The UCSD shortness of breath questionnaire has longitudinal construct validity in idiopathic pulmonary fibrosis

SummaryBackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that often causes disabling dyspnea. In IPF and other lung diseases, patient-reported outcomes (PROs)—questionnaires designed to gather information from the patient's perspective—can determine whether therapies affect dyspnea or other outcomes meaningful to patients. Before a PRO can be used confidently as an outcome measure in a longitudinal trial, studies must demonstrate the PRO's ability to capture change over time in the target population. Our goal in this study was to examine whether the UCSD Shortness of Breath Questionnaire does so in patients with IPF.MethodsWe used data from the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP-IPF) to perform analyses that examined associations between UCSD scores and five external measures (anchors) at baseline and over time. Anchors included the Activity domain from St. George's Respiratory Questionnaire (SGRQ-A), the Physical Functioning domain from the SF-36 (SF36-PF), forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and distance walked during a timed walk test (6MWD). Linear regression models were used to examine relationships between UCSD scores and anchors over time.ResultsAt baseline, UCSD scores were weakly correlated with percent predicted FVC (−0.21, p = 0.005) and percent predicted DLCO (−0.20, p = 0.008), moderately correlated with 6MWD (−0.39, p < 0.0001) and strongly correlated with SGRQ-A (0.79, p < 0.0001) and SF36-PF (−0.72, p < 0.0001). Change over time in UCSD scores was associated with change in FVC (estimate = 2.54, standard error [SE] = 1.23, p = 0.04), SGRQ-A (estimate = 7.94, SE = 1.11, p < 0.0001), SF36-PF (estimate = 6.00, SE = 1.13, p < 0.0001), and 6MWD (estimate = 4.23, SE = 1.18, p = 0.0004) but not DLCO (estimate = 0.33, SE = 1.33, p = 0.80).ConclusionsThese results support the validity of the UCSD to assess change in dyspnea over time in patients with IPF

Association of antinuclear antibody seropositivity with inhaled environmental exposures in patients with interstitial lung disease

Background: Interstitial lung diseases (ILDs) are diffuse parenchymal lung disorders that cause substantial morbidity and mortality. In patients with ILD, elevated antinuclear antibody (ANA) titres may be a sign of an autoimmune process. Inhalational exposures contribute to ILD pathogenesis and affect prognosis and may trigger autoimmune disease. The association of inhalational exposures with ANA seropositivity in ILD patients is unknown. Methods: This was a retrospective cohort study of adult ILD patients from five centres in the United States. Exposures to tobacco, inhaled organic antigens and inhaled inorganic particles were extracted from medical records. A multivariable logistic regression model was used to analyse the effects of confounders including age, ILD diagnosis, gender and exposure type on ANA seropositivity. Results: Among 1265 patients with ILD, there were more ANA-seropositive (58.6%, n=741) than ANA-seronegative patients (41.4%, n=524). ANA-seropositive patients had lower total lung capacity (69% versus 75%, p\u3c0.001) and forced vital capacity (64% versus 70%, p\u3c0.001) than patients who were ANA-seronegative. Among patients with tobacco exposure, 61.4% (n=449) were ANA-positive compared to 54.7% (n=292) of those without tobacco exposure. In multivariable analysis, tobacco exposure remained independently associated with increased ANA seropositivity (OR 1.38, 95% CI 1.12-1.71). This significant difference was similarly demonstrated among patients with and without a history of inorganic exposures (OR 1.52, 95% CI 1.12-2.07). Conclusion: Patients with ILD and inhalational exposure had significantly higher prevalence of ANA-seropositivity than those without reported exposures across ILD diagnoses. Environmental and occupational exposures should be systematically reviewed in patients with ILD, particularly those with ANA-seropositivity

Evaluation of Pulmonary Fibrosis Outcomes by Race and Ethnicity in US Adults

Importance: Pulmonary fibrosis (PF) is characterized by progressive scarring of lung tissue and poor survival. Racial and ethnic minority populations face the greatest risk of morbidity and mortality from disparities impacting respiratory health, but the pattern of age at clinically relevant outcomes across diverse racial and ethnic populations with PF is unknown. Objective: To compare the age at PF-related outcomes and the heterogeneity in survival patterns among Hispanic, non-Hispanic Black, and non-Hispanic White participants. Design, setting, and participants: This cohort study included adult patients with a PF diagnosis and used data from prospective clinical registries: the Pulmonary Fibrosis Foundation Registry (PFFR) for the primary cohort and registries from 4 geographically distinct tertiary hospitals in the US for the external multicenter validation (EMV) cohort. Patients were followed between January 2003 and April 2021. Exposures: Race and ethnicity comparisons between Black, Hispanic, and White participants with PF. Main outcomes and measures: Age and sex distribution of participants were measured at the time of study enrollment. All-cause mortality and age at PF diagnosis, hospitalization, lung transplant, and death were assessed in participants over 14 389 person-years. Differences between racial and ethnic groups were compared using Wilcoxon rank sum tests, Bartlett 1-way analysis of variance, and χ2 tests, and crude mortality rates and rate ratios were assessed across racial and ethnic categories using Cox proportional hazards regression models. Results: In total, 4792 participants with PF were assessed (mean [SD] age, 66.1 [11.2] years; 2779 [58.0%] male; 488 [10.2%] Black, 319 [6.7%] Hispanic, and 3985 [83.2%] White); 1904 were in the PFFR and 2888 in the EMV cohort. Black patients with PF were consistently younger than White patients (mean [SD] age at baseline, 57.9 [12.0] vs 68.6 [9.6] years; P Conclusions and relevance: In this cohort study of participants with PF, racial and ethnic disparities, especially among Black patients, were found in PF-related outcomes, including earlier onset of death. Further research is essential to identify and mitigate the underlying responsible factors.</p

Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease

BACKGROUND: Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. METHODS: A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. RESULTS: Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.013 and 0.015 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p=0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p=0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. CONCLUSIONS: A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function

Predictors of survival in coexistent hypersensitivity pneumonitis with autoimmune features.

BackgroundHypersensitivity pneumonitis (HP), an immune-mediated inflammatory interstitial lung disease (ILD), can result from exposure to several well-recognized antigens. Despite antigen avoidance, progressive pulmonary fibrosis and death can occur, suggesting that additional factors may contribute to disease activity. We hypothesized that the presence of autoimmunity might impact clinical course in patients with HP. In this study, we examined an HP cohort to identify those with HP and autoimmune features (HPAF), and determine its prevalence and outcomes.MethodsThe University of Chicago ILD registry was screened to identify patients with HP. Patients were characterized as HPAF if they had an autoimmune disease or features of autoimmunity, defined as the presence of specific connective tissue disease (CTD) symptoms and serologies. Demographics, clinical characteristics, and outcomes were compared between groups. Survival analysis was performed using Cox regression to identify predictors of transplant-free survival in this cohort.ResultsOne hundred twenty patients with chronic, fibrotic HP were identified. Of these, 18/120 (15%) were characterized as HPAF. Compared to those without evidence of autoimmunity, patients with HPAF had a higher proportion of females (54% vs. 83%, respectively; p&nbsp;=&nbsp;0.02) but were otherwise similar with regard to clinical characteristics. The presence of autoimmunity was an independent predictor of increased mortality (HR 4.45; 95% CI 1.43-13.88; p&nbsp;=&nbsp;0.01) after multivariable adjustment.ConclusionsFifteen percent of patients with chronic, fibrotic HP displayed evidence of a concurrent defined autoimmune disease or autoimmune features suggestive of CTD. The presence of autoimmunity in patients with chronic, fibrotic HP may portend a poorer prognosis. Future studies are needed to validate these findings and determine the impact of immunosuppressive treatment

Predictors of survival in coexistent hypersensitivity pneumonitis with autoimmune features.

BackgroundHypersensitivity pneumonitis (HP), an immune-mediated inflammatory interstitial lung disease (ILD), can result from exposure to several well-recognized antigens. Despite antigen avoidance, progressive pulmonary fibrosis and death can occur, suggesting that additional factors may contribute to disease activity. We hypothesized that the presence of autoimmunity might impact clinical course in patients with HP. In this study, we examined an HP cohort to identify those with HP and autoimmune features (HPAF), and determine its prevalence and outcomes.MethodsThe University of Chicago ILD registry was screened to identify patients with HP. Patients were characterized as HPAF if they had an autoimmune disease or features of autoimmunity, defined as the presence of specific connective tissue disease (CTD) symptoms and serologies. Demographics, clinical characteristics, and outcomes were compared between groups. Survival analysis was performed using Cox regression to identify predictors of transplant-free survival in this cohort.ResultsOne hundred twenty patients with chronic, fibrotic HP were identified. Of these, 18/120 (15%) were characterized as HPAF. Compared to those without evidence of autoimmunity, patients with HPAF had a higher proportion of females (54% vs. 83%, respectively; p = 0.02) but were otherwise similar with regard to clinical characteristics. The presence of autoimmunity was an independent predictor of increased mortality (HR 4.45; 95% CI 1.43-13.88; p = 0.01) after multivariable adjustment.ConclusionsFifteen percent of patients with chronic, fibrotic HP displayed evidence of a concurrent defined autoimmune disease or autoimmune features suggestive of CTD. The presence of autoimmunity in patients with chronic, fibrotic HP may portend a poorer prognosis. Future studies are needed to validate these findings and determine the impact of immunosuppressive treatment

Autoimmune Hypothyroidism As a Predictor of Mortality in Chronic Hypersensitivity Pneumonitis

BackgroundChronic hypersensitivity pneumonitis (CHP) is a fibrotic parenchymal lung disease that occurs when inhalation of environmental antigens leads to immune dysregulation. Autoimmune features have recently been identified as potentially important among patients with CHP. However, the relationship between hypothyroidism (HT) and CHP is unknown. In this study, we investigate the prevalence and impact of HT among patients with CHP.MethodsWe conducted a retrospective, case–control analysis. We identified 121 patients at the University of Chicago Interstitial Lung Disease Center with a multidisciplinary diagnosis of CHP. These patients were matched 3:1 according to age, sex, and race to 363 control subjects with asthma from 2006 to 2015. We analyzed demographics, clinical characteristics, and survival between both groups and assessed the relationship of HT with CHP. Survival analysis was performed using Cox proportional hazards modeling.ResultsPatients with CHP had higher prevalence of HT (25.6%, n = 31) compared to controls (10.7%, n = 39; OR, 2.86; 95% CI, 1.62–4.99; P &lt; 0.0001). Compared to CHP alone, patients with CHP/HT were more likely to be female (80.6 vs 51.1%, P = 0.004), have increased incidence of autoimmune disease (19.4 vs 3.3%, P = 0.009), antinuclear antibody seropositivity (80.6 vs 57.0%, P = 0.019), and higher TSH levels (4.0 vs 1.9 mIU/L, P &lt; 0.0001). HT was a significant independent predictor of mortality among CHP patients with seropositive ANA (HR, 3.39; 95% CI, 1.31–8.80; P = 0.012).ConclusionHT is common in patients with CHP and may carry prognostic significance in patients with features of autoimmunity. Further research exploring common pathogenic pathways between autoimmune HT and CHP may illuminate the association of HT with survival

CT Findings, Radiologic-Pathologic Correlation, and Imaging Predictors of Survival for Patients With Interstitial Pneumonia With Autoimmune Features.

ObjectiveThe objective of this study is to determine the CT findings and patterns of interstitial pneumonia with autoimmune features (IPAF) and to assess whether imaging can predict survival for patients with IPAF.Materials and methodsThe study included 136 subjects who met the criteria for IPAF and had diagnostic-quality chest CT scans obtained from 2006 to 2015; a total of 74 of these subjects had pathologic samples available for review within 1 year of chest CT examination. CT findings and the presence of an usual interstitial pneumonitis (UIP) pattern of disease were assessed, as was the UIP pattern noted on pathologic analysis. Analysis of chest CT findings associated with survival was performed using standard univariate and multivariate Cox proportional hazards methods as well as the unadjusted log-rank test. Survival data were visually presented using the Kaplan-Meier survival curve estimator.ResultsMost subjects with IPAF (57.4%; 78/136) had a high-confidence diagnosis of a UIP pattern on CT. Substantially fewer subjects (28.7%; 39/136) had a pattern that was inconsistent with UIP noted on CT. The presence of a UIP pattern on CT was associated with smoking (p &lt; 0.01), male sex (p &lt; 0.01), and older age (p &lt; 0.001). Approximately one-fourth of the subjects had a nonspecific interstitial pneumonitis pattern on CT. Of interest, nearly one-tenth of the subjects had a CT pattern that was most consistent with hypersensitivity pneumonitis rather than the customary CT patterns ascribed to lung disease resulting from connective tissue disease. Most subjects with a possible UIP pattern on CT (83.3%) had UIP diagnosed on the basis of pathologic findings. Focused multivariate analysis showed that honeycombing on CT (hazard ratio, 2.17; 95% CI, 1.05-4.47) and pulmonary artery enlargement on CT (hazard ratio, 2.08; 95% CI, 1.02-4.20) were independent predictors of survival.ConclusionIPAF most often presents with a UIP pattern on CT and is associated with worse survival when concomitant honeycombing or pulmonary artery enlargement is present