Case
Ava, a 21-month-old female, presented to her primary care provider’s office with 4 days of fever and a macular rash that started yesterday. The rash began on her face and has spread to the trunk, arms and legs. Her lips became red and cracked today and her eyes have been red. Today, she has had minimal oral intake and no urine output. There has been no associated cough, runny nose, vomiting, or diarrhea.
There is no one else currently ill at home. A few weeks ago her father had COVID-19 but recovered with outpatient management. Ava did not develop any symptoms at that time.
Because of her minimal intake and urine output, her pediatrician sends her to the Children’s Hospital of Philadelphia ED where she is found to have lymphopenia, thrombocytopenia, hyponatremia, elevated transaminases, and a significantly elevated ESR and CRP.
Discussion
Given her cytopenias, hyponatremia, and significant inflammation, Ava was admitted to the general pediatrics service at CHOP. She had an infectious workup that was unrevealing, and the team became concerned about multisystem inflammatory syndrome in children associated with COVID-19, or MIS-C. Further bloodwork showed significant elevation in levels of troponin and brain naturietic peptide. An echocardiogram showed decreased left ventricular function but no coronary artery dilation.
Rheumatology and Infectious Diseases were consulted and agreed that Ava had MIS-C, and recommended treatment with intravenous immunoglobulin (IVIG), as recommended in the CHOP MIS-C clinical pathway. Twenty-four hours after administration of IVIG, she continued to have fever and inflammatory marker elevation. She received a single dose of IV corticosteroids, after which her symptoms and laboratory markers improved. Follow-up echocardiogram showed improved LV function.
Two days later she was discharged home on a steroid taper. She was seen in follow-up in Rheumatology and Infectious Diseases clinics a couple weeks later, and the parents reported that she had returned to school and normal activities.
MIS-C Surfaced in April 2020
Since it was first described in China in December 2019, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2), rapidly evolved into a worldwide pandemic affecting millions. Unlike adults, the vast majority of children with COVID-19 typically have had mild symptoms. In April 2020, reports emerged of children with a different clinical syndrome resembling Kawasaki disease and toxic shock syndrome. While these children typically did not have symptoms suggestive of COVID-19, they frequently had serologic evidence of prior exposure to SARS–CoV-2. Since those initial reports in Europe, increased numbers of patients with MIS-C have typically followed the various waves of the pandemic, including the recent Delta and Omicron waves.
Clinically, these patients, in many ways, resemble those with Kawasaki disease. There is typically a prolonged fever, along with a rash, mucous membrane changes, lymphadenopathy, and conjunctivitis. In both conditions, patients may present in shock. However, there are some important features that distinguish MIS-C from KD. Patients with MIS-C tend to be older, often in the second decade of life. Patients with MIS-C frequently present with prominent GI symptoms, including abdominal pain and diarrhea, and neurologic symptoms, including headache, neck pain, and occasional encephalopathy. Whereas KD usually causes elevated white blood cell and platelet counts, in MIS-C, patients frequently have leukopenia and thrombocytopenia. In MIS-C, the adenopathy is frequently in multiple locations and the conjunctivitis frequently involves the limbus, unlike the cardinal unilateral cervical lymphadenopathy and limbic-sparing conjunctivitis seen in KD.
The most significant clinical difference between the 2 conditions is the type of cardiac involvement seen. Whereas the most well-recognized sequelae of KD is coronary artery changes, in MIS-C there is prominent myocardial involvement, with decreased ventricular function seen commonly. Indeed, this can lead to cardiogenic shock with patients frequently requiring ICU-level care.
Good Outcomes with Treatment
Fortunately, since the start of the pandemic, MIS-C outcomes have been quite good with treatment. Because these patients resembled KD from the outset, treatment paradigms followed with IVIG used as first-line therapy. This continues to be the standard of care, with the addition of corticosteroids if patients have severe presentations or do not respond to initial treatment with a single dose of IVIG. Unlike KD, a second dose of IVIG is not recommended. If the child’s clinical status is not improving, biologic therapies, including anakinra or infliximab, are recommended. The vast majority of patients at CHOP and around the world treated in this fashion have had resolution of symptoms and have remained well at follow-up.
At CHOP, we have been active in developing clinical recommendations for the care of patients with MIS-C and performing research to understand the etiologies behind this new condition. Working as an interdisciplinary team made of up of international experts from Rheumatology, Infectious Diseases, Cardiology, Oncology, Immunology, and other teams, we will continue these efforts as the pandemic evolves.
Clinical/Historical Features to Guide Need for Evaluation of MIS-C:
- Rash (more common)
- Polymorphic, maculopapular, petechial, NOT vesicular
- GI symptoms (more common)
- Diarrhea, abdominal pain, vomiting
- Extremity changes
- Erythema and edema of the hands and feet in acute phase
- Oral of mucosal changes
- Erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa
- Conjunctivitis (more common)
- May be bulbar or limbic-involving, without exudate
- Lymphadenopathy (less common)
- Cervical > 1.5 cm, unilateral (infrequently observed)
- Neurologic symptoms
- Headache, irritability, lethargy, altered mental status, neck stiffness, cranial nerve palsies
- Epidemiologic link to COVID-19
- Patient with history of COVID disease or close contact with known positive COVID case in past 4-6 weeks, or person placed in quarantine
Case
Ava, a 21-month-old female, presented to her primary care provider’s office with 4 days of fever and a macular rash that started yesterday. The rash began on her face and has spread to the trunk, arms and legs. Her lips became red and cracked today and her eyes have been red. Today, she has had minimal oral intake and no urine output. There has been no associated cough, runny nose, vomiting, or diarrhea.
There is no one else currently ill at home. A few weeks ago her father had COVID-19 but recovered with outpatient management. Ava did not develop any symptoms at that time.
Because of her minimal intake and urine output, her pediatrician sends her to the Children’s Hospital of Philadelphia ED where she is found to have lymphopenia, thrombocytopenia, hyponatremia, elevated transaminases, and a significantly elevated ESR and CRP.
Discussion
Given her cytopenias, hyponatremia, and significant inflammation, Ava was admitted to the general pediatrics service at CHOP. She had an infectious workup that was unrevealing, and the team became concerned about multisystem inflammatory syndrome in children associated with COVID-19, or MIS-C. Further bloodwork showed significant elevation in levels of troponin and brain naturietic peptide. An echocardiogram showed decreased left ventricular function but no coronary artery dilation.
Rheumatology and Infectious Diseases were consulted and agreed that Ava had MIS-C, and recommended treatment with intravenous immunoglobulin (IVIG), as recommended in the CHOP MIS-C clinical pathway. Twenty-four hours after administration of IVIG, she continued to have fever and inflammatory marker elevation. She received a single dose of IV corticosteroids, after which her symptoms and laboratory markers improved. Follow-up echocardiogram showed improved LV function.
Two days later she was discharged home on a steroid taper. She was seen in follow-up in Rheumatology and Infectious Diseases clinics a couple weeks later, and the parents reported that she had returned to school and normal activities.
MIS-C Surfaced in April 2020
Since it was first described in China in December 2019, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2), rapidly evolved into a worldwide pandemic affecting millions. Unlike adults, the vast majority of children with COVID-19 typically have had mild symptoms. In April 2020, reports emerged of children with a different clinical syndrome resembling Kawasaki disease and toxic shock syndrome. While these children typically did not have symptoms suggestive of COVID-19, they frequently had serologic evidence of prior exposure to SARS–CoV-2. Since those initial reports in Europe, increased numbers of patients with MIS-C have typically followed the various waves of the pandemic, including the recent Delta and Omicron waves.
Clinically, these patients, in many ways, resemble those with Kawasaki disease. There is typically a prolonged fever, along with a rash, mucous membrane changes, lymphadenopathy, and conjunctivitis. In both conditions, patients may present in shock. However, there are some important features that distinguish MIS-C from KD. Patients with MIS-C tend to be older, often in the second decade of life. Patients with MIS-C frequently present with prominent GI symptoms, including abdominal pain and diarrhea, and neurologic symptoms, including headache, neck pain, and occasional encephalopathy. Whereas KD usually causes elevated white blood cell and platelet counts, in MIS-C, patients frequently have leukopenia and thrombocytopenia. In MIS-C, the adenopathy is frequently in multiple locations and the conjunctivitis frequently involves the limbus, unlike the cardinal unilateral cervical lymphadenopathy and limbic-sparing conjunctivitis seen in KD.
The most significant clinical difference between the 2 conditions is the type of cardiac involvement seen. Whereas the most well-recognized sequelae of KD is coronary artery changes, in MIS-C there is prominent myocardial involvement, with decreased ventricular function seen commonly. Indeed, this can lead to cardiogenic shock with patients frequently requiring ICU-level care.
Good Outcomes with Treatment
Fortunately, since the start of the pandemic, MIS-C outcomes have been quite good with treatment. Because these patients resembled KD from the outset, treatment paradigms followed with IVIG used as first-line therapy. This continues to be the standard of care, with the addition of corticosteroids if patients have severe presentations or do not respond to initial treatment with a single dose of IVIG. Unlike KD, a second dose of IVIG is not recommended. If the child’s clinical status is not improving, biologic therapies, including anakinra or infliximab, are recommended. The vast majority of patients at CHOP and around the world treated in this fashion have had resolution of symptoms and have remained well at follow-up.
At CHOP, we have been active in developing clinical recommendations for the care of patients with MIS-C and performing research to understand the etiologies behind this new condition. Working as an interdisciplinary team made of up of international experts from Rheumatology, Infectious Diseases, Cardiology, Oncology, Immunology, and other teams, we will continue these efforts as the pandemic evolves.
Clinical/Historical Features to Guide Need for Evaluation of MIS-C:
- Rash (more common)
- Polymorphic, maculopapular, petechial, NOT vesicular
- GI symptoms (more common)
- Diarrhea, abdominal pain, vomiting
- Extremity changes
- Erythema and edema of the hands and feet in acute phase
- Oral of mucosal changes
- Erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa
- Conjunctivitis (more common)
- May be bulbar or limbic-involving, without exudate
- Lymphadenopathy (less common)
- Cervical > 1.5 cm, unilateral (infrequently observed)
- Neurologic symptoms
- Headache, irritability, lethargy, altered mental status, neck stiffness, cranial nerve palsies
- Epidemiologic link to COVID-19
- Patient with history of COVID disease or close contact with known positive COVID case in past 4-6 weeks, or person placed in quarantine