Challenges in the diagnosis of idiopathic pulmonary fibrosis: the importance of a multidisciplinary approach.

INTRODUCTION: The diagnosis of Idiopathic pulmonary fibrosis (IPF) requires the careful exclusion of secondary causes of interstitial lung disease (ILD), and the collaboration among different specialists is considered paramount to establish a diagnosis with high diagnostic confidence. The multidisciplinary discussion (MDD) has assumed an increasing importance over the years in the different phases of the IPF diagnostic work-up. AREAS COVERED: The role of MDD in the diagnosis and management of IPF will be described. Practical insights will be provided into how and when to perform MDD based on the available scientific evidence. Current limitations and future perspectives will be discussed. EXPERT OPINION: In the absence of high diagnostic confidence, agreement between different specialists during MDD is recognized as a surrogate indicator of diagnostic accuracy. Often, despite a lengthy evaluation, the diagnosis remains unclassifiable in a significant percentage of patients. MDD therefore appears to be pivotal in attaining an accurate diagnosis of ILDs. The discussion among different specialists can also include other specialists, such as rheumatologists and thoracic surgeons, in addition to the core group of pulmonologists, radiologists, and pathologists. Such discussions can allow greater diagnostic accuracy and have important effects on management, pharmacologic therapies, and prognosis.

Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs. OBJECTIVE: To develop recommendations for the diagnosis and management of DIILD in cancer patients. METHODS: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events. RESULTS: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis. CONCLUSIONS: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.

Role of Stenotrophomonas maltophilia isolation in patients with non-CF bronchiectasis.

INTRODUCTION: Stenotrophomonas maltophilia is a bacteria whose role in patients with cystic fibrosis (CF) bronchiectasis has been previously studied; little is known about its role in non-CF bronchiectasis. MATERIALS AND METHODS: Aim of our study is to investigate the risk factors for S. maltophilia acquisition and its clinical impact on bronchiectasis patients. A retrospective observational cohort study enrolling patients attending the Bronchiectasis Clinic at the Royal Infirmary of Edinburgh, Scotland, UK. A total of 167 bronchiectasis patients undergoing intravenous (IV) antibiotic therapy were selected and divided according to single or chronic S. maltophilia isolation in sputum. The risk factors and prognostic impact were studied. RESULTS: Single isolation was independently associated with lower baseline % predicted forced expiratory volume in 1 s [odds ratio (OR) 0.98; 95% confidence interval (CI) 0.970-1.044; P = 0.025] and with less radiological involvement (OR 0.379; 95% CI 0.175-0.819; P = 0.01). Chronic isolation was associated with the number of IV antibiotic courses in the year before and after the first isolation (OR 1.2; 95% CI 1.053-1.398; P = 0.007) and with the absence of Pseudomonas aeruginosa colonization (OR 0.207; 95% CI 0.056-0.764; P = 0.02). In the chronic isolation group, there were more exacerbations and more need of IV antibiotics in the year after the first isolation. CONCLUSIONS: Poor lung function is the main independent risk factor for single isolation of S. maltophilia. For chronic colonization, the main independent risk factor is the number of IV antibiotic courses and the absence of P. aeruginosa chronic colonization. Only when chronically present, S. maltophilia had a clinical impact with more exacerbations.

Evaluation of the lung microbiome as a therapeutic target in the management of idiopathic pulmonary fibrosis: role of antioxidant/antibiotic combination therapy.

OBJECTIVE: Changes in the composition of the lung microbiome influence many lung diseases, including idiopathic pulmonary fibrosis (IPF), with a demonstrated association between the progression of IPF and the assessed pulmonary microbial community. A hypothesis to explain the pathogenesis of IPF is that an oxidant-antioxidant imbalance causes repeated epithelial cell injury and endogenous and exogenous antioxidants/redox modulators influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. MATERIALS AND METHODS: The present article is focused on Lung Microbiome in Idiopathic Pulmonary Fibrosis and the role of Antioxidant/Antibiotic Combination Therapy. RESULTS: N-Acetylcysteine (NAC) at concentrations possibly achievable by nebulization showed an in vitro synergy with colistin against S. maltophilia isolates (a common coloniser of the respiratory tract of patients with chronic lung disease). Combined NAC plus colistin seems to have a beneficial role in restoring oxidant injury which may be related to its antioxidant effect. Progress has been made in the identification of the lung microbiome and the possible causal role of bacteria in the IPF pathogenesis. Recent studies suggest that antibacterial therapy in combination with antioxidant therapy may be a promising avenue for the treatment of this untreatable disease. Novel routes of administration are also an important area of research and studies assessing the use of inhaled NAC in patients with IPF could be considered.

How we will diagnose IPF in the future.

The recent approval of two safe and effective treatments for patients with idiopathic pulmonary fibrosis (IPF) had as a direct consequence the absolute need for an accurate and early diagnosis. The standard approach to IPF diagnosis has proven to be effective and emphasized the importance of clinical and laboratory evaluations to exclude known causes of pulmonary fibrosis. At the same time, chest high-resolution computed tomography (HRCT) has proven to be the crucial initial diagnostic test, by identifying those patients who should undergo surgical lung biopsy to secure a confident diagnosis and an adequate treatment. However, this diagnostic approach showed over the years some limitations. First, many suspected IPF patients present with atypical HRCT appearances and at the same time are unfit (or unwilling) for surgical lung biopsy, therefore making a confident diagnosis of IPF impossible. Although the current recommendations indicate the need for an iterative multidisciplinary process incorporating available clinical, laboratory, imaging and histological features, recent work has identified new tools which might improve the overall accuracy of this process. Genomic techniques have been already applied to molecularly phenotype patients with interstitial lung disease and it is likely that in the near future clinicians will utilize blood or lung-specific molecular markers in combination with other clinical, physiological, or imaging features. The availability of new sampling procedures (e.g. transbronchial cryobiopsies), together with innovative imaging technologies (e.g. microCT) will most likely support and enhance diagnostic efforts, refine prognostic recommendations and ultimately influence therapeutic options.

Idiopathic pulmonary fibrosis: Recent advances on pharmacological therapy.

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias with an estimated 5-year survival of approximately 20%. In the last two decades our understanding of disease pathogenesis has substantially evolved and novel compounds have been developed consequent to the increasing knowledge of the mechanisms underlying disease pathobiology. The disease appears to be driven - following chronic injury - by abnormal/dysfunctional alveolar epithelial cells that promote fibroblast recruitment and proliferation, resulting in scarring of the lung and irreversible loss of function. With very few exceptions, clinical trials evaluating novel potential therapies have provided disappointing results. More recently, pirfenidone and nintedanib, two compounds with pleiotropic mechanisms of action, have proven effective in slowing functional decline and disease progression in IPF patients with mild to moderate functional impairment, highlighting the importance of timely diagnosis and administration of treatment in early stages of disease. However, due to the complexity and uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient, after evaluation of potential benefits and risks. This article provides an overview of the most recent clinical trials in IPF and discusses how their results are going to change the clinical and clinical research landscape in IPF. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.

Long-term management of IPF with pirfenidone - a clinical case study with 5 years follow-up.

Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-5 years from initial diagnosis. To date, the search for an effective treatment has involved numerous clinical trials of investigational agents but without significant success. Nevertheless, research over the past 10 years has provided us with a wealth of information on its histopathology, diagnostic work-up, and a greater understanding of its pathophysiology. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade. The development of therapeutic targets has therefore shifted in accordance with this paradigm change. Emerging clinical data from recently published and ongoing trials investigating new potential pharmacological agents should be considered in the routine clinical management of these patients. Based upon encouraging results from randomised-controlled trials showing a positive effect in slowing decline in pulmonary function and reducing disease progression, pirfenidone was approved in 2011 as the first treatment in patients with IPF. This case study describes the clinical course of a patient enrolled into the Phase III and open-label extension studies of pirfenidone.

Co-trimoxazole effect on human alveolar macrophages of AIDS patients.

Compelling evidence suggests that co-trimoxazole prophylaxis reduces mortality in HIV-infected patients, although it is unclear whether these effects are directly related to antimicrobial activities. We evaluated in vitro phagocytosis and killing of Staphylococcus aureus in alveolar macrophages (AM) obtained from AIDS patients who smoke, treated (n=19) or not treated (n=13) with co-trimoxazole, as compared to non-HIV-infected healthy smokers (n=15). Phagocytosis and killing of Staphylococcus aureus by AM obtained from non-co-trimoxazole treated AIDS patients were significantly lower compared to non-HIV-infected healthy smokers. In contrast, AIDS patients treated with co-trimoxazole prophylaxis showed phagocytosis and killing levels similar to those of healthy controls. These results might help to clarify the observed positive effect of co-trimoxazole on survival in HIV-infected patients.

Tuberculosis infection in foreign-born children: a screening survey based on skin and blood testing.

This study, carried out in a low tuberculosis (TB) prevalence country with high immigration rates from high TB prevalence countries, deals with the interferon-gamma release assay, QuantiFERON®-TB Gold In-Tube, for the diagnosis of latent TB infection (LTBI) in foreign-born children. The results of our study highlight the potential advantages and concerns of using a blood test for diagnosing LTBI in a 'two-step' strategy in foreign-born children.

Pulmonary eosinophilic infiltrates.

Pulmonary eosinophilic infiltrates include an heterogeneous group of disorders characterized by the presence of eosinophils in the lungs as detected by bronchoalveolar lavage or tissue biopsy, with or without blood eosinophilia. The disease can be idiopathic (simple pulmonary eosinophilia, acute and chronic eosinophilic pneumonia, hypereosinophilic syndrome), secondary (to drugs, parasites, fungal and mycobacterial infection, irradiation, toxic products) or associated with diffuse lung diseases (connective tissue diseases and some neoplasms). Pathologists faced with eosinophils in the lungs (either on cytology or biopsy) should keep in mind several possibilities, although a diagnosis of certainty is rarely based on morphology alone. Correlation with laboratory tests, imaging studies and clinical presentation has a key role, even if some pulmonary eosinophilic diseases are sufficiently characteristic on clinico-radiologic ground to not require a biopsy (e.g. some drug reactions, parasitic infections, idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis). Nevertheless, pathologists can play a central role because they can be the first to note eosinophils in the lungs of a very sick patient. Knowledge of histologic features and a striking collaboration with other physicians are necessary to achieve correct diagnosis and to establish adequate treatments.

Endogenous blood maximal interferon-gamma production may predict response to interferon-gamma 1beta treatment in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disorder with a mean survival of 3 years after diagnosis. Treatment with interferon-gamma (IFN-gamma) 1beta has been reported to significantly improve lung function and arterial oxygen saturation in a first randomized controlled trial; unexpectedly, these findings have not been confirmed in a subsequent large placebo-controlled randomized study. Another larger placebo-controlled randomized trial has been stopped because data analyzed at interim analysis excluded the possibility that treatment with IFN-gamma 1beta would cause a significant reduction in the risk of death. METHODS: Seven Italian male patients diagnosed with IPF were treated with IFN-gamma 1beta (200 microg/die subcutaneously three times a week), accordingly to the indications of the Italian Drug Agency. Based on available studies the response to treatment was pre-defined as changes in either lung function (FVC and DLCO) or oxygen arterial saturation. All patients consented to provide a peripheral blood sample for endogenous IFN-gamma production measurement with the ELISpot assay before treatment and 6 months thereafter. RESULTS: Four of 7 patients improved or stabilized their lung function after 6 months treatment. Using the ELISpot assay to quantify the maximal production of endogenous IFN-gamma on peripheral blood samples, these 4 patients had a significantly higher endogenous IFN-gamma production before therapy, as compared to the 3 patients who deteriorated (91.3 +/- 49.6 vs. 277.8 +/- 34.2 spot forming cells, p = 0.023). No significant differences were observed after 6 months of treatment. DISCUSSION: These preliminary results suggest that some IPF patients might benefit from treatment with IFN-gamma 1beta and may help to interpret the results of large randomized trials, suggesting that individual susceptibility could determine clinical response to treatment.

Macrolides in the treatment of asthma and cystic fibrosis.

Asthma and cystic fibrosis are two respiratory diseases characterized by chronic inflammation, leading to remodelling of the airways. Macrolides are widely used antibiotics, with a peculiar anti-inflammatory effect. On the basis of the methodologies used by the Cochrane collaboration, this review discusses the evidence for their long-term use as anti-inflammatory agents in these two diseases. Three randomized-controlled trials (RCTs) were identified for both asthma and cystic fibrosis. A positive effect of macrolides on reducing eosinophil numbers and markers of eosinophilic inflammation was demonstrated in patients with asthma. Data on cystic fibrosis demonstrated an effect on lung function with an increase of 5.4% in forced vital capacity (FVC) in patients treated with macrolide vs. placebo, but without a significant effect on FEV1. Side-effects were rare, mild and reversible on withdrawal of treatment. Although preliminary data from small studies are promising, the role of macrolides in the treatment of these chronic disorders needs to be more firmly established with larger, well-designed trials, targeted to investigate major clinical outcomes.

Major histocompatibility locus genetic markers of beryllium sensitization and disease.

Hypersensitivity to beryllium (Be) is found in 1-16% of exposed workers undergoing immunological screening for beryllium disease using the beryllium lymphocyte proliferation test (BeLPT). However, only approximately 50% of BeLPT-positive workers present with lung granulomas (i.e. berylliosis). As berylliosis is associated with the human leukocyte antigen (HLA)-DP supratypic marker DPGlu69, the authors asked whether this marker is differentially associated with disease presentation. A population of 639 workers from a beryllium factory undergoing BeLPT screening was evaluated in a nested case-control study for the prevalence of HLA-DPGlu69, the HLA-DPB1, HLA-DQ and HLA-DR alleles and of the biallelic tumour necrosis factor (TNF)-alpha polymorphism TNF-alpha-308 in 23 individuals presenting as "sensitized" (i.e. BeLPT-positive without lung granulomas) and in 22 presenting as "diseased" (i.e. BeLPT-positive with granulomas in the lung biopsy). The HLA-DPGlu69 marker was associated with "disease" (odds ratio (OR) 3.7, p=0.016, 95% confidence interval (CI) 1.4-10.0), whilst the high TNF-alpha production-related TNF-alpha-308*2 marker was associated with both a positive BeLPT (OR 7.8, corrected p<0.0001, 95% CI 3.2-19.1) with no difference between "sensitization" and "disease". Furthermore, the HLA-DRArg74 marker was associated with "sensitization" without disease (OR 3.96, p=0.005, 95%, CI 1.5-10.1). The data indicate that tumour necrosis factor-alpha, human leukocyte antigen-DR and human leukocyte antigen-DP markers play different roles in beryllium sensitization and granuloma formation in beryllium-exposed workers.