Chikungunya fever

Abstract

Chikungunya virus is widespread throughout the tropics, where it causes recurrent outbreaks of chikungunya fever. In recent years, outbreaks have afflicted populations in East and Central Africa, South America and Southeast Asia. The virus is transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Chikungunya fever is characterized by severe arthralgia and myalgia that can persist for years and have considerable detrimental effects on health, quality of life and economic productivity. The effects of climate change as well as increased globalization of commerce and travel have led to growth of the habitat of Aedes mosquitoes. As a result, increasing numbers of people will be at risk of chikungunya fever in the coming years. In the absence of specific antiviral treatments and with vaccines still in development, surveillance and vector control are essential to suppress re-emergence and epidemics.

Fig. 1 |. Phylogenetic tree of alphaviruses and spread of CHIKV lineages.

a, The sylvatic and urban cycle of chikungunya virus (CHIKV) transmission. b, Phylogenetic tree of human pathogenic alphaviruses that are transmitted by mosquitoes, including CHIKV lineages, based on structural protein sequences. The mosquito-transmitted alphaviruses can be broadly classified according to their main pathogenic characteristics, with CHIKV and related viruses causing arthritic symptoms as compared to the more distantly related alphaviruses causing encephalitis in affected persons. c, World map showing the spread of CHIKV lineages and the dominant Aedes mosquito vectors. Dotted patterns indicate contemporary presence of Aedes mosquitoes and projected spread by 2050 is indicated by coloured area shading. Predictions of future spread of the Aedes mosquitoes account for their potential for invading expanding urban areas and increased environmental suitability following climate change. In the coming 5–15 years, expansion is expected to be mainly due to invasion of anthropogenic niches (environmental changes caused by humans) after long-distance introductions driven by global air transport or along well-travelled ground routes of people and goods. Aedes aegypti is expected to spread largely within its tropical range and sufficiently temperate regions in the USA and China while largely avoiding Europe apart from southern Italy and Turkey. Aedes albopictus, of which dormant eggs allow survival in colder winters, are projected to become established throughout Europe, the northern USA, highland regions of South America and eastern Africa^,,. Only after this period of 5–15 years are climate change factors, mainly increased temperatures, expected to drive further Aedes mosquito habitat expansions. ECSA, East Central South African lineage; EEEV, eastern equine encephalitis virus; IOL, Indian Ocean lineage; MAYV, Mayaro virus; ONNV, O’nyong’nyong virus; RRV, Ross River virus; SFV, Semliki Forest virus; SINV, Sindbis virus; VEEV, Venezuelan equine encephalitis virus; WA, West African lineage; WEEV, western equine encephalitis virus.

Fig. 2 |. CHIKV replication.

Chikungunya virus (CHIKV) replication cycle with indication of genomic replication steps (1–4). Infection starts with cellular entry after receptor binding and clathrin-mediated endocytosis^–. Direct fusion at the plasma membrane, clathrin-independent endocytosis and macropinocytosis have also been implicated but their contribution to in vivo infection remains unclear. Viral genomic RNA (gRNA) is released into the cytoplasm following E1-mediated fusion of virion and endosomal membrane, and is translated to produce the non-structural proteins (nsPs) that form the replicase complex (step 1)^,. nsPs are produced as polyproteins nsP1–3 and nsP1–4 after ribosomal readthrough. The four nsPs are sequentially separated by the protease activity of nsP2 to coordinate the timed maturation of the replicase complex (extensively reviewed in refs. 308,309). The replicase complex is then translocated to the plasma membrane (step 2) to form replication spherules, the neck of which is formed by a 12-mer nsP1 ring and in which nsP4 RNA-dependent, RNA polymerase activity-mediated, negative-strand and new positive-strand viral gRNA and subgenomic RNA (sgRNA) production takes place (step 3)^–. The newly formed positive-strand RNAs are 5′ m7GMP Cap-0 capped by concerted action of nsP1 and nsP2 and 3′ polyadenylated by nsP4 (refs. –61). After expulsion from the replication spherule, sgRNA is translated to produce the structural polyprotein C–E3–E2–6K/TF-E1 (step 4), from which capsid is autoproteolytically cleaved through its own protease activity to remain cytoplasmic while the envelope proteins are produced at the endoplasmic reticulum membrane and mature after cleavage by trans-Golgi network-localized furin proteases and glycosylation^,. Packaging of viral gRNA into virions is induced by capsid binding to gRNA-specific sequences, avoiding packaging of sgRNA. E2 and E1 are type I transmembrane proteins and form heterodimers, three of which form a trimeric spike; 80 of these trimeric spikes are presented on the viral particle. E1 is a pH-dependent type II fusion protein and its association with the E3–E2 precursor (p62) during maturation prevents premature activation of its fusion loop^–. Following presentation of the envelope proteins on the plasma membrane, interactions between the cytoplasmic C-terminal region of E2 and capsid coordinate enveloping of the nucleocapsid in budding virions. The 6K/TF structural protein, with TF being produced after a frameshift of the 6K gene, has not been identified in CHIKV virions but functional studies in related alphaviruses indicate their function as ion channels in the endoplasmic reticulum to stimulate efficient budding.

Fig. 3 |. CHIKV infection and symptoms.

a, Chikungunya virus (CHIKV) infection occurs through bites of infected mosquitoes, resulting in a dermal infection phase. Initial rounds of CHIKV replication occur after infection of skin-resident cells such as dermal macrophages expressing high levels of Ly6C on their surface, fibroblasts, mesenchymal stromal cells (MSCs) and Langerhans cells expressing CD1a. b, Further CHIKV replication occurs in peripheral organs, including the lymph nodes, spleen and, in severe cases, the liver, brain and other organs. Acute symptoms are diverse and can occur in various organs and tissues with differing prevalence. In the chronic phase, joints tend to be affected in a symmetrical manner, with the highest prevalence in peripheral joints.

Fig. 4 |. CHIKV-associated immunopathology.

Chikungunya virus (CHIKV) infection results in inflammation. Following dissemination into the bloodstream, viraemia occurs, which triggers the production of pro-inflammatory immune mediators, resulting in acute disease. Markers of acute disease include interferon-α (IFNα), IL-6, IP10 and MCP1 (ref. 311). Viraemia (CHIKV RNA) typically clears by 14 days post-infection. However, chronic disease develops in some patients, indicated by increased levels of chronic disease markers such as granulocyte-macrophage colony-stimulating factor (GM–CSF) and IL-6 (refs. 134,135). RT-PCR, reverse transcription–PCR.

Fig. 5 |. Management of chikungunya fever.

The management and treatment of patients with chikungunya fever differs according to the stage of disease The treatment of uncomplicated acute chikungunya fever requires resting, oral hydration and simple, well-conducted analgesia. Multimodal analgesia is recommended for acute pain management and NSAIDs are an integral part of the management of inflammation following chikungunya fever. Corticosteroids are not recommended during the acute phase but do have a place in the management of the post-acute and chronic phase of infection and can be combined with other analgesics (level 1 and level 2) in the event of ineffectiveness of NSAID treatment. Disease-modifying antirheumatic drugs act on the rheumatological symptoms often observed during the chronic phase. Adjuvant physical and rehabilitation medicine complete patient care and aim to limit the general effects of joint and musculoskeletal disorders. ^aIn case of proven inflammatory polyarthritis and after specialist advice from a rheumatologist. ICU, intensive care unit; IV, intravenous; TNF, tumour necrosis factor.