We're talking about the little adults today! In particular, we're diving into the reported Multi-System Inflammatory Syndrome/Kawasaki Disease that has been reported in association with COVID-19 in kids.

 

COVID in Peds: what we know

• Epidemiology
  • Infection rates are generally low: children seem to account for 1-5% of confirmed cases1
  • Only about 1% of cases in Canada seem to be in those < 19 years2 (though testing was previously not available to those with mild illness)
  • Seems to be distributed reasonably evenly among age groups3
• Presentations
  • Symptoms are similar to adults; cases are generally mild3,4,5
  • Fever and cough are most commonly reported3,4,5
  • Reports of causing isolated fever in young infants6
• Investigations
  • Lab data seems variable; only 3.5% had lymphopenia in one study7
  • CXR: similar to adults; may be normal or may demonstrate patchy consolidations4
  • POCUS: similar to adults à irregular pleura, patchy B-lines8
• Treatment
  • Supportive care!
  • Antivirals generally recommended only in the context of clinical trials9
    • For severe/critical disease, if used, panel recommends remdesivir over others9
  • Severity and outcomes
    • Most children have mild disease and do well: in one case series of over 700 pediatric cases from China, 55% were mild or asymptomatic, 40% were moderate, 5% were severe, and <1% were critical10
    • Small number of children have been identified who develop a significant systemic inflammatory response
      • This has features that overlap with other paediatric inflammatory conditions including Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis and macrophage activation syndrome

 

Kawasaki Disease11

• KD: childhood vasculitis characterized by systemic inflammation and fever
• Classic KD
  • Fever for > 5 days PLUS
  • 4 of 5: conjunctival injection, peripheral extremity changes such as desquamation, edema, or erythema; mucous membrane changes such as strawberry tongue or injected pharynx; polymorphous rash; cervical lymphadenopathy
• Complications
  • Primarily cardiac, including coronary artery aneurysm
  • Can rarely be associated with macrophage activation syndrome and shock
• Treatment
  • IVIG and ASA
• Cause?
  • Association with respiratory viruses? A retrospective chart review of 222 patients with KD found that 42% tested positive for a viral respiratory infection; most commonly rhinovirus or enterovirus12
    • No differences in presenting features or clinical outcomes in this compared to those who did not test positive

  

MIS-C and COVID-associated KD?

• There is very little published research on this topic
  • One case report of a 6-month old girl presenting with classic KD, without respiratory symptoms, whose swab was positive for COVID. She was treated with IVIG and high-dose ASA (standard KD Tx)13
  • One series of infographics from out of NYC14
  • A couple guideline statements and media releases on the basis on expert anecdotal experience15,16
  • A couple recent case series: one from the UK, one from Bergamo17,18
• This is what we seem to know from guideline statements:
  • There has been a small rise in the number of cases of critically ill children presenting with an unusual clinical picture
    • Many of these children had tested positive for COVID-19 previously, and are now presenting with common overlapping features of toxic shock syndrome, Kawasaki disease, and MAS
  • Presenting symptoms
    • Prolonged fever (>5 days, >38.5 degrees)
    • GI symptoms: severe abdominal pain, nausea, diarrhea, vomiting
    • Conjunctival injection
    • Maculopapular rash
    • Other: cyanosis or pallor, dysphagia, dyspnea, palpitations, tachycardia, chest pain, lethargy, irritability, confusion
  • Lab abnormalities
    • Inflammatory markers: high CRP, ESR, ferritin; hypoalbuminemia
      • High IL-6 and IL-10 (if available)
    • Lymphopenia
    • Coagulopathy: high D-dimer, high fibrinogen
    • Cardiac involvement: elevated troponin/BNP (sometimes)
    • May be present: AKI, high CK, transaminitis, high trigs
  • Imaging features (may be present in some cases)
    • EKG: changes consistent with myopericarditis
    • Echo: coronary artery dilation; pericardial effusion
    • CXR: patchy symmetrical infiltrates; may have pleural effusion
    • Abdo US: HSMG, ileitis, colitis, ascites
  • Treatment recommendations
    • Early consultation with multiple specialists (peds ID, Rheum, Cardio, Crit Care)
    • Early antibiotics if appropriate in accordance with sepsis protocols
    • IVIG if meets KD or toxic shock criteria
    • ASA if meets KD criteria
    • COVID-specific:
      • Supportive care
      • Antivirals only in the context of clinical trials
      • Immunomodulatory therapy in discussion with subspecialists
    • More details from the NYC media releases: 82 cases on day of release (May 13)14
      • Relationship to COVID
        • 60% of kids test positive for COVID PCR, 40% test positive for COVID antibodies (and 14% are positive for both)
      • Severity of illness: 71% admitted to ICU, 19% intubated
        • 71% admitted to ICU
        • 19% intubated
      • Seen in most age groups: few cases < 1yr; most in age 5-9 and 10-14
    • UK series17
      • 8 children with overlapping features of KD/KD shock syndrome/TSS
        • 1 death from a large cerebral infarct while on ECMO; others discharged
      • All previously well
      • All had no respiratory symptoms, but 7 required mechanical ventilation for cardiovascular stabilization
      • All initially tested negative for COVID; 2 tested positive post-discharge
    • Bergamo series18
      • Retrospective review of KD cases before vs after COVID
      • Found that the monthly incidence was 30x greater than the historical average since the COVID pandemic (0.3 vs 10 cases per month)
      • 10 cases identified; compared to historical cases (19 in previous 5-year period)
        • Older on average (7yrs vs 3.5yrs)
        • More cardiac involvement (60% vs 10%)
        • More severe disease: 50% met criteria for KD-shock syndrome or MAS (compared to 0% of controls)
        • More were treated with adjunctive steroid therapy (80% vs 16%)
      • Relationship to COVID
        • 2 had positive RT-PCR, but 8 had positive IgG to COVID – previous exposure
      • Overall, there have still been very few cases of critically unwell children with COVID-19

  

Sources

1. Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088. doi:10.1111/apa.15270
2. Canada COVID-19 situational awareness dashboard. Ottawa, ON: Public Health Agency of Canada; 2020. Available from: https://phac-aspc.maps.arcgis.com/apps/opsdashboard/index.html#/e968bf79f4694b5ab290205e05cfcda6. Accessed 2020 May 17.
3. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422. Apr 2020. doi:10.15585/mmwr.mm6914e4
4. Lu X, Zhang L, Du H et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663. Mar 2020. doi:10.1056/NEJMc2005073
5. Parri N, Lenge M, Buonsenso D et al. Children with Covid-19 in Pediatric Emergency Departments in Italy. New Eng J Med, May 2020. doi:10.1056/NEJMc2007617
6. Paret M, Lighter J, Pellett Madan R et al. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress. Clin Infect Dis, Apr 2020. doi:10.1093/cid/ciaa452
7. Jiang M, Guo Y, Luo Q et al. T cell subset counts in peripheral blood can be used as discriminatory biomarkers for diagnosis and severity prediction of COVID-19. J Infect Dis, May 2020. doi:10.1093/infdis/jiaa252
8. Denina M, Scolfaro C, Silvestro E et al. Lung Ultrasound in Children With COVID-19. Pediatrics, May 2020. doi:10.1542/peds.2020-1157
9. Chiotos K, Hayes M, Kimberlin DW et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc, Apr 2020. doi:10.1093/jpids/piaa045
10. Dong Y, Mo X, Hu Y et al. Epidemiology of COVID-19 Among Children in China. Pediatrics, Mar 2020. doi:10.1542/peds.2020-0702
11. Kawasaki disease: clinical features and diagnosis. UpToDate. Updated Dec 2019.
12. Turnier JL, Anderson MS, Heizer HR et al. Concurrent Respiratory Viruses and Kawasaki Disease. Pediatrics, 2015 Sep;136(3):e609-14. doi:10.1542/peds.2015-0950
13. Jones VG, Mills M, Suarez D et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020; doi:10.1542/hpeds.2020-0123
14. Twitter, @MarkLevineNYC. May 13 2020. https://twitter.com/MarkLevineNYC/status/1260579970138636289
15. Paediatric Intensive Care Society (PICS) Statement. Increased number of reported cases of novel presentation of multisystem inflammatory disease. Apr 2020. https://picsociety.uk/news/pics-statement-regarding-novel-presentation-of-multi-system-inflammatory-disease/
16. Royal College of Paediatrics and Child Health (RCPH). Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. May 2020. https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19
17. Riphagen S, Gomez X, Gonzalez-Martinez C et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet, May 2020. doi:10.1016/S0140-6736(20)31094-1
18. Verdoni, L., Mazza, A., Gervasoni A et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet, May 2020. doi:10.1016/ S0140-6736(20)31129-6