Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19 (FL INITIAL Autonomous Practice – Differential Diagnosis)

In April of 2020, amidst the global crisis of the COVID-19 pandemic, the Rheumatology Study Group of the Italian Society of Pediatrics noted a sudden spike in the number of children presenting with multisystem inflammatory symptoms (La Torre et al., 2023).  They noted the affected children were presenting with signs and symptoms similar to those commonly seen in Kawasaki Disease, but with a few noticeable differences such as an older average age of affected children, abdominal symptoms, and higher rates of myocarditis and cardiogenic shock (La Torre et al., 2023).

Shortly after the alert by Italian physicians, similar cases began popping up all over the world and it was quickly linked to a recent SARS-CoV-2 infection (within the last 2-4 weeks), a disease process now referred to as COVID-19 (La Torre et al., 2023).

COVID-19 itself has impacted individuals worldwide and was the third leading cause of death in the United States in 2020. To date, it has caused 6.9 million hospitalizations and over 1.1 million deaths in the United States alone (Centers for Disease Control and Prevention [CDC], 2024a).

Since the connection was made between MIS-C and COVID-19, the incidence of these two conditions has been tracked alongside each other, specifically watching for trends. Fluctuation in incidence for each condition is largely the same, with increases and decreases in numbers aligning with a delay of about 4 weeks between COVID-19 spikes to MIS-C spikes.

While the incidence rate is linked to the rate of COVID-19 cases, the actual occurrence of post-COVID MIS-C is rare. In the early days of the pandemic, the incidence of MIS-C following COVID-19 infection was about 1 in 3,000-4,000 children and teens. Now, according to the most recent data, the incidence seems to be rapidly dropping, and the severity of the illness may be decreasing as well (Yousaf et al., 2024).

There are many factors that may affect this change in incidence rate, including changes in use of and access to accurate testing, differences in systemic effects of SARS-CoV-2 virus strains, and development and use of the COVID-19 vaccine.

Five years after the condition first emerged, as of January 2025, there have been 9,750 cases that meet criteria and 80 deaths among children and teens (CDC, 2024b). Repeat occurrences in children who have already had MIS-C are extremely rare.

While we still have a poor understanding of exactly what causes the systemic inflammatory response of MIS-C to occur, we do know with confidence that it is closely linked to a recent case of COVID-19.

COVID-19 is the disease process that follows infection with the SARS-CoV-2 virus, a novel organism in the coronavirus family that was first identified in humans in late 2019 in Wuhan, China. Coronaviruses cause acute respiratory illnesses and are spread easily from person to person (Mayo Clinic, 2024; Cascella et al., 2023). SARS-CoV-2 is most commonly spread through respiratory droplets from infected individuals, even if they are asymptomatic (Mayo Clinic, 2024). Airborne transmission and fomite transmission from contaminated inanimate objects is also possible but less common. And rarely, but still possible, is fecal-oral contamination and vertical transmission from pregnant mothers to their infants (Cascella et al., 2023).

Once a person encounters the virus from an infected host, the virus then begins replicating inside the new host. Coronaviruses are covered in crown-shaped spike proteins that give it its name; corona means crown in Spanish (Mayo Clinic, 2024).

Image 1:
Coronavirus

As with many viruses, the SARS-CoV-2 virus has evolved over time, making small shifts in its genetic makeup and surface antigen proteins, creating many variants. There are sometimes discernible changes in the virulence, transmissibility, and even signs and symptoms of COVID-19 depending on which variant is the dominant one in circulation at the time (Cascella et al., 2023; Mayo Clinic, 2024).

For children, COVID-19 is typically a mild illness, often much milder than when adults are infected. Typical symptoms include (Lee & Hsueh, 2023; Sick-Samuels, 2021):

• Sore throat
• Fever
• Nasal congestion or rhinorrhea
• Fatigue
• Nausea
• Vomiting
• Diarrhea
• Myalgia

These signs and symptoms generally last between 7-14 days (Lee & Hsueh, 2023; Sick-Samuels, 2021).

Severe illness requiring intensive care, and deaths from COVID-19 are rare in children. However, for poorly understood reasons, sometimes a widespread, dysregulated inflammatory response occurs during or shortly after SARS-CoV-2 infection in children. This is what is known as MIS-C.

Affected children may have experienced COVID-19 symptoms or may have been asymptomatic and unaware they even had the virus. The disease may occur within the first week or two of viral infection or may be delayed as much as six weeks after (Lee & Hsueh, 2023; Sick-Samuels, 2021).

The hallmark symptoms of MIS-C include (Lee & Hsueh, 2023; Sick-Samuels, 2021):

• Persistent fever
• Systemic inflammation
• Organ dysfunction

Children affected by MIS-C almost unanimously present with a persistent fever lasting more than 3-4 days, fatigue, and malaise that do not respond well to pain relievers and antipyretics. Gastrointestinal symptoms like nausea, vomiting, diarrhea, and abdominal pain are common and often severe or worsening (Lee & Hsueh, 2023; Sick-Samuels, 2021). In fact, these are the symptoms that may be what initially brings children to the emergency room for evaluation (Lee & Hsueh, 2023; Sick-Samuels, 2021).

Vascular swelling causes conjunctival injection, erythema, and edema of the mouth and tongue, lymphadenopathy, edema of the hands and feet, and sometimes a generalized macular or even purpuric rash (Lee & Hsueh, 2023; Sick-Samuels, 2021). Children may have neck pain, chest pain, and altered mental status. These children appear ill, and the constellation of symptoms are not likely to be ignored or minimized by parents or clinicians (Lee & Hsueh, 2023; Sick-Samuels, 2021).

One of the most dangerous features of this condition is involvement of the heart. Nearly all parts of the heart may be affected, with coronary artery dilation and aneurysm, pericarditis, myocarditis, valvulitis, and abnormal electrical conductivity all being common (Lee & Hsueh, 2023; Sick-Samuels, 2021). Dysfunction of the left ventricle and reduced ejection fraction can lead to acute heart failure and cardiogenic shock (Lee & Hsueh, 2023; Sick-Samuels, 2021).

A cascade of inflammatory markers consistent with a cytokine storm and hyperinflammation are commonly present, with elevation of interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin, and ferritin (Lee & Hsueh, 2023; Sick-Samuels, 2021). Low platelet counts may also occur and then a rebound effect of coagulopathy from increased d-dimer and fibrinogen may lead to erratic blood clotting and stroke (Lee & Hsueh, 2023; Sick-Samuels, 2021). Elevated WBCs and neutrophils with a shift to the left are common as well as hypoalbuminemia and hyponatremia. Acute kidney and liver injury may occur, and fluid accumulation leads to widespread edema, pericardial effusion, pleural effusion, and ascites. Hemodynamic instability, shock, and heart failure are among the most serious symptoms that may need aggressive support (Lee & Hsueh, 2023; Sick-Samuels, 2021).

Please use the following table to organize achild’s signs and symptoms of MIS-C by body system.

(Lee & Hsueh, 2023; Sick-Samuels, 2021)

Of the possible conditions, Kawasaki Disease (KD) is the most similar and important to differentiate; in fact, during the early days of MIS-C being identified, it was thought to be an atypical KD presentation (Lee & Hsueh, 2023; Rabb & Kimmel, 2023).

KD is also a systemic inflammatory disorder that is thought to occur as a dysfunctional post-viral reaction, though there is no specific virus known to be associated with KD (Lee & Hsueh, 2023; Rabb & Kimmel, 2023). It is associated with (Lee & Hsueh, 2023; Rabb & Kimmel, 2023):

• Fever for more than 5 days
• Bilateral conjunctivitis
• Erythema
• Edema to oral mucosa
• Bilateral swelling of hands and feet
• Cervical lymphadenopathy
• Generalized rash
• Eventual desquamation of lips, palms, and soles

KD’s most dangerous symptoms are coronary artery dilation and aneurysm (Lee & Hsueh, 2023; Rabb & Kimmel, 2023).

Despite those many similarities, there are also some important differences that distinguish MIS-C from KD. The median age of occurrence is one of them; KD typically occurs in children under the age of 5, while MIS-C occurs most often in children 6-11 years old (La Torre et al., 2023; Lee & Hsueh, 2023). Children with MIS-C also only need to have fever for one day or more, whereas KD is usually ≥ 5 days (La Torre et al., 2023; Lee & Hsueh, 2023).

There is also more widespread organ involvement with MIS-C and cardiac involvement is often more outwardly noticeable before echocardiogram is done. Cardiac, gastrointestinal, and neurological symptoms are more pronounced with MIS-C and laboratory dysregulation, including coagulopathy, inflammatory markers, elevated cardiac enzymes, and altered renal function, are much more serious (La Torre et al., 2023; Lee & Hsueh, 2023). Myocarditis and shock are also more common with MIS-C than with KD (La Torre et al., 2023; Lee & Hsueh, 2023).

The most reliable evidence for a diagnosis of MIS-C is a recent infection with SARS-CoV-2 (La Torre et al., 2023; Lee & Hsueh, 2023). This can be determined with exposure history to contacts with a known infection or positive virological test either in the presence or absence of symptomatic disease (La Torre et al., 2023; Lee & Hsueh, 2023).

Please use the following table to help differentiate a diagnosis of MIS-C from KD.

(La Torre et al., 2023; Lee & Hsueh, 2023)

Viral pathogens that may manifest with multisystem involvement of myocardium inflammation can include (Kang & Chippa, 2023):

• Adenovirus
• Cytomegalovirus (CMV)
• Epstein-Barr virus (EBV)
• Enteroviruses

The major difference in eliminating this differential is that these viruses very rarely lead to severe multisystem disease in children who are healthy and not immunocompromised (Kang & Chippa, 2023). Polymerase chain reaction (PCR) tests can help identify one of these viruses to distinguish it from COVID-19-related MIS-C (Kang & Chippa, 2023).

Stevens-Johnson Syndrome (SJS) is a rare condition that is characterized by blistering skin and mucous membranes as well as many other dermatological complications (Ebrahimi et al., 2023; Karimi et al., 2021). These are very similar clinical manifestations to that of MIS-C. It has even been suggested in one study that COVID-19 might initially present as what would be first assumed to be SJS, but after knowledge of a recent history of COVID-19 or a finding of COVID-19 antibodies, a diagnosis of MIS-C is more likely (Ebrahimi et al., 2023).

Toxic shock syndrome (TSS) is a rapid-onset illness that is associated with a fever, sunburn-like rash, hypotension, and potentially multisystem organ damage (Ross, 2023). It is associated with a toxin-producing Staphylococcus aureus that leads to an over-activation of cytokines and inflammatory cells in the body (Ross, 2023).

MIS-C can be very challenging to differentiate from TSS. In one study where data was collected from over 500 patients across four different healthcare institutions, patients with TSS were more likely to be female and non-Hispanic White (Godfred-Cato et al., 2022). They were also found to be more likely to demonstrate shock, hypotension, and low rates of cardiovascular issues (Godfred-Cato et al., 2022).

Juvenile idiopathic arthritis (JIA) is the most common type of arthritis that is found in the pediatric population (Arthritis Foundation, n.d.). The rare and even more serious subtype of JIA, systemic juvenile idiopathic arthritis (sJIA), is identified in between 10-20% of these children (Arthritis Foundation, n.d.). The “systemic” distinction means that not only are the joints affected, but that other parts of the body such as the heart, lungs, and liver may also be affected (Arthritis Foundation, n.d.). It is the only subtype of juvenile arthritis that is thought to be autoinflammatory in nature rather than an autoimmune condition (Arthritis Foundation, n.d.).

It is known that some of the clinical criteria for sJIA overlaps with MIS-C and KD, including fever, arthritis, elevated leukocyte count, elevated platelet counts, anemia, and widespread rash (Boyarchuk & Kovalchuk, 2023). In children who have symptoms of a pattern of recurrent, spiking fever, especially with the addition of hepatomegaly and polyarthritis (arthritis affecting multiple joints at the same time), sJIA should be considered (Boyarchuk & Kovalchuk, 2023).

Bacterial sepsis is a life-threatening organ dysfunction that is the result of a bacterial infection getting into the bloodstream and overwhelming the body, contributing to significant tissue and organ damage (Bullock, 2023). It is a leading cause of mortality and morbidity in children across the world (Bullock, 2023).

Both sepsis and MIS-C present with fever, hypotension or shock, coagulopathy, elevated inflammatory markers, and multiple organ dysfunction (Hernández-García, 2023). In one retrospective study comparing MIS-C and sepsis patients, a diagnostic score was developed to help differentiate the two conditions and assist in quicker, more accurate diagnoses of one versus the other, a MISSEP score (MIS for MIS-C and SEP for sepsis) (Hernández-García, 2023). The main conclusions of this diagnostic scoring study included that children with MIS-C tended to be older, had more prolonged fever, more skin-mucosal symptoms, greater myocardial dysfunction, and more gastrointestinal symptoms than children with sepsis (Hernández-García, 2023). It was also concluded that sepsis had a higher incidence rate and higher mortality and morbidity than their cases of MIS-C (Hernández-García, 2023).

The setting in which nurses work will impact the stage of the disease where they encounter children with MIS-C and, consequently, nursing interventions for these patients.

In a public health or primary care setting, the focus is going to center on prevention and early detection of disease. Nurses working in pediatric and family medicine clinics, health departments, and schools are in a perfect position to impact vaccination rates for COVID-19, which is the most effective way to prevent occurrence of MIS-C cases.

The current recommendation is for all children ages 6 months and older to receive an initial COVID-19 vaccine and at least 1 updated vaccine (CDC, 2024c). Children ages 6 months to 4 years receive the pediatric dosage and children 5 years and older receive the regular dosage (CDC, 2024c). The need for second and third doses for initial vaccination varies depending on the type of vaccine received, Pfizer-BioNTech (3 doses) or Moderna (2 doses) (CDC, 2024c). Children should also receive the most recent updated vaccine available, currently the 2024-2025 update (CDC, 2024c).

Parents and children should be educated about the significantly decreased risk of MIS-C for children who are fully up to date on COVID-19 vaccines (Yousaf et al., 2024). Recent data indicates 80% of MIS-C cases are in children who have never received a COVID-19 vaccine (Yousaf et al., 2024).

Early identification of MIS-C is also an important nursing intervention. For children who are seen in the pediatric office with mild or even asymptomatic COVID-19, parents should be educated about signs and symptoms to be aware of in the coming weeks and when to seek further evaluation (Lee & Hsueh, 2023). Any children presenting with fever, conjunctival injection, GI symptoms, neurologic symptoms, or other inflammatory symptoms should be questioned about recent viral illness or contact with someone with COVID-19 (Lee & Hsueh, 2023). Awareness of risk factors, including age, gender, and race or ethnicity can help nurses identify children who require a high level of suspicion for MIS-C with presentation of an inflammatory process (Lee & Hsueh, 2023).

Nurses working in acute care settings like emergency departments and inpatient pediatric units or intensive care units (ICUs) may encounter children who are more obviously and acutely ill with MIS-C. Nurses should be highly suspicious of the disease with children who present with severe abdominal symptoms, hemodynamic instability, cardiac dysfunction, severely elevated inflammatory labs, or shock (Lee & Hsueh, 2023).

For children in which MIS-C has been identified, nursing care will involve (Lee & Hsueh, 2023):

• Support of vital signs
• Possible use of mechanical ventilation or ECMO
• Administration of various medications to treat hypotension, cardiac dysfunction, and hyperinflammation

Nurses should be prepared to educate families about the risks of widespread inflammation and blood clots on the various organ systems and be able to explain the use of aspirin, IVIG, corticosteroids, and even immunomodulatory agents to reduce the inflammatory process and preserve organ function (Lee & Hsueh, 2023).

An affected child’s condition can deteriorate rapidly, and close monitoring of vital signs, neurologic function, and organ function is necessary so that quick intervention can be initiated should a child experience acute heart failure, cardiac arrest, or shock (Lee & Hsueh, 2023).

Nurses working in primary care or specialty settings may encounter children recovering from MIS-C. These children may still be taking or tapering aspirin, corticosteroids, or immunomodulatory agents and their medication lists should be kept up to date (Lee & Hsueh, 2023). They will need repeated lab draws to track the decline of inflammatory markers and close cardiac follow-up with echocardiograms to ensure coronary artery dilation or left ventricular dysfunction is resolving (Lee & Hsueh, 2023). It is important to explain to families that exercise and physically strenuous activity will likely need to be limited until the child is cleared by cardiology, which might not occur until several months after initial diagnosis (Children’s Minnesota, 2024).

It should also be noted the IVIG administration is associated with a temporary inhibition of the immune response and so attenuated viral vaccines such as MMR and varicella should be delayed for 11-12 months after a child receives IVIG (Rabb & Kimmel, 2023). This is most relevant for children ages 1 and 4 when MMR and varicella are routinely given (Rabb & Kimmel, 2023). Although this is not the most likely age group for MIS-C, this is still an important factor to consider in order to ensure appropriate immune response to vaccines (Rabb & Kimmel, 2023).

There is also the consideration of Reye’s syndrome, a rare complication of viral illnesses like influenza experienced by children taking aspirin (Rabb & Kimmel, 2023). Children treated with high dose aspirin should be cautioned about this risk and encouraged to stay up to date with seasonal influenza vaccines (Rabb & Kimmel, 2023).

A Black 8-year-old male patient, Caleb, is brought to the emergency department by his mother for fever and abdominal pain for the last 48 hours. His mother reports that he seems to be getting worse in the last few hours. She reports that his 6-year-old brother had cold symptoms last week, but otherwise everyone else has been healthy.

On physical exam, Caleb is found to have an oral temp of 101.2°F, 1.5 cm cervical lymphadenopathy, bilateral conjunctival injection, and pharyngeal edema. He had generalized abdominal pain that worsens with palpation, and he vomited twice over the course of his emergency department visit. He is also noted to have a generalized, fine, macular rash.

Caleb’s lab results are significantly abnormal, with an elevated c-reactive protein (CRP), elevated erythrocyte sedimentation rate (ESR), and elevated cardiac enzymes. His platelet count is also low at 80,000/L. A viral panel is positive for SARS-CoV-2. His mother reports that he had a COVID-19 vaccine when they were first eligible in 2021, but he has not had any updated vaccines since.

Given Caleb’s age, race, inflammatory markers, and involvement of multiple organ systems (cardiac, GI, skin), in addition to the positive SARS-CoV-2 and recent cold symptoms, the patient is tentatively diagnosed with MIS-C and transferred to the nearest children’s hospital.

There, he is given IVIG, low dose aspirin, and oral corticosteroids. An echocardiogram reveals myocarditis and coronary artery dilation, and he stays at the hospital for another 6 days. He is eventually discharged and makes a full recovery after several more weeks of aspirin therapy and cardiac monitoring.

This child experienced early identification of disease and prompt treatment; however, Caleb was really only a few days into symptoms and this diagnosis could have been missed or delayed for many more days while his condition worsened. Appropriate knowledge of risk factors and thorough testing were integral to appropriate management of his case.

Thorough laboratory testing and identification of risk factors helped with the quick identification and timely treatment of Caleb’s condition, a major strength of this case. If the provider had ignored the recent cold symptoms and not conducted a viral panel since the cold had resolved, the positive SARS-CoV-2 would not have been discovered and may have delayed the MIS-C diagnosis.

Weaknesses of this case include the primary care prevention for this child. He was not up to date on his COVID-19 vaccines, increasing his risk of MIS-C as a complication of COVID-19. Additional information about vaccine risks and benefits as well as follow-up reminders from his pediatrician may have helped keep him fully vaccinated and less at risk for MIS-C.