Pediatric Inflammatory Multisystem Syndrome (PIMS)

In the Rapid Review series, we briefly review the key points of a clinical review paper (or three). The topic this time: Pediatric Inflammatory Multisystem Syndrome (PIMS) – also known as multisystem inflammatory syndrome in children (MIS-C).

The papers:

Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical Characteristics of 58 Children with a Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2. JAMA – J Am Med Assoc. 2020;2. PMID: 32511692

Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem inflammatory syndrome in children in New York state. N Engl J Med. 2020;3. PMID: 32598830          

Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem inflammatory syndrome in U.S. Children and adolescents. N Engl J Med. 2020. PMID: 32598831 [free full text]

What is Pediatric Inflammatory Multisystem Syndrome (PIMS)?

Simply put, PIMS is a febrile hyperinflammatory syndrome that can present with dermatologic, mucocutaneous, or gastrointestinal manifestations. The danger lies in its ability to rapidly progress to multi-organ dysfunction, requiring critical care, and the potential for coronary aneurysm development in a small proportion of pediatric patients.

A word of caution: This is a new clinical syndrome that was only first described in the last 6 months. Everything we know about it comes from cases reports and retrospective data. This is the most up to date information possible, as of September 2020, but you should anticipate that our understanding will change with time.

What causes it?

The exact cause is unknown. A temporal association with COVID-19 is clear, with the onset of PIMS typically occurring 3 to 6 weeks following exposure to the virus. In a study of 99 patients with confirmed PIMS, 51% tested positive for COVID-19 using reverse transcription (RT)-PCR from nasopharyngeal (NP) swabs and 100% tested positive via serological assay for IgG antibodies.

Who gets it?

PIMS appears to predominantly affect previously healthy children and adolescents. As with adult patients, there is a documented elevated incidence of SARS CoV-2 infection among Black and Hispanic populations. PIMS, however, affects children of all racial and ethnic backgrounds.

How does it present?

Aside from persistent fever >3 days, symptoms are non-specific:

• Gastrointestinal [80%] – abdominal pain, nausea, vomiting, diarrhea
• Dermatologic [62%] – rash, swollen hands or feet
• Mucocutaneous [61%] – conjunctivitis, mucosal changes, cracked lips
• Neurologic [62%] – altered mentation, headache
• Musculoskeletal [30%] – myalgias, joint pain
• Upper respiratory [27%] – congestion, sore throat
• Lower respiratory [20%] – cough, SOB, wheeze

Three general presentations for PIMS have been described:

1. Fever and hyperinflammation (unexplained fever for 3 or more days, suspected COVID exposure, and laboratory findings of a hyper-inflammatory state.)
2. Symptoms similar to Kawasaki disease
3. Hypotension or shock

The majority of patients have involvement of at least 4 organ systems, with the heart being affected in 80% of cases. Myocarditis prevalence increases with age, affecting around 40% of patients < age 5, and affecting over 70% in those aged 13 and older.

Editor’s note from Justin: These are really just the symptoms of COVID in adult patients. Diagnostically, I can’t see anything that really separates the diagnosis of “PIMS” from “severe COVID infection”. Like in Kawasaki disease, these children are developing coronary artery aneurysms, which we don’t see in adults. (Is anyone looking?) The concern, as is discussed below, is that even children without classic Kawasaki disease symptoms are developing coronary aneurysms.

How is the diagnosis made?

Given the non-specific symptoms with significant overlap with most viral syndromes, PIMS will be difficult to diagnose. Several sets of diagnostic criteria exist (see Table below from Whitaker et al.). In simple terms, PIMS can be diagnosed based on 6 key elements:

• Pediatric age
• Persistent fever (>38.0°C)
• Elevated markers of inflammation
• Involvement of ≥ 2 organ systems
• Lack of an alternative diagnosis
• Laboratory-confirmed COVID-19 infection or history of exposure

Supporting labs include elevated ESR, CRP, neutrophilia, lymphopenia, thrombocytopenia, elevated ferritin, hypoalbuminemia, prolonged INR, high fibrinogen and d-dimer levels, in addition to elevated troponin and NT-proBNP.

What is the differential diagnosis?

Other diseases to consider include Kawasaki disease, atypical Kawasaki disease, Kawasaki disease shock syndrome, toxic shock syndrome, and macrophage activation syndrome.

How is it treated?

At this point we only have retrospective data, so it is unclear what, if any, treatments work. Extrapolating from the management of Kawasaki disease, the most common treatments for PIMS include intravenous immune globulin (IVIG) and/or systemic glucocorticoids. Other treatments include interleukin-6 (IL-6) inhibitors or interleukin-1Ra inhibitors. Approximately 50% of patients require inotropic support.

What is the prognosis?

About 80% of patients with PIMS are admitted to an intensive care unit, with 10-20% receiving mechanical ventilation. The mean length of hospitalization is around 7 days. When PIMS is diagnosed and treated promptly, most patients have favourable outcomes, but mortality is about 2%.

What are the complications?

Most complications are cardiac, with about 50% of patients having some degree of ventricular dysfunction. Others include pericardial effusion, high-risk arrythmias, and coronary aneurysms.

What about the coronary aneurysms?

The biggest concern with Kawasaki disease is the development of coronary aneurysms, and they also seem to develop in a significant proportion of PIMS patients (9-14%). Unfortunately, coronary aneurysms appear to be equally likely whether or not the child has classic Kawasaki disease symptoms, so it will not be good enough to simply rely on our existing diagnostic pathways.

Bottom Line:

While this syndrome may be rare, emergency physicians must be vigilant in considering this critical diagnosis in children presenting with persistent fever and history of COVID exposure. Early recognition of PIMS, and subsequent consultation with our pediatric colleagues, can inform prompt supportive care & facilitate appropriate therapeutic options.  

Other Resources:

Canadian Pediatric Society Position Statement

PIMS on Don’t Forget the Bubbles