Geographic epidemiology

Since its discovery, CHIKV has been somewhat ignored by scientists, except when it has caused large human outbreaks of infection. Historically, the disease may be older than expected; an episode of epidemic fever–arthralgia symptoms in 1779 was widely but mistakenly cited as the first documentation of dengue fever and is now believed to be an outbreak of CHIKV infection fever. CHIKV infection was reported as an epidemic febrile disease in Batavia (now Jakarta, Indonesia) .

After the first report of confirmed CHIKV infection fever outbreak in 1952, in Makonde Plateau in Tanzania, East Africa , CHIKV infection was frequently reported in numerous African countries , in Central and Southern Africa including Sudan , Uganda , Malawi, Zimbabwe, Democratic Republic of Congo , the Central African Republic , South Africa and Kenya. CHIKV has also been isolated in West African countries, including Senegal , Benin, the Republic of Guinea , Ivory Coast and Nigeria .

CHIKV infection outbreaks were reported in Asia since 1958, when the virus was first isolated in Bangkok . CHIKV infection has been documented in many parts of Southern and Southeast Asia. India reported its first confirmed epidemic in 1963, in Calcutta , and subsequently in Madras, affecting more than 3 million people . Frequent outbreaks have been observed in Malaysia, Indonesia, the Philippines, Cambodia, Vietnam, Myanmar, Pakistan, Singapore and Thailand .

The virus was considered an important emerging arbovirus after two major epidemics. The first apparently began on the coast of Kenya in 2004, before reaching the Comoros in 2005. The virus rapidly disseminated to other islands in the Indian Ocean, most notably Reunion Island, where about 270 000 cases were reported, with an attack rate of about 35% .

In Europe, cases of CHIKV infection were reported in several countries, including Italy, UK, Belgium, Germany, Czech Republic, Norway, Poland, Spain and France . These cases were directly associated with the return of tourists from India and affected islands in the Indian Ocean. However, imported cases could be a risk for local outbreak, as was illustrated in Emilia-Romagna, Italy, where an infected man came back from India and local transmission involved 205 cases .

Other cases associated with travellers were reported in some Asian countries, such as Taiwan , Hong Kong , Sri Lanka , Japan and China . Cases of CHIKV infection have rarely been reported among international travellers in Canada, the United States and Australia .

Mode of transmission

Typically, CHIKV has two distinct transmission cycles: sylvatic and human–mosquito–human. Sylvatic transmission involves wild primates, such as monkeys and forest-dwelling Aedes species of mosquitoes, primarily Aedes furcifer , Aedes taylori , Aedes luteocephalus , Aedes africanus and Aedes Neoafricanus . This cycle is confined to Africa (Senegal, Ivory Coast, Central African Republic and South Africa) and is responsible for sporadic human cases and small outbreaks. The human–mosquito–human transmission cycle maintains CHIKV infection in urban areas. It involves primarily a vector, the Aedes aegypti mosquito, which is an extremely efficient urban vector because it preferentially feeds on humans, often bites several people during a single blood meal and is adapted to live and breed peridomestically; the mosquito is therefore the most likely initiator of the large regional and global outbreaks of the disease .

In recent years, A. albopictus has emerged as the second vector to efficiently transmit CHIKV; this mosquito has shown importance in areas where A. aegypti is absent . The distribution of A. albopictus is more northern than that of A. aegypti because the former is better adapted to cold weather. Thus, globalisation of A. albopictus has created new risk areas for outbreak of CHIKV infection .

Thus, in the event of epidemics, humans have served as the CHIKV reservoir, and outside of epidemic periods, monkeys, birds, rodents and other vertebrate species are the vectors .

Recently, authors suspected that CHIKV could be transmitted by blood transfusion. The CHIKV transfusion risk was assessed for Reunion Island and northern Italian outbreaks, although the relatively short duration of viraemia and high proportion of symptomatic infections that could identify and exclude potential donors from donating are factors limiting the risk of CHIKV transmission by transfusion .

Mode of transmission

Typically, CHIKV has two distinct transmission cycles: sylvatic and human–mosquito–human. Sylvatic transmission involves wild primates, such as monkeys and forest-dwelling Aedes species of mosquitoes, primarily Aedes furcifer , Aedes taylori , Aedes luteocephalus , Aedes africanus and Aedes Neoafricanus . This cycle is confined to Africa (Senegal, Ivory Coast, Central African Republic and South Africa) and is responsible for sporadic human cases and small outbreaks. The human–mosquito–human transmission cycle maintains CHIKV infection in urban areas. It involves primarily a vector, the Aedes aegypti mosquito, which is an extremely efficient urban vector because it preferentially feeds on humans, often bites several people during a single blood meal and is adapted to live and breed peridomestically; the mosquito is therefore the most likely initiator of the large regional and global outbreaks of the disease .

In recent years, A. albopictus has emerged as the second vector to efficiently transmit CHIKV; this mosquito has shown importance in areas where A. aegypti is absent . The distribution of A. albopictus is more northern than that of A. aegypti because the former is better adapted to cold weather. Thus, globalisation of A. albopictus has created new risk areas for outbreak of CHIKV infection .

Thus, in the event of epidemics, humans have served as the CHIKV reservoir, and outside of epidemic periods, monkeys, birds, rodents and other vertebrate species are the vectors .

Recently, authors suspected that CHIKV could be transmitted by blood transfusion. The CHIKV transfusion risk was assessed for Reunion Island and northern Italian outbreaks, although the relatively short duration of viraemia and high proportion of symptomatic infections that could identify and exclude potential donors from donating are factors limiting the risk of CHIKV transmission by transfusion .

Risk factors for epidemics

Massive urbanisation has facilitated the spread of contagious diseases in human populations as has increased fast travel over greater distances and worldwide trade. In light of this, CHIKV transmission is closely associated with travel . Furthermore, the risk of emerging or re-emerging CHIKV disease epidemics is associated with the worldwide distribution of well-adapted vectors and the pronounced viraemia in acutely infected humans . The high-titre viraemia in humans is sufficient to infect mosquitoes, which permits an urban transmission cycle between humans and mosquitoes.

Climate change is also considered a risk factor. Studies have shown that an increase of 1–2 °C in temperature results in augmented virus replication . Further, CHIKV outbreaks heavily depend on mosquito density, which increases after a period of heavy rainfall . However, other factors such as virus evolution, especially emergence of CHIKV strains better adapted to mosquitoes, are important . Several studies of viral isolates and infectious clones have elegantly shown that a single mutation can result in high viral replication and dissemination rates in A. albopictus and thereby shorten the extrinsic incubation period. The length of the extrinsic incubation period determines the infective life span of a vector and therefore has a great influence on the epidemic potential of the virus–vector partnership. Absence of herd immunity and the lack of vector controls have been associated with the re-emergence of CHIKV infection.

Clinical manifestations

Most infected individuals show symptoms . CHIKV infection has two consecutive phases. After an incubation period typically ranging from 3 to 7 days , the initial phase is characterised by three classic symptoms: abrupt febrile illness (temperature often exceeding 38.9 °C); maculopapular rash, which typically involves the trunk and extremities but sometimes the palms, soles and face; and the most characteristic symptom, joint pain responsible for a stooped walk. Other common, nonspecific symptoms include headache, fatigue, nausea, diarrhoea, vomiting, abdominal pain, chills, conjunctivitis, neuritis, pharyngitis and myalgias. The acute signs and symptoms usually resolve in <2 weeks; then the disease progresses to a second stage, with chronic rheumatic manifestations as a major feature .

Severe forms of CHIKV infection with complications have been described ( Table 1 ). During the 2005–2006 outbreak in Reunion Island, of 610 cases reported, 222 were severe; the overall mortality was 10.6% and increased with age. Hypertension and underlying respiratory or cardiological conditions were independent risk factors for disease severity . CHIKV disease is more severe and is accompanied by more joint disorders in adults than in children.

Rheumatic manifestations

Historically, the epidemic febrile disease in Batavia (now Jakarta, Indonesia) in 1779 is now believed to be an outbreak of CHIKV infection. An infected person, David Bylon, described his disease: “It was last May 25, in the afternoon at 5:00 when I noted while talking with two good friends of mine, a gnawing pain in my right hand, and in the joints of the hand and arm, which gradually increased, extending to the shoulder and then over my whole body, so that at 9:00 that evening I was in my bed with high fever … it’s now been three weeks since I… was stricken by the illness, and because of that had to stay home for 5 days: but even until today I have continuously pain and stiffness in the joint[s] of both feet, with swelling of both ankles; so much so, that when I get up in the morning, or have sat up for a while and start to move again, I cannot do so very well and going up and down stairs is very painful.” .

Polyarthralgia has been described in more than 90% of patients; typically, it ensues within a few minutes or several hours of fever onset and results in a characteristic stooped walking position, the hallmark of the disease .

In the acute stage, joint pain is usually symmetric, involving large and small joints of the upper and lower limbs. Joint pain occurs commonly in wrists, elbows, fingers, knees and ankles; nevertheless, the knee is the most commonly involved joint, and the proximal joints, hip and shoulder, are less affected . A swollen joint is frequently reported, and often in the acute stage of the illness, the arthritis is symmetrical.

The chronic stage is characterised by chronic rheumatic manifestations. Up to 64% of patients with CHIKV fever report joint stiffness and/or pains more than a year after the initial infections . Persistent and/or recurring joint stiffness and/or pain lasting more than 1 year after the initial infection affected more than half of all CHIKV-infected patients in La Reunion Island during the 2005–2006 outbreak . Likewise, chronic arthritis after CHIKV infection has been well documented . Rheumatic manifestations fluctuate; symmetrical arthritis has been described, but it can be asymmetrical and even present as oligoarthritis or monoarthritis. This arthritis mimics rheumatoid arthritis (RA); indeed, 21 cases fulfilling the American College of Rheumatology (ACR) criteria for RA after CHIKV infection were reported in Reunion Island outbreak. ⁵¹⁻⁵³ Furthermore, some deformity and limitations in joint mobility have been described, but redness of joints was never seen .

Apart from arthralgia, other rheumatic manifestations have been reported. Pain in the sacroiliac joint and lumbosacral and cervical vertebral joints was found in some patients . Pain within or around tendons is a common trait and evolves to tenosynovitis or enthesopathy. Back pain was described in some reports of CHIKV infection .

Chronic CHIKV infection-related arthritis is highly debilitating and results in high economic cost and human suffering. During the 2006 epidemic in India, the disability-adjusted life year (DALY), which is a measure of the loss of healthy days in a society, was used to estimate the burden due to CHIKV infection. It exceeded 265 per million in some states, which accounted for up to 69% of the total DALYs . In a recent longitudinal follow-up study of 203 patients with serologically confirmed CHIKV infection, fatigue accompanied joint pain when the disease entered the second month and added to the morbidity .

Radiographic abnormalities

In the previously described cohort in India , radiographs showed lesions that suggested bony erosion; on magnetic resonance imaging (MRI), the inflammatory findings were joint effusion, bone-marrow oedema or erosion and synovial thickening, tendinitis and tenosynovitis.

Manimunda et al. showed with relative certainty that chronic CHIKV infection-related arthritis is an inflammatory erosive arthritis ; this finding is in agreement with previous studies finding bony erosion in several cases as well as tenosynovitis and enthesopathy seen on ultrasonography .

Biological abnormalities

By analogy to infection with other alphaviruses, in CHIKV infection, laboratory values remain largely within the normal range; nevertheless, the acute infectious phase of CHIKV disease is characterised by pronounced lymphopaenia and moderate thrombocytopaenia .

According to several previous studies , the common haematological and biochemical abnormalities described in CHIKV infection include leucopaenia, neutropaenia, lymphopaenia, thrombocytopaenia and elevated transaminase, creatinine and creatinine kinase levels. In a recent study describing the daily haematological values, lymphopaenia was most prominent during days 2–3 of the illness, whereas leucopaenia reached its nadir from days 3–5. Interestingly, mild thrombocytopaenia persisted from days 3–9, with a corresponding increase in haematocrit value . Win et al. noted that lymphopaenia preceded the decrease in total leucocyte count. The erythrocyte sedimentation rate was elevated in most patients during the 10th month of illness in the study in India .

Furthermore, Chopra et al. found a high level of C-reactive protein (CRP) in more than 70% of the studied cohort . However, Borgherini et al. suggested that elevated levels of CRP and transaminases and reduced calcium level and polymorphonuclear neutrophil count were associated with more severe illness .

Two main methods of laboratory diagnosis are available, namely real-time polymerase chain reaction (RT-PCR) and serology for antibodies to CHIKV (immunoglobulin M (IgM) or IgG). During the initial viraemic phase, RT-PCR is very useful, although classic serological methods are simpler; hence, IgM antibodies are detectable after 2 days, on average, by enzyme-linked immunosorbent assay (ELISA) and persist for several weeks to 3 months . IgG antibodies are detected in convalescent samples and persist for years.

Factors associated with persistence of arthralgia after infection

Identifying factors associated with persistent arthralgia after CHIKV infection is of special interest. Independent markers for persistent joint pain include age ≥45 years, initial severity of joint pain and underlying osteoarthritis . However, a recent study in Singapore found age not associated with persistent arthralgia , and the only significant marker associated with persistent joint pain in this study was low creatinine level; however, women were more likely to have persistent arthralgia and tended to have lower creatinine levels. Furthermore, thrombocytopaenia and elevated liver enzyme levels were suggested as associated with slow recovery from joint pain . The occurrence of a new viral mutation was suspected to be related to the more aggressive clinical burden of the disease and a higher risk of chronic arthralgia . As well, previously injured joints were especially susceptible .

Similar epidemics

In recent years, the number of outbreaks of arboviral-induced arthralgia and severe and long-lasting arthritis has increased in frequency. Apart from CHIKV, six viruses of the alphavirus group (comprising 29 viruses) can cause arthralgia evolving to arthritis; these include O’nyong nyong virus (ONNV), Semliki Forest virus (SFV), Ross River virus (RRV), Sindbis virus (SINV), Mayaro virus (MAYV) and Barmah Forest virus (BFV) .

SINV is the most widely distributed of all known arbovirus. Antibodies to SINV are detected in humans in various geographical areas, but clinical infections are reported mostly from Finland, where the SINV infection is associated with fever, rash and arthritis, known as Pogosta disease. A major Pogosta disease outbreak has occurred every 7 years in Finland since 1974, involving hundreds or even thousands of patients .

RRV is a mosquito-borne alphavirus endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis (EPA), an explosive epidemic that also swept through several islands of the South Pacific and resulted in tens of thousands of cases; the principal symptoms of EPA are arthritis or arthralgia, which is often severe and usually lasts 30–40 weeks, with about 25% of patients experiencing symptoms for a year or more .

ONNV (family Togaviridae, genus Alphavirus ) was first isolated from human blood and anopheline mosquitoes in Gulu, Uganda, in 1959, and has been responsible for several outbreaks in humans that occurred in East Africa (Kenya, Uganda, Tanzania, Malawi and Mozambique). Between 1959 and 1962, an epidemic of O’nyong nyong (ONN) fever in Africa affected at least 2 million people .

MAYV has been isolated only in northern South America and in French Guyana and is responsible for acute illness with rash, fever and severe arthralgia. The last-named lasts for several weeks and affects principally the ankles, wrists and toes but also can affect major joints. The most recent outbreak occurred in a settlement in Santa Barbara, northern Brazil .

SFV has been described only in Africa. Its clinical manifestations include fever, severe persistent headache, myalgia, arthralgia and a long convalescence marked by asthenia. This virus was responsible for an outbreak of febrile illnesses in Bangui, Central African Republic, during October–December 1987 .

BFV is currently found only in Australia. This virus can cause arthritis, myalgia and fatigue for 6 months or longer, which result in substantial morbidity and economic impact. During the summers of 2005 and 2006, the largest BFV epidemic on record occurred in Australia, with 1895 notifications .

Other viruses can cause major outbreaks and joint disorders, particularly dengue virus, which is a member of the Flaviviridae family, genus Flavivirus . The dengue virus shares many characteristics with CHIKV, including some of the factors associated with its emergence. In addition, dengue virus and CHIK infection are the two most important arboviral infections of global significance. An estimated 50–100 million cases of dengue fever and about 250 000–500 000 cases of dengue haemorrhagic fever occur every year . Haemorrhage and shock syndrome distinguish dengue virus infection from CHIKV infection. Despite the similarities in clinical presentations of the infections, the differential diagnosis is still difficult .