Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C)
The Council of State and Territorial Epidemiologists (CSTE) and CDC have developed a new CSTE/CDC MIS-C surveillance case definition, corresponding case report form [441 KB, 3 pages], and case report form guidance document [329 KB, 10 pages] to be used starting January 1, 2023. MIS-C cases with illness onset before January 1, 2023, but reported after January 1, 2023, will be assigned using the 2020 CDC MIS-C case definition but reported using the new case report form. An interim case reporting guidance document [181 KB, 4 pages] will be provided for these cases.
The Council of State and Territorial Epidemiologists (CSTE) and CDC have developed a standardized surveillance case definition for multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 infection, effective January 1, 2023. This case definition (hereafter referred to as the CSTE/CDC MIS-C surveillance case definition) was developed after consultation with MIS-C experts, review of data from 2020–2022, and retrospective application of different criteria to data from MIS-C cases previously reported to CDC. The definition is intended to be easier for public health surveillance staff to implement and help reduce misclassification.
The CSTE/CDC MIS-C surveillance case definition establishes clinical, laboratory, and epidemiological reporting criteria to identify cases as confirmed, probable, or suspect. CSTE and CDC recommend all state, local, territorial, and tribal health departments use this definition to conduct case surveillance and report all cases of confirmed, probable, or suspect MIS-C with illness onset on or after January 1, 2023, to CDC.
MIS-C cases reported after January 1, 2023, but with illness onset before January 1, 2023, should be assigned using the 2020 case definition and reported using the new case report form. See the Interim Reporting Guide below for detailed instructions.
CDC will continue to present MIS-C data collected from health departments in 2023 on the CDC COVID Data Tracker MIS-C webpage. All cases reported prior to 2023, using the 2020 CDC MIS-C case definition, will remain on the web page.
Case Definition for MIS-C
As described in the CSTE position statement, “Standardized Case Definition for Surveillance of Multisystem Inflammatory Syndrome in Children,” and available on CDC’s National Notifiable Diseases Surveillance System website, the CSTE/CDC case definition for MIS-C is as follows:
Any illness in a person aged less than 21 years that meets:
- The clinical AND the laboratory criteria (Confirmed), OR
- The clinical criteria AND epidemiologic linkage criteria (Probable), OR
- The vital records criteria (Suspect)
|Clinical Criteria||Laboratory Criteria for SARS-CoV-2 Infection||Epidemiologic Linkage Criteria||Vital Records Criteria|
|An illness characterized by all of the following, in the absence of a more likely alternative diagnosis*
||Close contact‡ with a confirmed or probable case of COVID-19 disease in the 60 days prior to hospitalization||A person whose death certificate lists MIS-C or multisystem inflammatory syndrome as an underlying cause of death or a significant condition contributing to death|
*If documented by the clinical treatment team, a final diagnosis of Kawasaki Disease should be considered an alternative diagnosis. These cases should not be reported to national MIS-C surveillance.
** Clinician documentation of shock meets this criterion.
***Positive molecular or antigen results from self-administered testing using over-the-counter test kits meet laboratory criteria.
^Includes a positive serology test regardless of COVID-19 vaccination status. Detection of anti-nucleocapsid antibody is indicative of SARS-CoV-2 infection, while anti-spike protein antibody may be induced either by COVID-19 vaccination or by SARS-CoV-2 infection.
‡Close contact is generally defined as being within 6 feet for at least 15 minutes (cumulative over a 24-hour period). However, it depends on the exposure level and setting; for example, in the setting of an aerosol-generating procedure in healthcare settings without proper personal protective equipment (PPE), this may be defined as any duration.
Healthcare providers should report cases among patients younger than 21 years of age meeting the CSTE/CDC MIS-C surveillance case definition to their state, local, territorial, or tribal health department. Clinicians can report by submitting either completed case report forms or medical records for review to their state, local, territorial, or tribal health department.
Case Report Form and Instructions
- Fillable Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 Infection Case Report Form
- CSTE/CDC Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 Infection Surveillance Case Report Form Guidance, Effective January 1, 2023
- CSTE/CDC Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 Infection Surveillance Interim Case Reporting Guide
Patients with MIS-C usually present with fever, abdominal pain, vomiting, diarrhea, skin rash, mucocutaneous lesions and, in severe cases, with hypotension and shock.1-3 They have elevated laboratory markers of inflammation (e.g., CRP, ferritin), a majority have laboratory markers indicating damage to the heart (e.g., elevated troponin), and many have low absolute lymphocyte counts (lymphopenia).1-3 Some patients develop cardiac dysfunction (e.g., decreased left ventricular function) and coronary artery dilatation or aneurysm.1,2,4 Gastrointestinal inflammation can manifest as abdominal pain, vomiting, and diarrhea; children may have signs and symptoms similar to those of acute appendicitis.5 Neck pain has also been described, sometimes with development of phlegmon on radiographic imaging.6 Children with MIS-C can also have neurologic involvement which is usually transient and presents as headache or altered mental status.7,8 Children with MIS-C can develop severe neurologic manifestations such as severe encephalopathy, stroke, demyelination, and fulminant cerebral edema, although this is rare.7,8
Not all children will have the same signs and symptoms, and some children may have symptoms not listed here. MIS-C may begin weeks after a child is infected with SARS-CoV-2. The child may have been infected from an asymptomatic contact, and, in some cases, the child and their caregivers may not even know they had been infected.
- A C-reactive protein ≥3.0 mg/dL (30 mg/L) is required for the CSTE/CDC MIS-C surveillance case definition; other laboratory tests may also indicate evidence of inflammation (e.g., erythrocyte sedimentation rate, fibrinogen, procalcitonin, and ferritin).
- Similarly, SARS-CoV-2 laboratory testing is indicated. Although detection of anti-nucleocapsid antibody or anti-spike protein antibody fulfill criteria for the case definition, when feasible SARS-CoV-2 anti-nucleocapsid antibody testing is recommended, particularly in children with a history of COVID-19 vaccination because anti-nucleocapsid antibody is indicative of SARS-CoV-2 infection, while anti-spike protein antibody may be induced either by COVID-19 vaccination or by SARS-CoV-2 infection. Serology testing should be obtained prior to administering intravenous immunoglobulin (IVIG) or any other exogenous antibody treatments whenever possible.
Given the frequent association of MIS-C with cardiac involvement, the following testing is usually performed:
Other imaging should be directed by patient signs or symptoms but could include:
- Imaging to evaluate for acute appendicitis
- Imaging to evaluate for pharyngeal space infection
It is important to evaluate children with suspected MIS-C for alternative diagnoses, particularly as MIS-C clinical manifestations overlap with those of other etiologies. Testing to evaluate for other potential diagnoses should be directed by patient signs or symptoms. Alternate diagnoses to consider include:
- Acute viral infection (e.g., SARS-CoV-2, Influenza, Adenovirus)
- Acute viral infection myocarditis (e.g., Influenza, Enteroviruses)
- Kawasaki Disease
- Rickettsial disease (e.g., Typhus)
Initial treatment is tailored according to the patient’s presenting signs and symptoms and may include:
- Fluid resuscitation
- Inotropic support
- Respiratory support
Anti-inflammatory measures have included the frequent use of IVIG and steroids. There is some evidence that MIS-C with milder manifestations can be treated with steroid monotherapy.9 Per NIH guidelines, steroid monotherapy is recommended if IVIG is unavailable or contraindicated. Conversely, IVIG monotherapy is recommended if steroids are contraindicated. Prolonged duration of outpatient steroids should be avoided.10 The use of other anti-inflammatory medications (e.g. anakinra) and the use of anti-coagulation treatments have been variable. Aspirin has commonly been used due to concerns for coronary artery involvement, and antibiotics are routinely used to treat potential sepsis while awaiting bacterial cultures. Thrombotic prophylaxis is often used given the hypercoagulable state typically associated with MIS-C.
The American College of Rheumatology has developed clinical guidance for pediatric patients diagnosed with MIS-C associated with SARS-CoV-2. The National Institutes of Health have also developed guidance for the clinical management of children with MIS-C.
ICD-10-CM Diagnosis Code for MIS: M35.81
- Applicable to:
- Multisystem inflammatory syndrome in adults
- Multisystem inflammatory syndrome in children
- Pediatric inflammatory multisystem syndrome
- Use additional code, if applicable, for:
- Code first, if applicable, COVID-19 (U07.1)
- Code also any associated complications
Patients with a diagnosis of MIS-C should have close outpatient follow-up, which may include their primary care physician, pediatric cardiology, and other subspecialty clinics such as hematology or rheumatology depending on their MIS-C symptomatology and management.
For more information, see American Academy of Pediatrics Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance and American College of Rheumatology Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C).
MIS-C and Vaccination
CDC has created Considerations for initiating COVID-19 vaccination in people with a history of MIS-C. COVID-19 vaccination is effective at reducing the risk of MIS-C with two studies finding that two doses of Pfizer-BioNTech COVID-19 vaccine had a greater than 90% estimated effectiveness at preventing MIS-C.11,12
- American Academy of Pediatrics Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance
- American College of Rheumatology Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19
- CDC Health Advisory (5/14/20): Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19)
- Clinical Outreach and Communication Activity (COCA) Webinar, Dec 8, 2022: Updates on Multisystem Inflammatory Syndrome in Children (MIS-C): Epidemiology, Case Definition, and COVID-19 Vaccination
- Considerations for initiating COVID-19 vaccination in people with a history of MIS-C or MIS-A
- CSTE Position Statement: Standardized Case Definition for Surveillance of Multisystem Inflammatory Syndrome in Children
- How to Protect Yourself and Others
- MMWR Recommendations and Reports: CSTE/CDC Surveillance Case Definition for MIS-C in Children Associated with SARS-CoV-2 Infection — United States
- National Institutes of Health Therapeutic Management of Hospitalized Pediatric Patients with MIS-C
- National Notifiable Diseases Surveillance System (NNDSS)
- New ICD-10-CM code for the 2019 Novel Coronavirus (COVID-19)
- Vaccine Adverse Event Reporting System
- Miller AD, Yousaf AR, Bornstein E, et al. Multisystem Inflammatory Syndrome in Children During Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta and Omicron Variant Circulation-United States, July 2021-January 2022. Clin Infect Dis. Oct 3 2022;75(Supplement_2):S303-S307. doi:10.1093/cid/ciac471
- Miller AD, Zambrano LD, Yousaf AR, et al. Multisystem Inflammatory Syndrome in Children-United States, February 2020-July 2021. Clin Infect Dis. Aug 24 2022;75(1):e1165-e1175. doi:10.1093/cid/ciab1007
- Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. May 23 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1
- Belhadjer Z, Meot M, Bajolle F, et al. Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic. Circulation. Aug 4 2020;142(5):429-436. doi:10.1161/CIRCULATIONAHA.120.048360
- Valitutti F, Verde A, Pepe A, et al. Multisystem inflammatory syndrome in children. An emerging clinical challenge for pediatric surgeons in the COVID 19 era. J Pediatr Surg Case Rep. Jun 2021;69:101838. doi:10.1016/j.epsc.2021.101838
- Jenkins E, Sherry W, Smith AGC, et al. Retropharyngeal Edema and Neck Pain in Multisystem Inflammatory Syndrome in Children (MIS-c). J Pediatric Infect Dis Soc. Oct 27 2021;10(9):922-925. doi:10.1093/jpids/piab050
- LaRovere KL, Poussaint TY, Young CC, et al. Changes in Distribution of Severe Neurologic Involvement in US Pediatric Inpatients With COVID-19 or Multisystem Inflammatory Syndrome in Children in 2021 vs 2020. JAMA Neurol. Nov 7 2022;doi:10.1001/jamaneurol.2022.3881
- LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol. May 1 2021;78(5):536-547. doi:10.1001/jamaneurol.2021.0504
- Villacis-Nunez DS, Jones K, Jabbar A, et al. Short-term Outcomes of Corticosteroid Monotherapy in Multisystem Inflammatory Syndrome in Children. JAMA Pediatr. Jun 1 2022;176(6):576-584. doi:10.1001/jamapediatrics.2022.0292
- Son MBF, Berbert L, Young C, et al. Postdischarge Glucocorticoid Use and Clinical Outcomes of Multisystem Inflammatory Syndrome in Children. JAMA Netw Open. Nov 1 2022;5(11):e2241622. doi:10.1001/jamanetworkopen.2022.41622
- Nygaard U, Holm M, Hartling UB, et al. Incidence and clinical phenotype of multisystem inflammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a Danish nationwide prospective cohort study. Lancet Child Adolesc Health. Jul 2022;6(7):459-465. doi:10.1016/S2352-4642(22)00100-6
- Zambrano LD NM, Olson SM, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12–18 Years — United States, July–December 2021. MMWR Morb Mortal Wkly Rep. January 14 2022;71:52–58. doi:http://dx.doi.org/10.15585/mmwr.mm7102e1