Pathology of Chikungunya Virus Infection: Emergence and Clinical Insights

Chikungunya: A Re-emerging Worldwide Epidemic

Chikungunya (CHIK) is a re-emerging mosquito-borne disease due to an alphavirus (arbovirus) of the Togaviridae family.^[1,2] The alphavirus group comprises 29 viruses, six of which can cause human joint disorders (arthralgia evolving to arthritis), namely Chikungunya virus (CHIKV; in Africa, Indian Ocean, India and Southeast Asia), O'Nyong-Nyong virus (in Africa), Semliki forest virus (in Africa, Asia and Europe), Ross River virus (in Australia and the Pacific), Sindbis virus (cosmopolitan) and Mayaro virus (in South America and French Guyana).^[3] The tropical disease CHIK is transmitted by the Aedes mosquito and is characterized by fever, headache, rashes and debilitating arthralgia.^[4] CHIK was initially believed to be mainly an incapacitating disease and nonfatal, but severe forms and deaths have been reported on the Indian Ocean island of La Réunion^[5] and in India.^[6] A total of 3 years after the 2005–2007 epidemic, as the main feature of the disease remains the persistence of chronic arthralgia, the disease is now recognized as a major public health issue.^[2,7]

Chikungunya virus was first isolated in Tanganyika (now Tanzania) in 1953.^[4,8] Epidemics were then reported in West Africa,^[9–11] the Central African Republic^[12] and in Southern Africa.^[13] Many outbreaks were reported in Southeast Asia and the Western Pacific,^[14] Indonesia^[15] and India.^[16] Neither Europe nor the Americas experienced outbreaks of CHIKV during these years. The last epidemic wave of CHIK in the Indian Ocean emerged in Kenya (Lamu) in July 2004, then reached the Comoros in January 2005, and the Seychelles in March 2005, followed by Mauritius. Serologic studies showed a high attack rate, with a prevalence of 75% in the population of Lamu,^[17] and 63% in Comoros.^[18] The virus reached La Réunion in March–April 2005, with a prevalence of over 38% (266,000 cases).^[19] For the first time, deaths were directly or indirectly attributed to CHIKV (254 in La Réunion).^[20] Afterwards, several outbreaks expanded to India^[6] and Southeast Asian countries. In India, it is estimated that more than 1.4 million people in 13 states were infected. Moreover, imported cases of CHIK in exposed travelers from the affected areas were observed in most countries in Europe, the USA, Canada, Hong Kong and, more recently, in China.^[21] In Italy, where Aedes albopictus is present, an outbreak of more than 200 cases occurred in the Ravenna region during the summer of 2007.^[22] Previous phylogenetic studies showed that CHIKV strains were clustered into three distinct genotypes separated primarily by location into West African, Central/East/South African and Asian genotypes.^[23,24] Earlier outbreaks in Southeast Asia, India and Indonesia prior to 2004 were caused by strains of the Asian genotype.^[24] Explosive epidemics in the Indian Ocean islands and India since 2005 and the worldwide increase in travel have changed the distribution of CHIKV genotypes. Recent studies have shown that different lineages of CHIKV strains of the Central/East/South African genotype have expanded^[25] and have spread to new areas in Africa during 2006–2007, Europe (2007), India (2006), Bangladesh (2008) and Malaysia (2008–2009) and caused the most recent epidemics.^[6,26] This highlights the evolutionary dynamics of CHIKV, and probably involves the vector, the Aedes mosquito species.

Although the urban mosquito Aedes aegypti is the primary vector for Dengue and CHIKV transmission in Asia, the Ae. albopictus mosquito, initially a less efficient vector, was recently identified as the main or alternate vector in CHIK outbreaks in Central and East Africa, India and Europe. The increased fitness of CHIKV in Ae. albopictus has important consequences. Given the worldwide distribution of Ae. albopictus, not only tropical and subtropical countries, but also temperate countries where Ae. aegypti is rare (e.g., the Americas, China and Japan) are at risk of epidemics.^[27,28]

Moreover, recent studies have suggested that the increased outbreaks caused by CHIKV strains might have been associated with the A226V mutation in the E1 protein. This mutation appeared to be exclusively found in CHIKV isolated from Ae. albopictus;^[29] it improves virus adaptation to the mosquito, with an increased ability to invade mosquito cells and to replicate.^[30] For example, this mutation is responsible for a significant increase in CHIKV infectivity for Ae. albopictus and leads to a more efficient viral dissemination into mosquito secondary organs.^[31] The enhanced fitness would be due to the loss of cholesterol dependence for growth by CHIKV, thereby allowing the virus to adapt and replicate more efficiently in Ae. albopictus and other mosquito species, which usually lack cholesterol.^[31,32] Together with the absence of herd immunity and increased urbanization, this might explain the magnitude of the La Réunion outbreak, where more than a third of the population has been infected.^[33] Genetic studies showed cocirculation of Asian genotype and Central/East/South African genotype during 2006–2009 in Taiwan.^[26] The E1-A226V mutation only occurred in the 2007 outbreak in India.^[34] Singapore was concerned by a CHIKV outbreak without the E1-A226V mutation in January 2008, and the vector was Ae. aegypti.^[35] In 2010, there is an ongoing epidemic in India, Thailand and in the southeast coast of Madagascar (Mananjary), where more than 2000 cases were reported by March 8, 2010.^[101] Moreover, imported cases from these countries have led to a resurgence of a dozen indigenous cases per week of CHIKV in La Réunion since March 2010.^[102]