Abstract
Background
The emergence of Multisystem Inflammatory Syndrome in Children (MIS-C) during the COVID-19 pandemic has posed new challenges in differentiating it from classical Kawasaki disease (KD). Understanding their distinct presentations and outcomes is crucial for appropriate management strategies. We aimed to characterize and compare the clinical presentations, laboratory findings, cardiac manifestations, and treatment outcomes of KD and MIS-C in pediatric patients during the COVID-19 pandemic at a tertiary care center in Saudi Arabia.
Methods
In this retrospective cohort study, we analyzed data from 41 pediatric patients (ages 0–14 years) diagnosed with either KD (n = 31) or MIS-C (n = 10) between January 2020 and December 2023. Diagnoses were established using the American Heart Association criteria for KD and World Health Organization criteria for MIS-C. Clinical features, laboratory parameters, cardiac findings, and treatment responses were compared between groups.
Results
Among the 41 patients (median age 5.6 years, 56.1% male), KD patients demonstrated significantly higher rates of conjunctivitis (64.5% vs. 0%, p < 0.001) and rash (80.6% vs. 40%, p = 0.014) compared to MIS-C patients. Laboratory findings showed distinct patterns: KD patients had higher ESR (92.9 ± 50.7 vs. 58.4 ± 28.6 mm/hr, p = 0.042) and albumin levels (3.4 ± 0.4 vs. 3.1 ± 0.3 g/dL, p = 0.026), while MIS-C patients exhibited higher ferritin (1907 ± 3602 vs. 239 ± 397 ng/mL, p = 0.05), AST (398 ± 554.7 vs. 39.03 ± 23.8 U/L, p = 0.013), and LDH levels (973 ± 991.1 vs. 297.0 ± 96.6 U/L, p = 0.006). Coronary artery abnormalities were more frequent in KD (35.5% vs. 10% for diameter > 2 mm), with one case developing a coronary aneurysm. One mortality occurred in the MIS-C group due to sepsis.
Conclusions
This study identifies distinct clinical and laboratory profiles between KD and MIS-C during the COVID-19 pandemic. While both conditions can affect the coronary arteries, our findings suggest potentially different pathophysiological mechanisms. These observations may help inform diagnostic approaches and treatment strategies, though larger multicenter studies are needed to validate these findings.
Keywords: Kawasaki disease, Multisystem inflammatory syndrome in children, COVID-19, SARS-CoV-2, Coronary artery abnormalities, Pediatric vasculitis
Introduction
Kawasaki disease (KD) is an acute, self-limiting systemic vasculitis that predominantly affects medium- and small-sized arteries in children, particularly those under 5 years of age. Since its first description by Tomisaku Kawasaki in 1967, KD has emerged as the leading cause of acquired heart disease in children in developed countries [1]. In the absence of prompt diagnosis and appropriate treatment, coronary artery aneurysms develop in approximately 25% of cases, potentially leading to significant cardiac complications [2].
The diagnosis of KD remains primarily clinical, based on characteristic features including persistent fever, bilateral non-purulent conjunctivitis, changes in the lips and oral mucosa, polymorphous rash, cervical lymphadenopathy, and changes in the extremities [2]. The standard treatment protocol involves intravenous immunoglobulin (IVIG) and high-dose aspirin, which effectively reduces the risk of coronary artery abnormalities from 25% to less than 5% when administered within the first 10 days of illness [3–5].
The global COVID-19 pandemic has brought unprecedented challenges to pediatric healthcare, including the emergence of a new clinical entity: Multisystem Inflammatory Syndrome in Children (MIS-C). First reported in Europe in early 2020, MIS-C shares several clinical features with KD but demonstrates distinct characteristics [6]. This temporal association with SARS-CoV-2 infection has reinvigorated interest in the potential infectious triggers of KD and raised important questions about the pathophysiological mechanisms underlying both conditions [7].
The relationship between SARS-CoV-2 infection and these inflammatory conditions in children remains incompletely understood. Some studies suggest that implementing non-pharmaceutical interventions during the COVID-19 pandemic affected the incidence of KD [7], while others report clusters of severe Kawasaki-like disease in areas with high SARS-CoV-2 transmission [6]. Understanding the distinctions between classical KD and MIS-C is crucial for appropriate diagnosis, management, and monitoring of affected children.
In this context, we conducted a comprehensive analysis of all cases of KD and MIS-C presenting to our center during the COVID-19 pandemic. Our study aimed to characterize the clinical presentations, laboratory findings, and outcomes of both conditions, with particular attention to cardiac complications. This analysis provides valuable insights into the spectrum of inflammatory conditions affecting children during the COVID-19 era and may help inform diagnostic and therapeutic approaches in similar healthcare settings.
Methods
Study design and setting
This retrospective cohort study was conducted at Mouwasat Hospital, a tertiary care center in the Eastern Province of Saudi Arabia. We analyzed data from pediatric patients diagnosed with either Kawasaki Disease (KD) or Multisystem Inflammatory Syndrome in Children (MIS-C) between January 2020 and December 2023. The study protocol received approval from the institutional review board of Mouwasat Hospital (approval number (approval number#2023-D006), and written informed consent was obtained from all participants’ parents or legal guardians. The research protocol was conducted in accordance with the Declaration of Helsinki.
Study population and case definition
We enrolled pediatric patients aged 0–14 years presenting with febrile illness lasting three or more days, who met diagnostic criteria for either KD or MIS-C in Children. For KD diagnosis, we adhered to the American Heart Association guidelines, requiring fever for ≥ 5 days plus four of the five principal clinical criteria (bilateral non-exudative conjunctivitis, oropharyngeal changes, polymorphous exanthem, peripheral extremity changes, and cervical lymphadenopathy) or fewer criteria in the presence of coronary artery abnormalities. MIS-C diagnosis followed World Health Organization criteria, requiring fever, elevated inflammatory markers, multi-system involvement, and evidence of SARS-CoV-2 infection or exposure. We excluded patients with alternative diagnoses that could explain their presentation or those with incomplete clinical data [8, 9].
Clinical assessment and data collection
A comprehensive standardized data collection form was used to record patient information, including demographic characteristics, clinical presentations, laboratory findings, and cardiac evaluations. Clinical assessment documented specific manifestations including rash, bilateral non-purulent conjunctivitis, mucocutaneous inflammation (involving oral cavity, hands, or feet), cardiovascular abnormalities (hypotension, shock, cardiac dysfunction, pericarditis, valvulitis, coronary abnormalities), coagulation disorders (prolonged prothrombin time, elevated D-dimer), and gastrointestinal symptoms (diarrhea, vomiting, abdominal pain). Laboratory evaluation included inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, procalcitonin), complete blood count, comprehensive metabolic panel, cardiac biomarkers, and coagulation studies. SARS-CoV-2 exposure was confirmed through PCR testing, serological studies, antigen testing, or documented contact with confirmed COVID-19 cases. Echocardiographic studies were performed by pediatric cardiologists using standardized protocols, with coronary artery dimensions indexed to body surface area and expressed as Z-scores according to established normative data.
Treatment protocol
Management strategies adhered to current clinical guidelines. Standard therapy for KD consisted of intravenous immunoglobulin (IVIG) administration at 2 g/kg as a single infusion, combined with high-dose aspirin (80–100 mg/kg/day). For MIS-C patients, treatment was individualized based on clinical severity and organ involvement, following a predetermined protocol that included immunomodulation and supportive care as needed. Treatment response was monitored through clinical parameters and serial laboratory assessments, with additional therapy initiated for refractory cases according to established algorithms [4].
Follow-up and outcomes assessment
All patients underwent systematic follow-up evaluations at predetermined intervals. These assessments included clinical examination, laboratory testing, and echocardiographic studies. The primary outcomes of interest included resolution of clinical symptoms, normalization of inflammatory markers, and development or resolution of cardiac complications. Coronary artery dimensions were tracked over time and classified according to established z-score criteria.
Statistical analysis
Data analysis was performed using SPSS software version 28 (IBM Corp., Armonk, NY, USA). We expressed continuous variables as mean ± standard deviation or median (range) based on their distribution, as assessed by the Kolmogorov-Smirnov test. Categorical variables were presented as frequencies and percentages. Comparisons between KD and MIS-C groups employed Student’s t-test or Mann-Whitney U test for continuous variables and chi-square or Fisher’s exact test for categorical variables, as appropriate. Statistical significance was set at a two-sided p-value of less than 0.05.
Results
Study population demographics
The study comprised 41 pediatric patients, with 31 (75.6%) diagnosed with KD and 10 (24.4%) with MIS-C. The overall median age was 5.6 years (range: 1–14 years), with a mean of 6.1 ± 3.1 years. Male patients constituted 56.1% of the study population. The majority of participants (80.5%) were of Saudi nationality. The mean height and weight of participants were 107.8 ± 22.1 cm and 21.3 ± 16.3 kg, respectively. Notably, there were no statistically significant differences between KD and MIS-C groups regarding age (p = 0.25), gender (p = 0.77), nationality (p = 0.97), height (p = 0.48), or weight (p = 0.31), Table 1.
Table 1.
Demographic and anthropometric characteristics of study participants by disease group
| Characteristic | Total (N = 41) | KD (n = 31) | MIS-C (n = 10) | P-value |
|---|---|---|---|---|
| Age, years | ||||
| Mean ± SD | 6.1 ± 3.1 | 5.6 ± 2.6 | 7.4 ± 4.2 | 0.24 |
| Median (range) | 5.6 (1–14) | 5.3 (1-11.2) | 6.7 (1.5–14) | |
| Gender, n (%) | ||||
| Female | 18 (43.9) | 14 (45.2) | 4 (40.0) | 0.77 |
| Male | 23 (56.1) | 17 (54.8) | 6 (60.0) | |
| Nationality, n (%) | ||||
| Saudi | 33 (80.5) | 25 (80.6) | 8 (80.0) | 0.96 |
| Other | 8 (19.5) | 6 (19.4) | 2 (20.0) | |
| Anthropometric measures | ||||
| Height, cm | 107.8 ± 22.1 | 105.6 ± 17.2 | 114.8 ± 33.4 | 0.48 |
| Weight, kg | 21.3 ± 16.3 | 18.1 ± 6.7 | 31.4 ± 29.8 | 0.31 |
| BMI | 16.8 ± 3.9 | 15.8 ± 2.3 | 19.7 ± 6.4 | 0.11 |
| BMI percentile, % | 45.7 ± 35.7 | 40.3 ± 34.7 | 62.5 ± 34.9 | 0.12 |
Abbreviations: KD, Kawasaki Disease; MIS-C, Multisystem Inflammatory Syndrome in Children; SD, standard deviation; BMI, body mass index. Other nationalities included Colombian (n = 1), Indian (n = 1), and Egyptian (n = 6). Values are presented as mean ± SD or frequency (percentage). P-values were calculated using Student’s t-test or Mann-Whitney U for continuous variables and Chi-square test for categorical variables. BMI calculated as weight in kilograms divided by height in meters squar
Laboratory findings
Significant differences in inflammatory markers and biochemical parameters were observed between the two groups. KD patients demonstrated higher mean ESR levels (92.9 ± 50.7 vs. 58.4 ± 28.6 mm/hr, p = 0.042) and albumin concentrations (3.4 ± 0.4 vs. 3.1 ± 0.3 g/dL, p = 0.026) compared to MIS-C patients. Conversely, MIS-C patients exhibited significantly elevated levels of AST (398 ± 554.7 vs. 39.03 ± 23.8 U/L, p = 0.013) and LDH (973 ± 991.1 vs. 297.0 ± 96.6 U/L, p = 0.006). Notably, ferritin levels were markedly higher in the MIS-C group (1907 ± 3602 ng/mL) compared to the KD group (239 ± 397 ng/mL, p = 0.05), Table 2.
Table 2.
Laboratory findings by disease group
| Characteristic | Total (N = 41) | KD (n = 31) | MIS-C (n = 10) | P-value |
|---|---|---|---|---|
| Inflammatory markers | ||||
| CRP, mg/L | 83.1 ± 89.9 | 87.3 ± 93.1 | 69.9 ± 82.4 | 0.50 |
| ESR, mm/hr | 84.5 ± 48.4 | 92.9 ± 50.7 | 58.4 ± 28.6 | 0.042 |
| Ferritin, ng/mL | 645.5 ± 1887.7 | 239 ± 397 | 1907 ± 3602 | 0.05 |
| Hematologic parameters | ||||
| TLC, ×10³/µL | 9.5 ± 6.3 | 9.8 ± 5.5 | 8.6 ± 7.7 | 0.18 |
| Hemoglobin, g/dL | 10.4 ± 10.3 | 10.4 ± 0.9 | 10.4 ± 2.1 | 0.73 |
| Platelets, ×10³/µL | 395.9 ± 270.3 | 427.3 ± 294.2 | 298.4 ± 149.3 | 0.23 |
| Biochemical parameters | ||||
| Albumin, g/dL | 3.3 ± 0.4 | 3.4 ± 0.4 | 3.1 ± 0.3 | 0.026 |
| ALT, U/L | 79.1 ± 164.7 | 30.8 ± 30.7 | 228.6 ± 290.8 | 0.16 |
| AST, U/L | 126.6 ± 306.6 | 39.0 ± 23.8 | 398.0 ± 554.7 | 0.013 |
| LDH, U/L | 461.9 ± 560.7 | 297.0 ± 96.6 | 973.0 ± 991.1 | 0.006 |
| Electrolytes | ||||
| Sodium, mEq/L | 137.1 ± 3.2 | 137.0 ± 3.0 | 136.0 ± 4.0 | 0.58 |
| Potassium, mEq/L | 4.3 ± 0.7 | 4.3 ± 0.7 | 4.3 ± 0.4 | 0.64 |
| Urinalysis, n (%) | ||||
| Pyuria present | 11 (26.8) | 8 (25.8) | 3 (30.0) | 0.79 |
| No pyuria | 30 (73.2) | 23 (74.2) | 7 (70.0) |
Abbreviations: KD, Kawasaki Disease; MIS-C, Multisystem Inflammatory Syndrome in Children; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TLC, total leukocyte count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase. Values are presented as mean ± SD or frequency (percentage). P-values were calculated using Student’s t-test for continuous variables and Chi-square test for categorical variables
Clinical manifestations
Clinical presentation patterns differed significantly between the two groups. Rash was more prevalent in KD patients compared to MIS-C patients (80.6% vs. 40%, p = 0.014). Additionally, conjunctivitis was exclusively observed in KD patients (64.5% vs. 0%, p < 0.001).
Cardiac manifestations
Echocardiographic findings revealed coronary artery involvement in both groups, though with different patterns. The mean left anterior descending (LAD) coronary artery diameter was 2.7 ± 0.7 mm in KD patients and 2.5 ± 0.5 mm in MIS-C patients, while the right coronary artery (RCA) diameter averaged 2.1 ± 0.5 mm and 2.1 ± 0.3 mm respectively. Coronary artery dilation (diameter > 2 mm) was more frequent in KD patients (35.5%) compared to MIS-C patients (10%), although this difference did not reach statistical significance. More severe dilation (> 2.5 mm) was observed in 22.6% of KD patients, while no MIS-C patients exhibited this degree of involvement. One notable case in the KD group developed a coronary artery aneurysm with an absolute diameter of approximately 5 mm, Fig. 1.
Fig. 1.
Coronary artery aneurysm in a patient with Kawasaki Disease. (A) Two-dimensional echocardiogram at initial presentation showing coronary artery aneurysm with maximal diameter of 5.0 mm. (B) Follow-up echocardiogram demonstrating partial regression of the aneurysm with reduction in maximal diameter to 4.0 mm. Images were obtained using standard parasternal short-axis view. Scale bars represent 1 mm
Treatment response and outcomes
Two cases in the KD group demonstrated resistance to initial IVIG treatment, necessitating a second dose of IVIG and additional corticosteroid therapy. The study recorded one mortality case (2.4%) in the MIS-C group, though this was attributed to sepsis rather than primary disease complications, Table 3. Overall, treatment responses were generally favorable, with most patients showing improvement with standard therapeutic protocols.
Table 3.
Echocardiographic findings by disease group
| Parameter | Total (N = 41) | KD (n = 31) | MIS-C (n = 10) | P-value |
|---|---|---|---|---|
| Coronary artery measurements | ||||
| LAD diameter, mm | 2.6 ± 0.7 | 2.7 ± 0.7 | 2.5 ± 0.5 | 0.59 |
| RCA diameter, mm | 2.1 ± 0.5 | 2.1 ± 0.5 | 2.1 ± 0.3 | 0.89 |
| Z-scores | ||||
| LAD Z-score | 0.9 ± 1.8 | 1.26 ± 1.72 | 0.14 ± 2.06 | 0.26 |
| RCA Z-score | 0.2 ± 1.4 | 0.30 ± 1.35 | -0.24 ± 1.62 | 0.54 |
| LAD dilation, n (%) | ||||
| ≥2.0 mm | 12 (29.3) | 11 (35.5) | 1 (10.0) | 0.12 |
| ≥2.5 mm | 7 (17.1) | 7 (22.6) | 0 (0.0) | 0.09 |
| RCA dilation, n (%) | ||||
| ≥2.0 mm | 4 (9.8) | 3 (9.7) | 1 (10.0) | 1.00 |
| ≥2.5 mm | 3 (7.3) | 3 (9.7) | 0 (0.0) | 0.56 |
Abbreviations: KD, Kawasaki Disease; MIS-C, Multisystem Inflammatory Syndrome in Children; LAD, left anterior descending coronary artery; RCA, right coronary artery. Values are presented as mean ± SD or frequency (percentage). P-values were calculated using Student’s t or Mann-Whitney U tests for continuous variables and Chi-square or Fisher’s exact tests for categorical variables
Discussion
Our study contributes significant insights into the distinction between KD and MIS-C during the COVID-19 pandemic. While both conditions share some clinical features, our findings reveal important differences in presentation, laboratory markers, and cardiac manifestations that may reflect distinct pathophysiological mechanisms [10, 11]. These observations are particularly relevant given the ongoing debate about the relationship between SARS-CoV-2 infection and inflammatory conditions in children.
Our findings reveal significant differences in the clinical presentation between KD and MIS-C. The higher prevalence of rash (80.6% vs. 40%, p = 0.014) and conjunctivitis (64.5% vs. 0%, p < 0.001) in KD patients represents a distinctive pattern [12]. The laboratory profile also showed notable differences, with KD patients exhibiting elevated ESR and albumin levels [13], while MIS-C patients demonstrated higher transaminases and LDH. These findings align with a recent large-scale study from China [14], suggesting consistency in clinical and laboratory manifestations across different ethnic groups.
A key finding of our study was the pattern of coronary involvement. While statistical significance was not reached between groups, we observed more frequent coronary dilatation in KD patients. Most cases showed only mild dilatation, with a single case developing significant coronary aneurysm (> 5 mm). This pattern of less severe and more transient coronary involvement in MIS-C compared to classical KD aligns with previous findings [15]. However, our observations contrast with some studies reporting more severe cardiac involvement and higher requirements for second-line treatment [16, 17]. These differences might be attributed to population-specific genetic variations influencing disease phenotype.
Our study builds upon previous research in Saudi Arabia, including work from the Albaha region in 2019 [18]. Our investigation is distinguished by its timing during the COVID-19 pandemic and its focus on the eastern province. The apparent increase in KD and KD-like cases during the COVID-19 era, coupled with positive SARS-CoV-2 testing in many cases, suggests a potential association between SARS-CoV-2 prevalence and disease incidence. This association is further supported by our observation that SARS-CoV-2 was the predominant respiratory virus circulating during the study period, as evidenced by respiratory multiplex PCR results.
Our study has several notable strengths. First, it represents one of the first comprehensive analyses of KD and MIS-C in the eastern province of Saudi Arabia during the COVID-19 pandemic, providing valuable regional epidemiological data. Second, our detailed clinical and laboratory characterization of both conditions contributes to the growing body of evidence differentiating these entities. Third, our standardized approach to diagnosis and treatment allows for reliable comparison with other studies.
However, we acknowledge several limitations. The single-center design and relatively small sample size, particularly in the MIS-C group (n = 10), may limit the generalizability of our findings. The retrospective nature of the study introduces potential for selection and information bias. Additionally, not all patients underwent routine SARS-CoV-2 testing, which may have affected our ability to fully characterize the relationship between viral infection and disease manifestation. Finally, the relatively short follow-up period limits our ability to assess long-term outcomes and complications.
The strength of this study is that all patients in a defined population from a single pediatric center in the middle east.
Limitation
The main limitation of our study was the small sample size and observational nature of retrospective data collection, but we aim at expanding the study to include more data from other centers in the region in the near future.
Conclusion
This study provides compelling evidence for increased incidence of Kawasaki disease and KD-like illness in children during the SARS-CoV-2 pandemic. The findings highlight the need for healthcare providers and authorities to be aware for potential increases in different spectrum of Kawasaki disease and Kawasaki like disease. Our analysis of clinical and laboratory characteristics in this population during the COVID-19 pandemic offers valuable insights into disease patterns and management strategies. However, further multi-center studies are warranted to fully understand the implications of these findings and their impact on patient care. We are actively planning collaborative efforts with other centers to expand upon this research and deepen our understanding of this significant pediatric condition.
Acknowledgements
Not applicable.
Abbreviations
- KD
Kawasaki disease
- MIS-C
Multisystem inflammatory syndrome in children
- CRP
C-reactive protein
- ESR
Erythrocyte sedimentation rate
- TLC
Total leukocyte count
- ALT
Alanine aminotransferase
- AST
Aspartate aminotransferase
- LDH
Lactate dehydrogenase
Authors contributions
1 YS is the primary investigator and contributed in data collection, clinical work and wrote the final draft of the manuscript and approved the final version. 2 SW contributed in data collection, clinical work and wrote the final draft of the manuscript and approved the final version. 3 SA contributed in data collection, clinical work and wrote the final draft of the manuscript and approved the final version. 4 SA contributed in data collection, clinical work and wrote the final draft of the manuscript and approved the final version. 5 YF contributed in data collection, clinical work and wrote the final draft of the manuscript and approved the final version. 6 ET wrote the final draft of the manuscript and approved the final version. 7 HA wrote the final draft of the manuscript and approved the final version. 8 GM contributed in data collection, clinical work and wrote the final draft of the manuscript and approved the final version.
Funding
Not applicable, nothing to disclose. We did not receive any funding and we have nothing to declare.
Data availability
The datasets generated during and/or analyzed during the current study are not publicly available due hospital policy not violating the patient’s privacy, but are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Written informed consent was obtained from all participants’ parents or legal guardians. The research protocol was conducted in accordance with the Declaration of Helsinki.
Consent for publication
All authors approved the final version for publication and consent is available upon request to the corresponding author.
Competing interests
Not applicable.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are not publicly available due hospital policy not violating the patient’s privacy, but are available from the corresponding author on reasonable request.