Unique transcriptomic profile of peripheral blood monocytes in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Though interstitial lung disease (ILD) contributes to excess morbidity and mortality in rheumatoid arthritis (RA), RA-ILD pathogenesis remains incompletely defined. As intermediate, non-classical and suppressed CD14+ monocytes are expanded in RA-ILD, this study sought to characterize gene expression profiles of circulating monocytes in RA-ILD. METHODS: Peripheral blood mononuclear cells were collected from patients with RA without lung disease (N = 5), RA-ILD (N = 5), idiopathic pulmonary fibrosis (IPF; N = 5), and controls without lung and autoimmune disease (N = 4). RNA was extracted from CD14+ isolated monocytes and subjected to transcriptional analysis of 1365 genes. Gene enrichment and pathway analyses were performed. RESULTS: Unsupervised clustering grouped patients with RA-ILD together with IPF for myeloid innate genes. For fibrosis genes, patients with RA-ILD clustered independent of comparator groups. There were 103, 66, and 64 upregulated and 66, 14, and 25 downregulated genes for RA-ILD, RA, and IPF, vs controls, respectively. For RA-ILD, there was increased expression of genes involved in regulating inflammation and fibrosis (SOCS3, CECAM1, LTB4R2, CLEC7A, IRF7, PHYKPL, GBP5, RAPGEF), epigenetic modification (KDM5D, KMT2D, OGT), and macrophage activation. Top canonical pathways included macrophage differentiation-activation, IL-12, neuroinflammatory, glucocorticoid receptor, and IL-27 signalling. CONCLUSIONS: Circulating monocytes in RA-ILD patients demonstrate unique gene expression profiles with innate immune gene features more aligned with IPF as opposed to RA in the absence of clinical lung disease with fibrosis gene expression that was distinct from RA and IPF. These studies are important for understanding disease pathogenesis and may provide information for future therapeutic targets in RA-ILD.

Intrapartum antibiotic exposure for group B Streptococcus treatment did not increase penicillin allergy in children.

BACKGROUND: Group B Streptococcus (GBS) is the leading infectious cause of neonatal morbidity and mortality in the United States. Intrapartum administration of antibiotics to mothers with positivity to GBS is performed for prevention, with penicillin being the drug of choice. Previous studies have noted an increase in atopic diseases other than drug allergy associated with intrapartum antibiotic exposure. OBJECTIVE: To determine whether intrapartum exposure to penicillin for GBS increases the likelihood of penicillin allergy in children. METHODS: Retrospective chart review was performed for patients from a birth cohort. The birth cohort included children born in 2007 at a tertiary care hospital and had local addresses. Information on GBS status of the mother, intrapartum antibiotic exposure, delivery mode, and birth order was collected and analyzed. RESULTS: Of 927 children identified, 804 were included in the cohort. Eighty children (10%) had a reported penicillin allergy; most were white (79%) and boys (61%). Intrapartum exposure to penicillin (odds ratio 0.84, 95% confidence interval 0.45-1.57, P = .59) or to amoxicillin or ampicillin (odds ratio 0.22, 95% confidence interval 0.01-3.71, P = .29) did not increase the risk of penicillin allergy in children. In addition, all other factors evaluated did not affect the risk of penicillin allergy in children. CONCLUSION: To the authors' knowledge, this is the first study to evaluate intrapartum exposure to penicillin for GBS treatment and subsequent development of penicillin allergy in the child. In contrast to other atopic diseases, intrapartum antibiotic exposure does not alter the risk of penicillin allergy. Parents and obstetricians should be reassured when using penicillin for prevention of neonatal GBS.

Effects of secondhand smoke exposure on asthma morbidity and health care utilization in children: a systematic review and meta-analysis.

BACKGROUND: Secondhand smoke (SHS) exposure can trigger asthma exacerbations in children. Different studies have linked increased asthma symptoms, health care use, and deaths in children exposed to SHS, but the risk has not been quantified uniformly across studies. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate and quantify asthma severity and health care use from SHS exposure in children. METHODS: A systematic review was undertaken to assess the association between asthma severity and SHS in children. Inclusion criteria included studies that evaluated children with SHS exposure and reported outcomes of interest with asthma severity including exacerbations. Random effect models were used to combine the outcomes of interest (hospitalization, emergency department or urgent care visits, severe asthma symptoms, wheeze symptoms, and pulmonary function test results) from the included studies. RESULTS: A total of 1,945 studies were identified and 25 studies met the inclusion criteria. Children with asthma and SHS exposure were twice as likely to be hospitalized for asthma (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.20-2.86, P = .01) than children with asthma but without SHS exposure. SHS exposure also was significantly associated with emergency department or urgent care visits (OR 1.66, 95% CI 1.02-2.69, P = 0.04), wheeze symptoms (OR 1.32, 95% CI 1.24, 1.41, P < .001), and lower ratio of forced expiratory volume in 1 second to forced vital capacity (OR -3.34, 95% CI -5.35 to -1.33, P = .001). CONCLUSION: Children with asthma and SHS exposure are nearly twice as likely to be hospitalized with asthma exacerbation and are more likely to have lower pulmonary function test results.

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.

Burden of chronic obstructive pulmonary disease: healthcare costs and beyond.

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating respiratory condition that leads to significant burden, both medically and financially. It affects millions of people worldwide and causes significant morbidity and mortality. Most detailed information related to its prevalence, morbidity, and mortality comes from high-income countries, but 90% of COPD-related deaths occur in low- and middle-income countries. Cigarette smoking is the main risk factor for developing COPD, but other risk factors do exist and need to be recognized. A majority of morbidity and mortality as well as health care costs occur from acute exacerbations of COPD with a known phenotype of patients being "frequent exacerbators." Health care costs for COPD are not only from treatment of exacerbations, such as hospitalization, but also medication costs for maintenance therapy and outpatient treatment. COPD has been linked with many comorbidities leading to significant burden of disease. The goal of this review is to evaluate the overall burden of disease including prevalence, morbidity, mortality, health care costs, and economic costs.

Perioperative cefazolin prescribing rates following suppression of alerts for non-IgE-mediated penicillin allergies.

BACKGROUND: Cefazolin is the preferred antimicrobial for the prevention of surgical site infections (SSIs) in many procedures. The presence of penicillin allergies can influence prescribing of alternative agents like vancomycin. In April 2022, Nebraska Medicine implemented a suppression of alerts for non-IgE-mediated and nonsevere penicillin allergies in the electronic medical record (EMR) upon cephalosporin prescribing. The objective of this study was to evaluate changes in perioperative cefazolin for SSI prophylaxis. METHODS: This was a quasi-experimental study of patients undergoing procedures for which cefazolin was the preferred agent per institutional guidance. Education on the change was distributed via e-mail to surgical staff and pharmacists. Pre- and post-intervention data were collected from April 2021 through March 2022 and April 11, 2022, through October 2022, respectively. Chart review was performed on patients with reported penicillin allergies for the top surgical procedures with <50% cefazolin utilization pre-intervention. The primary outcome was the administration of perioperative cefazolin in patients with penicillin allergies, including unknown reactions. RESULTS: A total of 6,676 patients underwent surgical procedures (pre-intervention n = 4,147, post-intervention n = 2,529). Documented penicillin allergies were similar between the pre- and post-intervention group (12.3% vs. 12.6%). In individuals with documented penicillin allergies, cefazolin prescribing increased from 49.6% to 74.3% (p < 0.01). Chart review for safety outcomes identified no difference in new severe reactions, rescue medication, SSIs, acute kidney injury, postoperative Clostridioides difficile infection, or methicillin-resistant Staphylococcus aureus infections. CONCLUSION: Following the suppression of EMR alerts for non-IgE-mediated and nonsevere penicillin allergies, cefazolin prescribing rates for SSI prophylaxis significantly improved.

Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls. METHODS: Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression. RESULTS: There was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical (CD14++CD16-) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes. CONCLUSIONS: Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16+ monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.

Use of a beta-lactam graded challenge process for inpatients with self-reported penicillin allergies at an academic medical center.

Background: The Antimicrobial Stewardship Program (ASP) at Nebraska Medicine collaborated with a board-certified allergist to develop a penicillin allergy guidance document for treating inpatients with self-reported allergy. This guidance contains an algorithm for evaluating and safely challenging penicillin-allergic patients with beta-lactams without inpatient allergy consults being available. Methods: Following multi-disciplinary review, an order set for beta-lactam graded challenges (GC) was implemented in 2018. This contains recommended monitoring and detailed medication orders to challenge patients with various beta-lactam agents. Inpatient orders for GC from 3/2018-6/2022 were retrospectively reviewed to evaluate ordering characteristics, outcomes of the challenge, and whether documentation of the allergy history was updated. All beta-lactam challenges administered to inpatients were included, and descriptive statistics were performed. Results: Overall, 157 GC were administered; 13 with oral amoxicillin and 144 with intravenous (IV) beta-lactams. Ceftriaxone accounted for the most challenges (43%). All oral challenges were recommended by an Infectious Diseases consult service, as were a majority of IV challenges (60%). Less than one in five were administered in an ICU (19%). Almost all (n = 150, 96%) were tolerated without any adverse event. There was one reaction (1%) of hives and six (4%) involving a rash, none of which had persistent effects. Allergy information was updated in the electronic health record after 92% of the challenges. Conclusion: Both intravenous and oral beta-lactam graded challenges were implemented successfully in a hospital without a regular inpatient allergy consult service. They were well-tolerated, administered primarily in non-ICU settings, and were often ordered by non-specialist services. In patients with a self-reported penicillin allergy, these results demonstrate the utility and safety of a broadly adopted beta-lactam GC process.

A Clinical Process Change and Educational Intervention to Reduce the Use of Unnecessary Preoperative Tests.

BACKGROUND: Internal medicine residents receive limited training on how to be good stewards of health care dollars while preserving high-quality care. INTERVENTION: We implemented a clinical process change and an educational intervention focused on the appropriate use of preoperative diagnostic testing by residents at a Veterans Administration (VA) medical center. METHODS: The clinical process change consisted of reducing routine ordering of preoperative tests in the absence of specific indications. Residents received a short didactic session, which included algorithms for determining the appropriate use of perioperative diagnostic testing. One outcome was the average cost savings on preoperative testing for a continuous cohort of patients referred for elective knee or hip surgery. Resident knowledge and confidence prior to and after the intervention was measured by pre- and posttest. RESULTS: The mean cost of preoperative testing decreased from $74 to $28 per patient after the dual intervention (P < .001). The bulk of cost savings came from elimination of unnecessary blood and urine tests, as well as reduced numbers of electrocardiograms and chest radiographs. Among residents who completed the pretest and posttest, the mean score on the pretest was 54%, compared with 80% on the posttest (P  =  .027). Following the educational intervention, 70% of residents stated they felt "very comfortable" ordering appropriate preoperative testing (P  =  .006). CONCLUSIONS: This initiative required few resources, and it simultaneously improved the educational experience for residents and reduced costs. Other institutions may be able to adopt or adapt this intervention to reduce unnecessary diagnostic expenditures.