Multisystem Inflammatory Syndrome in children (MIS-C) and COVID-19: What providers should know

Multisystem inflammatory syndrome in children, or MIS-C, is a new syndrome that has been reported worldwide in an increasing number of children who had or were exposed to COVID-19. MIS-C shares many characteristics with Kawasaki disease, an inflammatory disease of childhood that can affect blood vessels.

This Q & A with Dr. Negar Ashouri, a pediatric infectious disease specialist at CHOC Children’s, explores what providers should know about MIS-C, including recently released guidance from the American Academy of Pediatrics.

What is MIS-C?

MIS-C is a rare complication temporally associated with COVID-19. Here is the case definition, per a U.S. Centers for Disease Control Health Advisory:

  • An individual aged <21 years presenting with fever (>38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours); laboratory evidence of inflammation (Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin.); and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological); AND
  • No alternative plausible diagnoses; AND
  • Positive for current or recent SARS-CoV-2 (COVID-19) infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the four weeks prior to the onset of symptoms.

Is MIS-C dangerous?

MIS-C can be serious, but most children have recovered. MIS-C, like Kawasaki disease, can be a very uncomfortable illness because it causes prolonged fever, irritation and inflammation in many tissues of the body. The main concern with MIS-C and Kawasaki disease is heart and blood vessel involvement.

Conditions that involve inflammation in the heart, such as MIS-C or Kawasaki disease, can affect the heart in different ways. They may cause the heart muscle to be irritated and inflamed, affecting the overall function of the heart.

They may also weaken the wall of one or more of the coronary arteries causing them to bulge or balloon out. Blood clots can form in the ballooned area and possibly block the blood flow through the coronary artery. When this happens, the heart muscle will no longer receive an adequate supply of oxygen-rich blood, and the heart muscle can be damaged.

Dr. Negar Ashouri, pediatric infectious disease specialist, CHOC Children’s

What are the symptoms of MIS-C?

Though clinicians have described differing presentations, sign and symptoms can include an ongoing fever, inflammation detected by blood test, and evidence of organ dysfunction or shock. Here are additional common symptoms:

  • Kawasaki disease-like features including conjunctivitis; red eyes; red or swollen hands and feet; rash; red cracked lips; and swollen glands. Some children have presented with coronary artery enlargement or aneurysms. Some children may present with  more gastrointestinal (abdominal pain or diarrhea) or neurologic (headaches/meningitis) manifestations.
  • Toxic shock syndrome-like features with hemodynamic instability.
  • Cytokine storm/macrophage activation or hyperinflammatory features.
  • Shortness of breath suggestive of congestive heart failure.
  • Respiratory symptoms typically reported in adults with COVID-19 may not be present in pediatric patients with MIS-C.

Patients with the following symptoms ought to seek emergency care:

  • Persistent fevers
  • Trouble breathing
  • Pain or pressure in the chest that does not go away
  • New confusion
  • Inability to wake or stay awake
  • Bluish lips or face
  • Severe abdominal pain

How is MIS-C diagnosed?

Children who present with symptoms may undergo expanded laboratory testing and a cardiac workup that may include:

  • Routine screening labs including CBC with diff, CRP, CMP, and appropriate cultures;
  • If expanded work-up is warranted for hospitalized patients, it may include  troponin, pro-B-type natriuretic peptide, triglycerides, creatine kinase, ,  D-dimer, prothrombin time/partial thromboplastin time, international normalized ratio,  ferritin, lactic acid dehydrogenase,  and fibrinogen, if not already conducted;
  • COVID-19 testing performed with RT-PCR assay and serologic testing in every case;
  • echocardiogram;
  • electrocardiogram;
  • chest X-ray; and
  • abdominal ultrasound.

When should a provider suspect MIS-C?

Per the AAP, any child with suspected MIS-C should also be evaluated for infectious and noninfectious etiologies.

An initial sign may be a persistent fever without a clear clinical source. Providers should be suspicious of any fever accompanied by symptoms concerning in their severity or coincident with recent exposure to COVID-19.

Some children clinically progress rapidly and may develop hemodynamic compromise. These children should be followed and cared for in a hospital with tertiary pediatric/cardiac intensive care units.


How is MIS-C treated?

Kawasaki and MIS-C are best treated in the hospital by a qualified multidisciplinary group of pediatric specialists who will work to reduce inflammation and minimize long-term heart damage.

Here is the APP guidance for treatment:

  • Some patients with MIS-C have been treated with IVIG, Occasionally,  Patients have also been treated with steroid therapy  and or biologics that may require taper of the medications overtime.
  • Given the need for early intervention and the need to initiate treatment for multiple possible etiologies, many patients have received concurrent antibiotic therapy.
  • A multidisciplinary group is generally involved which may include Infectious disease specialists, cardiologists, intensivists, hospitalists and rheumatologists.

What is the follow-up for patients with MIS-C?

Children who have had serious cases of MIS-C should have close outpatient follow-up care by a group of specialists which may include cardiology, hematology and infectious diseases.

Refer a patient to the infectious disease team at CHOC Children’s.

Leprosy antibiotic is safe treatment for M. abscessus infections, CHOC infectious disease team finds

An oral antibiotic used to treat leprosy is safe and well-tolerated in the treatment of children with challenging-to-treat mycobacterium abscessus infections, the CHOC Children’s infectious disease team has found.

In their study, clofazimine was given to 27 patients during an outbreak of odontogenic mycobacterial infections as part of a multidrug regimen. Though clofazimine performed well in test-tube experiments against M. abscessus, reports in children were previously limited.

This group of patients represents the highest number of children to receive clofazimine outside of leprosy treatment settings.

The study findings were published in the July 2019 Journal of the Pediatric Infectious Disease Society. Its authors are CHOC infectious disease specialists Dr. Felice Adler-Shohet; Dr. Jasjit Singh; Dr. Delma Nieves; Dr. Negar Ashouri; and Dr. Antonio Arrieta; as well as Cathy Flores, a CHOC clinical research nurse coordinator, and Tuan Tran, an infectious disease pharmacist at CHOC.

The patients who received the antibiotic were among a large group of children who underwent pulpotomy procedures at a dental practice with a contaminated water system.

CHOC’s team added clofazimine to its original first-line medication regimen after receiving special use approval from the Food and Drug Administration.

An additional benefit of use of clofazimine was the ability to stop use of an intravenous antibiotic given thrice daily that prompted many side effects, the team found.

Learn how to refer a patient to CHOC Children’s infectious disease specialists.

CHOC Encourages Appropriate Use of Antimicrobial Agents

By: M. Tuan Tran, infectious disease pharmacist at CHOC, and Dr. Negar Ashouri, infectious disease specialist at CHOC

With the Centers for Medicare and Medicaid Services (CMS) and the Joint Commission set to require the adoption of core elements of antimicrobial stewardship in 2017, CHOC Children’s will continue to uphold the appropriate use of antimicrobial agents through its existing antimicrobial stewardship program.

CHOC’s multidisciplinary collaborative’s goals include:

    • Optimizing selection, dosing and duration of therapy
    • Reducing adverse events including secondary infection (e.g. clostridium difficile infection)
    • Improving patient outcomes
    • Slowing the emergence of antimicrobial resistance
    • Preserving supply especially during critical shortages and reduce health care expenditures

The collaborative’s strategies include:

    • Pre-authorization of broad spectrum agents such as meropenem, cefepime, vancomycin, daptomycin and linezolid
    • Daily review (prospective audit with feedback) of antimicrobial orders
    • Development of care guidelines, dosing protocols and order sentences in the electronic health record
    • Dose optimization based on PK/PD principles (e.g. prolonged infusion of beta-lactams)
    • Document indication and duration for all antimicrobial orders
    • Antibiotic time-out at 48-72 hours to: reevaluate need to continue treatment; streamline, de-escalate based upon culture result; convert intravenous to oral route when appropriate; reassess optimal treatment duration
    • Track trends and share antibiotic utilization data as well as resistance trends
    • Provide education for staff, patients and family of optimal antimicrobial therapy use

Changes to clinical practice patterns to promote the appropriate use of antibiotics is a patient safety issue and public health imperative:  Antibiotics are the second most commonly used class of drugs in the United States, and studies indicate that 30 to 50 percent of antibiotics prescribed in hospitals are unnecessary or inappropriate. Further, antibiotic exposure is the single most important risk factor for the development of clostridium difficile infection.


“Through education and teamwork we can reduce the unnecessary use of antibiotics, therefore minimizing the risk of potential side effects to ensure we have effective antibiotics available for the generations to come.”

– Dr. Negar Ashouri, infectious disease specialist at CHOC


The Centers for Disease Control and Prevention (CDC) estimates that 2 million illnesses and 23,000 deaths are caused annually by drug-resistant bacteria in the U.S. alone. Avoidable costs from antibiotic misuse range from $27 billion to $42 billion per year in the U.S. At the same time, the discovery and development of new antibiotics have dropped precipitously from the 1980s onward. All antibiotics approved for use in patients today are derived from a limited number of classes of agents that were discovered by the mid-1980s (see figure 1).

Figure 1.

figure1

Source: A Scientific Roadmap for Antibiotic Discovery. The Pew Charitable Trusts, May 2016.

Here are some common reasons for misuse of antibiotics in health care settings:

  • Use of antibiotics when not needed
  • Continued treatment when no longer necessary
  • Use of broad-spectrum agents when more targeted/narrower options are available
  • Wrong antibiotic given to treat an organism/infection
  • Incorrect dosing and frequency

Antibiotics can also affect beneficial bacteria that are part of our normal flora:

  • An average child receives 10 to 20 courses of antibiotics before age 18
  • Antibiotics affect microbiota flora which may not fully recover after a course of antibiotics
  • Overuse of antibiotics may be contributing to obesity, diabetes, inflammatory bowel disease and asthma

For information about the appropriate use of antibiotics for your patients and families, please visit our CHOC Blog.