Clinical course of IPF in Italian patients during 12 months of observation: results from the FIBRONET observational study.

BACKGROUND: FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF). METHODS: Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted). RESULTS: 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study. CONCLUSIONS: FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF. TRIAL REGISTRATION: NCT02803580.

Where do we stand with IPF treatment?

Despite receiving 'weak no' recommendations in the updated guidelines on treating patients with Idiopathic Pulmonary Fibrosis (IPF), two key treatment options are pirfenidone and N-acetylcysteine (NAC), and both are used in clinical practice. The efficacy of pirfenidone is supported by a number of Phase III trials as well as a Cochrane meta-analysis. Tolerability data are also provided by clinical trials and a long-term extension phase of these studies. Pirfenidone is approved in Europe for the treatment of patients with mild-to-moderate IPF. NAC-based therapy has no such approval, but is commonly used to treat patients. A Phase III trial suggested some benefit of the NAC, prednisone and azathioprine regimen for IPF patients, but the study had many limitations. A further study to investigate this regimen, compared with a placebo alone arm, was recently stopped due to increased mortality in the triple-therapy arm. Discussion of these data and recent findings highlight the importance of a further update to the existing guidelines, so that IPF specialists can provide the most up-to-date advice and treatment to patients in clinical practice.

Effectiveness and safety of a new helmet CPAP configuration allowing tidal volume monitoring in patients with COVID-19.

BACKGROUND: High generated tidal volumes (Vt) have been correlated with higher risk of self-induced lung injury and worse clinical outcome. This study aimed to evaluate the effectiveness and safety of a new helmet continuous positive airway pressure delivered (h-CPAP) configuration allowing Vt monitoring in patients affected by COVID-19. METHODS: This prospective observational study was performed in the respiratory intermediate care unit of University Hospital in Turin, Italy, between March 24th, and June 15th, 2020. Included patients were treated with CPAP via a single-limb intentional leak configuration by a turbine-driven ventilator, provided with a dedicated patch. Effectiveness and safety of the configuration and healthcare workers safety were the outcomes of the study. MAIN FINDINGS: Thirty-five patients were included in this study. Median age was 67 years (IQR 57-76 years), and 30 patients (85.7%) were men. Median value of overall leaks (intentional plus unintentional) was 68 L/min (IQR 63-75). Reliability of Vt measurements was 100%. An out of scale of Vt (above 50% compared to the previous values) was never recorded. Six patients (17.1%) needed more than two helmet replacements, due to leak test >10 l/min. Arm oedema and skin breakdowns were reported in sixteen (45.7%) and seven (20%) patients respectively. Among the 63 healthcare workers involved in the care of COVID-19 patients during the study only one was positive at RT-PCR nasopharyngeal swab testing. CONCLUSIONS: The use of h-CPAP for treating COVID-19 in this configuration allowed for reliable Vt monitoring. Further studies evaluating this configuration in larger patients' cohorts are needed.

Repopulation of human pulmonary epithelium by bone marrow cells: a potential means to promote repair.

After lung injury and damage to the alveolar epithelium, the underlying basement membranes become exposed. Proliferation of type II pneumocytes and their differentiation to the type I phenotype have been considered to be the mechanism by which repopulation of the alveolar epithelium occurs. A growing body of evidence has shown that tissues can be repaired by cells acquired via the circulation. For the lung, bone marrow stem cells have been shown in mice to regenerate epithelium as well as give rise to the expected mesodermal derivatives. We hypothesized that extrapulmonary cells, including those from the bone marrow, can contribute to the reepithelialization of human alveoli. To investigate this, we examined samples of peripheral lung from patients who had undergone cross-gender transplantation of lung or bone marrow. Thus, archival blocks of peripheral lung were analyzed from male patients (surgical samples, n = 8) who had received a lung transplant from a female donor and female patients (postmortem samples, n = 3) who had male bone marrow transplants. In both cases, male cells were identified in the female lungs by Y chromosome in situ hybridization. Male cells could be identified in the alveolar epithelium where, in the better preserved, transplanted lungs, it was possible to show that some had differentiated to type II pneumocytes. In addition, Y chromosomes were found to be widespread in cells of mesenchymal lineage, including macrophages and endothelial cells. Concomitant visualization of Y and X chromosomes, using fluorescence immunolabeling, yielded no evidence of cellular fusion, although the poor quality of the autopsy samples studied meant that the possibility could not be excluded. These observations suggest that, as occurs in rodents, the epithelium of the adult human lung has the capacity to renew itself, using cells recruited from extrapulmonary sources, including the bone marrow. This finding could provide new therapeutic opportunities for a range of pulmonary diseases by providing means to repair the lung and a novel route for gene therapy.

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study.

BACKGROUND: In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS: We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS: At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS: In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

Lomefloxacin versus amoxicillin in the treatment of acute exacerbations of chronic bronchitis: an Italian multicenter study.

Nine centers in Italy participated in a worldwide, multicenter study comparing the effectiveness and safety of lomefloxacin and amoxicillin in patients with acute exacerbations of chronic bronchitis caused mainly by gram-negative pathogens. The 157 enrolled patients received either 400 mg lomefloxacin once daily (n = 78) or 500 mg amoxicillin every 8 hours (n = 79) for 7-10 days. A total of 131 patients were evaluable for bacteriologic efficacy and 154 for clinical efficacy. At 2-4 days after the conclusion of treatment, the bacterial eradication rate was 84.8% for lomefloxacin-treated patients and 64.6% for amoxicillin-treated patients (p = 0.0065); the clinical success rate (cure plus improvement) for lomefloxacin was 94.7% and for amoxicillin was 83.3% (p = 0.0212). The reinfection rate was lower in the lomefloxacin group than in the amoxicillin group (3.0% vs 13.8%, p = 0.0382). Both drug regimens were well tolerated. Once-a-day treatment with 400 mg lomefloxacin was more effective than 500 mg amoxicillin three times daily for the treatment of acute exacerbations of chronic bronchitis caused by gram-negative pathogens.

Alveolar immune mediators in HIV-related pneumonia. Different role of IL-2 and IL-1 in inducing lung damage.

In order to elucidate the role played by alveolar cytokines in the pathogenesis of HIV-related lung damage, levels of interleukin (IL) 1 beta, IL-2, IL-6, tumor necrosis factor (TNF)-alpha, and interferon (Ifn) were assessed on supernatant of bronchoalveolar lavage fluid from 30 consecutive HIV-1 seropositive (HIVAb+) patients with clinical and radiologic evidence of pneumonia, from 20 HIV- seronegative (HIVAb-) patients with pulmonary sarcoidosis, and from 10 HIVAb- healthy control subjects. Cytokine levels were expressed as picogram (IL-1, TNF), nanogram (IL-6), and international unit (IL-2, Ifn) per milligram of albumin per deciliter. Total and differential cell counts, cytofluorimetric enumeration of CD3+, CD3+/DR+, CD4+, CD8+, and CD8+/CD16+ cells, as well as microbiologic investigations for opportunistic agents were performed on lavage pellets. HIV-related pneumonia was characterized by higher mean alveolar level of IL-2 (12 +/- 5 IU), and by more elevated mean counts of T cells (109 +/- 16), activated T cells (60 +/- 12), and CD8+ cells (90 +/- 13)/microliters if compared with both active sarcoidosis and control subjects, where respective values of 0.2 +/- 0.1 and 0.3 +/- 0.2 IU IL-2/mgAlb/dl, of 52 +/- 11 and 7 +/- 2 T cells, of 20 +/- 5 and 1.2 +/- 0.3 activated T cells, and of 11 +/- 2 and 3 +/- 0.6 CD8+ cells per microliter were found. HIV-infected patients with opportunistic lung infections (OIs) showed the highest mean IL-2 level (21 +/- 4 IU), and higher counts of both CD8+ (117 +/- 20) and CD8+/CD16+ (36 +/- 7) cells per microliter if compared with patients without evidence of OIs (respectively, 62 +/- 13 CD8+ and 18 +/- 3 CD8+/CD16+ cells per microliter). By contrast, extremely high IL-1 levels (1,463 +/- 760 pg), and IL-2 levels similar to control subjects (3.4 +/- 1.2 IU), were found in the absence of OIs. Different mechanisms depending respectively on IL-2-mediated cytotoxic cell recruitment and activation, or IL-1-mediated tissue injury may account for HIV-related lung damage, depending on the presence or absence of opportunistic agents.

Tachykinin activation of human alveolar macrophages in tobacco smoke and sarcoidosis: a phenotypical and functional study.

Substance P (SP) and neurokinin A (NKA), which exert bronchoconstrictor effects on human airways, are known to interact with inflammatory and immune cells, including monocyte macrophages. We have evaluated the effects of SP, NKA and the NK2 selective agonist [beta-Ala8]-NKA(4-10) on alveolar macrophages (AM) isolated from 4 healthy smokers and 4 non-smoker active pulmonary sarcoid patients. An accumulation of activated mononuclear phagocytes, as well as elevated angiotensin-converting enzyme (ACE) activity, has been evidenced in both clinical conditions. The phenotype of AMs in the studied subjects was characterized by an elevated expression of CD68+, HLA-DR+ and CD14+, CD14+ being significantly less in sarcoidosis as compared to smokers. SP, NKA and the NK2 selective agonist evoked superoxide anion (O2-) production in AMs obtained from sarcoid patients or healthy smokers. While SP acted in a non-dose-dependent manner in both conditions, NKA and [beta-Ala8]-NKA(4-10) evoked a dose-dependent respiratory burst (ED50 = 0.25 and 0.26 nM, respectively) in smokers, but not in sarcoidosis. The more marked phenotypical expression correlated well with the ability of NK2 receptors to activate AMs in smoker subjects.

Tachykinin activation of human monocytes from patients with interstitial lung disease, healthy smokers or healthy volunteers.

Three types of tachykinin receptors, NK(1), NK(2)and NK(3), have been described to preferentially interact with substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) respectively. Experimental evidence indicates that SP and NKA modulate the activity of inflammatory and immune cells, including mononuclear ones, and points to their involvement in lung pathophysiology. We previously reported that NK(1)and NK(2)receptors are present on monocytes (MO) isolated from healthy donors or rheumatoid patients - a greater sensitivity to NK(2)receptor stimulation was observed in the latter condition. This study evaluated the effects of SP and NKA, as well as NK(1)and NK(2)selective agonists and antagonists, on MO obtained from healthy volunteers, healthy smokers or patients with interstitial lung diseases (e.g. sarcoidosis and idiopathic pulmonary fibrosis). Superoxide anion (O(2)(-)) production was chosen as a parameter of cell activation. SP and NKA dose-dependently evoked O(2)(-)production from MO in all the conditions evaluated, their effects being competitively antagonized by selective antagonists (CP 96 345 and MEN 10 627, respectively). When selective NK(1)and NK(2)agonists were used, [Sar(9)Met(O(2))(11)]SP, a selective NK(1)agonist, induced a more than doubled O(2)production in MO obtained from patients with interstitial lung diseases as compared to healthy volunteers, whereas MO isolated from healthy volunteers were more sensitive to NK(2)receptor stimulation.

Combination salvage chemotherapy with MIZE (ifosfamide-mesna, idarubicin and etoposide) for relapsing or refractory lymphoma.

In this study, 54 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) were treated in a phase II, multicentric trial with ifosfamide-mesna 1500 mg/m2 IV days 1-3, idarubicin 12 mg/m2 IV day 1 and etoposide 100 mg/m2 IV day 1-3 (MIZE). Overall response was 72%; complete response (CR) and partial response (PR) were 46% and 26% respectively. In Stage I-II pts CR was 59% and in Stage III-IV pts CR was 40.5%. Patients who relapsed from an initial CR had a 64% CR rate when treated with MIZE, in contrast to refractory disease's patients who only had 19% CR (p = 0.004). The group of pts that had an objective response (CR + PR) to front line therapy had a 2 year survival rate of 55% compared with none for refractory disease (p = 0.029) after salvage therapy. Median survival for the entire group was 17.5 months. Better survival was seen in pts who were asymptomatic with low levels of LDH, previous CR, non high-grade histology, and limited disease stage at relapse. Toxicity was mainly hematologic: 91.5% had neutropenia, (56.5% grade III-IV), and 9.5% died from infectious complications. Other clinical toxicities including cardiac toxicity were negligible. MIZE chemotherapy was effective in patients with relapsed and refractory lymphoma and showed limited clinical and cardiac toxicity. Myelosupression was the most frequent single toxicity.

[Diagnosis of tuberculosis today]. / La diagnosi di tubercolosi oggi.

Authors analyse the main aspects about the diagnosis of tuberculosis and they emphasize that the bacteriological and immunological tests are very important, beside the clinical, radiologic and hematic picture. As regards bacteriological research, Authors dwell upon the significance of repeated sputum specimens and they reevaluate the use of fluorochrome staining. The immunological "in vivo" tests are represented by tuberculin skin test, that must be correctly made and valued to avoid wrong unresponsiveness, at the other hand also caused by host factors. About immunological "in vitro" tests, Authors report the good prospects opened by the serological diagnosis with an immunoenzymatic method specific for S antigen of M. tuberculosis.

[Alveolar macrophage subpopulations and circulating monocytes. Immunophenotypic study in healthy non-smokers]. / Sottopopolazioni macrofagiche alveolari e monociti circolanti. Studio immunofenotipico in soggetti sani non fumatori.

Peripheral blood monocytes of 10 non-smoker normal subjects and the macrophages of their bronchoalveolar lavage fluid (BAL) were investigated with two commercially available monoclonal antibodies (MAC 387, CD14). Surface membrane monocyte cells show simultaneously both markers. Instead alveolar macrophage (MA) can be divided in three different phenotype groups by the expression of the two markers (MAC 387+/CD14-, MAC 387+/CD14+, MAC 387-/CD14+). Particularly, MA with MAC 387+/CD14+ phenotype are adherent cells and morphologically lack anthracosis. Their alveolar presence in non-smokers can be due to normal turnover of monocytes from blood into alveoli. By contrast MA with MAC 387+/CD14- phenotype are non-adherent cells without anthracosis. At last MA with MAC 387-/CD14+ phenotype are non-adherent cells but different amounts of anthracosis in their cytoplasm can be observed.

[Evaluation of leukocyte migration inhibition (LIF) in patients with carcinoma of the lung before and after the use of levamisole in vitro]. / Valutazione dell'inibizione della migrazione leucocitaria (LIF) su pazienti portatori di carcinoma del polmone prima e dopo l'uso di levamisolo in vitro.

Aspecific immunosuppression in neoplasia has long been known, even though all its biological aspects are not yet fully understood. Inhibition of leukocyte migration (LIF) was studied before and after the use of levamisole in vitro to determine whether changes occurred in cell reactivity. The results of the investigation are discussed in the light of modern immunopathological theories.

First report of the Italian register for diffuse infiltrative lung disorders (RIPID).

RIPID was established in 1998 as a joint project of the major Italian scientific societies for Respiratory Medicine, with the aim to create an Italian Register on diffuse infiltrative lung disorders that can provide the basis for epidemiological and clinical studies of adequate sample size. In the period from May 1998 to December 2000, 1,382 cases were submitted from 54 Centers in 15 regions of Italy, 54.2% males (mean age +/- SD 50.5 +/- 16.8 years) and 45.8% females (50.2 +/- 15.3 years). A current smoking habit emerges in 18% of subjects; former smokers and never-smokers represent 26% and 56% of the total case series, respectively. The most frequent disease registered is idiopathic pulmonary fibrosis (37.6%), followed in decreasing order by sarcoidosis (29.2%), and Langherans' cell hystiocytosis (6.6%). High resolution computed tomography (HRCT) was considered as the most important tool for final diagnosis in the majority of cases (74.4%); 39.4% of patients underwent transbronchial biopsies, 39.2% bronchoalveolar lavage (BAL). A surgical biopsy was performed in 20.5% of patients. A web site has been activated from December 2000 (www.pneumonet.it/ripid), allowing prompt access to all information and scientific material concerning the project and to an electronic form for data collection that can be completed on-line.

Challenges in idiopathic pulmonary fibrosis trials: the point on end-points.

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias and is associated with both a variable clinical course and a poor prognosis. Investigators involved in clinical trials and clinicians reviewing the IPF literature are confronted with daunting challenges in selecting reliable outcome measures, interpreting the clinical and statistical importance of these findings, and applying this knowledge to the clinical care of their patients. In order to evaluate the efficacy of new treatment regimens, a number of studies have been performed, employing a range of clinical and surrogate end-points. In most studies, the primary end-point consists of a single outcome measure. A desirable single clinical end-point for IPF should be reliable, valid, responsive to changes in disease status, clinically meaningful, predictive of clinical outcome and responsive to treatment effect of a given intervention. Proper consideration and effective choice of outcome measures used in IPF studies will help establish effective and achievable drug development programmes and will enable clinicians and investigators to make informed critical decisions in recommending a treatment regimen to their IPF patients.

Chronic administration of lonidamine in untreated non-small cell lung cancer of stage III M0-1.

Lonidamine (LND) interferes with the energy mechanisms of neoplastic cells and decreases the oxygen consumption in human and experimental tumors. The present study was performed in advanced non-small cell lung cancer patients, previously untreated, to confirm the preliminary data of activity against this kind of tumor. LND was given orally in three divided doses increasing to 250 mg/m2 over 4 days. Thirty-six patients were evaluable for toxicity and 33 for response. Partial responses were 3 (9%) and stabilization of disease 15 (45,5%). Recorded side effects (testicular pain, nausea and vomiting, skin hyperesthesia) were mostly mild to moderate with the exclusion of myalgias. Chronic treatment was devoid of haematological, renal, cardiac and pulmonary toxicities. LND as single agent seems to be marginally active in advanced non-small cell lung cancer.

Relationship between circulating immune complexes, serum interferon and clinical features in sarcoidosis.

In order to assess the importance of circulating interferons and immune complexes as hypothetical mediators of some immune derangements observed in sarcoidosis, we evaluated serum interferon and immune complex levels in 45 patients with active disease. In none of our patients could circulating interferon be detected, suggesting that an infectious (viral) etiology is very unlikely, and that a great difference exists between sarcoidosis and true autoimmune diseases. On the other hand, circulating immune complexes could be found in 64.4% of our patients. A good correlation could be found with disease stage and duration, but only with 67Ga lung scan among other activity indexes.