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Evaluation of predictors of severe‐moderate COVID‐19 infections at children: A review of 292 children

Abstract Although the underlying disease is associated with a severe course in adults and laboratory abnormalities have been widely reported, there are not sufficient data on the clinical course of coronavirus disease 2019 (COVID‐19) in children with pre‐existing comorbid conditions and on laboratory findings. We aimed to describe the independent risk factors for estimating the severity of the COVID‐19 in children. All children between 1 month and 18 years old who were hospitalized during the period of March 11–December 31, 2020, resulting from COVID‐19 were included in the study. Patients were categorized into mild (group 1) and moderate + severe/critically (group 2) severity based on the criteria. Demographic characteristics, comorbidities, and laboratory variables between the two groups were compared. A total of 292 children confirmed to have COVID‐19 infection were included in the study. The most common associated diseases were obesity (5.1%) and asthma bronchiale (4.1%). We observed that disease progressed more severely in patients with underlying diseases, especially obesity and asthma bronchiale (for patients with obesity odds ratio [OR] 9.1, 95% confidence interval [CI] 1.92–43.28, p = 0.005 and for patients with asthma bronchiale OR 4.1, 95% CI 1.04–16.80, p = 0.044). In group 2 patients, presence of lymphopenia and hypoalbuminemia, and also an elevation in serum levels of C‐reactive protein, procalcitonin, and uric acid were detected and these results were statistically significant (p values; p < 0.001, p = 0.046, p = 0.006, p = 0.045, p < 0.001, respectively). The strongest predictor of moderate‐severe COVID‐19 infections in the children was uric acid, with an odds ratio of 1.6 (95% CI 1.14–2.13, p = 0.005) and lymphocytes with an odds ratio of 0.7 (95% CI 0.55–0.88, p = 0.003). Although children are less susceptible to COVID‐19, the pre‐existing comorbid condition can predispose to severe disease. In addition, lymphopenia and high uric acid are indicators that COVID‐19 infection may progress more severely.


| INTRODUCTION
Coronavirus disease 2019 (COVID-19) is a disease that was detected in December 2019 in Wuhan, China, and has become one of the worst infectious disease outbreaks of recent times, with over 96 million cases and 2 million deaths so far. 1 Clinical manifestations in children are not typical, and mainly milder. 2 The pediatric severe and life-threatening forms are rare excluding patients with multisystemic inflammatory syndrome associated in children (MIS-C)-associated with COVID-19. 3 Population data from China and Italy indicate that children are mildly affected in comparison with adults, representing approximately 5% of cases and less than 1% of admissions to hospital. 2,4 Moreover, the fatality rate of children with COVID-19 is extremely low (0%-0.69%) [5][6][7] compared with that of the adult population (8%-14.8%). 8 As the novel coronavirus continues to evolve, there are still many limitations to our knowledge of who exactly this virus would impact severely. In adults, comorbidities, including advanced age, diabetes mellitus, respiratory, or cardiovascular disease are associated with more severe disease and also a higher risk of mortality. 8,9 Currently, there are limited studies concerning the COVID-19 in children with comorbidity. Laboratory abnormalities in adults with mild and severe COVID-19 have been widely reported and appear to be somewhat consistent, but the majority of laboratory data on COVID-19 pediatric patients stems from case reports and case series. In this study, we aimed to describe the independent risk factors for estimating the severity of the COVID-19 in children.

| METHODS
This analytical cross-sectional study was conducted in the University of Health Sciences Dr. Behçet Uz Children's Hospital in İzmir, Turkey, during the period of March 11-December 31, 2020. This current hospital is a 400-bed and tertiary care hospital with an annual approximately 600 000 outpatients and 24 000 hospitalizations.
All children between 1 month and 18 years old who were hospitalized only resulting from COVİD-19 were included in the study.
Newborns and cases whose data were not available were excluded from the study. Diagnosis of COVID-19 was documented by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) positivity. The protocol of RT-PCR was consistent with the recommendation of the WHO. 10 Demographic characteristics, pre-existing comorbidities, and laboratory parameters on admission were collected from the electronic database of the hospital. Of the comorbid diseases, obesity was defined as a body mass index (BMI) at or above the 95th percentile for children and teens of the same age and sex. 11 The severity of COVID-19 was defined based on the clinical features, laboratory testing, and chest X-ray imaging, including asymptomatic infection, mild, moderate, severe, and critical cases. 12 Defining level of severity in COVID-19 is indicated in Table 1.
According to this table, the severe and critically ill patient criteria were accepted as pediatric intensive care admission criteria. Patients were divided into two groups. Those with mild cases were determined as group 1, moderate and severe/critically cases as group 2, further demographic characteristics and laboratory variables between the two groups were compared and the effects of laboratory parameters on disease severity were investigated.

| Demographic comparison
The rate of males was 65.8%. (100) and 34.2% (52) at group 1 and group 2. There was no significant difference regarding gender between the two groups (p > 0.05). The mean age of the patients in group 1 was 6.4 ± 5.7 years (range 1 months-17.9 years) and the mean age in group 2 was 11.5 ± 5.4 years (range 1 months-17.7 years), and significantly higher in group 2 (p < 0.001).
Underlying disease was present in 24 (38.7%) of the patients in group 1 and 38 (61.3%) of the patients in group 2, and significantly higher in group 2 (p = 0.002). The ratio of the asthma bronchiale patients was significantly higher in group 2 compared with group 1 (9 patients; 9.6% vs. 3 patients, 1.5% consecutively) (p = 0.002). The ratio of patients with obesity was 1.0% (two cases) in group 1 and 13.8% (13 cases) in group 2 and significantly higher in group 2 (p < 0.001). There was no statistical difference in terms of immunosuppression rates in these two groups (p > 0.05) (4.3% vs. 1.5%) ( Table 2).

| Laboratory findings
The comparison of the laboratory variables between the two groups was summarized in Table 3. The mean absolute lymphocyte count was 3.05 ± 2.1 × 10 3 /μl in group 1 and 2.07 ± 1.24 × 10 3 /μl in group 2, significantly lower in group 2 (p < 0.001) ( Table 3). The mean CRP and PCT values were 0.75 ± 1.8 mg/dl and 0.11 ± 0.61 ng/ml in group 1 and 2.1 ± 4.4 mg/dl and 3.9 ± 15.5 ng/ml in group 2. Both of the CRP and PCT values were significantly higher in group 2 compared with group 1 (p = 0.0006 and p = 0.045). The plasma albumin level was significantly lower in group 2 compared with group 1 (p = 0.046) ( Table 3). The mean uric acid level was significantly higher in group 2 (4.2 ± 0.6 mg/dL) compared with group 1 (3.6 ± 1.2 mg/dl) (p < 0.001).

| Logistic regression analysis of factors affecting the severity of the COVID-19 infections
In this part, the logistic regression was performed in two different models. One model included the variables including age, obesity, and asthma bronchiale (possible predisposing factors) and the second model included the laboratory tests including lymphocyte count, CRP, PCT, albumin, and uric acid. to the intensive care unit, 7 (15%) were obese, and obesity was found to be remarkable comorbidity, especially in older children. 17 From the perspective of asthma bronchiole, it is unclear whether it affects COVID-19 sensitivity or severity in children. In a systematic review of whether asthma bronchiale is associated with higher COVID-19 risk or severity in children, only two reports described asthma bronchiale or recurrent wheeze as a COVID-19 risk factor. 18 Paradoxically, asthma bronchiale may also be protective as the ACE2 receptor, required for coronavirus infection, maybe underexpressed in the lungs of atopic children. 19 A retrospective review of COVID-19 cases in children with asthma bronchiale in Spain noted no demographic differences between asthmatic children with probable COVID-19 and those without infection, including lung function, need for oral steroids, other measures of asthma bronchiale control, or comorbidities. 20 In this study, it was seen that both asthma and obesity were riskier in terms of moderate and severe disease development.
Moreover, the children with obesity were 9.1 times and children with asthma bronchiale were 4.1 times more likely to have moderate- higher levels of procalcitonin, and increased D-dimer levels. 26 Laboratory data from eight severe pediatric cases showed normal or increased leukocyte count, and high levels of CRP, procalcitonin, and lactate dehydrogenase. 27 In a study of 67 children, admission to an ICU was associated with higher levels of CRP, procalcitonin, and an increased platelet count. 28 As a result, although a distinct pattern of laboratory findings has not emerged as being associated with severity of the disease in pediatric cases of COVID-19, similar to other studies, also in this study indicated that lymphopenia, high CRP, and high procalcitonin levels can be a guide in determining the severity of the disease. In fact, lymphopenia was found as a stronger predictor of moderate to severe COVID-19 infections in children with an odds ratio of 0.7. In addition, in this study hypoalbuminemia and high uric acid levels were found to be associated with moderate-severe disease differently from similar studies. Moreover, for uric acid the odds ratio was 1.6, which means for every additional increase of uric acid by 1 mg/dL, were 1.6 times likely to have moderate-severe COVID-19 infections.
Although all age groups were infected with SARS-CoV-2, the youngest (<1 year) and oldest children/young adults (15-25 years of age) were more likely to be hospitalized. 29 İn this study, we found an association between increased age and worse outcomes. In a recently published multicenter study from Turkey, similar to this study, the moderate disease was observed with a higher rate in patients over the age of 15 (p < 0.01) 30 Another study of 177 children from the Children's National Hospital in Washington, DC reported that the adolescents and young adults were more commonly to have critical illness than the younger children, supporting our study. 29 This study has several limitations. First its retrospective design therefore all laboratory parameters of interest were not available in the patients included in the study. Secondly, comorbid condition groups did not contain enough patients therefore cannot be extolled as representing all children with comorbidities. İn the future, prospective studies with larger series in children with comorbidities will better demonstrate the effect of COVID-19 in children with comorbidity.

| CONCLUSION
COVID-19 infection was seen to have a more severe course in children with underlying diseases especially obesity and asthma bronchiale. Additively, observed that lymphopenia and uric acid are indicators that COVID-19 infection may progress more severely. We recommend clinicians must be more aware of deterioration in the children with comorbidities and monitor lymphocyte count, and uric acid levels as predictors for severe infection.