There are some limitations to this study. First, this was a retrospective study with a small number of subjects. Because of the small numbers of AEs and deaths, riskfactors and prognostic factors were adjusted only by treatment with an immunosuppressive agent in the mul- tiple Cox analysis. Because the associations among sev- eral factors seem to be complex, further study in a larger patient cohort is needed to analyze independent risk fac- tors for AE-IPF and prognostic factors for IPF. Second, although the present study suggests that alveolar inflam- mation may be one of the key pathways activated prior to the development of an AE-IPF, the precise biological mechanisms of AE-IPF remain unknown. Third, this study included only Japanese patients. Therefore, further studies are needed to ascertain whether these results can be applied equally to other ethnic groups. The relative rarity of AE-IPF suggests that these research questions should be answered by multicenter collaborations.
ABSTRACT Recognising recent advances, the definition and diagnostic criteria for acuteexacerbation of idiopathicpulmonaryfibrosis (AE-IPF) have been updated by an international working group. The new definition describes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterised by evidence of new widespread alveolar abnormality. The new criteria require a previous or concurrent diagnosis of IPF, an acute worsening or development of dyspnoea typically less than 1 month in duration, chest imaging evidence on computed tomography (CT) of new bilateral ground-glass opacity and/or consolidation superimposed on a background imaging pattern of usual interstitial pneumonia not fully explained by cardiac failure or fluid overload. Due to high in-hospital mortality rates, current treatment guidelines say that the majority of patients with AE-IPF should not receive mechanical ventilation. However, new data suggest that the prognosis may have improved. This modest improvement in overall survival seen in more recent studies may be the result of differences in the diagnostic criteria, study design, baseline clinical riskfactors and/or improvements in management. Based on our updated knowledge of possible preventive and therapeutic measures, including mechanical ventilation and pharmacological therapies, the current approach to the treatment of AE-IPF requires careful decision-making.
Purpose: Acuteexacerbation (AE) is an important outcome of idiopathicpulmonaryfibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). Recombinant human soluble thrombomodu- lin (rhTM) is a new drug for the treatment of disseminated intravascular coagulation in Japan. The objective of this study was to evaluate the efficacy of rhTM for AE of IPF/NSIP. Methods: Twenty-two patients with AE-idiopathic interstitial pneumonia (16 patients with IPF and six patients with NSIP) were enrolled in our study. Among them, eleven patients were treated with rhTM (rhTM group), and eleven patients were treated without rhTM (non-rhTM group). Patients admitted to our hospital prior to December 2013 were treated with rhTM, while those admitted after January 2014 were treated without rhTM. The primary endpoint was mortality at 90 days after AE treatment. The secondary endpoint was the safety of rhTM for AE-IPF/ AE-NSIP. In addition, we examined prognostic factors of AE-IPF/AE-NSIP.
Subjects in STEP-IPF who experienced a respiratory serious adverse event during the course of the study (as determined by the site principal investigator) were con- sidered acute respiratory worsenings for the purposes of the current study. As part of the STEP-IPF trial, possible acuteexacerbation events were pre-specified as serious acute events and study sites were asked to collect de- tailed information about these events from the treating physician (not always at the study site). STEP-IPF did not identify definite and suspected acuteexacerbation as specified by the IPFnet investigators in a perspective piece published after STEP-IPF was designed , so the original STEP-IPF adjudication results for acute exacer- bation were not used in this analysis. All acute respira- tory worsenings were reviewed independently by three of the authors (HC, CG, LR) and categorized as definite acuteexacerbation suspected acuteexacerbation, or other acute worsening . Briefly, acuteexacerbation was defined by acute onset of symptoms (<30 days in duration), new radiographic abnormalities (bilateral ground glass or consolidation on HRCT), and the absence of an identified infectious or alternative etiology (Additional file 2: Table E1). Suspected acuteexacerbation of IPF was defined as an idiopathicacute respiratory worsen- ing that could not be classified as a definite acute ex- acerbation due to missing data or criteria . In cases considered as other acute worsenings, a cause was spe- cified were possible (e.g. lower respiratory tract infec- tion, pulmonary embolism). After individual reviews, all events were discussed as a group, and in cases of dis- agreement, a consensus result for each was determined.
The survival rate among patients who experience their first AE-IPF episode has improved; consequently, some patients experienced two or more AE episodes, which is very rare because historically, almost all patients with IPF died at the time of their first AE event. Pulmonologists must pay close attention to the care of patients with AE- IPF. Prevention of exacerbations is an essential strategy for improvement of both the IPF-associated mortality rate and quality of life. A recent randomized placebo- controlled trial showed that azithromycin significantly decreased the rate of exacerbations in patients with chronic obstructive pulmonary disease . One small study showed that the use of azithromycin in patients with IPF was associated with a lower rate of admission for AE- IPF . Further studies to assess the effectiveness of maintenance treatment with azithromycin are needed.
damage healing [13, 17]. A direct link between injury to type II alveolar epithelial cells and the accumulation of interstitial collagen by M2 pathway activation was reported , which could stimulate repair by fibroblast proliferation and epithelial–mesenchymal transition. This repair process, however, appears to fail in AE-IPF, thus resulting in persist- ent M2 pathway activation and irreversible lung fibrosis . A recent study on lungs of transplanted IPF patients showed that inflammatory infiltration and DAD are even present in IPF with an accelerated functional decline, sug- gesting that inflammation may play a role in disease pro- gression . Further evidence that the cytokine profile in the rapidly deteriorating IPF patient appears predominantly proinflammatory rather than profibrotic, approximating that of ARDS of any etiology rather than an accelerated in- trinsic fibrotic process, has been provided by Papiris et al. .
Similarly, we divided patients with I-AE and T-AE, respectively, into survivors and non-survivors and iden- tified their respective predictors of in-hospital deaths (online supplementary tables 2–4). In the I-AE group, non-survivors showed higher WBC counts (p=0.03), blood urea nitrogen (BUN; p=0.04), CRP levels (p<0.01) and antibiotic therapy rates (p=0.03) and lower Hb levels (p=0.01) and P/F (p=0.02) than survivors (online supplementary table 2). WBC, Hb, BUN, CRP and anti- biotic therapy were detected as possible confounding factors by univariate analysis; age and P/F were included in multivariate logistic regression analysis. Consequently, the WBC count (OR 1.87; 95% CI 1.09 to 4.95; p=0.01) and Hb level (OR 0.26; 95% CI 0.04 to 0.78; p=0.01) were also identified as independent predictors of in-hos- pital deaths in I-AE (online supplementary table 3). In contrast, in the T-AE group, a significant difference in the characteristics of non-survivors and survivors was not found (online supplementary table 4); predictors of in-hospital deaths were not identified.
IdiopathicPulmonaryFibrosis (IPF) is a debilitating chronic lung disease. Despite recent advances in antifi- brotic therapy, the prognosis is poor with a median sur- vival of 2–5 years [1, 2]. The diagnosis of IPF can be challenging, and due to its rarity, few physicians gain enough expertise to become familiar with the disease. In addition, the diagnosis often requires a multidisciplinary team, which is not available in all centres [3, 4]. Surveys and retrospective studies have shown a significant diag- nostic delay from the onset of symptoms until the final diagnosis is made [5–8]. This results in a delayed start of effective antifibrotic treatment and lung transplant evaluation, and can affect the disease course and
The various functional studies on the two miRNAs, miR- 25-3p and let-7d-5p, should not be neglected. First, a reduc- tion of let-7d in epithelial cells causes epithelial- mesenchymal transition and over-expression of let-7d in fi- broblasts can reduce their mesenchymal properties [22, 23], suggesting that the effect of let-7d is pro-fibrotic, a process occurring in both S-IPF and AE-IPF, but significantly en- hanced in latter. On the other hand, miR-25 has been found to be increased in various cancers and may act as an onco- miRNA [24–28]. The specific large increase of miR-25-3p in AE-IPF, but reduced in S-IPF, suggested that the disease may have gained a pro-growth condition. Our findings have etiological implications that acuteexacerbation in IPF may be due to the collapse of anti-fibrosis mechanisms and the gain of tumorigenic molecular tendency locally or systemic- ally. Whether the two processes are parallel or mutually interacted is not known. More importantly, whether AE-IPF may obtain a neoplastic disease-like alteration is extremely provoking, but needs cellular and pathological evidence.
All autopsied lung materials were fixed in 10% formalin for more than seven days. At least one tissue block was prepared from the gross AE-IPF lesions in each lobe, and the tissue blocks were embedded in paraffin. Sections (4 μm thick) were cut and stained with hematoxylin and eosin (H&E) using standard procedures. The pathological diagnosis of UIP was made according to the current guidelines . The criteria for DAD were the presence of hyaline membranes in addition to at least one of the following findings: alveolar type I cell or endothelial cell necrosis, edema, organizing interstitial fibrosis or prom- inent alveolar type II cell proliferation . We also per- formed phosphotungstic acid hematoxylin staining for fibrin in patients without a hyaline membrane on H&E staining. OP was pathologically defined as the presence of buds of granulation tissue in the distal air spaces pro- gressing from fibrin exudates to loose collagen-containing fibroblasts . Alveolar hemorrhage was diagnosed in cases involving acute hemorrhage in the alveoli and airways as well as the presence of macrophages (i.e., siderophages) that stained positively for hemosiderin with Berlin-blue stain. Right ventricular hypertrophy was defined as a right ventricular free wall thickness of ≥ 5 mm .
Emphysema and IPF, which have different radiological, pathological, functional, and prognostic characteristics, have long been regarded as separate entities. However, the coexistence of emphysema and pulmonaryfibrosis in individuals is being increasingly recognized . In 2005, Cottin et al. first proposed defining a syndrome termed “combined pulmonaryfibrosis and emphysema (CPFE),” which is characterized by a heavy smoking history, exer- cise hypoxemia, upper lobe emphysema and lower lobe fibrosis, unexpectedly subnormal lung volumes, and se- vere reduction of carbon monoxide transfer . The pathogenesis of CPFE has not yet been fully elucidated. However, emphysema, IPF, and CPFE have common riskfactors, such as smoking . The survival rates of pa- tients with CPFE are known to be poor [8, 9]. Several studies [6, 10–17] have evaluated the clinical course and complications of CPFE. Among them, some reports have stated that patients with CPFE have a higher risk of lung cancer development and death compared with emphy- sema patients [11, 16]. Nevertheless, the exact clinical course and complications of CPFE are unclear, especially when the condition is comorbid with lung cancer.
ABSTRACT Acuteexacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acuteexacerbation in idiopathicpulmonaryfibrosis (IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acuteexacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are riskfactors for acuteexacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acuteexacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acuteexacerbation management have been performed. Although there are no formal strategies to prevent the development of acuteexacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acuteexacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available.
methodology used to assess AEx-IPF in different studies, but AEx-IPF are believed to occur in between 5 and 10% of patients with IPF every year. Riskfactors for AEx-IPF are unclear, but there is evidence that poorer lung function increases the risk of an AEx-IPF and reduces the chances of a patient surviving an AEx-IPF. The presence of comorbidities such as gastroesophageal reflux disease (GERD) and pulmonary hypertension may also increase the risk of an AEx-IPF. AEx-IPF are associated with high morbidity and mortality. Patients who experience an AEx-IPF show a worsened prognosis and AEx-IPF are believed to reflect disease progression in IPF. Current treatments for AEx-IPF have only limited data to support their effectiveness. The latest international treatment guidelines state that supportive care remains the mainstay of treatment for AEx-IPF, but also give a weak recommendation for the treatment of the majority of patients with AEx-IPF with corticosteroids. There is emerging evidence from clinical trials of investigational therapies that chronic treatment of IPF may reduce the incidence of AEx-IPF. Additional clinical trials investigating this are underway.
Abstract: Idiopathicpulmonaryfibrosis is a chronic fibrotic lung disease of unknown cause that occurs in adults and has a poor prognosis. Its epidemiology has been difficult to study because of its rarity and evolution in diagnostic and coding practices. Though uncommon, it is likely underappreciated both in terms of its occurrence (ie, incidence, prevalence) and public health impact (ie, health care costs and resource utilization). Incidence and mortality appear to be on the rise, and prevalence is expected to increase with the aging population. Potential riskfactors include occupational and environmental exposures, tobacco smoking, gastroesophageal reflux, and genetic factors. An accurate understanding of its epidemiology is important, especially as novel therapies are emerging.
The current focus of IPF research is on the molecular genetics of pathologic events likely to occur at the epi- thelial-mesenchymal interface of the alveolus -. In vitro, studies using lung fibroblast from IPF patients have contributed to the theory that myofibroblasts have a prolonged survival after being activated by an un- known injury, shortened survival of lung epithelial cells, or both . Even though, riskfactors have been iden- tified for this disease (e.g. environmental, exposures, genetic determinants, smoking , pollutants, gastro- esophageal reflux  , occupational exposures, , viral infections  and old age ). IPF’s origin and onset are not fully understood. It has been previously suggested that the onset involves alveolar epithelium micro-injuries that lead to dysregulation of cellular homoeostasis in the alveolar epithelial-mesenchymal unit and the reactivation of developmental signaling pathways (e.g. transforming growth factor: TGF- β , wing- less-type like (Wnt) , sonic hedgehog (SHH) , and Notch ). The resultant cell dysfunction and death result in progressive scar tissue formation, and eventual distortion of pulmonary anatomical structural relation- ships with disruption of lung homoeostasis . Some authors hypothesize that IPF originates from long term recurring stretch injury to the peripheral and basal lung in individuals with a genetic predisposition. One of the proposed triggers could be ventilatory efforts associated with obstructive sleep apnea (OSA), which may trigger the process of “aberrant healing”. The generated disease is present in more peripheral areas of the lung based on well-known heightened mechanical stretch factors in this anatomical compartment; in essence a mechanical ra- ther than inflammatory damage .
At present, the diagnosis of AKI is delayed and missed by using increased SCr and decreased urine output. Therefore, a variety of markers related to AKI diagnosis have been clinically developed, mainly divided into two categories: 1 Physiological indicators of the disease: includ- ing renal blood perfusion, oxygen combined state, glomer- ular ﬁ ltration rate, urinary ﬂ ow rate, etc.; 2 Structural damage indicators: including urine related to renal tubular structure damage, immune in ﬂ ammation, oxidative stress, abnormal cell metabolism, detection of protein, enzyme, nucleic acid, sediment, etc. The purpose of testing the above indicators is to assist the AKI risk assessment, early diagnosis, and judgment of the etiology, course pro- gression and prognosis. However, the clinical application value of these biomarkers is still being evaluated. 17 – 19
On a more optimistic note, there are promising clinical trial results with the first-in-class non-prostanoid IP receptor agonist selexipag [34, 38]. Selexipag is a potent, orally active molecule which is rapidly hydrolysed to an active metabolite, ACT- 333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors such as EP, DP, FP and TP [2, 34–36, 38]. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side-effects (e.g. nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimised . In addition, the selexipag metabolite has a half- life of 7.9 h, thus permitting oral dosing twice daily . Selexipag has been studied in a randomised, double-blind, placebo-controlled, phase II, proof-of-concept trial in 43 patients with PAH . Approximately one-third of patients were receiving both an ERA and sildenafil as background therapy. Selexipag was up-titrated in 200 m g b.i.d. increments to the maximum tolerated dose. More than 60% of patients were on a final selexipag dose of 600–800 m g b.i.d. Throughout the study selexipag was well tolerated with the majority of adverse events being mild or moderate in severity. Selexipag significantly lowered pulmonary vascular resistance (PVR) in comparison with placebo at week 17 (treatment effect of -30.3%; p50.0045). In addition, there was an improvement in 6MWD (treatment effect of +24.7 m), although this did not reach statistical significance. Compared with placebo, selexipag treatment was associated with a significant increase in cardiac index (treatment effect of + 0.5 L ? min -1 ? m -2 ; p 5 0.01). Further investigation of selexipag is ongoing in the double-blind, randomised, placebo- controlled, phase III GRIPHON (Prostaglandin (PGI 2 ) Receptor