Do Pre-existing Comorbid Conditions Inuence the Clinical Course of COVID-19 Infection in Childhood?

Background COVID-19 has a milder clinical course in childhood with signicantly lower mortality than in adulthood. The presence of comorbid conditions such as cardiovascular disease and respiratory disease is thought to be associated with increased mortality in adults. There is very little information on the clinical course of COVID-19 in children with pre-existing comorbid conditions. Methods We retrospectively evaluated laboratory-conrmed pediatric COVID-19 at the Children’s Hospital of Ankara City Hospital. The patients were classied as those with and without pre-existing comorbid conditions and the two groups were compared for age, gender, clinical picture at presentation, the presence of severe disease, and pediatric intensive care unit (PICU) requirement.


Introduction
COVID-19 infection only results in mild symptoms and signs in 80% of the patients and mortality mostly occurs in patients aged 60 years or more or those who have pre-existing comorbid conditions. 1   can affect every pediatric age group. 2 It generally has a milder clinical course in children than in adults. 3 Children make up 2% of all COVID-19 cases in China, 1.2% in Italy, and 5% in the USA. In Turkey, the total number of COVID-19 cases was 198.284 on 2 July 2020, and 2% of all COVID-19 cases were in the 15 years or younger age group and 13.7% in the 15-24 years age group. 4 The presence of comorbid conditions such as cardiovascular disease and respiratory disease is thought to be associated with increased mortality in adults. 3 There is very little information on the clinical course of COVID-19 in children with pre-existing comorbid conditions. 2,3 The impact of preexisting comorbid conditions on the prognosis of COVID-19 in children is therefore not clear yet.
This study was conducted at the Ankara City Hospital, which is one of the hospitals designated as pandemic hospital in Ankara, Turkey. The Children's Hospital section of the Ankara City Hospital was the only hospital designated as a pandemic hospital for children in Ankara at the beginning of the pandemic.
Filiation procedures were strictly observed in Turkey from the time the rst COVID-19 case was diagnosed in the country. Every person with exposure to a COVID-19 case was found and a nasopharyngeal swab sample was obtained for a polymerase chain reaction (PCR) assay, together with an exposure history. Every PCR-positive child who presented at the Ankara City Hospital during the study period was hospitalized. Following discharge, every patient was followed-up by telephone for 14 days. We retrospectively evaluated our pediatric COVID-19 patients and investigated whether accompanying comorbid conditions in uence the clinical presentation and prognosis of COVID-19 in children in the current study.

Materials And Methods
We retrospectively evaluated all laboratory-con rmed pediatric COVID-19 cases between 22 March 2020 and 28 May 2020 at the Children's Hospital of Ankara City Hospital. The COVID-19 diagnosis was con rmed by PCR assay on nasopharyngeal and oropharyngeal swabs. Demographic characteristics, preexisting comorbidities, and laboratory parameters on admission were collected from the electronic database of the hospital. The patients were classi ed as those with and without pre-existing comorbid conditions and the two groups were compared for age, gender, clinical picture at presentation, the presence of severe disease, and pediatric intensive care unit (PICU) requirement. We also compared the two groups as regards the laboratory parameters.
We categorized the patients' clinical pictures at presentation according to our observations. The COVID- 19  The age and gender distribution were similar in the two patient groups.

Discussion
COVID-19 has a milder clinical course in childhood with signi cantly lower mortality than in adulthood. The COVID-19 infection is asymptomatic or has a mild to moderate clinical course in 90% of pediatric cases. 5 The mortality in children is also lower than that of adults. The mortality rate has been reported as 2.2% a study involving 44672 con rmed COVID-19 infected patients. The same study reported that 1 child died in the 10-19 years age group, and there was no death in the 0-9 years age group. 6 The mortality rate among pediatric cases has been reported as 1% across the European region. 7 High ow nasal oxygen therapy or PICU admission is rarely required in this group. 8 The reported rates for laboratorycon rmed pediatric COVID-19 cases was 5% for hypoxemia and dyspnea, 0.4-0.6% for acute respiratory distress syndrome, respiratory failure or multiorgan failure, 4% for mechanical ventilation requirement, 3% for inotrope requirement, and 8-9.7% for PICU admission in various studies. 5,7,8,9 The risk factors related to a severe and complicated clinical COVID-19 infection course in children have not been clearly determined yet.
Pre-existing comorbidities are more common in adults who need hospitalization or intensive care unit (ICU) admission. Such pre-existing comorbidities have been found in 71% of the hospitalized adult patients, 78% of those admitted to the ICU, and 94% of those who died due to COVID-19. 10 Comorbid conditions related to severe disease in adulthood have been reported as hypertension, diabetes, coronary heart disease, chronic obstructive lung disease, and chronic kidney disease. 11,12,13 Another series has reported cardiovascular or cerebrovascular disease to be related with increased fatality, whereas there was no difference as regards the frequency of diabetes, chronic digestive disorders, tuberculosis, chronic hepatic and renal insu ciency, peripheral vascular disease, or malignancy. 14 There is little data on the clinical course of COVID-19 infection in children with pre-existing comorbid conditions. A study evaluating 48 children treated in the PICU has reported that pre-existing comorbidities were present in more than 80% of the children with COVID-19 admitted to the PICU and the most common of these were developmental delay and/or genetic anomalies. The authors mentioned that prehospitalization comorbidities appear to be an important risk factor for PICU admission. 15 A pediatric series including 171 COVID-19 cases has reported that three patients needed PICU admission and all three had pre-existing comorbidities consisting of hydronephrosis, leukemia, and intussusception. 16 In a multicenter study from Europe including 582 children with con rmed COVID-19 infection, pre-existing medical conditions were found to create a risk for PICU admission requirement. 7 Four patients died and all were aged older than 10 years. Two had a pre-existing comorbid condition: one had undergone human stem cell transplantation and the other one was receiving chronic palliative care. 7 The other two fatal cases did not have comorbidities. These data suggest that preexisting comorbid conditions may be a risk factor for PICU admission and also for fatality.
There was no severe disease and no PICU admission in either group in this study. However, lower respiratory tract infection was more common among patients with pre-existing comorbidities.
We did not come across severe disease or PICU admission requirement in our patients, even in those with pre-existing conditions. Viral co-infection with COVID-19 has been reported as an important risk factor for PICU admission requirement. 2,7 Viral co-infection was not evaluated in the current study. However, the rst COVID-19 case in Turkey was seen on 11 March 2020. The fact that the COVID-19 epidemic was seen in Turkey after the winter period when other viral respiratory tract infections, especially RSV and in uenza virus, show their peak incidence rate, could indicate a low co-infection rate in our cohort. The strict liation procedures, early closure of schools, and the curfew imposed on children may also have reduced the circulation of other viruses as well as COVID-19. Our patients' good clinical data may result from the absence of other viral co-infections. It has been reported that 15.8-16% of children and adolescents with COVID 19 infection are asymptomatic. 7,16 In our cohort, the asymptomatic patient ratio was higher in patients, both with and without preexisting comorbid conditions, than reported previously (35.6% vs. 32.9%). Our rate of asymptomatic cases could be high because PCR assays were performed on any person who had contact with an index case during this study period.
Some laboratory parameter changes have been reported as prognostic factors in COVID-19 infection. A high level of procalcitonin (PCT) and lymphopenia have been reported to be associated with a severe clinical course in adults. Serum C-reactive protein (CRP) and PCT levels have been reported to be signi cantly higher in patients who develop severe disease and are correlated with the severity of COVID-19 in adults. Higher ferritin levels and a d-dimer level > 1 µg/mL have been found to be associated with severe pneumonia in adults. Another study found that patients with a d-dimer level ≥ 2 µg/mL had a higher mortality rate. A Troponin I level > .05 ng/mL has also been found to be associated with increased mortality. 2,3,11,12,13,14,17,18 We did not nd any difference between the patients with and without comorbidities as regards the laboratory parameters in this study.
Although COVID-19 infection is mostly benign in the acute period in children, a new in ammatory syndrome developing in association with COVID-19 in some healthy children and adolescents has recently been noted and named the multisystem in ammatory syndrome in children (MIS-C). 19,20 None of the patients in our study cohort developed this syndrome during follow-up.

Conclusion
The number of patients with a comorbid condition was low in this study and the comorbid condition groups did not contain enough patients to demonstrate how they individually in uenced the clinical picture in children. We believe our study re ects some aspects of the clinical picture of COVID-19 in children with comorbid conditions as our hospital is a reference hospital for pediatric COVID-19 infection cases and our cohort included all pediatric COVID-19 cases in our hospital between the dates speci ed.
Our results indicate that the clinical course of COVID-19 in children with pre-existing comorbid conditions may not be as severe as in adults, and lower respiratory infection may be more common in children with pre-existing comorbidities.