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What's new in allergy and immunology

What's new in allergy and immunology
Authors:
Anna M Feldweg, MD
Elizabeth TePas, MD, MS
Literature review current through: Nov 2022. | This topic last updated: Nov 29, 2022.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ASTHMA AND COPD

Persistence of asthma control after stopping omalizumab therapy (November 2022)

Omalizumab, an anti-IgE monoclonal antibody, is an effective add-on therapy for uncontrolled moderate-to-severe asthma but the optimal duration of therapy and the persistence of benefit after discontinuation are unclear. In an analysis of the French national healthcare database that included over 19,000 patients with asthma (over 2000 children) who received omalizumab for a median duration of approximately 4.5 years, rates of asthma hospitalizations were reduced by 75 percent and the need for oral corticosteroids by 30 percent after two years of treatment [1]. Among patients with asthma control during treatment, symptoms remained controlled in a significant percentage one, two, and three years after discontinuation (76, 44, and 33 percent in children and 70, 39, and 24 percent in adults, respectively). These findings indicate a lasting benefit after discontinuation of omalizumab in patients with controlled asthma and provide a basis for anticipatory guidance for those who discontinue treatment. (See "Anti-IgE therapy", section on 'Observations post-treatment'.)

Insulin resistance in severe asthma (November 2022)

Several studies have identified an increased prevalence of asthma and difficult-to-control asthma among obese individuals, although the exact reason for the association is not known. A recent study of patients with severe asthma included extensive metabolic phenotyping as well as long-term follow-up [2]. Patients with insulin resistance demonstrated more rapid decline in lung function and increased resistance to beta-agonist and oral glucocorticoid therapies compared with patients having normal insulin sensitivity. Whether targeting insulin resistance can impact these severe asthma features requires further investigation. (See "Severe asthma phenotypes", section on 'Asthma associated with obesity'.)

COVID-19 and asthma control in children (November 2022)

Initial data suggested that COVID-19 did not increase asthma morbidity in children, contrary to that expected for a viral respiratory infection. However, asthma control may have improved during the early waves of the pandemic due to an overall decrease in viral respiratory infections. A comparison of nearly 62,000 children with asthma from 108 health care systems in the United States from March 2020 through February 2021 found that a SARS CoV-2 polymerase chain reaction-positive test was associated with increased rates of emergency department visits, hospitalizations, and use of short-acting beta agonist and oral glucocorticoids in the six months following the positive test compared with those who tested negative [3]. This reinforces the importance of patients continuing medications necessary to maintain optimal asthma control so as to better weather COVID-19 and other viral respiratory infections. (See "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies", section on 'Advice related to Covid-19'.)

Mepolizumab for childhood asthma in urban under-served populations (October 2022)

Among adults and adolescents with severe eosinophilic asthma, treatment with mepolizumab (a monoclonal antibody to interleukin-5) reduces exacerbation rates; however, data in children are limited. Mepolizumab was compared with placebo in a trial of children and adolescents recruited from low-income, primarily urban environments in the United States who presented with poorly controlled asthma and elevated blood eosinophils. Mepolizumab reduced asthma exacerbation rates compared with placebo in this population (1.0 versus 1.3 per year, relative risk 0.73), but the improvement was less than that observed in prior trials of adults and adolescents (relative risk approximately 0.50) [4]. Whether this lesser performance is due to ongoing environmental exposure, higher levels of noneosinophilic inflammation, biologic changes between childhood and adult asthma, or other differences in the overall study populations is not well understood. (See "Treatment of severe asthma in adolescents and adults", section on 'Mepolizumab'.)

Bronchodilators in tobacco-exposed persons with symptoms and preserved lung function (September 2022)

Epidemiologic studies suggest that nearly 50 percent of current and former smokers have respiratory symptoms but do not have evidence of airway obstruction on pulmonary function testing. While many of these patients are treated off-label with bronchodilators or inhaled glucocorticoids, a recent trial failed to show improvement in respiratory symptoms or quality of life with dual long-acting bronchodilator therapy (indacaterol-glycopyrrolate) versus placebo in this population [5]. Based on these data, we do not offer bronchodilator treatment in symptomatic current or former smokers without airway obstruction. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging", section on 'Symptoms and pattern of onset'.)

Dupilumab-induced seronegative arthritis and enthesitis (September 2022)

Dupilumab is an IL-4/IL-13 inhibitor approved for the treatment of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. An analysis of nearly 38,000 adverse reactions to dupilumab reported to VigiBase, the World Health Organization's global pharmacovigilance database, found a 9 percent rate of musculoskeletal and connective tissue adverse effects [6]. Specifically, dupilumab was associated with diseases sharing T helper 17 (Th17) immunogenetics, including seronegative arthritis, enthesitis/enthesopathy, and iridocyclitis. Based on these data, we suggest that all patients initiating treatment with dupilumab be counseled about the risk of new-onset joint pain, which is mild in most cases and typically does not require discontinuation of treatment. (See "Treatment of atopic dermatitis (eczema)", section on 'Adverse effects'.)

Underdiagnosis of emphysema using race-based spirometric reference equations (July 2022)

The incorporation of race/ethnicity into reference equations for spirometry and other lung function tests is controversial. In one cohort study, the use of race-neutral equations increased the number of Black participants correctly diagnosed with emphysema by spirometry, such that racial differences in undiagnosed emphysema between White and Black participants were greatly attenuated [7]. These data suggest that one unintended consequence of race/ethnicity-specific equations is underdiagnosis of pulmonary disease in Black populations. Although it is reasonable to continue use of current reference equations for lung function testing until universal normative values have been well established, clinicians should be mindful of this evidence when interpreting results. Use of the "Global Lung Function Initiative (GLI)-other" spirometry reference equation for all races/ethnicities is another reasonable option. (See "Selecting reference values for pulmonary function tests", section on 'Effect of race/ethnicity'.)

Risk factors for thunderstorm asthma (July 2022)

"Thunderstorm asthma" refers to asthma exacerbations that occur in the hours after a thunderstorm, especially storms occurring during pollen seasons. The mechanism appears to involve rupture of water-logged pollen grains, which releases allergenic debris that is swept up by strong cross currents and deposited in concentrated form at ground level. In a multicenter study of adults with a past diagnosis of thunderstorm asthma and/or seasonal allergic rhinitis, risk factors for thunderstorm asthma included higher pollen-specific immunoglobulin E levels, eosinophil counts, and fractional exhaled nitric oxide levels as well as asthma that was not optimally controlled [8]. Clinicians and patients should be aware that thunderstorms can precipitate asthma and patients with pollen allergies and asthma should avoid the outdoors during and after thunderstorms occurring during pollen seasons. (See "Trigger control to enhance asthma management", section on 'Thunderstorms'.)

Asthma designation as a risk factor for COVID-19 (June 2022)

The United States Centers for Disease Control and Prevention (CDC) have recently identified asthma as a risk factor for severe COVID-19 [9]. Several studies including patients with well-controlled asthma do not indicate increased risk in this population; however, some data suggest higher rates of intubation and prolonged mechanical ventilation among all adults with asthma. These complications likely occur more frequently in those with poorly controlled asthma at baseline. Based on the CDC designation, patients with asthma may be prioritized for antiviral therapies if they develop COVID-19. (See "An overview of asthma management", section on 'Advice related to COVID-19 pandemic'.)

DRUG HYPERSENSITIVITY

Frequency of transfusion reactions in children and adults (August 2022)

Transfusion reactions range from bothersome to life threatening. A new meta-analysis of >1.3 million transfusion reactions has documented a nearly twofold higher frequency of acute transfusion reactions in children than in adults [10]. Children were more likely than adults to have reactions to red blood cells and platelets, but not to plasma. Allergic and febrile nonhemolytic transfusion reactions were most common. The only type of reactions seen more frequently in adults were delayed hemolytic and delayed serologic reactions. Early signs and symptoms may not distinguish between benign and more serious events, and all acute transfusion reactions must be considered potentially serious until fully evaluated. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Frequency of reactions'.)

FOOD ALLERGY AND INTOLERANCE

Timing of cow's milk protein introduction in infants and risk of allergy (November 2022)

Current guidelines recommend introducing highly allergenic foods, including cow's milk (CM) protein, in infants who are exclusively breast fed, beginning around four to six months of age. A prospective cohort study in 1298 children that examined the timing of receipt of CM-based formula supplementation after delivery and first reported introduction of CM-based formula or other CM products found that introduction at <2 weeks of age followed by continued exposure was associated with the lowest subsequent risk of development of parent-reported adverse reactions to CM (IgE- or non-IgE mediated) between 2 to 13 years of age [11]. This and other accumulating data suggest that very early introduction and continued ingestion of CM protein in some form (other than liquid, whole CM) may reduce the risk of developing CM allergy, although further studies are needed. (See "Introducing highly allergenic foods to infants and children", section on 'Introduction in the general population'.)

Diagnosis of cashew allergy (October 2022)

Traditional approaches to testing for food allergy can result in a high number of supervised food challenges to determine clinical reactivity or tolerance to the food. A systematic review and analysis of six studies demonstrated that use of a combination of skin prick testing, blood testing for whole cashew, and/or blood testing for cashew component protein(s) can minimize the number of food challenges performed and also limit the number of false positives that lead to unnecessary avoidance and false negatives that result in reactions on home reintroduction or supervised challenge [12]. A suggested approach to the diagnosis of cashew allergy is shown in the algorithm (algorithm 1); we agree with this approach. (See "Component testing for pollen-related, plant-derived food allergies", section on 'Cashew'.)

IMMUNODEFICIENCY

New inborn errors of immunity (October 2022)

Fifty-five novel monogenic gene defects that cause inborn errors of immunity (IEI) and one new phenocopy due to autoantibodies have been identified since 2020 in the International Union of Immunological (IUIS) Societies Expert Committee updated IEI classification, bringing the total number of IEI to nearly 500 [13]. Several key points were noted. Different pathogenic variants in a single gene can cause unique phenotypes. Conversely, defects in different genes can have a similar phenotype because they involve a shared pathway. Finally, identification of genetic causes of IEI unequivocally identifies redundant and nonredundant gene functions. (See "Inborn errors of immunity (primary immunodeficiencies): Classification", section on 'Key points'.)

Inborn errors of immunity and outcomes of COVID-19 (September 2022)

Case reports and small series published since the start of the COVID-19 pandemic have largely reported that patents with inborn errors of immunity (IEIs, previously called primary immunodeficiencies) generally fared well when infected with SARS-CoV-2. In the largest series to date (63 children and adults with various IEIs), COVID-19 (mostly due to the Omicron variant) resulted in mild disease in 90 percent [14]. Sixty percent were vaccinated and 48 percent received antiviral medications or monoclonal antibodies. More severe disease was associated with lymphopenia and low serum immunoglobulins. Rare defects in type I interferon signaling are an important exception, as these patients can develop life-threatening COVID-19. (See "Primary immunodeficiency: Overview of management", section on 'IEIs and the risk of COVID-19 disease'.)

RHINITIS AND RHINOSINUSITIS

Allergen immunotherapy for local allergic rhinitis (November 2022)

Local allergic rhinitis (LAR) describes the subset of patients with rhinitis symptoms who test negative for allergen-specific immunoglobulin E (IgE) on skin testing and in vitro immunoassays, but who react to nasal challenge with allergen. Growing evidence suggests that allergen-specific IgE is produced locally in the nasal tissues but is not detectable systemically for undefined reasons. The utility of allergen immunotherapy (AIT) for LAR was uncertain, but a systematic review and meta-analysis of four randomized trials, which included 156 patients, demonstrated that AIT improved short-term symptom and medication scores and quality of life, and resulted in immunologic changes associated with successful AIT [15]. A standardized approach to nasal challenges would be required before these findings could be widely applied. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy", section on 'Local allergic rhinitis'.)

URTICARIA AND ANGIOEDEMA

Review of all reported cases of aquagenic urticaria (September 2022)

Aquagenic urticaria is a rare form of physical urticaria in which patients develop 1 to 2 mm punctate hives (identical in appearance to cholinergic urticaria) and occasionally systemic symptoms upon exposure of the skin to water. A systematic review of case reports and small series identified 77 patients, which is the largest series to date [16]. The disorder can be acquired or familial, triggered by salt or fresh water and occasionally body fluids, and confirmed by placing a wet, room-temperature towel on the skin for 30 to 40 min, after which transient hives develop. Of 39 patients treated with standard doses of nonsedating H1 antihistamines, 28 experienced complete or marked control, with others responded to higher doses. This series provides support for nonsedating H1 antihistamines as the initial treatment of choice. (See "Physical (inducible) forms of urticaria", section on 'Treatment'.)

VACCINES AND VACCINE HYPERSENSITIVITY

No evidence that PEG is the cause of allergic reactions to mRNA COVID-19 vaccines (July 2022)

When initial reports of allergic reactions to SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccines appeared, the excipient polyethylene glycol (PEG) 2000 was implicated as the possible causative agent because higher molecular weight PEGs and related polysorbates have rarely caused anaphylaxis. However, several case series have documented uneventful mRNA vaccinations in a total of over 300 patients who had known or probable PEG allergy and past reactions to PEG-containing medications [17,18]. These findings suggest that PEG 2000 is not the likely cause of apparent anaphylaxis after vaccination with mRNA vaccines. Patients with past allergic reactions to PEG or polysorbate in other medications can safely receive mRNA COVID-19 vaccines without prior PEG skin testing or other special precautions. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Uncertain role of polyethylene glycol'.)

OTHER GENERAL ALLERGY AND IMMUNOLOGY

Allergen immunotherapy for atopic dermatitis (October 2022)

Allergen immunotherapy (AIT) is a well-established treatment for allergic rhinoconjunctivitis and asthma, but studies of its utility for atopic dermatitis (AD) are mixed. In a new meta-analysis, the addition of AIT (either subcutaneous or sublingual, mostly using house dust mites as the allergen) or placebo was evaluated in 23 randomized trials that enrolled nearly 2000 children and adults with AD who were not controlled with standard therapy (either topical corticosteroids or calcineurin inhibitors) [19]. Patients receiving add-on AIT more often experienced a clinically important decrease in AD severity and improvement in quality of life. Thus, add-on AIT may be beneficial for patients who have eczema that is not controlled with conventional therapies and proven sensitization to house dust mites. AIT may be especially helpful for patients with concomitant allergic rhinoconjunctivitis or asthma. (See "Treatment of atopic dermatitis (eczema)", section on 'Allergen immunotherapy'.)

Dupilumab-induced seronegative arthritis and enthesitis (September 2022)

Dupilumab is an IL-4/IL-13 inhibitor approved for the treatment of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. An analysis of nearly 38,000 adverse reactions to dupilumab reported to VigiBase, the World Health Organization's global pharmacovigilance database, found a 9 percent rate of musculoskeletal and connective tissue adverse effects [6]. Specifically, dupilumab was associated with diseases sharing T helper 17 (Th17) immunogenetics, including seronegative arthritis, enthesitis/enthesopathy, and iridocyclitis. Based on these data, we suggest that all patients initiating treatment with dupilumab be counseled about the risk of new-onset joint pain, which is mild in most cases and typically does not require discontinuation of treatment. (See "Treatment of atopic dermatitis (eczema)", section on 'Adverse effects'.)

  1. Humbert M, Bourdin A, Taillé C, et al. Real-life omalizumab exposure and discontinuation in a large nationwide population-based study of paediatric and adult asthma patients. Eur Respir J 2022; 60.
  2. Peters MC, Schiebler ML, Cardet JC, et al. The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma. Am J Respir Crit Care Med 2022; 206:1096.
  3. Chou CC, Morphew T, Ehwerhemuepha L, Galant SP. COVID-19 infection may trigger poor asthma control in children. J Allergy Clin Immunol Pract 2022; 10:1913.
  4. Jackson DJ, Bacharier LB, Gergen PJ, et al. Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet 2022; 400:502.
  5. Han MK, Ye W, Wang D, et al. Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function. N Engl J Med 2022; 387:1173.
  6. Bridgewood C, Wittmann M, Macleod T, et al. T Helper 2 IL-4/IL-13 Dual Blockade with Dupilumab Is Linked to Some Emergent T Helper 17‒Type Diseases, Including Seronegative Arthritis and Enthesitis/Enthesopathy, but Not to Humoral Autoimmune Diseases. J Invest Dermatol 2022; 142:2660.
  7. Liu GY, Khan SS, Colangelo LA, et al. Comparing Racial Differences in Emphysema Prevalence Among Adults With Normal Spirometry: A Secondary Data Analysis of the CARDIA Lung Study. Ann Intern Med 2022; 175:1118.
  8. Douglass JA, Lodge C, Chan S, et al. Thunderstorm asthma in seasonal allergic rhinitis: The TAISAR study. J Allergy Clin Immunol 2022; 149:1607.
  9. Centers for Disease Control and Prevention. Underlying medical conditions associated with high risk for severe COVID-19: Information for healthcare providers. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html (Accessed on June 27, 2022).
  10. Wang Y, Sun W, Wang X, et al. Comparison of transfusion reactions in children and adults: A systematic review and meta-analysis. Pediatr Blood Cancer 2022; 69:e29842.
  11. Switkowski KM, Oken E, Rifas-Shiman SL, et al. Timing of Cow's Milk Protein Introduction and Childhood Adverse Reactions to Cow's Milk. J Allergy Clin Immunol Pract 2022; 10:2713.
  12. Brettig T, Koplin JJ, Dang T, et al. Cashew allergy diagnosis: A two-step algorithm leads to fewer oral food challenges. J Allergy Clin Immunol Pract 2022; 10:1652.
  13. Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022; 42:1473.
  14. Conti F, Pacillo L, Amodio D, et al. SARS-CoV-2 infection and treatment in a cohort of patients with inborn errors of immunity. Pediatr Allergy Immunol 2022; 33:e13833.
  15. Hoang MP, Samuthpongtorn J, Chitsuthipakorn W, et al. Allergen-specific immunotherapy for local allergic rhinitis: a systematic review and meta-analysis. Rhinology 2022; 60:11.
  16. Rujitharanawong C, Kulthanan K, Tuchinda P, et al. A Systematic Review of Aquagenic Urticaria-Subgroups and Treatment Options. J Allergy Clin Immunol Pract 2022; 10:2154.
  17. Picard M, Drolet JP, Masse MS, et al. Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: A case series. J Allergy Clin Immunol Pract 2022; 10:620.
  18. Otani IM, Tsao LR, Tang M. Coronavirus disease 2019 vaccine administration in patients with reported reactions to polyethylene glycol- and polysorbate-containing therapeutics. Ann Allergy Asthma Immunol 2022; 129:88.
  19. Yepes-Nuñez JJ, Guyatt GH, Gómez-Escobar LG, et al. Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms. J Allergy Clin Immunol 2022.
Topic 8363 Version 11627.0

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