Kanj, Amjad

Background: Pneumocystis jirovecii pneumonia (PJP) is life-threatening for immunocompromised patients. No consensus exists on PJP prophylaxis for immunosuppressed patients without HIV, transplant, or cancer. Methods: We retrospectively reviewed the electronic health records of adult immunosuppressed patients with PJP diagnosed between 1990 and 2020 at Mayo Clinic. Patients with HIV, solid organ transplants, or cancer were excluded. Demographic data, treatments, and outcomes were manually abstracted. Results: The most common indications for immunosuppression were rheumatoid arthritis (19.7%), vasculitis (18.1%), and interstitial lung disease (ILD) not related to connective tissue disease (17.6%). Despite having high risk of PJP, 86.0% of patients did not receive PJP prophylaxis. Corticosteroids were the most common immunosuppressive agent used (84.5%), with 64.4% of patients receiving high-dose treatment. Nonbiologic disease-modifying antirheumatic drugs were used for 49.7%, including methotrexate (51.0%), azathioprine (22.9%), and hydroxychloroquine (11.5%). Biologics were prescribed for 25.4%, primarily rituximab (59.2%) and infliximab (22.4%). Hospitalization occurred for 76.7% of patients; 70.3% required intensive care unit (ICU) admission, and 46.6% received mechanical ventilation. The in-hospital mortality rate was 30.4% overall and 53.6% for patients on ventilation. Predictors of death included ILD [odds ratio (OR), 4.61; 95% CI, 1.75-13.00], ICU admission (OR, 3.60; 95% CI, 1.19-11.08), and ventilator use (OR, 3.46; 95% CI, 1.30-9.79). Biologic use was associated with lower odds of death (OR, 0.34; 95% CI, 0.11-0.89). Conclusions: Most patients in our cohort did not receive PJP prophylaxis, and outcomes were poor with high mortality rates. Standardized risk stratification and prophylaxis protocols are needed to improve outcomes.

Abstract Background: Bronchiectasis is a recognized pulmonary manifestation of ANCA-associated vasculitides (AAV). Although positive AAV workup has been observed in patients with isolated airway diseases, without other systemic involvement, AAV workup is not routinely obtained in patients presenting with bronchiectasis. Patients with bronchiectasis and positive AAV workup may represent a distinct subgroup with unique characteristics and outcomes. Objectives: To establish a cohort of patients with bronchiectasis who also have a positive AAV workup (i.e., presence of ANCA by indirect immunofluorescence AND elevated antibodies to PR3 or MPO) and to describe their characteristics. METHODS: There were 944 patients across Mayo clinic sites with bronchiectasis (J47.9, J47.0 and J 47.1) who underwent AAV workup. Of these 315 (33.36%) had evidence of ANCA on immunofluorescence and an abnormal level of antibodies to PR3 or MPO. Chest CT scans were reviewed, and 118 patients were excluded because their pulmonary disease was mostly interstitial or had no clear bronchiectasis. Co-morbidities were evaluated using respective ICD-10 codes and respiratory cultures were collected. RESULTS: A total of 197 patients were identified with Bronchiectasis (76% female; mean age 66 years, BMI 25 kg/m2), 112 (56.8%) were diagnosed before antibody detection and 85 (43.1%) after. MPO (positive [>0.9] or equivocal [0.4-0.9]) was detected in 177 (89.8%) patients; PR3 (positive [>0.9] or equivocal [0.4-0.9]) in 34 (17.2%). P-ANCA and c-ANCA patterns occurred in 185 (94%) and 15 (4%) patients, respectively. The most common antigen-target/ANCA combinations were MPO/p-ANCA (177, 89.8%), PR3/p-ANCA (22, 11.2%), and PR3/c-ANCA (14, 7.1%). Comorbidities included asthma (66, 33.5%), COPD (58, 29.4%), GERD (64, 32.5%), hypothyroidism (56, 28.4%), and autoimmune/inflammatory conditions (e.g., rheumatoid arthritis [23, 11.7%], IBD [25, 12.7%]). Neurologic (42, 23.9%) and renal (25, 14.7%) manifestations occurred. Respiratory cultures (n=122) isolated yeast (57, 46.7%), Aspergillus (34, 27.9%), and Pseudomonas (30, 24.6%); Mycobacteria and other molds (e.g., Penicillium) each appeared in 23-24 patients (∼19%). Conclusion: This work identifies a cohort of patients with bronchiectasis who also have a positive AAV workup, mostly MPO/p-ANCA. While AAV workup is not routine for patients presenting for bronchiectasis evaluation, some patients in this cohort had primarily airway disease with an abnormal AAV workup, in the absence of other common manifestations of AAV. Further research on this cohort will be conducted to determine whether these patients represent a distinct group with unique characteristics, treatment patterns, and outcomes.

Abstract RATIONALE: Absolute Blood Eosinophil Counts (BEC) in bronchiectasis patients offer insights into inflammatory patterns and potential treatments. In non-cystic fibrosis bronchiectasis (NCFB), BEC≥300 cells/μL characterizes Eosinophilic Bronchiectasis (EB), a type-2 inflammation endotype estimated in 20% of patients. Guidance on BEC assessment strategy (i.e., number, frequency and timing of BEC≥300 defining this endotype) is unclear. We hypothesize that EB incidence varies by BEC≥300 assessment strategy. We also investigate eosinophilic inflammation in CF for comparison. Objectives: Assess BEC≥300 incidence in NCFB and CF cohorts. METHODS: From January 2023 to October 2024, BEC were measured in 9,953 stable bronchiectasis patients across Mayo Clinic, including 9,806 with NCFB (J47.9; 66,780 CBCs) and 147 with CF (E84.0; 1,405 CBCs). Incidence of BEC≥300 was evaluated in relation to CBC frequency and timing (i.e., BEC≥300 on first, second, last, any, any two, first two simultaneously) and the number of CBCs per patient. RESULTS: In the NCFB cohort, median age was 74 years (IQR:66-82), with 59.5% female. Median CBCs/patient was 3 (IQR:1-7). Incidence of BEC≥300 on the first CBC was 19.8%. Among patients with ≥2 CBCs (n=7,075), incidence was 20.1% on the first, 19.8% on the second, and 20.0% on the last. This incidence rose to 36.3% when considering any CBC/patient. BEC≥300 on at least two CBCs was 29.3%, decreasing to 11.8% when considering consecutive BEC≥300 on both first and second CBCs. The incidence of BEC≥300 increased linearly with the number of CBCs obtained: 24.6% for those with 1-3 CBCs, up to 64.6% for >12 CBCs. In the CF cohort, median age was 36 years (IQR:27-52), with 55.1% female. Median CBCs/patient was 4 (IQR:2-8). BEC≥300 was present in 22.9% of first CBCs, rising to 36.3% when considering any CBC and 29.3% when present on at least two CBCs. Similar to the NCFB cohort, incidence increased with the number of CBCs: 26.5% for 1-3, up to 77.3% for >12. CONCLUSIONS: The incidence of BEC≥300 in our NCFB cohort remained steady at 20% at any specific measurement point, consistent with prospective literature. However, nearly half of those with BEC≥300 on the first or second CBC did not meet this threshold on both. Incidence significantly increased when any CBC was considered, and more CBCs were available. Similar observations were made in the CF cohort. Clearer BEC assessment strategies are needed to define clinically significant eosinophilic inflammation in bronchiectasis, to better identify patients who may most benefit from type 2 inflammation-targeted treatments.

Abstract Purpose: Frail and malnourished patients with bronchiectasis have worse outcomes. This study examines frailty and malnutrition as predictors of 30-day readmission after bronchiectasis exacerbation (BE). Methods: We utilized the 2018 Nationwide Readmissions Database to analyze hospitalizations for BE. Patients with BE were identified through principal and secondary ICD-10 diagnosis codes J47.0 and J47.1. Among those who survived the index hospitalization, only individuals discharged to home were included in the analysis. The primary objective was to identify predictors of 30-day readmission, with a specific focus on frailty and malnutrition. Frailty was measured using the validated Hospital Frailty Risk Score, as described by Gilbert et al. (Lancet, 2018), while malnutrition was identified using ICD-10 codes E43, E44.0, E44.1, and E46. Comorbidity burden was categorized using the Charlson Comorbidity Index: mild (score 0-2), moderate (3-5), and severe (≥6). A multivariate logistic regression model was employed to calculate adjusted odds ratios (ORs) for readmission, with statistical significance defined as p < 0.05. Results: Among 20,742 patients discharged home following bronchiectasis exacerbation, 4% (830) were readmitted within 30 days. Patients with readmission were younger (median age 63 vs. 69 years, p<0.01) and more likely to be treated at urban hospitals (84.9% vs. 80.0%, p=0.01). They also had higher rates of frailty (52.6% vs. 46.5%, p=0.01), malnutrition (21.0% vs. 14.7%, p<0.01), and Pseudomonas pneumonia (5.9% vs. 3.9%, p=0.03). The comorbidity burden was not different (p=0.29). After adjusting for age, malnutrition demonstrated a trend toward higher odds of readmission (OR 1.31, 95% CI 0.99-1.73, p=0.059), though this did not reach statistical significance. In contrast, frailty was significantly associated with increased readmission (OR 1.36, 95% CI 1.12-1.66). The presented Table describes the demographic characteristics and outcomes of ALL hospitalized patients with BE (n = 40, 789) stratified by frailty and malnutrition. Conclusions: Frailty is a significant predictor of 30-day readmission following BE. Targeted interventions addressing frailty in hospitalized patients with BE may help reduce readmission rates.

This review explores the ‘gut–lung axis’ in asthma with a focus on commensal fungal organisms. We explore how changes to the intestinal commensal fungal community composition alter lung immune function. We comprehensively review available studies that have profiled the composition of the gut mycobiome in adults and children with asthma, and discuss mechanisms of gut–lung interactions that have been described in animal models of asthma. Studies indicate that intestinal fungal dysbiosis, such as an increased abundance of certain fungi like Candida, can elevate the risk of asthma in children and exacerbate it in adults. This effect is mediated through various pathways: the host immune system’s sensing of dysbiosis via C-type lectin receptors (e.g., Dectin-2), the impact of pro-inflammatory fungal metabolites (e.g., 12,13-diHOME, prostaglandin E2), and the role of lung immune cells (e.g., group 2 innate lymphoid cells [ILC2], M2 macrophages). We also describe strategies for modulating the gut mycobiome as potential therapies for severe asthma. The review concludes by emphasizing the necessity for further research into the role of the gut mycobiome in asthma to deepen our understanding of these complex interactions.

Abstract Overgrowth of the fungus Wallemia mellicola in the intestines of mice enhances the severity of asthma. Wallemia mellicola interacts with the immune system through Dectin-2 expressed on the surface of myeloid and intestinal epithelial cells. Using Dectin-2-deficient mice, we show that the interaction of W. mellicola with Dectin-2 is essential for the gut-lung pathways, enhancing the severity of asthma in mice with W. mellicola intestinal dysbiosis. These findings offer better insight into dysbiosis-associated inflammation and highlight the role pattern recognition receptors have in immune recognition of commensal fungi in the gut, leading to alterations in immune function in the lungs.