Clinical Manifestations Laboratory Tests Abdominal Ultrasonic Findings and In-hospital Prognosis of COVID-19 in 185 Pediatric Cases in a Tertiary Center

Background: Despite the COVID-19 pandemic, there is little information about the different clinical aspects of COVID-19 in children. In this study, we assessed the clinical manifestations, outcome, ultrasound, and laboratory findings of pediatric COVID-19. Methods: This retrospective study was conducted on 185 children with definitive diagnosis of COVID-19 between 2021 and 2022. The patients’ information was retrieved from hospital records. Results: The average age of the patients was 5.18 ± 4.55 years, and 61.1% were male. The most frequent clinical manifestation was fever (81.1%) followed by cough (31.9%), vomiting (20.0%), and diarrhea (20.0%). Mesenteric lymphadenitis was common on ultrasound and found in 60% of cases. In-hospital death was identified in 3.8% of cases. The mean length of hospital stay was 8.5 days. Mandating intensive care unit (ICU) stay was found in 19.5% and 5.9% of cases were intubated. Acute respiratory distress syndrome (ARDS), lower arterial oxygen saturation, higher white blood cell (WBC) count, and higher C-reactive protein (CRP) were the main determinants of death. Lower age, respiratory distress, early onset of clinical manifestations, lower arterial oxygen saturation, lower serum hemoglobin (Hb) level, and higher CRP level could predict requiring ICU admission. Conclusion: We recommend close monitoring on CRP, serum Hb level, WBC count, and arterial level of oxygenation as clinical indicators for potential progression to critical illness and severe disease. Mesenteric lymphadenitis is a common sonographic finding in pediatric COVID-19 which can cause abdominal pain. Ultrasound is helpful to avoid unnecessary surgical interventions in COVID-19.

accurate assessment of clinical features, imaging and laboratory findings is necessary.In this study, in addition to detailed evaluation of clinical and paraclinical findings of children with COVID-19, we evaluate the clinical outcome of the patients as well as the relationship between the background findings and the prognosis of the disease in this age group.

Materials and Methods
This retrospective study was conducted on children with a definitive diagnosis of COVID-19 who were admitted to a referral children's hospital in Tehran between April 2022 and May 2022.Of 875 cases with suspicious clinical findings of pediatric COVID-19, 185 patients met the inclusion criteria.We used convenience sampling to recruit participants.The most important factors for inclusion in this study were positive PCR tests and clinical manifestations of COVID-19; all laboratory data, abdominal ultrasound data, and follow-up data were available during their hospitalization.All suspected patients with clinical manifestations of COVID-19, such as fever, cough, respiratory distress, diarrhea, and vomiting, were assessed by reverse transcriptasepolymerase chain reaction (RT-PCR) and only those patients with a final positive test were analyzed.We collected the demographics, clinical characteristics, laboratory findings, and radiological findings from the hospital-recorded files and the hospital information system.Positive findings of the abdominal ultrasounds were classified.The clinical outcome was evaluated by follow-up of the hospitalized patients.In this regard, the in-hospital survival status and need for ICU admission were considered as prognostic criteria.
For statistical analysis, continuous variables were compared using the independent sample t-test or Mann-Whitney U-test whenever the data did not appear to have normal distribution or when the assumption of equal variances was violated across the study groups.In the independent sample t-test, the assumption of variance homogeneity was assessed to choose the best result and in the Mann-Whitney U test, the assumption of equal variances was not important.The chi-square/ Fisher's exact test was used to compare the categorical variables according to the amount in the cross table.When more than 20% of cells had expected frequencies < 5, we used Fisher's exact.P values of ≤ 0.05 were considered statistically significant.SPSS version 23.0 for Windows (IBM, Armonk, New York) was used.

Results
In total, 185 children with COVID-19 were analyzed in this study.The demographic findings are summarized in Table 1.The average age of the patients was 5.18 ± 4.55 years.Considering gender, 61.1% were male.The most frequent clinical manifestation was fever (81.1%) followed by cough (31.9%), vomiting (20.0%), and diarrhea (20.0%).Regarding vital signs, the mean arterial oxygen saturation was 94.11 ± 3.56% and 13.5% had less than 90% saturation.Half of the affected children suffered from tachypnea.
On ultrasonographic assessment (Table 2), the positive findings were the following: increased renal echogenicity in 2.2% of cases, increased renal size in 4.9% of cases, mild bladder wall thickening in 1.1% of cases, sludge within the gallbladder in 3.8% of cases, splenomegaly in 8.1% of cases, and fatty liver in 5.4% of cases, pelvis fullness was detected in 3.2% with a mean anteroposterior diameter of 5 mm.
Enlarged mesenteric lymph nodes were found on ultrasonography in 32.4% of cases; cases with three or more nodes with a short-axis diameter of at least 5 mm clustered in the right lower quadrant were considered positive.The enlarged lymph nodes were located anterior to the right psoas muscle and in the small bowel mesentery.In 7 % of cases, the terminal ileum was thick-walled with a single layer of over 3mm (Figure 1).Evidence of pleural effusion was found in 2.2% of cases.Interestingly, appendicitis and appendectomy were found in 2.7%.Considering disease outcome, in-hospital death was found in 3.8% of cases.The mean length of hospital stay was 8.5 days.Need for ICU admission was found in 19.5%.Intubation was performed in 5.9% of cases.Of those who did not survive, four patients suffered from abdominal ascites, fatty liver, and raised liver enzymes, two patients had gallbladder abnormalities, and one had renal disorders requiring hemodialysis.

Discussion
This study aimed to evaluate the epidemiological, clinical, diagnostic, and prognostic aspects of COVID-19 in children.Also, a comprehensive evaluation of abdominal ultrasound data was undertaken to investigate the ultrasound findings of pediatric COVID-19.Our study showed that boys were more involved.Also, the evaluation of the age curve of the patients showed a high prevalence of hospitalization in children under 5 years, as 62% of the affected children were five years old or younger.This finding showed little difference from other similar studies in other communities.In a study by Karbuz et al 22 in Turkey, the majority of patients were between 6 and 12 years of age.In a review by Ding et al, the majority of pediatric patients with COVID-19 were older than 5 years of age 23 which is consistent with our study.In another study among Iranian pediatric patients, similar to our report, 60.4% were male while their mean age was 32 months. 24egarding history of exposure to COVID-19, 46.5% of our patients reported such exposure.The history of exposure to COVID-19 was recorded in 75.2% of cases in the study by Karbuz et al, 22 75.6% in a study by Hoang et al, 25 and 86.4% in the study by Ding et al. 26 It seems that the families in Iran are much more sensitive in decreasing the exposure of their children to the sources of the spread of the virus in the society.Social distancing has been implemented more favorably in this society.
Regarding the presence of underlying conditions, few of our children (below 5%) had predisposing and underlying diseases which was notably higher in other reports such as CDC-MMWR.According to the CDC-MMWR, 23% of pediatric patients had underlying conditions.The most common underlying conditions were chronic lung disease (including asthma) followed by cardiovascular disease and immunosuppression. 27In another report, 6.1% of all the included children had underlying diseases. 25According to another research, the most common underlying medical conditions were history of immunosuppression and history of respiratory or cardiac disease (65%). 26In our study, the most common underlying disorder was history of chronic renal disease found in only 4.9%.In other reports, lung disorders and congenital heart disease were the common underlying conditions. 26,2724][25]31 In laboratory parameters, in our sample, the two prominent laboratory findings were leukocytosis and high CRP level.They were also the main determinants for poorer prognosis.In other reports, the main laboratory findings were leukopenia, leukocytosis, increased creatine kinase, and thrombocytopenia.
One of the main findings on abdominopelvic ultrasound was common involvement of some abdominal organs including mesenteric lymph nodes and splenomegaly.According to the studies, involvement of these organs has always been an indication of the severity of the disease, especially in the context of multi-system inflammatory syndrome (MISC) in children with COVID-19. 32Mesenteric lymphadenitis (Figures 1 and 2) and splenomegaly were the most common findings in ultrasound.According to the previous studies, these findings have been the signs of the severity of COVID-19, especially in the context of MISC syndrome in children with COVID-19.MIS-C, first reported in April 2020, is currently a post-COVID-19 complication and could be related to the immune response to infection. 32Gastrointestinal symptoms are most significant in MIS-C, occurring in about 92% of cases, followed by cardiac involvement in about 80%. 33,34][34][35][36][37] As in our study, mesenteric lymphadenitis was the most common abdominal finding in 60% of cases with COVID-19 disease which was similar to previous studies.Considering previous studies, it has been shown that imaging studies, such as abdominal ultrasound or even abdominal computed tomography (CT), may simplify differentiating true surgical emergencies in questioned cases of the acute abdomen. 349][40][41][42] However, in a few studies, non-operative management of uncomplicated acute appendicitis accompanying COVID-19 infection with antibiotics has been documented. 43here is an association between the severity of COVID-19 and involvement of abdominal organs, including enlarged mesenteric lymph nodes, kidney involvement leading to dialysis, and liver involvement leading to increased liver enzymes and fatty liver disease.Therefore, ultrasound evidence related to the involvement of these organs can be also considered as a prognostic factor.
Our study has a variety of limitations to consider as it was conducted in a single-center pediatric department, in addition to the limitations of any retrospective analysis.Our research was conducted in a different region of the world compared to previous studies, and more so, a distinct region of Iran, which is another limitation of this study.Additionally, a broader period of data collection and larger sample sizes may have further demonstrated more cases of severe presentations, more complications, and favorable findings.Finally, the number of non-surviving cases in our study was seven cases which is one of the important limitations of our study.

Conclusion
Regarding prognostic factors, some baseline parameters including younger age, lower arterial oxygen saturation, and evidence of acute respiratory distress, raised CRP, and lowering Hb level could effectively predict poorer clinical outcomes including death and ICU requirement.A recent meta-analysis found acute respiratory distress syndrome and acute kidney injury as factors predicting admission to ICU; and shortness of breath, neurological symptoms, raised CRP level, and D-dimer level as predicting factors for progression to severe or critical disease and death. 44hese factors will be useful for designing models predicting hospital and long-term outcomes of children with COVID-19.
In general, the mortality rate of these children is still low and need for special care is raised in the minority of these patients.It seems that Iran has been very successful in managing such patients.We declare that no funds, grants, or other support were received during the preparation of this manuscript.

Figure 1 .
Figure 1.Ultrasound image demonstrates evidence of terminal ileitis in a 4-year-old girl with COVID disease.Gray-scale US shows the thickened terminal ileum, wall thickness (white calipers) and lumen (double-headed arrow)

Figure 2 .
Figure 2. Ultrasound Image Depicting Multiple Reactive Mesenteric Lymph Nodes with a Preserved Oval-Shape and Intact Outline (Mesenteric Lymphadenitis) Anterior to the Psoas Muscle in the Right Lower Quadrant in a 4-Year-Old Girl with COVID Disease

Table 3 .
Ultrasound Findings of the Study Population (n = 185)

Table 6 .
Comparison of Significant Clinical and Laboratory Findings based on Survival Status

Table 7 .
Comparison of Significant Demographic, Clinical and Laboratory Characteristics Based on ICU Status