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We present a 62-year-old woman with severe heart failure and who required cardiac transplantation. On postoperative day 22, she experienced anaphylaxis to peanut, with an elevated peanut-specific immunoglobulin E level. This case highlights the differential diagnosis of posttransplantation anaphylaxis as well as the appropriate evaluation.

Introduction: Although rare, some patients may have a vitamin B12 allergy. Crohn’s disease commonly leads to significant vitamin B12 deficiency, especially in those patients that have undergone ileal resection. In these difficult cases, vitamin B12 desensitization may be required. Case Presentation: Here, we report a successful case of a serial outpatient subcutaneous vitamin B12 desensitization protocol in a 35-year-old female with a past medical history of Crohn’s disease status post ileal resection, subsequent vitamin B12 deficiency, and allergy to subcutaneous vitamin B12. Conclusion: This is the first subcutaneous vitamin B12 desensitization protocol reported to have been safely performed in the outpatient setting.

Purpose To describe the socioeconomic and healthcare-related effects of the COVID-19 pandemic, and willingness to receive a free COVID-19 vaccine, among African American/Black (AA/B) and Hispanic/Latinx (H/L) adults with asthma currently enrolled in a large trial. Methods The present analysis is a sub-study of the PeRson EmPowered Asthma RElief (PREPARE) study, a pragmatic study of 1201 AA/B and H/L adults with asthma. A monthly questionnaire was completed by a subset of PREPARE participants (n = 325) during May–August, 2020. The 5-item questionnaire assessed self-reported impact of COVID-19 on respondents’ ability to obtain asthma medications, medical care quality, employment, income and ability to pay bills; and willingness to get a free COVID-19 vaccine. Bivariate analysis and multivariate logistic regression were performed to investigate factors associated with vaccine hesitancy. Results Of 325 survey respondents (25% AA/B, 75% H/L), the majority reported no impact of COVID-19 on medical care or ability to get asthma medications. Approximately half of employed respondents experienced a lower level of employment or job loss, and approximately half reported having difficulty paying bills during the pandemic. Thirty-five percent of respondents reported unwillingness and 31% reported being somewhat likely to receive a free COVID-19 vaccine. AA/B race/ethnicity and poorer reported physical health were associated with a higher likelihood of COVID-19 vaccine hesitancy. Conclusion AA/B and H/L adults with asthma may experience changes in the quality of their asthma care and increased socioeconomic stressors as a result of the COVID-19 pandemic and may be hesitant or unwilling to receive a COVID-19 vaccine.

Hypersensitivity reactions to ventriculoperitoneal (VP) or lumboperitoneal (LP) shunts are rare. Symptoms often resolve following shunt replacement with a silicone-free hypoallergenic shunt. We describe novel cases of allergies to both standard and hypoallergenic shunts and highlight the utility of patch testing. Patient 1, a 24-year-old female with Chiari I malformation, developed diarrhea, abdominal pain, and rash along the LP shunt tract. Patch testing was positive. The shunt was replaced with a hypoallergenic VP shunt with symptom improvement. Five weeks later, she developed a new rash. Subsequent patch testing to the hypoallergenic shunt was positive. Patient 2, a 37-year-old female with Chiari I malformation, developed pruritus along the VP shunt tract. Patch testing to the standard shunt was positive. The shunt was replaced with a hypoallergenic shunt, with symptomatic improvement. One month later, she developed neck pain, headache, and pruritis. Patch testing to the hypoallergenic shunt was positive. The development of a pruritic rash along the shunt tract with or without gastrointestinal symptoms should prompt shunt allergy evaluation and consideration of patch testing to the shunt material.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of β-muricholic acid and tauro-β-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to

Obesity-associated asthma is phenotypically characterized by low grade inflammation and resistance to standard therapies. Like many other asthma endotypes, the molecular mechanisms contributing to obesity-associated asthma are diverse and ambiguous. A panoply of metabolites that act as signaling mediators are altered by obesity and may also promote lung dysfunction and a pro-asthma phenotype. Recent metabolomics studies indicate that bile acid profiles are altered in individuals with asthma, thus these metabolites were investigated in a murine model of obesity-associated asthma and clinically. In obese mice with allergic airway disease (AAD), the levels of β-muricholic acid (βMCA) and tauro-β-muricholic (tβMCA) were significantly increased in serum and positively correlated with impaired lung function. Two conjugated bile acids, glycocholic acid (GCA) and glycoursodeoxycholic acid (GUDCA), were elevated in the plasma of high body mass index (BMI) individuals and correlated with both BMI and airway hyperreactivity as measured by FEV1, forced expiratory volume in one second. In vitro differentiated T helper (Th) cells were treated with tβMCA and βMCA, which resulted in changes in T cell metabolism that were specific to Th17 cells. In addition, tβMCA treatment increased IL-17 production from Th17 cells upon stimulation. Finally, the anti-inflammatory and metabolic regulatory activities of nitro-oleic acid (NO2-OA) were evaluated in the murine model of obesity-associated asthma. NO2-OA reduced levels of βMCA and tβMCA, with a concomitant reduction in tissue resistance and elastance, providing a potential approach to improving the current standard of care for obese individuals with asthma. Supported by R01HL146445 (MLM), S10OD023402 (SGW), R61HL157069 (SGW, BAF, FH), R01HL132550 (BAF)

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. Alarge proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients’ biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Background: Terminal complement component deficiencies are risk factors for neisserial infections. Objective: To review the clinical characteristics, the diagnosis and the management of patients with a terminal complement component deficiency. Methods: Pertinent articles were selected and reviewed in relation to a case presentation of C6 deficiency. Results: A case of a 56-year old patient with a history of meningitis, chronic rash, and C6 deficiency was presented, followed by discussion of clinical characteristics, diagnosis, and management of terminal complement component deficiencies. Clinical pearls and pitfalls were reviewed for the practicing allergist/immunologist and fellow-in-training. Conclusion: C6 deficiency is the most common terminal complement component deficiency and can present later in age with N. meningitidis infections. Patients can be screened for terminal complement component deficiency by checking CH50.

Rationale: Chronic spontaneous urticaria (CSU) is characterized by recurrent hives without a known trigger. While certain drugs are associated with urticaria exacerbations, the overall drug allergy incidence in CSU is unknown. We hypothesized that the incidence of drug allergy in CSU would be greater than the general population and that there would be distinguishing clinical features of drug-allergic CSU patients. Methods: 362 adult CSU patients seen over a 10-year period at a University Allergy/Asthma clinic were identified. Patients reported no drug allergies or any drug allergy. Multiple drug allergies were defined as allergies to ≥ 2 chemically unrelated drugs. Using Chi-square or Wilcoxon analysis, we compared demographic features of CSU with and without drug allergy and with multiple vs. single drug allergy. Results and Discussion: Overall, 202 CSU patients (56%) reported drug allergy. Drug allergic CSU patients were older, with a greater proportion of whites and higher BMI vs. CSU without drug allergy (p=0.002, p=0.047, p=0.004, respectively). Penicillin was the most common drug allergy, with urticaria the most frequently reported reaction. Female sex, white race, older age at the visit, and co-existing asthma were more common in multiple drug allergy (n=115) vs. single drug allergy (p=0.002, p=0.02, p=0.03, p=0.0002, respectively). Conclusion: In CSU, the prevalence of self-reported drug allergies was higher than the general population. Drug allergy is associated with older age, white race and higher BMI, while multiple drug allergy was also associated with asthma. These CSU sub-populations should be studied to avoid the potential for morbidity associated with less efficacious and more costly drugs.

As allergists, we are frequently consulted to evaluate patients with swelling presumed to be angioedema. Patients with presumed angioedema can have multiple possible underlying triggers. We present the case of a hospitalized 72-year-old woman with a history of hypertension and metastatic chordoma who developed marked periorbital swelling that precluded eye opening 2 days after a neurosurgical operation (chordoma resection and T10-11 hardware repair). After a detailed evaluation of her swelling, a broad differential diagnosis was made; she did not respond to high-dose antihistamines, systemic steroids, icatibant and angiotensin-converting enzyme inhibitor cessation. Ultimately, computed tomography imaging confirmed a specific diagnosis. The differential diagnosis for swelling is complex, and this case illustrated the importance of considering alternative causes of swelling when evaluating cases of possible angioedema.

Background Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. Methods To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6–18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. Results From pre−/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. Conclusions These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. Trial registration ClinicalTrials.gov registration number: NCT01748175. Electronic supplementary material The online version of this article (10.1186/s12890-018-0612-x) contains supplementary material, which is available to authorized users.

Vocal cord dysfunction (VCD) is a functional disorder of the vocal cords characterized by exaggerated adduction of vocal cords during inspiration and/or expiration causing respiratory and laryngeal symptoms. VCD can exist in isolation and coexist with asthma, or it can mimic asthma. The missteps during the VCD and asthma diagnostic process and subsequent faulty clinical conclusions can lead to mistreatment and increased health care utilization that can last for years. Therefore, diagnostic precision in conjunction with optimal therapeutics is a prerequisite for the best patient outcomes in this patient population. An integrated approach is frequently required using multiple diagnostic modalities to make a correct diagnosis. The treatment options, usually applied in a step-wise progression, depend on the severity of presentation and the underlying type of VCD. Future studies should address the better identification of specific phenotypes of VCD and their corresponding treatments.

Background Allergen immunotherapy (AIT) is an effective treatment option for allergic rhinitis. Although conventional AIT takes 6 months to reach maintenance dosing, rush AIT accelerates the build-up period and reaches the maintenance dose months earlier. However, accelerated schedules of AIT carry an increased risk of systemic reactions (SR). Objective We aimed to describe a novel 1-day, eight-step modified environmental rush immunotherapy (MERIT) protocol, characteristics of the patients who underwent this therapy, and the safety of this procedure. We also compared distinguishing features of those patients with SRs. Methods We retrospectively analyzed demographic and clinical data of 362 adult patients seen in an outpatient university allergy clinic, from January 2005 to January 2015, and who underwent MERIT protocol treatment for allergic rhinitis. Results In a univariate analysis, the factors significantly associated with SR were lower body mass index (BMI); younger age; a higher number of allergens in the extracts; and the presence of cat, dust mite, and certain weed pollens. In a multivariate analysis, cat, dust mite, and mugwort were significantly associated with SRs. Over the 10-year period, 50 patients experienced SRs (13.81%), with a total number of 68 SRs. Only 4.7% of the SRs occurred on the MERIT day. Most SRs occurred >30 minutes and were mild. Our MERIT protocol continuation rate for all the patients was 49.2% and did not seem to be influenced by having an SR versus no SR. Conclusion We present a modified rush AIT protocol that seems to be effective and safe. Most patients tolerated therapy, and only a minority of patients developed SRs, which generally were mild. We identified novel risk factors for SRs that may help determine optimal dosing to decrease the risk of SRs. Ultimately, future studies will be needed to compare the safety of our MERIT protocol with traditional AIT.

Asthma is a common disease but many other conditions, often referred to as asthma mimics, can produce similar symptoms, often resulting in an incorrect asthma diagnosis. Misdiagnosis becomes more likely if objective testing is omitted when a diagnosis of asthma is made. In addition to other pulmonary and cardiac conditions, vocal cord dysfunction (VCD) is a common asthma mimic that can be challenging to distinguish from asthma and should be considered in any asthma differential. Many asthma mimics can also co-exist with asthma and, if not recognized, make it difficult to control. In addition to objective testing, a thorough consideration of these conditions should be undertaken both at the time of initial asthma diagnosis and again in any asthma patient whose disease is unresponsive to therapy or difficult to control.

Rationale: Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain. Objectives: To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation. Methods: We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase. Measurements and Main Results: We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all P values

Radiocontrast media allergy is a severe and potentially life-threatening condition. This creates a clinical dilemma for cardiac patients who require urgent interventions with radiocontrast media. Several pretreatment regimens have been suggested for patients with prior immediate hypersensitivity reactions to radiocontrast media. Despite using pretreatment regimens, breakthrough reactions have been reported in 2.1%-18% of patients with radiocontrast media allergy. Little is known about management of patients with a history of breakthrough radiocontrast media anaphylaxis who require urgent lifesaving procedures.We report a retrospective analysis of 2 cardiac cases with a history of breakthrough radiocontrast media anaphylaxis despite standard pretreatment. These patients required urgent cardiac intervention with the use of radiocontrast media.We present a novel pretreatment regimen for high-risk cardiac patients with breakthrough radiocontrast media anaphylaxis despite prior pretreatment who need urgent coronary interventions.This protocol is both safe and effective in mitigating anaphylaxis in cardiac patients.

Introduction: Worldwide, iron deficiency anemia is the most common nutritional disorder. Treatment with oral iron supplementation may not be well tolerated due to gastrointestinal side effects. Therapy with Intravenous (IV) iron supplementation is more effective and better tolerated, especially in patients with underlying Inflammatory Bowel Disease (IBD) or malignancy. However, Hypersensitivity Reactions (HSR) and anaphylaxis to IV iron have been described. Methods: We evaluated the literature and developed an eleven step desensitization protocol for ferric carboxymaltose to be administered in high risk patients. Results: We present the first case series demonstrating the safety of ferric carboxymaltose desensitization in patients with a history of anaphylaxis to IV iron and iron deficiency anemia. Conclusion: While there are many IV iron formulations available, ferric carboxymaltose can replenish iron stores with fewer doses. Ferric carboxymaltose is contraindicated in patients with prior hypersensitivity reactions to iron formulations. This novel eleven step desensitization protocol was well tolerated without any adverse reactions and allowed the patients to receive iron supplementation when limited therapeutic options existed.

Background The effect of age on asthma severity is poorly understood. Objectives The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. Methods SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. Results Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. Conclusions The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.

BACKGROUND. In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA). METHODS. ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47]). RESULTS. Bronchoalveolar lavage (BAL) fluid LXA4 and 15-epi-LXA4 were decreased and SAA was increased in SA relative to NSA. BAL macrophage ALX expression was increased in SA. Subjects with LXA4loSAAhi levels had increased BAL neutrophils, more asthma symptoms, lower lung function, increased relative risk for asthma exacerbation, sinusitis, and gastroesophageal reflux disease, and were assigned more frequently to SA clinical clusters. SAA and aliquots of LXA4loSAAhi BAL fluid induced IL-8 production by lung epithelial cells expressing ALX receptors, which was inhibited by coincubation with 15-epi-LXA4. CONCLUSIONS. Together, these findings have established an association between select ALX receptor ligands and asthma severity that define a potentially new biochemical endotype for asthma and support a pivotal functional role for ALX signaling in the fate of lung inflammation. TRIAL REGISTRATION. Severe Asthma Research Program-3 (SARP-3; ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01606826","term_id":"NCT01606826"}}NCT01606826) FUNDING Sources. National Heart, Lung and Blood Institute, the NIH, and the German Society of Pediatric Pneumology.

RationalePhenotypic distinctions between severe asthma (SA) and nonsevere asthma (NONSA) may be confounded by differential adherence or incorrect use of corticosteroids.ObjectivesTo determine if there are persistent phenotypic distinctions between SA (as defined by 2014 American Thoracic Society/European Respiratory Society guidelines) and NONSA after intramuscular triamcinolone acetonide (TA), and to identify predictors of a corticosteroid response in these populations.MethodsA total of 526 adults age 18 years and older (315 SA) and 188 children age 6 to less than 18 years (107 SA) in the NHLBI Severe Asthma Research Program III were characterized before and 3 weeks after TA. The primary outcome for corticosteroid response was defined as greater than or equal to 10-point improvement in percent predicted FEV1.Measurements and main resultsAdult asthma groups exhibited a small but significant mean FEV1% predicted improvement after TA (SA group mean difference, 3.4%; 95% confidence interval, 2.2-4.7%; P = 0.001), whereas children did not. Adult SA continued to manifest lower FEV1 and worse asthma control as compared with NONSA after TA. In children, after TA only prebronchodilator FEV1 distinguished SA from NONSA. A total of 21% of adults with SA and 20% of children with SA achieved greater than or equal to 10% improvement after TA. Baseline bronchodilator response and fractional exhaled nitric oxide had good sensitivity and specificity for predicting response in all groups except children with NONSA.ConclusionsOne in five patients with SA exhibit greater than or equal to 10% improvement in FEV1 with parenteral corticosteroid. Those likely to respond had greater bronchodilator responsiveness and fractional exhaled nitric oxide levels. In adults, differences in airflow obstruction and symptoms between SA and NONSA persist after parenteral corticosteroids, suggesting a component of corticosteroid nonresponsive pathobiology in adults with SA that may differ in children. Clinical trial registered with www.clinicaltrials.gov (NCT 01606826).

Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6−CCR4− T helper 1–enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4–exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.

Background Airway type 2 inflammation is usually corticosteroid sensitive, but the role of type 2 inflammation as a mechanism of asthma in patients receiving high-dose inhaled corticosteroids (ICSs) is uncertain. Objective We sought to determine whether airway type 2 inflammation persists in patients treated with ICSs and to evaluate the clinical features of patients with steroid-resistant airway type 2 inflammation. Methods We used quantitative PCR to generate a composite metric of type 2 cytokine gene expression (type 2 gene mean [T2GM]) in induced sputum cells from healthy control subjects, patients with severe asthma receiving ICSs (n = 174), and patients with nonsevere asthma receiving ICSs (n = 85). We explored relationships between asthma outcomes and T2GM values and the utility of noninvasive biomarkers of airway T2GM. Results Sputum cell T2GM values in asthmatic patients were significantly increased and remained high after treatment with intramuscular triamcinolone. We used the median T2GM value as a cutoff to classify steroid-treated type 2–low and steroid-resistant type 2–high (srT2-high) subgroups. Compared with patients with steroid-treated type 2–low asthma, those with srT2-high asthma were older and had more severe asthma. Blood eosinophil cell counts predicted srT2-high asthma when body mass index was less than 40 kg/m 2 but not when it was 40 kg/m 2 or greater, whereas blood IgE levels strongly predicted srT2-high asthma when age was less than 34 years but not when it was 34 years or greater. Conclusion Despite ICS therapy, many asthmatic patients have persistent airway type 2 inflammation (srT2-high asthma), and these patients are older and have more severe disease. Body weight and age modify the performance of blood-based biomarkers of airway type 2 inflammation.

Mast cells (MCs) are among the first cell types associated with allergies and asthma. Studies in human asthma have identified their presence in the lung submucosa and smooth muscle and also in the airway epithelium. As our understanding of the distribution and location of these MCs in the human airway has increased, it is clear that much remains to be understood regarding the presence and subtype of these MCs in relationship to asthma phenotypes, defined both clinically and on the basis of immunologic pathways. Human MCs have traditionally been divided into two major subtypes based on the protease granule content, with tryptase representing total MCs. There is emerging evidence that in the epithelium, MCs of an altered subtype (with tryptase, chymase, and/or carboxypeptidase A3) may play a role in the pathophysiology of poorly controlled, severe, Th2-associated asthma.

Vocal cord dysfunction (VCD) is often misdiagnosed as asthma or complicates coexisting asthma. This study aimed to identify distinguishing clinical characteristics in patients with VCD, asthma, and coexisting VCD and asthma. We conducted a retrospective analysis of demographic and clinical data from 292 patients with VCD, asthma, coexisting VCD and asthma, and control subjects from an outpatient university asthma/allergy clinic. Concomitant asthma was present in 32.6% of VCD subjects. Overall, 42.4 % of all VCD subjects were previously misdiagnosed as having asthma for an average of 9.0 years. Upper airway symptoms were more prevalent in the VCD population and nocturnal apnea was more prevalent in comorbid VCD and asthma compared with either condition alone. Irritable bowel syndrome and chronic pain were identified as new comorbidities associated with VCD. VCD subjects who had been misdiagnosed with asthma had significantly more health care and asthma medication use compared to VCD subjects who had not mimicked asthma. There was no difference in asthma severity between those with and without VCD. Comorbid VCD and asthma led to an increase in long-acting β-agonist use only, but no difference in health care usage, compared with asthma alone. These findings suggest that the main morbidity associated with VCD may not lie in its inherent disease process, but instead in its ability to mimic asthma.

Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined.To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA.Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP-1 + 2 cohort.Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index units, and 1.2 [1.1-1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4-2.1] and 1.6 [1.3-2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP-1 + 2 multivariable model.EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Background Vocal cord dysfunction (VCD) is frequently misdiagnosed and mistreated as asthma, which leads to morbidity secondary to unnecessary medication use and increased health care utilization. Objective We identified discriminating symptoms and triggers, and analyzed the costs, morbidity, and health care burden associated with misdiagnosis of VCD as asthma. We sought to determine if current measures of asthma control contributed to these findings. We evaluated if a simple set of breathing exercises would be an effective low-cost treatment option for those with VCD. Methods We compared the demographics, comorbidities, clinical symptoms, and symptom triggers of subjects with VCD misdiagnosed as asthma compared with those not misdiagnosed as asthma. Costs secondary to asthma misdiagnosis were quantified, and the effectiveness of breathing exercises as a treatment option was evaluated. Results We identified symptoms of shortness of breath, wheezing, chest tightness, and a trigger of exercise as being more common in the subjects with VCD misdiagnosed as asthma. Asthma medication use and health care utilization and costs were also higher in this group. The subjects with VCD had Asthma Control Questionnaire scores that labelled them as having uncontrolled asthma. Breathing exercises appeared to offer an inexpensive and effective treatment option for subjects with VCD. Conclusion Misdiagnosis of VCD as asthma leads to significant morbidity and increased costs, and misuse of measures of asthma control may be contributing to these findings. Timely and accurate diagnosis of VCD and the use of breathing exercises have the potential to eliminate or minimize the burdens on the patient and the health care system.