Chikungunya fever: a clinical and virological investigation of outpatients on Reunion Island, South-West Indian Ocean

Abstract

Background: Chikungunya virus (CHIKV) is responsible for acute febrile polyarthralgia and, in a proportion of cases, severe complications including chronic arthritis. CHIKV has spread recently in East Africa, South-West Indian Ocean, South-Asia and autochthonous cases have been reported in Europe. Although almost all patients are outpatients, medical investigations mainly focused on hospitalised patients.

Methodology/principal findings: Here, we detail clinico-biological characteristics of Chikungunya (CHIK) outpatients in Reunion Island (2006). 76 outpatients with febrile arthralgia diagnosed within less than 48 hours were included by general practitioners during the CuraChik clinical trial. CHIK was confirmed in 54 patients and excluded in 22. A detailed clinical and biological follow-up was organised, that included analysis of viral intrahost diversity and telephone survey until day 300. The evolution of acute CHIK included 2 stages: the 'viral stage' (day 1-day 4) was associated with rapid decrease of viraemia and improvement of clinical presentation; the 'convalescent stage' (day 5-day 14) was associated with no detectable viraemia but a slower clinical improvement. Women and elderly had a significantly higher number of arthralgia at inclusion and at day 300. Based on the study clinico-biological dataset, scores for CHIK diagnosis in patients with recent febrile acute polyarthralgia were elaborated using arthralgia on hands and wrists, a minor or absent myalgia and the presence of lymphopenia (<1G/L) as major orientation criteria. Finally, we observed that CHIKV intra-host genetic diversity increased over time and that a higher viral amino-acid complexity at the acute stage was associated with increased number of arthralgia and intensity of sequelae at day 300.

Conclusions/significance: This study provided a detailed picture of clinico-biological CHIK evolution at the acute phase of the disease, allowed the elaboration of scores to assist CHIK diagnosis and investigated for the first time the impact of viral intra-host genetic diversity on the disease course.

Figure 1. Clinical features of ambulatory CHIKV+ve patients* at days 1, 7 and 25.

These clinical data were collected from three consultations with a general practitioner on day 1, day 7 (mean 6.4, SD = 1.4) and day 25 (mean 26.5, SD = 9.8) of the disease during the Reunion island outbreak 2005–2006. * Since clinical assessment during the first medical visit was obtained prior to the beginning of the treatment, all CHIKV+ve patients (N = 54) could be used for analysis. By contrast, only patients who received the placebo (N = 27) were included in the study of disease evolution (second and third medical visits).

Figure 2. Quality of life assessed by ambulatory CHIKV+ve patients* from day 1 until day 14.

Three kind of quality of life (health status, capacity to perform normal activity and quality of sleep) were assessed by self reported visual analogic scale (VAS) from “very bad” (VAS = 0) to “very good” (VAS = 100) and are represented here by box plot diagrams. Box plot is a representative diagram of continuous variables. The bottom and the top of the box are the 25^th and 75^th percentile, the band near the middle is the median and the ends of the whiskers are the 1.5 inter-quartile of the lower and upper quartile. The data not included between the whiskers are plotted as an outlier with small circles (if between 1.5 to 3 inter-quartile of the lower or upper quartile) or with a star (if higher than 3 inter-quartile of the lower or upper quartile). The outliers are tagged with their patient numbers to follow them at different time period. * Clinical assessment at D1 was obtained from all CHIKV+ve patients (N = 54) during the Reunion island outbreak 2005–2006. Only patients receiving placebo (N = 27) were included in D2–D14 clinical assessment.

Figure 3. Number and intensity of arthralgic joints for CHIKV+ve* patients.

Figure 3A: Self reported number of arthralgic joints reported per person (day 1–day 14). Figure 3B: Percentage of patients with absent, minimal, moderate or severe arthralgia (day 1–day 14). * Characteristics of patients included and details of box plots are the same as reported in figure 2 .

Figure 4. Clinical and clinico-biological score for the diagnosis of CHIK.

These scores were based on patients who reported fever and arthralgia for less than 48 hours. * MCP+: arthralgia on at least one metacarpophalangeal joint. * W+: arthralgia on at least one wrist. We propose a clinical score based exclusively on clinical data (W+, MCP+ and Myalgia absent or minor) and a clinico-biological score that further includes lymphopenia (<1G/L). The result of the score represents the predicted probability to have chikungunya (see calculation of scores in the main text).