Paediatric Multisystem Inflammatory Syndrome

Cite this article as:
Team DFTB. Paediatric Multisystem Inflammatory Syndrome, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.25760

It has become increasingly clear that children are less frequently affected by severe COVID-19 than adults. However, a new ‘hyperinflammatory syndrome’ in children associated with SARS-CoV-2 has recently been widely reported in the media with notable clusters of cases in New York City and London. This review will outline what we know so far about this new syndrome and what it means for us as clinicians.

This hyperinflammatory syndrome has similarities to Kawasaki disease, Toxic Shock Syndrome, and hyperinflammatory syndromes such as Haemophagocytic Lymphocytic Histiocytosis (HLH) and SLE. 

 

Why does Kawasaki disease keep being mentioned?

Kawasaki disease (KD) is a vasculitis of childhood characterized by a prolonged fever in addition to some characteristic changes. There are many other features that are not present in all children leading to the concept of an incomplete KD presentation.  KD is most common in children aged 6 months to 5 years, however, it can occur in children of any age.

The exact trigger of KD is unknown. There is a huge list of viral pathogens that have previously been associated with KD, including coronavirus though there is no known consistent trigger. Because of this, there is no specific test that can diagnose KD and it is diagnosed on clinical criteria alone.

Early recognition of KD is critical as treatment with aspirin and IVIG in the acute phase decreases the risk of significant coronary artery aneurysm but even with treatment observational studies have shown even with treatment early CAA can occur in up to 20%  of cases. KD is one of the most common causes of acquired heart disease in children (alongside rheumatic heart disease). Despite being well recognized by the paediatric community, KD is still quite poorly understood.

A mixture of the clinical features of KD seems to be apparent in many children with this new hyperinflammatory syndrome.

 

How does SARS-CoV-2 and PIM-TS fit in?

PIM-TS stands for Paediatric  Multisystem Inflammatory Syndrome – Temporally Associated with SARS-CoV-2. It is the current name given to the hyperinflammatory state seen in children with exposure to SARS-CoV-2. 

There are many similarities between the clinical presentation of PIM-TS and Kawasaki Disease, in particular, the unrelenting fever, rash, conjunctivitis and peripheral oedema. Vascular involvement has also been demonstrated with echo-bright coronary arteries in all children, and a giant coronary artery aneurysm in one child.

A case definition was rapidly produced by the RCPCH and is helpful to define PIM-TS further:

      1. A child presenting with persistent fever, inflammation (neutrophilia, elevated CRP, and lymphopaenia) with evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurological disorder) with additional features. This may include children fulfilling full or partial criteria for Kawasaki Disease
      2. Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus
      3. SARS-CoV-2 PCR testing may be positive or negative

There are some particularly notable features of PIMS-TS including abdominal pain and gastrointestinal symptoms that are predominantly early symptoms. They are less commonly seen in Kawasaki Disease

Then the Centre for Disease Control (CDC) in America came up with another name for the same syndrome, MIS-C, which stands for Multisystem Inflammatory Syndrome in Children.

    1. An individual aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological) AND
    2. No alternative plausible diagnoses AND
    3. Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms

 

What evidence do we have currently?

The first case series to describe this cluster of children was published on May 7 2020 in Lancet by Riphagen et al. Subsequently, an observational cohort study of children in the Bergamo province, Italy, was published on May 13 2020 showing a 30-fold increased incidence of KD during the SARS-CoV-2 pandemic. Interestingly, they highlighted a higher rate of cardiac involvement and features of inflammation (‘macrophage activation syndrome’). A preprint from France has described a cluster of 17 cases within 2 weeks presenting in a similar manner. Clusters of children with similar presentations have been reported by news outlets in the United States and Spain. Abdominal pain, vomiting and diarrhoea have been the predominant early features so far in all cohorts.

Of note, there are yet to be similar reports from the  Asian epicentres that were first affected by the virus.

6 of 8 children described by Riphagen et al were of Afro-Caribbean ethnicity.  A higher rate of KD in Afro-Caribbean children in the United Kingdom has also been shown in previous reports. After the publication of this case series, Evelina London Children’s Hospital has managed >20 such cases in children. Informal reports have indicated that 20/21 are from BAME groups. The majority have been tested for SARS-CoV-2 serology and been found positive (indicating a previous infection), despite a minority of them testing positive for the virus at the time of admission. This is the same in the French cohort where 88% tested positive for SARS-CoV-2 antibodies.

The general picture is of children persistent high-grade fever, limited or no respiratory compromise, fluid refractory shock, extremely high inflammatory markers and frequent cardiac dysfunction.

 

How should PIMS-TS be managed?

At this stage, we have more questions than answers about both the short and long term management of PIMS-TS. The RCPCH guidelines provide extensive advice on the suggested early medical management and investigations, coupled with ongoing monitoring and treatment. Importantly, robust discussion with a tertiary centre that includes paediatric infectious diseases, cardiology and rheumatology, must be part of the child’s management. 

All children described in the Riphagen study were treated with intravenous immunoglobulin (IVIG) and most were treated with aspirin, as a child with Kawasaki disease would be. In addition, all children received broad-spectrum antibiotics. The role of other immunomodulatory therapy is uncertain at this time.

For the emergency or general paediatrician, normal supportive measures for critically ill children should be instigated with early involvement of specialist teams. The RCPCH guidelines also suggest taking additional blood when gaining venous access for research purposes.

What research is being done?

As this is a new entity research is of huge importance, and in the UK children are actively being recruited into clinical studies. There are many questions that need answering. What ongoing investigations do we need to do? What is the long-term consequence of this syndrome? Should all children with Kawasaki Disease be tested for SARS-CoV-2 (either PCR or serology)? Could mild cases of COVID-19 be associated with cardiac sequelae? Should PIMS-TS be treated acutely with IVIG and aspirin as is the case with KD? These questions are hard to answer. Given the low incidence of SARS-CoV-2 in children, perhaps there needs to be an international registry of PIMS-TS cases.

 

How does PIMS-TS affect you?

There has clearly been a lot of media interest in PIMS-TS but it is still an extremely uncommon disease entity in the context of all children presenting to emergency and acute care services. The vast majority of children, including those who were critically ill, have made a good recovery. With a new condition for us to consider, there is a two-fold danger:

      • The potential for lack of recognition and failure to escalate care effectively if it is misdiagnosed as sepsis. Failure to prevent, or subsequently miss, a coronary artery aneurysm may be significant for the child.
      • The potential for worrying that every child with fever, abdominal pain and an elevated CRP has PIMS-TS. This will overload services, unnecessarily worry families and result in the mismanagement and overtreatment of children with common infectious conditions.

So far, the majority of children have been very unwell. It seems reasonable to really only think about this condition in admitted children that have signs, symptoms and investigations outside your normal frames of reference. If a clear cause for the presenting illness isn’t known and inflammatory markers high (CRP > 150) then further review and investigation is probably warranted. Otherwise performing investigations which we are usually unfamiliar with such as ferritin, d-dimer and troponins in all children with a persistent fever is likely to cause more problems than it will solve. Certainly, these children should have regular observations in keeping with your departmental policy and ensure that escalation processes are followed.

Conclusion

A new hyperinflammation syndrome has emerged in children. It seems to be temporally associated with the COVID-19 pandemic. The majority test positive for previous SARS-CoV-2 infection.

There is an overlap with some features of Kawasakis disease and other hyperinflammatory syndromes, often with shock, and with little to no respiratory compromise

The mechanism of the illness is unknown but research has already begun.

There are no specific management options at present, though early discussion with paediatric sub-specialists (especially infection/rheumatology/cardiology) seems prudent.

 

 

Also, take a look at

Multisystem inflammatory syndrome in children from Brad Sobolewski at PEMblog

Selected references

RCPCH Guideline

Riphagen, S., et al., Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet.

McCrindle, B.W., et al., Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation, 2017. 135(17): p. e927-e999.

Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, Bonanomi E, D’Anitga L. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020. Advance online publication, doi: 10.1016/ S0140-6736(20)31129-6

Wilkins, A.L., et al., Toxic shock syndrome – the seven Rs of management and treatment. J Infect, 2017. 74 Suppl 1: p. S147-s152.

Kawasaki’s Disease

Cite this article as:
Alyssa Courtney. Kawasaki’s Disease, Don't Forget the Bubbles, 2017. Available at:
https://doi.org/10.31440/DFTB.12282
A four-year-old Japanese boy was brought into Emergency with 5 days of fevers, non-exudative bilaterally injected sclerae, erythematous pharynx and irritability.

Wondering about the possibility of Kawasaki Disease, I turned to check the 2017 update of the American Heart Association Scientific Statement, focusing on considering a diagnosis of Incomplete Kawasaki Disease.

 

Bottom line:

  • Unchanged diagnostic criteria of complete Kawasaki Disease (KD)
  • Refined algorithm for evaluation of suspected incomplete KD (15-20% of cases)
  • Recommended ECHO at diagnosis, and repeated at 1-2 weeks and 4-6 weeks after treatment
  • Unchanged acute management– Intravenous immunoglobulin (IVIG) single dose 2g/kg over 10-12 hours. Ideally prior to day 10. Some countries continue to use high dose aspirin for varying durations.
  • Additional therapeutic options are outlined for the 10-20% with persistent or recurrent fever
  • New model of KD vasculopathy

 

What is Kawasaki Disease?

An acute, self-limited febrile illness of unknown cause, predominantly in children <5 years. It is the most common cause of acquired heart disease in developed countries. Without pathognomonic tests, we need to detect it clinically!

 

Epidemiology

  • Most common in Japan (where it was first described) with an annual incidence of 264.8 per 100 000 children in 2012. The estimated incidence in North America is 25 cases per 100 000 children <5 years of age per year. Australia has one of the lowest reported rates (3.7 per 100 000 <5 years of age), equivalent to 50–60 cases Australia-wide per year. It is likely that the current Australian incidence is higher.
  • Highest relative risk is in Asian children, especially of Japanese ancestry
  • The ratio of males to females is 1.5:1
  • Predominantly affects children 6 months to 4 years
  • Predisposing factors have been reported inconsistently
  • In Japan, the recurrence rate is 3%, and the relative risk in siblings is ten-fold higher

 

What is the aetiology?

We have no idea why…. BUT the resultant systemic inflammation leads to associated clinical findings: liver (hepatitis), lung (interstitial pneumonitis), gastrointestinal tract (abdominal pain, vomiting, diarrhoea, gallbladder hydrops), meninges (aseptic meningitis, irritability), heart (myocarditis, pericarditis, valvulitis), urinary tract (pyuria), pancreas (pancreatitis), and lymph nodes (lymphadenopathy).

A new model of Kawasaki disease vasculopathy involves three processes impacting muscular arteries. The first is a necrotising arteritis, followed by subacute/chronic vasculitis. The final process is luminal myofibroblastic proliferation.

 

How do we diagnose it in Australia?

Diagnostic Criteria

Fever for 5 days or more (typically high spiking (>39°C to 40°C) and remittent)

Plus 4/5 of:

  • polymorphous rash (usually within 5 days of fever onset)
  • bilateral (non-purulent) conjunctival injection (usually begins shortly after fever onset and often spares the limbus, an avascular zone around the iris)
  • mucous membrane changes e.g. reddened or dry cracked lips, strawberry tongue, diffuse redness of oral or pharyngeal mucosa (oral ulcers and pharyngeal exudates are not consistent with KD)
  • peripheral changes, e.g. erythema of the palms or soles, oedema of the hands or feet, and in convalescence desquamation
  • cervical lymphadenopathy (> 15 mm diameter, usually unilateral, single, non-purulent and painful in the anterior cervical chain)

AND exclusion of diseases with a similar presentation

  • Staphylococcal infection (e.g. scalded skin syndrome, toxic shock syndrome)
  • Streptococcal infection (e.g. scarlet fever, toxic shock-like syndrome not just isolation from throat)
  • Measles
  • Viral exanthems
  • Steven’s Johnson syndrome
  • Drug reactions
  • Juvenile rheumatoid arthritis.

Trickily, these children may have a concurrent viral infection, often adenovirus. Adenovirus is more likely with exudative pharyngitis and conjunctivitis and positive PCR assay. Kawasaki disease is more likely with erythema/swelling of hands and feet, a strawberry tongue, and a desquamating groin rash.

Inflammation and crusting of a recent Bacille-Calmette-Guérin (BCG) injection site may occur.

Consider an alternative diagnosis to Kawasaki Disease if there is exudative conjunctivitis, exudative pharyngitis, ulcerative intraoral lesions, bullous or vesicular rash, generalized adenopathy, or splenomegaly.

 

What is Incomplete Kawasaki Disease?

Scarily, this is so easily missed. They make up 15-20% of all cases!!
Patients with incomplete KD, particularly those <6 months of age and older children, may experience significant delays in diagnosis and these children are at high risk of developing coronary artery abnormalities.

Consider KD if:

  • Infants <6 months old with prolonged fever and irritability
  • Infants with prolonged fever and unexplained aseptic meningitis
  • Infants or children with prolonged fever and unexplained or culture-negative shock
  • Infants or children with prolonged fever and cervical lymphadenitis unresponsive to antibiotic therapy
  • Infants or children with prolonged fever and retropharyngeal oroparapharyngeal phlegmon unresponsive to antibiotic therapy

Evaluation of suspected incomplete Kawasaki disease (via McCrindle BW et al. 2017)

What can we investigate?

As suggested by RCH Melbourne guidelines, all patients should have

  • ASOT / Anti DNAase B
  • Echocardiography (at least twice: at initial presentation and, if negative, again at 6 – 8 weeks).
  • Platelet count (marked thrombocytosis common in the second week of illness)
  • Consider Mycoplasma

In addition, findings can provide support when considering Incomplete Kawasaki Disease – refer to the above algorithm.

Evolution of laboratory findings via Tremoulet et al.

  • KD is unlikely if ESR, CRP, and platelet count are normal after day 7 of illness.
  • Low WBC and lymphocyte predominance suggests an alternative diagnosis
  • Leukocytosis is typical in the acute stage, with granulocyte predominance
  • Normocytic, normochromic anaemia is common during inflammation
  • CRP and ESR elevation is nearly universal, CRP normalizes more quickly with inflammation resolution. ESR is elevated by IVIG therapy.
  • Minimally elevated ESR in the setting of severe clinical disease should prompt investigation for disseminated intravascular coagulation.
  • Thrombocytosis is a characteristic feature that generally doesn’t occur until the second week, peaking in the third week, normalizing by 4 to 6 weeks
  • Thrombocytopenia can be a sign of disseminated intravascular coagulation and is a risk factor for the development of coronary artery abnormalities
  • Mild to moderate elevations in serum transaminases or gammaglutamyl transpeptidase occur in 40% to 60% of patients, and mild hyperbilirubinemia occurs in ≈10%.
  • Hypoalbuminaemia is common and associated with more severe and more prolonged acute disease
  • Urinalysis may show pyuria in up to 80% of children, non-specific for KD
  • In children who undergo lumbar puncture, ≈30% demonstrate pleocytosis with a mononuclear cell predominance, normal glucose levels, and generally normal protein levels

 

Pitfalls

Fever and pyuria in an infant or young child may be diagnosed as a urinary tract infection, with subsequent development of rash, red eyes, and red lips attributed to an antibiotic reaction. Irritability and a culture-negative pleocytosis of the cerebrospinal fluid in an infant with prolonged fever suggestive of aseptic meningitis (or if antibiotics have been given, partially treated meningitis) may cause a diagnosis of KD to be overlooked. Cervical lymphadenitis as the primary clinical manifestation can be misdiagnosed as having bacterial adenitis. Gastrointestinal symptoms are considered for surgical causes, other physical findings of KD can be overlooked.

 

What is the treatment?

We’re aiming to prevent important coronary artery abnormalities. Timely (as soon as possible, ideally within 10 days) IVIG treatment reduces the incidence of coronary artery aneurysms (defined from absolute luminal dimensions) from 25% to 4%. Studies with additional therapies to IVIG have not substantially reduced this residual risk of 4%. Adverse effects are rare but include Coomb’s positive haemolytic anaemia and aseptic meningitis. The measles, mumps, and varicella vaccine should be deferred for 11 months unless at high risk (seek advice, may need repeat vaccination). If the diagnosis is delayed, IVIG should still be given (after the tenth day of illness) IF there is presence of fever, or continued elevation of ESR or CRP>3, indicating ongoing inflammation. Aspirin is used with the theoretical rationale of reducing coronary artery aneurysms (although there is no well-established evidence for this). In Australia, a dose of 3-5mg/kg daily from diagnosis until cardiology review at 6 weeks is routine. The newly released statement advises the administration of moderate to high-dose (80–100 mg/kg/day) aspirin is reasonable until the patient is afebrile. Patients should receive a seasonal influenza vaccination.

Fever usually resolves within 36 hours after IVIG infusion has been completed; if not, the patient is considered to have resistance to IVIG. 10-20% of patients will not respond to the single IVIG treatment dose. There is minimal data to support therapeutic agents for the child with IVIG resistance. Repeating the IVIG dose, 3 days of high-dose pulsed steroids, or 2-3 weeks of tapering prednisolone are all options. There are lower levels of evidence for infliximab and cyclosporine.

 

Coronary artery abnormalities

An angiographic study of 1100 patients showed coronary artery lesions in 24%, with aneurysms in 8% and a number of patients with stenoses and occlusions. Valvular regurgitation is usually mild to moderate in severity and resolves prior to follow-up. MR can occur after the acute stage from myocardial ischaemia. Patients after KD have been shown to have functional and anatomic abnormalities of the aorta with unknown long-term implications. Myocarditis is common during the acute illness but complete resolution is expected. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up.

 

What is the prognosis?

  1. The case fatality rate is <0.1% in Japan, virtually all from cardiac sequelae.
  2. Peak mortality occurs 15 to 45 days after onset of fever, during which time well-established coronary artery vasculitis occurs concomitantly with marked elevation of the platelet count and a hypercoagulable state
  3. Coronary artery aneurysms from KD account for 5% of acute coronary syndromes (ACS) in adults <40 years of age

 

In Summary:

  • Be aware of the diagnostic criteria of complete Kawasaki Disease (KD)
  • Highest relative risk in Asian children, especially Japanese ancestry
  • Always consider incomplete KD (15-20% of cases) and refer to the algorithm if concerns, there are pitfalls!
  • Liaise with cardiology regarding an ECHO
  • Unchanged acute management– Intravenous immunoglobulin (IVIG) single dose 2g/kg over 10-12 hours. Ideally prior to day 10. Some countries continue to use high dose aspirin for varying durations.
  • Additional therapeutic options are outlined for the 10-20% with persistent or recurrent fever, minimal evidence for these
  • New model of KD vasculopathy but we are still in the dark regarding aetiology
  • Coronary artery aneurysms from KD account for approximately 5% of acute coronary syndromes (ACS) in adults <40 years of age

 

 Selected references

McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation2017;Mar 29

Yim D, Curtis N, Cheung M, Burgner D. Update on Kawasaki disease: Epidemiology, aetiology and pathogenesis. Journal of Paediatrics and Child Health 49 (2013) 704–708

Clinical Practice Guidelines, Royal Children’s Hospital, Melbourne

Kim DS, Kawasaki Disease. Yonsei Medical Journal. 47 (2006) (6): 759–72. PMC 2687814 PMID 17191303. doi:10.3349/ymj.2006.47.6.759

Yim D, Curtis N, Cheung M, Burgner D. An update on Kawasaki disease II: Clinical features, diagnosis, treatment and outcomes. Journal of Paediatrics and Child Health 49 (2013) 614–623

Tremoulet AH, Jain S, Chandrasekar D, Sun X, Sato Y, Burns JC. Evolution of laboratory values in patients with Kawasaki disease. Pediatr Infect Dis J. 2011;30:1022–1026

Dengler LD, Capparelli EV, Bastian JF, Bradley DJ, Glode MP, Santa S, Newburger JW, Baker AL, Matsubara T, Burns JC. Cerebrospinal fluid profile in patients with acute Kawasaki disease. Pediatr Infect Dis J. 1998;17:478–481