Dermatologic manifestations of multisystem inflammatory syndrome in children during the COVID-19 pandemic


                  Objectives
                  multi-system ınflammatory syndrome in children (MIS-C) is an immune-mediated process that develops after infections like SARS-CoV-2. The authors aimed to reveal the mucocutaneous findings of patients diagnosed with MIS-C at presentation and evaluate the frequency of these mucocutaneous findings and their possible relationship with the severity of the disease.
               
                  Methods
                  A prospective study was conducted of 43 children admitted to a tertiary hospitals between January 2021 and January 2022 who met Centers for Disease Control and Prevention criteria for MIS-C.
               
                  Results
                  43 children (25 [58.1%] male); median age, 7.5 years [range 0.5‒15 years]) met the criteria for MIS-C. The most common symptom was cutaneous rash 81.4%, followed by gastrointestinal symptoms 67.4%, oral mucosal changes 65.1%, and conjunctival hyperemia 58.1%, respectively. The most common mucosal finding was fissured lips at 27.9%, diffuse hyperemia of the oral mucosa at 18.6%, and strawberry tongue at 13.9%. Urticaria (48.8%) was the most common type of cutaneous rash in the present study’s patients. The most common rash initiation sites were the trunk (32.6%) and the palmoplantar region (20.9%), respectively. The presence or absence of mucocutaneous findings was not significantly associated with disease severity.
               
                  Study limitations
                  The number of patients in the this study was small.
               
                  Conclusions
                  The present study’s prospective analysis detected mucocutaneous symptoms in almost 9 out of 10 patients in children diagnosed with MIS-C. Due to the prospective character of the present research, the authors think that the characteristic features of cutaneous and mucosal lesions the authors obtained will contribute to the literature on the diagnosis and prognosis of MIS-C.
               

There is no specific, well-defined characteristic of the skin and mucosal lesions in literature due to the variability of MIS-C patterns. In this study, the authors aimed to reveal the mucocutaneous findings of patients diagnosed with MIS-C at the presentation and evaluate the frequency of these mucocutaneous findings and their possible relationship with the severity of the disease.

Method
Forty-five patients who applied to the Faculty of Medicine, Farabi Hospital with MIS-C diagnosis between January 2021 and January 2022 were included in the present study. One patient was evaluated as having scarlet fever and one as Crimean-Congo Hemorrhagic Fever during follow-up, and therefore were excluded from the study.
According to the Centers for Disease Control and Prevention (CDC) diagnostic criteria, [6] 43 patients with a definite diagnosis of MIS-C were included in this study. The MIS-C definition provided by the CDC was used in this study, which considers the following criteria: 1) An individual aged < 21 years presenting with fever (temperature 38.0°C for 24h, or report of subjective fever lasting 24h); 2) Laboratory evidence of inflammation, including, but not limited to, one or more of the following: an elevated CRP, Erythrocyte Sedimentation Rate (ESR), fibrinogen, procalcitonin, Ddimer, ferritin, Lactic Acid Dehydrogenase (LDH), or Interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes, and low albumin; 3) Evidence of a clinically severe illness requiring hospitalization, with multisystem (two or more) organ involvement (cardiac, renal, respiratory, hematological, gastrointestinal, dermatological, or neurological); 4) A lack of an alternative plausible diagnoses, and 5) Positivity for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test, or exposure to a suspected or confirmed COVID-19 case within the 4-weeks prior to the onset of symptoms. The MIS-C definition provided by the CDC was summarized in the Online Supplementary Table S1. All patients underwent a complete dermatological physical examination at the presentation by the same dermatologist, and their rashes were followed up prospectively. The age, gender, contact or history of COVİD-19, and the severity of COVİD-19 in the family and the participants who gave consent to the study were recorded. Rash origin, involvement sites, and rash type (urticarial rash, maculopapular lesions, livedoid/necrotic lesions, pseudopernio, vesicular rash) were recorded.
According to the CDC diagnostic criteria, MIS-C severity was divided into three groups mild, moderate, and severe, and the treatment protocols recommended in the guidelines were started. [7] Disease severity classification is determined by the Vasoactive Inotropic Score (VIS), the degree of respiratory support, and evidence of organ injury. [8] Mild cases have no vasoactive requirement, minimal respiratory support, and minimal signs of organ injury. In contrast, moderate cases have a VIS ≤10, significant supplemental oxygen requirement, and mild or isolated organ injury. Severe cases have a VIS >10, non-invasive or invasive ventilatory support, and moderate or severe organ injury, including moderate to severe ventricular dysfunction. [9] The blood value parameters of the patients at the time of diagnosis (White blood cell count, absolute lymphocyte count, d-dimer, procalcitonin, C-Reactive Protein [CRP], ferritin, pro-Brain Natriuretic Peptide [pro-BNP], troponin, sodium, albumin), the treatments they are receiving, the length of stay in the hospital and intensive care unit was recorded.
Ethics approval for this study was obtained from the local ethics committee. Comparisons of measurement data between independent groups; ANOVA and Student-t-Test were used when the normal distribution condition was met, and Kruskal-Wallis and Mann-Whitney U tests were used when they were not met. The Chi-Square test was used to analyze the differences between the ratios of categorical variables in independent groups. The statistical significance level was accepted as p < 0.05.

Results
Of 43 patients diagnosed with MIS-C, 18 (41.9%) were female and 25 (58.1%) were male. The median age of the patients is 7.5 (0.5-15) years old. The onset of MIS-C was observed at a median of 4 (1-12) weeks after COVID-19 exposure. The sociodemographic and clinical characteristics of the patients are summarized in Table 1.

J o u r n a l P r e -p r o o f
The polymerase chain reaction tests for SARS-CoV-2 were positive for 4 (9.3%) patients, and the results of SARS-CoV-2 immunoglobulin G tests were positive for 39 (90.7%) patients. 42 (97.7%) of the patients were completely healthy before infection, and 1 (2.3%) had a shunt.
In the present study, a median one day after the first symptom of MIS-C (fever, abdominal pain), the patients developed a mucocutaneous rash. There wasn't any mucocutaneous involvement in 3 (6.9%) of the patients. Skin rash did not develop in 8 (18.6%) patients, and in 14 (32.6%) patients, the first site of the rash was the trunk. The mucocutaneous findings of the patients are summarized in Table 2. Some samples of clinical images are shown in Figures 1a, 1b, 1c, 1d , and 1e. Maculopapular rash on the trunk is seen in Figure 1a, erythematous urticarial plaque on the gluteal skin in Figure 1b Table 3.
In the present study, mucocutaneous involvement was found in 66.7% of patients under five years of age, while mucocutaneous involvement was found in all patients over five years of age (p = 0.007). The mean total hospital stay under five years of age was 12.89 ± 15.431; the average length of stay in the ICU is 3.00 ± 1.414. The mean full length of hospital stay above five years of age was 7.47 ± 3,395; the average length in ICU was 3.38 ± 2.13. There was no statistically significant difference between patients younger than five years old and over five years old in total hospital stay (respectively p = 0.462, p = 0.133).
Comparisons and p values between mild and moderate/severe groups according to MIS-C severity are summarized in Table 4.
The most powerful aspect of the present study is that the authors followed the patients prospectively on a daily basis and thus, we were able to present a wide range of MISC-related mucocutaneous findings. In addition, all patients in the present study had the same ethnic origin, which made it a more homogeneous group in terms of genetic influence. However, some limitations should be noted. The authors couldn't take a skin biopsy from the cutaneous lesions. This was the most important limitation of the present study.
Pouletty et al. [9] showed mucocutaneous involvement at 94%, and diffuse skin rash at 81%, and J o u r n a l P r e -p r o o f Toubiana et al. [10] showed polymorphous skin rash in 76% in MIS-C. In the present study, the frequency of mucocutaneous involvement (93%) and cutaneous inflammation (81.4%) was observed at similar rates to the literature. The data obtained in the present study and other studies are summarized in Table 5. [2,5,7,[11][12][13][14] The first site of the rash was the trunk (32.6%), and the second most common was the palmoplantar region (20.9%). Urticaria (48.8%) was the most common type of cutaneous rash in the studied patients. In literature different from the authors' findings, Yuksel et al. showed that maculopapular rash was the most common elementary lesion in 7 cases (41.2%). [13] The authors observed oral mucosal involvement in 65.1% of the patients; the most common mucosal finding was fissured lips in 27.9%, diffuse hyperemia of the oral mucosa in 18.6% of the patients, and strawberry tongue in 13.9% of the patients. In Young et al.'s study, conjunctival injection (n = 21), palmoplantar erythema (n = 18), lip hyperemia (n = 17), chapped lips (n = 13), periorbital erythema and edema (n = 7), strawberry tongue (n = 8) and malar erythema (n = 6) were reported as the most common findings. [11] In the present study, oral mucosal lesions were evaluated in detail in daily follow-ups compared to the literature; the frequency of oral involvement was higher.
The conjunctival injection was observed in 58.1% of patients, and periorbital edema was observed in 9.3%. Similar results were observed in the literature, with the rates of conjunctival injection at 57% and 55%. [2,15] Kawasaki disease is a vasculitis that affects small to medium vessels and usually affects infants and children under five. In more than 90% of cases, a diffuse maculopapular rash appears 3-5 days after the onset of fever. An urticarial inflammation is rare. There may be erythema on the palms and soles, and periungual desquamation is usually observed 2 to 3 weeks after the onset of fever. [16] However, unlike Kawasaki's disease, MIS-C has been suggested to predominantly affect adolescents and children older than five years of age and be associated with more frequent cardiovascular involvement. [17][18][19] Similar features were observed in the present study as well.
The median age of the patients is 7.5 (0.5-15). In the literature, Kaushik et al.showed that the median patient age was ten years; 61% of patients were male. [12] Feldstein et al.reported a median age of 8.3 years; 62% were male. [2] In contrast with the infantile age distribution of Kawasaki disease, MIS-C is predominantly a disease in older children and adolescents. Consistent with the literature in the present study, the male sex ratio was higher, and the median age was 7.5 years.
Although Black or Hispanic/Latin ethnicity was reported most frequently in most studies, [1,12] the present study revealed a more homogeneous group data as there was only one ethnicity (Turkish).
In the present study, systemic symptoms appeared a median of 4 (1-12) weeks after exposure to COVID-19. A study by Belot et al. [20] reported 4-5 weeks after the peak of COVID-19 cases.
J o u r n a l P r e -p r o o f COVID-19 in adults is typically more severe in patients with underlying conditions such as hypertension, diabetes mellitus, and other cardiovascular diseases, including cardiac and cerebrovascular disease. [21,22] In contrast, more than half of MIS-C children seemed to have been previously healthy. In literature, comorbidity was not observed at 74%; in another study, 73% of the patients. [2,5] In the present study, 97.7% of patients were completely healthy and compatible with the literature.
In the present study, the median time to develop mucocutaneous complaints after the first symptom (fever, abdominal pain) was one day (range 1-7 days). In the study of Torreset al., the median length of symptoms before admission was four days (range 2-9 days), and there was no data on the occurrence of mucocutaneous symptoms. [5] The median hospitalization duration is 6.5 days in most studies. [1] The median length of hospitalization was seven days among the patients who were discharged alive and five days among those who died. [2] In the present study, the median length of hospital stay was seven days, and the median length of stay in the ICU was three days (1-7).

Conclusion
Dermatologic and mucocutaneous symptoms of MIS-C were commonly reported in the literature.

Data availability statement
The data that support the findings of this study are available from the corresponding author.