https://orcid.org/0000-0003-2151-7327
Abstract
To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support.
This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease.
Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease.
Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.
Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease.
Risk factors were identified predominantly during the disease course, not during admission, highlighting the need for careful monitoring.
Patients with MIS-C presenting with a Kawasaki-like phenotype were less likely to require inotropic support.
Introduction
In children and adolescents, SARS-CoV-2 infection generally leads to mild, self-limited respiratory symptoms, compared with more severe forms reported in adults. However, rare severe and fatal outcomes from direct SARS-CoV-2 infection were reported in paediatric series [1, 2].
Children with Kawasaki disease (kDa) and concurrent COVID-19 were first reported in the United States and the United Kingdom during April 2020 [3, 4]; these were followed by multiple additional reports [5–10]. The clinical picture resembled kDa, but with discrete features. Eventually, this resulted in the description of a new syndrome named paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in Europe, and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, in the USA [11, 12]. The syndrome presents with features of kDa and toxic shock syndrome, and may be attributed to a post-viral immunological reaction [13]. Differences from classic kDa presentation include a high frequency of gastrointestinal symptoms such as abdominal pain, diarrhoea and occasional overt colitis. Laboratory tests are characterized by neutrophilia, lymphopenia and hypoalbuminemia, and elevated cardiac and inflammatory markers; while some patients present features of macrophage activation syndrome (MAS) [5–13].
MIS-C may be severe, with some studies reporting a majority of patients presenting with shock, requiring admission to the intensive care unit (ICU) and inotropic support [5–12]. Treatment strategies include intravenous immunoglobulin, corticosteroids and biologic agents such as anakinra and infliximab [14–17].
Although MIS-C has been described in children from various countries [5–10], information is lacking regarding the risk factors that may be associated with a more severe clinical course and outcome. Therefore, in this multicentre study, we aimed to identify predictors for severe disease as defined by the need for inotropic support. To this end, we analysed various demographic, clinical, laboratory and imaging variables at the time of admission and during hospitalization, among Israeli and US patients with MIS-C.
Methods
Study design
This is a retrospective cohort study of children hospitalized in nine Israeli medical centres and one US medical centre (Chicago, IL) who were admitted either to a paediatric ward or an ICU with a suspected diagnosis of MIS-C [according to criteria of the US Centres of Disease Control (CDC) [12]] between July 2020 and March 2021.
The CDC MIS-C case definition includes all of the following: age under 21 years, fever, laboratory evidence of inflammation, the requirement of hospital admission, multisystem (≥2) organ involvement (cardiac, renal, respiratory, haematological, gastrointestinal, dermatological or neurological), the absence of an alternative diagnosis, and either known COVID-19 exposure within 4 weeks before symptom onset or laboratory confirmation of SARS-CoV-2 infection by RT-PCR, serology or an antigen test.
Data were collected on demographics, clinical manifestations at presentation, and imaging and laboratory findings at the time of admission and during hospitalization. COVID-19 serology and PCR tests were included if applicable. Therapies including medications, inotropic support and mechanical (invasive and non-invasive) ventilation were recorded. For laboratory findings, minimal or maximal values throughout hospitalization were documented, in addition to values at the time of admission.
Due to the expected variability between centres in regard to clinical approaches, therapies and admission to the ICU [14–17], and as haemodynamic compromise is a major complication of MIS-C, we defined severe disease course as the need for inotropic support.
CNS involvement was defined as symptoms of headaches, dizziness or any deterioration in the consciousness state.
The study complies with the Declaration of Helsinki, and was approved by the IRB committee of each collaborating centre including the Rabin medical centre (study number 0501–20-RMC). In addition, the research protocol was approved specifically by the local ethic committee of each collaborating centre. Due to the retrospective design of the study, the requirement to obtain informed consent was waived by the IRB committees.
Statistical analysis
Demographic and medical variables were compared between children who did and did not receive vasopressors or inotropic agents during their course of treatment for MIS-C.
All the analyses were done using IBM SPSS Statistics (Statistical Package for the Social Sciences), version 24. The univariate analyses included the use of Pearson’s χ2 test for nominal variables, the Student’s t test for continuous variables that matched parametric criteria, and the Wilcoxon and Mann–Whitney U tests for ordinal variables and continuous variables that did not match parametric criteria. Statistical significance was set at a P-value of 0.05. First, a univariate regression model to assess odds ratio (OR) for the primary outcome (i.e. the use of inotropic support during hospitalization) was calculated for each variable. For the laboratory and continuous parameters, binary limits were determined as the median of each parameter, rounded by author consensus. Binary limits were chosen in order to provide a decision-making tool for clinicians. Second, a multivariate logistic regression analysis was performed to assess the contribution of each risk factor to the primary outcome, adjusted to demographic characteristics and other risk factors.
The results of the univariate model were presented to all the authors. The relatively small cohort size necessitated limiting the number of variables for the multivariate model. The authors chose the most clinically relevant parameters according to their clinical experience and the statistical significance of the variables found in the univariate model. Consensus for each of the chosen variables was achieved by at least 80% of the authors.
Due to the retrospective nature of the study, some data were missing. Medical history and physical exam findings were considered negative when not reported in the files. For specific tests such as imaging or SARS-COV2 workup, the analysis was done for available tests only, omitting the missing data, and the numbers of patients included are reported in the tables. For continuous variables such as vitals or laboratory results, the missing data were omitted from the analysis.
Results
Of the 111 patients clinically suspected to have MIS-C during the study period, 100 met the CDC criteria [12] and were included in the final cohort (Fig. 1). Seventy-eight (78%) were patients admitted to Israeli medical centres and 22% to a single US medical centre.
Study design and outcome. Overall, 111 patient charts were reviewed for the study. One hundred patients were included in the final analysis
Demographic, clinical and laboratory data were compared between patients who did and did not receive inotropic treatment [Supplementary Table S1 and S2 (available at Rheumatology online) for the time of admission, and Tables 1 and 2 for the entire hospitalization]. The majority (61%) of the patients were male. The mean age (s.d.) was 9.65 (4.48) years. Eleven percent of the patients fulfilled the kDa criteria (four or more clinical signs in addition to the mandatory criterion of fever) and 87% had gastrointestinal symptoms (abdominal pain, vomiting or diarrhoea) on admission. Twelve patients had documented medical history including comorbidities. Asthma presented in three patients, obesity in two and other comorbidities in one patient each.
Demographics, clinical characteristics, therapy, and clinical outcomes, during the entire hospitalization, of patients diagnosed with MIS-C, according to the need for inotropic support
| w/o inotropic support | With inotropic support | P-value | Total | |
|---|---|---|---|---|
| n = 56 (56%) | n = 44 (44%) | n = 100 (100%) | ||
| Demographic characteristics | ||||
| Sex (female) | 19 (34%) | 20 (46%) | 0.241 | 39 (39%) |
| Age (years) | 9.0 [5.70–12.50] | 11.0 [7.31–13.38] | 0.075 | 10.0 [6.75–13.0] |
| Medical history (positive) | 9 (16%) | 9 (20%) | 0.571 | 18 (18%) |
| Clinical characteristics | ||||
| Shortness of breath | 11 (20%) | 12 (27%) | 0.368 | 23 (23%) |
| Gastrointestinal symptoms | 46 (82%) | 41 (93%) | 0.103 | 87 (87%) |
| Arthralgia | 9 (16%) | 7 (16%) | 0.982 | 16 (16%) |
| Mucosal changes | 21 (38%) | 9 (21%) | 0.065 | 30 (30%) |
| Rash | 35 (63%) | 21 (48%) | 0.140 | 56 (56%) |
| Conjunctivitis | 27 (48%) | 17 (39%) | 0.338 | 44 (44%) |
| Extremity changes | 6 (11%) | 7 (16%) | 0.443 | 13 (13%) |
| Lymphadenopathy | 12 (21%) | 11 (25%) | 0.674 | 23 (23%) |
| CNS involvement | 8 (14%) | 11 (25%) | 0.175 | 19 (19%) |
| Heart murmur (all by admission) | 5 (9%) | 8 (18%) | 0.172 | 13 (13%) |
| Hepatosplenomegaly | 19 (34%) | 14 (32%) | 0.824 | 33 (33%) |
| Lung involvement (all by admission) | 6 (11%) | 4 (9%) | 0.788 | 10 (10%) |
| Throat involvement | 16 (29%) | 11 (25%) | 0.690 | 27 (27%) |
| No. of Kawasaki clinical criteria w/o fever | 2 [1–3] | 1 [0.25–2] | 0.261 | 1 [1–3] |
| Maximum fever during hospitalization | 39.15 [38.98–39.73] | 39.40 [38.70–40.9] | 0.361 | 39.25 (0.78) |
| High fever ≥39.5 (°C) | 21 (51%) | 20 (49%) | 0.450 | 41/97 (42%) |
| Hypotension | 24 (44%) | 41 (93%) | <0.001 | 65 (65%) |
| Minimal systolic BP | 88 [80–92] | 76 [68–80] | <0.001 | 80 [73–90] |
| Minimal diastolic BP | 46 [40–57] | 40 [31–45] | <0.001 | 43 [36–54] |
| Maximum HR | 136 [122–150] | 140 [130–155] | 0.139 | 137 [126–150] |
| Minimal O2 saturation | 95 [93–97] | 95 [92–98] | 0.708 | 95 [92–98] |
| Abnormal CXR | 13 (27%) | 24 (57%) | 0.004 | 37/90 (41%)a |
| Abnormal US | 16 (57%) | 18 (67%) | 0.467 | 34/55 (62%)a |
| Abnormal endoscopy | 2 (13%) | 1 (10%) | 0.846 | 3/26 (12%)a |
| Cardiac involvement | ||||
| Coronary ectasia (acute) | 5 (9%) | 5 (12%) | 0.681 | 10 (10%) |
| Coronary aneurysm (acute) | 1 (2%) | 1 (2%) | 0.859 | 2 (2%) |
| Coronary brightness | 8 (14%) | 5 (12%) | 0.698 | 13 (13%) |
| LV dysfunction | 13 (23%) | 24 (56%) | 0.001 | 37 (37%) |
| ECG changes | 8 (14%) | 10 (23%) | 0.251 | 18 (18%) |
| Pericardial effusion | 10 (18%) | 14 (33%) | 0.091 | 24 (24%) |
| Other echo findings | 11 (20%) | 9 (21%) | 0.828 | 20 (20%) |
| SARS-COV-2 workup | ||||
| Covid-19 PCR (positive) | ||||
| during hospitalization | 7 (13%) | 6 (14%) | 0.814 | 13/97 (13%)a |
| prior test | 12 (22%) | 7 (17%) | 19/97 (20%)a | |
| Covid-19 serology (positive) | 43 (84%) | 34 (81%) | 0.669 | 77/93 (83%)a |
| Covid-19 exposure (positive) | 24 (46%) | 20 (47%) | 0.972 | 44/95 (46%)a |
| Therapies | ||||
| IVIG | 42 (75%) | 36 (82%) | 0.414 | 78 (78%) |
| Corticosteroids: | ||||
| none | 8 (14%) | 1 (2%) | 9 (9.0%) | |
| steroids PO/i.v. | 23 (41%) | 19 (43%) | 0.107 | 42 (42%) |
| pulse therapy | 25 (45%) | 24 (55%) | 49 (49%) | |
| Anti TNF | — | — | — | |
| Anakinra | 8 (14%) | 14 (32%) | 0.036 | 22 (22%) |
| Tocilizumab | — | — | — | |
| Antibiotics | 29 (52%) | 42 (95%) | <0.001 | 71 (71%) |
| High dose aspirin | 4 (8%) | 0 | 0.066 | 4 (4%) |
| Low dose aspirin | 18 (33%) | 20 (46%) | 0.196 | 38 (38%) |
| Anticoagulation | 22 (40%) | 22 (50%) | 0.320 | 44 (44%) |
| Clinical outcomes | ||||
| Length of hospitalization (days) | 6 [5–9] | 10 [7–11] | <0.001 | 8 [5–11] |
| ICU admission | 20 (36%) | 43 (100%) | <0.001 | 63 (63%) |
| Days from disease onset of ICU admission | 0 [0–1] | 1 [1–2] | 0.002 | 1 [0–2] |
| Length of ICU hospitalization (days) | 0 [0–2] | 5 [3–7] | <0.001 | 2 [0–5] |
| Respiratory support | ||||
| non invasive | 7 (13%) | 16 (36%) | <0.001 | 23 (23%) |
| invasive | 1 (2%) | 8 (18%) | 9 (9.0%) |
| w/o inotropic support | With inotropic support | P-value | Total | |
|---|---|---|---|---|
| n = 56 (56%) | n = 44 (44%) | n = 100 (100%) | ||
| Demographic characteristics | ||||
| Sex (female) | 19 (34%) | 20 (46%) | 0.241 | 39 (39%) |
| Age (years) | 9.0 [5.70–12.50] | 11.0 [7.31–13.38] | 0.075 | 10.0 [6.75–13.0] |
| Medical history (positive) | 9 (16%) | 9 (20%) | 0.571 | 18 (18%) |
| Clinical characteristics | ||||
| Shortness of breath | 11 (20%) | 12 (27%) | 0.368 | 23 (23%) |
| Gastrointestinal symptoms | 46 (82%) | 41 (93%) | 0.103 | 87 (87%) |
| Arthralgia | 9 (16%) | 7 (16%) | 0.982 | 16 (16%) |
| Mucosal changes | 21 (38%) | 9 (21%) | 0.065 | 30 (30%) |
| Rash | 35 (63%) | 21 (48%) | 0.140 | 56 (56%) |
| Conjunctivitis | 27 (48%) | 17 (39%) | 0.338 | 44 (44%) |
| Extremity changes | 6 (11%) | 7 (16%) | 0.443 | 13 (13%) |
| Lymphadenopathy | 12 (21%) | 11 (25%) | 0.674 | 23 (23%) |
| CNS involvement | 8 (14%) | 11 (25%) | 0.175 | 19 (19%) |
| Heart murmur (all by admission) | 5 (9%) | 8 (18%) | 0.172 | 13 (13%) |
| Hepatosplenomegaly | 19 (34%) | 14 (32%) | 0.824 | 33 (33%) |
| Lung involvement (all by admission) | 6 (11%) | 4 (9%) | 0.788 | 10 (10%) |
| Throat involvement | 16 (29%) | 11 (25%) | 0.690 | 27 (27%) |
| No. of Kawasaki clinical criteria w/o fever | 2 [1–3] | 1 [0.25–2] | 0.261 | 1 [1–3] |
| Maximum fever during hospitalization | 39.15 [38.98–39.73] | 39.40 [38.70–40.9] | 0.361 | 39.25 (0.78) |
| High fever ≥39.5 (°C) | 21 (51%) | 20 (49%) | 0.450 | 41/97 (42%) |
| Hypotension | 24 (44%) | 41 (93%) | <0.001 | 65 (65%) |
| Minimal systolic BP | 88 [80–92] | 76 [68–80] | <0.001 | 80 [73–90] |
| Minimal diastolic BP | 46 [40–57] | 40 [31–45] | <0.001 | 43 [36–54] |
| Maximum HR | 136 [122–150] | 140 [130–155] | 0.139 | 137 [126–150] |
| Minimal O2 saturation | 95 [93–97] | 95 [92–98] | 0.708 | 95 [92–98] |
| Abnormal CXR | 13 (27%) | 24 (57%) | 0.004 | 37/90 (41%)a |
| Abnormal US | 16 (57%) | 18 (67%) | 0.467 | 34/55 (62%)a |
| Abnormal endoscopy | 2 (13%) | 1 (10%) | 0.846 | 3/26 (12%)a |
| Cardiac involvement | ||||
| Coronary ectasia (acute) | 5 (9%) | 5 (12%) | 0.681 | 10 (10%) |
| Coronary aneurysm (acute) | 1 (2%) | 1 (2%) | 0.859 | 2 (2%) |
| Coronary brightness | 8 (14%) | 5 (12%) | 0.698 | 13 (13%) |
| LV dysfunction | 13 (23%) | 24 (56%) | 0.001 | 37 (37%) |
| ECG changes | 8 (14%) | 10 (23%) | 0.251 | 18 (18%) |
| Pericardial effusion | 10 (18%) | 14 (33%) | 0.091 | 24 (24%) |
| Other echo findings | 11 (20%) | 9 (21%) | 0.828 | 20 (20%) |
| SARS-COV-2 workup | ||||
| Covid-19 PCR (positive) | ||||
| during hospitalization | 7 (13%) | 6 (14%) | 0.814 | 13/97 (13%)a |
| prior test | 12 (22%) | 7 (17%) | 19/97 (20%)a | |
| Covid-19 serology (positive) | 43 (84%) | 34 (81%) | 0.669 | 77/93 (83%)a |
| Covid-19 exposure (positive) | 24 (46%) | 20 (47%) | 0.972 | 44/95 (46%)a |
| Therapies | ||||
| IVIG | 42 (75%) | 36 (82%) | 0.414 | 78 (78%) |
| Corticosteroids: | ||||
| none | 8 (14%) | 1 (2%) | 9 (9.0%) | |
| steroids PO/i.v. | 23 (41%) | 19 (43%) | 0.107 | 42 (42%) |
| pulse therapy | 25 (45%) | 24 (55%) | 49 (49%) | |
| Anti TNF | — | — | — | |
| Anakinra | 8 (14%) | 14 (32%) | 0.036 | 22 (22%) |
| Tocilizumab | — | — | — | |
| Antibiotics | 29 (52%) | 42 (95%) | <0.001 | 71 (71%) |
| High dose aspirin | 4 (8%) | 0 | 0.066 | 4 (4%) |
| Low dose aspirin | 18 (33%) | 20 (46%) | 0.196 | 38 (38%) |
| Anticoagulation | 22 (40%) | 22 (50%) | 0.320 | 44 (44%) |
| Clinical outcomes | ||||
| Length of hospitalization (days) | 6 [5–9] | 10 [7–11] | <0.001 | 8 [5–11] |
| ICU admission | 20 (36%) | 43 (100%) | <0.001 | 63 (63%) |
| Days from disease onset of ICU admission | 0 [0–1] | 1 [1–2] | 0.002 | 1 [0–2] |
| Length of ICU hospitalization (days) | 0 [0–2] | 5 [3–7] | <0.001 | 2 [0–5] |
| Respiratory support | ||||
| non invasive | 7 (13%) | 16 (36%) | <0.001 | 23 (23%) |
| invasive | 1 (2%) | 8 (18%) | 9 (9.0%) |
The values refer to the patients with valid parameter data.
The data are presented as numbers (percentages) or as medians and interquartile ranges.
BP: blood pressure; CXR: chest X-ray; HR: heart rate; ICU: intensive care unit; LV: left ventricle; PO: per os.
Demographics, clinical characteristics, therapy, and clinical outcomes, during the entire hospitalization, of patients diagnosed with MIS-C, according to the need for inotropic support
| w/o inotropic support | With inotropic support | P-value | Total | |
|---|---|---|---|---|
| n = 56 (56%) | n = 44 (44%) | n = 100 (100%) | ||
| Demographic characteristics | ||||
| Sex (female) | 19 (34%) | 20 (46%) | 0.241 | 39 (39%) |
| Age (years) | 9.0 [5.70–12.50] | 11.0 [7.31–13.38] | 0.075 | 10.0 [6.75–13.0] |
| Medical history (positive) | 9 (16%) | 9 (20%) | 0.571 | 18 (18%) |
| Clinical characteristics | ||||
| Shortness of breath | 11 (20%) | 12 (27%) | 0.368 | 23 (23%) |
| Gastrointestinal symptoms | 46 (82%) | 41 (93%) | 0.103 | 87 (87%) |
| Arthralgia | 9 (16%) | 7 (16%) | 0.982 | 16 (16%) |
| Mucosal changes | 21 (38%) | 9 (21%) | 0.065 | 30 (30%) |
| Rash | 35 (63%) | 21 (48%) | 0.140 | 56 (56%) |
| Conjunctivitis | 27 (48%) | 17 (39%) | 0.338 | 44 (44%) |
| Extremity changes | 6 (11%) | 7 (16%) | 0.443 | 13 (13%) |
| Lymphadenopathy | 12 (21%) | 11 (25%) | 0.674 | 23 (23%) |
| CNS involvement | 8 (14%) | 11 (25%) | 0.175 | 19 (19%) |
| Heart murmur (all by admission) | 5 (9%) | 8 (18%) | 0.172 | 13 (13%) |
| Hepatosplenomegaly | 19 (34%) | 14 (32%) | 0.824 | 33 (33%) |
| Lung involvement (all by admission) | 6 (11%) | 4 (9%) | 0.788 | 10 (10%) |
| Throat involvement | 16 (29%) | 11 (25%) | 0.690 | 27 (27%) |
| No. of Kawasaki clinical criteria w/o fever | 2 [1–3] | 1 [0.25–2] | 0.261 | 1 [1–3] |
| Maximum fever during hospitalization | 39.15 [38.98–39.73] | 39.40 [38.70–40.9] | 0.361 | 39.25 (0.78) |
| High fever ≥39.5 (°C) | 21 (51%) | 20 (49%) | 0.450 | 41/97 (42%) |
| Hypotension | 24 (44%) | 41 (93%) | <0.001 | 65 (65%) |
| Minimal systolic BP | 88 [80–92] | 76 [68–80] | <0.001 | 80 [73–90] |
| Minimal diastolic BP | 46 [40–57] | 40 [31–45] | <0.001 | 43 [36–54] |
| Maximum HR | 136 [122–150] | 140 [130–155] | 0.139 | 137 [126–150] |
| Minimal O2 saturation | 95 [93–97] | 95 [92–98] | 0.708 | 95 [92–98] |
| Abnormal CXR | 13 (27%) | 24 (57%) | 0.004 | 37/90 (41%)a |
| Abnormal US | 16 (57%) | 18 (67%) | 0.467 | 34/55 (62%)a |
| Abnormal endoscopy | 2 (13%) | 1 (10%) | 0.846 | 3/26 (12%)a |
| Cardiac involvement | ||||
| Coronary ectasia (acute) | 5 (9%) | 5 (12%) | 0.681 | 10 (10%) |
| Coronary aneurysm (acute) | 1 (2%) | 1 (2%) | 0.859 | 2 (2%) |
| Coronary brightness | 8 (14%) | 5 (12%) | 0.698 | 13 (13%) |
| LV dysfunction | 13 (23%) | 24 (56%) | 0.001 | 37 (37%) |
| ECG changes | 8 (14%) | 10 (23%) | 0.251 | 18 (18%) |
| Pericardial effusion | 10 (18%) | 14 (33%) | 0.091 | 24 (24%) |
| Other echo findings | 11 (20%) | 9 (21%) | 0.828 | 20 (20%) |
| SARS-COV-2 workup | ||||
| Covid-19 PCR (positive) | ||||
| during hospitalization | 7 (13%) | 6 (14%) | 0.814 | 13/97 (13%)a |
| prior test | 12 (22%) | 7 (17%) | 19/97 (20%)a | |
| Covid-19 serology (positive) | 43 (84%) | 34 (81%) | 0.669 | 77/93 (83%)a |
| Covid-19 exposure (positive) | 24 (46%) | 20 (47%) | 0.972 | 44/95 (46%)a |
| Therapies | ||||
| IVIG | 42 (75%) | 36 (82%) | 0.414 | 78 (78%) |
| Corticosteroids: | ||||
| none | 8 (14%) | 1 (2%) | 9 (9.0%) | |
| steroids PO/i.v. | 23 (41%) | 19 (43%) | 0.107 | 42 (42%) |
| pulse therapy | 25 (45%) | 24 (55%) | 49 (49%) | |
| Anti TNF | — | — | — | |
| Anakinra | 8 (14%) | 14 (32%) | 0.036 | 22 (22%) |
| Tocilizumab | — | — | — | |
| Antibiotics | 29 (52%) | 42 (95%) | <0.001 | 71 (71%) |
| High dose aspirin | 4 (8%) | 0 | 0.066 | 4 (4%) |
| Low dose aspirin | 18 (33%) | 20 (46%) | 0.196 | 38 (38%) |
| Anticoagulation | 22 (40%) | 22 (50%) | 0.320 | 44 (44%) |
| Clinical outcomes | ||||
| Length of hospitalization (days) | 6 [5–9] | 10 [7–11] | <0.001 | 8 [5–11] |
| ICU admission | 20 (36%) | 43 (100%) | <0.001 | 63 (63%) |
| Days from disease onset of ICU admission | 0 [0–1] | 1 [1–2] | 0.002 | 1 [0–2] |
| Length of ICU hospitalization (days) | 0 [0–2] | 5 [3–7] | <0.001 | 2 [0–5] |
| Respiratory support | ||||
| non invasive | 7 (13%) | 16 (36%) | <0.001 | 23 (23%) |
| invasive | 1 (2%) | 8 (18%) | 9 (9.0%) |
| w/o inotropic support | With inotropic support | P-value | Total | |
|---|---|---|---|---|
| n = 56 (56%) | n = 44 (44%) | n = 100 (100%) | ||
| Demographic characteristics | ||||
| Sex (female) | 19 (34%) | 20 (46%) | 0.241 | 39 (39%) |
| Age (years) | 9.0 [5.70–12.50] | 11.0 [7.31–13.38] | 0.075 | 10.0 [6.75–13.0] |
| Medical history (positive) | 9 (16%) | 9 (20%) | 0.571 | 18 (18%) |
| Clinical characteristics | ||||
| Shortness of breath | 11 (20%) | 12 (27%) | 0.368 | 23 (23%) |
| Gastrointestinal symptoms | 46 (82%) | 41 (93%) | 0.103 | 87 (87%) |
| Arthralgia | 9 (16%) | 7 (16%) | 0.982 | 16 (16%) |
| Mucosal changes | 21 (38%) | 9 (21%) | 0.065 | 30 (30%) |
| Rash | 35 (63%) | 21 (48%) | 0.140 | 56 (56%) |
| Conjunctivitis | 27 (48%) | 17 (39%) | 0.338 | 44 (44%) |
| Extremity changes | 6 (11%) | 7 (16%) | 0.443 | 13 (13%) |
| Lymphadenopathy | 12 (21%) | 11 (25%) | 0.674 | 23 (23%) |
| CNS involvement | 8 (14%) | 11 (25%) | 0.175 | 19 (19%) |
| Heart murmur (all by admission) | 5 (9%) | 8 (18%) | 0.172 | 13 (13%) |
| Hepatosplenomegaly | 19 (34%) | 14 (32%) | 0.824 | 33 (33%) |
| Lung involvement (all by admission) | 6 (11%) | 4 (9%) | 0.788 | 10 (10%) |
| Throat involvement | 16 (29%) | 11 (25%) | 0.690 | 27 (27%) |
| No. of Kawasaki clinical criteria w/o fever | 2 [1–3] | 1 [0.25–2] | 0.261 | 1 [1–3] |
| Maximum fever during hospitalization | 39.15 [38.98–39.73] | 39.40 [38.70–40.9] | 0.361 | 39.25 (0.78) |
| High fever ≥39.5 (°C) | 21 (51%) | 20 (49%) | 0.450 | 41/97 (42%) |
| Hypotension | 24 (44%) | 41 (93%) | <0.001 | 65 (65%) |
| Minimal systolic BP | 88 [80–92] | 76 [68–80] | <0.001 | 80 [73–90] |
| Minimal diastolic BP | 46 [40–57] | 40 [31–45] | <0.001 | 43 [36–54] |
| Maximum HR | 136 [122–150] | 140 [130–155] | 0.139 | 137 [126–150] |
| Minimal O2 saturation | 95 [93–97] | 95 [92–98] | 0.708 | 95 [92–98] |
| Abnormal CXR | 13 (27%) | 24 (57%) | 0.004 | 37/90 (41%)a |
| Abnormal US | 16 (57%) | 18 (67%) | 0.467 | 34/55 (62%)a |
| Abnormal endoscopy | 2 (13%) | 1 (10%) | 0.846 | 3/26 (12%)a |
| Cardiac involvement | ||||
| Coronary ectasia (acute) | 5 (9%) | 5 (12%) | 0.681 | 10 (10%) |
| Coronary aneurysm (acute) | 1 (2%) | 1 (2%) | 0.859 | 2 (2%) |
| Coronary brightness | 8 (14%) | 5 (12%) | 0.698 | 13 (13%) |
| LV dysfunction | 13 (23%) | 24 (56%) | 0.001 | 37 (37%) |
| ECG changes | 8 (14%) | 10 (23%) | 0.251 | 18 (18%) |
| Pericardial effusion | 10 (18%) | 14 (33%) | 0.091 | 24 (24%) |
| Other echo findings | 11 (20%) | 9 (21%) | 0.828 | 20 (20%) |
| SARS-COV-2 workup | ||||
| Covid-19 PCR (positive) | ||||
| during hospitalization | 7 (13%) | 6 (14%) | 0.814 | 13/97 (13%)a |
| prior test | 12 (22%) | 7 (17%) | 19/97 (20%)a | |
| Covid-19 serology (positive) | 43 (84%) | 34 (81%) | 0.669 | 77/93 (83%)a |
| Covid-19 exposure (positive) | 24 (46%) | 20 (47%) | 0.972 | 44/95 (46%)a |
| Therapies | ||||
| IVIG | 42 (75%) | 36 (82%) | 0.414 | 78 (78%) |
| Corticosteroids: | ||||
| none | 8 (14%) | 1 (2%) | 9 (9.0%) | |
| steroids PO/i.v. | 23 (41%) | 19 (43%) | 0.107 | 42 (42%) |
| pulse therapy | 25 (45%) | 24 (55%) | 49 (49%) | |
| Anti TNF | — | — | — | |
| Anakinra | 8 (14%) | 14 (32%) | 0.036 | 22 (22%) |
| Tocilizumab | — | — | — | |
| Antibiotics | 29 (52%) | 42 (95%) | <0.001 | 71 (71%) |
| High dose aspirin | 4 (8%) | 0 | 0.066 | 4 (4%) |
| Low dose aspirin | 18 (33%) | 20 (46%) | 0.196 | 38 (38%) |
| Anticoagulation | 22 (40%) | 22 (50%) | 0.320 | 44 (44%) |
| Clinical outcomes | ||||
| Length of hospitalization (days) | 6 [5–9] | 10 [7–11] | <0.001 | 8 [5–11] |
| ICU admission | 20 (36%) | 43 (100%) | <0.001 | 63 (63%) |
| Days from disease onset of ICU admission | 0 [0–1] | 1 [1–2] | 0.002 | 1 [0–2] |
| Length of ICU hospitalization (days) | 0 [0–2] | 5 [3–7] | <0.001 | 2 [0–5] |
| Respiratory support | ||||
| non invasive | 7 (13%) | 16 (36%) | <0.001 | 23 (23%) |
| invasive | 1 (2%) | 8 (18%) | 9 (9.0%) |
The values refer to the patients with valid parameter data.
The data are presented as numbers (percentages) or as medians and interquartile ranges.
BP: blood pressure; CXR: chest X-ray; HR: heart rate; ICU: intensive care unit; LV: left ventricle; PO: per os.
Laboratory findings of patients diagnosed with MIS-C, during the entire hospitalization, according to the need for inotropic support
| Laboratory characteristics | w/o inotropic support | With inotropic support | P-value | Total |
|---|---|---|---|---|
| n = 56 (56.0%) | n = 44 (44.0%) | n = 100 (100%) | ||
| Haemoglobin, min (g/dL) | 10.40 [9.33–11.28] | 9.15 [8.43–9.67] | <0.001 | 9.60 [8.83–10.67] |
| White cells, min (K/µL) | 8.10 [5.65–9.43] | 5.70 [4.60–8.50] | 0.015 | 6.90 [5.20–9.10] |
| White cells, max (K/µL) | 13.85 [10.55–18.78] | 20.40 [13.23–25.08] | 0.044 | 15.95 [11.10–21.80] |
| Platelets, min (K/µL) | 167.50 [102.25–218.50] | 116.50 [88.25–146.25] | 0.001 | 138.0 [96.25–192.5] |
| Lymphocytes, min (K/µL) | 0.80 [0.50–1.10] | 0.50 [0.30–0.78] | <0.001 | 0.70 [0.40–0.91] |
| Neutrophils, max (K/µL) | 11.28 [7.43–15.20] | 15.48 [9.75–19.82] | 0.011 | 12.35 [8.68–17.85] |
| ESR, max (mm/h) | 70.00 [42.75–80.25] | 46.50 [29.50–77.50] | 0.107 | 58.50 [10.50–23.80] |
| C-reactive protein, max (mg/dL) | 16.90 [11.55–23.71] | 25.50 [17.85–29.45] | 0.001 | 20.0 [12.76–27.70] |
| Ferritin (µg/dL) | 536.00 [216.50–1003.0] | 561.0 [359.25–982.50] | 0.393 | 546.0 [288.0–959.0] |
| AST, max (units/L) | 42.0 [28.25–73.50] | 52.50 [28.0–129.0] | 0.345 | 45.0 [28.0–91.0] |
| ALT, max (units/L) | 40.0 [21.0–82.0] | 70.50 [33.25–106.25] | 0.061 | 50.0 [21.0–94.0] |
| Albumin, min (g/dL) | 3.0 [2.5–3.4] | 2.50 [2.30–2.70] | 0.002 | 2.65 [2.30–3.20] |
| Sodium, min (mEq/L) | 132.0 [129/0–134.0] | 131.0 [129.0–133.0] | 0.456 | 131.00 [129.00–134] |
| Potassium, minimum (mEq/L) | 3.40 [3.13–3.80] | 3.10 [2.70–3.50] | 0.002 | 3.30 [3.00–3.70] |
| LDH, maximum (units/L) | 363.0 [250.0–587.0] | 442.0 [296.50–730.75] | 0.229 | 417.00 [269.00–624.00] |
| Creatinine, maximum (mg/dL) | 0.60 [0.42–0.70] | 0.70 [0.51–0.88] | 0.005 | 0.62 [0.48–0.80] |
| Triglycerides (mg/dL) | 148.00 [121.50–240.0] | 192.0 [122.25–250.0] | 0.424 | 171.00 [122.50–245.50] |
| Troponin, max (ng/mL) | 18.45 [0–100.75] | 81.0 [25.0–233.0] | 0.001 | 41.00 [10.00–141.50] |
| BNP, max (pg/mL) | 3869.50 [1045.0–6724.0] | 11 781.0 [2868.75–21 020] | 0.004 | 6173.50 [1772–15 238] |
| D-dimer, max (ng/mL) | 2167.5 [833.00–4757.75] | 2312.0 [8.66–4627.0] | 0.665 | 2300 [98.13–4648.5] |
| Interleukin 6 (pg/mL) | 31.0 [24.40–61.40] | 49.90 [0–285.75] | 0.772 | 31.00 [7.48–174.30] |
| Creatine kinase, max(units/L) | 61.00 [43.0–100.0] | 73.00 [40.0–278.0] | 0.317 | 62.00 [40.00–168.75] |
| INR, max | 1.30 [1.16–1.40] | 1.30 [1.21–1.40] | 0.319 | 1.30 [1.20–1.40] |
| Laboratory characteristics | w/o inotropic support | With inotropic support | P-value | Total |
|---|---|---|---|---|
| n = 56 (56.0%) | n = 44 (44.0%) | n = 100 (100%) | ||
| Haemoglobin, min (g/dL) | 10.40 [9.33–11.28] | 9.15 [8.43–9.67] | <0.001 | 9.60 [8.83–10.67] |
| White cells, min (K/µL) | 8.10 [5.65–9.43] | 5.70 [4.60–8.50] | 0.015 | 6.90 [5.20–9.10] |
| White cells, max (K/µL) | 13.85 [10.55–18.78] | 20.40 [13.23–25.08] | 0.044 | 15.95 [11.10–21.80] |
| Platelets, min (K/µL) | 167.50 [102.25–218.50] | 116.50 [88.25–146.25] | 0.001 | 138.0 [96.25–192.5] |
| Lymphocytes, min (K/µL) | 0.80 [0.50–1.10] | 0.50 [0.30–0.78] | <0.001 | 0.70 [0.40–0.91] |
| Neutrophils, max (K/µL) | 11.28 [7.43–15.20] | 15.48 [9.75–19.82] | 0.011 | 12.35 [8.68–17.85] |
| ESR, max (mm/h) | 70.00 [42.75–80.25] | 46.50 [29.50–77.50] | 0.107 | 58.50 [10.50–23.80] |
| C-reactive protein, max (mg/dL) | 16.90 [11.55–23.71] | 25.50 [17.85–29.45] | 0.001 | 20.0 [12.76–27.70] |
| Ferritin (µg/dL) | 536.00 [216.50–1003.0] | 561.0 [359.25–982.50] | 0.393 | 546.0 [288.0–959.0] |
| AST, max (units/L) | 42.0 [28.25–73.50] | 52.50 [28.0–129.0] | 0.345 | 45.0 [28.0–91.0] |
| ALT, max (units/L) | 40.0 [21.0–82.0] | 70.50 [33.25–106.25] | 0.061 | 50.0 [21.0–94.0] |
| Albumin, min (g/dL) | 3.0 [2.5–3.4] | 2.50 [2.30–2.70] | 0.002 | 2.65 [2.30–3.20] |
| Sodium, min (mEq/L) | 132.0 [129/0–134.0] | 131.0 [129.0–133.0] | 0.456 | 131.00 [129.00–134] |
| Potassium, minimum (mEq/L) | 3.40 [3.13–3.80] | 3.10 [2.70–3.50] | 0.002 | 3.30 [3.00–3.70] |
| LDH, maximum (units/L) | 363.0 [250.0–587.0] | 442.0 [296.50–730.75] | 0.229 | 417.00 [269.00–624.00] |
| Creatinine, maximum (mg/dL) | 0.60 [0.42–0.70] | 0.70 [0.51–0.88] | 0.005 | 0.62 [0.48–0.80] |
| Triglycerides (mg/dL) | 148.00 [121.50–240.0] | 192.0 [122.25–250.0] | 0.424 | 171.00 [122.50–245.50] |
| Troponin, max (ng/mL) | 18.45 [0–100.75] | 81.0 [25.0–233.0] | 0.001 | 41.00 [10.00–141.50] |
| BNP, max (pg/mL) | 3869.50 [1045.0–6724.0] | 11 781.0 [2868.75–21 020] | 0.004 | 6173.50 [1772–15 238] |
| D-dimer, max (ng/mL) | 2167.5 [833.00–4757.75] | 2312.0 [8.66–4627.0] | 0.665 | 2300 [98.13–4648.5] |
| Interleukin 6 (pg/mL) | 31.0 [24.40–61.40] | 49.90 [0–285.75] | 0.772 | 31.00 [7.48–174.30] |
| Creatine kinase, max(units/L) | 61.00 [43.0–100.0] | 73.00 [40.0–278.0] | 0.317 | 62.00 [40.00–168.75] |
| INR, max | 1.30 [1.16–1.40] | 1.30 [1.21–1.40] | 0.319 | 1.30 [1.20–1.40] |
ALT: alanine transaminase; AST: aspartate transaminase; BNP: brain natriuretic peptide; INR: international normalized ratio; LDH: lactate dehydrogenase.
The data are presented as medians and interquartile ranges.
Laboratory findings of patients diagnosed with MIS-C, during the entire hospitalization, according to the need for inotropic support
| Laboratory characteristics | w/o inotropic support | With inotropic support | P-value | Total |
|---|---|---|---|---|
| n = 56 (56.0%) | n = 44 (44.0%) | n = 100 (100%) | ||
| Haemoglobin, min (g/dL) | 10.40 [9.33–11.28] | 9.15 [8.43–9.67] | <0.001 | 9.60 [8.83–10.67] |
| White cells, min (K/µL) | 8.10 [5.65–9.43] | 5.70 [4.60–8.50] | 0.015 | 6.90 [5.20–9.10] |
| White cells, max (K/µL) | 13.85 [10.55–18.78] | 20.40 [13.23–25.08] | 0.044 | 15.95 [11.10–21.80] |
| Platelets, min (K/µL) | 167.50 [102.25–218.50] | 116.50 [88.25–146.25] | 0.001 | 138.0 [96.25–192.5] |
| Lymphocytes, min (K/µL) | 0.80 [0.50–1.10] | 0.50 [0.30–0.78] | <0.001 | 0.70 [0.40–0.91] |
| Neutrophils, max (K/µL) | 11.28 [7.43–15.20] | 15.48 [9.75–19.82] | 0.011 | 12.35 [8.68–17.85] |
| ESR, max (mm/h) | 70.00 [42.75–80.25] | 46.50 [29.50–77.50] | 0.107 | 58.50 [10.50–23.80] |
| C-reactive protein, max (mg/dL) | 16.90 [11.55–23.71] | 25.50 [17.85–29.45] | 0.001 | 20.0 [12.76–27.70] |
| Ferritin (µg/dL) | 536.00 [216.50–1003.0] | 561.0 [359.25–982.50] | 0.393 | 546.0 [288.0–959.0] |
| AST, max (units/L) | 42.0 [28.25–73.50] | 52.50 [28.0–129.0] | 0.345 | 45.0 [28.0–91.0] |
| ALT, max (units/L) | 40.0 [21.0–82.0] | 70.50 [33.25–106.25] | 0.061 | 50.0 [21.0–94.0] |
| Albumin, min (g/dL) | 3.0 [2.5–3.4] | 2.50 [2.30–2.70] | 0.002 | 2.65 [2.30–3.20] |
| Sodium, min (mEq/L) | 132.0 [129/0–134.0] | 131.0 [129.0–133.0] | 0.456 | 131.00 [129.00–134] |
| Potassium, minimum (mEq/L) | 3.40 [3.13–3.80] | 3.10 [2.70–3.50] | 0.002 | 3.30 [3.00–3.70] |
| LDH, maximum (units/L) | 363.0 [250.0–587.0] | 442.0 [296.50–730.75] | 0.229 | 417.00 [269.00–624.00] |
| Creatinine, maximum (mg/dL) | 0.60 [0.42–0.70] | 0.70 [0.51–0.88] | 0.005 | 0.62 [0.48–0.80] |
| Triglycerides (mg/dL) | 148.00 [121.50–240.0] | 192.0 [122.25–250.0] | 0.424 | 171.00 [122.50–245.50] |
| Troponin, max (ng/mL) | 18.45 [0–100.75] | 81.0 [25.0–233.0] | 0.001 | 41.00 [10.00–141.50] |
| BNP, max (pg/mL) | 3869.50 [1045.0–6724.0] | 11 781.0 [2868.75–21 020] | 0.004 | 6173.50 [1772–15 238] |
| D-dimer, max (ng/mL) | 2167.5 [833.00–4757.75] | 2312.0 [8.66–4627.0] | 0.665 | 2300 [98.13–4648.5] |
| Interleukin 6 (pg/mL) | 31.0 [24.40–61.40] | 49.90 [0–285.75] | 0.772 | 31.00 [7.48–174.30] |
| Creatine kinase, max(units/L) | 61.00 [43.0–100.0] | 73.00 [40.0–278.0] | 0.317 | 62.00 [40.00–168.75] |
| INR, max | 1.30 [1.16–1.40] | 1.30 [1.21–1.40] | 0.319 | 1.30 [1.20–1.40] |
| Laboratory characteristics | w/o inotropic support | With inotropic support | P-value | Total |
|---|---|---|---|---|
| n = 56 (56.0%) | n = 44 (44.0%) | n = 100 (100%) | ||
| Haemoglobin, min (g/dL) | 10.40 [9.33–11.28] | 9.15 [8.43–9.67] | <0.001 | 9.60 [8.83–10.67] |
| White cells, min (K/µL) | 8.10 [5.65–9.43] | 5.70 [4.60–8.50] | 0.015 | 6.90 [5.20–9.10] |
| White cells, max (K/µL) | 13.85 [10.55–18.78] | 20.40 [13.23–25.08] | 0.044 | 15.95 [11.10–21.80] |
| Platelets, min (K/µL) | 167.50 [102.25–218.50] | 116.50 [88.25–146.25] | 0.001 | 138.0 [96.25–192.5] |
| Lymphocytes, min (K/µL) | 0.80 [0.50–1.10] | 0.50 [0.30–0.78] | <0.001 | 0.70 [0.40–0.91] |
| Neutrophils, max (K/µL) | 11.28 [7.43–15.20] | 15.48 [9.75–19.82] | 0.011 | 12.35 [8.68–17.85] |
| ESR, max (mm/h) | 70.00 [42.75–80.25] | 46.50 [29.50–77.50] | 0.107 | 58.50 [10.50–23.80] |
| C-reactive protein, max (mg/dL) | 16.90 [11.55–23.71] | 25.50 [17.85–29.45] | 0.001 | 20.0 [12.76–27.70] |
| Ferritin (µg/dL) | 536.00 [216.50–1003.0] | 561.0 [359.25–982.50] | 0.393 | 546.0 [288.0–959.0] |
| AST, max (units/L) | 42.0 [28.25–73.50] | 52.50 [28.0–129.0] | 0.345 | 45.0 [28.0–91.0] |
| ALT, max (units/L) | 40.0 [21.0–82.0] | 70.50 [33.25–106.25] | 0.061 | 50.0 [21.0–94.0] |
| Albumin, min (g/dL) | 3.0 [2.5–3.4] | 2.50 [2.30–2.70] | 0.002 | 2.65 [2.30–3.20] |
| Sodium, min (mEq/L) | 132.0 [129/0–134.0] | 131.0 [129.0–133.0] | 0.456 | 131.00 [129.00–134] |
| Potassium, minimum (mEq/L) | 3.40 [3.13–3.80] | 3.10 [2.70–3.50] | 0.002 | 3.30 [3.00–3.70] |
| LDH, maximum (units/L) | 363.0 [250.0–587.0] | 442.0 [296.50–730.75] | 0.229 | 417.00 [269.00–624.00] |
| Creatinine, maximum (mg/dL) | 0.60 [0.42–0.70] | 0.70 [0.51–0.88] | 0.005 | 0.62 [0.48–0.80] |
| Triglycerides (mg/dL) | 148.00 [121.50–240.0] | 192.0 [122.25–250.0] | 0.424 | 171.00 [122.50–245.50] |
| Troponin, max (ng/mL) | 18.45 [0–100.75] | 81.0 [25.0–233.0] | 0.001 | 41.00 [10.00–141.50] |
| BNP, max (pg/mL) | 3869.50 [1045.0–6724.0] | 11 781.0 [2868.75–21 020] | 0.004 | 6173.50 [1772–15 238] |
| D-dimer, max (ng/mL) | 2167.5 [833.00–4757.75] | 2312.0 [8.66–4627.0] | 0.665 | 2300 [98.13–4648.5] |
| Interleukin 6 (pg/mL) | 31.0 [24.40–61.40] | 49.90 [0–285.75] | 0.772 | 31.00 [7.48–174.30] |
| Creatine kinase, max(units/L) | 61.00 [43.0–100.0] | 73.00 [40.0–278.0] | 0.317 | 62.00 [40.00–168.75] |
| INR, max | 1.30 [1.16–1.40] | 1.30 [1.21–1.40] | 0.319 | 1.30 [1.20–1.40] |
ALT: alanine transaminase; AST: aspartate transaminase; BNP: brain natriuretic peptide; INR: international normalized ratio; LDH: lactate dehydrogenase.
The data are presented as medians and interquartile ranges.
Echocardiographic evaluation showed that 10% of the patients had acute coronary ectasia or aneurysm and 37 (37%) patients had left ventricular dysfunction (LVD), all during the acute phase of the disease. The mean age of the patients with LVD was 10 (5) years vs 9 (4) years for patients without LVD (P-value = 0.230).
Sixty-five percent of the patients were hypotensive, and 44% required inotropic support. Sixty-three patients (63%) were admitted to the ICU; of them, 13 (21%) on the day of admission. The majority (79%) of patients were transferred to the ICU later during hospitalization.
All the patients received immunosuppressive treatment; 78% were treated with IVIG and 91% with corticosteroids. Of the latter, 49% were treated with corticosteroid intravenous pulse therapy (i.e. 10–30 mg/kg, max 1 g of methylprednisolone for 3–5 consecutive days) followed by oral therapy. Combination therapy, which included both regimens, was administered to 76% of the patients. Mucosal changes and conjunctivitis on admission (Supplementary Table S1, available at Rheumatology online), but not during the entire hospitalization, were significantly less common among patients in need of inotropic support (14% vs 32%, P = 0.031 and 27% vs 48%, P = 0.033, respectively). Compared with those who did not require inotropic support, among patients who needed inotropic support, the median diastolic blood pressure was lower on admission (53 vs 60 mmHg, P = 0.006, Supplementary Table S1, available at Rheumatology online) and the median minimal systolic and diastolic blood pressure measures were lower during the entire hospitalization period (P < 0.001) (Table 1). Among those who received inotropic medication, abnormal chest X-ray was described more often (57% vs 27%, P = 0.004), and LVD was more common (56% vs 23%, P = 0.001). However, coronary involvement and other echocardiographic findings as pericardial effusion or vulvar insufficiency did not differ significantly between those with and without a severe course. The differences between laboratory studies during hospitalization are shown in Table 2.
Statistically significant differences between patients hospitalized in Israel and in the US were not found in any of the variables examined (data not shown).
Fig. 2 present the results of the univariate model for the primary outcome, the need for inotropic support. LVD was strongly correlated with the need for inotropic support [OR 4.178 (1.760, 9.917)], as was the use of antibiotics [OR 19.552 (4.309, 88.706)] and anakinra [OR 2.800 (1.050, 7.469)] for these cases. Conjunctivitis and mucosal changes on admission [OR 0.403 (0.173, 0.938) and OR 0.333 (0.119, 0.931), respectively], and the use of high dose aspirin [OR 0.533 (0.440, 0.645)] were found to correlate inversely with the need for inotropic support. The abnormal laboratory parameters that were correlated with the use of inotropic support were low haemoglobin levels, high leucocyte and neutrophil counts, thrombocytopenia, low lymphocyte count, low albumin and potassium levels, and high troponin and brain natriuretic peptide (BNP) (Fig. 2B). The full univariate analysis including parameters collected at time of admission and was not found significant is presented in Supplementary Tables S3 and S4, available at Rheumatology online.
Univariate analysis of risk factors associated with inotropic support in MIS-C patients. (A) Univariate analysis of clinical risk factors associated with the need for inotropic support in patients with MIS-C. LVD, use of antibiotics and anakinra were strongly correlated with the need for inotropic support; whereas conjunctivitis, mucosal changes on admission and the use of high dose aspirin were inversely correlated with the need for inotropic support. (B) Univariate analysis of laboratory risk factors associated with the need for inotropic support in patients with MIS-C. Low haemoglobin levels, high leukocyte and neutrophil counts, thrombocytopenia, low lymphocyte count, low albumin and potassium levels, and high troponin and brain natriuretic peptide were correlated with the need for inotropic support
Patients with ESR >20 mm/h were more than twice at risk for inotropic support [OR 2.111 (1.606, 2.776)]; however, for an ESR >60 mm/h, no significant association was found [OR 0.444 (0.158, 1.249)]. The risk for severe disease was 3.3 times higher among those with BNP levels above 6000 pg/ml [OR 3.298 (1.164, 9.338)], and 8.4 times higher for those with BNP levels above 8000 pg/ml [OR 8.357 (2.363, 29.560)].
Multivariate analysis showed associations of clinical signs with inotropic support, namely involvement of the central nervous system [OR 3.85, CI (1.09, 3.85)] and fever above >39.5°C [OR 5.34, CI (1.63, 17.5)]. Mucosal involvement was associated with a lower risk for severe disease by 6.2 [OR 0.16, CI (0.04, 0.61)]. A positive, but not statistically significant association was observed between gastrointestinal symptoms and severe disease [OR 6.8, CI (0.98, 26.40)] (Fig. 3A). Multivariate analysis also showed associations of a number of laboratory parameters with the need for inotropic support: minimal haemoglobin level ≤9.5 g/dl [OR 3.356 (1.06, 10.61)], minimal platelet count <150 K/µL [OR 4.26 (1.40, 12.96)], maximal CRP value ≥20 mg/dl [OR 4.44 (1.45, 13.58)] and troponin level >13 ng/ml [OR 4.59 (1.18, 17.83)] (Fig. 3B).
Multivariate analysis of risk factors associated with inotropic support in MIS-C patients. (A) Multivariate analysis of associations of clinical risk factors with the need for inotropic support in patients with MIS-C. CNS involvement and fever above >39.5°C were positively correlated with inotropic support, whereas mucosal involvement was protective. (B) Multivariate analysis of laboratory risk factors associated with the need for inotropic support in patients with MIS-C. Haemoglobin level ≤9.5 g/dl, platelet count <150 K/µL, CRP ≥20 mg/dl and troponin level >13 ng/mL were positively correlated with the need for inotropic support
Discussion
In this study, we aimed to identify clinical and laboratory features predictive of a severe course of MIS-C, as defined by the need for inotropic support, as data are scarce regarding these risk factors. Therefore, for example, the National Health Service of England were compelled to use an expert consensus to identify risk factors for severe disease by a Delphi process, as part of their national clinical management [18].
We identified several specific risk factors that may predict severe disease course. These include the presence of LVD, fever >39.5°C, and central nervous system involvement. Conjunctivitis and mucosal changes on admission were found as protective factors. The abnormal laboratory parameters that correlated with the use of inotropic support were low haemoglobin, platelet, lymphocyte, albumin and potassium levels; and high leucocyte, neutrophil, troponin and BNP levels.
We defined our primary outcome for disease severity as the need of inotropic support. The rationale is that such a relatively objective measure would reduce the impact of subjective clinical decisions by different attending physicians. For example, the use of outcomes such as whether to admit a patient to the ICU or hospital length of stay could cause selection bias. Indeed, 36% of the patients who did not receive any vasopressors or inotropic agents in our study were admitted to the ICU.
To assure the inclusion of only patients with demonstrated MIS-C, according to the full CDC criteria, we ascertained documented exposure or test results for positive past SARS-COV2 infection.
Our findings of high levels of troponin, BNP and CRP, and low platelet and lymphocyte counts, as risk factors for severe disease are comparable to those of Abrams et al. [19]. In their investigation of correlations of clinical and laboratory findings with disease severity, the severe outcomes of interest were admission to an ICU, decreased cardiac function, coronary artery abnormalities (aneurysm or dilatation), shock and myocarditis. Shortness of breath, abdominal pain, ferritin and D-dimer levels were risk factors for severe disease, defined at ICU admission, in their study, but not ours. However, our study is novel in the identification of low haemoglobin levels, albumin and potassium levels, and high leucocyte and neutrophil counts as risk factors for severe disease; while the presence of conjunctivitis and mucosal involvement were protective factors.
Factors for severity by the National Health Service Delphi process included physiological factors such as extended capillary refill time, persistent hypotension or tachycardia, the requirement for fluid bolus, and low oxygen saturation. The haematological and biochemical features include C-reactive protein >30 mg/dl; increased levels of troponin, NT-proBNP, lactate, ferritin, D-dimer, creatinine and lactate dehydrogenase; and high or low fibrinogen. The cardiac features include abnormal electrocardiogram, coronary artery aneurysms on echocardiogram and left ventricular failure [18].
Fever, gastrointestinal symptoms, central nervous system involvement, neutrophilia, hypoalbuminemia, low platelet count, low absolute lymphocyte count and elevated inflammatory markers, and high cardiac markers are all key features of MIS-C diagnosis. However, close monitoring during hospitalization is important because significant abnormalities (including specific out-of-range laboratory values defined for this study) may predict a severe disease course.
We found that patients with ESR >20 mm/h were more than twice at risk for inotropic support. Interestingly, this association was not found when analysing higher ESR levels of ≥60–100 mm/h, and may be attributed to the macrophage activation that may complicate the course of MIS-C, which is associated with a lower level of ESR [9, 20]. MAS prevalence could not be assessed in this cohort due to insufficient data regarding the full MAS criteria. Of note, as ESR levels are not informative after IVIG treatment (falsely elevated), ESR levels were not routinely taken after treatment initiation.
As expected, elevated BNP levels were associated with more severe disease. Average maximum BNP was three times greater in the high-risk group. Interestingly the risk for severe disease was 3.3 times higher for BNP levels above 6000 pg/ml, the OR rose to 8.4 for BNP levels above 8000 pg/ml.
The associations of severe disease course with maximal high white blood cell and neutrophil count [OR 2.397 (1.060, 5.422) and OR 2.419 (1.022, 5.729), respectively] must be interpreted with caution. This is because 91% of the patients were treated with corticosteroids during hospitalization, which can increase WBC count. At the time of admission, WBC levels were not statistically different between patients who did and did not need inotropic support. For these respective groups, the difference in median creatinine level (0.6 vs 0.7 mg/dl) was statistically significant; however, the small magnitude of this difference is not clinically significant.
Although not common in MIS-C, CNS involvement was seen in 16% of the patients at the time of admission and in 19% during hospitalization. The association of this finding with the need for inotropic support was statistically significant in the multivariate analysis. However, the possibility that CNS involvement might be a consequence of severe shock or therapy should be considered.
Interestingly, the presentation only at the time of admission, and not during hospitalization, of conjunctivitis [OR 0.403 (0.173, 0.938)] and mucosal changes [0.333 (0.119, 0.931)] appeared protective for a severe disease course.
The difficulty in identifying other risk factors at admission emphasizes the unexpected deterioration in the disease course and raises the need for close monitoring during hospitalization. Notably, 79% of the patients who eventually needed inotropic support were not admitted to the ICU on the day of admission to the hospital.
Of the 100 patients included in this study, 65% were hypotensive for their age, and 44% required inotropic or vasoactive support; only 24 (56%) of the latter had LVD. This discrepancy and other possible mechanisms leading to hypotension are yet to be revealed. Our data compare with a study of children with kDa in the US, of whom 7% presented with kDa shock syndrome, which led to the use of vasopressors or inotropic support in 3.7% of the patients [21].
While kDa features present in MIS-C patients, only 11 (11%) of the study’s patients fulfilled the full set of kDa criteria. This is in comparison with a study which included patients diagnosed with classic or atypical kDa, in which 60% of patients presented with the full kDa criteria [22]. As mentioned above, mucosal involvement and conjunctivitis were found to be protective factors, and their presence lowered the risk for severe disease.
Our findings corroborate a study by Flood et al. [23] which used Latent Class Analysis to compare patients with MIS-C, by categorizing them to groups according to shared clinical features. In one of the groups, >75% of the patients had kDa features of rash, conjunctivitis or lip/mucosal signs. The prevalence of hypotension among patients in this category was the lowest (18.2%), and statistically different from the other groups.
Both kDa and MIS-C may cause coronary artery damage. Coronary artery aneurysms are a common feature of kDa, reportedly affecting 16% in the first 10 days (i.e. acute phase) of untreated kDa [24]. In our MIS-C cohort, 13% of the patients had some coronary involvement, and 10% had acute coronary ectasia or aneurysm. Data are lacking regarding long-term follow up, but cardiac involvement of MIS-C has been suggested to have a more favourable prognosis [25–27].
Since the onset of MIS-C cases during the pandemic, physicians have learned about the syndrome, through personal experience, as well as from emerging medical literature and guidelines, such as the ACR guidelines [14]. However, treatment strategies remained similar throughout the period of this study. The initial treatment of MIS-C includes IVIG and/or corticosteroids. Seventy-eight percent of our patients were treated with IVIG and 91% with corticosteroids. Combination therapy, which included both regimens, was administered to 76% of patients. No association was found between treatment choice and disease severity. Anakinra was given significantly more frequently to those with severe disease, but only to 22% of our entire cohort. This reflects the inconsistency of treatment decisions, and the lack of agreement in the literature [15–17].
The Pfizer-BioNTech COVID-19 vaccine was available for adolescents aged 16 years and above in Israel and the US since December 2020, and for younger persons only after the end of the study period. Nevertheless, none of the patients with MIS-C had been vaccinated.
The limitations of this study include its retrospective design and the retrieval of data from multiple centres, which may have had different clinical approaches, including no uniform policy for inotropic support (although this could have been the best objective measurement). In addition, due to the inability to retrospectively standardize timelines of data collections in multiple centres (e.g. blood sample draw, clinical interventions, etc.), data were collected of values at the time of admission, and of minimal and maximal values throughout the hospitalization. Therefore, risk factors may have been identified from data accessed during hospitalization and not at admission.
Notably, this study summarized MIS-C incidences of the first three COVID-19 pandemic waves in Israel, which included only the ancestral strain and the alpha variant strain; individual patient data of the variants were not available.
The relatively small sample size limited the number of parameters included in the multivariate models. Yet, significant clinical and statistical parameters were chosen to produce the clinical and laboratory multivariate models, and to identify key risk factors. These multivariate models can be used to develop a scoring system for a severe disease, which should be validated in future research.
Finally, various variables such as severe GI involvement (colitis) and macrophage activating syndrome can negatively affect outcomes in patients with MIS-C. Haemodynamic compromise was selected as the marker for severity in this study, as it represents the merging end point of all the severe complications. However, other outcomes should be acknowledged and investigated in future studies.
The findings of this study may help clinicians to identify clinical and laboratory signs to predict a severe disease course, as reflected by the need for inotropic support. Identification of patients at high risk to develop a severe disease course may lead to earlier, more aggressive treatment decisions. While the pandemic continues, future larger prospective cohorts will be needed to validate these findings.
Supplementary material
Supplementary material is available at Rheumatology online.
Data availability
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary material. Derived data supporting the findings of this study are available from the corresponding author on request.
Funding
No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: The authors have declared no conflicts of interest.
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