key: cord-271814-a2vlkwce
authors: Brough, Helen A.; Kalayci, Omer; Sediva, Anna; Untersmayr, Eva; Munblit, Daniel; Rodriguez del Rio, Pablo; Vazquez‐Ortiz, Marta; Arasi, Stefania; Alvaro‐Lozano, Montserrat; Tsabouri, Sophia; Galli, Elena; Beken, Burcin; Eigenmann, Philippe A.
title: Managing childhood allergies and immunodeficiencies during respiratory virus epidemics – The 2020 COVID‐19 pandemic: A statement from the EAACI‐section on pediatrics
date: 2020-05-31
journal: Pediatr Allergy Immunol
DOI: 10.1111/pai.13262
sha: 
doc_id: 271814
cord_uid: a2vlkwce

While the world is facing an unprecedented pandemic with COVID‐19, patients with chronic diseases need special attention and if warranted adaptation of their regular treatment plan. In children, allergy and asthma are among the most prevalent non‐communicable chronic diseases, and healthcare providers taking care of these patients need guidance. At the current stage of knowledge, children have less severe symptoms of COVID‐19, and severe asthma and immunodeficiency are classified as risk factors. In addition, there is no evidence that currently available asthma and allergy treatments, including antihistamines, corticosteroids, and bronchodilators, increase the risk of severe disease from COVID‐19. Most countries affected by COVID‐19 have opted for nationwide confinement, which means that communication with the primary clinician is often performed by telemedicine. Optimal disease control of allergic, asthmatic, and immunodeficient children should be sought according to usual treatment guidelines. This statement of the EAACI Section on Pediatrics puts forward six recommendations for the management of childhood allergies and immunodeficiencies based on six underlying facts and existing evidence.

Viruses interact with most living organisms, mostly in a symbiotic way. Nevertheless, this equilibrium can be disturbed in many occasions and lead to outbreaks of disease. In the case of the delicate interaction between viruses and human beings, many significant epidemic outbreaks of viral disease are linked to respiratory symptoms. 

While all humans are at risk of being infected regardless of age, gender, or health, vulnerable populations at higher risk of developing a severe form of COVID-19 disease have been identified.

Among them, older age is a major risk factor. Since the beginning of the pandemic, it has become rapidly apparent that children less often present symptoms and that these are less often severe. The only systematic review bringing together data on children has been published recently and concluded that children account for 1%-6% of the diagnosed COVID-19 cases often have milder disease than adults, and mortality rates are extremely low. 3 However, with hundreds of papers published on COVID-19 in the past few months, the problem of reporting the same patients in different manuscripts was raised 4 ; duplicate reporting may lead to inaccurate scientific record and thus potentially misleading results in any systematic review and meta-analysis. The first reliable data came from more than 72.000 case reports reviewed by the Chinese Center for Disease Control and Prevention showing that less than 1% of cases were younger than 10 years of age. 5 However, as discussed in the paper and outlined in an accompanying editorial one should bear in mind that in this study testing for other viruses was not standardized, and two-thirds of cases were control of allergic, asthmatic, and immunodeficient children should be sought according to usual treatment guidelines. This statement of the EAACI Section on Pediatrics puts forward six recommendations for the management of childhood allergies and immunodeficiencies based on six underlying facts and existing evidence.

allergy, asthma, biologics, children, coronavirus, corticosteroids, COVID-19, immunodeficiency, SARS-CoV-2, treatment clinically diagnosed, but not virologically confirmed. 9 In addition, more of the severe and critical cases were in the suspected than the confirmed group which suggests that some suspected cases might be caused by other respiratory infections.

The CDC in the United States recently published a review of laboratory-confirmed COVID-19 in children between February 12 and April 2, 2020. 10 Among 149 082 (99.6%) reported cases for which age was known, 2572 (1.7%) were among children aged <18 years. The majority of pediatric cases (57%) were male, and male predominance persisted even in infants. Among 345 pediatric cases with information on underlying conditions, 23% (n = 80) had at least one underlying condition, most commonly chronic lung disease (including asthma) (n = 40), followed by cardiovascular disease (n = 25), and immunosuppression (n = 10). Information on hospitalization status for children was available for only 745 (29%) cases. Infants accounted for the highest percentage of hospitalizations; of the 95 infants with known hospitalization status, 62% (n = 59) were hospitalized, including five who were admitted to intensive care. There was little variation in the percentage hospitalized among children >1 year of age. Limitations of this study included substantial missing data; thus, statistical comparisons were not possible and need to be interpreted with caution. However, similarly to the Wuhan review of pediatric cases, children were less severely affected than adults, and infants were more likely to be hospitalized. Of note, given the higher percentage of asymptomatic children in the population, the real percentage of pediatric subjects with severe or critical disease may be even lower.

The reason for the relatively milder clinical presentation in children is mostly unknown. As outlined in the Chinese study, several factors in relation to the exposure and host factors may account for this observation; in addition, since the children's immune system is still developing, it may react to pathogens differently than do adults. 11 Angiotensin-converting enzyme II (ACE-2) which acts as the receptor for coronaviruses may be structurally and functionally less mature in the airways of children. [12] [13] [14] As children attend daycare/ schools, they are exposed to a variety of viruses including other types of coronaviruses, and they may be better equipped with general antiviral defense mechanisms of the immune system. Another potential hypothesis 14 suggested that the simultaneous presence of other viruses in the respiratory tract mucosa, which is very typical for young children, may limit the growth of SARS-CoV-2 by direct virus-to-virus interactions and competition. 15 Similar to the observation made in children with SARS, 16 the children with COVID-19 infection may not be mounting a generalized cytokine storm but rather may be responding with elevation of specific cytokines. In a recent study with clusters of adults with pneumonia cases in Wuhan, China, the cytokine profile associated with COVID-19 disease severity was characterized by increased interleukin (IL)-2, IL-7, granulocyte colony-stimulating factor, interferon-γ-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis factor-α. 11 It is also possible that children have less severe disease because they have fewer chronic health conditions. It is important to note that although children have less severe COVID-19 disease, they are still able to pass on the virus, even while asymptomatic. 17

In addition to age, chronic health conditions such as renal failure, diabetes, hypertension, and heart disease are major risk factors for developing more severe symptoms of COVID-19. 18 Patients with asthma (particularly severe or uncontrolled asthma) and immunodeficiency have also been classified to be at increased risk of developing more severe COVID-19, based more on common sense rather than mounting evidence. 19 However, recently, the CDC in the United States released a Morbidity and Mortality Weekly Report which suggested that adults with a history of asthma were more likely to be hospitalized with COVID-19; those hospitalized with COVID-19 had a higher rate of a history of asthma (17.0%) than the general population (7.7%).

While public policy is majorly focusing on "flattening the curve," that is, preventing a too rapid spread of COVID-19 and on providing adequate health care for patients with severe respiratory symptoms in this very aggressive disease, many health providers are faced with questions about safe management of their patients with chronic health conditions. Many elective face-to-face hospital services have been discontinued, in favor of remote consultations that have also been substantially scaled back, which provides its own challenges.

The care of children with allergies or immune conditions is being adapted to the current situation, with more remote working and providing guidance to children to reduce likelihood of infection in children who would be deemed at higher risk of severe COVID-19 disease.

Guidance is strongly needed on how to manage children with allergic diseases during the pandemic, particularly, as the pandemic is hitting the Northern Hemisphere during the tree and grass pollen pollination season. How to run a clinic under the condition of the COVID-19 pandemic is reviewed in the EAACI position paper. 21

Although the current COVID-19 pandemic may fade away and hopefully eventually a vaccine may be available, it is unavoidable that new respiratory viruses will appear and that similar questions will arise again in the future. Hopefully, these recommendations will be helpful also in future similar events.

It became rapidly evident that severe COVID-19 infections were particularly prevalent in specific risk groups. A retrospective cohort involving 191 adults hospitalized in Wuhan at the early onset of the disease identified pre-existing comorbidities in 48% of the patients. 18 Hypertension was most common followed by diabetes, and by coronary heart disease. Chronic obstructive lung disease was a pre-existing condition in only 6 patients with 4 of them having a fatal outcome due to COVID-19. Asthma or allergy was not mentioned as a risk factor in this population. Older age was associated with increased odds of in-hospital death; this observation has now been confirmed during the course of the disease in Europe and North America.

Evaluating asthma and allergy more specifically as potential risk factors, a retrospective study based on electronic medical records from 140 hospitalized COVID-19 adult patients investigated pre-existing asthma or allergic diseases. 22 In this adult population, drug hypersensitivity was self-reported in 11.4% and urticaria in 1.4%. However, asthma or other allergic diseases were not reported by any of the patients. Even though there are no data specifically addressing this question, CDC states that people of all ages with chronic lung disease including moderate to severe asthma are listed as having high risk. 19 Pre-existing allergies have not been classified as risk a factor.

Concerns have also been raised regarding a more severe course of There are no data regarding whether the treatment with inhaled corticosteroids (ICS) modifies the susceptibility to or severity of COVID-19. Previous studies have shown that ICS especially when used at high doses may be associated with an increased risk of pneumonia in adult patients with chronic obstructive pulmonary disease.

In this regard, one should keep in mind that children have different phenotypes of asthma than adults. In children, however, a recent meta-analysis has shown that regular use of ICS may not increase the risk of pneumonia or other respiratory infections in children with asthma. 30 Early childhood is a time associated with frequent infections due to common respiratory viruses such as respiratory syncytial virus (RSV) or rhinovirus. In children with increased bronchial hyperactivity, recurrent viral infections predispose to episodes of bronchoconstriction. In order to prevent this, these patients are frequently treated with ICS. During such treatments, increased severity or frequency of viral infection has not been observed. 31 Since asthma itself may be a risk factor for the severity of COVID- 

Since primary immunodeficiencies (PID) are congenital disorders, patients with PID might represent a potential group-at-risk in the current pandemic of COVID-19. From the very onset of the pandemic, a special focus was given to this patient group predisposed to infections with respiratory viruses. An international consensus recently summarized how to best manage patients with PID during the pandemic. 33 According to current knowledge in April 2020, it

is not yet known whether any specific form of immunodeficiency poses a particular threat to patients. As a joint project, question- The current COVID-19 pandemic might also pose a risk to pediatric patients with secondary immunodeficiencies, such as patients on immunosuppressive therapy for autoimmune or severe allergic diseases. It is recommended to continue the treatment, including immunosuppressants. In the case a secondary deficiency is treated by immunoglobulin substitution, continuation is recommended. The use of convalescent plasma might be considered in these cases in the future, when this now emerging COVID-19 treatment option is scientifically established. 35

Precautionary recommendations for patients with immunodeficiencies follow the national guidelines for the general population and include strict hygiene and social distancing measures to limit exposure. A general consensus has been reached to continue established therapies for the immune disorder, even immunosuppressive therapy for autoimmune complications of the underlying disease. 36 However, the current pandemic poses an exceptional challenge and safety concern for patients treated with cellular therapies, not only limited to the field of PID. 37 The main drawback to define tailored safety recommendations for patients with immunodeficiencies arises from our lack of knowledge regarding immune mechanisms during COVID-19. Cytotoxic lymphocytes, essential to control viral infections, were described to be markedly decreased in total cell numbers, and NK and CD8 + T cell function was exhausted in patients with COVID-19 infection. 38 Moreover, Toll-like receptor 7 activation associated with alpha-interferon and TNF-alpha as well as IL-12 and IL-6 production seem to play an essential role in the control of the viral infection. 39 To increase our knowledge in disease mechanisms, we need to learn from clinical and immunologic characteristics of patients with severe in contrast to moderate disease. 40 In children and young adults, COVID-19 mainly occurs mildly and without life-threatening complications. If COVID-19 causes severe to lethal disease as observed in sporadic cases in these age groups without other comorbidities, it is tempting to speculate that severity is due to a defect in defense against the infection. Therefore, a targeted search for possible monogenic immunodeficiencies by next generation sequencing and further advanced methods was launched in these patients, 41 which will greatly advance our understanding of immune protection against COVID-19. 

There has been no scientific evidence that allergy treatments either increase susceptibility to SARS-CoV-2 or the severity of COVID-19 disease. Pediatric allergists should treat patients with allergic asthma, allergic rhinitis, or other allergy conditions according to usual guidelines, 24 without restricting the use of any specific medication. One exception to this is the advice to withhold biologics during acute COVID19 disease. In addition, there is also reason to believe that proper treatment of these diseases might prevent unnecessary visits to physicians and hospitals and thus reduce the risk of being exposed to the SARS-COV-2 virus. Of note, the Global Initiative for Asthma (GINA) recommends avoiding the use of nebulizers for asthma attacks due to the increased risk of disseminating COVID-19 (to other patients and to physicians, nurses, and other personnel); thus, pressurized metered-dose inhaler (pMDI) via a spacer is the preferred treatment during severe attacks. 28 

A novel coronavirus from patients with pneumonia in China

Genomic epidemiology of novel coronavirus -Global subsampling

Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults

Editorial concern-Possible reporting of the same patients with COVID-19 in different reports

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

SARS-CoV-2 infection in children

Detection of Covid-19 in Children in Early

Epidemiological characteristics of 2143 pediatric patients with 2019 Coronavirus disease in China

COVID-19 in children: Initial characterization of the pediatric disease

CDCMMWR. Coronavirus Disease 2019 in Children -United States

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Are children less susceptible to COVID-19?

Cleavage of the SARS Coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells in vitro

Why is COVID-19 so mild in children? Acta Paediatr

Virus-virus interactions impact the population dynamics of influenza and the common cold

Inflammatory cytokine profile in children with severe acute respiratory syndrome

A well infant with coronavirus disease 2019 with high viral load

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Cent Dis Control Prev

Most Recent National Asthma Data

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

cal-manag ement -of-sever e-acute -respi rator y-infec tion-when-novel -coron aviru s-(ncov)-infec tion-is-suspe cted

A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis

Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial

COVID-19 illness in native and immunosuppressed states: A Clinical-Therapeutic Staging Proposal

COVID-19: GINA Answers to Frequently Asked Questions on asthma management

BTS Advice for Healthcare Professionals treating patients with asthma

Inhaled corticosteroids and respiratory infections in children with asthma: A Meta-analysis

Preventing exacerbations in preschoolers with recurrent wheeze: A Meta-analysis

Considerations on biologicals for patients with allergic disease in times of the COVID-19 pandemic

COVID 19_WORLD WIDE_ Joint _ St ate ment _ 2020 0 311_120 0 C E T_FINAL .pdf. Accessed

Deployment of convalescent plasma for the prevention and treatment of COVID-19

COVID-19: Pandemic contingency planning for the allergy and immunology clinic

Impact of COVID-19 and future emerging viruses on hematopoietic cell transplantation and other cellular therapies. Stem Cells Dev

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Why the immune system fails to mount an adaptive immune response to a COVID -19 infection

Clinical and immunologic features in severe and moderate Coronavirus Disease

Parenting in a time of COVID-19

Shielding advice for very high-risk groups

American College of Allergy, Asthma & Immunology Position Paper on the Use of Telemedicine for Allergists

Managing childhood allergies and immunodeficiencies during respiratory virus epidemics -The 2020 COVID-19 pandemic: A statement from the EAACI-section on pediatrics