acute infection, during the first five days of disease for best results. On the other hand, viral serology using enzyme-linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA) is used for detection of anti-chikungunya antibodies IgM (present from five days to several weeks) and IgG (present from two weeks to several years), depending on the stage of disease.[36][37] The CDC and WHO recommend gathering serology for CHIKV, DENV, and Zika virus (ZV) for all patients with suspicious clinical symptoms.[38]
Chikungunya fever is a nationally notifiable condition.
Treatment / Management
Symptomatic relief is the mainstay treatment for Chikungunya fever, including adequate hydration, rest, and pain/fever relief preferably with acetaminophen.[39] WHO discourages the use of aspirin and most nonsteroidal anti-inflammatory drugs (NSAIDs) during the first 48 hours due to the risk of aggravating platelet dysfunction, especially in cases of possible DENV coinfection. Other studies advocate for the efficacy of low-dose corticosteroid drugs for the first 2 months of post-acute disease.[40] Ocular manifestations including anterior and posterior uveitis have been treated with topical steroids and cycloplegics.[41](A1)
Chronic manifestations, including persistent or relapsing-remitting polyarthralgia, polyarthritis, and myalgia, have been found to respond adequately to hydroxychloroquine in combination with corticosteroids or other disease modifying anti-rheumatic drugs (DMARDs).[42][43] Specific antivirals targeting viral replication using siRNAs[44] and virus entry/replication[45] are showing promising results but have not been approved for human use.[46](A1)
Management of CHIKV is based on avoidance of mosquito bites. Use of repellents containing DEET, wearing protective clothing, bed nets, and air-conditioned buildings are great ways to prevent exposure.[47] Furthermore, prevention of mosquito proliferation should be implemented by reduction of peri-domiciliary water puddles.[23] Insecticides have been another means of vector management using four types of drugs: carbamates, organochlorides, organophosphates, and pyrethroids. Nonetheless, insecticide resistance of Ae. aegypti and Ae. albopictus has been of increasing concern.[48] Vaccines are also a hot topic for research and development, but none have yet been approved for patient use.[49]
Differential Diagnosis
Given the non-specific findings of arthralgia, high fever, and rash, the differential diagnosis for the acute and chronic manifestations of Chikungunya fever can be extensive. As mentioned above, DENV and ZK share not only clinical findings but also identical vectors with CHIKV, which prompts serology testing for all 3 viruses when a patient presents with the above symptoms.[38] Other infections that should be considered include:
- Malaria
- Yellow fever
- Leptospirosis
- Measles
- Mononucleosis
- African tick bite fever
Chronic arthralgia caused by Chikungunya fever can be easily confused with other more common causes. Furthermore, worse outcomes and increased morbidity has been demonstrated for patients with underlying joint disease and are super-infected with CHIKV.[50] The differential diagnosis for chronic manifestations includes:
- Seronegative rheumatoid arthritis
- Reiter arthritis
- Rheumatoid arthritis
- Hepatitis C
- Systemic lLupus erythematosus
Prognosis
Despite a low case fatality ratio (CFR), Chikungunya fever is highlighted by a substantial post-chikungunya chronic polyarthralgia, defined as joint pains lasting longer than 6 weeks.[51] A study published in 2018, composed of Aruba CHIKV cases, reported that 26% of all serology-confirmed infected patients presented with post-chikungunya polyarthritis.[52] Another study published in 2018, from 2014 French Guiana, reported post-CHIKV rheumatic or musculoskeletal pain at 3 and 6 months of 40% and 31.3% respectively of all RT-PCR proven cases.[50]
Complications
As mentioned previously, chronic arthritis is the most common and serious complication of Chikungunya fever. Ocular manifestations of disease can include conjunctivitis, optic neuritis, iridocyclitis, episcleritis, retinitis, and uveitis.[53] The most common complications are iridocyclitis and retinitis and have been found to be typically benign and self-limited.[54]
Consultations
Chronic arthritis from Chikungunya fever has emerged as a concern for rheumatologist specialists worldwide due to swelling and recurrent pain that poorly responds to treatment with analgesics, and because it is a debilitating disease that mimics rheumatic arthritis and compromises the quality of life.[55][56]
Deterrence and Patient Education
Chikungunya fever is a virus transmitted to people by mosquitoes found mainly in tropical and sub-tropical environments. Originating from Asia, this disease has caused serious outbreaks in the Western Hemisphere since 2013. The most common symptoms of this disease are high fevers and joint pain, although headaches, muscle pains, and rash may also occur. Risk factors for the disease consist of travel to affected areas or anywhere with mosquitoes and mosquito bites. Treatment consists of rest, adequate hydration, and pain relief with acetaminophen. Prevention is key and is based on protection from mosquito bites with clothing, DEET, and mosquito nets. Given the risk of co-infection with other viruses from the mosquito bite, individuals with these symptoms must seek medical care immediately.
Pearls and Other Issues
- Chikungunya fever is an arthropod-borne alphavirus from the Togaviridae family endemic to Asia that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and has caused serious worldwide outbreaks with a preference for tropical and sub-tropical climates.
- The Aedes mosquito vectors are also responsible for transmitting Dengue virus and Zika virus, so co-infection is possible.
- Acute clinical manifestations of high fevers, polyarthralgia, and maculopapular rash begin after a 3- to 7-day incubation accompanied by a headache and myalgia. Ocular, neurological, and fetal manifestations have been found in rare instances.
- Chronic arthritis is the most common and severe complication leading to specialist rheumatologic care.
- Diagnosis is obtained with the above clinical findings accompanied by a history of recent travel to an affected area or exposure to mosquito bites. Diagnosis confirmation is performed with RT-PCR or viral serology. The CDC recommends that all patients with exposure and symptoms be tested for CHIKV, DENV, and ZK.
- Supportive care with rest, hydration, and analgesic agents is the mainstay treatment. Aspirin and NSAIDs should be avoided initially for risk of co-infection with DENV. Chronic manifestations can be treated with steroids and disease-modifying anti-rheumatic drugs (DMARDs). No antivirals or vaccines are commonly used.
- Prevention with avoidance of mosquito bites is paramount. DEET, clothing with coverage, and mosquito nets. Insecticides have been used as a public health measure, but resistance is a factor of increased concern.
- Chikungunya fever is a reportable disease to the CDC.
Enhancing Healthcare Team Outcomes
Mosquitoes represent the arthropod-vector with the most impact in the world, transmitting diseases from Chikungunya fever to malaria with incalculable morbidity and mortality. Given the lack of specific treatment for most of these diseases, vector control remains the main form of prevention. Insecticide public health campaigns have proven to be effective in the past, but widespread resistance has put a dent on these efforts.[57] (Level V) Another focus of prevention proven in Brazilian studies has been personal protection and individual actions including use of DEET, bed nets, light-colored long-sleeve clothing, and reduction of peri-domiciliary water puddles/reservoirs.[58] (Level I)
When it comes to improving outcomes, the CDC has highlighted the dangers of CHIKV and DENV co-infection and the differences in treatment modalities, important for all healthcare professionals, to avoid Dengue fever-related deaths.[59] A 2018 review highlighted the importance of proper diagnosis (gathering serology DENV, CHIKV, and ZV serology on affected individuals), surveillance, and management to avoid poor prognosis.[60] (Level I)
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Level 1 (high-level) evidence