Idiopathic pulmonary fibrosis: Molecular mechanisms and potential treatment approaches

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.     

Predictors of acute exacerbation in biopsy-proven idiopathic pulmonary fibrosis

BackgroundAcute exacerbation (AE) is a major cause of death in patients with idiopathic pulmonary fibrosis (IPF). Current evidence on AE-IPF has been largely based on clinical, rather than pathological, analyses.MethodsWe investigated AE incidence and its predictors using clinical, radiological, and pathological data of patients diagnosed with IPF by multi-disciplinary discussion.This study, a secondary analysis of previous research, included 155 patients with IPF who underwent surgical lung biopsy (SLB). Cumulative AE incidence was evaluated by the Kaplan–Meier method. Predictors of AE-IPF were analyzed with a Fine-Gray sub-distribution hazard model. Sub-analysis was performed using propensity score-matching analysis.ResultsIn this cohort, the median age of the patients was 66 years and the median percent-predicted forced vital capacity was 82.8%. The cumulative AE incidence rates at 30 days and one year post SLB were 1.9% and 7.6%, respectively. On multivariable analysis, a lower percent-predicted diffusing capacity of the lung for carbon monoxide (%DL_CO) (hazard ratio 0.98 per 1% increase, P = 0.02) and fibroblastic foci (FF)-present (vs. absent; hazard ratio 3.01, P = 0.04) were independently associated with a higher incidence of AE. The propensity score-matching analysis with adjustment for age, gender, and %DL_CO revealed that the cumulative AE incidence rate was significantly higher in the FF-present subgroup than in the FF-absent subgroup (1-year incidence rate, 10.5% vs. 0%, respectively; P = 0.04 by Gray's test).ConclusionsFF and %DL_CO were independent predictors of AE in patients with biopsy-proven IPF. FF may be associated with the pathogenesis of AE-IPF.     

A modified GAP model for East-Asian populations with idiopathic pulmonary fibrosis

BackgroundThe easy-to-calculate gender, age, and lung physiology (GAP) model shows good predictive and discriminative performance in the prognosis of idiopathic pulmonary fibrosis (IPF). However, the GAP model was not effective in predicting the prognosis accurately in previous Japanese and Korean IPF cohort studies. Therefore, we developed a modified GAP model for the East-Asian populations by weighing the GAP variables. The validity of the modified GAP model was subsequently evaluated in East-Asian IPF patients.MethodsThe derivation cohort comprised 326 patients with IPF. Weights of the variables were adjusted on the basis of coefficients derived from Cox regression models. The total points were distributed to the three stages of the disease so that the number of patients included in each stage was appropriate. The validity of the modified model was analyzed in another Japanese cohort of 117 patients with IPF and a nationwide cohort of Korean patients with IPF.ResultsPredicted survival rates differed significantly in the derivation cohort using the modified GAP model for each stage of IPF (log-rank test: stage I vs. stage II, p < 0.001; stage II vs. stage III, p < 0.001). Model performance improved according to Harrell's C-index (at three years: 0.696 in the original GAP model to 0.738 in the modified model). The performance of the modified model was validated in the Japanese validation and Korean national cohorts.ConclusionsOur modification of the original GAP model showed improved performance in East-Asian IPF patient populations.     

The role of viral infections in pulmonary exacerbations of patients with non-cystic fibrosis bronchiectasis: A systematic review

BackgroundBronchiectasis is a cause of increased morbidity of the respiratory system. Exacerbations among patients with non-CF (cystic fibrosis) bronchiectasis result in reduced pulmonary function and poor quality of life. While the role of bacteria in triggering exacerbations in patients with non- CF bronchiectasis has been well studied, little is known about viral infections in these patients. We aimed to review the evidence on the role of respiratory viruses in the exacerbations of non-CF bronchiectasis.MethodsRelevant literature was searched on the MEDLINE/PubMed database. Seven studies satisfied the criteria and were included in this review.ResultsAccording to the included articles, respiratory viruses are often identified in exacerbations of patients with non-CF bronchiectasis with the most frequent being human rhinovirus and influenza viruses. When a virus is isolated during an exacerbation patients have more symptoms from the upper respiratory tract. One study showed that detection of Epstein- Barr virus among patients with non-CF bronchiectasis is correlated with faster reduction of pulmonary function and progression of the disease.ConclusionViruses seem to have a role in the exacerbation of patients with non-CF bronchiectasis. However, the exact nature and importance of this role remain elusive. Viruses are also isolated during the stable period of the disease. Further well-designed studies are necessary to clarify this complex issue.     

Clinical course and prognosis in survivors of acute exacerbations of idiopathic pulmonary fibrosis

BackgroundPatients with idiopathic pulmonary fibrosis (IPF) are at risk of acute exacerbations (AEs) that manifest as respiratory distress. However, the clinical course after AEs of IPF (AE-IPFs) has not been well described. Therefore, we aimed to elucidate the clinical course and prognosis in survivors of AE-IPFs.MethodsConsecutive patients with IPF who presented to our institution with their first AE-IPFs between January 2008 and December 2019 were included in this study. Data were retrospectively collected, and the clinical course, survival, and cause of death were further analyzed.ResultsNinety-seven patients were included in this retrospective study. Among them, 67 (69.1%) were discharged alive, with a median survival time after discharge of 1081 days. AE recurrence and pneumonia were the most common causes of death, each accounting for 22.2% of cases among survivors of AE-IPFs. AEs were the most frequent during the first 3 years after discharge, whereas pneumonia was more common thereafter.ConclusionsSurvivors of AE-IPFs have a relatively favorable long-term prognosis. Among the survivors of first AE-IPFs, AE recurrence and pneumonia were the most common causes of death after discharge. Therefore, preventing AE recurrence and lung infections is crucial for prolonging survival in survivors of AE-IPFs.     

Pulse oximetry saturation can predict prognosis of idiopathic pulmonary fibrosis

BackgroundIn Japan, the severity staging system for idiopathic pulmonary fibrosis (IPF) has been used to determine medical care subsidies. However, this system requires invasive procedures to measure arterial oxygen tension. Recently, noninvasive and simple measurements of oxygen saturation by pulse oximetry (SpO₂) have been used for severity assessments. We propose a pulse oximetry saturation (POS) staging system consisting of SpO₂ parameters to predict prognosis.MethodsWe developed four prototype staging systems based on SpO₂ at rest and desaturation, and adopted the system with the highest C-statistic as the POS staging system. The cutoff SpO₂ values at rest were 96% and 90%, and desaturation was defined as SpO₂ < 90% at the end of the 6-min-walk test.ResultsTwo-hundred and nineteen IPF patients were studied and the C-statistic values of models 1, 2, 3, and 4 were 0.633, 0.643, 0.630, and 0.673, respectively. We judged model 4 to be a superior POS staging system; it defined SpO₂ ≥ 96% at rest without desaturation as stage Ⅰ; SpO₂ ≥ 96% at rest with desaturation or SpO₂ 90%–95% at rest without desaturation as stage Ⅱ; and SpO₂ 90%–95% at rest with desaturation or SpO₂ < 90% at rest as stage Ⅲ. The hazard ratios of POS stage Ⅰ, Ⅱ, and Ⅲ were 1.00, 2.25, and 4.99, respectively. The C-statistic of the POS staging system produced from 1000 bootstrap samples was similar (0.673), suggesting good internal validation.ConclusionA noninvasive and simple POS staging system defined by SpO₂ can easily predict prognosis.     

Characteristics and association with survival of respiratory-related hospitalization in Japanese idiopathic pulmonary fibrosis patients

BackgroundThe characteristics and significance of respiratory-related hospitalization in patients with idiopathic pulmonary fibrosis (IPF) in Asian countries remain unknown. The purpose of this study was to define the characteristics of respiratory-related hospitalization and to inspect the relationship between respiratory-related hospitalization and subsequent survival in patients with IPF in Japanese general practice.MethodsPatients with IPF who underwent clinical evaluation between February 2008 and August 2017 were screened. Only those who had undergone evaluation within 1 year after the diagnosis of IPF were included in the study. The post-diagnosis pulmonary function tests were considered the registration point. We then performed a 6-month landmark analysis including only patients who were alive 6 months after the registration. The characteristics of respiratory-related hospitalizations during the 6 months after registration and the association between respiratory-related hospitalization and survival were investigated.ResultsA total of 106 patients with IPF were included in the study. The mean forced vital capacity (FVC) at registration was 80.2 ± 25.1% predicted. Seventeen patients (16.0%) had respiratory-related hospitalization during the 6 months after registration. Pneumonia was the most frequent reason for hospitalization (47.0%), followed by acute exacerbation of IPF (29.4%). In multivariate analysis, % predicted FVC (hazard ratio: 0.98, 95% confidence interval: 0.96–0.99, p = 0.004), 6-month decrease in % predicted FVC (1.05, 1.02–1.08, 0.005), and respiratory-related hospitalization (2.45, 1.24–4.85, 0.009) were significantly associated with survival.ConclusionsPneumonia is the most frequent cause of respiratory-related hospitalization in Japanese IPF patients. Furthermore, respiratory-related hospitalization is significantly associated with subsequent poor survival.     

Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF.MethodsThirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated.ResultsThe serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = −0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012).ConclusionThe serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF.     

Safety and tolerability of combination therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A multicenter retrospective observational study in Japan

BackgroundPhase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited.MethodsThe retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records.ResultsNintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender–Age–Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax).ConclusionsReal-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile.     

Extent of pulmonary fibrosis on high-resolution computed tomography is a prognostic factor in patients with pleuroparenchymal fibroelastosis

BackgroundSeveral prognostic factors for pleuroparenchymal fibroelastosis (PPFE) have recently been reported. However, detailed high-resolution computed tomography (HRCT) findings have not yet been evaluated as prognostic factors. This study retrospectively investigated whether HRCT findings are prognostic factors in patients with PPFE compared to those with idiopathic pulmonary fibrosis (IPF).MethodsPatients with PPFE and IPF diagnosed at our hospital between January 2008 and December 2016 were enrolled. Clinical and HRCT characteristics were obtained. In addition to our patients, we also analyzed data of PPFE patients whose cause of death had been identified in previous studies.ResultsWe enrolled 15 patients with PPFE and 75 patients with IPF. Consolidation and maximum pleural thickening were significantly higher in patients with PPFE than in those with IPF (both P < .001). Fibrosis score, honeycomb area, and traction bronchiectasis were not significantly different between these patient groups but were significant prognostic factors in patients with PPFE in univariate analysis (P = .021, P = .017, and P = .014, respectively). The proportions of deaths by acute exacerbation or lung cancer were significantly lower in patients with PPFE than in those with IPF (P < .001 and P = .001, respectively), whereas death by respiratory failure was significantly more frequent in PPFE patients (P < .001).ConclusionsHRCT findings, such as fibrosis score, honeycomb area, and traction bronchiectasis, were independent prognostic factors in patients with PPFE. Respiratory failure, but not acute exacerbation and lung cancer, was the main cause of death in patients with PPFE.     

Bronchoscopy for the diagnosis of nontuberculous mycobacterial pulmonary disease: Specificity and diagnostic yield in a retrospective cohort study

BackgroundBronchoscopy is a recognized method for obtaining specimens for the diagnosis of nontuberculous mycobacterial pulmonary disease (NTM-PD). However, its diagnostic properties remain to be elucidated. The aim of this study was to determine the specificity of bronchoscopy for the diagnosis of NTM-PD, and to examine the diagnostic yield of bronchoscopy for detecting nontuberculous mycobacteria (NTM) when patients cannot expectorate sputum with NTM.MethodsThis retrospective cohort study included 2657 patients who underwent bronchoscopy and mycobacterial culture between January 2004 and June 2018 in a tertiary care center in Tokyo, Japan. To examine the specificity of bronchoscopy, the first cohort comprised patients who underwent bronchoscopy for the diagnosis of lung cancer and mycobacterial culture. To investigate the diagnostic yield, patients with nodular bronchiectasis who underwent bronchoscopy for the diagnosis of NTM-PD were enrolled into the second cohort.ResultsIn total, 919 patients were diagnosed with lung cancer, 19 patients showed positive culture for NTM, and 14 patients showed findings for NTM-PD. Accordingly, the specificity was calculated as 900/905 (99.4%). In addition, NTM-PD was suspected before bronchoscopy in 199 patients; the diagnostic yield was 105/199 (52.8%). Four factors were associated with NTM-PD: upper lobe examination, absence of specific bacteria, absence of connective tissue disease, and a higher total computed tomography score.ConclusionsBronchoscopy has a high specificity for the diagnosis of NTM-PD. In addition, even when NTM is undetected in sputum, bronchoscopy may detect mycobacteria in approximately half of the patients suspected of having NTM-PD.     

Human pancreatic tissue dissociation enzymes for islet isolation: Advances and clinical perspectives

Background and aimsSuccessful clinical human allo or auto-islet transplantation requires the recovery of a sufficient number of functional islets from either brain-dead or chronic pancreatitis pancreases respectively.MethodsIn the last two decades (2000–2019), significant progress has been made in improving the human islet isolation procedures and in standardizing the use of different tissue dissociation enzyme (TDE; a mixture of collagenase and protease enzymes) blends to recover higher islet yields.Results and ConclusionsThis review presents information focusing on properties and role of TDE blends during the islet isolation process, particularly emphasizing on the current developments, associated challenges and future perspectives within the field.     

Prevalence of pulmonary embolism in patients with obstructive sleep apnea and chronic obstructive pulmonary disease: The overlap syndrome

ObjectiveGrowing evidence indicates that both obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) may be closely associated with the prevalence of pulmonary embolism (PE). However, the relationship of overlap syndrome (OS) (coexistence of OSA and COPD) with PE is unclear. The purpose of this study was to investigate whether OS were associated with increased PE prevalence.MethodsWe performed a retrospective chart review of patients who underwent sleep study at Beijing An Zhen Hospital from 2011 to 2014. The association of OS with PE prevalence was estimated by using logistic regression models.ResultsIn contrast to control patients (neither OSA nor COPD), those subjects with OS had higher odds of PE (OR9.61; 95%CI 4.02–21.31, p < 0.001) with significance persisting after adjusting for covariates (OR 5.66; 95%CI 1.80–16.18, p = 0.004). Meanwhile, patients with OS compared with those with isolated OSA also had significantly higher odds of PE in univariate (OR 4.79; 95%CI 2.04–10.33, p = 0.0007) and adjusted models (OR 3.89; 95%CI 1.27–10.68, p = 0.019). In subgroup analysis, patients with OS had higher odds of PE than control group among male subjects (OR 8.12, 95%CI1.86–31.87, p = 0.007) and patients ≥ 58years (OR 5.50, 95%CI 1.51–18.14, p = 0.012) in multivariable models. Percentage of total sleep time with saturation lower than 90% (T90) ≥ 2.6% was significantly associated with prevalence of PE (OR 4.72, 95%CI1.34–19.83, p = 0.015) in subgroup of patients older than 58.ConclusionsOS is independently associated with PE prevalence. Longitudinal studies are needed to better understand the relationship with incident PE.     

Incidence and changes in treatment of acute exacerbation of idiopathic pulmonary fibrosis in Japan: A claims-based retrospective study

BackgroundAcute exacerbation is an essential prognostic factor in idiopathic pulmonary fibrosis (IPF) and is the leading cause of death in Japanese patients with IPF. Its epidemiology, treatment status, and effect on IPF progression have been insufficiently investigated. We examined the incidence of acute exacerbation and treatment status before and after the onset of acute exacerbation in Japanese patients with IPF to provide basic information for treatment strategies.MethodsA Japanese claims database (April 2008–March 2019) from acute-care hospitals was analyzed. Incidence of acute exacerbation, time to the next event, and percentages of patients who received each treatment by the year before and after the onset of acute exacerbation were examined in patients diagnosed with IPF at least once. Acute exacerbation was defined according to the use of steroid pulse therapy.ResultsWe identified 9961 patients with IPF and 2629 acute exacerbations (average age at the time of acute exacerbation: 74.8 years, percentage of men: 79%). The annual incidence of acute exacerbation was approximately 10% between 2010 and 2018. The time to the next acute exacerbation shortened with increasing number of these events. The percentage of patients receiving antifibrotic drugs remained constant (30%–40%) throughout the period. The percentages of patients receiving steroid therapy, immunosuppressive drugs, and oxygen therapy increased after the onset of acute exacerbation compared with before the onset.ConclusionsThe annual incidence of acute exacerbation was approximately 10% in recent years. It is suggested that acute exacerbation worsens respiratory function in patients with IPF.     

Unilateral upper lung-field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis after thoracic surgery: Clinical and radiological courses with autopsy findings

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by pleural and parenchymal involvements predominantly in the upper lobes. Unilateral upper-lung field pulmonary fibrosis (upper-PF) radiologically consistent with PPFE was recently reported in patients with a history of open thoracotomy and presented with impaired thoracic movements in the operated side with unknown mechanisms. This retrospective study aimed to elucidate the clinical and radiological courses and pathological findings of unilateral upper-PF.MethodsAll the consecutive patients diagnosed as having unilateral upper-PF between March 2012 and April 2018 were included. Radiological images and clinical courses before and after the diagnosis were thoroughly reviewed.ResultsFourteen patients were included. Unilateral upper-PF was diagnosed after a median of 4.8 years from the open thoracotomy or video-assisted thoracic surgery for treating lung or esophageal cancer, or bronchiectasis. Before or at diagnosis, 12 (85.7%) of 14 patients developed aberrant intrathoracic/extrathoracic air suggestive of pleural fistula, although the degree was slight. Of note, the upper-PF lesion apparently deteriorated once aberrant air emerged in all the patients. After diagnosis, the upper-PF lesion transformed into cystic lesion in 9 patients, 4 of whom eventually developed pulmonary aspergillosis. The prognosis was poor, with a median overall survival of 49.3 months. The autopsy in one patient demonstrated findings consistent with PPFE and chronic pleuritis.ConclusionsUnilateral upper-PF developed after thoracic surgeries and had many clinical, radiological, and pathological characteristics in common with idiopathic PPFE. Our results indicate that the commonly observed aberrant air may be correlated with disease development and progression.