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Rheumatic manifestations of chikungunya: emerging concepts and interventions

Nature Reviews Rheumatology volume 15, pages 597–611 (2019)Cite this article

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Abstract

The largest epidemic ever recorded for chikungunya, a disease caused by infection with the chikungunya virus (CHIKV), began in Africa in 2004 and spread to >100 countries on four continents. The epidemic caused >10 million cases of often debilitating rheumatic disease, classically involving rapid onset of fever and polyarthralgia, often with polyarthritis. The clinical diagnosis of chikungunya is often complicated by infections with dengue or Zika virus. For many individuals with chikungunya, the disease is benign and self-limiting; however, some patients have a complex spectrum of atypical and severe manifestations. Many patients also experience a chronic phase of the disease, primarily involving arthralgia (which can be protracted (>1 year)), and a number of sequelae are also recognized. CHIKV-induced arthropathy arises from infection of multiple cell types in the joint and the infiltration of mainly mononuclear cells. Innate responses (primarily involving type I interferon responses and natural killer cells) and cognate responses (primarily involving CD4 T helper 1 cells), alongside activation of macrophages and monocytes, mediate CHIKV-induced arthritic immunopathology. Ideally, improved anti-inflammatory treatments should not compromise antiviral immunity. New concepts in mosquito control are being field tested and a number of CHIKV vaccines are being developed.

Key points

  • After the 2004–2019 epidemic of chikungunya virus (CHIKV), the largest chikungunya epidemic ever recorded, this disease remains a global problem.

  • New treatment options are needed for patients with chikungunya arthropathy, in particular for patients with chronic arthralgia and/or life-threatening manifestations, which primarily present in the very young and the elderly.

  • The mechanisms by which CHIKV or viral material persists in joint tissues and drives chronic disease are unclear; characterizing the processes involved might open up new avenues for clinical interventions.

  • Better control and evaluation measures are required to prevent transmission of arboviral diseases such as chikungunya.

  • The unpredictable nature of chikungunya outbreaks complicates phase III field trials of vaccines; new solutions for trialling these vaccines are needed, which could involve human challenge models and systems vaccinology.

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Fig. 1: Emergence and spread of the 2004–2019 CHIKV epidemic.
Fig. 2: Joints affected by chikungunya arthralgia.
Fig. 3: Potential mechanisms of arthritic immunopathology in chikungunya.

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Acknowledgements

A.S. would like to thank Rocio Jimenez Martinez, Viviana Lutzky, Yee Suan Poo, Jillann F. Farmer, Patrick Gerardin and David Warrilow for their help with the preparation and review of various aspects of the article. A.S. is a Principal Research Fellow with the National Health and Medical Research Council of Australia.

Competing interests

A.S. declares that he is a consultant for Sementis Ltd., a company that is developing vaccines against chikungunya virus and Zika virus. A.S. declares that he has been a consultant for Valneva and GSK, which are also developing CHIKV vaccines.

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  1. Inflammation Biology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Andreas Suhrbier

  2. Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia

    Andreas Suhrbier

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Correspondence to Andreas Suhrbier.

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Glossary

Pandemic

An epidemic of disease that has spread across a large region; for instance, multiple continents, or even worldwide.

Attack rate

The total number of new cases of a disease divided by the total population (that is, the percentage of a defined population that is affected by a disease).

Viraemia

The presence of virus in the circulating blood.

Arboviruses

Viruses that can be transmitted by arthropod vectors (for example, mosquitoes) to vertebrate hosts (for example, humans)

IgG class switching

The switching of B cell immunoglobulin production from IgM to IgG antibodies

Efferocytosis

The process whereby dying or dead cells are removed by phagocytic cells.

Replicons

Viral RNAs that can self-replicate as they encode genes required for viral RNA replication (including RNA-dependent RNA polymerase), but that are unable to form an infectious virus because of defects in, or loss of, one or more structural genes required for virus particle assembly.

Virus-like-particle vaccine

A protein-based vaccine that recapitulates the appearance and structure of a virus particle, but that has no capacity to replicate in the vaccine recipient because, for instance, the viral genome is (in part or wholly) missing.

Human challenge model

In a CHIKV vaccine context, volunteers are vaccinated with a CHIKV vaccine and are then infected with CHIKV (likely an attenuated CHIKV for safety reasons) in a controlled hospital setting (distinct from conventional phase III trials where vaccine recipients are released into the community and can acquire CHIKV naturally).

Systems vaccinology

A systems-based approach in which transcriptional profiling (followed by bioinformatic analyses) is used to obtain a detailed picture of changes in gene expression following vaccination.

Systems serology

A systems-based approach that measures biophysical and functional characteristics of antigen-specific antibody responses (for example, responses to vaccination); measured characteristics include immunoglobulin isotypes, Fc receptor binding profiles, antibody glycosylation patterns and antibody affinity.

Serogroup

For viruses, a serogroup means that viral infection with one member of that serogroup will generate antibodies capable of recognizing (cross-reacting with) other members of that serogroup.

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Suhrbier, A. Rheumatic manifestations of chikungunya: emerging concepts and interventions. Nat Rev Rheumatol 15, 597–611 (2019). https://doi.org/10.1038/s41584-019-0276-9

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