Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses. OBJECTIVE: We evaluated whether tezepelumab, a human monoclonal anti-TSLP antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis. METHODS: We conducted a double-blind parallel design trial in patients with cat allergy. A total of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study. RESULTS: At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve [AUC0-1h] and as peak score [Peak0-1h] during the first hour after NAC) were significantly reduced in patients receiving tezepelumab/SCIT compared to SCIT alone. At week 104, one year after stopping treatment, the primary end point TNSS AUC0-1h was not significantly different in the tezepelumab/SCIT group compared to SCIT alone, while TNSS Peak0-1h was significantly lower in those receiving combination treatment versus SCIT. Transcriptomic analysis of nasal epithelial samples demonstrated that treatment with the combination of SCIT/tezepelumab, but neither monotherapy, caused persistent downregulation of a gene network related to type 2 inflammation that was associated with improvement in NAC responses. CONCLUSIONS: Inhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196).

The Use of Contrast Agents in Interventional Pain Procedures: A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

COVID-19 vaccine-related presumed allergic reactions and second dose administration by using a two-step graded protocol.

Background: Acute allergic reactions to messenger RNA (mRNA) vaccines are rare but may limit public health immunization efforts. Objectives: To characterize suspected allergic reactions to the first dose of coronavirus disease 2019 (COVID-19) mRNA vaccine and to assess the safety and utility of a two-step graded-dose protocol for the second dose of the Pfizer-BioNTech vaccine in patients with a history of low suspicion of anaphylaxis to their first dose. Methods: This was a retrospective evaluation of referrals to the allergy and immunology clinic for a presumed allergic reaction to the first dose of the COVID-19 mRNA vaccine (Pfizer-BioNTech or Moderna) between December 17, 2020, and February 28, 2021. Recommendations for the second dose and outcomes were evaluated by trained board-certified allergists. Results: Seventy-seven patients presented with a Pfizer-BioNTech reaction (56 [72.7%]) or with a Moderna reaction (21 [27.3%]). Most patients (69.7%) had symptom onset within 4 hours. Most commonly reported symptoms were cutaneous (51.9%), cardiovascular (48.1%), and respiratory (33.8%) symptoms. Recommendations included to proceed with the single dose (70.1%), two-step graded dose (19.5%), or deferral (10.4%). Twelve of 15 patients completed the second dose with a graded-dose protocol. Of these patients, five reported at least one or more similar symptoms as experienced with their first dose. Conclusion: Of the patients with presumed allergic reactions to their first dose of COVID-19 mRNA vaccine, most were able to safely receive the second dose. For those with a low suspicion of anaphylaxis, the two-step graded protocol with the Pfizer-BioNTech vaccine was well tolerated. A graded-dose protocol could be an effective strategy for second-dose vaccination in those who may otherwise defer the second dose.

Prevalence and characterization of asthma in hospitalized and nonhospitalized patients with COVID-19.

BACKGROUND: The Centers for Disease Control and Prevention advises that patients with moderate to severe asthma belong to a high-risk group that is susceptible to severe coronavirus disease 2019 (COVID-19). However, the association between asthma and COVID-19 has not been well-established. OBJECTIVE: The primary objective was to determine the prevalence of asthma among patients with COVID-19 in a major US health system. We assessed the clinical characteristics and comorbidities in asthmatic and nonasthmatic patients with COVID-19. We also determined the risk of hospitalization associated with asthma and/or inhaled corticosteroid use. METHODS: Medical records of patients with COVID-19 were searched by a computer algorithm (March 1 to April 15, 2020), and chart review was used to validate the diagnosis of asthma and medications prescribed for asthma. All patients had PCR-confirmed COVID-19. Demographic and clinical features were characterized. Regression models were used to assess the associations between asthma and corticosteroid use and the risk of COVID-19-related hospitalization. RESULTS: Of 1526 patients identified with COVID-19, 220 (14%) were classified as having asthma. Asthma was not associated with an increased risk of hospitalization (relative risk, 0.96; 95% CI, 0.77-1.19) after adjusting for age, sex, and comorbidities. The ongoing use of inhaled corticosteroids did not increase the risk of hospitalization in a similar adjusted model (relative risk, 1.39; 95% CI, 0.90-2.15). CONCLUSIONS: Despite a substantial prevalence of asthma in our COVID-19 cohort, asthma was not associated with an increased risk of hospitalization. Similarly, the use of inhaled corticosteroids with or without systemic corticosteroids was not associated with COVID-19-related hospitalization.

Hypersensitivity pneumonitis: A fibrosing alveolitis produced by inhalation of diverse antigens.

Hypersensitivity pneumonitis (HP) is a TH1 lymphocyte-biased fibrosing alveolitis caused by antigens ranging from avian excreta, fungi, thermophilic bacteria, and protozoa to reactive chemicals found in the workplace. Mimicking a viral syndrome, acute exposures to inciting antigens cause abrupt onset of nonproductive cough, dyspnea, and chills with arthralgias or malaise usually from 4 to 8 hours later so that the temporal relationship between antigen exposure and symptoms might be unsuspected. The histology of HP reveals prominent lymphocyte infiltrates that thicken the alveolar septa with poorly formed granulomas or giant cells. Bronchoalveolar lavage fluid demonstrates greater than 20% lymphocytes in nearly all patients. Abnormalities on high-resolution computed tomographic examinations range from nodular centrilobular opacities in acute/subacute disease to increased reticular markings and honeycombing fibrosis, which typically are predominant in the upper lobes, in patients with advanced disease. Descriptors include "mosaic" attenuation and ground-glass opacities. Repeated episodes can result in nodular pulmonary infiltrates and suspected nonspecific interstitial pneumonia or idiopathic pulmonary fibrosis. Clinicians require a high level of suspicion to make an early diagnosis of HP before extensive pulmonary fibrosis or restrictive lung disease has occurred.

Potentially (near) fatal asthma.

Potentially (near) fatal asthma (PFA) defines a subset of patients with asthma who are at increased risk for death from their disease. The diagnosis of PFA should motivate treating physicians, health professionals, and patients to be more aggressive in the monitoring, treatment, and control of this high-risk type of asthma. A diagnosis of PFA is made when any one of the following are present: (1) a history of endotracheal intubation from asthma, (2) acute respiratory acidosis (pH < 7.35) or respiratory failure from acute severe asthma, (3) two or more episodes of acute pneumothorax or pneumomediastinum from asthma, (4) two or more episodes of acute severe asthma, despite the use of long-term oral corticosteroids and other antiasthma medications. There are two predominant phenotypes of near-fatal exacerbations: "subacute" exacerbation and "hyperacute" exacerbation. The best way to "treat" acute severe asthma is 3-7 days before it occurs (i.e., at the onset of symptoms or change in respiratory function) and to optimize control of asthma by decreasing the number of symptomatic days and the days and/or nights that require rescue therapy and increasing baseline respiratory status in "poor perceivers." PFA is treated with a multifaceted approach; physicians and health-care professionals should appreciate limitations of pharmacotherapy, including combination inhaled corticosteroid-long-acting ß-agonist products as well as addressing nonadherence, psychiatric, and socioeconomic issues that complicate care.

Lessons learned from clinical trials of asthma.

Exacerbations of persistent or intermittent asthma should be anticipated by physicians and health-care professionals. Patients who are likely to experience an exacerbation often have a history of an exacerbation in the previous year, and the absolute eosinophil count in peripheral blood is ≥ 400/µL. Similarly, expectorated or induced sputum eosinophilia of ≥2% is associated with exacerbations. These phenotypic findings have led to effective biologic therapies, which target eosinophils or immunoglobulin E or the T-helper type 2 phenotype, especially in children, adolescents, and adults with frequent exacerbations. In children, a reduced forced expiratory volume in the first second of expiration (FEV1) to forced vital capacity ratio can be associated with future exacerbations, although the FEV1 may be in the normal range, even with children who have persistent severe asthma. Asthma control questionnaires did not differentiate between children with or children without a future exacerbation. Alternatively, in adults, the lower baseline FEV1 (2.3 L [74% predicted] versus 2.5 L [78% predicted]) identified patients more likely to have a future exacerbation compared with patients who were not having an exacerbation. After correcting for FEV1, the asthma control questionnaire data were associated with exacerbations. In adolescents (ages ≥ 12 years) and adults with persistent mild asthma, most (73%) did not have sputum eosinophilia, and some of these patients responded well to the anticholinergic, tiotropium, which would argue differently from administration of an inhaled corticosteroid as first-line controller therapy. In a three-track study of patients with persistent mild asthma, as-needed budesonide-formoterol and scheduled budesonide were associated with approximately one-half of the annual exacerbation rate of as-needed albuterol. In patients with persistent moderate-to-severe asthma, tiotropium added to controller therapy caused an increase in FEV1 without improving the asthma control questionnaire findings. There were two studies that explored whether either quadrupling or quintupling the inhaled corticosteroid at the first sign of loss of control of asthma would provide meaningful reductions of severe exacerbations of asthma, but the findings did not support this strategy. Both biologic therapies and environmental control (dust mite impermeable encasings) have resulted in reductions of exacerbations in patients with persistent moderate and severe asthma.

Drug allergy.

Drug allergy describes clinical adverse reactions that are proved or presumed to be immunologically based. Allergic drug reactions do not resemble pharmacologic actions of the incriminated drug and may occur at fractions of what would be the therapeutic dosage. Allergic drug reactions are unpredictable; nevertheless, there is increased risk of drug hypersensitivity in (1) patients with cystic fibrosis who receive antibiotics; (2) patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) who receive trimethoprim-sulfamethoxazole or if human leukocyte antigen (HLA)-B*5701+ and receive the antiretroviral agent abacavir; (3) other genetically susceptible populations, e.g., Han-Chinese with HLA-B*1502+ who develop Stevens-Johnson syndrome and toxic epidermal necrolysis from carbamazepine, with HLA-B*5801+ who are at increased risk for such reactions from allopurinol, those with HLA-A*32:01 and receive vancomycin and develop drug reaction with eosinophilia and systemic symptoms syndrome; and (4) patients with a history of compatible allergic reactions to the same medication, similar class, or potentially unrelated medication. Specific patient groups at higher risk for drug allergy include patients with Epstein-Barr virus infection, chronic lymphatic leukemia, HIV/AIDS, cystic fibrosis, patients with seizures who are being treated with anti-epileptic medications, and patients with asthma (especially severe asthma) who are at increased risk of anaphylaxis from any cause, including drugs, compared with patients without asthma. In patients with a history of penicillin allergy, skin testing helps clarify the current level of risk for anaphylaxis by using the major (penicilloyl polylysine) and minor penicillin determinants in which sensitivity is 99%. If penicilloyl polylysine and penicillin G are used for skin testing, then the sensitivity is approximately 85-95%. When skin test results are negative, graded challenges are performed to administer optimal or truly essential antibiotics.

Allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) occurs in patients with asthma or cystic fibrosis, and results in pulmonary infiltrates, tenacious mucus plugs that harbor hyphae of Aspergillus fumigatus, elevations of total serum immunoglobulin E concentration and peripheral blood and sputum eosinophilia. Bronchiectasis is an irreversible complication of ABPA. The key to early diagnosis is to consider ABPA in anyone with asthma or cystic fibrosis and with a positive skin test result for Aspergillus, and/or recurrent infiltrates on radiographs. The differential diagnosis for ABPA in patients with asthma includes diseases in which there is an overlap of asthma, peripheral blood eosinophilia, and radiographic infiltrates. Examples include chronic eosinophilic pneumonia, Churg-Strauss syndrome, drug-induced pulmonary infiltrates, infection with a parasite, asthma with atelectasis, and lymphoma. Mucus plugging that causes a "tree in bud" pattern on computerized tomography examination of the lungs may be from ABPA or other conditions, such as nontuberculous (atypical) mycobacteria (Mycobacteria avium-Mycobacteria intracellulare complex). Prednisone is indicated to clear pulmonary infiltrates, and a usual course is for 3 months. Itraconazole and voriconazole are adjunctive, and drug-drug interactions must be considered because azoles decrease elimination of various medications. Although not familial in most patients, presentation of Aspergillus fumigatus f1 (Asp f1) antigen is restricted to specific major histocompatibility complex (MHC) class II molecules, Human Leukocyte Antigen-DR2 (HLA-DR2), and HLA-DR5. There is an increased number of CD4+ T-helper type 2 lymphocytes in bronchoalveolar lavage, and A. fumigatus can serve as a growth factor of eosinophils potentiating the effects of interleukin (IL) 3, IL-5, and Granulocyte-colony stimulating factor (G-CSF). Eosinophils interact directly with A. fumigatus spores and generate extracellular traps, which can injure the bronchial epithelium.

Idiopathic anaphylaxis.

Idiopathic anaphylaxis (IA) is defined as anaphylaxis without any identifiable precipitating agent or event. The clinical manifestations of IA are the same as allergen-associated (immunologic) anaphylaxis and include urticaria, angioedema, hypotension, tachycardia, wheezing, stridor, pruritus, nausea, vomiting, flushing, diarrhea, dysphagia, light-headedness, and loss of consciousness. Patients usually tend to have the same manifestations on repeated episodes. IA is a prednisone-responsive disease that is ultimately a diagnosis of exclusion. Approximately 40% of patients are atopic. Serum tryptase (or urine histamine or its metabolite) will be elevated acutely, but, if elevated in the absence of anaphylaxis, should suggest alternative diagnoses, including indolent systemic mastocytosis. A focused history, examination, and follow-up will dictate whether a patient's symptoms may be attributable to disorders that mimic anaphylaxis, such as indolent systemic mastocytosis, carcinoid syndrome, pheochromocytoma, hereditary angioedema or acquired C1 esterase inhibitor deficiency, or panic attacks. The presence of urticaria may help limit the differential diagnosis because urticaria does not usually accompany any of the above-mentioned disorders, except for indolent systemic mastocytosis. IA is classified according to the symptoms as well as the frequency of attacks. Patients who experience six or more episodes in a year, or two or more episodes in 2 months are classified as having IA-frequent (IA-F). Patients who experience fewer episodes are classified as having IA-infrequent (IA-I). This distinction is important because patients with IA-F will initially require prednisone as disease-modifying therapy, whereas most patients who with IA-I will not require prednisone. Patients with IA must carry and know when and how to self-administer epinephrine.

Stinging insect allergy and venom immunotherapy.

The Hymenoptera order is divided into three families: Apidae, Vespidae, and Formicidae. Apidae include the honeybee, bumblebee, and sweat bee, which are all docile and tend to sting mostly on provocation. The Africanized killer bee, a product of interbreeding between the domestic and African honeybee, is very aggressive and is mostly found in Mexico, Central America, Arizona, and California. The yellow jacket, yellow hornet, white (bald) faced hornet, and paper wasp all belong to the Vespidae family. The Formicidae family includes the harvester ant and the fire ant. When a "bee" sting results in a large local reaction, defined as >10 cm induration and lasting > 24 hours, the likelihood of anaphylaxis from a future sting is approximately 5%. For comparison, when there is a history of anaphylaxis from a previous Hymenoptera sting and the patient has positive skin test results to venom, at least 60% of adults and 20-32% of children will develop anaphylaxis with a future sting. Both patient groups should be instructed about avoidance measures and about carrying and knowing when to self-inject epinephrine, but immunotherapy with Hymenoptera venom is indicated for those patients with a history of anaphylaxis from the index sting and not for patients who have experienced a large local reaction. Immunotherapy is highly effective in that, by 4 years of injections, the incidence of subsequent sting-induced reactions is 3%. This incidence may increase modestly after discontinuation of injections but has not been reported to be > 10% in follow up.

Unproved and controversial methods and theories in allergy/immunology.

Unproved methods and controversial theories in the diagnosis and management of allergy/immunology are those that lack scientific credibility. Some definitions are provided for perspective, as in chronic medical conditions, frequently nonscientifically based treatments are developed that can have a profound psychological effect on the patients in the absence of objective physical benefit. Standard practice uses methods of diagnosis and treatment used by reputable physicians in a particular subspecialty or primary care practice, with the understanding that diagnosis and treatment options are consistent with established mechanisms of conditions or diseases. Conventional medicine (Western or allopathic medicine) is that which is practiced by the majority of physicians, osteopaths, psychologists, registered nurses, and physical therapists. Complementary medicine involves diverse practices or products that are used with the practice of conventional medicine, such as using acupuncture in addition to opioids for pain relief. Alternative medicine implies use of complementary practices in place of conventional medicine. Unproved and controversial methods and theories do not have supporting data, validation, or sufficient scientific scrutiny, and they should not be used in the practice of allergy/immunology. Some examples of unproven theories about allergic/immunologic conditions include allergic toxemia, idiopathic environmental intolerance, and toxic disease from indoor molds. Unconventional diagnostic methods for allergic conditions include cytotoxic tests, provocation-neutralization, electrodermal diagnosis, applied kinesiology assessments, chemical analysis of body fluids, and serum immunoglobulin G (IgG) or IgG4 testing. Unproven treatments and intervention methods for allergic/immunologic conditions include acupuncture, homeopathy, halotherapy, and autogenous urine injections.

Eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is defined by symptoms related to esophageal dysfunction, persistent esophageal eosinophilia, and exclusion of other etiologies that may be contributing to the condition. EoE is different from erosive esophagitis. In children, symptoms vary by age groups, such as feeding disorders in 2 year olds; vomiting in 8 year olds; and abdominal pain, dysphagia, and/or food impaction in adolescents. Most adults present with dysphagia, food impaction, heartburn, or chest pain. Common endoscopic features in adults with EoE include linear furrows (creases that orient longitudinally), mucosal rings (esophageal "trachealization"), small-caliber esophagus, white plaques or exudates (which are microabscesses of eosinophils), and strictures. Children often present with similar endoscopic features, yet one-third of pediatric patients with EoE have a normal result in an endoscopic examination. Histologic features of EoE include increased intramucosal eosinophils in the esophagus (≥15 eosinophils per high power field), without similar findings in the stomach or duodenum. There also may be eosinophilic microabscesses. In addition to evidence of mast cell activation, mucosa from patients with EoE have increased levels of interleukin 5; supporting eosinophilia; and upregulation of gene expression of eotaxin-3, a chemokine important in eosinophil migration. The majority of patients have evidence of either aeroallergen and/or food sensitization. Dietary therapy is considered first-line therapy for patients with EoE because it is inexpensive and effective, without requiring pharmacologic therapy. Removal of food antigens has been shown to improve symptoms in patients with EoE. Topical corticosteroids improve esophageal eosinophilia and symptoms, and have become the criterion standard of pharmacotherapy.

Contemporary issues in anaphylaxis and the evolution of epinephrine autoinjectors: What will the future bring?

BACKGROUND: Food allergy and anaphylaxis appear to be increasing in the United States, especially in young children, and preparedness is paramount to successful emergency management in the community. Although the treatment of choice for anaphylaxis is epinephrine delivered by autoinjection, some devices are challenged by less user-friendly designs or pose the risk of injury, especially in young patients. Human factors engineering has played a larger role in the development of more recent epinephrine autoinjector technologies and will continue to play a role in the evolution and future design of epinephrine autoinjectors. OBJECTIVE: To discuss contemporary issues related to the identification and management of anaphylaxis, current and future epinephrine autoinjector design, and unmet needs for the treatment of special populations, namely, young children weighing less than 15 kg. METHODS: The literature was reviewed and select articles retrieved to support expert clinical opinions on the need for improved recognition of anaphylaxis, epinephrine autoinjector design, and unmet needs in special populations. RESULTS: Anaphylaxis may be underrecognized and poorly defined in infant- and toddler-aged children, current devices may not be adequate to safely treat these patients (ie, inappropriate needle length), and health care professionals may not be aware of these issues. CONCLUSION: As epinephrine autoinjector technology continues to evolve, device characteristics that promote safe, user-friendly experiences and give clinicians and their patients confidence to successfully treat anaphylaxis during an emergency, without injury, will be favored.

Diurnal variations in subcutaneous allergen immunotherapy reactions.

BACKGROUND: Circadian rhythms underlie many immune responses and allergic diseases. Subcutaneous immunotherapy (SCIT) can result in adverse reactions; however, it is unclear whether such reactions have a diurnal pattern. OBJECTIVE: To assess whether the timing of SCIT affects the rate of adverse reactions. METHODS: This study was a retrospective medical record review of adult patients (n = 289) who received SCIT at the Northwestern Medical Faculty Foundation, Chicago, Illinois, during a 10-year period (2004-2014). Injections were given in the outpatient setting. There were a total of 17,457 injections with 574 reactions. Covariates included age, sex, median income, asthma status, vial contents, number of injections, and previous immunotherapy reactions. Logistical regression was used to calculate the odds of having a reaction with time of SCIT administration as the primary determinate. RESULTS: Immunotherapy reactions occurred more frequently after afternoon or evening (pm) injections (328/8721 = 3.8%) vs morning (am) injections (246/8736 = 2.8%), (χ2 = 12.26, P < .01). Systemic reactions, defined as World Allergy Organization grade 1 or higher, did not have diurnal variation (59/8721 = 0.67% for pm vs am 56/8736 = 0.64% for morning; χ2 = 0.08; P = .77). pm injections resulted in higher odds of reaction compared with am injection in a fully adjusted logistic regression model (odds ratio = 1.43; 95% confidence interval, 1.20-1.70; P < .01). When considering time as 4 categories, the highest odds of reaction were noted for the period from 15:01 to 17:30 (odds ratio, 1.55; 95% confidence interval, 1.21-2.00; P < .01). CONCLUSION: pm injections of SCIT are associated with increased cutaneous reaction rates when compared with am injections. In patients experiencing bothersome local reactions, it may be beneficial to administer SCIT in the morning.