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An evaluation of global Chikungunya clinical management guidelines: A systematic review

Summary Background Chikungunya virus (CHIKV) has expanded its geographical reach in recent decades and is an emerging global health threat. CHIKV can cause significant morbidity and lead to chronic, debilitating arthritis/arthralgia in up to 40% of infected individuals. Prevention, early identification, and clinical management are key for improving outcomes. The aim of this review is to evaluate the quality, availability, inclusivity, and scope of evidence-based clinical management guidelines (CMG) for CHIKV globally. Methods We conducted a systematic review. Six databases were searched from Jan 1, 1989, to 14 Oct 2021 and grey literature until Sept 16, 2021, for CHIKV guidelines providing supportive care and treatment recommendations. Quality was assessed using the appraisal of Guidelines for Research and Evaluation tool. Findings are presented in a narrative synthesis. PROSPERO registration: CRD42020167361. Findings 28 CMGs were included; 54% (15/28) were produced more than 5 years ago, and most were of low-quality (median score 2 out of 7 (range 1–7)). There were variations in the CMGs’ guidance on the management of different at-risk populations, long-term sequelae, and the prevention of disease transmission. While 54% (15/28) of CMGs recommended hospitalisation for severe cases, only 39% (11/28) provided guidance for severe disease management. Further, 46% (13/28) advocated for steroids in the chronic phase, but 18% (5/28) advised against its use. Interpretation There was a lack of high-quality CMGs that provided supportive care and treatment guidance, which may impact patient care and outcomes. It is essential that existing guidelines are updated and adapted to provide detailed evidence-based treatment guidelines for different at-risk populations. This study also highlights a need for more research into the management of the acute and chronic phases of CHIKV infection to inform evidence-based care. Funding The UK Foreign, Commonwealth and Development Office, Wellcome Trust [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135].


Introduction
Chikungunya is a disease caused by the Chikungunya virus (CHIKV); an arthropod-borne virus transmitted to humans primarily by Aedes mosquitoes. Since its description in 1952, CHIKV has caused ten million of human infections. 1,2 An outbreak in 2004 affected more than 100 countries with over 10 million cases. 2 This was followed by another large outbreak across Latin America (2013). 2 Multiple factors contributed to these outbreaks including limited mosquito control in densely populated urban areas, climate change, and lack of vaccines and effective treatments. 3 It is estimated that 1.3 billion people live in areas at risk of CHIKV infection, 4,5 including Europe. 4,6,7 The recent expansion in geographical range, and localised travel-imported outbreaks have increased CHIKV's recognition as an emerging global health threat.
Chikungunya has a wide spectrum of clinical presentation, classified into three phases (acute, sub-acute and chronic). 8,9 Acute CHIKV generally manifests as a febrile illness with predominantly polyarthralgia, rash, and headache. This can be followed by a subacute phase for up to three months. 8,9 Although the acute infection rarely is life-threatening, it can result in severe illness and mortality in neonates, older adults (over 65 years) and people with comorbidities. 2,9−12 Severe and atypical manifestations include failure of at least one major organ or system and includes neurological, cardiovascular, renal, dermatological and respiratory manifestations, 13 with life threatening complications such as myocarditis 12 and encephalitis/encephalopathy 14 being reported. Pregnant women are at particular risk of severe complications. 15 The chronic manifestations of CHIKV can affect an estimated 40% of individuals and can include debilitating symptoms of chronic arthralgia, arthritis/arthralgia, fatigue which may lead to disability and diminished quality of life, 16 with severe impact on an individual's ability to work and can last up to 6 years. 8,9,16−21 CHIKV infection is a serious global public health problem, predominantly affecting populations and health systems in lower resourced settings, and with risk of importation into new, na€ ıve regions. Yet, to date, there is no specific treatment approved for CHIKV. Although vaccines have been developed and tested in humans, none are yet available. 22,23 Thus, supportive care is essential for improving patient outcomes and reduce the long-term chronic burden. 24 The aim of this systematic review is to explore the quality, availability, inclusivity, and scope of evidence-based CHIKV clinical management guidelines (CMGs) for different populations globally.

Study design
We defined CMGs as per the World Health Organisation (WHO) definition of a guideline information that

Research in context
Evidence before this study Chikungunya virus (CHIKV) is an emerging tropical, mosquito-borne virus, identified in more than 60 countries globally causing regular epidemics predominantly impacting vulnerable populations in lower-resourced settings. To assess availability of clinical management guidelines, their scope, inclusivity, and quality we searched Ovid in Medline, Embase, Global Health, Scopus, Web of Science Core Collection and WHO Global Index Medicus, complemented by a grey literature search and a targeted search of national public health databases in seven languages. The searches were completed on Oct 14, 2021 using a list of terms relating to clinical management guidelines for Chikungunya. We identified 28 CMGs, most of low quality and with limited and at times contradictory treatment advice.

Added value of this study
Our data highlights a global scarcity of CMGs for CHIKV providing guidance on optimal care and treatment for different at-risk populations and settings. There was limited guidance available on care for severe cases, and available guidance was heterogenous and discordant (e.g., on use of analgesia, corticosteroids). Moreover, there was limited guidance on referral criteria and level of monitoring of pregnant women and infants at higher risk of severe disease.
Implications of all the available evidence`Ò ur data highlights an urgent need for research into effective treatment strategies to reduce morbidity and prevent risk of long-term sequelae, and for new evidence to be incorporated into clinical management guidelines, for different at-risk populations. We propose development of a harmonised 'living' clinical management guideline framework for infectious diseases, to improve standardisation of recommendations, inclusivity, and quality of CMGs, to improve access to evidence based recommendations to improve long term outcomes.
contains recommendations to guide practice, providing recommendations as statements designed to help endusers make informed decisions on whether, when and how to undertake specific actions such as clinical interventions, with the aim of achieving the best possible individual health outcomes. 25 We conducted a systematic review of Chikungunya CMGs using Cochrane systematic review methodologies, 26 structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (supplementary file S1 and S2). 27 The protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42020167361). 28

Search strategy
We conducted a systematic database search through Ovid Medline, Ovid Embase, Ovid Global Health, Scopus, Web of Science Core Collection and WHO Global Index Medicus from inception to 14 th October 2021. Search strategies applied the Canadian Agency for Drugs and Technologies in Health (CADTH) database guidelines search filter (supplementary file S1). 29 Previous reviews have observed that CMGs are not always available indexed in databases. Therefore, we also performed a grey literature search up to 16 th September 2021. We searched Google and Google Scholar using predefined keywords in Arabic, English, French, German, Mandarin, Russian, and Spanish. We also contacted expert members of the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) network requesting CMGs. 30 A full search strategy is presented in the supplementary file.

Eligibility criteria
We included Chikungunya CMGs that provided treatment and/or supportive care recommendations. There were no language limitations. We excluded CMGs providing solely recommendations on diagnostics, animal health, or public health. The most recent versions of CMGs were included.

Screening and data extraction
Search results were screened by title and abstract, followed by full text by two reviewers using the Rayyan systematic review software. 31 Data was extracted by one reviewer using a standardised Excel form and validated by a second reviewer (Supplementary file S2). We extracted data on bibliography, populations covered, supportive care treatment recommendations and preventive measures to reduce community transmission. Disagreements were resolved via consensus or by a third reviewer. Non-English language CMGs were translated using Google translate and screened, and data extracted by reviewers with good to excellent knowledge of the language.

Quality appraisal
Quality was assessed independently by two reviewers using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) Instrument. 32 This tool provides an objective framework for assessing the guideline development process and quality. It is s a 23-item tool that spans six domains comprising different aspects: 1) scope and purpose; 2) stakeholder involvement; 3) rigour of development; 4) clarity of presentation; 5) applicability and 6) editorial independence. Each domain has several sub-criteria which assess whether the criteria are met using a seven-point Likert scale, from 1 (strongly disagree) to 7 (strongly agree). A score of 100% is achieved if the CMG scores 7 for all domain items; 0% if each reviewer scored 1 for all items. When there was limited information about the methodology presented, efforts were made to search for additional information via associated webpages. The final score for each domain was calculated as per the AGREE II domain formula. 32 CMGs were considered of high quality if they scored more than 60% in domain three (rigour of development; as this is considered a high-quality indicator) and two other non-specified domains moderate quality if they scored more than 60% in any three or more domains but not in domain three; low quality if they did not meet these criteria. Additionally, each CMG was given an overall guideline assessment score based on the domain scores, ranging from one to seven (a score ≥6 = high quality; 4−5 = medium quality; ≤ 3 = low quality) together with a recommendation for use with or without further modifications. 32 CMGs with a total overall quality score of 1 were not recommended for use, total overall scores of 2−5 were recommended for use with modifications and 6−7 recommended for use without modifications. 32 AGREE II domain calculation formula : obtained score À minimum possible score Maximum possible score À minimum possible score

Data analysis
The availability of CMGs was assessed by whether opensourced CMGs could be identified and stratified by origin/producer: (1) international and regional organisations (e.g., WHO; Pan-American Health organisation (PAHO)); (2) national organisations (e.g., Ministries of Health) and (3) clinical reference websites (e.g., Medscape, UptoDate). We assessed inclusivity based on inclusion of recommendations for different at-risk groups, including infants/children, pregnant women, older people, and people living with HIV or those with comorbidities. The ggplot2 library and Tableau software were used to produce graphics. 33,34 The data is presented in a narrative way. Role of the funding source All authors had access to the data presented in the study and were involved in the decision to submit for publication. The funders of the study had no role in study design, data collection, data analysis, data interpretation. The funders had a role in writing the report but do not stand to materially benefit from the work.

Patient public involvement
There was no patient or public involvement due to the ongoing pandemic restrictions.

Ethical approval
None required.

Acute phase of CHIKV infection (
Antimalarials. None of the CMGs advocated for use of empiric antimalarials for acute infection, but two (10%) 8,50 advised including malaria in the differential diagnosis. Antimalarial chloroquine derivatives were discussed for the treatment of long-term chronic manifestations in (24%, 4/17) CMGs. 39,43,50,51 Analgesia. All CMGs recommended analgesia; 75% (21/28) 35     However, the risk of haemorrhage is rare in CHIKV in comparison to dengue and more than half advised the cautious use of NSAIDs (due to the risk of precipitating acute kidney failure) in acute CHIKV infection. NSAIDs have been recognised as a risk factor for severe disease.

Discussion
This systematic review highlights limited availability of high-quality guidelines for the management of Chikungunya infection globally. In those identified in this review, we found significant heterogeneity in recommendations. Although there was a consensus on the symptomatic treatment of acute non-severe illness, there was a general lack of detailed management advice to guide supportive care. Furthermore, there was significant heterogeneity in recommendations about the use of corticosteroids, with some advocating for their use in the acute phase, while a third advising against during the acute phase. The duration of steroid treatment for both acute and chronic disease was another point of contention between CMGs. There was also variable and contradictory advice on the use of NSAIDs in the acute phase. Further, a lack of standardisation within the classification of the disease stages of sub-acute, acute, and chronic disease may impact on the recommendations and on the management of patients.
The heterogeneity observed, including in the recommendations for the use of corticosteroids in these CMGs reflect the uncertainty for the management of acute Chikungunya and scarcity of research. One prospective randomized parallel group study of 120 patients with acute CHIKV in South India demonstrated that the addition of corticosteroid to NSAIDs reduced pain and improved quality of life. 63 Another study of 19 cases observed an improvement in mobility with short term corticosteroids in acute CHIKV, however noted that there was a risk of rebound symptoms after treatment cessation. 64 Several reviews advise caution against the use of corticosteroids due to the risks of rebound symptoms and immunosuppression causing potential disease exacerbation. 65,66 Although CHIKV has a low overall mortality risk, it can cause significant morbidity and be fatal for more vulnerable population groups, through associated complications or by triggering decompensation in patients with pre-existing co-morbidities. 67 Joint pain caused by CHIKV infection may be debilitating, limiting daily activities. 8 Polyarthralgia is recurrent in 30−40% of infected individuals and may persist for years. 3,24, The risk of prolonged sequelae in populations in lower resourced settings can have a profound impact on livelihoods, with wider socio-economic impact on individuals, their families and society. Public health interventions adopted during the COVID-19 pandemic may have had a negative impact on vector surveillance and control. 68,69 As we are transitioning out of the pandemic, we need to prepare to shift resources to identify and mitigate the wider pandemic consequences and strengthen our capacity to respond to future epidemics. Considering the high number of people affected by and at risk of CHIKV infection, the scarcity of treatments, and heterogeneous and at times contradictory supportive care recommendations identified are reasons for concern.
While many CMGs identified children and neonates as high-risk groups for more severe illness, referral and monitoring criteria differed, and the advice on how to reduce risk of MTCT during delivery was limited. Although there are novel approaches suggested to prevent the risk of MTCT, such as anti-CHIKV hyperimmunoglobulins, the evidence-base is limited and there is currently no approved treatment. 70−72 The CMGs were also limited in specific advice for older people and for those with co-morbidities, both of whom are at higher risk of more severe disease. 2 Although most CMGs provided recommendations for post-acute follow-up care and treatment of chronic complications, the recommendations were heterogenous and with limited evidence provided to support them. There was variation in the recommendations on use of DMARDs, especially for hydroxychloroquine and methotrexate in the management of chronic Chikungunya. A study examined combination DMARD therapy versus hydroxychloroquine treatment in 72 patients with post-Chikungunya arthritis and found that a combination of DMARDs were superior to hydroxychloroquine monotherapy with improvements in disability, reduction in pain and disease activity. 73 Despite acknowledging this lack of benefit, four CMGs recommended hydroxychloroquine as a first line DMARD. 39,43,50,51 Existing interventional clinical studies are limited, and with a lack of standardised methodologies, the ability to conduct meta-analyses is restricted, thus limiting our evidence base in determining the most effective therapies for treating chronic manifestations of CHIKV infection. 74 This review is not without limitations. Despite a systematic search, additional local guidelines may exist. Approximately half of the included CMGs were in a language other than English, and although these were assessed by a reviewer with good knowledge of that language, there may have been slight nuances lost in translation. Furthermore, the AGREE-II tool 32 assess methodological aspects relevant to guideline development, but not the validity of the clinical management recommendations, conclusions about the validity of the clinical guidance made can therefore not be derived from the AGREE assessment. 32 Despite these limitations, this review identifies concerning gaps and disparities within the CMGs. Firstly, there is an issue of accessibility, with the two highest quality CMGs identified in this review not being freely accessible 38,75 Developing CMGs is resource intensive, and given the changing epidemiology, it requires systems for regular reviews, updates, and re-dissemination. CHIKV disproportionally impacts lower resourced settings, where such resources may not be readily available. Further, other infections may take priority when there is international pressure and/or funding to develop research and guidelines (e.g., SARS-CoV-2, HIV, malaria). International high-quality and easily accessible CMGs, that can be adapted to different settings may fill this gap, as long as implementation is supported in different resourced settings. A living guideline framework, such as the platform developed by WHO during the COVID-19 pandemic providing a living covid-19 CMG, regularly updated by a wider range of expert stakeholders, may improve availability of up-todate guidelines. 76 WHO is a normative body and their guidelines are adopted by many healthcare systems globally, 77 besides saving local resources, it also facilitates standardisation of care between sites. Wide stakeholder engagement, including clinicians from endemic regions and patient groups is important and may improve inclusivity and applicability, and ensure that guidelines address local needs. Further research to explore implementation and impact of CMGs in different setting is recommended to inform CMG development frameworks.
Our findings highlight a lack of high-quality, standardised Chikungunya CMGs globally, especially for those at higher risk of severe illness. Given the risk that CHIKV infection poses globally and in particular to vulnerable groups such as children, pregnant women, older adults and those with co-morbidities, it is essential that existing guidelines are updated with latest evidence and inclusive of all risk groups. Our data also highlights an urgent need for trials to identify optimal treatment and supportive care strategies for different population groups to improve long term outcomes and for new evidence to be incorporated into guidelines. A new 'living guideline' framework for infectious diseases is recommended, 78 to improve availability of up-to-date guidelines, developed using robust methodologies, codeveloped by diverse stakeholders to support inclusivity and implementation to improve long term patient outcomes in any resourced settings.

Contributors
AD, VC, LS, SL, EH, STJ, EW, MM, IR developed the study protocol. EH, AD carried out the database search with input from MM, EW and IR. EW, MM, IR, AD, EC conducted the grey literature search. EW, RJ, AD, MM screened articles for inclusion. AD, EW, IR, RJ, MM extracted the data and completed the risk of bias analysis. EW, MM, RJ, DD, SL, and IR led on data analysis, and presentation of the results. EW, MM, and IR verified the underlying data. All co-authors informed the interpretation of the findings. EW led on writing the manuscript with inputs from LS, IR, MM, DD, RN, PPJ, ES, KG, and MC. LS, PWH, TF and STJ provided overall supervision, leadership, and advice. PWH, HG, STJ, TF, PWH, LS, AD, and LB conceptualised the project. All authors had full access to the data presented in the study, reviewed, approved the final version of the manuscript and accept responsibility to submit for publication.

Data sharing statement
All data generated or analysed during this study that are not available in this manuscript, or the supplementary file can be reasonably requested from the corresponding author.

Declaration of interests
All authors have completed the ICMJE uniform disclosure form. Peter Hart is a senior research advisor and Helen Groves is a research manager at the Wellcome Trust, which provided part of the funding for this work, but, neither had a role in data collection, analysis nor interpretation of the findings. Wellcome supports a range of research funding activities including awards made to ISARIC.