Perioperative management of mastocytosis.

PURPOSE: Patients with mastocytosis have an increased risk of anaphylaxis during surgical procedures with general anesthesia. Therefore, we reviewed the anesthesia course of a large cohort of patients with mastocytosis. METHODS: We retrospectively reviewed adult and pediatric patients with mastocytosis who underwent surgical procedures with general anesthesia at Mayo Clinic from January 1, 2000, through June 30, 2021. We also included any procedures with general anesthesia that occurred during the 3-year period preceding mastocytosis diagnosis and designated the patients who underwent these procedures as having an unknown diagnosis at the time of their surgical procedure. We analyzed whether patients received chronic antimediator treatment for mastocytosis and/or prophylactic medications before the procedures. We also determined whether medications indicative of mastocytosis-related adverse events were intraoperatively administered. RESULTS: We identified 113 patients who underwent 219 procedures during the study period; 25 procedures were performed before mastocytosis diagnosis. Of 194 procedures in patients with known mastocytosis, patients received chronic antimediator therapy and/or perioperative prophylactic medications for 178 (91.8%) procedures. Among these procedures, 10 were potentially complicated by mast cell activation, which was inferred from administration of inhaled albuterol (n = 3) or intravenous diphenhydramine (n = 8). In addition, there was only one case of intraoperative anaphylaxis which occurred in a patient who underwent anesthesia before mastocytosis diagnosis and therefore did not receive prophylaxis. CONCLUSION: Intraoperative anaphylaxis can be the first presenting sign of mastocytosis. Patients with mastocytosis who received chronic antimediator therapy and/or preoperative prophylactic medications had an uneventful surgical course.

A diagnostic codes-based algorithm improves accuracy for identification of childhood asthma in archival data sets.

OBJECTIVE: While a single but truncated ICD code (493) had been widely used for identifying asthma in asthma care and research, it significantly under-identifies asthma. We aimed to develop and validate a diagnostic codes-based algorithm for identifying asthmatics using Predetermined Asthma Criteria (PAC) as the reference. METHODS: This is a retrospective cross-sectional study which utilized two different coding systems, the Hospital Adaptation of the International Classification of Diseases, Eighth Revision (H-ICDA) and the International Classification of Diseases, Ninth Revision (ICD-9). The algorithm was developed using two population-based asthma study cohorts, and validated in a validation cohort, a random sample of the 1976-2007 Olmsted County Birth Cohort. Performance of the diagnostic codes-based algorithm for ascertaining asthma status against manual chart review for PAC (gold standard) was assessed by determining both criterion and construct validity. RESULTS: Among eligible 267 subjects of the validation cohort, 50% were male, 70% white, and the median age at last follow-up was 17 (interquartile range, 8.7-24.4) years. Asthma prevalence by PAC through manual chart review was 34%. Sensitivity and specificity of the codes-based algorithm for identifying asthma were 82% and 98% respectively. Associations of asthma-related risk factors with asthma status ascertained by the code-based algorithm were similar to those by the manual review. CONCLUSIONS: The diagnostic codes-based algorithm for identifying asthmatics improves accuracy of identification of asthma and can be a useful tool for large scale studies in a setting without automated chart review capabilities.

Outcomes among patients with COVID-19 and asthma: A systematic review and meta-analysis.

Background: It remains unclear if asthma is a risk factor associated with worse outcomes among patients with coronavirus disease 2019 (COVID-19). Methods: We performed a comprehensive database search for studies published from January 1, 2019, to October 2, 2020. We included studies that evaluated outcomes among patients with COVID-19 and underlying asthma. Outcomes of interest included the need for hospitalization, length of hospitalization, intensive care unit (ICU) admission, and death. The meta-analysis was conducted by using random-effects methodology. Results: A total of 389 studies were identified through data base searches. After abstract and full-text screening, 16 observational studies with 92,275 patients were included in the analysis. Of the 16 studies, 15 were retrospective and 1 was a prospective cohort study. The average age was 39.6 years, with 48% female patients. Six of the studies included pediatric patients, and one of these studies only evaluated pediatric patients. One study only evaluated pregnant patients. Among patients with COVID-19, the presence of asthma was not associated with any significant increase in risk of hospitalization (odds ratio [OR] 1.46 [95% confidence interval {CI}, 0.29-7.28]), length of hospitalization (1.59 days [-0.55 to 3.74]), ICU admission (OR 1.65 [95% CI, 0.56-4.17]), or death (OR 0.73 [95% CI, 0.38-1.40]). The overall risk of bias of the included studies was high. Conclusion: Among the patients with COVID-19, asthma did not seem to significantly increase the risk of hospitalization, length of hospitalization, ICU admission, or death.

Asthma in the older adult.

Objective: The older adult population is increasing worldwide, and a significant percentage has asthma. This review will discuss the challenges to diagnosis and management of asthma in older adults. Data Sources: PubMed was searched for multiple terms in various combinations, including asthma, older adult, elderly, comorbid conditions, asthma diagnosis, asthma treatment, biologics and medication side effects, and adverse events. From the search, the data sources that were utilized included peer reviewed scholarly review articles, peer reviewed scientific research articles, and peer reviewed book chapters. Study Selections: Study selections that were utilized included peer reviewed scholarly review articles, peer reviewed scientific research articles, and peer reviewed book chapters. Results: Asthma in older adults is frequently underdiagnosed and has higher morbidity and mortality rates compared to their younger counterparts. A detailed history and physical examination as well as judicious testing are essential to establish the asthma diagnosis and exclude alternative ones. Medical comorbidities, such as cardiovascular disease, cognitive impairment, depression, arthritis, gastroesophageal reflux disease (GERD), rhinitis, and sinusitis are common in this population and should also be assessed and treated. Non-pharmacologic management, including asthma education on inhaler technique and self-monitoring, is vital. Pharmacologic management includes standard asthma therapies such as inhaled corticosteroids (ICS), inhaled corticosteroid-long acting ß-agonist combinations (ICS-LABA), leukotriene antagonists, long acting muscarinic antagonists (LAMA), and short acting bronchodilators (SABA). Newly approved biologic agents may also be utilized. Older adults are more vulnerable to polypharmacy and medication adverse events, and this should be taken into account when selecting the appropriate asthma treatment. Conclusions: The diagnosis and management of asthma in older adults has certain challenges, but if the clinician is aware of them, the morbidity and mortality of this condition can be improved in this growing population.

Relationship between asthma status and antibody response pattern to 23-valent pneumococcal vaccination.

Objective: Asthma poses an increased risk for serious pneumococcal disease, but little is known about the influence of asthma status on the 23-valent serotype-specific pneumococcal antibody response. We examined differences in antibody titers between pre- and post-vaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV-23) in relation to asthma status. Methods: Asthma status was retrospectively ascertained by the Predetermined Asthma Criteria in an existing vaccine cohort through comprehensive medical record review. Twenty-three serotype-specific pneumococcal antibody titers measured at baseline and 4-6 weeks post-vaccination were analyzed. Vaccine responses to PPSV-23 were calculated from pre- to post-vaccine titers for each of the serotypes. Results: Of the 64 eligible and enrolled subjects, 18 (28%) had asthma. Controls (i.e., subjects without asthma) demonstrated a statistically significant fold change response compared to their baseline for all serotypes, while those with asthma did not mount a significant response to serotypes 7F, 22F, and 23F. The overall vaccine response as measured by fold change over baseline was lower in subjects with asthma than controls. Conclusions: Poorer humoral immune responses to PPSV-23 as measured by fold change were more likely to be observed in subjects with asthma compared to controls. We recommend the consideration of asthma status when interpreting vaccine response for immune competence workup through larger studies. Further studies are warranted to replicate these findings.

Heterogeneity of asthma and the risk of celiac disease in children.

BACKGROUND: Although human leukocyte antigen (HLA)-DR and HLA-DQ genes and gluten play crucial roles in developing celiac disease (CD), most patients with these risk factors still do not develop CD, which indicates additional unrecognized risk factors. OBJECTIVE: To determine the association between asthma and the risk of CD in children. METHODS: We conducted a population-based retrospective case-control study in children who resided in Olmsted County, Minnesota. We identified children with CD (cases) between January 1, 1997, and December 31, 2014, and compared these with children without CD (controls) (1:2 matching). Asthma status was ascertained by using the predetermined asthma criteria (PAC) and the asthma predictive index (API). Data analysis included conditional logistic regression models and an unsupervised network analysis by using an independent phenome-wide association scan (PheWAS) data set. RESULTS: Although asthma status as determined by using PAC was not associated with the risk of CD (odds ratio [OR] 1.4 [95% confidence interval {CI}, 0.8-2.5]; p = 0.2), asthma status by using the API was significantly associated (OR 2.8 [95% CI, 1.3-6.0]; p = 0.008). A subgroup analysis indicated that children with both asthma as determined by using PAC and a family history of asthma had an increased risk of CD compared with those without asthma (OR 2.28 [95% CI, 1.11-4.67]; p = 0.024). PheWAS data showed a cluster of asthma single nucleotide polymorphisms and patients with CD. CONCLUSION: A subgroup of children with asthma who also had a family history of asthma seemed to be at an increased risk of CD, and, thus, the third factor that underlies the risk of CD might be related to genetic factors for asthma. Heterogeneity of asthma plays a role in determining the risk of asthma-related comorbidity.

Predictors of granulomatous lymphocytic interstitial lung disease in common variable immunodeficiency.

BACKGROUND: A subset of patients with common variable immunodeficiency (CVID) develop granulomatous lymphocytic interstitial lung disease (GLILD), which is associated with early mortality. OBJECTIVE: To determine a set of clinical and/or laboratory parameters that correlate with GLILD. METHODS: A retrospective, nested case-control (patients with CVID diagnosed with GLILD compared with patients with CVID without a diagnosis of GLILD) medical record review was undertaken at Mayo Clinic, Rochester, MN. Network and univariate analysis was used to identify clinical and laboratory parameters at the time of diagnosis that are associated with GLILD. RESULTS: Twenty-six cases with radiologic evidence of GLILD were included in this study. Eighteen cases (69%) cases had coexistent splenomegaly with lower IgA levels (P = .04) compared with the controls. Patients with low IgA levels (<13 mg/dL) also had percentage expansion of low CD21 B cells (CD21low >5%) (P = .007). Univariate analysis revealed that splenomegaly (odds ratio [OR], 17.3; 95% confidence interval [CI], 3.9-74.5), history of immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) (OR, 4.8; 95% CI, 1.1-20.2), low IgA level (OR, 3.6; 95% CI, 1.2-11.9), and percentage expansion of CD21low (OR, 5.8; 95% CI, 1.6-24.7) were independently associated with GLILD. Logistic regression analysis revealed that splenomegaly, history of ITP or AIHA, low IgA level, and percentage expansion of CD21low B cells are highly sensitive in predicting presence of GLILD (area under the receiver operating curve of 0.86). CONCLUSION: Presence of splenomegaly, history of ITP or AIHA, low serum IgA level, and percentage expansion of CD21low B cells may be useful to identify a group of patients at high risk for development of GLILD.

Unlocking proteomic heterogeneity in complex diseases through visual analytics.

Despite years of preclinical development, biological interventions designed to treat complex diseases such as asthma often fail in phase III clinical trials. These failures suggest that current methods to analyze biomedical data might be missing critical aspects of biological complexity such as the assumption that cases and controls come from homogeneous distributions. Here we discuss why and how methods from the rapidly evolving field of visual analytics can help translational teams (consisting of biologists, clinicians, and bioinformaticians) to address the challenge of modeling and inferring heterogeneity in the proteomic and phenotypic profiles of patients with complex diseases. Because a primary goal of visual analytics is to amplify the cognitive capacities of humans for detecting patterns in complex data, we begin with an overview of the cognitive foundations for the field of visual analytics. Next, we organize the primary ways in which a specific form of visual analytics called networks has been used to model and infer biological mechanisms, which help to identify the properties of networks that are particularly useful for the discovery and analysis of proteomic heterogeneity in complex diseases. We describe one such approach called subject-protein networks, and demonstrate its application on two proteomic datasets. This demonstration provides insights to help translational teams overcome theoretical, practical, and pedagogical hurdles for the widespread use of subject-protein networks for analyzing molecular heterogeneities, with the translational goal of designing biomarker-based clinical trials, and accelerating the development of personalized approaches to medicine.

Asthma-associated comorbidities in children with and without secondhand smoke exposure.

BACKGROUND: Secondhand smoke (SHS) exposure is known to trigger asthma, but asthma disease severity and comorbidities in children exposed to SHS are not very well quantified. OBJECTIVE: To identify comorbidities and understand health care usage in children with asthma exposed to SHS (cases) compared with children with asthma but without SHS exposure (controls). METHODS: A retrospective nested matched case-and-control study was conducted with children 5 to 18 years old who were enrolled in the Pediatric Asthma Management Program. Pulmonary function testing (spirometry, methacholine challenges, and exhaled nitric oxide) and body mass index were reviewed. Influenza vaccination rates, oral steroid usage, emergency department visits, and hospitalizations were assessed. Network analysis of the 2 groups also was conducted to evaluate for any associations between the variables. RESULTS: Cases had significantly higher body mass index percentiles (>75%, odds ratio [OR] 1.64, 95% confidence interval [CI] 1.22-2.2, P = .001). Cases were less likely to have had a methacholine challenge (OR 0.49, 95% CI 0.36-0.68, P < .001) and an exhaled nitric oxide (OR 0.6, 95% CI 0.37-0.97, P = .04) performed than controls. The ratio of forced expiration volume in 1 second to forced vital capacity and forced expiration volume in 1 second were lower in cases than in controls (P < .05). Cases were less likely to have received an influenza vaccination (OR 0.61, 95% CI 0.45-0.82, P = .001) than controls. Unsupervised multivariable network analysis suggested a lack of discrete and unique subgroups between cases and controls. CONCLUSION: Children with asthma exposed to SHS are more likely to have comorbid conditions such as obesity, more severe asthma, and less health care usage than those not exposed to SHS. Smoking cessation interventions and addressing health disparities could be crucial in this vulnerable population.

Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance.

Dendritic cells (DCs) have been shown to play a major role in oral tolerance, and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive regulatory T cells. In this study, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-myelin oligodendrocyte glycoprotein (MOG) carrying the MOG(35-55) epitope was orally administered into either T cell-sufficient or -deficient mice, only the T cell-sufficient hosts yielded CD8α(+) and CD8α(-) LP DCs that were able to transfer tolerance to a variety of MHC class II-restricted effector T cells. Surprisingly, these LP DCs upregulated programmed cell death ligand 1 during the initial interaction with MOG-specific T cells and used this inhibitory molecule to suppress activation of T cells regardless of Ag specificity. Furthermore, oral Ig-MOG was able to overcome experimental autoimmune encephalomyelitis induced with CNS homogenate, indicating that the DCs are able to modulate disease involving diverse T cell specificities. This previously unrecognized attribute potentiates DCs against autoimmunity.

Heterogeneity of asthma in society.

There has been an increased interest in studying other factors that affect asthma pathogenesis and cause heterogeneity in prevalence and incidence of asthma. The reason there are such varied expression patterns of disease in asthmatics is because of multiple variables that affect the pathogenesis of asthma. As an exemplar of an epidemiologic variable, we will discuss geographical location, obesity and vitamin D status of the individual, and their effects on asthma burden in humans. There is varying data regarding the prevalence or severity of asthma in urban versus rural setting which is likely related to the difference of the populations studied, complexity of causal variables involved, and local geographic factors. In addition to cross-sectional and cohort studies in humans, animal models and studies have established a link between asthma and obesity by investigating the mechanisms affecting both disease processes. The complicated interrelationship between obesity and asthma is an active area of epidemiological and experimental research with new insights being discovered at a rapid pace. Finally, vitamin D, an important immunomodulator thought to be important in pathogenesis of asthma, has both mechanistic and therapeutic implications in treatment of asthma. The influences of these factors on the clinical expression of asthma are discussed below.

The role of visual analytics in asthma phenotyping and biomarker discovery.

The exponential growth of biomedical data related to diseases such as asthma far exceeds our cognitive abilities to comprehend it for tasks such as biomarker discovery, pathway identification, and molecular-based phenotyping. This chapter discusses the cognitive and task-based reasons for why methods from visual analytics can help in analyzing such large and complex asthma data, and demonstrates how one such approach called network visualization and analysis can be used to reveal important translational insights related to asthma. The demonstration of the method helps to identify the strengths and limitations of network analysis, in addition to areas for future research that can enhance the use of networks to analyze vast and complex biomedical datasets related to diseases such as asthma.

Management of Aspirin-Exacerbated Respiratory Disease: What Does the Future Hold?

Aspirin-exacerbated respiratory disease (AERD) is a subtype of chronic rhinosinusitis with polyps (CRSwNP) and asthma with higher recurrence of nasal polyps after surgery and severe asthma. Patients with CRSwNP and asthma should be screened for AERD by detailed history of aspirin/nonsteroidal anti-inflammatory drug reactions and review of medications that may mask aspirin reaction or directly by aspirin challenge. Treatment of AERD may require more intensive therapy, including endoscopic sinus surgery, daily aspirin therapy, leukotriene modifiers, or biologics.

Symptom-based controller therapy: a new paradigm for asthma management.

Appropriate management of persistent asthma, according to US and international guidelines, requires daily use of controller medications, most generally, inhaled corticosteroids (ICS). This approach, although effective and well established, imposes burdens of treatment and side effects onto asthma patients. A growing body of evidence suggests that patients with persistent asthma need not be managed with daily ICS, but rather can use them on an intermittent basis, occasioned by the occurrence of symptoms sufficient to warrant treatment with a rescue inhaler. Large, randomized, controlled studies, over a range of asthma severity, and in a range of ages from pediatrics to adults, suggest that, in well-selected patients, a symptom-based approach to administering controller therapy may produce equivalent outcomes, while reducing exposure to ICS. The concept of providing anti-inflammatory treatment to the patient, at the time inflammation is developing, is termed 'temporal personalization'. The evidence to date suggests that symptom-based controller therapy is broadly useful in selected asthma patients, and is a management approach that could be incorporated into US and international guidelines for asthma.

T cell dynamics during induction of tolerance and suppression of experimental allergic encephalomyelitis.

The cell dynamics associated with induction of peripheral T cell tolerance remain largely undefined. In this study, an in vivo model was adapted to two-photon microscopy imaging, and T cell behavior was analyzed on tolerogen-induced modulation. FcγR-deficient (FcγR(-/-)) mice were unable to resist or alleviate experimental allergic encephalomyelitis when treated with Ig-myelin oligodendrocyte glycoprotein (MOG) tolerogen, an Ig carrying the MOG35-55 peptide. However, when FcγR(+/+) dendritic cells (DCs) are adoptively transferred into FcγR(-/-) mice, uptake and presentation of Ig-MOG occurs and the animals were able to overcome experimental allergic encephalomyelitis. We then fluorescently labeled FcγR(+/+) DCs and 2D2 MOG-specific TCR-transgenic T cells, transferred them into FcγR(-/-) mice, administered Ig-MOG, and analyzed both T cell-DC contact events and T cell motility. The results indicate that tolerance takes place in lymphoid organs, and surprisingly, the T cells do not become anergic but instead have a Th2 phenotype. The tolerant Th2 cells displayed reduced motility after tolerogen exposure similar to Th1 cells after immunization. However, the Th2 cells had higher migration speeds and took longer to exhibit changes in motility. Therefore, both Th1 immunity and Th2 tolerance alter T cell migration on Ag recognition, but the kinetics of this effect differ among the subsets.

Unified Airway Disease: Diagnosis and Subtyping.

The concept of a unified airway posits that pathology affects the respiratory tract in a continuum and that disease in one part of the respiratory tract may be associated with or directly or indirectly affect the function of a different part. Transcriptomic analysis has shown 91% homology between the genes expressed in the upper and the lower airway. Approaching inflammatory airway disorders using the unified airway hypothesis allows for a better clarification of disease process and provides a detailed and a high-level overview of dysfunction. There are several tools available to the clinician to use to subtype and diagnose accurately the abnormal pathways operating in inflammatory airway disorders. These tools include clinical history, physical examination findings, imaging (computed tomography and MRI), allergy and laboratory testing, pulmonary function testing (PFT), and tissue histopathology. Tests can be categorized based on platform, by specimen, or the marker being studied.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. OBJECTIVE: The aim of this study is to characterize disease progression in N-ERD. METHODS: Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. RESULTS: Patients (N = 240) were mostly female (68%) and self-identified as non-White (77%). Half (N = 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.06-1.7, P = .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR = 3.3, 95% CI: 1.5-7.4, P = .004) and pollution exposure (OR = 4.4, 95% CI: 1.6-11.9, P = .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P = .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). CONCLUSIONS: In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Aspirin-Exacerbated Respiratory Disease and the Unified Airway: A Contemporary Review.

Aspirin-exacerbated respiratory disease (AERD) is characterized by abnormal arachidonic acid metabolism leading to chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and upper and/or lower respiratory symptoms after ingestion of cyclooxygenase-1 inhibiting nonsteroidal antiinflammatory drugs. Diagnosis is clinical and may involve an aspirin challenge. Inflammatory biomarkers may be useful for diagnosis and treatment monitoring. Conventional medical management for asthma and CRSwNP is often inadequate. Endoscopic sinus surgery followed by continued medical management with or without aspirin desensitization frequently improves symptoms and objective disease measures. Biological agents targeting eosinophilic inflammation are promising alternatives to conventional management.