Paediatric multisystem inflammatory syndrome (PIMS)

What is paediatric multisystem inflammatory syndrome?

Paediatric multisystem inflammatory system (PIMS) is a condition observed in paediatric populations diagnosed with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19.

PIMS is also known as multisystem inflammatory syndrome in children (MIS-C), paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-Ts), paediatric hyperinflammatory shock, and paediatric hyperinflammatory syndrome.

It results from an excessive inflammatory response due to COVID-19 infection in children, often presenting with shock, fever, organ dysfunction, and mucocutaneous manifestations. 

Who gets paediatric multisystem inflammatory syndrome?

PIMS is a relatively rare condition, occurring in <1% of children with serology suggestive of current or past SARS-CoV-2 infection. The average age of diagnosis is 11 years old, and it occurs more commonly in children with underlying health conditions. 

Some data suggest that Asian, African, and Afro-Caribbean children have an increased risk of developing PIMS, although other studies have noted disproportionately low case reports from countries with high rates of COVID-19 cases early in the pandemic, including China and other Asian countries.

Three case series conducted across the United Kingdom and United States noted that 25​​–45% of cases occurred in Black children, 30–40% in Hispanic children, 15–35% in white children, and 5–28% in Asian children. 

What causes paediatric multisystem inflammatory syndrome?

The pathogenesis of PIMS is not fully understood, although it is suspected to be secondary to immune dysregulation in the setting of SARS-CoV-2 infection. 

• The exact mechanism by which this occurs is thought to be a post-infectious process, supported by findings that most children have positive SARS-COV-2 serology but negative polymerase chain reaction (PCR) testing, indicating that immune dysregulation is occurring after the acute phase of infection.
• This area is being actively investigated, and preliminary studies in PIMS patients have found persistent immunoglobulin G (IgG) antibodies with enhanced ability to activate monocytes, and thus trigger strong immune response, as well as activation of CD8+ T cells and persistent cytopaenias.
• Viral sequences between children with PIMS versus children with acute COVID-19 infection without PIMS showed no differences, indicating that host factors, not viral factors, are likely responsible for causing the upregulated immune response. 

While PIMS is very similar to conditions like Kawasaki disease (KD) and macrophage activation syndrome (MAS), the immunophenotype is quite distinct from these diseases.

What are the clinical features of paediatric multisystem inflammatory syndrome? 

Mucocutaneous features

Mucocutaneous findings in PIMS can present variably, and may include:

• Rash
• Palmoplantar erythema
• Strawberry tongue
• Periorbital and/or malar erythema
• Hyperaemia of lips
• Conjunctivitis. 

The rash can display the following characteristics:

• Small-to-medium annular plaques with an urticarial appearance (most common)
  • These lesions can have purpuric centres, and thus mimic erythema multiforme.
• Morbilliform eruptions with macules, papules, and plaques coalescing
• Reticulated (livedoid-like) plaques and patches. 

These findings can be seen over the whole body, with predominance on the chest and upper limbs, as well as mucosal involvement. In some children, the rash is mildly pruritic.

These rashes do not desquamate, a key distinguishing feature between PIMS and Kawasaki disease. 

Non-cutaneous features

Other clinical features vary, but can include:

How do clinical features vary in differing types of skin?

Cutaneous findings have been similarly observed in children with Fitzpatrick phototype II–V.

What are the complications of paediatric multisystem inflammatory syndrome?

Potential complications include:

• Myocardial dysfunction
• Coronary artery aneurysms
• Systemic thrombosis
• Serious neurological event (eg, seizure, encephalopathy, stroke, coma)
• Respiratory failure
• Hepatitis
• Shock
• Death (2% of affected children).

How is paediatric multisystem inflammatory syndrome diagnosed?

There is no single test able to diagnose PIMS. Diagnosis is made based on the presence of various clinical and laboratory findings.

The World Health Organisation (WHO) case definition is as follows:

• Children or adolescent (0-19 years) PLUS fever for ≥3 days AND two of the following:
  • Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammatory signs (oral, hands, or feet)
  • Hypotension or shock within 24 hours of presentation
  • Cardiac features: myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities
  • Coagulopathy
  • Gastrointestinal symptoms.
• AND elevated inflammatory markers
• AND exclusion of alternate infective causes of inflammation
• AND evidence of SARS-CoV-2 infection or confirmed contact with a person with SARS-CoV-2 infection.

What is the differential diagnosis for paediatric multisystem inflammatory syndrome?

• Kawasaki disease
• Toxic shock syndrome
• Bacterial or viral sepsis
• Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)
• Other viral infections
• Systemic lupus erythematosus (SLE)
• Vasculitis

What is the treatment for paediatric multisystem inflammatory syndrome?

General measures

• PIMS patients commonly present with rash, fever, and systemic instability, for which differentials are broad.
• As such, supportive management should be commenced immediately.
• This can include fluid resuscitation, inotropes, supplemental oxygen, and prompt administration of broad-spectrum antibiotics. 

Specific measures

In patients who fulfil the diagnostic criteria for PIMS, intravenous immune globulin (IVIG) and glucocorticoids are the mainstay of treatment. 

• IVIG is administered as a single infusion at 2g/kg.
• Glucocorticoid therapy usually begins with intravenous methylprednisolone at a dose of 1–2mg/kg/day, split into twice daily dosing.
  • Once clinical improvement is seen, stepdown to oral steroids (eg, prednisolone) is appropriate, and the patient should continue on a tapering dose over 2–3 weeks.
• In patients who are unable to receive glucocorticoids or have refractory disease despite combination IVIG and glucocorticoids, biologic agents, such as anakinra and infliximab, are used as alternative treatment.

Given PIMS patients are at risk of thrombotic complications, most are treated with low-dose aspirin for 4–6 weeks. Anti-coagulation, typically with low-molecular-weight heparin [LMWH], should also be considered, especially for patients with coronary aneurysm, severe cardiac dysfunction, or previous venous thromboembolism.

The multisystem nature of PIMS requires a multidisciplinary approach, which should include paediatricians, infectious disease specialists, cardiologists, intensivists, haematologists, and specialist nursing care.

How do you prevent paediatric multisystem inflammatory syndrome?

There is no way to prevent PIMS, however measures such as social distancing, mask wearing, hand washing, and vaccination for COVID-19 during the COVID-19 pandemic and subsequently the development of PIMS. 

What is the outcome for paediatric multisystem inflammatory syndrome?

Our longitudinal understanding of this multisystem syndrome in children is limited given SARS-CoV-2 was only declared a pandemic in March 2020, and as such, long-term outcomes have not been studied. 

While the disease course can be severe, overall prognosis is positive as most children achieve a full clinical recovery. Death is rare, occurring in less than 2% of children with PIMS.