Gyimah, C

Abstract Introduction Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by NADPH oxidase defects, leading to impaired reactive oxygen species (ROS) production and defective intracellular pathogen killing. Typically diagnosed in childhood, CGD manifests as recurrent infections by catalase-positive bacteria and fungi. Immune dysregulation with hyperinflammatory responses may occur even without infection. We present a case of severe immune dysregulation in CGD with concomitant pulmonary nocardiosis. Case Summary A 37-year-old man presented with one month of progressive productive cough, fevers, malaise, vomiting, poor oral intake and high ileostomy output. He was diagnosed with X-linked CGD at age 5 which was complicated by recurrent skin infections and fulminant colitis requiring subtotal colectomy. Laboratory studies showed elevated WBC and CRP of 282.77mg/l. CT scan of chest showed widespread pulmonary nodules and dense consolidation in the left upper lobe with heterogeneous diminished enhancement suggesting necrosis (Fig 1). Cell-free pathogen DNA sequencing testing on sputum identified Nocardia cyriacigeorgica DNA. Fungal cultures on bronchoalveolar lavage grew Nocardia cyriacigeorgica. He was treated with imipinem-cilastin, sulfamethoxazole-trimethoprim, and posaconazole. His course was complicated by refractory fevers (T.max 40.5 C), septic shock, and ARDS. He had two episodes of extubation failure characterized by sudden recrudescence of fever, hemodynamic change, and worsening oxygenation. Each of these episodes occurred during steroid tapers and improved after reinitiating full stress doses. Immune dysregulation was suspected, and he was maintained on 0.8mg/kg/day of methylprednisone with plans for a prolonged taper. He gradually improved, was weaned off oxygen, and discharged home. Discussion Pulmonary nocardiosis is common in CGD, particularly without prophylaxis. Case series report that some patients fail to improve with antimicrobials alone and require adjunctive corticosteroids to control excessive inflammation, as seen in this patient. Immune dysregulation in CGD involves both defective microbial killing and excessive inflammation. Absent ROS results in persistent NF-κB and inflammasome activation, driving production of pro-inflammatory cytokines, leading to granuloma formation, autoimmunity, and IBD-like colitis. Granulomatous inflammation may cause gastrointestinal or genitourinary obstruction, and up to half of patients develop colitis. Exaggerated inflammatory responses to infection or environmental triggers can also mimic hemophagocytic lymphohistiocytosis (HLH). Concurrent susceptibility to infections and inflammation complicates diagnosis and management. Corticosteroids remain first-line for inflammatory episodes and may be combined with antibiotics, as in disseminated nocardiosis, to control hyperinflammation. However, long-term use is limited by adverse effects, and steroid-sparing agents lack proven efficacy in CGD. Hematopoietic stem cell transplantation remains the only curative option in CGD. This abstract is funded by: None

Abstract Rationale Patients with idiopathic pulmonary fibrosis (IPF) living in disadvantaged neighborhoods have worse composite outcomes and pulmonary function. Although the current FDA approved drugs reduce lung function decline and may improve mortality for this progressive and fatal disease, equitable access to therapy remains a challenge, which may be contributing to low antifibrotic uptake. Existing understanding of social determinants of health in IPF is derived from local registries and special subpopulations, such as Veterans. The aim of our study is to investigate the association between neighborhood-level deprivation indicators and both the distribution of patients with IPF and outcomes in a large national database. Methods We performed a retrospective cohort analysis between October 1st, 2014, and December 31st 2022, using the Optum Labs Data Warehouse, a large de-identified administrative claims database. We used claims data from commercial, Medicare Advantage, and Medicare Fee-for-Service enrollees across the United States. Diagnosis of IPF was defined using ICD-9 and ICD-10 codes. Social deprivation index (SDI), assessed at the zip code tabulation area level, was determined based on 7 demographic characteristics from the 2015-2019 American Community Survey. Patients were grouped in quintiles based on SDI at diagnosis, where higher values reflect greater deprivation. Hazard ratios (HR) were calculated for all-cause mortality as primary and hospitalization as secondary outcome. Results A total of 96,143 patients (mean age 75.1 years ± 6.9 years) were included in the study, 23.5% received antifibrotics. As area deprivation increased, proportion of female, Black, and Hispanic patients increased, whereas, proportion of male, White, and Asian patients decreased. Similarly, antifibrotic use declined slightly, while prescription of steroids and oxygen increased with SDI. Residing in most disadvantaged neighborhoods increased risk of hospitalization (HR, 1.13 [95% CI 1.09 - 1.17] and all-cause mortality (HR, 1.15 [95% CI 1.11 - 1.19]) after adjusting for covariates over median follow-up of 301 days and 680 days, respectively. Conclusion Gender and racial disparities were evident among IPF patients who live in resource-limited areas. Our study shows that greater proportion of female, Black, and Hispanic IPF patients were disproportionately represented in more socioeconomically deprived areas. Furthermore, as area-level disadvantage increased, fewer patients received antifibrotics, while more patients were on steroids and oxygen therapy potentially indicating more advanced disease. Moreover, living in disadvantaged neighborhoods was associated with worse all-cause mortality and hospitalizations. Identifying individuals who live in socioeconomically disadvantaged areas is essential to provide equitable care and improve outcomes for this life-threatening disease. This abstract is funded by: None

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing interstitial lung disease that continues to have high morbidity and mortality. There are only 3 approved medications, (nintedanib, pirfenidone and nerandomilast) which marginally slow FVC decline and only nerandomilast having some mortality benefit. All three have no effect on quality of life (exacerbations and hospitalizations). There is an urgent need to find more effective treatment options. Since IPF is predominantly a disease of the elderly with a peak prevalence in those 65 and older, it is common for these individuals to have other comorbidities such as Hyperlipidemia (HLD). Interestingly, in a prior small study of IPF patients, there is evidence to suggest clinical benefit from ezetimibe, a medication used to treat HLD. This study aims to further evaluate the clinical benefits of ezetimibe in patients with IPF in a large national cohort. Methods We conducted this study using the Optum Labs Data Warehouse (OLDW). The OLDW contains de-identified administrative claims data, including medical and pharmacy claims and enrollment records. This study used claims data from commercial, Medicare Advantage (MA), and Medicare Fee-for-service (FFS) enrollees between October 1st, 2014, and December 31st, 2021. Diagnosis of IPF was defined using ICD-9 and ICD-10 codes. Patients without a diagnosis of IPF were excluded. P < 0.05 was set to determine statistical significance. Two matched patient cohorts depending on ezetimibe use were defined. Primary outcome was all-cause mortality, and secondary outcome was hospitalizations. Results We identified 7724 patients with IPF. After adjusting for age, age group, gender, race, health plan, year of IPF diagnosis, smoking, diabetes, statin treatment, and antifibrotic treatment, two cohorts were identified and matched, patients treated with ezetimibe (n = 3862) and patients not treated with ezetimibe (n = 3862). Among the patients with IPF treated with ezetimibe, ezetimibe use was associated with a reduction in all-cause mortality (hazard ratio [95% CI]: 0.704 [0.660 - 0.752], p-value: <0.001) and hospitalizations(hazard ratio [95% CI]: 0.907 [0.857 - 0.959], p-value: 0.001) compared to patients not treated with ezetimibe. Conclusion In patients with IPF, treatment with ezetimibe may be associated with improved clinical outcomes. Further studies are necessary to confirm benefits, assess anti-fibrotic effects, and inform implementation in management of IPF. As IPF remains a disease with limited treatment options, repurposing drugs continues to offer an avenue to find affordable, safe and already approved medications for use. This abstract is funded by: None