key: cord-0997807-4ymks8z7
authors: Pick, Justin; Rao, Mounica Y.; Dern, Kathryn; Wang, Shuo; Szmuszkovicz, Jacqueline; Wagner-Lees, Sharon; Badran, Sarah; Wong, Pierre C.; Votava-Smith, Jodie K.
title: Coronary Artery Changes in Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) : Los Angeles Experience
date: 2021-09-21
journal: J Pediatr
DOI: 10.1016/j.jpeds.2021.09.026
sha: ebc6f47f1a636819ec3ec0037232624ba5c96eb6
doc_id: 997807
cord_uid: 4ymks8z7

We compared cardiac findings in patients with multisystem inflammatory syndrome in children and Kawasaki disease in the first 6 months of the 2020 coronavirus disease pandemic to patients with Kawasaki disease during 2016-2019. We saw a high rate of coronary aneurysms in 2020, with a similar rate of coronary involvement but greater volume and incidence of cardiac dysfunction compared with previous years.

Multisystem inflammatory syndrome in children (MIS-C) is likely related to a recent SARS-CoV-2 infection. 1 The patients have heterogeneous clinical manifestations, with some Kawasaki-like features. 2 It is unclear whether MIS-C and Kawasaki disease are related entities. SARS-CoV-2infection may be a potent trigger of traditional KD, and others assert that MIS-C has a predilection toward a KD shock syndrome phenotype. 3, 4 Cardiac involvement is a frequent finding, often presenting with decreased left ventricular (LV) systolic function and/or sometimes with coronary artery aneurysms (CAA). 3, 5 One study demonstrated a high incidence of cardiogenic shock and low incidence of coronary artery changes. 6 Our experience at Children's Hospital Los Angeles (CHLA) has been different. We sought to compare CAAs and LV changes in patients who have MIS-C/KD phenotypes in the first six months of the pandemic in 2020 with patients with KD during the corresponding months of prior years.

The CHLA Kawasaki disease database contains records of all patients meeting criteria for KD (complete and incomplete) as well as MIS-C. We included all inpatients ages 1 month to 21 years diagnosed with MIS-C ( based on meeting Centers for Disease Control criteria as having positive COVID-19 antibody, a recent positive PCR or antigen test for SARS-CoV-2 on nasopharyngeal specimen, or COVID-19 exposure within the 4 weeks prior to onset of symptoms) or KD (defined based on American Heart Association guidelines) between March 1 and August 31, 2020, and then identified those who had coronary artery changes or cardiac J o u r n a l P r e -p r o o f dysfunction. 1, 5 This group was defined as the post-pandemic MIS-C/KD Group.

Patients with the diagnosis of KD with coronary changes or cardiac dysfunction between March and August of 2016 to 2019 were included for comparison. CAA were defined as coronary artery Z score >2.5 as per KD diagnostic guidelines, and cardiac dysfunction was defined as patients with a reduced LV systolic function (fractional shortening <29% or ejection fraction <55%) measured according to pediatric echocardiogram interpretation guidelines. 5, 7 The proximal right coronary artery, left main coronary artery, and left anterior descending coronary artery were re-measured in each patient by a single reviewer for consistency. Z scores were obtained using values from Boston Children's Hospital Z score system. 8 The largest post-pandemic Z scores for each coronary artery included right coronary artery Z score +34, left main coronary artery +10.5, and left anterior descending +28.6 compared with Z scores in the pre-pandemic group's CAAs of +18.8, +9.11, and +10.9, respectively. The median age of patients with isolated coronary changes between both groups was not significant, 2.3 years pre-pandemic compared with 1.3 years in the post-pandemic group (p=0.83). There was a significant difference in the age of patients with LV dysfunction, as post-pandemic MIS-C/KD patients with LV dysfunction were significantly older (median 10 years of age) than those in the pre-pandemic group (4 years of age); p=0.03. There was no difference between the two groups in the median size of CAA of the left main J o u r n a l P r e -p r o o f (p=0.62), left anterior descending (p=0.12), or right coronary artery (p=0.96) segments (Table) .

The subgroup of patients within the post-pandemic group who met CDC criteria for MIS-C and additionally had cardiac involvement (N=19) was additionally compared with the pre-pandemic group (Table) . In this subgroup, 13 patients had CAA, (46% of the 28 patients meeting CDC criteria for MIS-C ), and all 11 of the postpandemic LV dysfunction subjects met MIS-C criteria (39% of 28), with 5 overlapping both CAA and LV dysfunction groups. The proportion of patients with CAA was not statistically different between the groups (Table, 34% (Table, p=0 .19). There continued to be no significant difference in median age among those with isolated CAA (2.4 years prepandemic vs. 0.9 years post-pandemic MIS-C, p = 0.67), and there was again seen to be a significantly older age in MIS-C patients with LV dysfunction (2.4 years prepandemic vs. 8 years MIS-C, p=0.005), as well as higher weight and height in the MIS-C subgroup with cardiac involvement, likely driven by the higher age (Table) . In isolation, the Z scores for proximal right (p=0.62) and left main (p=0.46) coronary artery sizes were not significantly different, but there was a significantly larger median left anterior descending coronary Z score in the post-pandemic MIS-C subgroup (LAD Z score +3.0 vs. +4.6, p=0.03).

Our data demonstrate that during the first 6 months of the COVID-19 pandemic, although the number of cases of MIS-C/KD were higher than those of KD in prior years, the proportion of those with coronary artery findings and the types of aneurysms did not significantly differ from those who presented with KD during the same months prior to the pandemic. We found a greater incidence of LV dysfunction in our post-pandemic MIS-C/KD group compared with pre-pandemic, and all LV dysfunction was seen in patients meeting CDC criteria for MIS-C. The subgroup patients meeting CDC criteria for MIS-C in the first 6 months of the pandemic who had cardiac findings included infants, and we saw major coronary artery changes, including giant CAA with dramatically high Z scores exceeding +30 in some subjects with MIS-C.

Our findings have notable differences from prior reports and further raise the question of whether MIS-C is a new or related pathologic mechanism to KD. 9, 10 Matsubara et al describe MIS-C as having a predominance of LV dysfunction independent of coronary artery changes, and report a single CAA among 28 MIS-C cases. 6 One of the first descriptions of MIS-C from the Italian epicenter of COVID-19 mentioned two subjects with CAA >4mm of 10 total cases. 9 Another study from France in the early pandemic described 21 cases of MIS-C of which 5 had coronary dilation but no aneurysms. 11 A study from London described 8 of 58 MIS-C patients with CAA, and the Centers for Disease Control reported that 16.5% of 1733 MIS-C patients had coronary involvement. 12, 13 These four studies have rates of coronary changes of 4%, 20%, 24%, 14%, and 16.5% respectively, 6, 9, 11, 12 in contrast to our J o u r n a l P r e -p r o o f study which had a higher rate of CAA at 39% in the full MIS-C/KD group and 43% in the subgroup meeting CDC criteria for MIS-C.

The reasons for the differences seen in our population are unclear. One possible explanation is the variability in regional environmental triggers as described for KD. 14 The differences may be indicative of ethnic population differences as well, as Los Angeles has a large Hispanic population that is known to be particularly affected by MIS-C. 2, 13 Our center is also a large referral center for KD and MIS-C and located in a large metropolitan area as well as covering a large geographic area within Southern California, and we have a high rate of CAA in our KD population at baseline as well. We additionally saw several patients with coexisting LV dysfunction and CAA in our MIS-C group, which was only seen in two patients in the Italian study and no patients in the other studies. 6, 9, 11 These differences distinguish our experience from other parts of the world.

A limitation in our study is that we combined patients with KD and MIS-C into a single post-pandemic group. However, in a subgroup analysis of those meeting CDC criteria for MIS-C, the results compared with the pre-pandemic did not significantly differ from the MIS-C/KD combined results compared with prepandemic. Many of our subjects fit under diagnostic criteria for both diagnoses. In April 2020, we had a high seroprevalence of SARS-CoV-2 in Los Angeles County, such that there is potential to incompletely capture past exposure to satisfy the CDC criteria for MIS-C. 1, 15 We had many subjects with positive SARS-CoV-2 antibodies who were unaware of having prior COVID-19. If KD and MIS-C have greater differences than similarities, then this study may underestimate those differences.

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