Meteorological and environmental factors that impact pollen counts, allergenicity, and thresholds: A scoping review.

Background: Pollen is a key source of aeroallergens responsible for allergic rhinitis, conjunctivitis, and asthma. Objective: The goal of this scoping review was to summarize current available literature on the factors that affect pollen counts, allergenicity, and thresholds that induce symptoms in individuals who were sensitized. Methods: Several databases showed no published articles with a similar scope as of January 2022. A search of these data bases yielded 373 articles for assessment. These were then reviewed for relevance, and articles were selected to demonstrate the breadth of available data on pollen counts, allergenicity, and thresholds that induce symptoms in individuals who were sensitized. Additional articles were identified through examination of bibliographies of search-identified articles. Results: Several environmental factors have shown a correlation with pollen counts and allergen load, including the distance from the source, wind characteristics, pollen size, terrain, urban environments, air composition (particulate matter, CO2 levels, ozone, NO2), and weather conditions (humidity, thunderstorms, precipitation). Pollen thresholds at which symptoms were induced varied by study, pollen type, symptom, disease, and location. In addition, there was heterogeneity in study designs, threshold definition, and outcome measures. Conclusion: This scoping review demonstrates the plethora of variables that influence the relationship between pollen and the symptoms of allergic diseases. Analysis of the available data sheds light on the complex interaction between environmental and biologic factors that affect pollen's role in allergic diseases and provides guidance on multiple areas for further investigation.

A prediction model for asthma exacerbations after stopping asthma biologics.

BACKGROUND: Little is known regarding the prediction of the risks of asthma exacerbation after stopping asthma biologics. OBJECTIVE: To develop and validate a predictive model for the risk of asthma exacerbations after stopping asthma biologics using machine learning models. METHODS: We identified 3057 people with asthma who stopped asthma biologics in the OptumLabs Database Warehouse and considered a wide range of demographic and clinical risk factors to predict subsequent outcomes. The primary outcome used to assess success after stopping was having no exacerbations in the 6 months after stopping the biologic. Elastic-net logistic regression (GLMnet), random forest, and gradient boosting machine models were used with 10-fold cross-validation within a development (80%) cohort and validation cohort (20%). RESULTS: The mean age of the total cohort was 47.1 (SD, 17.1) years, 1859 (60.8%) were women, 2261 (74.0%) were White, and 1475 (48.3%) were in the Southern region of the United States. The elastic-net logistic regression model yielded an area under the curve (AUC) of 0.75 (95% confidence interval [CI], 0.71-0.78) in the development and an AUC of 0.72 in the validation cohort. The random forest model yielded an AUC of 0.75 (95% CI, 0.68-0.79) in the development cohort and an AUC of 0.72 in the validation cohort. The gradient boosting machine model yielded an AUC of 0.76 (95% CI, 0.72-0.80) in the development cohort and an AUC of 0.74 in the validation cohort. CONCLUSION: Outcomes after stopping asthma biologics can be predicted with moderate accuracy using machine learning methods.

Asthma biologic trial eligibility and real-world outcomes in the United States.

OBJECTIVE: To compare the outcomes of real-world patients who would have been eligible for asthma biologics to those who would not have been eligible. METHODS: We used data from the OptumLabs Data Warehouse (OLDW) to categorize patients into eligible and ineligible groups based on clinical trials (n = 19 trials) used for Food and Drug Administration (FDA) approval. We then compared the change in the number of asthma exacerbations before and after biological initiation between the two groups. RESULTS: The percentage of people who would have been eligible for asthma biologic clinical trials ranged from 0-10.2%. The eligible group had a greater reduction in number of asthma exacerbations compared to the ineligible group based on eligibility criteria from 1 omalizumab trial (1.52, 95% CI 1.25, 1.8 in eligible vs. 0.47, 95% CI 0.43, 0.52 in ineligible) and from 1 dupilumab trial (1.6, 95% CI 0.92, 2.28 in eligible vs. 0.52, 95% CI 0.38, 0.65 ineligible). Notably, 15 of the 19 trials had fewer than 11 eligible people, limiting additional comparisons. CONCLUSIONS: Fewer than 1 in 10 people in the United States treated with asthma biologics would have been eligible to participate in the trial for the biologic they used. Where comparisons could be made, trial eligible people have a greater reduction in exacerbations.Supplemental data for this article is available online at https://doi.org/10.1080/02770903.2021.2010749 .

Persistence of asthma biologic use in a US claims database.

BACKGROUND: Little is known on the persistence of asthma biologic use in clinical practice. OBJECTIVE: To evaluate the persistence of asthma biologic use and time to clinical response in clinical practice. METHODS: A cohort of people with asthma who used at least 1 asthma biologic was constructed using data from 2003 to 2019 in the OptumLabs Data Warehouse. Treatment persistence was defined by the length of time that a person continuously used an asthma biologic, allowing for a lapse in use up to 4 months before confirming that a person stopped. Clinical response to treatment (defined as a decline in asthma exacerbations of at least 50% compared with the 6 months before starting an asthma biologic) was described over time and in relation to biologic persistence. RESULTS: There were 9575 people who had at least 1 episode of asthma biologic use. There were 5319 people (64%, 95% confidence interval, 63%-65%) who completed 6 months or more on an asthma biologic and 3284 (45%, 95% confidence interval, 44%-46%) who completed 12 months or more. Of people with 1 or more asthma exacerbation 6 months before index biologic use, 63%, 76%, 80%, and 81% realized a 50% or more reduction in postindex asthma exacerbations in the first 6 months, 6 to 12 months, 12 to 18 months, and 18 to 24 months, respectively. CONCLUSION: Between 48% and 64% of people remained on an asthma biologic for 6 months or more after first use. Most people who achieved a reduction in asthma exacerbations did so in the first 6 months of treatment.

Asthma Patients Who Stop Asthma Biologics Have a Similar Risk of Asthma Exacerbations as Those Who Continue Asthma Biologics.

BACKGROUND: There is limited information about outcomes associated with stopping asthma biologics. OBJECTIVE: To compare outcomes in people who stopped or continued asthma biologics. METHODS: We identified a cohort of people with asthma who stopped or continued asthma biologics in the Optum Labs Database Warehouse, using a propensity matching method for case and control groups with the variables of age, sex, race, region, insurance, income, specialist access, Charlson comorbidity, specific medical conditions, pre-index exacerbation count, pre-index rescue inhaler pharmacy fills, and pre-index inhaled corticosteroid with or without long-acting ß-agonist pharmacy fills. Primary outcome used to assess failure of stopping was an increase of 50% or more in the asthma exacerbation rate in the 6 months after discontinuing the biologic compared with the 6-month period before biologic initiation. RESULTS: Among a cohort of 4960 asthma biologic users, 1249 were observed to stop use after 6 to 12 months of use. We identified a matched cohort of 1247 stoppers and 1247 people who continued biologic use for at least 18 months. In the first 6 months after stopping or sham stopping, 10.2% of stoppers and 9.5% of continuers had an increase of 50% or more in asthma exacerbations. We found a similar adjusted odds of failing among stoppers and continuers (odds ratio = 1.085; 95% confidence interval, 0.833-1.413). CONCLUSIONS: An increase in asthma exacerbations is infrequently observed in people who stopped asthma biologics and was observed at similar rates as in matched controls who continued asthma biologics.

Adherence to Asthma Biologics: Implications for Patient Selection, Step Therapy, and Outcomes.

BACKGROUND: Little is known about adherence to asthma biologics. RESEARCH QUESTION: Is adherence to inhaled corticosteroid (ICS) associated with subsequent asthma biologic adherence? STUDY DESIGN AND METHODS: We analyzed individuals with asthma who started asthma biologics in the OptumLab Data Warehouse and used that data until October 2019. We calculated proportion days covered (PDC) for ICS ± long-acting ß-agonists in the 6 months before and after asthma biologics were started and asthma biologic PDC for the first 6 months of use. We performed a multivariable analysis to identify factors associated with asthma biologic PDC ≥0.75, ICS PDC ≥0.75 during the 6-month period after asthma biologic were started, and achievement of a ≥50% reduction in asthma exacerbations during the first 6 months of asthma biologic use. RESULTS: We identified 5,319 people who started asthma biologics. The mean PDC for asthma biologics was 0.76 (95% CI, 0.75-0.77) in the first 6 months after starting, higher than the mean PDCs for ICS in the 6 months before (0.44 [95% CI, 0.43-0.45]) and after (0.40 [95% CI, 0.39-0.40]) starting the asthma biologic. PDC ≥0.75 for ICS 6 months before index biologic use is associated with PDC for asthma biologics ≥0.75 (OR, 1.25; 95% CI, 1.10-1.43) and for ICS during the first 6 months of biologic use (OR, 9.93; 95% CI, 8.55-11.53). Neither ICS PDC ≥0.75 (OR, 0.92; 95% CI, 0.74-1.14) nor asthma biologic PDC ≥0.75 (OR, 1.15; 95% CI, 0.97-1.36) is associated with a statistically significant reduction in asthma exacerbations during the first 6 months of asthma biologic use among people with any exacerbation in the 6 months before first use. INTERPRETATION: Adherence to asthma biologic is higher than to ICS and is associated with different factors.

Trends and Disparities in Asthma Biologic Use in the United States.

BACKGROUND: From 2003 to 2015, only 1 biologic was approved for the treatment of moderate to severe asthma in the United States. Since 2015, 4 new asthma biologics were approved by the US Food and Drug Administration. OBJECTIVE: To describe trends and disparities of asthma biologic use in the United States from 2003 to 2018. METHODS: We conducted a retrospective analysis using a cohort developed from the OptumLabs Data Warehouse. Prevalent and incident asthma biologic users were identified, and characteristics of users and nonusers were analyzed using regression analysis. Clinician prescribing behavior was described. RESULTS: Use of biologic medications remains uncommon among individuals with asthma, with prevalence peaking in 2006 at 3 in 1000 individuals with asthma. Several factors are associated with a higher likelihood of asthma biologic use: middle age, higher income, commercial insurance, and access to a specialist. Most clinicians (65%) in the cohort prescribed only 1 biologic. CONCLUSIONS: We report low overall use of asthma biologics and evidence of disparities in access to asthma biologics.

Esophageal Actinomycosis Presenting as an Obstructive Esophageal Mass.

Esophageal actinomycosis is a rare type of esophageal infection, with only approximately 24 cases previously reported in the United States. Most of these cases were described as erosions or ulcers when examined endoscopically. We present a 47-year-old woman who presented with dysphagia. Endoscopy showed a lower esophageal fungating mass, mimicking a malignant mass. Although there was a high suspicion of esophageal carcinoma, biopsy results showed esophageal actinomyces infection.

Clinical Review of the Pharmacogenomics of Direct Oral Anticoagulants.

PURPOSE: There is growing interest in the use of pharmacogenomics to optimize the safety and efficacy of anticoagulation therapy. While the pharmacogenomics of warfarin have been well-studied, the pharmacogenomics of direct oral anticoagulants (DOACs) continue to be a fledgling, but growing, field of interest. We present a pertinent clinical review of the present state of research on the pharmacogenomics of DOACs. METHODS AND RESULTS: The present article is a review of pertinent clinical and scientific research on the pharmacogenomics of DOACs between January 2008 and December 2017 using MEDLINE and the United States National Institutes of Health Clinical Trials Registry. Many studies have identified single-nucleotide polymorphisms (SNPs) in genes responsible for DOAC metabolism that impacted serum DOAC concentration but had uncertain clinical significance. CONCLUSIONS: As such, there is currently no strong evidence for the use of pharmacogenomic testing in optimizing the safety and efficacy of DOAC therapy. Nonetheless, genes of interest have been identified for each DOAC that may be of potential clinical utility. Further research is currently underway to elucidate the value of pharmacogenomics in this increasingly prescribed therapy.

Evaluation of Recombinant Attenuated Salmonella Vaccine Strains for Broad Protection against Extraintestinal Pathogenic Escherichia coli.

Antibiotic-resistant bacterial infections are difficult to treat, producing a burden on healthcare and the economy. Extraintestinal pathogenic Escherichia coli (ExPEC) strains frequently carry antibiotic resistance genes, cause infections outside of the intestine, and are causative agents of hospital-acquired infections. Developing a prevention strategy against this pathogen is challenging due to its antibiotic resistance and antigenic diversity. E. coli common pilus (ECP) is frequently found in ExPEC strains and may serve as a common antigen to induce protection against several ExPEC serotypes. In addition, live recombinant attenuated Salmonella vaccine (RASV) strains have been used to prevent Salmonella infection and can also be modified to deliver foreign antigens. Thus, the objective of this study was to design a RASV to produce ECP on its surface and assess its ability to provide protection against ExPEC infections. To constitutively display ECP in a RASV strain, we genetically engineered a vector (pYA4428) containing aspartate-ß-semialdehyde dehydrogenase and E. coli ecp genes and introduced it into RASV χ9558. RASV χ9558 containing an empty vector (pYA3337) was used as a control to assess protection conferred by the RASV strain without ECP. We assessed vaccine efficacy in in vitro bacterial inhibition assays and mouse models of ExPEC-associated human infections. We found that RASV χ9558(pYA4428) synthesized the major pilin (EcpA) and tip pilus adhesin (EcpD) on the bacterial surface. Mice orally vaccinated with RASV χ9558(pYA3337) without ECP or χ9558(pYA4428) with ECP, produced anti-Salmonella LPS and anti-E. coli EcpA and EcpD IgG and IgA antibodies. RASV strains showed protective potential against some E. coli and Salmonella strains as assessed using in vitro assays. In mouse sepsis and urinary tract infection challenge models, both vaccines had significant protection in some internal organs. Overall, this work showed that RASVs can elicit an immune response to E. coli and Salmonella antigens in some mice, provide significant protection in some internal organs during ExPEC challenge, and thus this study is a promising initial step toward developing a vaccine for prevention of ExPEC infections. Future studies should optimize the ExPEC antigens displayed by the RASV strain for a more robust immune response and enhanced protection against ExPEC infection.

Evaluation of the prevalence and production of Escherichia coli common pilus among avian pathogenic E. coli and its role in virulence.

Avian pathogenic Escherichia coli (APEC) strains cause systemic and localized infections in poultry, jointly termed colibacillosis. Avian colibacillosis is responsible for significant economic losses to the poultry industry due to disease treatment, decrease in growth rate and egg production, and mortality. APEC are also considered a potential zoonotic risk for humans. Fully elucidating the virulence and zoonotic potential of APEC is key for designing successful strategies against their infections and their transmission. Herein, we investigated the prevalence of a newly discovered E. coli common pilus (ECP) for the subunit protein of the ECP pilus (ecpA) and ECP expression amongst APEC strains as well as the role of ECP in virulence. A PCR-based ecpA survey of a collection of 167 APEC strains has shown that 76% (127/167) were ecpA+. An immunofluorescence assay using anti-EcpA antibodies, revealed that among the ecpA+ strains, 37.8% (48/127) expressed ECP when grown in DMEM +0.5% Mannose in contact with HeLa cells at 37°C and/or in biofilm at 28°C; 35.4% (17/48) expressed ECP in both conditions and 64.6% (31/48) expressed ECP in biofilm only. We determined that the ecp operon in the APEC strain χ7122 (ecpA+, ECP-) was not truncated; the failure to detect ECP in some strains possessing non-truncated ecp genes might be attributed to differential regulatory mechanisms between strains that respond to specific environmental signals. To evaluate the role of ECP in the virulence of APEC, we generated ecpA and/or ecpD-deficient mutants from the strain χ7503 (ecpA+, ECP+). Deletion of ecpA and/or ecpD abolished ECP synthesis and expression, and reduced biofilm formation and motility in vitro and virulence in vivo. All together our data show that ecpA is highly prevalent among APEC isolates and its expression could be differentially regulated in these strains, and that ECP plays a role in the virulence of APEC.

New insights into the bacterial fitness-associated mechanisms revealed by the characterization of large plasmids of an avian pathogenic E. coli.

Extra-intestinal pathogenic E. coli (ExPEC), including avian pathogenic E. coli (APEC), pose a considerable threat to both human and animal health, with illness causing substantial economic loss. APEC strain χ7122 (O78∶K80∶H9), containing three large plasmids [pChi7122-1 (IncFIB/FIIA-FIC), pChi7122-2 (IncFII), and pChi7122-3 (IncI(2))]; and a small plasmid pChi7122-4 (ColE2-like), has been used for many years as a model strain to study the molecular mechanisms of ExPEC pathogenicity and zoonotic potential. We previously sequenced and characterized the plasmid pChi7122-1 and determined its importance in systemic APEC infection; however the roles of the other pChi7122 plasmids were still ambiguous. Herein we present the sequence of the remaining pChi7122 plasmids, confirming that pChi7122-2 and pChi7122-3 encode an ABC iron transport system (eitABCD) and a putative type IV fimbriae respectively, whereas pChi7122-4 is a cryptic plasmid. New features were also identified, including a gene cluster on pChi7122-2 that is not present in other E. coli strains but is found in Salmonella serovars and is predicted to encode the sugars catabolic pathways. In vitro evaluation of the APEC χ7122 derivative strains with the three large plasmids, either individually or in combinations, provided new insights into the role of plasmids in biofilm formation, bile and acid tolerance, and the interaction of E. coli strains with 3-D cultures of intestinal epithelial cells. In this study, we show that the nature and combinations of plasmids, as well as the background of the host strains, have an effect on these phenomena. Our data reveal new insights into the role of extra-chromosomal sequences in fitness and diversity of ExPEC in their phenotypes.