Challenges in the management of idiopathic pulmonary fibrosis from a low- and middle-income country.

Idiopathic pulmonary fibrosis (IPF) is the most common progressive form of interstitial lung disease (ILD) that leads to gradual deterioration of lung function and ultimately death. Data from low- and middle-income countries (LMIC) on IPF is scarce. In this communication, we report the challenges encountered in managing IPF from Pakistan's largest tertiary care centre. A total of 108 patients with IPF were evaluated at the Aga Khan University Hospital in Karachi, Pakistan from January 2017 to March 2020. A significant concern was that most patients with IPF presented late during their disease. A bigger challenge encountered in clinical practice was the cost and nonavailability of antifibrotic therapy in the country until mid-2020. Successfully addressing these limitations, it is anticipated that better care will be available for the patients suffering from IPF in this part of the world.

Assessment of the impact of social deprivation, distance to hospital and time to diagnosis on survival in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive condition associated with a variable prognosis. The relationship between socioeconomic status or distance travelled to respiratory clinics and prognosis is unclear. RESEARCH QUESTION: To determine whether socioeconomic status, distance to hospital and time to referral affects survival in patients with IPF. STUDY DESIGN AND METHODS: In this retrospective cohort study, we used data collected from the British Thoracic Society Interstitial Lung Diseases Registry, between 2013 and 2021 (n = 2359) and calculated the quintile of Index of Multiple Deprivation 2019 score, time from initial symptoms to hospital attendance and distance as the linear distance between hospital and home post codes. Survival was assessed using Cox proportional hazards models. RESULTS: There was a significant association between increasing quintile of deprivation and duration of symptoms prior to hospital presentation, Gender Age Physiology (GAP) index and receipt of supplemental oxygen and antifibrotic therapies at presentation. The most deprived patients had worse overall survival compared to least deprived after adjusting for smoking status, GAP index, distance to hospital and time to referral (HR = 1.39 [1.11, 1.73]; p = 0.003). Patients living furthest from a respiratory clinic also had worse survival compared to those living closest (HR = 1.29 [1.01, 1.64]; p = 0.041). INTERPRETATION: The most deprived patients with IPF have more severe disease at presentation and worse outcomes. Living far from hospital was also associated with poor outcomes. This suggests inequalities in access to healthcare and requires consideration in delivering effective and equitable care to patients with IPF.

Assessment and Management of Cough in Idiopathic Pulmonary Fibrosis: A Narrative Review.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease with an unknown cause. It is characterized by symptoms such as cough and breathlessness, which significantly impact patients' quality of life. Cough, in particular, has emerged as a burdensome symptom for individuals with IPF. The etiology of cough in IPF patients is believed to be complex, involving factors related to the disease itself, such as increased sensitivity of cough nerves, lung structural changes, inflammation, and genetic factors, as well as comorbidities and medication effects. Unfortunately, effective treatment options for cough in IPF remain limited, often relying on empirical approaches based on studies involving chronic cough patients in general and the personal experience of physicians. Medications such as opioids and neuromodulators are commonly prescribed but have shown suboptimal efficacy, imposing significant physical, psychological, and economic burdens on patients. However, there is hope on the horizon, as specific purinergic P2 receptor ligand-gated ion channel (P2X3) inhibitors have demonstrated promising antitussive effects in ongoing clinical trials. This review aims to provide a comprehensive overview of the evaluation and management of cough in IPF patients, as well as highlight emerging pharmacological and non-pharmacological approaches that target the cough reflex and are currently being investigated in clinical settings.

Idiopathic pulmonary fibrosis in the United States: time to diagnosis and treatment.

OBJECTIVE: Create a timeline of diagnosis and treatment for IPF in the US. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed in collaboration with the OptumLabs Data Warehouse using an administrative claims database of Medicare Fee for Service beneficiaries. Adults 50 and over with IPF were included (2014 to 2019). EXPOSURE: To focus on IPF, the following diagnoses were excluded: post-inflammatory fibrosis, hypersensitivity pneumonitis, rheumatoid arthritis, sarcoidosis, scleroderma, and connective tissue disease. MAIN OUTCOMES AND MEASURES: Data were collected from periods prior, during, and following initial clinical diagnosis of IPF. This included prior respiratory diagnoses, number of respiratory-related hospitalizations, anti-fibrotic and oxygen use, and survival. RESULTS: A total of 44,891 with IPF were identified. The most common diagnoses prior to diagnosis of IPF were upper respiratory infections (47%), acute bronchitis (13%), other respiratory disease (10%), chronic obstructive pulmonary disease and bronchiectasis (7%), and pneumonia (6%). The average time to a diagnosis of IPF was 2.7 years after initial respiratory diagnosis. Half of patients had two or more respiratory-related hospitalizations prior to IPF diagnosis. Also, 37% of patients were prescribed oxygen prior to diagnosis of IPF. These observations suggest delayed diagnosis. We also observed only 10.4% were treated with anti-fibrotics. Overall survival declined each year after diagnosis with median survival of 2.80 years. CONCLUSIONS AND RELEVANCE: Our retrospective cohort demonstrates that IPF is often diagnosed late, usually preceded by other respiratory diagnoses and hospitalizations. Use of available therapies is low and outcomes remain poor.

Assessment of small airway dysfunction by impulse oscillometry (IOS) in COPD and IPF patients.

OBJECTIVE: Small airway dysfunction is a pathological component of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), and impulse oscillometry is an easy-to-administer, effort-independent non-invasive test reflecting small airway dysfunction. We aimed to compare the impulse oscillometry (IOS) measurements between COPD and IPF patients and investigate their correlation with severity of both diseases and other conventional parameters. PATIENTS AND METHODS: This was a prospective, longitudinal study. We longitudinally evaluated the baseline demographic characteristics, COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale, Pulmonary Function Test (PFT), Carbon Monoxide Diffusing Capacity (DLCO), Hemogram and Impulse Oscillometry measurements of the patients diagnosed with COPD and IPF. RESULTS: The study included 60 IPF patients and 48 COPD patients. The CAT and mMRC scores were higher in COPD patients. The majority of COPD patients were classified into Category B (46%), while 68% of IPF patients had Stage 1 GAP. The mean FEF 25-75%, which is typically considered to reflect small airway disease, was 93% in IPF patients, while it was significantly lower in COPD patients (29%). Impulse oscillometry measurements were consistent with spirometry parameters. IOS resistance and reactance values were significantly higher in COPD patients than in IPF patients. CONCLUSIONS: IOS is advantageous in COPD and IPF patients who cannot exhale due to severe dyspnea, as it is easy to administer and reflects small airway resistance better. Diagnosis of small airway dysfunction may be beneficial in the management of patients with IPF and COPD.

Disparities in Antifibrotic Medication Utilization Among Veterans With Idiopathic Pulmonary Fibrosis.

BACKGROUND: Two antifibrotic medications, pirfenidone and nintedanib, are approved for the treatment of idiopathic pulmonary fibrosis (IPF). Little is known about their real-world adoption. RESEARCH QUESTION: What are the real-world antifibrotic utilization rates and factors associated with uptake among a national cohort of veterans with IPF? STUDY DESIGN AND METHODS: This study identified veterans with IPF who received care either provided by the Veterans Affairs (VA) Healthcare System or non-VA care paid for by the VA. Patients who had filled at least one antifibrotic prescription through the VA pharmacy or Medicare Part D between October 15, 2014, and December 31, 2019, were identified. Hierarchical logistic regression models were used to examine factors associated with antifibrotic uptake, accounting for comorbidities, facility clustering, and follow-up time. Fine-Gray models were used to evaluate antifibrotic use by demographic factors, accounting for the competing risk of death. RESULTS: Among 14,792 veterans with IPF, 17% received antifibrotics. There were significant disparities in adoption, with lower uptake associated with female sex (adjusted OR, 0.41; 95% CI, 0.27-0.63; P < .001), Black race (adjusted OR, 0.60; 95% CI, 0.49-0.73; P < .001), and rural residence (adjusted OR, 0.88; 95% CI, 0.80-0.97; P = .012). Veterans who received their index diagnosis of IPF outside the VA were less likely to receive antifibrotic therapy (adjusted OR, 0.15; 95% CI, 0.10-0.22; P < .001). INTERPRETATION: This study is the first to evaluate the real-world adoption of antifibrotic medications among veterans with IPF. Overall uptake was low, and there were significant disparities in use. Interventions to address these issues deserve further investigation.

Evaluation for clinical benefit of metformin in patients with idiopathic pulmonary fibrosis and type 2 diabetes mellitus: a national claims-based cohort analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high morbidity and limited treatment options. Type 2 diabetes mellitus (T2DM) is a common comorbid illness among patients with IPF and is often treated with metformin, the first-line agent in the management of T2DM. There is growing evidence demonstrating metformin's anti-fibrotic properties; however, there is little real-world clinical data regarding its potential effectiveness in IPF. This study aims to evaluate the clinical benefit of metformin in patients with IPF and T2DM. METHODS: This nationwide cohort study used de-identified administrative claims data from OptumLabs® Data Warehouse to identify 3599 adults with IPF and concomitant T2DM between January 1, 2014 and June 30, 2019. Two cohorts were created: a cohort treated with metformin (n = 1377) and a cohort not treated with metformin (n = 2222). A final 1:1 propensity score-matched cohort compared 1100 patients with IPF and T2DM receiving metformin to those with both diagnoses but not receiving metformin; matching accounted for age, sex, race/ethnicity, residence region, year, medications, oxygen use, smoking status, healthcare use, and comorbidities. Outcomes were all-cause mortality (primary) and hospitalizations (secondary). RESULTS: Among 2200 patients with IPF and T2DM included in this matched analysis, metformin therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.36-0.58; p < 0.001) and hospitalizations (HR, 0.82; 95% CI, 0.72-0.93; p = 0.003) compared to patients not receiving metformin. CONCLUSIONS: Among patients with IPF and T2DM, metformin therapy may be associated with improved clinical outcomes. However, further investigation with randomized clinical trials is necessary prior to metformin's broad implementation in the clinical management of IPF.

Neighborhood-Level Disadvantage Impacts on Patients with Fibrotic Interstitial Lung Disease.

Rationale: Fibrotic interstitial lung disease (fILD) is a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILD is lacking. Objectives: To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplantation, and mortality in patients with fILD from the United States and Canada. Methods: We performed a multicenter, international, prospective cohort study of 4,729 patients with fILD from one U.S. and eight Canadian ILD registry sites. Neighborhood-level disadvantage was measured by the area deprivation index in the United States and the Canadian Index of Multiple Deprivation in Canada. Measurements and Main Results: In the U.S. but not in the Canadian cohort, patients with fILD living in neighborhoods with the greatest disadvantage (top quartile) experience the highest risk of mortality (hazard ratio = 1.51, P = 0.002), and in subgroups of patients with idiopathic pulmonary fibrosis, the top quartile of disadvantage experienced the lowest odds of lung transplantation (odds ratio = 0.46, P = 0.04). Greater disadvantage was associated with reduced baseline DLCO in both cohorts, but it was not associated with baseline FVC or FVC or DLCO decline in either cohort. Conclusions: Patients with fILD who live in areas with greater neighborhood-level disadvantage in the United States experience higher mortality, and patients with idiopathic pulmonary fibrosis experience lower odds of lung transplantation. These disparities are not seen in Canadian patients, which may indicate differences in access to care between the United States and Canada.

The prognostic value of the COPD Assessment Test in fibrotic interstitial lung disease.

BACKGROUND: The COPD Assessment Test (CAT) has been studied as a measure of health status in idiopathic pulmonary fibrosis (IPF) and interstitial lung disease associated with connective tissue disease. However, its prognostic value is unknown. The present study explored the association between CAT score and mortality in fibrotic interstitial lung disease (FILD), including IPF and other forms of ILD. METHODS: We retrospectively analyzed 501 consecutive patients with FILD who underwent clinical assessment, including pulmonary function test and CAT. The association between CAT score and 3-year mortality was assessed using Cox proportional hazard analysis, Kaplan-Meier plots, and the log-rank test for trend. To handle missing data, the imputed method was used. RESULTS: The patients' median age was 68 years, and 320 were male (63.9%). Regarding CAT severity, 203 patients had a low impact level (score <10), 195 had a medium level (10-20), 80 had a high level (21-30), and 23 had a very high level (31-40). During the 3-year study period, 118 patients died. After adjusting for age, sex, forced vital capacity, diffusion capacity for carbon monoxide, IPF diagnosis, and usual interstitial pneumonia pattern on high-resolution computed tomography, the CAT score was significantly associated with 3-year mortality (hazard ratio in increments of 10 points: 1.458, 95% confidence interval 1.161-1.830; p < 0.001). In addition, patients with high and very high impact levels had twofold and threefold higher mortality risk than those with low levels, respectively. CONCLUSION: The CAT has prognostic value in FILD.

R-scale for pulmonary fibrosis: a simple, visual tool for the assessment of health-related quality of life.

RATIONALE: Patients with idiopathic pulmonary fibrosis (IPF) experience impaired health-related quality of life (HRQoL). Several tools have been developed to objectively assess HRQoL in this patient population, but none are in use in routine clinical practice. OBJECTIVES: To develop a rapid, specific tool that can be used for patients with IPF during routine clinic visits. METHODS: A novel and simple five-item numerical rating scale was developed and compared with two other previously validated tools. 100 consecutive patients with IPF managed at a centre for interstitial lung disease were recruited to complete the Raghu scale for pulmonary fibrosis (R-Scale-PF), King's Brief Interstitial Lung Disease questionnaire (K-BILD), and the EuroQol Five-Dimensional Five-Level questionnaire (EQ-5D-5L) in addition to pulmonary function and 6-min walk tests. MEASUREMENTS AND MAIN RESULTS: All 100 patients successfully completed the three HRQoL tools with 53 completing them again at follow-up visits. Internal consistency was high (Cronbach's α 0.825) with minimal floor/ceiling effect. Concurrent validity of the R-Scale-PF was moderate to high compared with the K-BILD (r=-0.713) and the EQ-5D-5L (r=-0.665). Concurrent validity was moderate with physiologic measures (forced vital capacity, r=-0.307, 6-min walking distance, r=-0.383). The R-Scale-PF demonstrated good known-groups validity when comparing scores across stages of disease severity. CONCLUSIONS: The R-Scale-PF correlates well with the K-BILD and EQ-5D-5L. It is hoped that this novel simple numerical rating scale tool, subject to validation in patients from other centres, will provide an opportunity to objectively measure HRQoL in routine clinical practice for patients with IPF.

Longitudinal serological assessment of type VI collagen turnover is related to progression in a real-world cohort of idiopathic pulmonary fibrosis.

BACKGROUND: Remodeling of the extracellular matrix (ECM) is a central mechanism in the progression of idiopathic pulmonary fibrosis (IPF), and remodeling of type VI collagen has been suggested to be associated with disease progression. Biomarkers that reflect and predict the progression of IPF would provide valuable information for clinicians when treating IPF patients. METHODS: Two serological biomarkers reflecting formation (PRO-C6) and degradation (C6M) of type VI collagen were evaluated in a real-world cohort of 178 newly diagnoses IPF patients. All patients were treatment naïve at the baseline visit. Blood samples and clinical data were collected from baseline, six months, and 12 months visit. The biomarkers were measured by competitive ELISA using monoclonal antibodies. RESULTS: Patients with progressive disease had higher (P = 0.0099) serum levels of PRO-C6 compared to those with stable disease over 12 months with an average difference across all timepoints of 12% (95% CI 3-22), whereas C6M levels tended (P = 0.061) to be higher in patients with progressive disease compared with stable patients over 12 months with an average difference across all timepoints of 12% (95% CI - 0.005-27). Patients who did not receive antifibrotic medicine had a greater increase of C6M (P = 0.043) compared to treated patients from baseline over 12 months with an average difference across all timepoints of 12% (95% CI - 0.07-47). There were no differences in biomarker levels between patients receiving pirfenidone or nintedanib. CONCLUSIONS: Type VI collagen formation was related to progressive disease in patients with IPF in a real-world cohort and antifibrotic therapy seemed to affect the degradation of type VI collagen. Type VI collagen formation and degradation products might be potential biomarkers for disease progression in IPF.

Pirfenidone vs. nintedanib in patients with idiopathic pulmonary fibrosis: a retrospective cohort study.

BACKGROUND: Two antifibrotic drugs, pirfenidone and nintedanib, are licensed for the treatment of patients with idiopathic pulmonary fibrosis (IPF). However, there is neither evidence from prospective data nor a guideline recommendation, which drug should be preferred over the other. This study aimed to compare pirfenidone and nintedanib-treated patients regarding all-cause mortality, all-cause and respiratory-related hospitalizations, and overall as well as respiratory-related health care costs borne by the Statutory Health Insurance (SHI). METHODS: A retrospective cohort study with SHI data was performed, including IPF patients treated either with pirfenidone or nintedanib. Stabilized inverse probability of treatment weighting (IPTW) based on propensity scores was applied to adjust for observed covariates. Weighted Cox models were estimated to analyze mortality and hospitalization. Weighted cost differences with bootstrapped 95% confidence intervals (CI) were applied for cost analysis. RESULTS: We compared 840 patients treated with pirfenidone and 713 patients treated with nintedanib. Both groups were similar regarding two-year all-cause mortality (HR: 0.90 95% CI: 0.76; 1.07), one-year all cause (HR: 1.09, 95% CI: 0.95; 1.25) and respiratory-related hospitalization (HR: 0.89, 95% CI: 0.72; 1.08). No significant differences were observed regarding total (€- 807, 95% CI: €- 2977; €1220) and respiratory-related (€- 1282, 95% CI: €- 3423; €534) costs. CONCLUSION: Our analyses suggest that the patient-related outcomes mortality, hospitalization, and costs do not differ between the two currently available antifibrotic drugs pirfenidone and nintedanib. Hence, the decision on treatment with pirfenidone versus treatment with nintedanib ought to be made case-by-case taking clinical characteristics, comorbidities, comedications, individual risk of side effects, and patients' preferences into account.

Combined assessment of the GAP index and body mass index at antifibrotic therapy initiation for prognosis of idiopathic pulmonary fibrosis.

Antifibrotic therapy (AFT) slows disease progression in patients with idiopathic pulmonary fibrosis (IPF). The Gender-Age-Physiology (GAP) index, was developed based on data at IPF diagnosis before the introduction of AFT and has not been evaluated in the AFT context. Further, recent advances have revealed the importance of body-composition factors in prognosis of IPF treated with AFT. This multi-centre, retrospective study aimed to evaluate the GAP index and body mass index (BMI) at the time of AFT initiation for predicting prognosis in patients with IPF. This study included two patient cohorts of IPF receiving AFT, Hamamatsu cohort (n = 110) and Seirei cohort (n = 119). The distribution of GAP stages I, II, and III was 38.2%, 43.6%, and 18.2%, respectively, in Hamamatsu cohort; in Seirei cohort, it was 41.2%, 50.4%, and 8.4%, respectively. In both cohorts, the GAP index distinctly classified prognosis into three groups (log-rank test). Interestingly, a lower BMI showed prognostic value independent of the GAP index in multivariate analyses. Subsequently, combining the GAP index with BMI at AFT initiation successfully divided the patients with IPF into four distinct prognoses. Assessment of the GAP index and BMI measurement at AFT initiation are important for predicting prognosis in patients with IPF.

Labial salivary gland assessment in idiopathic pulmonary fibrosis patients with sicca symptoms.

OBJECTIVE: Patients with idiopathic pulmonary fibrosis (IPF) commonly present with sicca symptoms. This study aimed to assess labial minor salivary glands (LMSGs) in those patients to rule out Sjögren's syndrome (SS), in which sicca symptoms are the clinical hallmark. STUDY DESIGN: Cases of patients with IPF with sicca symptoms referred to the oral medicine clinic at the University of Florida within the last 13 years were selected with institutional review board approval. Demographic characteristics, clinical findings, laboratory results, and histomorphologic parameters were retrospectively analyzed. RESULTS: A total of 12 patients (9 men and 3 women, ages 55-76 years) were identified. History of exposure to asbestos or chemicals, smoking, and medication information was obtained. All patients reported sicca symptoms with 57% of those exhibiting objective or borderline dryness. Anti-SSA/Ro and anti-SSB/La were positive in 25% and 8% of the cases, respectively. Microscopically, 1 out of 12 patients was biopsy positive in the absence of anti-SSA/Ro, fulfilling the 2016 SS criteria with positive sialometry. CONCLUSIONS: A LMSG biopsy is critical to identify SS in patients with diagnosed IPF and present sicca symptoms, especially those with negative serology, as revealed in our study.

Idiopathic pulmonary fibrosis: exploring the clinical and economic implications of the evolving treatment landscape.

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia, a form of interstitial lung disease characterized by abnormal wound healing in the lung that leads to progressive scarring and loss of lung function. Comorbidities are highly prevalent in IPF and often lead to further complications and worse outcomes. In fact, undetected and untreated comorbidities are independently associated with poor outcomes. IPF not only affects patient quality of life (QOL) but also requires significant cost for delivering care. Given the potential for rapid progression of IPF and the associated risk for mortality, early diagnosis is critical for retaining the highest lung function and QOL for as long as possible. Delayed diagnosis of IPF is associated with increased costs in terms of investigations performed, and delayed referral can result in lower survival rates independent of disease severity or associated prognostic factors. Significant progress has been made in understanding IPF pathogenesis, which has, in turn, led to the development of novel therapeutic options that improve outcomes, extend life, and minimize disease burden on patients' daily lives. For patients with IPF in the absence of underlying liver disease, pirfenidone and nintedanib are licensed for the treatment of IPF. Additionally, a number of investigational therapeutic options are currently in development. The extent of clinical effectiveness compared with the cost of therapy has led to a lack of consensus on the cost-vs-benefit analyses for the drugs.

Histopathologic Assessment of Suspected Idiopathic Pulmonary Fibrosis: Where We Are and Where We Need to Go.

CONTEXT.­: Accurate diagnosis of idiopathic pulmonary fibrosis (IPF) requires multidisciplinary diagnosis that includes clinical, radiologic, and often pathologic assessment. In 2018, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and the Latin American Thoracic Society (ATS/ERS/JRS/ALAT) and the Fleischner Society each published guidelines for the diagnosis of IPF, which include criteria for 4 categories of confidence of a histologic usual interstitial pneumonia (UIP) pattern. OBJECTIVE.­: To (1) identify the role of the guidelines in pathologic assessment of UIP; (2) analyze the 4 guideline categories, including potential areas of difficulty; and (3) determine steps the Pulmonary Pathology Society and the greater pulmonary pathology community can take to improve current guideline criteria and histopathologic diagnosis of interstitial lung disease. DATA SOURCES.­: Data were derived from the guidelines, published literature, and clinical experience. CONCLUSIONS.­: Both guidelines provide pathologists with a tool to relay to the clinician the likelihood that a biopsy represents UIP, and serve as an adjunct, not a replacement, for traditional histologic diagnosis. There are multiple challenges with implementing the guidelines, including (1) lack of clarity on the quantity and quality of histologic findings required, (2) lack of recognition that histologic features cannot be assessed independently, and (3) lack of guidance on how pathologists should incorporate clinical and radiographic information. Current criteria for "probable UIP" and "indeterminate for UIP" hinder accurate reflection of the likelihood of IPF. These challenges highlight the need for further morphologic-based investigations in the field of pulmonary pathology.

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial.

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120.