The coronavirus disease 2019 (COVID-19) pandemic has largely passed children by, with fewer infections and a minute proportion of deaths in this age group. However, some adverse outcomes do occur, such as the multisystem inflammatory syndrome in children (MIS-C).

Study: Risk factors for severe PCR-positive SARS-CoV-2 infection in hospitalized children: a multicenter cohort study. Image Credit: SURAKIT SAWANGCHIT/ Shutterstock

A new preprint available on the medRxiv* preprint server describes an effort to describe the risk factors for severe COVID-19 in children.

Background

Earlier studies in this area have identified the presence of obesity, other chronic medical conditions, and inflammation as putting the children at risk of severe COVID-19. Still, most have been small and from richer countries.

The current study examined data from children hospitalized with symptomatic SARS-CoV-2 infection (including MIS-C), confirmed by polymerase chain reaction (PCR), to pull out the risk factors in children with severe outcomes. These were defined according to the Clinical Progression scale of the World Health Organization (WHO), which requires non-invasive ventilation or mechanical ventilation, high-flow oxygen via nasal cannula, vasopressors, or death.

What did the study show?

The researchers looked through the data for over 400 COVID-19 hospitalizations, for children with a median age of approximately 3.8 years, between March 19, 2020, to May 31, 2021. The cases came from Canada, Costa Rica, and Iran, contributing two-thirds, just over a quarter and 7% of cases.

Disease severity increased proportionally with age, so that <2% of newborn babies developed severe COVID-19 compared with over a third of children over 12 years of age. Overall, more than one in three children with the infection developed severe COVID-19.

In Canadian cases, the median age was higher, at 5.8 years, compared to the other two countries. Canada also had a higher adolescent percentage, comprising a third of pediatric cases, compared to <6% in the other two countries. The cases in this country belonged to a later period of the pandemic, with more than two-thirds having been admitted during 2021.

Almost half the children had one additional illness, and almost a fifth had more than one. Children with one additional illness became severely sick in ~32% of cases, compared to 37% in those with two illnesses, but 20% of healthy children.  

Presenting symptoms included fever in >82% of children, while more than half presented with cough. Approximately 32% had vomiting, the same proportion had rhinitis, while < 30% had diarrhea and abdominal pain. Of the total, less than a third had to be admitted to the intensive care unit (ICU).

Six of the patients died, all with a history of other illnesses. Two of these were cancer patients in palliative care.

After adjusting for confounding factors, the risk of multiple illnesses was linked to more than double the risk of severe disease. People with anemia or hemoglobin disorders were at almost six times higher odds for disease severity.

Obesity was linked to almost three times higher odds. The presence of a neurological disorder, having coinfections with bacteria or viruses, or if the patient had a chest imaging result indicative of COVID-19 increased the odds of severe disease more than three times.  

Having a symptom such as shortness of breath increased the odds of severe disease by 4.8 times. The diagnosis of MIS-C is linked to higher risk as well, by almost four times. Children with elevated neutrophil counts had higher odds, by 2.6 times.

Obesity was reported in over 40% of children with severe disease, but only 4% of those with mild infection. A higher proportion of already sick children were adolescents.

In children younger than 12 years, neurological disorders increased the risk of disease severity more than three times. Conversely, obesity was associated with 3.2 times more risk in adolescents when the underlying medical conditions were listed by age group.

The scientists checked their accuracy by recalculating the odds if no MIS-C case was included, which showed that their results were well within limits.

What are the implications?

The results of this study showed that COVID-19 among children was more severe among those with other illnesses, obesity, and neurological disorders. The presence of anemia and/or hemoglobinopathy, shortness of breath, or coinfections with bacterial or viral pathogens were also risk factors for severe disease.

Finally, children whose chest X-ray findings agreed with a diagnosis of COVID-19, those with high neutrophil counts, and those with MIS-C were also at higher risk. Older children were far more likely to have severe disease. Hypertension, chromosomal anomalies, and low albumin levels were associated with a severity that disappeared when confounding factors were accounted for.

Among younger children (below the age of 12 years), the presence of neurological disease was a strong predictor of severe disease, but in adolescents, obesity was a risk factor.

Surprisingly, immunocompromised children did not appear to be at an elevated risk of severe disease. Less than 5% of severe cases had weakened immunity in this cohort, agreeing with earlier studies. This finding seems to bear out the hypothesis that it is not the lack of a robust immune response but its lack of regulation that leads to severe COVID-19 in most individuals who require hospitalization.  

In this study, the proportion of infants from Canada of hospitalized pediatric COVID-19 cases was more than four times higher than that in the general Canadian population. This indicates that infants were more likely to be hospitalized. Some of these infants may not have had severe illness but may have been admitted for observation following the development of severe symptoms.

This is more likely with infants during the first part of the pandemic, especially if serious bacterial pathogens were thought to be a possible cause of the symptoms. However, few of these infants, if any, had a recorded severe outcome, despite the known fact that illness and death among infants are higher at baseline than older children. Symptomatic disease among infants did not, therefore, have a greater risk of turning severe compared to other children.

The second peak of severity, observed among adolescents, was not seen to persist in adjusted models. With obese adolescents being at increased risk of severity, this agrees with earlier studies in children and adults, underlining the key role of metabolic factors in deciding severity.

Risk factors involving blood counts, acute phase reactants such as C-reactive protein, and albumin levels were not evaluated because of the lack of data, nor could ethnic factors be assessed for their risk. However, it was a multicenter study, with over a hundred severe cases among the ~400 hospitalized COVID-19-positive children whose risk factors had been comprehensively recorded. This allowed differences in risk factors to be identified by age group.

In conclusion, we identified several independent risk factors for severe disease in children hospitalized for symptomatic PCR-positive SARS-CoV-2 infection. Based on our analysis, age was not an independent risk factor, but the apparent increased risk in adolescents is mainly secondary to the presence of age-specific comorbidities. Furthermore, age appears to modify the effect of specific comorbidities such as obesity.”

Such studies could help develop targeted vaccination programs for high-risk children and guide treatment protocols for monitoring such groups following the diagnosis of COVID-19 among them.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.