The challenge of COVID-19 that permeates the practice of allergy/immunology

This issue of the Proceedings continues to feature the spectrum of articles that comprise the domain of diseases, seen by the allergist/immunologist, which range from rhinitis, asthma, urticaria, drug hypersensitivity, immune deficiency disorders hereditary angioedema (HAE), to immunotherapy. Yet, through this continuum of disease entities, the daunting presence of coronavirus 2019 (COVID-19) continues to permeate the practice of the allergist/immunologist and is also seen within the pages of this issue.

In an accompanying special editorial in this issue, Bellanti and Settipane¹ introduce the readership to a call to arms for the allergist/immunologist in meeting the many challenges posed by this devastating coronavirus. By using a military metaphor, they write about the important role the public will play in ending the war against COVID-19 that the United States and the world are currently engaged in by receiving the soon to be available COVID-19 vaccines.¹ Unfortunately, many of our patients and the public have questions and concerns about the safety and efficacy of these vaccines, as reflected by recent polls that indicate that the share of Americans who say they would get vaccinated has declined sharply since earlier this year. This special editorial addresses the many ways that the allergist/immunologist can positively contribute to the war effort through education of our patients and the public by providing scientific, fact-based evidence to help allay public concerns and build confidence in COVID-19 vaccine candidates that have been shown to be safe and effective. Because of the importance of the information contained within the special editorial, it was chosen as a basis for this issue's “For the Patient” section entitled “COVID-19 Vaccines and the Public: Challenges and Solutions.” This segment, found in the final pages of the print version of this issue and also available online, consists of a one-page article synopsis written in a readily comprehensible fashion to help patients better understand the content of the full special editorial.

To provide further COVID-19 insights in children, Frenkel et al.² reviewed the unique features of epidemiology, immunopathogenesis, clinical course, and management of COVID-19 disease in the pediatric population. The authors concluded that children have milder disease because of their immature immune systems; however, they caution that, although children are largely spared from severe respiratory disease, they can present with a SARS CoV-2(severe acute respiratory syndrome coronavirus 2) associated multisystem inflammatory syndrome in children, a rare but severe condition similar to Kawasaki disease that has been reported ∼2–4 weeks after the onset of COVID-19 in children and adolescents.²

Other areas of COVID-19 management of particular interest to the allergist/immunologist include the following: optimal management of patients with asthma who are at risk of contracting COVID-19, whether asthma and steroids are risk factors for severe COVID-19, and the risk of transmission of SARS CoV-2 infection in the pediatric population. In the “Clinical Pearls and Pitfalls” section of this issue, Pitlick and Joshi³ provided allergists and other clinicians with pearls that pertain to these management issues. The authors concluded that asthma did not seem to be associated with an increased risk of COVID-19 and that, although no evidence has been established to guide the use of biologic therapy, continued use of inhaled corticosteroids seemed to be safe.³

Allergy immunotherapy (AIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), is an effective and safe treatment for allergic rhinitis and allergic asthma due to inhalant allergens. This issue of the Proceedings features two articles that characterize important inhalant allergens (i.e., dust mite and oak pollen) and two additional articles on AIT safety, efficacy, and outcomes. Guided by the aim to improve house-dust mite AIT in southern China, Zou et al.⁴ measured serum levels of specific immunoglobulin E to Dermatophagoides pteronyssinus allergen components (Der p 1, 2, 3, 5, 7, 10, and 23) in patients with allergic rhinitis and/or allergic asthma who were sensitized to D. pteronyssinus. The authors found that Der p 1 and Der p 2 were the main sensitizing components of D. pteronyssinus and concluded that these findings can provide potential guidance for personalized house-dust mite specific immunotherapy in southern China.⁴

In transitioning from perennial allergens in southern China to seasonal allergens in North America, Bernstein et al.⁵ reviewed clinical and epidemiologic aspects of allergy to oak pollen, oak taxonomy, and oak allergen cross-reactivity. The authors concluded that allergic sensitization to oak pollen was common in North America and not only had a substantial clinical impact but also that cross-reactivity between oak and birch pollen allergens may have had implications for AIT.⁵ In transitioning from allergens to AIT, Bisyuk et al.⁶ performed a comparative analysis of the efficacy and safety of SLIT versus SCIT. The study focused on U.S. Food and Drug Administration approved SLIT tablets and included a detailed analysis of timothy grass pollen, five-grass pollen, ragweed, and house-dust mite SLIT tablets compared with SCIT.⁶Stone et al.⁷ attempted to fill the void of real-world evidence AIT studies by analyzing claims data of > 2.3 million patients with allergic rhinitis who resided in the United States to assess patient characteristics and health outcomes. They found 103,207 patients who had at least one AIT claim, with 45,279 of these patients (43.9%) reaching maintenance.⁷ The authors concluded that patients who initiated AIT presented the greatest need for therapeutic intervention, as evidenced by higher allergy-related comorbidities; those who reached maintenance demonstrated improved outcomes after the initiation of therapy, which suggested that continued efforts to increase patient awareness and adherence to AIT are needed.⁷

Primary immunodeficiency diseases (PIDD) consist of a heterogeneous group of disorders characterized by various aspects of immune dysregulation. Although the most common clinical manifestation of PIDD is an increased susceptibility to infections, there is a growing body of evidence that patients with PIDD often have a higher incidence of noninfectious complications of PIDD as well. Dilley et al.⁸ sought to better understand these noninfectious complications by determining the comorbid disease prevalence across various age groups, genders, and immunoglobulin replacement types compared with the general population. They found higher comorbid diagnoses in the PIDD population, including chronic obstructive pulmonary disease–asthma in 51.5%, rheumatoid disease in 14%, deficiency anemia in 11.8%, hypothyroidism in 21.2%, lymphoma in 16.7%, neurologic disorders in 9.7%, arrhythmias in 19.9%, electrolyte disorders in 23.6%, coagulopathies in 16.9%, and weight loss in 8.4%.⁸ The authors suggested that increased awareness of these noninfectious complications may allow for better monitoring, care coordination, targeted treatments, and improved prognosis in patients with PIDD.⁸

Specific antibody deficiency is a type of PIDD characterized by normal immunoglobulins but an inadequate antibody response to immunization with polysaccharide vaccines. Clinical manifestations include recurrent bacterial infections, most commonly, sinopulmonary infections. There are limited clinical data to help guide the selection of the best treatment options for this disease. In an effort to address this information gap, Pandya et al.⁹ conducted a retrospective chart review to compare the rate of infections for patients who had been managed with clinical observation versus those administered prophylactic antibiotics versus immunoglobulin replacement therapy. Although the study was limited by the small number, 26 subjects, the authors found that prophylactic antibiotics seemed to be equally effective as immunoglobin supplementation therapy for the treatment of specific antibody deficiency.⁹

Six articles in this issue focus on the topic of asthma, beginning with a report by Aydin et al.,¹⁰ who sought to evaluate wheat flour sensitivity and determine the rate of asthma in workers of a large bread factory in Ankara. The authors reported finding sensitivity to wheat flour in 14.2% of 162 workers, with 4.32% being diagnosed with asthma and specific inhalation tests being positive in 2.46%.¹⁰ In a unique report, Mat et al.¹¹ sought to determine the association between the risk of obstructive sleep asthma (OSA) and asthma control. The asthma control test and the Berlin questionnaire were used to determine the asthma control levels and OSA risk in 137 participants with asthma.¹¹ The authors found that the subjects with a low OSA risk were more likely to have controlled asthma than those with a high OSA risk. In the subjects with asthma who adhered to therapy and used inhalers with the correct technique, a high risk of OSA was found to be associated with poor asthma control.¹¹ This association was independent of other factors, including rhinitis, gastroesophageal reflux, and smoking.¹¹

Tashkin et al.¹² sought to assess the performance of the recently approved generic fluticasone propionate and salmeterol dry powder inhaler. Findings from three studies with regard to device usability, function, and robustness were reviewed. The authors report that across all studies, the generic device demonstrated an excellent safety profile and was well tolerated.¹² Tiotiu¹³ conducted a literature review to explore the role of personalized medicine in adult severe asthma management. He observed that, in association with the increasing availability of monoclonal antibodies that target type 2 (T2) inflammation pathways, severe asthma therapy is transitioning to a personalized medicine approach.¹³ The author concluded that future research is necessary to identify biomarkers that best predict the response to available biologic therapies for T2 asthma and to help guide the development of therapies for non-T2 asthma.¹³

By providing novel research on the development of asthma biomarkers, Yormaz et al.¹⁴ sought to compare the utility of measuring periostin and thymus and activation-regulated chemokine (TARC). In a study conducted with 87 patients with asthma and 42 healthy control subjects, TARC and periostin levels were found to be significantly higher in the asthma group than in the control group; and TARC seemed to be the more reliable biomarker than periostin.¹⁴ In clinical practice, once a decision is made to initiate biologic treatment for asthma, the next step is in obtaining prior authorization approval from the patient's health insurance. This process can take a significant amount of time and result in delayed initiation of treatment. Dudiak et al¹⁵ sought to quantify the times for approval and filling of biologics, and to determine whether patients were at risk of asthma exacerbations during this time frame. The authors reported that the mean ± standard deviation time from submission of the prescription to the first dose available for injection was 44.0 ± 23.2 days.¹⁵ They concluded that the prior authorization process for biologics was slow and that patients were at high risk of exacerbations during this time.¹⁵ They recommended that the prior authorization system needs to be improved to expedite approval and initiation of biologics.¹⁵

In transitioning from asthma to chronic urticaria, Magen et al.¹⁶ investigated hematologic parameters as potential biomarkers for antihistamine (AH) and omalizumab resistance in chronic spontaneous urticaria (CSU). The authors conducted a retrospective, observational study by using the electronic patient record data base of patients with CSU and sex- and age-matched controls. The patients with CSU were divided into three study groups: the CSU group (patients who responded to AHs), the AH resistant (AH-CSU) group (patients refractory to a fourfold AH dose), and the control group.¹⁶ The AH-CSU group was characterized by mean ± standard deviation higher plasma (high-sensitivity C-reactive protein) (6.4 ± 3.7 mg/L), than the CSU (4.3 ± 1.4 mg/L; p < 0.001) and control groups (3.1 ± 1.8 mg/L; p < 0.001).¹⁶ There were no significant differences in the mean levels of lymphocytes, monocytes, eosinophils, basophils, and platelets, and the rates of eosinopenia and basopenia between the patients with AH-CSU who responded and those who were resistant to omalizumab.¹⁶

HAE is a rare genetic disorder that has recently been addressed in the “HAE Primer” supplemental issue of the Proceedings.^17–29 Emotional stress has been reported as the most common trigger factor for C1 esterase inhibitor (C1-INH) HAE attacks. Savarese et al.³⁰ conducted a systematic review of the literature to shed light on the advancements made in the study of how stress and psychological processes impact C1-INH–HAE. The authors retrieved, examined, and classified 21 articles related to the keywords used for their search. Based on their review, the authors concluded that, although the literature does confirm that stress and psychological processes do impact C1-INH–HAE, it is important to take into account the complexity of factors that contribute to C1-INH–HAE expression.³⁰

With regard to HAE treatment, in many regions of the world, patients are fortunate to have access to a growing number of therapeutic choices for prophylaxis against attacks; however, for almost 3 decades, the only available long-term prophylactic agent was attenuated androgens. The current availability of effective and more tolerable long-term prophylactic therapies has led to a continuing decline in the use of attenuated androgens. Because a consensus on the best approach for discontinuing or tapering off attenuated androgen therapy in patients with HAE does not exist, Johnston et al.³¹ conducted a physician survey and literature review with the goal of developing a consensus on androgen tapering. Based on their findings, specific recommendations are provided.³¹

In transitioning to the evaluation of drug hypersensitivity reactions, Wolfson and Banerji³² reviewed the important role of the allergist to elucidate this problem. The authors outlined how the allergist uses the clinical history, skin testing, and/or drug challenge to specifically identify the causative drug(s), and, more importantly, enable the use of the exonerated drug(s).³² In their review, the authors focused on the evaluation of drug hypersensitivity reactions to antibiotics, perioperative agents, biologics, and chemotherapeutics.

In continuing with the theme of drug hypersensitivity reactions, this issue's Patient-Oriented Problem Solving (POPS) case presentation explores the differential diagnosis of periprocedural anaphylaxis in a 2-year-old girl. The POPS case presentation is a recurring feature of the Proceedings, which, as per tradition, is written by an allergy/immunology fellow-in-training from one of the U.S. allergy/immunology training programs. The purpose of the POPS series is to provide an innovative and practical learning experience for the allergist/immunologist in-training by using a didactic format of clinical presentation and deductive reasoning. In this issue's POPS, Chow et al.,³³ from the Division of Allergy and Immunology at University of Texas Southwestern Medical Center (Dallas, TX), lead the reader through this learning process by illustrating the complexity of the differential diagnostic process for this clinical presentation and the importance of a detailed history, physical examination, and appropriate laboratory assessment in arriving at a correct diagnosis.

In summary, the collection of articles found within the pages of this issue provides further insight into the intersecting crossroads of inflammation and disease, which manifest as allergic, immunologic, and respiratory disorders that afflict patients whom the allergist/immunologist serves. In particular, they exemplify how the complexities of COVID-19, PIDD, asthma, chronic urticaria, HAE, anaphylaxis, drug allergy, and AIT for allergic rhinitis and asthma continue to challenge the allergist/immunologist. In keeping with the overall mission of the Proceedings, which is to distribute timely information with regard to advancements in the knowledge and practice of allergy, asthma, and immunology to clinicians entrusted with the care of patients, it is our hope that the articles found within this issue will help foster enhanced patient management and outcomes. On behalf of the Editorial Board, we hope that you are able to make practical use of the diversity of literature offered in this issue of the Proceedings.