Heterogeneity in the evaluation of suspected MIS-C: a cross-sectional vignette-based survey

Multisystem Inflammatory Syndrome in Children (MIS-C) is an emerging, rare but severe complication of COVID-19 that can result in life-threatening multisystem organ failure and death. MIS-C develops weeks to months following infection with SARS-CoV-2 and presents with unremitting fever and a constellation of symptoms including rash, gastrointestinal symptoms, edema of the hands/feet, oral mucosal changes, conjunctivitis, lymphadenopathy, and neurological symptoms [1, 2]. Cardiac involvement is common; almost half of patients require vasopressor support and 80% require intensive care [3]. Because of the range of clinical presentations and risk for rapid progression, early diagnosis and treatment are key [1, 2]. The pathophysiology of MIS-C is not well understood, but SARS-CoV-2 antigenemia from gastric sources triggering a superantigen-like hyperinflammation post-viral inflammatory process is suggested [4‐6]. The criteria for MIS-C diagnosis established by the Center for Disease Control include patients less than 21 years old presenting with fever (> 38.0℃) for more than 24 h, laboratory evidence of inflammation and multisystem involvement, who require hospitalization, without an alternative diagnosis, and with known infection or exposure to COVID-19 within the four weeks prior to the onset of symptoms [1]. Currently, no definitive diagnostic test for MIS-C exists.

Guidelines have evolved to aid in the diagnosis of MIS-C, but existing laboratory tests lack specificity. Several professional associations have put forward guidelines for a MIS-C diagnostic approach, including the American College of Rheumatology [7] and the American Academy of Pediatrics [8]. From these guidelines, it is recommended that patients with persistent fever and other accompanying symptoms have lab work performed to look for evidence of inflammation and assess cardiac, renal, hematologic, and hepatic function. Given the potential for rapid progression, there is a low threshold to initiate this workup. These guidelines have significantly changed the standard of care and shifted the paradigm for children who present with 1–2 days of fever. If there is no evidence of bacterial infection, providers would routinely send febrile children home with a diagnosis of a viral illness prior to the COVID-19 pandemic; however, with the current guidelines, many of these patients now have labs drawn, imaging done, and are admitted to the hospital for monitoring. The laboratory tests obtained are non-specific and difficult to interpret. While certain findings may increase a clinician's suspicion for MIS-C, such as elevated inflammatory or cardiac markers, diagnosis remains challenging, and practitioners face variable degrees of uncertainty.

Given the lack of a definitive diagnostic test for MIS-C, the spectrum of clinical features associated with the disease, and the lack of evidence-based guidelines for evaluation, we sought to understand practitioners' preferences for workup in a pediatric patient presenting with possible MIS-C through a vignette-based survey.

MIS-C is a rare but severe sequela of COVID-19 in children; early diagnosis and treatment are critical to reduce or avoid MIS-C morbidity and mortality. Unfortunately, the number of pediatric illnesses that present with similar symptoms is broad, making it challenging to differentiate MIS-C from other more benign childhood illnesses, as well as distinguish it from bacterial infections and Kawasaki disease. Because of the non-specific presenting symptoms, potential for rapid progression, and the life-threatening nature of MIS-C, there is a low threshold for initiating workup. Our study shows significant heterogeneity amongst providers as to when they initiate MIS-C workup, components of the workup, and how to confirm MIS-C diagnosis.

Given how extensive the MIS-C workup is, it is important to carefully consider which patients warrant an evaluation. Current guidelines, however, lack explicit screening criteria. While the CDC case definition of MIS-C includes fever for at least 24 h, guidelines are unclear on the duration of fever that should generate a workup. This lack of clarity is reflected in our study, where providers were divided when asked about the duration of fever that would prompt them to initiate workup. Additional thought also must be put into excluding other febrile illnesses, such as viral illnesses, bacterial infections, or Kawasaki disease, which can be particularly challenging given the overlapping clinical features [11].

Providers who had seen more COVID-19 cases were more likely to initiate MIS-C workup, suggesting that the more exposure providers have to COVID-19, the more likely they are to consider MIS-C. Our study also shows that providers are more likely to initiate a workup in younger children than in older children; however, current guidelines do not differ based on age. Such heterogeneity could lead to missed or delayed diagnosis.

Once it is determined that a child warrants workup for MIS-C, there is a recommended set of “Tier 1” screening labs, which if abnormal, prompt additional evaluation, including “Tier 2” labs, EKG, and echocardiogram [7]. Both tiers of labs are non-specific and their ability to distinguish MIS-C from other causes of acute febrile illnesses. Our study shows that providers often do obtain lab work, which is consistent with the existing guidelines, but it is unclear how these results help guide diagnosis. For example, the majority of providers would obtain SARS-CoV-2 serology. However, with over 13 million children under 18 years old testing positive for COVID-19 thus far in the pandemic in the United States alone, we can expect that most children will develop post-vaccination and/or post-infectious antibodies at some point. Thus, relying on serology as a laboratory marker will become even less specific [9]. Additional workup that providers obtained beyond laboratory work, including consults and imaging, was largely heterogeneous and inconsistent.

Once a patient is diagnosed with MIS-C, they are usually treated with IVIG and/or systemic steroids, which are thought to improve clinical outcomes. The most common findings that our respondents perceived to confirm MIS-C diagnosis were elevated cardiac enzymes, abnormal echocardiogram, or severe illness requiring admission to a pediatric intensive care unit. While cardiac involvement is one of the most feared complications of MIS-C and is present in up to 80% of cases, it is not necessary to diagnose MIS-C [10]. Therefore, heavy reliance on cardiac findings to confirm MIS-C diagnosis could mean that providers are missing or under-reporting cases of MIS-C. This highlights the need for more clear diagnostic criteria.

Limitations of this study include it being a cross-sectional survey of self-reported preferences in providers, with potential for sampling and response biases. We did not examine the medical records to compare with real observed cases to ascertain accuracy. Our sample was skewed toward providers from academic medical centers where access to laboratory tests, imaging, and specialized consultants is readily available. Further research is needed to assess what happens in other clinical settings (e.g., rural primary care offices) where access to testing, imaging, and specialized consultants would be limited. Identifying MIS-C and differentiating it from other illness is an important step in the diagnostic process. While our study focused on the process of identifying MIS-C, we did not ask providers to specify how they would exclude other illnesses, such as bacterial infections. However, this study highlights the need to better understand the initial presentation that should prompt further diagnosis, as well as a simplified diagnostic test that is more specific and widely accessible to help facilitate timely diagnosis and treatment.

Our study illustrates significant heterogeneity among healthcare providers as to when to initiate MIS-C workup, the order and context of the workup, and the criteria for MIS-C diagnosis. The current guidelines are designed to be sensitive as to minimize missed or delayed diagnoses. However, this subsequently results in high healthcare resource utilization. A diagnostic test is needed that is highly sensitive and specific in order to expedite diagnosis and treatment. With the United States in its fourth wave of the COVID-19 pandemic, it is evident that SARS-CoV-2 and MIS-C will likely remain a threat for the foreseeable future. The scientific community therefore needs to urgently build on existing research and refine clinical guidelines to minimize pediatric MIS-C morbidity and mortality.