Challenges in Diagnosing MIS-C

By Farah G. Hassan, MBBS, and Philip R. Fischer, MD, DTM&H

Dr. Hassan is a third-year pediatric resident at Tawam Hospital in Al Ain, United Arab Emirates.
Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates.

SYNOPSIS: Even though there are clear diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C), the initial diagnosis is not always certain, and there can be overlapping concurrent bacterial, viral, and parasitic infections that also require prompt treatment.

SOURCE: Kaneta K, Malhotra S, Szmuszkovicz J, et al. Expanding the differential for alternative diagnoses in the workup of multisystem inflammatory syndrome in children. Pediatr Infect Dis J 2023; Mar 10. doi: 10.1097/INF.0000000000003903. [Online ahead of print].

Multisystem inflammatory syndrome in children (MIS-C) is an uncommon sequela of SARS-CoV-2, with an estimated incidence rate of two in 100,000 children. About three to six weeks after an initial COVID illness, affected patients present with a variety of symptoms. Most patients present with fever. Gastrointestinal symptoms (such as abdominal pain, vomiting, and diarrhea) also are common. Patients often have rash and conjunctivitis. Shock, often of cardiac origin, is possible.

With such a variety of symptoms, the diagnosis of MIS-C may be challenging. Care needs to be taken to make the diagnosis in a timely manner and begin proper treatment with corticosteroids and intravenous immune globulin to avoid poor outcomes. At the same time, it is important not to miss other possible diagnoses, particularly those with the potential for fatal outcomes for which effective treatments are available.

Kaneta and colleagues in Los Angeles reviewed their experience to describe alternate diagnoses that mimic MIS-C. From August 2020 through July 2021, they identified a total of 359 patients younger than the age of 21 years who were admitted to their quaternary care, urban, freestanding children’s hospital with initial clinical suspicion for MIS-C and/or Kawasaki disease based on their admitting history and physical exam findings. Patients admitted with fever were evaluated using an algorithm based on then-current Centers for Disease Control and Prevention (CDC) diagnostic criteria. Patients who, based on initially available information, seemed to fit the diagnosis of MIS-C were included in the study and underwent additional diagnostic evaluation, including consultation with pediatric infectious disease physicians and pediatric cardiologists. Eventual final diagnoses were identified through retrospective chart review one month after admission.

Of the 359 patients identified, 126 (35.1%) were confirmed to have had MIS-C, 28 (7.8%) had Kawasaki disease, and 11 (3.1%) met criteria for both MIS-C and Kawasaki disease. The remaining 54% of patients were considered to be “MIS-C mimickers.” Comparing those with and without MIS-C (and/or Kawasaki disease), patients with MIS-C were older (9 vs. 6.7 years), were more likely male (65% vs. 45%), and had a higher body mass index (73rd vs. 64th percentile for age), whereas the MIS-C mimickers had a longer duration of fever (8.6 vs. 6.9 days) and fewer complaints of rash, conjunctivitis, changes in extremities, and neurological complaints. MIS-C mimickers also were less likely to require admission to an intensive care unit (7% vs. 36%).

Among diagnoses considered to be MIS-C mimickers, infectious diseases were the most common (78.9%), with about half due to bacteria and half due to viruses. Among bacterial illnesses, febrile urinary tract infection, pneumonia, and murine typhus (which is endemic in Los Angeles) were the most common, accounting for 37%, 13%, and 13% of bacterial diagnoses, respectively. In addition, bacterial enteritis, otitis media, sinusitis, skin and soft tissue infection, and bacteremia also were seen in several patients each. Group A streptococcal infections and Staphylococcus aureus bacteremia also were identified. One patient had non-typhoid Salmonella bacteremia.

Among the viral illnesses mimicking MIS-C, adenovirus (14%), rhinovirus/enterovirus (15%), and new acute SARS-CoV-2 (15%) were the most common. One patient, recently arrived from Nigeria, had Plasmodium ovale malaria.

Ten patients received a new rheumatologic diagnosis (systemic lupus erythematosus in two), six had appendicitis, and four had new diagnoses of acute lymphocytic leukemia. Even a month after initial presentation, 10 patients were left with a diagnosis of “fever of unknown origin,” having had at least eight days of fever without evidence of SARS-CoV-2 infection or exposure, and without identification of any alternative diagnosis.

The authors noted that COVID-related precautions during the time of the study made seasonal respiratory viruses, such as influenza and respiratory syncytial virus, less common than during preceding and subsequent years. They postulated that with increasing COVID vaccination and with increasing seasonal virus infections, the likelihood of mimickers of MIS-C also will increase. They advocate for individualized assessment of infectious and non-infectious causes of MIS-C-like symptoms based on individual patient presentations.

COMMENTARY

Knowledge about MIS-C is growing rapidly. We now have definitions, diagnostic criteria, and management pathways for potential MIS-C patients that are further updated as new information becomes available. However, there remains no specific diagnostic test for MIS-C. Clinical suspicion and careful consideration of presenting findings are essential.

As Kaneta and colleagues demonstrated, there are challenges associated with diagnosing MIS-C. For purposes of this discussion, we consider four specific challenges in diagnosing MIS-C.

First, the CDC provides clear evidence-based guidelines for diagnosing MIS-C, which can be summarized as:¹

An individual aged < 21 years presenting with:

• fever (> 38.0°C for ≥ 24 hours);

• laboratory evidence of inflammation;

• clinically severe illness requiring hospitalization;

• multisystem (> 2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic);

AND

no alternative plausible diagnoses;

AND

positive for current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR), serology, or antigen test;

OR

exposure to a suspected or confirmed COVID-19 case within the four weeks prior to the onset of symptoms.

Since results to evaluate the second and fourth numbered criteria might not be known at the time of initial presentation, clinicians should consider the possibility of MIS-C and think about testing inflammatory markers and seeking evidence of actual SARS-Co-V infection. Of note, a positive serology “counts” toward meeting the criteria even if the child had been vaccinated.

The second challenge, which also was noted by Kaneta and colleagues, is the overlap in the criteria between MIS-C and Kawasaki disease. The lines distinguishing these two conditions can be blurry, and some children are appropriately treated for both conditions. The criteria for diagnosing Kawasaki disease (as per the American Heart Association) can be summarized as follows:²

• fever for at least five days

AND

• at least four of the five following principal clinical features:

– erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa;

– bilateral bulbar conjunctival injection without exudate;

– rash — maculopapular, diffuse erythroderma, or erythema multiforme-like;

– erythema and edema of the hands and feet in acute phase and/or periungual desquamation in subacute phase;

– cervical lymphadenopathy (≥ 1.5 cm diameter), usually unilateral.

As noted and classified by Kaneta and colleagues, of their 359 patients admitted with concern for possible MIS-C, 35% had MIS-C alone, 8% ended up being diagnosed with only Kawasaki disease, and 3% qualified for concurrent diagnoses of both MIS-C and Kawasaki disease. Of course, some children who do not meet full criteria for Kawasaki disease still should be treated for “incomplete” or “atypical” Kawasaki disease.² Thus, consideration of a diagnosis of MIS-C also often should include consideration of a concurrent diagnosis of Kawasaki disease.

The third challenge in diagnosing MIS-C is the key point of Kaneta’s paper; specifically, approximately half of patients admitted with concern for MIS-C actually ended up with a different, unrelated diagnosis. Consistent with CDC recommendations, a diagnosis of MIS-C depends on having no plausible alternative diagnosis to account for the clinical findings. The new data from Los Angeles remind clinicians to carefully consider infectious diseases that are relevant (either by local epidemiology, such as murine typhus in southern California, or by individual patient risk factors, such as malaria in a traveler recently arrived from Nigeria) as well as non-infectious conditions. Concurrently, as seen in California, a significant number of patients had serious infections, such as colitis and bacteremia, for which rapid treatment also is essential. The search of alternative diagnoses beyond MIS-C should be tailored to the specific patient and focused on potentially life-threatening conditions.

Another recent example of the importance of avoiding too-rapid exclusion of other diagnostic possibilities in a patient suspicious for MIS-C is that of a 6-year-old boy who initially presented with fever, cough, myalgia, and later abdominal pain and painful (non-swollen joints).³ His inflammatory marker results (C-reactive protein, procalcitonin, IL-6) were elevated. An electrocardiogram showed sinus tachycardia with diffuse ST segment elevation, and an echocardiogram revealed left ventricular dysfunction with decreased ejection fraction. A chest X-ray was notable for cardiomegaly. He initially was given the diagnosis of myocarditis secondary to MIS-C, but his blood cultures were positive for Neisseria meningitidis. His course was complicated later by secondary meningococcal septic arthritis of his right elbow. In this case, the patient fulfilled most of the CDC criteria for MIS-C but did not have evidence of recent SARS-CoV-2 infection. It is vital to keep in mind that MIS-C is a serious illness and efforts should made to avoid missing both the diagnosis of MIS-C and concurrent coexisting diagnoses of serious infections.

A fourth challenge in making proper diagnoses in patients suspected of having MIS-C is that concurrent diagnoses are possible and that the finding of one diagnosis (whether MIS-C or a viral infection, for instance) does not necessarily preclude the possibility that another diagnosis is concurrently correct and relevant. Just as when a child who meets diagnostic criteria for Kawasaki disease should be treated whether or not a test comes back positive for a respiratory virus, so a child who meets diagnostic criteria for MIS-C and has concurrent infection or colonization by a virus still might best be treated for both MIS-C and, if treatment is available, the viral infection.² In Kaneta’s study, however, children who met MIS-C criteria but also had plausible evidence of a virus infection were considered to be MIS-C mimickers; this could have left them without necessary MIS-C treatment.

To highlight this fourth challenge of overly attributing symptoms to a positive test for infection, a study conducted during two respiratory viral seasons in 2019 and 2020 aimed to establish the carriage state vs. causative role of certain viruses in causing lower respiratory tract infections by testing children with lower respiratory infections and healthy children on three separate visits.⁴ Among those with acute lower respiratory infection (community-acquired alveolar pneumonia and bronchiolitis), certain viruses (respiratory syncytial virus, influenza, parainfluenza, and human metapneumovirus) dominated, with a declining prevalence with each visit implying a causative role. This is in contrast to other viruses (adenovirus, rhinovirus/enterovirus, and seasonal human coronavirus), which had a similar prevalence during each visit in healthy controls, indicating an asymptomatic carrier state. The take-away message from this fourth challenge is that a positive nasopharyngeal swab (or any other positive finding for that matter) does not rule out MIS-C since coincidental coexisting conditions are possible.

In conclusion, when MIS-C is suspected, careful diagnostic consideration is important, and treatment can be life-saving. At the same time, however, patients suspected of having MIS-C also should be carefully evaluated for the presence of both infectious and non-infectious conditions that could be contributing to their findings, and they should be appropriately treated in light of all possible diagnoses.

REFERENCES

1. Centers for Disease Control and Prevention. Information for healthcare providers about Multisystem Inflammatory Syndrome in Children (MIS-C). Last reviewed Jan. 2, 2023. www.cdc.gov/mis/mis-c/hcp_cstecdc
2. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association. Circulation 2017;135:e927-e999.
3. Stanzelova A, Debray A, Allali S, et al. Severe bacterial infection initially misdiagnosed as MIS-C: Caution needed. Pediatr Infect Dis J 2023; Mar 2: doi: 10.1097/INF.0000000000003896. [Online ahead of print].
4. Ben-Shimol S, Ramilo O, Leber AL, et al. A hypothesis-generating prospective longitudinal study to assess the relative contribution of common respiratory viruses to severe lower respiratory infections in young children. Pediatr Infect Dis J 2023;42:396-404.