key: cord-0963632-f6krmvwx
authors: LAMRANI, Loubna; Manlhiot, Cedric; Elias, Matthew D.; Choueiter, Nadine F.; Dionne, Audrey; Harahsheh, Ashraf S.; Portman, Michael A.; McCrindle, Brian W.; DAHDAH, Nagib
title: Kawasaki Disease Shock Syndrome versus classical Kawasaki Disease, a Meta-analysis and comparison with SARS-CoV-2 Multisystem Inflammatory Syndrome
date: 2021-06-06
journal: Can J Cardiol
DOI: 10.1016/j.cjca.2021.05.014
sha: d4d20649cd12f44583b1a46d9c33ff293b93402f
doc_id: 963632
cord_uid: f6krmvwx

Background The emergence of increasing reports worldwide of a severe inflammatory process and shock in pediatric patients resembling Kawasaki disease (KD) and more specifically Kawasaki disease shock syndrome (KDSS), prompted us to explore KDSS in a preamble of a systematic comparison between the two conditions. Methods We completed a systematic review of KDSS and performed a meta-analysis comparison between reported KDSS cases and KD controls. Results A total of ten case-control series were included in the meta-analysis. KDSS patients were older (38.4 ± 30.6 vs. 21.9±19.5 months; P<0.001) compared to standard KD with equal sex distribution and completeness of clinical diagnostic criteria. KDSS present higher CRP (59.4±29.2 mg/dL vs. 20.8±14.8 mg/dL; p<0.001), lower albumin (2.7±0.5 g/dL vs. 3.3±0.5 g/dL; p<0.01), and lower platelets (255±149 109/L vs. 394±132 109/L; p<0.001) but only borderline higher WBC's (p=0.06). Differences in ALT, AST and ESR were non-significant. The odds of IVIG resistance (44.4% vs. 9.6%; (p<0.001) and the hospital length of stay (10.9±5.8 vs. 5.0±3.0 days; p<0.001) were higher in KDSS as were the odds of coronary artery abnormalities (33.9% vs. 8.6%; p<0.001). Conclusion This first meta-analysis on KDSS versus KD represents a basis for future works on KDSS and opens the opportunity for future multicenter studies in the search of causal relationships between presenting elements and the eventual complications of KDSS. The similarities between SARS-CoV-2 multisystem inflammatory syndrome in children (MIS-C) and KDSS open new horizons to the understanding of the etiology and pathophysiology related to KDSS.

Kawasaki disease (KD) is the leading cause of acquired childhood heart diseases in developed countries mostly affecting children under the age of five. It is classified among the acute immune vasculitis and may result in coronary artery aneurysms, as they account for the most severe complication since they occur in 25% of untreated KD cases (1). A single high-dose of intravenous immunoglobulin (IVIG) combined with aspirin is the most efficient primary treatment for KD, as it reduces the risk of coronary arteries abnormalities and resolves inflammation (1). The generalized aspect of KD sometimes implies a multi-organ involvement, which might include cerebral involvement (e.g. aseptic meningitis, cerebral stoke (2), renal involvement (e.g. proteinuria, hematuria, sterile pyuria, renal failure) (3), gastrointestinal involvement (e.g. diarrhea, vomiting, abdominal pain), hepatic involvement (raised liver enzymes), and other organs (4). This multi-organ dysfunction is also observed in a rare form of KD called Kawasaki disease shock syndrome (KDSS). Cases of KDSS were reported over the last decade and a half, but remain rare, representing 1% to 7% of KD (5). KDSS is described as KD involving a patient with complete or incomplete criteria who requires resuscitation, inotropic / vasoactive agents support, and or ECMO, with the shock being unrelated to an acute coronary event.

Form another perspective, the etiology of KD remains unknown, but the widely accepted hypothesis is that KD is a result of immunological response to non-specific infection (6, 7) . Previous studies have shown associations between viral respiratory infections and KD (8) (9) (10) . Thus, preceding exposure to an environmental trigger, such as a viral antigen in a genetically susceptible child, persists as the prevailing hypothesis to explain the hyperimmune response characteristic of KD. In 2005, a circumstantial association between the New Haven coronavirus outbreak and KD was advanced but was not supported by further assessment (11) . Subsequent reports unsuccessfully attempted to link KD to other types of coronaviruses (8, (12) (13) (14) .

In late 2019 early 2020 the SARS-CoV-2 pandemic caused lower respiratory tract infection and an acute respiratory syndrome in adults (COVID-19) (15) . Initial pediatric case series focused on characterizing SARS-CoV-2 rare respiratory illness in children as less than 4% of pediatric cases require admission to intensive care units for inotropic or circulatory mechanical support (16) . In April 2020, a group of KD experts published a warning letter regarding the possibility of a missed or delayed KD diagnosis amid the SARS-CoV-2 pandemic crisis, either by under-diagnosis or by parental sheltering of their children by fear of contracting the virus while consulting. The concern was that worse outcomes will ensue in severe cardiac consequences, such as coronary artery abnormalities (17) . Subsequent reports on children developing other types of critical illness secondary to SARS-CoV-2 exposure, caused by a hyper-immune reaction with features of KD (18) (19) (20) . This clinical syndrome is now termed by the U.S. Centers for Disease Prevention and Control (CDC) as the Multisystem Inflammatory Syndrome in Children (MIS-C) and requires evidence of SARS-CoV-2 exposure to fulfill the case definition (21, 22) .

As MIS-C reports emerged, similarities with KDSS surfaced from the clinical and the biological perspectives. Therefore, the increased prevalence of KDSS-like cases during the SARS-CoV-2 pandemic is an opportunity to further investigate KDSS and its possible complications. We herein review and summarize case series and reports pertaining to KDSS prior to the SARS-CoV-2 pandemic as a basis for a better understanding of KDSS and future comparison between the two entities. The objective of this paper was to describe the features of KDSS by performing a systematic review and a meta-analysis comparing KDSS to their KD controls. Since the immunogenic triggers of the two conditions (KDSS/KD and MIS-C/SARS-CoV-2) bear some similarities, this manuscript displays qualitative comparison between the two entities.

For the KDSS systematic review and to perform the meta-analysis, we searched PubMed for case reports and case series reporting Kawasaki Disease with shock. The search terms used were "Kawasaki Disease", "Kawasaki Disease shock syndrome", "Kawasaki Disease + shock" and "Kawasaki Disease + hypotension." Abstracts were reviewed to identify relevant articles. Studies were excluded if they were not in English or if they did not present sufficient information about their shock patients (e.g. shock intervention and treatment). The following data were collected from each article: patient demographics (including age, sex, ethnicity), clinical criteria for KD (complete or incomplete), elements of shock (low blood pressure, low perfusion, myocardial dysfunction), laboratory findings, treatment received for KD and shock, intensive care unit (ICU) length of stay and outcome, cardiac complications (coronary artery aneurysms or dilatation, residual cardiac dysfunction).

A total of 70 publications relating to KDSS were identified, including 52 case reports and 18 case series. After review, 39 case reports presenting 47 patients were included in the aggregated data collection, whereas 14 case reports were excluded (2 were not in English (one was in Chinese and the other in German) and 11 included patients without shock). There were 18 case series; 4 of which were excluded for insufficient information. Of the remaining 14 case series, 4 case series did not have KD controls and were excluded from the meta-analysis but used for the aggregated data collection and presented a total of 85 KDSS patients (23) (24) (25) (26) . The following 10 case series composed the elements for meta-analysis (5, 27-35) (Figure 1 ). The KDSS group was composed of 280 patients, while the control group was composed of 9943 patients (9350 controls from Lin MT et al. (35) . KDSS diagnostic criteria used across the 10 studies were either KD patients admitted to the ICU for hypotension and/or shock or KD patients presenting with systolic hypotension for age following Kanegaye's definition (36) .

We only included case-control studies for our meta-analysis. Therefore, the KDSS/control comparison includes only data from the 10 reports that included a control group from the same population (5, (27) (28) (29) (30) (31) (32) (33) (34) (35) . Data from the 4 case series without KD controls were excluded from meta-analysis (24) (25) (26) 36) . For the meta-regression, a sensitivity analysis was done without the series by Lin MT, et al (given the high control N, the standard error of the difference is very low). The results are comparable and thus the sensitivity analysis is not reported. Meta-regression was performed only if at least 5/10 studies reported a specific parameter. Meta-regressions were performed using the Metafor package for R. For each parameter we report separately the weighted average for the 10 reports that are included in the KDSS/control comparisons and the weighted average for the 14 series and the combined case reports. A weighted average was performed for the aggregated data, which included the case reports and the excluded case series from the meta-analysis. When necessary mean and standard deviations were estimated from median and interquartile range (IQR) or median and min/max using the method proposed in Wan X et al (37) . Mean, standard deviation, median and frequencies were extracted, and presented as number (percentage), median [range], or mean  SD.

The combined effect p-value was calculated. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for appropriate metaanalysis methodology (38) . This study was exempt from ethics review. (Table 1 ). The admitting diagnosis of KDSS cases is not KD in general leading possibly to longer hospital stay, with the lowest study (27) having 22% of their patients presenting with KD as initial diagnosis and the highest study (31) presenting with 65%, KDSS is associated with slightly higher WBC and significantly lower platelet counts than controls (Figure 3 (Table 1) . Other cardiac biomarkers such as troponin were only reported in 2 studies, and Gamma-glutamyl transferase was only reported in a single study. Elevated D-dimers, while rarely reported due to unavailable data, were particularly present in KDSS accompanying the cytokine storm. Only recent reports presented patients with the macrophage activation syndrome (MAS) (31) .

Multi-organ components. Multi-organ dysfunction and myocardial systolic dysfunction were reported in a small number of studies and were therefore insufficient for comparative analysis. In general, KDSS patients were reported to develop higher proportions of depressed left ventricular systolic function (12.4%), pericardial effusions (22.2%), or atrio-ventricular valve regurgitation (32.8%) compared to KD (Table 1) . Due to an overall low reporting on cardiac involvement in the references we did not perform statistical comparison. From the pathophysiology perspective, 5 patients presented with a cardiogenic shock while 3 presented with a distributive shock, suggesting that KDSS might cause various mechanisms of shock (25) Figure 2-d) . The definition of CAA was not uniformly defined among the source series however, which limits the qualitative discrimination between aneurysms and dilatation, as well as the quantitative determination of size of the CAA. For instance, Gamez-Gonzalez et al. (39) reported a very high prevalence of CAA in the control group (58%), which makes the CAA rate in in that group questionable.

IVIG therapy was reported in all but one study for KDSS. In many studies, treatment with IVIG was among the inclusion criteria and as such, rate of IVIG is universally high. No meta-regression analyses were performed for IVIG, aspirin and corticosteroid use due to insufficient variance between studies. Overall, KDSS patients received IVIG in 98.9% (n=280), aspirin in 98.8% (n=252) and corticosteroids in 36.7% (n=98) whereas KD controls received IVIG in 99.9% (n=9593), aspirin in 100% (n=9514) and corticosteroids in 11.0% (n=219). KDSS was associated with increased odds of IVIG resistance (44.4%) compared to controls (9.6%) (Figure 2 (Table 2 ). In general, these patients presented a very similar profile to the KDSS patients from our meta-analysis.

There was identical male predominance (58%, 77/132), high IVIG resistance (44%), similar shock treatment with a predominance of fluid resuscitation and inotropic support with 35% receiving ventilation support. Some differences were seen between the group of the meta-analysis and the aggregated data. More KDSS patients presented with incomplete KD (50%) in the aggregated data compared to meta-analysis estimate (34.7%). Aspirin usage for the treatment of KDSS was much less reported in the aggregated data group compared to the meta-analysis. From the cardiac involvement perspective, systolic dysfunction was present in higher proportion in the aggregated data (34%) compared to the meta-analysis (12.4%), and CAA as well (reporting "abnormalities" in 15%, specifying dilatations and aneurysms in 31% and 22% respectively). The initial circumstantial evidence suggesting a causal link between MIS-C and COVID-19 is now supported by serology data and immunologic mechanisms. Patients initially presented with MIS-C within two to six weeks following the outbreak of the pandemic. The main characteristics of MIS-C present many similarities with KDSS which have been qualitatively compared in Table 3 . Although MIS-C is reportedly associated with lymphopenia, reports on KDSS do not provide lymphocyte counts.

In the spring of 2020, the CDC collected 570 suspected MIS-C cases in the U.S.(41). The ensuing report described three distinct classes based on Latent Class Analysis. Class 1, (203 patients (35.6%), median age 9 years) had severe multi-organ involvement; half of them with six or more organ system involvement, with a predominance for the gastrointestinal in 97.5% and the cardiovascular system in 100%.

This group had the highest rate of complications and high markers of inflammation and cardiac involvement (troponin rise, elevated BNP, shock, congestive heart failure, cardiac dysfunction, myocarditis, coronary abnormalities, pericardial effusion and mitral regurgitation). Class 2, (169 patients (29.6%), median age 10 years), where the respiratory system involvement was predominant including the acute respiratory distress syndrome had the highest death toll (5.3%). Class 3, (198 patients (34.7%), median age 6 years) was the youngest age group, had the lowest comorbidities, organ system involvement (including cardiac damage) and markers of inflammation. This latter class presented the highest prevalence of skin rash and mucocutaneous lesions, was "less (11) . The association between HCoV-NH and was refuted in the following years in Japan, the U.S., and Taiwan (46) (47) (48) , as the association between HCoV-NL63 and KD was likewise refuted (13, 14, 49) . Since then, Chang et al. proposed in 2014 that KD patients had higher chances of being infected by coronavirus than temporal local controls (8) , and their hypothesis was supported by Shirato et al. who found a possible association between another strain of coronavirus (HCoV-229E or the Sendai-H serotype) and KD (12) . In this line of thoughts, KDSS should be maintained in the list of differential diagnoses of MISC or shock with or without presenting features of KD notwithstanding the circumstantial association between the clinical presentation and the exposure and or infection with SARS-CoV-2.

Risk of bias. KDSS data are from retrospective series of consecutive cases in single institutions, which excludes selection bias. Controls varied between random selection (5, 31, 34, 35, 39) , seasonal, sex and age matching (27, 30) or date of admission (28, 32, 33) .

Limitations. The main limitation of the meta-analysis is related to the rarity of KDSS and therefore the number of eligible studies. As such, some information are not readily available for proper statistics. The case definition of coronary lesions and precision between dilatation, aneurysm and giant aneurysm are not uniformly considered in the reports. The numbers for coronary artery "abnormalities" may be overestimated, as a result of the mix of types of lesions in some reports. Finally, we could not perform a cause-to-effect analysis in the meta-analysis because basic characteristics and baseline biological and laboratory data were not available in association with outcomes in a patient-by-patient tabulated format in most series. We intend however, to further study cause-to-effect relationship in a multi-center retrospective study.

This first meta-analysis represents a basis for future works on KDSS and opens the opportunity for future multicenter studies in the search of causal relationships between presenting elements and the eventual complications of KDSS. KDSS is currently acknowledged to be a sub-entity of KD. However, the similarities between the new pediatric manifestations of SARS-CoV-2, MIS-C, and KDSS opens new horizons to the understanding of the etiology and pathophysiology related to KDSS. Funding/Support: No funding was necessary for this study. Orange frame: total cases included in the meta-analysis; Green frame: 132 total cases included in the aggregated data. 

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