Presentation and progression of MPO-ANCA interstitial lung disease.

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

Historical eye on IPF: a cohort study redefining the mortality scenario.

Rationale: Therapies that slow idiopathic pulmonary fibrosis (IPF) progression are now available and recent studies suggest that the use of antifibrotic therapy may reduce IPF mortality. Objectives: The aim of the study was to evaluate whether, to what extent, and for which factors the survival of IPF in a real-life setting has changed in the last 15 years. Methods: Historical eye is an observational study of a large cohort of consecutive IPF patients diagnosed and treated in a referral center for ILDs with prospective intention. We recruited all consecutive IPF patients seen at GB Morgagni Hospital, Forlì, Italy between January 2002 and December 2016 (15 years). We used survival analysis methods to describe and model the time to death or lung transplant and Cox regression to model prevalent and incident patient characteristics (time-dependent Cox models were fitted). Measurements and main results: The study comprised 634 patients. The year 2012 identifies the time point of mortality shift (HR 0.58, CI 0.46-0.63, p < 0.001). In the more recent cohort, more patients had better preserved lung function, underwent cryobiopsy instead of surgery, and were treated with antifibrotics. Highly significant negative prognostic factors were lung cancer (HR 4.46, 95% CI 3.3-6, p < 0.001), hospitalizations (HR 8.37, 95% CI 6.5-10.7, p < 0.001), and acute exacerbations (HR 8.37, 95% CI 6.52-10.7, p < 0.001). The average antifibrotic treatment effect estimated using propensity score matching showed a significant effect in the reduction of all-cause mortality (ATE coeff -0.23, SE 0.04, p < 0.001), acute exacerbations (ATE coeff -0.15, SE 0.04, p < 0.001), and hospitalizations (ATE coeff -0.15, SE 0.04, p < 0.001) but no effect on lung cancer risk (ATE coeff -0.03, SE 0.03, p = 0.4). Conclusion: Antifibrotic drugs significantly impact hospitalizations, acute exacerbations, and IPF survival. After the introduction of cryobiopsy and antifibrotic drugs, the prognosis of IPF patients has significantly improved together with our ability to detect IPF at an earlier stage.

Clinical implications of interstitial pneumonia with autoimmune features diagnostic criteria in idiopathic pulmonary fibrosis: A case control study.

Background: A subgroup of IPF patients can meet IPAF criteria (features suggesting an underlying autoimmune process without fulfilling established criteria for a CTD). This study was aimed to evaluate whether IPAF/IPF patients compared to IPF patients differ in clinical profile, prognosis and disease course. Methods: This is a retrospective, single center, case-control study. We evaluated 360 consecutive IPF patients (Forlì Hospital, between 1/1/2002 and 28/12/2016) and compared characteristics and outcome of IPAF/IPF to IPF. Results: Twenty-two (6%) patients met IPAF criteria. IPAF/IPF patients compared to IPF were more frequently females (N = 9/22, 40.9% vs. N = 68/338, 20.1%, p = 0.02), suffered more frequently from gastroesophageal reflux (54.5% vs. 28.4%, p = 0.01), and showed a higher prevalence of arthralgias (86.4% vs. 4.8%, p < 0.0001), myalgias (14.3% vs. 0.3%, p = 0.001) and fever (18.2% vs. 1.9%, p = 0.002). The serologic domain was detected in all cases (the most frequent were ANA in 17 and RF in nine cases) and morphologic domain (histology features) was positive in 6 out of 10 lung biopsies (lymphoid aggregates). Only patients with IPAF/IPF evolved to CTD at follow-up (10/22, 45.5%; six rheumatoid arthritis, one Sjögren's and three scleroderma). The presence of IPAF was a positive prognostic determinant (HR 0.22, 95% CI 0.08-0.61, p = 0.003), whereas the isolated presence of circulating autoantibody did not impact prognosis (HR 1.00, 95% CI 0.67-1.49, p = 0.99). Conclusion: The presence of IPAF criteria in IPF has a major clinical impact correlating with the risk of evolution to full blown-CTD during follow-up and identifying a subgroup of patients with a better prognosis.

Lung cancer in patients with idiopathic pulmonary fibrosis: A retrospective multicentre study in Europe.

BACKGROUND AND OBJECTIVE: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry. METHODS: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021. RESULTS: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/µl than patients with monocyte count ≥0.95 K/µl (HR [<0.60 vs. ≥0.95 K/µl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/µl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02). CONCLUSION: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed.

Combined Sarcoidosis and Idiopathic Pulmonary Fibrosis (CSIPF): A New Phenotype or a Fortuitous Overlap? Scoping Review and Case Series.

Idiopathic pulmonary fibrosis (IPF) and sarcoidosis are two distinct clinical entities with different aetiology, epidemiology, risk factors, symptoms and chest imaging. A number of papers have reported an overlap of the two diseases and have suggested the existence of a distinct phenotype defined as combined sarcoidosis and idiopathic pulmonary fibrosis (CSIPF). We used the scoping review protocol to review the literature on CSIPF. We also enrolled a cohort of nine CSIPF patients and compared them with lone-IPF and fibrotic sarcoidosis patients. Our CSIPF cohort showed male prevalence and only ex-smokers. Functional assessment at baseline showed mild to moderate restrictive impairment of lung volumes in lone-IPF and CSIPF patients, associated with moderate-to-severe reduction in DLco percentages. Although all CSIPF patients were on antifibrotic treatments, functional impairment occurred in the two years of follow up. This suggests the importance of considering these patients at high risk of rapid deterioration and lung damage.

Impact of Lung Biopsy Information on Treatment Strategy of Patients with Interstitial Lung Diseases.

Rationale: Lung biopsy (LBx) has a relevant role in the prediction of prognosis of interstitial lung diseases (ILDs), but its impact on the clinical management of patients remains unexplored. Objectives: This study evaluates whether LBx may change the therapeutic strategy and assesses the effect of diagnostic reclassification after LBx on long-term prognosis. Methods: We evaluated the LBx of 426 consecutive patients with ILDs, without a definite usual interstitial pneumonia pattern on high-resolution computed tomographic imaging. A total of 266 patients underwent transbronchial lung cryobiopsy (TBLC), and 160 patients underwent surgical lung biopsy (SLB). The multidisciplinary team (MDT) determined a diagnosis with high or low confidence, and a management strategy, both before and after the LBx data. Results: Final MDT diagnoses were 189 idiopathic pulmonary fibrosis (IPF), 143 non-IPF fibrotic ILDs, and 94 nonfibrotic ILDs. LBx data changed the management strategy in 145 cases (34%), with similar results for TBLC and SLB (the treatment strategy changed in 31.5% of TBLC cases, 84/266, P < 0.001, and in 38% of SLB, 61/160, P < 0.001). After LBx, the MDT was less inclined to "wait and see" (from 15% to 4% of cases, P < 0.001) or to prescribe steroids only (from 54% to 37%, P < 0.001) and was more confident to treat with antifibrotics (from 23% to 44%, P < 0.001) or immunosuppressive drugs (from 7% to 14%, P < 0.001). The therapeutic strategy changed in 70% of reclassified cases (60/85) and in 59% of cases in which LBx increased the MDT confidence (84/142). Reclassification significantly impacted the outcome. The cases classified as non-IPF by clinician and radiologist and then reclassified to be IPF after LBx showed a significantly worse survival compared with non-IPF confirmed cases (adjusted hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.75-8.3); P = 0.001. Cases initially classified as IPF and then reclassified as non-IPF after LBx showed a better prognosis compared with IPF confirmed cases (HR, 0.41; 95% CI, 0.18-0.94; P = 0.03). Conclusions: Reclassification of cases with LBx data increased diagnostic confidence and changed the therapeutic strategy in one-third of cases. Pathologic reclassification of cases refined prognosis prediction. Patients classified as non-IPF by clinician and radiologist and then reclassified IPF after LBx had worse prognosis compared with the non-IPF confirmed cases.

The Relevance of Family History Taking in the Detection and Management of Birt-Hogg-Dubé Syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal-dominant inherited disorder characterized by inactivation of the gene Folliculin (FLCN), pulmonary cysts with recurrent spontaneous pneumothorax, dermatological lesions, and an increased risk of developing renal malignancies. OBJECTIVES: We aimed to investigate the real prevalence of BHDS and its prevalence among patients with a familial history of pneumothorax. METHODS: From July 2014 to December 2016, we consecutively studied all patients with spontaneous pneumothorax and a positive family history for the same condition referring to our Institution. The suspicious cases underwent genetic analysis of the BHDS-causative gene FLCN. FLCN-positive cases were further evaluated with routine blood tests, chest radiography, chest CT, abdominal MRI, and dermatological evaluation. RESULTS: Among 114 patients admitted with spontaneous pneumothorax, 7 patients had a family history of pneumothorax, and 6/7 (85.7%) patients had positive genetic test for FLCN as well as 7/13 family members. Pulmonary cysts were found in all patients with a FLCN-positive genetic test. Most patients (10/13, 76.9%) had tiny pulmonary cysts less than 1 cm in diameter. The vast majority of cysts were intraparenchymal (12/13, 92.3%) and located in lower lobes. Dermatological lesions were found in 7/13 (54%) patients, renal cysts in 4/13 (31%) patients, and renal cancer in 1 (1/13, 7.7%) patient. CONCLUSIONS: Although BHDS is considered a rare disease, BHDS underlies spontaneous pneumothorax more often than usually believed, especially whenever a family history of pneumothorax is present. Diagnosis of BHDS is essential to start monitoring patients for the risk of developing renal malignancies.

Gorham-Stout Disease Management during Pregnancy.

Gorham-Stout Disease (GSD) is a rare lymphatic disorder affecting children or young adults with no predilection of sex. It is generally associated with vanishing bone osteolytic lesions, thoracic and abdominal involvement, and diffuse pulmonary lymphangiomatosis. Chylous effusions and chylothorax, consequent to the abnormal proliferation of lymphatic vessels, may induce respiratory failure with a high mortality risk. Extrapulmonary alterations may include chylous ascites, lymphopenia, and destructing bone disease for overgrowth of lymphatic vessels. Here, we report the case of a young woman who developed a severe and recalcitrant GSD with persistent unilateral chylothorax during pregnancy. The complex management of this patient during and after pregnancy was discussed and compared with literature data to contribute to the definition of a correct diagnostic and therapeutic approach to this rare lymphatic disease.

Fibrotic Lung Toxicity Induced by Hydroxycarbamide.

A patient treated for 4 months with hydroxycarbamide (hydroxyurea) for chronic myelomonocytic leukemia was admitted to hospital for recently developed severe dyspnea and acute respiratory failure. The computed tomographic scan of the chest showed diffuse ground glass opacities, some centrilobular low-density nodules (resembling hypersensitivity pneumonitis-like pattern), and minimal interstitial reticulation of the subpleural region. The analysis of bronchoalveolar lavage fluid excluded infection, as did serological examinations. The patient was started on oxygen therapy and with relief of thrombocytopenia and suspected hemolytic anemia, hydroxyurea treatment was discontinued. The patient underwent steroid therapy, with a rapid progressive improvement of clinical and radiological features. As hydroxyurea is increasingly used for a number of systemic disorders, physicians must be aware of its potential lung toxicity, requiring immediate cessation of the treatment and empiric corticosteroid therapy.

Increased Risk of Atherosclerosis in Patients with Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Recent studies demonstrated that its pathogenesis is related with enhanced oxidative stress (protein carbonylation and lipid peroxidation) and alterations in the circulating lipid profile. Alterations of lipid metabolism (including the reduction in high-density lipoprotein cholesterol levels and apolipoprotein A1 concentrations) induce plasma membrane, bronchial and lung capillary endothelial cell damage in sarcoidosis patients. Dyslipidemia is associated with increased oxidative stress, diminished overall antioxidative protection and increased risk for atherosclerosis. Very recently increased cardiovascular biomarkers (in particular alterations of lipoprotein A and d-dimer concentrations) were observed in sarcoidosis patients, mainly in those with a high risk of atherosclerosis. Chitotriosidase, a biomarker of sarcoidosis activity and macrophage activation, is increased in serum and bronchoalveolar lavage fluid of patients with sarcoidosis as well as in patients with atherosclerosis. Lipidomics and other recent methodologies allowed the discovery of proteins involved in lipid metabolism and sarcoidosis pathogenesis, such as serum amyloid A, a biomarker of sarcoidosis activity, involved in innate immune response, inflammation and apolipoprotein metabolism. In this review lipid metabolism alteration and atherosclerosis risk in sarcoidosis patients were discussed in order to contribute to this novel and interesting research topic.

Lung Cancer in Patients with Severe Idiopathic Pulmonary Fibrosis: Critical Aspects.

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease limited to the lung with an undefined etiopathogenesis and a very short life expectancy (less than 5 years). IPF susceptibility has been associated with several genetic and environmental risk factors and the prognosis is conditioned by comorbidities such as gastro-esophageal reflux, depression, venous thromboembolism, pulmonary hypertension and lung cancer. At 5 years follow-up, 15% of IPF patients develop lung cancer, which can significantly reduce their survival. Because diagnostic or therapeutic procedures such as surgical, radiation or pharmacological treatments may induce acute exacerbations and increase mortality, the management of lung cancer in IPF patients is a very difficult task. This study discusses advantages and disadvantages of lung cancer treatments in patients with severe IPF, highlighting several controversial aspects on this topic, including potential nintedanib treatment.

Trace metals in fluids lining the respiratory system of patients with idiopathic pulmonary fibrosis and diffuse lung diseases.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an undefined etiopathogenesis. Oxidative stress contributes to alveolar injury and fibrosis development and, because transition metals are essential to the functioning of most proteins involved in redox reactions, a better knowledge of metal concentrations and metabolism in the respiratory system of IPF patients may provide a valuable complementary approach to prevent and manage a disease which is often misdiagnosed or diagnosed in later stages. The present review summarizes and discusses literature data on the elemental composition of bronchoalveolar lavage (BAL), induced sputum and exhaled breath condensate (EBC) from patients affected by IPF and healthy subjects. Available data are scanty and the lack of consistent methods for the collection and analysis of lung and airways lining fluids makes it difficult to compare the results of different studies. However, the elemental composition of BAL samples from IPF patients seems to have a specific profile that can be distinguished from that of patients with other interstitial lung diseases (ILD) or control subjects. Suggestions are given towards standard sampling and analytical procedures of BAL samples, in the aim to assess typical element concentration patterns and their potential role as biomarkers of IPF.

The earlier, the better: Impact of early diagnosis on clinical outcome in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex disease with a highly variable clinical course and generally poor prognosis. Classified as a rare disease, significant increases in incidence have been recorded worldwide in recent years. Left untreated IPF is extremely debilitating with substantial personal, social and economic implications. OBJECTIVES: To discuss how IPF is diagnosed and managed in real life clinical practice with particular reference to Italy and to determine how new and effective therapies can be incorporated into a patient-centred management approach in order to improve the lives of patients with IPF. OUTCOMES: Barriers to early diagnosis are discussed. Cited reasons for delays in diagnosing IPF in Italy include: inherent difficulties in diagnosis; lack of knowledge/awareness of the condition among point-of-contact healthcare professionals; delays in referral to centres of excellence and underestimation of symptoms by both patients and healthcare workers. Valid therapeutic options with demonstrated efficacy in slowing the decline in lung function are now available for patients with IPF. The ASCEND trial confirmed the effects of pirfenidone, approved for the treatment of IPF on the basis of the four phase III trials. Nintedanib, a tyrosine kinase inhibitor that targets the PDGF receptors α/ß, FGF receptors 1 to 3, and VEGF receptors 1-3, is approved in the USA and the EU for the treatment of IPF. The TOMORROW and the INPULSIS placebo controlled trials in patients with IPF confirm the efficacy and safety of nintedanib and recent interim analyses endorse its long-term effects in slowing disease progression. CONCLUSIONS: The importance of early and accurate diagnosis of IPF cannot be underestimated and it is the duty of all healthcare professionals to be vigilant to the symptoms of IPF and to involve a multidisciplinary team in diagnosing and managing IPF early in the course of disease.

Perception of airway obstruction and airway inflammation in asthma: a review.

Dyspnea has a multifactorial nature and the exact mechanism that causes breathlessness in asthma is not fully understood. There is compelling evidence that factors other than merely mechanical ones take part in the pathophysiology of breathlessness. Some recent reports attribute airway inflammation, which may contribute to the unexplained variability in the perception of dyspnea associated with bronchoconstriction. Eosinophil airway inflammation has been proposed as a determinant of breathlessness via mechanisms affecting either the mechanical pathways that control breathlessness or the afferent nerves involved in perception of dyspnea. In this review, data on the interrelation between inflammation and dyspnea sensation and the impact of treatment on dyspnea sensation are discussed. We conclude that regardless of whether mechanical or chemical inflammatory factors are involved, much variability in dyspnea scores remains unexplained.

Cigarette smoking and dyspnea perception.

Cigarette smoking has been implicated as an important risk factor for the development of respiratory symptoms in adults. The relationship of dyspnea with cigarette smoking has been examined in smokers and ex-smokers and the beneficial effects of smoking cessation have been demonstrated. Recent studies reported that in subjects who smoke cigarettes the risk of developing respiratory symptoms is higher in a dose-dependent way. Environmental tobacco smoke heavily influences the incidence of respiratory symptoms in both adults and in children. Up to the present time, the mechanisms whereby cigarette smoking causes dyspnea perception remain to be defined. Abnormalities in sensory nerves might diminish the perception of bronchoconstriction in smokers. In this regard, it has been postulated that prolonged exposure to cigarette smoke may lead to chronic depletion of sensory nerve neurotransmitters. Eosinophil airway inflammation has been proposed as a determinant of breathlessness via mechanisms affecting either the mechanical pathways that control breathlessness or the afferent nerves involved in perception of dyspnea. An increased number of eosinophils in some smokers implies the possibility that smoking may trigger immunological or other reactions associated with eosinophilia. In conclusion, cigarette smoking is by far one of the greatest risk factors for most respiratory symptoms, including dyspnea. Smoking is associated with the development of symptoms in a dose-dependent way and eosinophilia and airway hyperresponsiveness (AHR) increase the risk of developing dyspnea.