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Abstract Extracorporeal blood purification with polymyxin B immobilized fiber column direct hemoperfusion (PMX-DHP), is reported to be effective in treating COVID-19 pneumonitis with oxygen demand. This multicenter prospective study evaluated the efficacy and safety of PMX-DHP in oxygen-requiring patients with COVID-19 admitted between September 28, 2020, and March 31, 2022. The primary endpoint was the percentage of clinical improvement 15 days after treatment. The secondary endpoint was the percentage of worsened disease status. Data from the COVID-19 patient registry were used for the synthetic control group. The improvement rate on Day 15 did not differ between PMX-treated patients and controls; however, the deterioration rate was 0.38 times lower in the PMX-treated group, and the death rates on Day 29 were 0 and 11.1% in the PMX-treated and control groups, respectively. The PMX group showed a 0.73 times higher likelihood for reduced intensive care demand, as 16.7% of PMX-treated patients and 22.8% of controls worsened. After treatment blood oxygenation improved, urinary β2-microglobulin and liver-type fatty acid-binding protein showed significant decreases, and IL-6 decreased once during treatment but did not persist. In this study, PMX treatment effectively prevented the worsening of COVID-19 pathology, accompanied by improved oxygenation. PMX treatment to remove activated cells may effectively improve patient outcomes.

Abstract This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

Introduction Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD).Methods and analysis In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, stratified by background nintedanib use. Patients must be diagnosed with pulmonary fibrosis other than IPF that is progressive, based on predefined criteria. Patients must have forced vital capacity (FVC) ≥45% predicted and haemoglobin-corrected diffusing capacity of the lung for carbon monoxide ≥25% predicted. Patients must be receiving nintedanib for at least 12 weeks, or not receiving nintedanib for at least 8 weeks, prior to screening. Patients on stable treatment with permitted immunosuppressives (eg, methotrexate, azathioprine) may continue their treatment throughout the trial. Patients with clinically significant airway obstruction or other pulmonary abnormalities, and those using immunosuppressives that may confound FVC results (cyclophosphamide, tocilizumab, mycophenolate, rituximab) or high-dose steroids will be excluded. The primary endpoint is absolute change from baseline in FVC (mL) at week 52. The key secondary endpoint is time to the first occurrence of any acute ILD exacerbation, hospitalisation for respiratory cause or death, over the duration of the trial.Ethics and dissemination The trial is being carried out in accordance with the ethical principles of the Declaration of Helsinki, the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The study results will be disseminated at scientific congresses and in peer-reviewed publications.Trial registration number NCT05321082.

Methods and analysis In this placebo-controlled, double-blind, phase III trial, patients are being randomised in a 1:1:1 ratio to receive 9 mg or 18 mg of BI 1015550 or placebo two times per day over at least 52 weeks, stratified by use of background antifibrotics (nintedanib/pirfenidone vs neither). The primary endpoint is the absolute change in FVC at week 52. The key secondary endpoint is a composite of time to first acute IPF exacerbation, hospitalisation due to respiratory cause or death over the duration of the trial.Ethics and dissemination The trial is being carried out in compliance with the ethical principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The results of the study will be disseminated at scientific congresses and in peer-reviewed publications.Trial registration number NCT05321069.

Sarcoidosis is a multisystem disease with an unknown etiology and is characterized by the formation of noncaseating granulomas in the affected organs. We present the case of a 69-year-old male Japanese patient with bilateral hilar lymphadenopathy on chest radiographs for more than 10 years, left without further investigation. The patient reported no clinical symptoms. Chest computed tomography revealed ground-glass opacities and reticular shadows in both lungs, along with bilateral hilar and mediastinal lymphadenopathy. Lymphocytosis was observed in bronchoalveolar lavage fluid. Pathological examination of transbronchial lung biopsy revealed noncaseating, epithelioid granulomas congruous with sarcoidosis, together with other findings. There were no abnormalities on electrocardiogram, echocardiogram, and ophthalmic examination. For progressive dyspnea on exertion, systemic corticosteroid therapy with oral prednisolone (25 mg/day) was initiated in 2017 and gradually tapered. Despite this intervention, the decline in forced vital capacity (FVC) was accelerated. Three years later, the patient noticed swelling in his right wrist. Further investigation revealed elevated anti-cyclic citrullinated peptide antibodies and absence of noncaseating epithelioid granuloma on surgical biopsy, leading to the diagnosis of rheumatoid arthritis (RA). Thereafter, the anti-fibrotic agent nintedanib was initiated, because interstitial lung disease (ILD) was considered to have converted into a progressive fibrosing phenotype (PF-ILD) with overlapping RA-associated lung involvement. With treatment, the progression of decline in FVC was slowed, although home oxygen therapy was introduced.

What is this summary about? This plain language summary describes the main findings from a trial in people with idiopathic pulmonary fibrosis (also called IPF) that was recently published in the New England Journal of Medicine. IPF is a rare disease, where the lungs become more and more scarred, with breathing and oxygen uptake becoming increasingly difficult. This trial looked at the medication BI 1015550 as a potential treatment for IPF. It compared BI 1015550 to placebo (a dummy drug that does not contain any active ingredients) to investigate the effectiveness of the drug in treating people with IPF. The study also looked at the additional medical issues (referred to as adverse events) reported during the study. Some participants took approved treatments to reduce scarring (nintedanib or pirfenidone), and some did not. What were the results? Overall, 147 people with IPF from 22 countries took part in the trial. The results showed that BI 1015550 prevented lung function from decreasing in people with IPF. There was no difference in the percentage of patients with medical issues rated as severe by the study physician with BI 1015550 or placebo. However, more people treated with BI 1015550 had diarrhoea. Among those treated with BI 1015550, 13 participants stopped their treatment due to medical issues, whereas treatment was not stopped due to medical issues for any participants treated with placebo. What do the results mean? These results provide evidence that BI 1015550 prevents lung function from worsening in people with IPF. Further clinical studies will be conducted in the future to test BI 1015550 in a larger group of people with IPF and other forms of lung scarring that get worse over time, and for a longer time period.

BackgroundPolymyxin B-immobilized fiber column (PMX; Toraymyxin column) was approved for the relief of systemic inflammatory response syndrome caused by bacterial infection or endotoxemia. PMX reduces lung damage by removing leukocytes and cytokines in addition to endotoxin removal in the setting of idiopathic pulmonary fibrosis. Acute exacerbation of interstitial pneumonia pathologically presents with diffuse alveolar damage (DAD). PMX direct hemoperfusion (PMX-DHP) demonstrated efficacy, improving oxygenation. The SARS-CoV-2 virus causes COVID-19, which emerged in December 2019. The condition may become severe about 1 week after onset, and respiratory failure rapidly develops, requiring intensive care management. A characteristic of COVID-19–related severe pneumonia is ground-glass opacities rapidly progressing in both lungs, which subsequently turn into infiltrative shadows. This condition could be classified as DAD. As for the congealing fibrinogenolysis system, D-dimer, fibrin/fibrinogen degradation product quantity, and prolonged prothrombin time were significant factors in nonsurviving COVID-19 cases, associated with aggravated pneumonia. Clinical trials are being conducted, but except for remdesivir and dexamethasone, no treatments have yet been approved. COVID-19 aggravates with the deterioration of oxygen saturation, decrease in lymphocytes, and the occurrence of an abnormal congealing fibrinogenolysis system, leading to diffuse lung damage. Once the condition transitions from moderate to severe, it is necessary to prevent further exacerbation by providing treatment that will suppress the aforementioned symptoms as soon as possible. ObjectiveThis study aims to access treatment options to prevent the transition from acute exacerbation of interstitial pneumonia to DAD. The mechanism of action envisioned for PMX-DHP is to reduce congealing fibrinogenolysis system abnormalities and increase oxygenation by removing activated leukocytes and cytokines, which are risk factors for the aggravation of COVID-19–related pneumonia. MethodsWe will conduct a multicenter, prospective, intervention, single-group study to evaluate the efficacy and safety of direct hemoperfusion using PMX-DHP for patients with COVID-19. Efficacy will be evaluated by the primary end point, which is the rate of Ordinal Scale for Clinical Improvement after PMX-DHP of at least 1 point from a status of 4, 5, or 6 on day 15. The effect of PMX-DHP will be estimated by setting a control group with background factors from non–PMX-DHP patients enrolled in the COVID-19 registry. This study will be carried out as a single-group open-label study and will be compared with a historical control. The historical control will be selected from the COVID-19 registry according to age, gender, and severity of pneumonia. ResultsThe study period is scheduled from September 28, 2020, through April 30, 2023. Patient enrollment was scheduled from the Japan Registry of Clinical Trials publication for March 31, 2022. Data fixation is scheduled for October 2022, with the publication of the results by March 2023. ConclusionsFrom a clinical perspective, PMX-DHP is expected to become an adjunctive therapy to address unmet medical needs and prevent the exacerbation from moderate to severe acute respiratory distress syndrome in COVID-19 cases. International Registered Report Identifier (IRRID)DERR1-10.2196/37426

Abstract Background Early detection of cardiac involvement in patients with sarcoidosis is important but currently unresolved. The aim of this study was to elucidate the utility of frequency domain microvolt T‐wave alternans (TWA), signal‐averaged ECG (SAECG), and heart rate turbulence (HRT) using 24‐hour Holter ECG for detecting cardiac involvement in patients with pulmonary sarcoidosis. Methods This study consisted of consecutive 40 pulmonary sarcoidosis patients (11 males, 62 ± 13 years) who underwent 24‐hour Holter monitoring with and without cardiac involvement. All patients underwent frequency domain TWA, SAECG, and HRT using 24‐hour Holter monitoring. Patients with atrial fibrillation pacing or wide QRS electrocardiogram were excluded. Results After 14 patients were excluded, a total of 26 patients (six males, 59 ± 14 years) were evaluated. Seven patients had cardiac involvement (cardiac sarcoidosis [CS] group). On the Holter SAECG, duration of low‐amplitude signals

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone. Methods We conducted a post-hoc analysis of the prospective, multicenter, randomized, placebo-controlled, phase 3 trial of pirfenidone in Japan (total, n = 267; pirfenidone, n = 163; placebo, n = 104). Logistic regression analysis was performed to extract parameters that predicted disease progression, defined by a ≥ 10% relative decline in vital capacity (VC) from baseline and/or death, at week 52. For assessment of serum surfactant protein (SP)-D, SP-A and Krebs von den Lungen (KL)-6, all patients were dichotomized by the median concentration of each biomarker at baseline to the high and low biomarker subgroups. Associations of these concentrations were examined with changes in VC at each time point from baseline up to week 52, along with progression-free survival (PFS). Additionally, the effect of pirfenidone treatment on serial longitudinal concentrations of these biomarkers were evaluated. Results In the multivariate logistic regression analysis, body mass index (BMI), %VC and SP-D in the pirfenidone group, and BMI and %VC in the placebo group were indicated as predictors of disease progression. Pirfenidone treatment reduced the decline in VC with statistical significance in the low SP-D and low SP-A subgroups over most of the treatment period, and also prolonged PFS in the low SP-D and low KL-6 subgroups. Furthermore, SP-D levels over time course were reduced in the pirfenidone group from as early as week 8 until the 52-week treatment period compared with the placebo group. Conclusions Serum SP-D was the most consistent biomarker for the efficacy of pirfenidone in the cohort trial of IPF. Serial measurements of SP-D might have a potential for application as a pharmacodynamic biomarker. Trial registration The clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13, 2005 (registration No. JapicCTI-050121; http://Clinicaltrials.jp )

We experienced a rare case of tubulointerstitial angiocentric granulomatous vasculitis with focal segmental glomerulosclerosis (FSGS) and associated sarcoidosis. Our patient was an 18-year-old man who presented with exertional cough and dyspnea. He also had overt proteinuria (3.0 g/24 h), normal renal function (eGFR 95 mL/min/1.73 m2), heart failure, and hypertension. He had no previous episode of hypertension. These manifestations immediately improved after the administration of antihypertensive therapy that contained an angiotensin-converting enzyme inhibitor, calcium antagonists, beta antagonists, and diuretics. However, he, later on, developed renal dysfunction, with worsening of both proteinuria and hypertension. Renal biopsy was performed and showed epithelioid cells that were arranged concentrically around small blood vessels in tubulointerstitial granulomas. In the glomeruli, the segmental sclerotic lesions were classified as a perihilar variant of FSGS. There were no inflammatory changes, such as a mesangial lesion, inflammatory cell infiltration, fibrinoid necrosis, or crescent formation, and no glomerular granuloma. In the tubulointerstitial granulomas, the intimal elastic lamina of the interlobular arteries was reduplicated, and the intimal wall thickness of renal arterioles was remarkable. After receiving oral prednisolone therapy, the overt proteinuria resolved, the eGFR recovered from 39.4 to 60.6 mL/min/1.73 m2, and hypertension was managed more easily. Thereafter, he did not experience any recurrence. The concurrent improvement of renal function and proteinuria by steroid treatment suggested a relationship between the glomerular lesions and the tubulointerstitial granulomatous vasculitis with associated sarcoidosis.

The disease concept of interstitial lung disease with idiopathic pulmonary fibrosis at its core has been relied on for many years depending on morphological classification. The separation of non-specific interstitial pneumonia with a relatively good prognosis from usual interstitial pneumonia is also based on the perception that morphology enables predict the prognosis. Beginning with dust-exposed lungs, initially, interstitial pneumonia is classified by anatomical pathology. Diagnostic imaging has dramatically improved the diagnostic technology for surviving patients through the introduction of high-resolution computed tomography scan. And now, with the introduction of therapeutics, the direction of diagnosis is turning. It can be broadly classified into to make known the importance of early diagnosis, and to understand the importance of predicting the speed of progression/deterioration of pathological conditions. For this reason, the insight of “early lesions” has been discussed. There are reports that the presence or absence of interstitial lung abnormalities affects the prognosis. Searching for a biomarker is another prognostic indicator search. However, as is the case with many chronic diseases, pathological conditions that progress linearly are extremely rare. Rather, it progresses while changing in response to environmental factors. In interstitial lung disease, deterioration of respiratory functions most closely reflect prognosis. Treatment is determined by combining dynamic indicators as faithful indicators of restrictive impairments. Reconsidering the history being classified under the disease concept, the need to reorganize treatment targets based on common pathological phenotype is under discussed. What is the disease concept? That aspect changes with the discussion of improving prognosis.

Background: TAS-115, a novel multi-kinase inhibitor, demonstrated antifibrotic effects in vitro and in vivo. Methods: This is an open-label, intra-patient comparison, exploratory phase 2 study of TAS-115 to evaluate the efficacy and safety in idiopathic pulmonary fibrosis (IPF) patients when orally administered at 200 mg once daily on a 5-day on and 2-day off regimen for 13 weeks. This study consists of three cohorts: previously treated with pirfenidone (Cohort P, n = 20), with nintedanib (Cohort N, n = 20), and treatment naïve (Cohort U, n = 10). Male or female patients aged ≥40 to

Background Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. Methods Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. Results Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. Conclusion Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it.

Abstract Background Diffuse panbronchiolitis (DPB) is a sinopulmonary disease mainly affecting Asian populations. Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder impairing ciliary structure and function. These two disorders are not easily distinguished by clinical signs and symptoms. Methods In 105 Japanese patients with recurrent sinopulmonary infection, initially diagnosed with DPB, and 37 patients with recurrent airway infection diagnosed in adulthood, the deletion allele of DRC1 or CCDC164, recently recognized as a pathogenic PCD gene variant, was searched using a multiplexed PCR‐based method, and the deletion breakpoints and other variants around the gene were determined by Sanger sequencing and targeted resequencing. Results A large homozygous deletion in DRC1 was identified in three of the 142 patients. Furthermore, heterozygous carriers of the deletion with the same breakpoint were found with the allele frequency of 0.002 in the healthy Japanese population, indicating that this loss‐of‐function variant may be acting as a common mutation causing PCD in Japanese. Conclusion PCD caused by the DRC1 defect is not readily identified by either high‐speed video‐microscopy or ciliary ultrastructure analysis, posing significant difficulties in reaching a correct diagnosis without the aid of genetic tests. Careful investigation of the causes of sinopulmonary diseases is warranted in Asian populations.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Although lymphocytes, especially CD4+CD25+FoxP3+ regulatory T cells (Tregs), have been implicated in the development of IPF, contradictory results have been reported regarding the contribution of Tregs to fibrosis both in animals and humans. The aim of this study was to investigate whether a specific T cell subset has therapeutic potential in inhibiting bleomycin (BLM)-induced murine pulmonary fibrosis. Methods C57BL/6 mice received BLM (100 mg/kg body weight) with osmotic pumps (day 0), and pulmonary fibrosis was induced. Then, splenocytes or Tregs were adoptively transferred via the tail vein. The lungs were removed and subjected to histological and biochemical examinations to study the effects of these cells on pulmonary fibrosis, and blood samples were collected by cardiac punctures to measure relevant cytokines by enzyme-linked immunosorbent assay. Tregs isolated from an interleukin (IL)-10 knock-out mice were used to assess the effect of this mediator. To determine the roles of the spleen in this model, spleen vessels were carefully cauterized and the spleen was removed either on day 0 or 14 after BLM challenge. Results Splenocytes significantly ameliorated BLM-induced pulmonary fibrosis when they were administered on day 14. This effect was abrogated by depleting Tregs with an anti-CD25 monoclonal antibody. Adoptive transfer of Tregs on day 14 after a BLM challenge significantly attenuated pulmonary fibrosis, and this was accompanied by decreased production of fibroblast growth factor (FGF) 9-positive cells bearing the morphology of alveolar epithelial cells. In addition, BLM-induced plasma IL-10 expression reverted to basal levels after adoptive transfer of Tregs. Moreover, BLM-induced fibrocyte chemoattractant chemokine (CC motif) ligand-2 production was significantly ameliorated by Treg adoptive transfer in lung homogenates, accompanied by reduced accumulation of bone-marrow derived fibrocytes. Genetic ablation of IL-10 abrogated the ameliorating effect of Tregs on pulmonary fibrosis. Finally, splenectomy on day 0 after a BLM challenge significantly ameliorated lung fibrosis, whereas splenectomy on day 14 had no effect. Conclusions These findings warrant further investigations to develop a cell-based therapy using Tregs for treating IPF.

Multidisciplinary team (MDT) diagnosis of interstitial lung disease (ILD) has been proposed as a gold standard, but there are no formal recommendations for MDT process or composition and limited knowledge regarding prevalence in routine practice. We performed a systematic evaluation of ILD diagnostic practice across a range of healthcare settings around the world. Electronic questionnaires were distributed across all global regions via society and collaborators networks. Responses from 457 unique centres across 64 countries were included in the analysis. Of the 350 (76.6%) centres holding formal meetings, the majority held face-to-face MDT meetings (80%), for a minimum of 30 min (93%), and discussed diagnosis (96.9%) and patient management (94.9%) at the meetings. Compared with non-academic and academic non-ILD centres, ILD academic centres reported a higher ILD caseload, held more formal MDT meetings, and were more likely to include histopathology and rheumatology specialists in their diagnostic team. Of the centres holding MDT meetings, 5.5% routinely discussed all new cases at such meetings. An MDT approach to ILD diagnosis is consistently interpreted and widely implemented across a range of routine care settings around the world. This observation will inform future ILD diagnostic agreement studies and diagnostic pathway recommendations.

In the present study, we investigated the role of Nrf2 in airway immune responses induced by diesel exhaust (DE) inhalation in mice. C57BL/6J Nrf2+/+ and Nrf2−/− mice were exposed to DE or clean air for 8 h/day and 6 days/week for 4 weeks. After DE exposure, the number of neutrophils and macrophage inflammatory protein (MIP)-2 level in bronchoalveolar lavage fluid (BALF) and interleukin (IL)-17 level in the lung tissue increased in Nrf2−/− mice compared with Nrf2+/+ mice; however, the lack of an increase in the level of tumor necrosis factor (TNF)-α in the lung tissue in Nrf2+/+ mice and mild suppression of the level of TNF-α in Nrf2−/− mice were observed; the level of granulocyte macrophage colony-stimulating factor (GM-CSF) in the lung tissue decreased in Nrf2−/− mice than in Nrf2+/+ mice; the number of DE particle-laden alveolar macrophages in BALF were larger in Nrf2−/− mice than in Nrf2+/+ mice. The results of electron microscope observations showed alveolar type II cell injury and degeneration of the lamellar body after DE exposure in Nrf2−/− mice. Antioxidant enzyme NAD(P)H quinone dehydrogenase (NQO)1 mRNA expression level was higher in Nrf2+/+ mice than in Nrf2−/− mice after DE exposure. Our results suggested that Nrf2 reduces the risk of pulmonary disease via modulating the airway innate immune response caused by DE in mice.

Real-world studies include a broader patient population for a longer duration than randomised controlled trials (RCTs) and can provide relevant insights for clinical practice. PASSPORT was a multicentre, prospective, post-authorisation study of patients who were newly prescribed pirfenidone and followed for 2 years after initiating treatment. Physicians collected data on adverse drug reactions (ADRs), serious ADRs (SADRs) and ADRs of special interest (ADRSI) at baseline and then every 3 months. Post hoc stepwise logistic regression models were used to identify baseline characteristics associated with discontinuing treatment due to an ADR. Patients (n=1009, 99.7% with idiopathic pulmonary fibrosis) had a median pirfenidone exposure of 442.0 days. Overall, 741 (73.4%) patients experienced ADRs, most commonly nausea (20.6%) and fatigue (18.5%). ADRs led to treatment discontinuation in 290 (28.7%) patients after a median of 99.5 days. Overall, 55 (5.5%) patients experienced SADRs, with a fatal outcome in six patients. ADRSI were reported in 693 patients, most commonly gastrointestinal symptoms (38.3%) and photosensitivity reactions/skin rashes (29.0%). Older age and female sex were associated with early treatment discontinuation due to an ADR. Findings were consistent with the known safety profile of pirfenidone, based on RCT data and other post-marketing experience, with no new safety signals observed.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a prognosis that can be worse than for many cancers. The initial stages of the condition were thought to mainly involve chronic inflammation; therefore, corticosteroids and other drugs that have anti-inflammatory and immunosuppressive actions were used. However, recently, agents targeting persistent fibrosis resulting from aberrant repair of alveolar epithelial injury have been in the spotlight. There has also been an increase in the number of available antifibrotic treatment options, starting with pirfenidone and nintedanib. These drugs prevent deterioration but do not improve IPF. Therefore, nonpharmacologic approaches such as long-term oxygen therapy, pulmonary rehabilitation, and lung transplantation must be considered as additional treatment modalities.

Pirfenidone is the first antifibrotic agent to be approved for the treatment of pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is one of the idiopathic interstitial pneumonias with the worst prognoses; approximately half of patients die within 3–5 years, and the need for an effective treatment has been unmet until recently. The etiology of IPF is still unknown and its pathogenesis is poorly understood. Anti-inflammatory drugs, such as corticosteroids and some immunosuppressants, have been empirically used to treat IPF, although they have not been objectively proven to be effective by large-scale randomized, controlled trials. Pirfenidone is an agent that can inhibit the decline of forced vital capacity (FVC)/vital capacity (VC) and that thereby can be hoped to decrease the mortality rate. The number of clinical trials of pirfenidone completed, ongoing, or planned is growing, and the present status of pirfenidone as treatment for IPF is summarized in this review.

Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is of serious clinical concern. Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is beneficial as a drug for treating non-small cell lung cancer; however, this drug induces ILD and the molecular mechanisms underpinning this condition remain unclear. We recently reported that expression of heat shock protein 70 (HSP70) protects against bleomycin-induced pulmonary fibrosis, an animal model of pulmonary fibrosis. In this study, we have examined the effects of drugs known to induce ILD clinically on the expression of HSP70 in cultured lung epithelial cells and have found that gefitinib has a suppressive effect. Results of a luciferase reporter assay, pulse-labelling analysis of protein and experiments using an inhibitor of translation or transcription suggest that gefitinib suppresses the expression of HSP70 at the level of translation. Furthermore, the results of experiments with siRNA for Dicer1, an enzyme responsible for synthesis of microRNA, and real-time RT-PCR analysis suggest that some microRNAs are involved in the gefitinib-induced translational inhibition of HSP70. Mutations in the EGFR affect the concentration of gefitinib required for suppressing the expression of HSP70. These results suggest that gefitinib suppresses the translation of HSP70 through an EGFR- and microRNA-mediated mechanism. In vivo, while oral administration of gefitinib suppressed the pulmonary expression of HSP70 and exacerbated bleomycin-induced pulmonary fibrosis in wild-type mice, these effects were not as distinct in transgenic mice expressing HSP70. Furthermore, oral co-administration of geranylgeranylacetone (GGA), an inducer of HSP70, suppressed gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis. Taken together, these findings suggest that gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis is mediated by suppression of pulmonary expression of HSP70 and that an inducer of HSP70 expression, such as GGA, may be therapeutically beneficial for the treatment of gefitinib-induced pulmonary fibrosis.