COVID-19-associated multisystem inflammatory syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Harmeet Kharoud M.D.[2] José Eduardo Riceto Loyola Junior, M.D.[3] Sahar Memar Montazerin, M.D.[4]

Synonyms and keywords: Multisystem Inflammatory Syndrome in Children (MIS-C)

Overview

COVID-19-associated multisystem inflammatory syndrome (also known as PIMS-TS - pediatric inflammatory multisystem syndrome temporally with SARS-CoV2 infection or MIS-C - multisystem inflammatory syndrome in children) is an uncommon clinical entity caused by SARS-CoV2 and seen mostly on children. It presents with: fever > 3 days and elevated markers of inflammation and 2 of the following 5 criteria: rash or conjunctivitis; hypotension or shock; myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities; evidence of coagulopathy and/or acute gastrointestinal problems along with evidence of COVID-19. It seems to be a severe form of COVID-19 in children presenting with symptoms that can be challenging to differentiate from other pediatric infectious diseases such as toxic shock syndrome and Kawasaki disease. The pathophysiology of this form of SARS-CoV2 infection remains unknown.

Historical Perspective

  • Reports of a new febrile pediatric entity began to appear in late April 2020 during the COVID-19 pandemic in Western Europe, characterized by systemic hyper inflammation, abdominal pain with gastrointestinal symptoms and multiorgan involvement affecting especially the myocardium causing cardiogenic shock which reminded the physicians of Kawasaki disease;[1]
  • Cases of children with such symptoms were quickly identified in the New York City area, which was then the most heavily affected city in the U.S. by the COVID-19 pandemic;[1]
  • A report of 8 cases from Evelina London Children's Hospital was published on 6 May 2020, showing very prominent markers of inflammation such as ferritin, D-dimers, triglycerides, elevated cardiac enzymes, high NT-pro-BNP levels and troponin, being empirically treated with IVIG;[1]
  • In 22 May, an article from the Journal of Pediatric Infectious Diseases Society addressed some of the similarities and differences of this new entity with Kawasaki's disease, noting that the demographics affected was significantly different, as it was not seen in Asia despite the pandemic also affecting such countries, but it was affecting mostly children of African ethnicity. The author also differentiated some of the laboratory findings, resembling the macrophage activation syndrome and not Kawasaki's disease.[1]

Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome

  • There is no established system for the classification of COVID-19-associated multisystem inflammatory syndrome.

Pathophysiology

  • The exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear.
  • Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and COVID-19 infection (median time: 25 days)[2] it is suspected to be a post-infectious phenomenon related to IgG antibody-mediated enhancement of disease. There are two arguments that support this theory: the presence of IgG antibodies against SARS-CoV2 and the presence of the lag time between COVID-19 symptoms and COVID-19-associated multisystem inflammatory syndrome.[3]
  • There is, however, another theory that states that it is still an acute viral presentation of the disease due to the fact that children presenting with such symptoms undergone exploratory laparotomy which found mesenteric adenitis, supporting GI infection. SARS-CoV2 is also known to easily infect enterocytes. Another interesting point to consider is that the worsening of illness has not been seen in patients with COVID-19 who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.[3]
  • There is another hypothesis for the cytokine storm seen on children with COVID-19-associated multisystem inflammatory syndrome is originated from the known ability of coronaviruses to block type I and type III interferon responses, delaying the cytokine storm in patients that could not control the viral replication on earlier phases of the disease.[3]

Differentiating Any Disease from other disease

Summary of laboratory parameters of a COVID-19-associated multisystem inflammatory syndrome cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome[4]
Parameters COVID-19-associated multisystem inflammatory syndrome (PIMS-TS) Kawasaki Disease (KD) Kawasaki Disease Shock (KDS) Toxic Shock Syndrome (TSS)
Age (median, IQR) 9 (5.7-14) 2.7 (1.4-4.7) 3.8 (0.2-18) 7.38 (2.4-15.4)
Total white cell count (*10^9/L) 17 (12-22) 13.4 (10.5-17.3) 12.1 (7.9-15.5) 15.6 (7.5-20)
Neutrophil count (*10^9/L) 13 (10-19) 7.2 (5.1-9.9) 5.5 (3.2-10.3) 16.4 (12-22)
Lymphocyte count (*10^9/L) 0.8 (0.5-1.5) 2.8 (1.5-4.4) 1.6 (1-2.5) 0.63 (0.41, 1.13)
Hemoglobin (g/L) 92 (83-103) 111.0 (105-119) 107 (98-115) 114 (98-130)
Platelet number (10^9/L) 151 (104-210) 365.0 (288-462) 235 (138-352) 155 (92- 255)
C-reactive protein (mg/L) 229 (156-338) 67.0(40-150) 193 (83-237) 201 (122, 317)
ALT (IU/L) 42 (26-95) 42.0 (24-112) 73 (34-107) 30.00 (22.10, 49.25)
Albumin (g/L) 24 (21-27) 38.0 (35-41) 30 (27-35) 27.00 (21.00, 31.00)
Ferritin (ug/L) 610 (359-1280) 200 (143-243) 301 (228-337) -
NT-Pro-BNP (pg/ml) 788 (174-10548) 41 (12-102) 396 (57-1520) -
Troponin (ng/L) 45 (8-294) 10.0 (10-20) 10 (10-30) -
D-dimer (ng/ml) 3578 (2085- 8235) 1650 (970-2660) 2580 (1460- 2990) -

Epidemiology and Demographics

  • Poor prognostic factors include age over 5 years and ferritin larger than 1400 µg/L.[7]

Age

  • Children aged age over 5 years seem to have a worse prognosis than younger ones.[7]
  • The median age found out in a study published by JAMA was 9 years.[4]

Gender

  • Most of the cases, estimated in two thirds, seem to happen in boys.[5][4]

Race

  • It seems to affect predominantly blacks and asians.[4][5]

Comorbidities

  • Clinical evidence of association with underlying diseases is still scarce since it is a rare presentation of COVID-19 in children and teenagers.[8]

Natural History, Complications, and Prognosis

Complications of COVID-19-associated multisystem inflammatory syndrome include:[9][10][11][12][13][14]

  • Ventricular dysfunction
  • Coronary artery changes
  • Atrioventricular valve regurgitation
  • Pericardial effusions
  • Shock
  • venous thromboembolic events
  • Cytokine storm syndrome

Diagnosis

Diagnostic Criteria

The table below describes various diagnostic criteria for COVID-19-associated multisystem inflammatory syndrome:[15][16][17]

Features World Health Organization  

Criteria

Royal College of Paediatrics and Child Health

(United Kingdom)  Criteria

Centers for Disease Control and Prevention

(United States)  Criteria

Age
  • 0-19 years old
  • Not specified
  • Younger than 21 years old
Clinical Features
  • Fever lasting more than 3 days
  • Persistent fever
  • Fever (body temperature, >38.0°C) or report of subjective fever present at least 24 hours
  • More than 2 of the followings:
  • Evidence of single or multi-organ involvement
  • Severe disease course leading to hospitalization
1. Rash or non-purulent conjunctival injection or mucocutaneous involvement
  • Multisystem organ involvement (at least two systems)
2. Low blood pressure/Shock
3. Findings consistent with myocarditis, pericarditis, valvulitis or coronary involvement
4. Acute gastrointestinal symptoms
Laboratory Findings 5. Laboratory evidence of coagulopathy
  • Laboratory evidence of inflammation
  • Laboratory evidence of inflammation
  • Laboratory evidence of inflammation
Diagnosis of SARS-CoV-2
  • Laboratory-confirmed SARS-CoV-2 infection
  • A history of COVID-19 exposure
  • Positive/Negative SARS-Cov-2 test
  • Laboratory-confirmed SARS-CoV-2 infection
  • A history of COVID-19 exposure within the 4 weeks prior to the onset of symptoms  
Others
  • Absence of other possible cause
  • Exclusion of other possible cause
  • Absence of other diagnoses

History and Symptoms

COVID-19 associated multisystem inflammatory syndrome is associated with the following symptoms:[15][14]

Physical Examination

COVID-19 associated multisystem inflammatory syndrome is associated with the following physical examination findings:[15]

Laboratory Findings

COVID-19 associated multisystem inflammatory syndrome is associated with the following laboratory findings:[15][18]

Less common laboratory findings include:

Inflammatory biomarkers

Elevation of inflammatory markers including ESR, C reactive protein, and procalcitonin are usually seen in MIS-C. Increased level of Interleukin-6 (IL-6), Interleukin-10(IL-10) d-dimer, serum ferritin, prothrombin time have also been seen in MIS-C.

Cardiac biomarkers

Elevation of cardic enzymes including cardiac troponins (cardiac troponin I(cTnI) and cardiac troponin T (cTnT)) and Brain natriuretic peptide (BNP)) has been observed in MIS-C patients.

  • To view the complete physical examination in COVID-19, click here.
  • To view the laboratory findings on COVID-19, click here.

X-ray

X-ray of patients with COVID-19 associated multiorgan system inflammatory syndrome may be normal. When abnormal, findings may include the followings:[19]

  • Peribronchial cuffing
  • Perihilar interstitial thickening
  • Perihilar opacification
  • Perihilar consolidation
  • Low volume pleural effusion affecting both lungs
  • Left lower lobe atelectasis

Echocardiography or Ultrasound

Abdominal ultrasound imaging of patients with COVID-19 associated multiorgan system inflammatory syndrome may include the following findings:[19]

  • Free-fluid
  • Localised inflammatory change within the right iliac fossa
  • A combination of echogenic expanded mesenteric fat and enlarged lymph nodes
  • Bowel wall thickening of parts of ileum and cecum
  • Gall bladder wall thickening and edema

To view the echocardiographic findings on COVID-19, click here.

CT scan

Chest CT scan of patients with COVID-19-associated multisystem inflammatory syndrome includes the following patterns:[19]

  • Consolidation and collapse of the lung bases
  • Pleural effusions
  • Diffuse bilateral ground-glass opacities with dense, patchy consolidation

Abdominal CT scan may show the following abnormalities:

  • Intestinal wall thickening particularly in terminal ileum and cecum

To view the CT scan findings on COVID-19, click here.

MRI

Other Imaging Findings

  • To view other imaging findings on COVID-19, click here.

Other Diagnostic Studies

  • To view other diagnostic studies for COVID-19, click here.

Treatment

Medical Therapy

Treatment of patients with COVID-19-associated multisystem inflammatory syndrome includes:[14]

  • Antibiotics: broad-spectrum antibiotics are recommended initially.
    • If the symptoms are mild, ceftriaxone may be sufficient.
    • If the gastrointestinal symptoms are predominant, then metronidazole is recommended.
    • In case of severe symptoms including shock the following antibiotics have been recommended:
      • Vancomycin, clindamycin, and cefepime
      • Vancomycin, meropenem, and gentamicin
  • Remdesivir is indicated in children with PCR positive COVID-19 and/or with a presentation consistent with typical COVID-19.
    • It should be administered 5 mg/kg loading dose IV once (max dose 200 mg) on day 1, then 2.5 mg/kg (100 mg max dose) IV daily for nine days.
  • Cardiac and respiratory support is recommended for patients presenting with shock.
  • IVIG and aspirin for Kawasaki-like disease
    • IVIG 2 g/kg for all patients with
    • Aspirin 20–25 mg/kg/dose every 6 h (80–100 mg/kg/day) for all patients with

Patients with KD-like illness in high-risk categories should receive IVIG with other agents. The high-risk category includes:

  • Infants
  • Those with KD shock syndrome
  • Those with CRP > 130 g/dL
  • Those with admission echo Z score > 2.5 or aneurysms
  • Asian race

The following treatment regimen is recommended for patients with KD-like illness in high-risk categories:

  • IVIG 2 g/kg as a single infusion with three-day pulse methylprednisolone. If fails, then:
  • The second dose of IVIG or infliximab (a Tumor necrosis factor (TNF)-alpha inhibitor)
  • VTE prophylaxis may be indicated as well.
  • Few studies have reported that interleukin-1 inhibitors may be effective in the treatment of severe cases.[20]
  • Tocilizumab (interleukin-6 inhibitor) is another agent that has been used in some cases.

Prevention

  • MIS-C can be prevented by reducing the risk of child exposure to COVID-19 infection.

References

  1. 1.0 1.1 1.2 1.3 Shulman, Stanford T. "Pediatric coronavirus disease-2019–associated multisystem inflammatory syndrome." Journal of the Pediatric Infectious Diseases Society (2020).
  2. 2.0 2.1 Feldstein, Leora R., et al. "Multisystem inflammatory syndrome in US children and adolescents." New England Journal of Medicine (2020).
  3. 3.0 3.1 3.2 Rowley, Anne H. "Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children." Nature Reviews Immunology (2020): 1-2.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Whittaker E, Bamford A, Kenny J, et al; PMIS-TS Study Group; EUCLIDS and PERFORM Consortia. Clinical and laboratory characteristics of 58 children with a pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2. JAMA. doi:10.1001/jama.2020.10369
  5. 5.0 5.1 5.2 Riphagen, Shelley, et al. "Hyperinflammatory shock in children during COVID-19 pandemic." The Lancet 395.10237 (2020): 1607-1608.
  6. Cheung, Eva W., et al. "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City." JAMA (2020).
  7. 7.0 7.1 Pouletty, Marie, et al. "Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort." Annals of the Rheumatic Diseases (2020).
  8. "World Health Organization - Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19". WHO. 07/13/2020. Check date values in: |date= (help)
  9. Riphagen, Shelley; Gomez, Xabier; Gonzalez-Martinez, Carmen; Wilkinson, Nick; Theocharis, Paraskevi (2020). "Hyperinflammatory shock in children during COVID-19 pandemic". The Lancet. 395 (10237): 1607–1608. doi:10.1016/S0140-6736(20)31094-1. ISSN 0140-6736.
  10. DeBiasi, Roberta L.; Song, Xiaoyan; Delaney, Meghan; Bell, Michael; Smith, Karen; Pershad, Jay; Ansusinha, Emily; Hahn, Andrea; Hamdy, Rana; Harik, Nada; Hanisch, Benjamin; Jantausch, Barbara; Koay, Adeline; Steinhorn, Robin; Newman, Kurt; Wessel, David (2020). "Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region". The Journal of Pediatrics. doi:10.1016/j.jpeds.2020.05.007. ISSN 0022-3476.
  11. Verdoni, Lucio; Mazza, Angelo; Gervasoni, Annalisa; Martelli, Laura; Ruggeri, Maurizio; Ciuffreda, Matteo; Bonanomi, Ezio; D'Antiga, Lorenzo (2020). "An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study". The Lancet. 395 (10239): 1771–1778. doi:10.1016/S0140-6736(20)31103-X. ISSN 0140-6736.
  12. Belhadjer, Zahra; Méot, Mathilde; Bajolle, Fanny; Khraiche, Diala; Legendre, Antoine; Abakka, Samya; Auriau, Johanne; Grimaud, Marion; Oualha, Mehdi; Beghetti, Maurice; Wacker, Julie; Ovaert, Caroline; Hascoet, Sebastien; Selegny, Maëlle; Malekzadeh-Milani, Sophie; Maltret, Alice; Bosser, Gilles; Giroux, Nathan; Bonnemains, Laurent; Bordet, Jeanne; Di Filippo, Sylvie; Mauran, Pierre; Falcon-Eicher, Sylvie; Thambo, Jean-Benoît; Lefort, Bruno; Moceri, Pamela; Houyel, Lucile; Renolleau, Sylvain; Bonnet, Damien (2020). "Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic". Circulation. doi:10.1161/CIRCULATIONAHA.120.048360. ISSN 0009-7322.
  13. Klok, F.A.; Kruip, M.J.H.A.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.A.M.; Huisman, M.V.; Endeman, H. (2020). "Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis". Thrombosis Research. 191: 148–150. doi:10.1016/j.thromres.2020.04.041. ISSN 0049-3848.
  14. 14.0 14.1 14.2 Hennon, Teresa R.; Penque, Michelle D.; Abdul-Aziz, Rabheh; Alibrahim, Omar S.; McGreevy, Megan B.; Prout, Andrew J.; Schaefer, Beverly A.; Ambrusko, Steven J.; Pastore, John V.; Turkovich, Stephen J.; Gomez-Duarte, Oscar G.; Hicar, Mark D. (2020). "COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach". Progress in Pediatric Cardiology. 57: 101232. doi:10.1016/j.ppedcard.2020.101232. ISSN 1058-9813.
  15. 15.0 15.1 15.2 15.3 Feldstein, Leora R.; Rose, Erica B.; Horwitz, Steven M.; Collins, Jennifer P.; Newhams, Margaret M.; Son, Mary Beth F.; Newburger, Jane W.; Kleinman, Lawrence C.; Heidemann, Sabrina M.; Martin, Amarilis A.; Singh, Aalok R.; Li, Simon; Tarquinio, Keiko M.; Jaggi, Preeti; Oster, Matthew E.; Zackai, Sheemon P.; Gillen, Jennifer; Ratner, Adam J.; Walsh, Rowan F.; Fitzgerald, Julie C.; Keenaghan, Michael A.; Alharash, Hussam; Doymaz, Sule; Clouser, Katharine N.; Giuliano, John S.; Gupta, Anjali; Parker, Robert M.; Maddux, Aline B.; Havalad, Vinod; Ramsingh, Stacy; Bukulmez, Hulya; Bradford, Tamara T.; Smith, Lincoln S.; Tenforde, Mark W.; Carroll, Christopher L.; Riggs, Becky J.; Gertz, Shira J.; Daube, Ariel; Lansell, Amanda; Coronado Munoz, Alvaro; Hobbs, Charlotte V.; Marohn, Kimberly L.; Halasa, Natasha B.; Patel, Manish M.; Randolph, Adrienne G. (2020). "Multisystem Inflammatory Syndrome in U.S. Children and Adolescents". New England Journal of Medicine. doi:10.1056/NEJMoa2021680. ISSN 0028-4793.
  16. "Guidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) | RCPCH".
  17. Cheung, Eva W.; Zachariah, Philip; Gorelik, Mark; Boneparth, Alexis; Kernie, Steven G.; Orange, Jordan S.; Milner, Joshua D. (2020). "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City". JAMA. doi:10.1001/jama.2020.10374. ISSN 0098-7484.
  18. 19.0 19.1 19.2 Hameed, Shema; Elbaaly, Heba; Reid, Catriona E. L.; Santos, Rui M. F.; Shivamurthy, Vinay; Wong, James; Jogeesvaran, K. Haran (2020). "Spectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19". Radiology: 202543. doi:10.1148/radiol.2020202543. ISSN 0033-8419.
  19. Shah, Satish K.; Munoz, Alvaro Coronado (2020). "Multisystem Inflammatory Syndrome in Children in COVID-19 Pandemic". The Indian Journal of Pediatrics. doi:10.1007/s12098-020-03440-7. ISSN 0019-5456.