key: cord-0720028-7bm9kviv authors: Navalpakam, Aishwarya; Secord, Elizabeth; Pansare, Milind title: The impact of COVID -19 on Pediatric Asthma in the United States. date: 2021-05-21 journal: Pediatr Clin North Am DOI: 10.1016/j.pcl.2021.05.012 sha: 79b44ed586d71e983315d8fa73ce22e303fb99f0 doc_id: 720028 cord_uid: 7bm9kviv COVID-19 pandemic has caused severe economic and health impact in United States and disproportionately more in socially disadvantages areas. The available data, albeit limited in children, suggest that the initial concerns of potential of serious impact of COVID-19 illness in children with asthma is unproven so far. The reduction in asthma morbidities is due to improved adherence, COVID-19 control measures, school closures and decrease exposure to allergens and viral infections in children. During pandemic asthma guidelines were updated to guide physicians in asthma care. In the face of unprecedented time, it is important to be vigilant, adhere to treatment guidelines, and implement preventive measures to eradicate the virus and improve outcomes in children with asthma. COVID-19 pandemic caused morbidities and mortalities of historic proportion and disrupted health care delivery in USA. Elderly and patients with chronic illnesses including asthma are at increased risks of poor outcomes. Limited data in US indicate children with asthma have done well despite multiple challenges to health care delivery. It is important to adhere to asthma treatment guidelines to maintain asthma control in children during the pandemic. COVID-19 pandemic has caused severe economic and health impact in United States and disproportionately more in socially disadvantages areas. The available data, albeit limited in children, suggest that the initial concerns of potential of serious impact of COVID-19 illness in children with asthma is unproven so far. The reduction in asthma morbidities is due to improved adherence, COVID-19 control measures, school closures and decrease exposure to allergens and viral infections in children. During pandemic asthma guidelines were updated to guide physicians in asthma care. In the face of unprecedented time, it is important to be vigilant, adhere to treatment guidelines, and implement preventive measures to eradicate the virus and improve outcomes in children with asthma.  The COVID-19 pandemic has caused catastrophic impact on health and wellbeing of humans globally.  Unlike children, adults with chronic illnesses and other health risk factors had poorer outcomes.  Current evidence suggests most children with chronic asthma were able to maintain asthma control during the pandemic.  It is important to adhere to recommendations of International and National asthma guidelines for treatment of both acute exacerbation and chronic asthma.  A multi-pronged measures including stepped pharmacotherapy based on asthma severity is necessary to maintain asthma control in children during the pandemic. Coronaviruses are a common cause of upper respiratory infections in children. 1 A novel human coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mutated in bats in Wuhan, China and has been attributed to be the cause of a global pandemic leading to illness and death in 2020. 2 Initially, asthma was thought to be a risk factor for poor clinical outcomes in adult patients with coronavirus disease (COVID-19). However, limited data, currently available has not shown significant COVID-19 illness or increase in asthma exacerbations in children during the pandemic. In this article, we aim to outline impact of COVID-19 on pediatric asthma in United States (US) and current recommendations for asthma care. The United States has become an epicenter during the pandemic reporting the highest number of cases and deaths due to COVID- 19 Practitioners and parents alike anticipated and rapidly prepared for the significant impact of SARS-CoV-2 infections on children with asthma. The reality was not what was anticipated. Asthma in children is often triggered by respiratory viruses. It is theorized that the type I interferon production, which is important for defense against viruses, is decreased in asthmatic individuals and is inhibited by Th2 inflammation seen in allergic asthma. 5 Studies also suggest that in atopic individuals certain respiratory viruses such as respiratory syncytial virus (RSV) or human rhinovirus (RV), due to the formation of specific IgE, may cause exacerbations. 5 concern that SARS-CoV-2 infection may also result in increased asthma exacerbations in children which surprisingly did not occur. The pathophysiologic hallmark of asthma is chronic airway inflammation. Generally, 2 types of inflammatory asthma are described; Type 2-high asthma (T2) and Type 2-low (T1) asthma based on the expression of T helper-cell type 2(TH2) cytokines. Type 2 high asthma is characterized by eosinophilic airway inflammation and elevated cytokines such as IL 4, IL5, IL13 and elevated IgE. This is also known as allergic asthma which appears earlier in life, is responsive to corticosteroids, and is a common phenotype in children. Type 2-low asthma phenotype is more common in adults, has later disease onset, has less allergic comorbidities, and is less responsive to corticosteroids. ACE2 receptor expression appears to vary with asthma phenotype. A study of two large adult asthma cohorts identified increased expression of ACE2 gene in the bronchial epithelium of Type 2-low or T1 high subjects. 7 Interestingly, these patients also tended to have higher known risk factors for COVID-19 including hypertension, lymphopenia, and male gender. 7, 8 This suggest that T2-low phenotype is likely associated with higher risk for COVID-19. Another study of cohort of children with asthma, the urban environment and childhood asthma cohort (URECA), revealed that allergic sensitization in children (positive IgE tests for allergens either skin or serum testing) with asthma was associated with decreased ACE2 expression in children. 9 J o u r n a l P r e -p r o o f The Type 2-high asthma phenotype characterized by elevated serum IgE level, fractionated exhaled nitric oxide (FeNO), and IL13 expression was associated with decreased ACE2 receptor expression in this URECA Cohort. 9 It suggests that T2 high-asthma and allergic sensitization is associated with decreased ACE2 receptor expression, may be a cause of decreased SARS-CoV-2 infection in these patients. This may be important to pediatric asthma patients who tend to have a T2 high asthma phenotype. Children, when compared to adults, have been due to IgE reacting to certain respiratory viruses such as RSV (respiratory syncytial virus) or human rhinovirus (RV) found to have lower ACE2 receptors in their nasal epithelium, which may account for the decreased incidence of COVID-19 in children. 10 The use of inhaled corticosteroids (ICS) may also provide a protective role for Asthma from COVID-19. Cultures of human nasal and tracheal epithelial cells reveal that combination of glycopyrronium, a long acting muscarinic antagonist (LAMA), formoterol, a long acting beta-2 agonist (LABA) and budesonide, an inhaled corticosteroid (ICS) inhibit replication of HCoV-229E, a virus that causes the common cold, by preventing receptor expression and decreases virus induced airway inflammation. 11 When gene expression for ACE2 and TMPRSS2 was analyzed in sputum cells from severe asthmatic patients, it was found that the use of ICS was associated with lower expression of these receptors. 12 These studies suggests asthma patients who are adherent to their ICS thus may have decreased risk for COVID-19. J o u r n a l P r e -p r o o f Adult patients with asthma hospitalized due to COVID-19 across the world is low with incidence reported from 1-2.7%. 13 An online questionnaire sent to 91 pediatric practitioners in 27 countries attempted to estimate the incidence of clinically relevant COVID-19 in pediatric asthma patients. They noted that incidence is 12.8 times less frequent in children than adults. 14 A retrospective study of a large cohort in Israel also showed that patients with asthma have a lower susceptibility for COVID-19 in pediatric and adult patients. The study did not find any difference in the rate of hospitalization in patients with COVID-19 with or without asthma. 15 A nationwide study in Japan examining asthma during COVID-19 outbreak found decreased asthma admissions in 2020 compared to previous years for children and adults. 16 A study of 212 children with allergic asthma in Spain found no significant difference in asthma control or severity between patients with and without COVID- 19. 17 In the United States, adult data suggests that there is no significant increased risk for mortality associated with a history of asthma. A matched cohort study of adult asthma patients admitted to Massachusetts General Hospital with COVID-19 found that asthmatic patients were less likely to require intensive care and mechanical ventilation and did not have increased risk for mortality. 18 A large COVID-19 registry with 11,405 patients from Mount Sinai Health System in NYC revealed that out of the 54.8% of patients who were COVID-19 positive, only 4.4% had asthma, suggesting there was no significant association between asthma history and disease. 19 J o u r n a l P r e -p r o o f The early data from Wuhan regarding hospitalized pediatric patients and those with severe COVID-19 does not list asthma as a risk factor. 20, 21 According to the CDC, in the United States, as of January 2021, 10.8% of 16, 212, 877 COVID-19 cases are found in children. However, this data is changing and not necessarily accurate of the true incidence in children due to lack of prioritization of testing in this population. Hospitalization is reported to be low among children when compared to adults (CDC). Due to paucity of data, there has been an urgent call for further studies in childhood asthma in the current pandemic. 22 Asthma exacerbations have a seasonal pattern and generally have increased prevalence in the late fall and spring and is seen across the North America and known as the "September peak" or asthma epidemic. 23. 24 This is attributed to viral URIs, air pollutants, weather changes, and increase in aeroallergens. 25 , each had at least one underlying medical condition and 55% of the underlying conditions were accounted for by chronic lung disease including asthma, emphysema, and COPD. 32 The final determination of COVID-19 impact towards pediatric asthma morbidity and mortality remains to be seen due to lack of a sufficiently powered studies to provide significant data. As the pandemic surged worldwide international and governmental agencies of countries across all the continents responded by implementing control measures to contain the spread of virus. In the US, Federal, State and local governments passed many unprecedented regulations including stay-at-home orders; the closing of local businesses, Universities, and schools; social distancing and facemask mandates. In the initial surge of disease health resources were targeted towards the care of seriously ill COVID-19 patients and non-urgent care was deferred to alternate delivery model. The federal government declared a public health emergency and also allocated resources to provide medical care. The Health Insurance Portability and Accountability Act (HIPAA) was relaxed which allowed physician to use their personal electronic devices to communicate with their patients during pandemic. 33 The Centers for Medicare and Medicaid services also J o u r n a l P r e -p r o o f promoted telemedicine (TM) by waiving previous restrictions of patient qualification for TM visits, permitting office-based and home-based video encounters on personal devices with patients, and by improving reimbursements. 34 In the US, practitioners actively responded by establishing virtual clinics and using telehealth tools in all medical specialties to curb the pandemic. 35 An ad-hoc expert panel of allergy/immunology specialists from the United States and Canada developed a consensus document to guide specialist in lieu of reduced services due to pandemic. 36 were not worse and have been better than expected, generally. This is likely due to initial fear of susceptibility to severe COVID-19 with asthma, which prompted families to adopt health safety measures and improve adherence with asthma medications. A study at a health system in Wisconsin using electronic medication monitors, noted a 14.5% relative increase in asthma controller adherence across all age groups from January to March 2020. 38 The increased adherence is due to parental concern about asthma control during outbreak. 39 School closures in particular also reduced exposures to allergens and viruses amongst children, which are important triggers of asthma thus enabling improved asthma control. There was some initial concern about continuing inhaled corticosteroids and oral corticosteroids for asthma due to fear of contracting the virus as steroids can impair the immune responses. A meta-analysis of 39 trials revealed that ICS use was not associated with higher risk of pneumonia or respiratory infection due to COVID-19. 40 A study of RNA expression in bronchial brushes of a cohort of adult asthmatic subjects in the UK found that there was no significant difference in expression of ACE2 R and TMPRSS between healthy controls and subjects with moderate and severe asthma with varying corticosteroid treatment. 41 There was no greater risk for asthmatics than the general population for risk of COVID-19 regardless of the severity of asthma and various corticosteroid treatment intensities. This supports the use of inhaled steroids in the management of asthma. In response to pandemic, The Global Initiative for Asthma (GINA) updated guidelines on asthma care during pandemic. 42 The guideline emphasized the importance of optimal asthma management and medication adherence to reduce the risk of asthma exacerbations. The guidelines also recommend continuing prescribed medications including daily inhaled corticosteroids and biologic therapy. 42 The American Academy of Allergy Asthma and Immunology (AAAAI) also reiterated that patients with asthma should continue to use their medications and aim for good control. 43 Both recommended the controller medication dose not be reduced or discontinued during pandemic unless there is clear-cut benefit after careful consideration of risk/benefit for the child. 36, 42, 43 Systemic or oral steroids are recommended for use in moderate to severe asthma exacerbations that are unimproved with bronchodilators. 42, 43 There is no evidence to suggest impairment of immune response to COVID-19 in patients treated with biologics for asthma and is 'reasonable' to continue administration of these agents during the pandemic. 42, 43, 44 Allergen immunotherapy used as an adjunct is also recommended to be continued with adjustment in doses and duration. 43 Many national and international societies including GINA, Australian National Asthma Council, American College of Asthma, Allergy and Immunology (ACAAI) recommend against using nebulizers to reduce the risk of spreading the virus and with a preference for pressurized metered dose inhalers (pMDI). 42 , 43 SARS-CoV2 is transmitted via droplets and aerosols. 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