Patient-Centered Practice Guidelines: GRADEing Evidence to Incorporate Certainty, Balance Between Benefits and Harms, Equity, Feasibility, and Cost-Effectiveness.

The practice of medicine in recent years has emphasized the use of evidence-based clinical guidelines to help inform treatment decisions. Since its development in 2004, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach has offered a systematic process for reviewing and summarizing the certainty of evidence found in the medical literature regarding various treatment options. To develop truly patient-centered care guidelines, this appraisal of the certainty of evidence must be combined with an understanding of the balance between benefits and harms, patient preferences, equity, feasibility, cost-effectiveness, and policy implications. This review examines each of these domains in detail, exploring the process and benefits of developing relevant, patient-focused guidelines directly applicable to the practice of modern medicine.

Urine Mast Cell Mediators in the Evaluation and Diagnosis of Mast Cell Activation Syndrome.

PURPOSE OF REVIEW: Mast cell activation syndrome is defined by severe, episodic, and recurrent symptoms induced by mast cell mediators with objective measurement of increase in biomarkers of mast cell activation and treatment response with mast cell therapies. Increase in serum tryptase from baseline during a mast cell activation episode is currently the most accepted biomarker measurement of mast cell release. However, during symptomatic episodes, serum tryptase can be difficult to obtain as it is a venipuncture procedure. Other objective measures of mast cell activation are needed to complement serum tryptase. RECENT FINDINGS: Urine mast cell mediators can be collected at home and are non-invasive tests. There is emerging evidence for the utility of urine mast cell mediators including histamine, cysteinyl leukotrienes, and prostaglandins in the diagnosis of mast cell activation syndrome. In this review, clinically available urine mast cell mediators will be discussed including N-methylhistamine, leukotriene E4, and 2,3-dinor-11beta-prostaglandin F2 alpha. We discuss the rationale for the use of these urine mast cell mediators and examine the studies analyzing their performance for identifying mast cell activation.

Rural Health Disparities in Allergy, Asthma, and Immunologic Diseases: The Current State and Future Direction for Clinical Care and Research.

Rural health disparities are well documented and continue to jeopardize the long-term health and wellness for the millions of individuals who live in rural America. The disparities observed between urban and rural residents encompass numerous morbidity and mortality measures for several chronic diseases and have been referred to as the "rural mortality penalty." Although the unmet health needs of rural communities are widely acknowledged, little is known about rural health disparities in allergies, asthma, and immunologic diseases. Furthermore, the intersection between rural health disparities and social determinants of health has not been fully explored. To achieve a more complete understanding of the factors that perpetuate rural health disparities, greater research efforts followed by improved practice and policy are needed that account for the complex social context within rural communities rather than a general comparison between urban and rural environments or focusing on biomedical factors. Moreover, research efforts must prioritize community inclusion throughout rural areas through meaningful engagement of stakeholders in both clinical care and research. In this review, we examine the scope of health disparities in the rural United States and the impact of social determinants of health. We then detail the current state of rural health disparities in the field of allergy, asthma, and immunology. To close, we offer future considerations to address knowledge gaps and unmet needs for both clinical care and research in addressing rural health disparities.

Hypersensitivity reactions to biologics used in the treatment of allergic diseases: clinical features, diagnosis and management.

Several monoclonal antibodies have been approved by the Food and Drug Administration (FDA) to treat allergic disorders, including omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, tralokinumab and tezepelumab, and their indications continue to expand. Although the risks associated with these agents are overall low, hypersensitivity reactions have been described and are reported more frequently with increased use. We provide a comprehensive review of clinical features, diagnosis and management of hypersensitivity reactions attributed to these agents. We aim to provide useful information for the clinician managing hypersensitivity reactions to these monoclonal antibodies, as well as highlight the need for future research to address specific gaps in knowledge.

False-Negative Testing for FIP1L1::PDGFRA by Fluorescence in situ Hybridization Is a Frequent Cause of Diagnostic Delay.

The imatinib-sensitive fusion gene FIP1L1::PDGFRA is the most frequent molecular abnormality identified in patients with eosinophilic myeloid neoplasms. Rapid recognition of this mutation is essential given the poor prognosis of PDGFRA-associated myeloid neoplasms prior to the availability of imatinib therapy. We report a case of a patient in whom delayed diagnosis resulted in cardiac transplantation for eosinophilic endomyocardial fibrosis. The delay in diagnosis was due, in part, to a false-negative result in fluorescence in situ hybridization (FISH) testing for FIP1L1::PDGFRA. To explore this further, we examined our cohort of patients presenting with confirmed or suspected eosinophilic myeloid neoplasms and found 8 additional patients with negative FISH results despite a positive reverse-transcriptase polymerase chain reaction test for FIP1L1::PDGFRA. More importantly, false-negative FISH results delayed the median time to imatinib treatment by 257 days. These data emphasize the importance of empiric imatinib therapy in patients with clinical features suggestive of PDGFRA-associated disease.

Clinical and histopathological features of hypereosinophilic syndrome with cutaneous involvement: The Mayo Clinic Experience.

BACKGROUND: Hypereosinophilic syndrome (HES) encompasses a group of diseases with blood hypereosinophilia and eosinophil-mediated organ dysfunction. HES-associated skin abnormalities, termed cutaneous HES (cHES) here, may influence diagnosis of HES. We sought to better define clinical and histopathological features of cHES. METHODS: We retrospectively reviewed clinical records and cutaneous histopathology of adult patients with HES evaluated at our institution from 2007 to 2018. RESULTS: Forty-one percent (61/150) patients with HES had cHES. The most common clinical morphologies were urticarial (30%) and eczematous (26%). Skin specimens most often showed a spongiotic pattern (31%) with abundant inflammation (50%) including eosinophils (85%). Two specimens (8%) showed interstitial granulomatous dermatitis, and two specimens showed eosinophilic fasciitis (8%). Vasculitis was not identified in any specimen. Eighty-four percent of patients with cHES had ≥1 other organ system involved: pulmonary 41%, ENT 26%, and nervous 23%. Sixty percent (53/89) of non-cHES patients had at least two organ systems involved. Cardiac or gastrointestinal involvement was more common in non-cHES than cHES (p < 0.05). CONCLUSION: Our review confirms that there are no specific clinical or histopathological cHES patterns, but HES should be considered in patients who have eczematous or urticarial reactions of unknown etiology and persistent peripheral hypereosinophilia.

Risks and safety of biologics: A practical guide for allergists.

Biologic agents are a rapidly expanding class of medications, and several options are now available for the management of allergic and immunologic disorders. The risks of biologic therapy need to be understood in order to adequately counsel patients and appropriately monitor for potential adverse events. We sought to provide a comprehensive review of the risks and adverse effects reported for the current FDA-approved biologics used in management of allergic and immunologic disorders, including omalizumab, benralizumab, dupilumab, mepolizumab, reslizumab, tezepelumab and tralokinumab. Our review focuses on the risk of hypersensitivity reactions, pregnancy-specific considerations, risk of infection and risk of malignancy. We also highlight drug-specific adverse events and unique safety issues identified in case reports.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

Avapritinib in Indolent Systemic MastocytosisIn a randomized trial, patients with indolent systemic mastocytosis were treated with avapritinib or placebo along with supportive care. The trial primary end point was the change in mean total symptom scores at 24 weeks. Avapritinib-treated patients had a decrease in mean total symptom score of 15.6 points compared with 9.2 points in the placebo group.

Rethinking blood eosinophil counts: Epidemiology, associated chronic diseases, and increased risks of cardiovascular disease.

Background: The distribution and determinants of blood eosinophil counts in the general population are unclear. Furthermore, whether elevated blood eosinophil counts increase risk for cardiovascular disease (CVD) and other chronic diseases, other than atopic conditions, remains uncertain. Objective: We sought to describe the distribution of eosinophil counts in the general population and determine the association of eosinophil count with prevalent chronic disease and incident CVD. Methods: A population-based adult cohort was followed from January 1, 2006, to December 31, 2020. Electronic health record data regarding demographic characteristics, prevalent clinical characteristics, and incident CVD were extracted. Associations between blood eosinophil counts and demographic characteristics, chronic diseases, laboratory values, and risks of incident CVD were assessed using chi-square test, ANOVA, and Cox proportional hazards regression. Results: Blood eosinophil counts increased with age, body mass index, and reported smoking and tobacco use. The prevalence of chronic obstructive pulmonary disease, hypertension, cardiac arrhythmias, hyperlipidemia, diabetes mellitus, chronic kidney disease, and cancer increased as eosinophil counts increased. Eosinophil counts were significantly associated with coronary heart disease (hazard ratio [HR], 1.44; 95% CI, 1.12-1.84) and heart failure (HR, 1.62; 95% CI, 1.30-2.01) in fully adjusted models and with stroke/transient ischemic attack (HR, 1.37; 95% CI, 1.16-1.61) and CVD death (HR, 1.49; 95% CI, 1.10-2.00) in a model adjusting for age, sex, race, and ethnicity. Conclusions: Blood eosinophil counts differ by demographic and clinical characteristics as well as by prevalent chronic disease. Moreover, elevated eosinophil counts are associated with risk of CVD. Further prospective investigations are needed to determine the utility of eosinophil counts as a biomarker for CVD risk.

White blood cells and chronic rhinosinusitis: a Mendelian randomization study.

BACKGROUND: Risk factors for the pathogenesis of chronic rhinosinusitis (CRS) remain largely undetermined, which is likely due to the heterogeneity of the disease. White blood cell counts have been largely unexplored as a risk factor for CRS even though different types of white blood cells are involved in the inflammatory process of CRS. OBJECTIVE: To investigate causal associations between different types of white blood cells on risk of CRS utilizing a Mendelian randomization (MR) analysis. METHODS: A two-sample MR analysis was performed using respective GWAS summary statistics for the exposure traits (neutrophil count, eosinophil count, basophil count, lymphocyte count, and monocyte count) and outcome trait (CRS). For the exposure traits, the European Bioinformatics Institute database of complete GWAS summary data was used. For the outcome trait, summary statistics for CRS GWAS were obtained from FinnGen. Primary analysis for MR was performed using inverse-variance weighted two-sample MR. Sensitivity analyses included weighted median, MR-Egger, and MR-PRESSO (raw and outlier-corrected). RESULTS: Eosinophils were associated with CRS (OR = 1.55 [95% CI 1.38, 1.73]; p = 4.3E-14). Eosinophil results were similar across additional MR methods. MR results did not demonstrate significant causal relationships between neutrophils, lymphocytes, monocytes, or basophils with CRS. No significant pleiotropic bias was observed. CONCLUSIONS: In a two-sample MR analysis, a potential causal link between blood eosinophil counts and CRS has been demonstrated. In addition, causal relationships between blood counts among other white blood cell types and CRS were not found. Further studies involving genetic variation in CRS are needed to corroborate genetic causal effects for CRS.

Combining Biologics Targeting Eosinophils (IL-5/IL-5R), IgE, and IL-4/IL-13 in Allergic and Inflammatory Diseases.

The indications for biologic therapy are expanding. Patients may benefit from different biologics for separate conditions or one condition with multiple pathogenic mechanisms targeted by different biologics. We sought to determine the frequency and safety of combining biologics targeting IgE, IL-5, IL-5R, and IL-4/IL-13 in patients referred to a large academic health system through retrospective chart review. Between January 1, 2015 and July 31, 2021, 25 patients receiving multiple biologics simultaneously were identified. Combinations included omalizumab + mepolizumab (n = 11), omalizumab + dupilumab (n = 6), omalizumab + benralizumab (n = 4), mepolizumab + dupilumab (n = 3), and omalizumab + dupilumab + mepolizumab (n = 1). Sixteen patients were receiving multiple biologics for the same condition, most commonly asthma (n = 10). Nine patients were treated for separate conditions, with chronic spontaneous urticaria and atopic dermatitis being the most common combination (n = 3). The median duration of combination biologic use was 17.5 months. There were no reports of anaphylaxis, other allergic reaction, immune dysfunction, pneumonia, or development of malignancy. The use of multiple biologics appears to be well tolerated in this case series. Prospective study is needed to better determine the efficacy, safety, and cost-effectiveness of this approach.

Current and emerging biologic therapies targeting eosinophilic disorders.

Eosinophilic disorders include a wide array of conditions in which eosinophils play a primary pathophysiologic role. While historically treated with corticosteroids and immunosuppressants, knowledge of eosinophil biology has led to the development of several biologics targeting eosinophils. In this review, we discuss the current US Food and Drug Administration (FDA) approved eosinophil-specific biologics targeting IL-5 (mepolizumab and reslizumab) and IL-5R (benralizumab) along with biologics under investigation targeting siglec-8 (lirentelimab). We discuss efficacy and safety data from trials of these medications in conditions including eosinophilic asthma, hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis (EoE), and eosinophilic gastrointestinal disease (EGID). Additionally, we discuss case reports utilizing these medications in conditions including drug reaction with eosinophilia and systemic symptoms (DRESS), allergic bronchopulmonary aspergillosis (ABPA), and eosinophilic pneumonia, among others. While eosinophilic targeting biologic therapy has been successful in eosinophilic asthma, HES, EGPA, and CRSwNP leading to FDA approval for these conditions, trials treating EoE and EGID have been disappointing to date. Given the increasing number of trials utilizing these biologics, it will be imperative for the allergist-immunologist to stay up to date on the latest treatment options to provide the most optimal care for eosinophilic disorders.

Pulmonary Procedures During the COVID-19 Pandemic: A Work Group Report of the AAAAI Asthma Diagnosis and Treatment (ADT) Interest Section.

The COVID-19 pandemic has placed increased demands on the ability to safely perform pulmonary procedures in keeping with Centers for Disease Control and Prevention (CDC), American Thoracic Society (ATS), and the Occupational Safety and Health Administration (OSHA) recommendations. Accordingly, the American Academy of Allergy, Asthma & Immunology (AAAAI) Asthma Diagnosis and Treatment convened this work group to offer guidance. The work group is composed of specialist practitioners from academic and both large and small practices. Individuals with special expertise were assigned sections on spirometry, fractional exhaled nitric oxide, nebulized treatments, and methacholine challenge. The work group met periodically to achieve consensus. This resulting document has recommendations for the allergy/asthma/immunology health care setting based on available evidence including reference documents from the CDC, ATS, and OSHA.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

Risk for Postmarket Black Box Warnings in FDA-Approved Monoclonal Antibodies.

OBJECTIVE: To estimate the potential risk for a future postmarket black box warning (BBW) of US Food and Drug Administration (FDA)-approved monoclonal antibodies (mAbs) because of the importance for medical clinicians to understand mAb risks and benefits, including unknown future risks, especially for recently approved mAbs. METHODS: The complete dates of the study were March 16, 2020, through May 12, 2021. We searched the FDALabel database online and reviewed the scientific literature to determine current and previous FDA-approved mAbs as of March 2020. The BBWs and initial FDA-issued safety warnings were identified. The BBWs were categorized as premarket or postmarket. For mAbs with specific postmarket BBWs, previous FDA labels were evaluated to identify the presence or absence of an initial corresponding specific FDA warning. RESULTS: In March 2020, a total of 83 mAbs had FDA approval; 33 had BBWs (27 premarket and 13 postmarket BBWs). Of these 33 mAbs, 55 individual specific BBWs existed (36 premarket and 19 postmarket specific warnings). On average, the specific BBWs occurred in the postmarket period at a rate of 3.4% (19/562) per year. Most (73.7%; 14/19) specific postmarket BBWs were preceded by an FDA warning in a median time of 3.61 (interquartile range, 1.36-5.78) years. Specific postmarket BBWs not preceded by a specific FDA product label warning occurred at an average rate of 0.9% (5/562) per year. CONCLUSION: Specific postmarket BBWs occurred in FDA-approved mAbs at a rate of 3.4% per year. Specific postmarket BBWs not preceded by a specific FDA product label warning had a rate of 0.9% per year.

AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.