Multicenter study of the natural history and therapeutic responses of patients with chikungunya, focusing on acute and chronic musculoskeletal manifestations – a study protocol from the clinical and applied research in Chikungunya (REPLICK network)
Authors: da Silva Duarte Giselle , Jones Alexandra D. , de Goes Cavalcanti Luciano Pamplona , de Melo Rêgo Moacyr Jesus Barreto , Ribeiro Guilherme S. , Boyton Rosemary J. , Pereira Dhelio Batista , Croda Julio Henrique Rosa , Costa Fabio Trindade Maranhão , Duarte Angela Pinto , Consolaro Marcia Edilaine Lopes , Stabeli Rodrigo Guerino , Negrão Fábio Juliano , Proenca-Modena Jose Luiz , Villalobos-Salcedo Juan Miguel , da Rocha Castelar Pinheiro Geraldo , de Barros Albuquerque Amanda Pinheiro , de Almeida Barreto Francisca Kalline , Moreira Jose , Ferrari Idalina Cristina , Évora Patricia Martinez , da Silva Vânia Ramos Sela , Lacerda Marcus Vinicius Guimarães , Altmann Daniel M. ,   REPLICK network, dos Santos Thyago Henrique Pereira , de Carvalho Araujo Fernanda Montenegro , Farias Luis Arthur Brazil Gadelha , de Vasconcelos Lara Moreira Teles , dos Santos Brena Ferreira , de Castro Shamyr Sulyvan , Barreto Marina Carvalho Arruda , Gomes Ileana Pitombeira , de Oliveira Jobson Lopes , Pinheiro Thayanne Vitoria Nunes , das Neves Samara Bezerra Guedes , Judice Carla Cristiana , de Souza Gabriela Fabiano , Martini Matheus Cavalheiro , Dall’Acqua Deusilene Souza Vieira , de Oliveira Marcela Macedo , Garbin Eduardo , Martines Alexia , da Rocha Pitta Maira Galdino , Demarchi Luiz , Soares Caroline Santos , Brasil Patricia , Trinta Karen , Pereira Claudia , Siqueira André M. 
Published: July 2023

Abstract
Background
Chikungunya is associated with high morbidity and the natural history of symptomatic infection has been divided into three phases (acute, post-acute, and chronic) according to the duration of musculoskeletal symptoms. Although this classification has been designed to help guide therapeutic decisions, it does not encompass the complexity of the clinical expression of the disease and does not assist in the evaluation of the prognosis of severity nor chronic disease. Thus, the current challenge is to identify and diagnose musculoskeletal disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course.

Methods
The study is the first product of the Clinical and Applied Research Network in Chikungunya (REPLICK). This is a prospective, outpatient department-based, multicenter cohort study in Brazil. Four work packages were defined: i. Clinical research; ii) Translational Science – comprising immunology and virology streams; iii) Epidemiology and Economics; iv) Therapeutic Response and clinical trials design. Scheduled appointments on days 21 (D21) ± 7 after enrollment, D90 ± 15, D120 ± 30, D180 ± 30; D360 ± 30; D720 ± 60, and D1080 ± 60 days. On these visits a panel of blood tests are collected in addition to the clinical report forms to obtain data on socio-demographic, medical history, physical examination and questionnaires devoted to the evaluation of musculoskeletal manifestations and overall health are performed. Participants are asked to consent for their specimens to be maintained in a biobank. Aliquots of blood, serum, saliva, PAXgene, and when clinically indicated to be examined, synovial fluid, are stored at -80° C. The study protocol was submitted and approved to the National IRB and local IRB at each study site.

Discussion
Standardized and harmonized patient cohorts are needed to provide better estimates of chronic arthralgia development, the clinical spectra of acute and chronic disease and investigation of associated risk factors. This study is the largest evaluation of the long-term sequelae of individuals infected with CHIKV in the Brazilian population focusing on musculoskeletal manifestations, mental health, quality of life, and chronic pain. This information will both define disease burden and costs associated with CHIKV infection, and better inform therapeutic guidelines.