Assessing severity of COVID-19 and the development of multi system inflammatory syndrome in children (MIS-C) in pediatric patients with atopic disease

Abstract

Background:

Research surrounding the coronavirus disease 2019 (COVID-19) pandemic and its impact on patients who are atopic has mainly focused on adults. After the delta variant showed increased rates of COVID-19 in children, the pediatric population needs to be assessed as well.

Objective:

The objective was to assess and report outcomes in patients with COVID-19 and with and without certain atopic diseases in our patient cohort at the University of Mississippi Medical Center.

Methods:

We conducted a retrospective review of patients by using a de-identified data base that allows querying via medical claims codes from the University of Mississippi Medical Center's Research Data Warehouse. We searched for patients who were COVID-19 positive and ages 0–21 years from January 1, 2020, to December 31, 2021. We then divided this population into two cohorts: an atopic population and a non-atopic population. The incidence of hospitalizations, intensive care unit (ICU) admissions, death, length of stay, inhaled corticosteroid prescription history, and the incidence of multi-system inflammatory syndrome in children (MIS-C) outcomes in the two populations were collected.

Results:

There were 5261 patients ages 0–21 years and with confirmed COVID-19. After exclusion criteria were applied, there were 1420 patients in the atopic cohort and 2525 patients in the non-atopic cohort. There were more hospitalizations and a longer length of stay in the atopic population. Mortality was equivalent in the atopic and non-atopic populations. There were more ICU admissions in the atopic population. There were 101 patients total with the diagnosis of MIS-C, and the incidence of MIS-C was similar in the atopic and non-atopic populations. There were more patients who were atopic on inhaled corticosteroid than were the patients who were non-atopic.

Conclusion:

This study sought to further elucidate whether asthma, atopic dermatitis, and allergic rhinitis in pediatric patients was associated with severe COVID-19. Our study showed increased hospitalizations, length of stay, and intensive care in the atopic population but similar outcomes in mortality and the development of MIS-C. Future longitudinal prospective studies are needed to assess the long-term effects on patient's atopic disease after COVID-19 infection.

The coronavirus disease 2019 (COVID-19) pandemic and its evolution of new variants presented a challenge in understanding the impact of COVID-19 on patients who are atopic. Initial research mainly surrounded the adult population but there was a gap in knowledge with regard to the pediatric patients. The need for further studies that involve children with COVID-19 expanded drastically after the delta variant showed increased rates of COVID-19 transmission in pediatric patients. In addition, the inflammatory COVID-19–related disease known as multi-system inflammatory syndrome in children (MIS-C) prompted more focus on the pediatric population.

Results of initial studies¹ suggest that individuals with asthma do not have an increased risk of severe COVID-19 if these patients are well controlled on inhaled corticosteroid (ICS) at the time of infection. A recent narrative review stated that data from three different cohorts of children and adults showed that asthma and respiratory allergy were associated with a lower expression of the angiotensin converting enzyme 2 (ACE2) gene in airway cells, as type 2 inflammatory mediators (such as interleukin 13) and allergen exposures may decrease ACE2 expression in bronchial epithelial cells.¹ It has been proposed that this reduced ACE2 expression could be secondary to ICS treatment, providing a protective response for patients with asthma.² Studies performed thus far in the pediatric population were conducted at the onset of the pandemic, when case rates in children were low and exposures were fewer due to lockdown, which could be an explanation for why some initial studies did not show significant impacts between pediatric patients with asthma and COVID-19.^3,4 Another confounding factor could be due to increased precautions with quarantine and hand washing/hygiene measures out of an abundance of caution in patients with asthma. In relation to MIS-C, the pathogenesis of this disease is not yet known; however, several theories have been suggested, as described in the review by Boechat et al.¹ If patients with atopic disease have a potential protective effect against COVID-19, then the prevalence of MIS-C in this population could be lower as well.

With the impact of the delta variant and increased exposures with the return to in-person schooling, re-evaluating for risk factors between individuals who are atopic and the severity of COVID-19 can be considered. This retrospective review assessed the severity of COVID-19 in pediatric patients at the University of Mississippi Medical Center, the state’s only children’s hospital and referral center for a widely diverse population.

METHODS

We conducted a retrospective review of patients by using the Patient Cohort Explorer (PCE). The PCE is an application that allows querying of diagnosis via the International Classification of Disease, Tenth Edition⁵ codes and extraction of de-identified data from the University of Mississippi Medical Center’s Research Data Warehouse. The data warehouse from which the information for this study was derived has been de-identified and date shifted so that it does not include any protected health information. Pursuant to 45 CFR 46,⁵ use of this data base does not meet the definition of human subjects’ research and does not require review by the institutional review board.⁵

We reviewed patients ages 0–21 years between January 1, 2020, to December 31, 2021. We searched for patients with a COVID-19–confirmed diagnosis to get our initial population. We then divided this population into two cohorts for comparison: an atopic population and a non-atopic population. To define our atopic population, we searched for the International Classification of Disease, Tenth Edition diagnosis codes of “allergic rhinitis,” “atopic dermatitis, “unspecified asthma,” “intermittent asthma,” “mild persistent asthma,” “moderate persistent asthma,” and “severe persistent asthma.” We used these diagnoses to define our atopic population because these are the most frequent manifestations of atopy.⁶ Our non-atopic population was absent of these diagnoses. Within the entire COVID-19 population, we also searched for a diagnosis of “multi-system inflammatory syndrome.” After gathering our diagnosis codes, we were then able to export data that included hospitalizations, ICU stays, deaths, lengths of stay, and medications. To get our final population from these two cohorts, exclusion criteria were applied. We excluded patients who had chronic lung disease of prematurity; immunodeficiency; and other chronic cardiac, neurologic, and psychologic diseases that could have potentially confounded our results. Our primary outcome was to compare hospitalization rates, hospital lengths of stay, ICU admissions, and deaths in our atopic and non-atopic populations. Our secondary outcome was to compare ICS prescription history and diagnosis of MIS-C in our atopic and non-atopic populations.

Statistical Analysis

Statistically significant differences in demographics between the atopic and non-atopic groups were investigated by using the Mann-Whitney test. Differences between outcomes in the atopic versus non atopic groups were assessed by using the Fisher exact test. A p > 0.05 was considered not significant.

RESULTS

After filtering between the dates of January 1, 2020, and December 31, 2021, for patients ages 0–21 years, there was a total of 5261 patients with COVID 19 confirmed. After exclusion criteria were applied, there were 1420 patients in the atopic cohort and 2525 patients in the non-atopic population with COVID-19 confirmed. Demographic information related to gender and race can be seen in Table 1. Most of the atopic population were African American boys, and most of the non-atopic population were African American girls. The demographic distribution was not statistically significant. The distribution of specific atopic diseases within the atopic cohort is reflected in Fig. 1. The majority of patients who were atopic and with COVID-19 had allergic rhinitis and/or asthma.

Table 1.

Demographics

	Atopic Population, n (%) (n = 1420)	Non-Atopic Population, n (%) (n = 2525)	p-value
Gender
Girls	676 (47.63)	1321 (52)	NS
Boys	744 (52.37)	1204 (47.7)	NS
Race
Black	860 (60.6)	1500 (59.4)	NS
White	479 (33.7)	810 (32)	NS
Asian	4 (0.3)	15 (0.6)	NS
Multiracial	20 (1.4)	30 (1.2)	NS
Hispanic	3 (0.2)	5 (0.1)	NS
American Indian	0	6 (0.2)	NS
Native Hawaiian	0	4 (0.2)	NS
MS Band Choctaw	0	6 (0.2)	NS
Other	38 (2.7)	92 (3.6)	NS
Patient refused	3 (0.2)	12 (0.5)	NS
Unknown	13 (0.9)	45 (1.8)	NS

MS = Mississippi; NS = no statistical significance (p > 0.05).

Figure 1.

Distribution of specific atopic diseases.

With regard to the primary outcomes, as seen in Table 2, there were 528 patients (37%) hospitalized in the atopic cohort and 421 patients (17%) hospitalized in the non-atopic cohort, which was statistically significant (p < 0.0001). The average length of stay in the atopic cohort was 1.86 days and in the non-atopic cohort was 1.34 days, which showed no statistical significance. There were 11 ICU admissions (0.8%) in the atopic cohort and 16 admissions (0.01%) in the non-atopic cohort, which was statistically significant (p = 0.0034). There were three deaths (0.2%) in the atopic cohort and seven deaths (0.3%) in the non-atopic cohort, which showed no statistical significance. With regard to the secondary outcomes, there were 101 patients total with MIS-C, 29 of whom were atopic (2%) and 72 were non-atopic (3%), which showed no statistical significance. There were 279 patients who were atopic (20%) and on inhaled steroid and 10 patients who were non-atopic (0.4%) and on inhaled steroid (p < 0.00001); however, it was unknown why they were on inhaled corticosteroid because the PCE cannot generate an data sheet if there are < 25 patients in a population. Of note, only three patients with MIS-C were also on an inhaled steroid at the time of diagnosis.

Table 2.

Outcomes

	Atopic Population	Non-Atopic Population	p-value
Primary outcomes
Hospitalizations, n (%)	528 (37)	421 (17)	<0.0001
Length of stay, no. days	1.86	1.34	NS
Intensive care, n (%)	11 (0.8)	16 (0.01)	0.0034
Mortality, n (%)	3 (0.2)	7 (0.3)	NS
Secondary outcomes, n (%)
On inhaled steroid	279 (20)	10 (0.4)	<0.00001
Patients with MIS-C	29 (2)	72 (3)	NS

NS = Not statistical significance (p >0.05); MIS-C = multi-system inflammatory syndrome in children.

DISCUSSION

Our study of a large population that compared patients who were atopic versus those who were non-atopic and with COVID-19 showed that the atopic population was associated with increased hospitalizations and more need for intensive care. There was not a large difference in mortality or length of stay. Most of our population had allergic rhinitis and/or asthma. Results of studies have shown that, although pediatric patients with atopic dermatitis may have an increased incidence of COVID-19 infection, they showed no greater risk than the general population with regard to COVID-19 complications, which is consistent with our findings.^7,8 A large proportion of our patients with asthma had “unspecified asthma” or “intermittent asthma,” the latter of which typically is treated with albuterol as needed. Of the total atopic population, only 20% were prescribed ICS. Both ICS and intranasal corticosteroid have been associated with a protective effect on patients with asthma and allergic rhinitis, which is thought to be due to corticosteroid influence on ACE receptor downregulation; however, this protective effect has been noted only if the patients are well controlled at the time of their infection.^9,10 It is possible that the increased rate of hospitalizations and duration of stay among our atopic population could be attributable to these patients, with “unspecified asthma” or with “intermittent asthma” being uncontrolled at the time of diagnosis due to noncompliance with ICS or subtherapeutically treated with albuterol alone. From a pathophysiologic perspective, it has been shown that the allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance.¹¹ Furthermore, secondary bacterial infection could be more frequent in the subjects who were atopic because it has been shown that development, aging, and elimination of neutrophils are accelerated in mice with a predisposition to type 2 immunity, which, in turn, causes susceptibility to infection with several bacteria.¹² It is a difficult topic because, in a large population study, it has been reported that severe asthma was associated with more severe COVID-19 outcomes but type 2 inflammation was not associated with more severe COVID-19 outcomes.¹³

There has been a paucity of data with regard to the association between atopic disease and development of MIS-C. A Swedish study found asthma to be a risk factor for developing MIS-C.¹⁴ In our study, MIS-C prevalence was similar among the two cohorts; however, the atopic diagnosis most seen associated with MIS-C was asthma. Only three of the patients who were atopic and with MIS-C were on an inhaled steroid and none of the patients who were non-atopic were on ICS, which could suggest an association with inhaled steroid use also being a protective factor with regard to the development of MIS-C. However, this is difficult to interpret with confidence due to such a small total number of patients with MIS-C.

We feel that a strength of our study includes the large number of pediatric patients we were able to extract for comparison between the two cohorts. Another strength of our study is generalizable to the population because our children’s hospital is the only children’s hospital in the state and draws patients of many races from both inner-city and rural communities across the state. Another study found a decreased association between atopy and COVID-19 hospitalizations and length of stay.¹¹ Although our findings are contradictory to these the aforementioned studies, we do feel that our findings are relevant because our atopic cohort correlates with the typical prevalence of these allergic conditions in the United States per the National Center for Health Statistics, in 2021.¹⁵ In this report, 27.2% of the children had one or more allergic conditions such as seasonal allergy or eczema.¹⁵ The boys were more likely to have allergy and asthma than the girls. Non-Hispanic black and white children were more likely to have seasonal allergy than were Hispanic and Asian populations. Non-Hispanic black children were more likely to have eczema and asthma when compared with non-Hispanic white children.¹⁵ Our atopic cohort was 26.9% of the infected COVID-19 population, and most of this population were non-Hispanic black boys. There are many limitations to this study. By the nature of the PCE, we were unable to confirm through chart review whether these patients were truly atopic (unable to confirm positive sensitization), and whether they had a true diagnosis of asthma as documented through history and lung function testing by an asthma specialist. In addition, we were unable to confirm whether the patients were compliant with their medications. Lastly, our study was a retrospective review but future studies are needed to look prospectively at the long-term effects of COVID-19 infection on patients who are atopic. Future studies that follow a larger population of patients with longer observation times and other parameters of COVID-19 would help to further delineate associations between COVID-19 and atopy.

CONCLUSION

Atopy and its impact on the severity of COVID-19 has largely focused on the adult population. This study sought to further elucidate whether asthma, atopic dermatitis, and allergic rhinitis were associated with severe COVID-19. Our study showed increased hospitalizations and the need for intensive care in the atopic population but similar outcomes for the atopic and non-atopic populations in mortality, length of stay, and the development of MIS-C. Future longitudinal prospective studies are needed to assess long-term effects on these patient’s atopic disease after COVID-19 infection.