Chikungunya Fever: An Epidemiological Review of a Re-Emerging Infectious Disease

1. J. Erin Staples1⇑, 
2. Robert F. Breiman2, and 
3. Ann M. Powers1

1. ¹Arboviral Diseases Branch, Division of Vector-borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado
2. ²International Emerging Infections Program-Kenya, Centers for Disease Control and Prevention, Nairobi, Kenya

1. Reprints or correspondence: Dr. J. Erin Staples, Centers for Disease Control and Prevention, 3150 Rampart Road, Fort Collins, CO 80521 (EStaples@cdc.gov).
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   Abstract

4. Chikungunya fever is an acute febrile illness associated with severe, often debilitating polyarthralgias.
5. The disease is caused by Chikungunya virus (CHIKV), an arthropod-borne virus that is transmitted to 
6. humans primarily via the bite of an infected mosquito. Since a re-emergence of CHIKV in 2004, the 
7. virus has spread into novel locations, such as Europe, and has led to millions of cases of disease 
8. throughout countries in and around the Indian Ocean. The risk of importation of CHIKV into new 
9. areas is ever present because of the high attack rates associated with the recurring epidemics, the 
10. high levels of viremia in infected humans, and the worldwide distribution of the vectors responsible 
11. for transmitting CHIKV. In this review, we will characterize the epidemiology and global expansion 
12. of CHIKV, describe the clinical features and laboratory testing for the disease, and discuss priorities
13.  for further studies needed for effective disease control and prevention.
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15. Chikungunya fever is an acute febrile illness caused by an arthropod-borne alphavirus, Chikungunya virus (CHIKV). The virus is primarily transmitted to humans via the bite of an infected Aedes species mosquito. CHIKV was first recognized as a human pathogen during the 1950s in Africa, and since then, cases have been identified in many countries in Africa and Asia [1, 2].
    In 2004, CHIKV re-emerged in Kenya and subsequently spread eastward, causing millions of disease cases throughout countries in and around the Indian Ocean [3–5]. The epidemics resulted in significant morbidity and taxed the health care and public health infrastructure in these regions. By 2007, CHIKV was imported into Europe, causing an outbreak of chikungunya fever in Italy [6]. This outbreak suggested for the first time the significant potential of the virus to move to novel ecological niches, including Europe, Australia, and the Western Hemisphere.
    In this review, we will briefly describe the epidemiology and global expansion of CHIKV then focus on the clinical features of chikungunya fever and the laboratory testing for the disease. In particular, we will reflect on what was learned during recent outbreak investigations and discuss priorities for further studies needed for effective disease control and prevention.

16. Epidemiology and Global Expansion of CHIKV

17. CHIKV likely originated in Central/East Africa [2, 7], where the virus has been found to circulate in a sylvatic cycle between forest-dwelling Aedesspecies mosquitoes and nonhuman primates. In these areas, sporadic human cases occur, but large human outbreaks are infrequent. However, in urban centers of Africa as well as throughout Asia, the virus can circulate between mosquitoes and naive human hosts in a cycle similar to that of dengue viruses. Aedes aegypti and Aedes albopictus mosquitoes are the main vectors responsible for urban transmission of CHIKV [4].

    The first significant urban outbreaks of chikungunya fever were documented in the early 1960s in Bangkok [8] and from 1963 through 1973 in India [9, 10]. Minor outbreaks periodically occurred over the next 30 years, but no major outbreaks were recorded until 2004, when a large epidemic started on the coast of Kenya [4, 5]. This outbreak started a 4-year-period in which CHIKV spread throughout numerous islands of the Indian Ocean, India and parts of Southeast Asia (table 1) [5, 11, 12]. In addition, at least 18 countries throughout Asia, Europe, and North America documented imported cases of chikungunya fever, with a few of these countries developing local autochthonous transmission of the virus [4].

18. Clinical Features of Chikungunya Fever

19. The first case series of patients infected with CHIKV, published in 1955, described 115 hospitalized patients in Tanzania with acute onset of high fever, severe joint pain, and rash [1]. The illness was initially diagnosed as a “dengue-like” disease until laboratory evaluation confirmed CHIKV as the source of illness. Since then, many CHIKV outbreaks have occurred that have helped to further characterize chikungunya fever [17, 30–32].

    The incubation period for chikungunya fever is typically between 3-7 days (range, 2-12 days). Not all individuals infected with the virus develop symptoms. Serosurveys indicate that 3%-25% of persons with antibodies to CHIKV have asymptomatic infections [33–35].

    Symptoms of CHIKV infection start abruptly with fever (temperature, usually >38.9°C). The fevers typically last from several days up to 2 weeks and can be biphasic in nature [36, 37]. Shortly after the onset of fever, the majority of infected persons develop severe, often debilitating polyarthralgias. The joint pains are usually symmetric and occur most commonly in wrists, elbows, fingers, knees, and ankles but can also affect more-proximal joints [38]. Arthritis with joint swelling can also occur. The lower extremity arthralgias can be severely disabling, resulting in a slow, broad-based, halting gait, which can persist for months.

20. Laboratory Diagnostic Tests for Chikungunya Fever

    Infections with CHIKV are confirmed by the detection of the virus, viral RNA, or CHIKV-specific antibodies in patient samples. The type of testing performed is typically dictated by the timing and volume of samples available. Historically, infections were diagnosed on the basis of serology, but with the advent of numerous molecular techniques, viral RNA can be easily detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in serum specimens obtained during the acute phase of infection.
    CHIKV infections cause high levels of viremia (up to 1×10^6.8 plaque-forming units per mL), which typically last for 4-6 days but can persist for up to 12 days after the onset of illness [24, 78]. Because of this, RT-PCR or viral culture performed on an acute-phase specimen can frequently be used to confirm CHIKV infection. Virus isolation is possible from serum specimens collected during the first 7 days of the illness, whereas viral nucleic acid is detected for a few additional days with use of real-time RT-PCR [24, 32]. In 2008, real-time assays, including those based on an assay developed at the Centers for Disease Control and Prevention (CDC), became commercially available (Focus Diagnostics) in limited markets; however, the validity and sensitivity of these new commercial assays have not yet been independently confirmed. RT loop-mediated isothermal amplification has also been used to detect CHIKV [79]. This technique has the advantage of not needing specialized equipment such as thermocyclers. Molecular assays can usually be completed within 1 day, whereas viral isolation often occurs within 48 h.

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Source: Oxford Journals