Diagnostic Challenges of MIS-C

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To attribute a patient’s symptoms to MIS-C, it is imperative that alternative diagnoses be reasonably evaluated. Given the heterogeneity of MIS-C-related inflammatory symptoms, it is, therefore, not surprising that mimics of MIS-C have been reported in case reports highlighting the pitfalls and challenges clinicians have encountered. MIS-C has mimicked other inflammatory diseases, including Takayasu arteritis, appendicitis, bacterial and viral infections, malignancy and autoinflammatory diseases including systemic juvenile idiopathic arthritis.^20,21

Comparisons of lab findings to understand the relationship between MIS-C-associated hyperinflammation and other conditions, such as macrophage activation syndrome and systemic juvenile idiopathic arthritis, may also aid in discriminating MIS-C. For example, T cell dysfunction and lymphopenia are consistent features of MIS-C and are proposed to underlie the pathogenesis of hyperinflammation.²²

Further, a cytokine called interferon gamma (IFNγ) has been implicated in MIS-C-associated hyperinflammation; consequently, a chemokine called CXCL9, which is driven by IFNγ, is also significantly elevated in MIS-C.^23,24 In contrast, IL-18, which is highly expressed in systemic juvenile idiopathic arthritis, is not significantly elevated in MIS-C.²⁴

As the inflammatory pathways in MIS-C are unraveled further, it is a possibility that this information could be used for diagnostic purposes and to provide rationale for therapeutic targets.

In Sum

Although our patient met the demo­graphics and case definition of MIS-C, his reassuring clinical appearance clinical appearance, duration of fever and lab findings notable for normal absolute lymphocyte count and a highly elevated ferritin suggested that we evaluate for alternative diagnoses, in particular systemic juvenile idiopathic arthritis and infection. Evaluation for common infectious processes was negative, but IL-18 was highly elevated.

Further, close outpatient follow-up revealed synovitis, providing additional support for a diagnosis of systemic juvenile idiopathic arthritis with subclinical macrophage activation syndrome. At present, the patient is doing well, and his disease is in remission on methotrexate and canakinumab.

Although more investigation is still needed to understand the pathogenesis and natural history of MIS-C, the information we have is clearly having a positive impact on our clinical abilities to distinguish MIS-C from other similar processes, which is critical because early recognition and treatment of MIS-C are associated with favorable patient outcomes.

Finally, accurate recognition and diagnosis of MIS-C may allow for the design of better studies to achieve a better understanding of how MIS-C fits among our other rheumatic conditions and to guide treatment.

Brian L.P. Dizon, MD, PhD, is a National Institute of Arthritis and Musculoskeletal and Skin Diseases Metzger Scholar in the laboratory of Susan Pierce, PhD, at the National Institutes of Health, Bethesda, Md., where he studies the regulation of B cells in chronic inflammatory diseases in humans.

Sangeeta Sule, MD, PhD, is chief of rheumatology at Children’s National Hospital, Washington, D.C., and associate professor at George Washington University School of Medicine and Health Sciences in Washington, D.C.

Acknowledgments

This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.

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