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The clinical profile of multisystem-inflammatory syndrome in Children (MIS-C), a complication of COVID-19, the illness caused by the SARS-CoV-2 virus, continues to evolve. Patients often have elevated C-reactive protein (CRP), D-dimer, and troponin levels, experience symptoms across major organ systems, and in some cases become severely ill. Moreover, MIS-C manifests differently in younger patients than older ones. As studies emerge on the demographics, clinical presentations, and lab values specific to this condition, experts have been crafting algorithms to optimize testing in children suspected of having this novel inflammatory disorder.

The American College of Rheumatology (ACR) in recent draft clinical guidance devised a testing algorithm that outlines a two-tiered approach. ACR recommends that children with fever >38℃, an epidemiologic link to SARS-CoV-2, and two suggestive clinical features undergo further lab testing (tier 1 lab tests). Tier 1 tests include routine, easily accessible clinical labs such as complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate (ESR), CRP, and serology/polymerase chain reaction tests for SARS-CoV-2. If tier 1 lab tests results include CRP ≥5 or ESR≥40 and one suggestive lab feature such as neutrophilia or platelet count <150,000µL, the child should undergo tier 2 testing, which includes a more complex lab work up along with an EKG and echocardiogram.

“The purpose of this two-tiered approach is to limit the number of patients who need to undergo a large and expensive diagnostic work up,” said Lauren Henderson, MD, MMSc, an attending rheumatologist at Boston Children's Hospital who heads the ACR’s MIS-C task force. “In children who are very sick (with shock), tier 1 and tier 2 testing should be done in all cases.”

Although MIS-C shares some features with Kawasaki disease (KD) and with toxic shock syndrome, several studies have identified MIS-C as a distinct syndrome. An evaluation of 17 children and adolescents in New York City who tested positive for SARS-CoV-2 found that clinical features overlapped with but also had differences from other diseases. The most common presenting symptoms are fever, rash, and gastrointestinal symptoms, said Eva Cheung, MD, assistant professor of pediatrics and medical director, pediatric ECMO at Columbia University Medical Center, and the study’s corresponding author.

Another study that evaluated the clinical and laboratory characteristics of 58 critically ill children who met criteria for MIS-C identified a wide range of symptoms, from fever to myocardial injury, shock, and coronary artery aneurysms. Authors in this study referred to this condition as severe acute respiratory syndrome coronavirus 2 (PIMS-TS). Comparing PIMS-TS patients with cohorts that had other inflammatory diseases such as KD, KD shock syndrome, and toxic shock syndrome, investigators found unique characteristics in the PIMS-TS patients.

Generally PIMS-TS patients were older, had more profound anemia and inflammation, and had higher white blood cell and neutrophil count in addition to higher CRP, fibrinogen, and troponin levels. The differences between MIS-C and other inflammatory disorders “could be associated with one or more factors influencing immunomodulation and susceptibility. These observations suggest some areas where susceptibility and immune-modulating factors for PIMS-TS and KD may contribute differently for each condition,” Brian W. McCrindle, MD, MPH, and Cedric Manlhiot, PhD, wrote in an editorial about the two studies.

Other research underscores the prevalence of severe illness in some children. Two papers in The New England Journal of Medicine offer a snapshot of MIS-C’s impact across the United States. One study of 186 patients with MIS-C in 26 states found that 92% had high levels of at least four biomarkers for inflammation. Investigators found KD-like features in 40% of the patients. The virus impacted gastrointestinal, cardiovascular, mucocutaneous, hematologic, and respiratory organs in a majority of the cases. Intravenous immune globulin was the most common therapy (77% of cases), followed by glucocorticoids (49%), and interleukin-6 or 1RA inhibitors (20%).

In a narrower study of 99 patients with MIS-C in New York State, 29% met clinical criteria for one of more of the symptoms: hypotension or shock, severe cardiac illness, or other severe end-organ illness. Investigators found elevated levels of CRP, D-dimer, and troponin in 100%, 91%, and 71% of the patients tested, respectively. They also identified abnormalities in lymphopenia and elevated b-type natriuretic peptide, procalcitonin, fibrinogen, ferritin, ESR, and interleukin-6.

Another study of 177 patients at Children’s National Hospital in Washington, D.C., that looked at severe COVID-19 in children and young adults, not MIS-C specifically, found that patients with certain types of underlying conditions were more likely to be hospitalized, including those with cardiac, oncologic, or hematologic issues.

While asthma didn’t increase hospitalization risk, children with cerebral palsy, microcephaly, or global developmental delay were more likely to be hospitalized. Less than half of all patients had fever and respiratory symptoms concurrently—two hallmark symptoms of the virus. The findings offer insights into which children might become more seriously ill, according to a statement from Children’s National.

Leaders of these studies agree that there is still much to learn and research about the immunology and causes of MIS-C.

The good news is these young patients generally experience good outcomes if given appropriate medical attention and supportive therapy. “Our early data of their outcomes out of the hospital after they are discharged are also quite favorable,” said Cheung.

Extending this conversation to all children testing positive for SARS-CoV-2, experts have offered varying advice on lab tests.

Authors of one article cited leukocyte count as an unreliable marker. Clinicians instead should monitor for elevated CRP, lactate dehydrogenase, and PCT—traits found often in severe cases—and for elevated creatine kinase-MB, a cardiac marker seen in mild cases. A letter to the editor in The Journal of Applied Laboratory Medicine suggested that laboratory findings differ little between children and adults, although infants have the highest rates of serious illness among children.