Clinical markers of post-Chikungunya chronic inflammatory joint disease: A Brazilian cohort

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Lazari, Carolina dos Santos ; Ramundo, Mariana Severo ; ten-Caten, Felipe ; Bressan, Clarisse S. ; de Filippis, Ana Maria Bispo ; Manuli, Erika Regina ; de Moraes, Isabella ; Pereira, Geovana Maria ; Cortes, Marina Farrel ; Candido, Darlan da Silva ; Gerber, Alexandra L. ; Guimaraes, Ana Paula ; Faria, Nuno Rodrigues ; Nakaya, Helder I. ; Vasconcelos, Ana Tereza R. ; Brasil, Patricia ; Paranhos-Baccala, Glaucia ; Sabino, Ester Cerdeira

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 17, n. 1, p. 17-pg., 2023-01-01.

Abstract

BackgroundChikungunya-fever (CHIKF) remains a public health major issue. It is clinically divided into three phases: acute, post-acute and chronic. Chronic cases correspond to 25-40% individuals and, though most of them are characterized by long-lasting arthralgia alone, many of them exhibit persistent or recurrent inflammatory signs that define post-Chikungunya chronic inflammatory joint disease (pCHIKV-CIJD). We aimed to identify early clinical markers of evolution to pCHIKV-CIJD during acute and post-acute phases. Methodology/Principal findingsWe studied a prospective cohort of CHIKF-confirmed volunteers with longitudinal clinical data collection from symptoms onset up to 90 days, including a 21-day visit (D21). Of 169 patients with CHIKF, 86 (50.9%) completed the follow-up, from whom 39 met clinical criteria for pCHIKV-CIJD (45.3%). The relative risk of chronification was higher in women compared to men (RR = 1.52; 95% CI = 1.15-1.99; FDR = 0.03). None of the symptoms or signs presented at D0 behaved as an early predictor of pCHIKV-CIJD, while being symptomatic at D21 was a risk factor for chronification (RR = 1.31; 95% CI = 1.09-1.55; FDR = 0.03). Significance was also observed for joint pain (RR = 1.35; 95% CI = 1.12-1.61; FDR = 0.02), reported edema (RR = 3.61; 95% CI = 1.44-9.06; FDR = 0.03), reported hand and/or feet small joints edema (RR = 4.22; 95% CI = 1.51-11.78; FDR = 0.02), and peri-articular edema observed during physical examination (RR = 2.89; 95% CI = 1.58-5.28; FDR = 0.002). Furthermore, patients with no findings in physical examination at D21 were at lower risk of chronic evolution (RR = 0.41, 95% CI = 0.24-0.70, FDR = 0.01). Twenty-nine pCHIKV-CIJD patients had abnormal articular ultrasonography (90.6% of the examined). The most common indings were synovitis (65.5%) and joint effusion (58.6%). ConclusionThis cohort has provided important insights into the prognostic evaluation of CHIKF. Symptomatic sub-acute disease is a relevant predictor of evolution to chronic arthritis with synovitis, drawing attention to joint pain, edema, multiple articular involvement including small hand and feet joints as risk factors for chronification beyond three months, especially in women. Future studies are needed to accomplish the identification of accurate and early biomarkers of poor clinical prognosis, which would allow better understanding of the disease's evolution and improve patients' management, modifying CHIKF burden on global public health. Author summaryChikungunya fever (CHIKF) is a vector-borne viral disease first described in 1952 in Africa, which recently reached the Americas, where it then originated epidemics of unprecedented magnitude. Its acute phase is characterized by fever associated with joint pain and edema, which resolve in about seven days for most patients. However, 25-40% of these patients develop chronic musculoskeletal and arthritic symptoms, which may be incapacitating and lead to permanent joint damage. We have conducted a prospective longintudinal cohort of CHIKF confirmed individuals, in Brazil, which aimed to identify clinical early markers of evolution to post-Chikungunya chronic inflammatory joint disease (pCHIKV-CIJD) after 90 days, using objective physical examination to define pCHIKV-CIJD. We have also performed joint ultrasonography to improve evaluation of chronic arthritis. We found that 45.3% of patients who completed the follow-up met criteria for pCHIKV-CIJD. Women were at higher risk of chronification, as well as individuals who remain symptomatic 21 days after the onset of symptoms. Abnormal ultrasonography results were seen in 90.6% of examined pCHIKV-CIJD patients, in whom synovitis and joint effusion were the most commom songraphic signs, affecting mostly ankles and knees. The adoption of objective criteria to define pCHIKV-CIJD is crucial to estimate accurately the proportion of patients who evolve to chronic rheumatism, and to indentify early risk factors to this outcome, which may add important information to tailor therapeutic strategies for this particular population. It may also help to understand the burden of CHIKF in developing countries, measuring either its impact in individual's quality of life, or its communitary repercussion after widespread outbreaks. (AU)

• FAPESP's process: 18/14389-0 - Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE)
• Grantee: Ester Cerdeira Sabino
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/20597-0 - A translational study for the identification, characterization and validation of severity biomarkers in arboviral infections
• Grantee: Ester Cerdeira Sabino
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• FAPESP's process: 18/09971-2 - Development of DNA aptamers against pathogenic multidrug resistant bacteria
• Grantee: Marina Farrel Côrtes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral