Pathogenesis and treatment of idiopathic and rheumatoid arthritis-related interstitial pneumonia. The possible lesson from COVID-19 pneumonia.

INTRODUCTION: Main clinical manifestations of SARS-CoV-2 infection are characterized by fever, dyspnea, and interstitial pneumonia, frequently evolving in acute respiratory distress syndrome (ARDS). AREAS COVERED: Features of coronavirus disease 2019 (COVID-19) presents some common points with interstitial lung disease (ILD) both idiopathic and related to rheumatoid arthritis (RA), typically characterized by a chronic progression over time and possibly complicated by acute exacerbation (AE). The study of common pathogenetic mechanisms, such as the involvement of toll-like receptor 4, could contribute to the knowledge and treatment of idiopathic and RA-ILD. Moreover, hyperinflammation, mainly characterized by increase of effector T-cells and inflammatory cytokines, and activation of coagulation cascade, observed in COVID-19 related ARDS have been already shown in patients with AE of idiopathic and RA-ILD. A literature search was performed in PubMed, Embase, Scopus, and Web of Science, together with a manual search in COVID-resource centers of the main journals. EXPERT OPINION: Despite the uncertainty about pathogenetic aspects about COVID-19- pneumonia, it could be a possible model for other forms of ILD and AE. The great amount of data from studies on COVID-19 could be helpful in proposing safe therapeutic approaches for RA-ILD, in understanding pathogenesis of usual interstitial pneumonia and to develop new therapeutic strategies for AE.

Diagnostic accuracy of a velcro sound detector (VECTOR) for interstitial lung disease in rheumatoid arthritis patients: the InSPIRAtE validation study (INterStitial pneumonia in rheumatoid ArThritis with an electronic device).

BACKGROUND: Interstitial lung disease (ILD) is a severe systemic manifestation of rheumatoid arthritis (RA). High-resolution computed tomography (HRCT) represents the gold standard for the diagnosis of ILD, but its routine use for screening programs is not advisable because of both high cost and X-ray exposure. Velcro crackles at lung auscultation occur very early in the course of interstitial pneumonia, and their detection is an indication for HRCT. Recently, we developed an algorithm (VECTOR) to detect the presence of Velcro crackles in pulmonary sounds and showed good results in a small sample of RA patients. The aim of the present investigation was to validate the diagnostic accuracy of VECTOR in a larger population of RA patients, compared with that of the reference standard of HRCT, from a multicentre study. METHODS: To avoid X-ray exposure, we enrolled 137 consecutive RA patients who had recently undergone HRCT. Lung sounds of all patients were recorded in 4 pulmonary fields bilaterally with a commercial electronic stethoscope (ES); subsequently, all HRCT images were blindly evaluated by a radiologist, and audio data were analysed by means of VECTOR. RESULTS: Fifty-nine of 137 patients showed ILD (43.1%). VECTOR correctly classified 115/137 patients, showing a diagnostic accuracy of 83.9% and a sensitivity and specificity of 93.2 and 76.9%, respectively. CONCLUSIONS: VECTOR may represent the first validated tool for the screening of RA patients who are suspected for ILD and who should be directed to HRCT for the diagnosis. Moreover, early identification of RA-ILD could contribute to the design of prospective studies aimed at elucidating unclear aspects of the disease.

Predictive value of isolated DLCO reduction in systemic sclerosis patients without cardio-pulmonary involvement at baseline.

Impaired diffusing capacity of the lung for carbon monoxide (DLCO) was frequently observed in systemic sclerosis (SSc) patients, generally related to the presence of interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). However, in clinical practice abnormally low DLCO values may be found also in the absence of these SSc complications. The objective was to investigate the prospective clinical relevance of isolated DLCO reduction at baseline in SSc patients. Ninety-seven SSc female patients (age at the diagnosis: 51.3±14.5 years; disease duration: 10.4±6.6 years; limited/diffuse skin subsets: 92/5), without any clinical, radiological (high resolution computed tomography), and echocardiographic manifestations of ILD or PAH at baseline, nor other lung or heart diseases able to affect DLCO, were recruited at our Rheumatology Centre. Patients with DLCO <55% (15 patients; group A) were compared with those with normal DLCO (82 patients; group B), at baseline and at the end of follow-up. At baseline, patients of group A showed significantly higher percentage of anticentromere autoantibodies compared to group B (13/15, 86.6% vs 48/82, 58.5%; p=0.044). More interestingly, at the end of long-lasting clinical follow-up (11.6±6.7 years), pre-capillary PAH (right heart catheterization) solely developed in some patients of group A (3/15, 20% vs 0/82; p=0.003). In SSc patients, the presence at baseline of isolated, marked DLCO reduction (<55% of predicted) and serum anticentromere autoantibodies might characterize a peculiar SSc subset that may precede the development of PAH. Therefore, careful clinical follow-up of patients with isolated moderate-severe DLCO reduction should be mandatory.

Evaluation of serum (1 → 3)-ß-D-glucan clinical performance: kinetic assessment, comparison with galactomannan and evaluation of confounding factors.

PURPOSE: We investigated the clinical performance of (1 → 3)-ß-D-glucan (BG), as an early marker of invasive fungal infections (IFI), in different clinical settings. METHODS: BG serum levels were assessed by Fungitell (Associates of Cape Cod, Inc), in parallel with galactomannan (GM) when requested by clinicians. By a prospective monocentric study, 270 episodes at risk or with suspect of IFI were enrolled, namely 58 proven-probable invasive aspergillosis (IA), 27 proven invasive candidiasis (IC), 11 possible IC, 16 P.jirovecii pneumonia (PJP), 4 episodes of other IFI and 154 non-IFI controls. RESULTS: We found that (a) the BG overall sensitivity, specificity, positive predictive value and negative predictive value (NPV) were 87.9, 80.5, 76.7 and 89.9 %, respectively; (b) the highest sensitivity was found in the IC groups, followed by PJP, IA and other IFI groups; (c) an association was observed between BG kinetics and patients outcome; (d) in the IA episodes, the combination of BG or GM vs GM alone increased sensitivity from 60.0 to 83.3 % in the haematological patients; (e) false-positive BG results were related to Gram-negative infections or infusion of polyclonal IgM-enriched immunoglobulins, where high levels of BG were indeed detected. CONCLUSION: Besides strengthening its overall good clinical performance, we provide evidence that serum BG correlates with clinical outcome and that, once used in combination with GM, BG allows to enhance IFI diagnosis rate. The high sensitivity and NPV, observed in the Intensive Care Unit setting, open to BG validation as a marker for assessment of antifungal treatment.

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.

Clinical performance of a commercial real-time PCR assay for Aspergillus DNA detection in serum samples from high-risk patients: comparison with a galactomannan enzyme immunoassay.

We investigated the clinical performance of a polymerase chain reaction (PCR)-based commercial platform, the Myconostica MycAssay™ Aspergillus (MAP), for fungal DNA detection in the serum of patients at risk of invasive aspergillosis (IA). Sixty-four hospitalized patients were prospectively enrolled and a total of 71 different episodes were investigated (30 episodes were clinically/microbiologically classified as IA and 41 as control episodes). When MAP was compared to the galactomannan (GM) assay, no significant differences were found in terms of sensitivity (46.7% vs. 50.0%), specificity (97.6% vs. 95.1%), positive predictive value (PPV) (93.3% vs. 88.2%), and negative predictive value (NPV) (71.4% vs. 72.2%). The corresponding areas under the curve (AUC) of the receiver operating characteristic (ROC) curves were also superimposable. Overall, because of the good agreement between the two assays and considering the high specificity and PPV of the MAP, we suggest the use of this PCR-based platform as a second-level examination for the evaluation of clinically undefined cases where culture or GM have provided positive results.

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.

Bronchoalveolar lavage and response to cyclophosphamide in scleroderma alveolitis.

OBJECTIVES: Systemic sclerosis (SSc) is characterized by abnormal fibrosis of the skin and internal organs, particularly the lungs. Recent reports have revealed a lack of correlation between bronchoalveolar lavage (BAL) variations and response to cyclophosphamide (CYC) in patients with scleroderma-related alveolitis. Our study aimed to evaluate whether the normalization of BAL cellularity correlates with long-term response to CYC. METHODS: We retrospectively studied 26 consecutive SSc patients with alveolitis diagnosed by BAL and treated with CYC therapy (cumulative dosage 26.5 +/- 11.7 g; 21.1 +/- 8.9 months of treatment). We evaluated high-resolution computed tomography (HRCT), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) variations before and after CYC. Radiological and functional parameters were re-evaluated in 23 patients after 1-year follow-up. RESULTS: BAL cellularity normalized after CYC therapy in 12/26 (46.2%) patients (group 1), while it remained abnormal in 14/26 (53.8%) (group 2). FVC and DLCO of group 1 slightly increased after CYC (p = 0.014 and p = 0.07, respectively) and remained stable at follow-up, whereas in group 2 they did not change after CYC and at follow-up (p = not significant). Moreover, at the end of CYC, FVC and/or DLCO showed a clinical improvement/stabilization in all patients of group 1 versus 8/14 of group 2, while at the re-evaluation 1 year after completing CYC, 2/11 patients of group 1 worsened versus 5/12 of group 2. HRCT progression was observed in 1/11 of group 1 and 8/12 of group 2 (p = 0.009). CONCLUSIONS: BAL fluid normalization after CYC therapy correlated with long-term response to treatment, contrary to what is observed in individuals with persistent alveolitis.

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.

Clusterin (CLU) and lung cancer.

Lung cancer is the leading cause of cancer-related mortality. It is categorized into two histological groups that have distinct clinical behaviors, the nonsmall cell lung cancers (NSCLC) and the small cell lung cancer (SCLC). When identified at an early stage, NSCLC is treated by surgical resection. However, patients who undergo surgical resection still have a relative low survival rate, primarily for tumor recurrence. Unfortunately, advances in cytotoxic therapy have reached a plateau and new approaches to treatment are needed together with new and better parameters for more accurate prediction of the outcome and more precise indication of the efficacy of the treatment. Several in vitro studies have examined the role of Clusterin (CLU) in carcinogenesis, lung cancer progression, and response to chemo- and radiotherapy. Studies performed in lung cancer cell lines and animal models showed that CLU is upregulated after exposure to chemo- and radiotherapy. A potential role proposed for the protein is cytoprotective. In vitro, CLU silencing by antisense oligonucleotides (ASO) and small-interfering RNAs (siRNA) directed against CLU mRNA in CLU-rich lung cancer cell lines sensitized cells to chemotherapy and radiotherapy and decreased their metastatic potential. In vivo, a recent work analyzed the prognostic role of CLU in NSCLC, showing that CLU-positive patients with lung cancer had a better overall survival and disease-free survival than those with CLU-negative tumors. These data are contradictory to the promising in vitro results. From the results of these studies we may hypothesize that in early-stage lung cancers CLU represents a positive biomarker correlating with better overall survival. In advanced patients, already treated with chemo- and radiotherapy, the induction of CLU may confer resistance to the treatments. However, many studies are needed to better understand the role of CLU in early-stage and advanced lung cancers with the aim to discriminate patients and specific local conditions that could benefit for a CLU knocking down treatment.

Role of comorbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is often associated with other chronic diseases. These patients are often admitted to hospital based rehabilitation programmes. OBJECTIVES: To determine the prevalence of chronic comorbidities in patients with COPD undergoing pulmonary rehabilitation and to assess their influence on outcome. DESIGN: Observational retrospective cohort study. SETTING: A single rehabilitation centre. PATIENTS: 2962 inpatients and outpatients with COPD (73% male, aged 71 (SD 8) years, forced expiratory volume in 1 s (FEV(1)) 49.3 (SD 14.8)% of predicted), graded 0, 1 or >/=2 according to the comorbidity categories and included in a pulmonary rehabilitation programme. MEASUREMENTS: The authors analysed the number of self-reported comorbidities and recorded the Charlson Index. They then calculated the percentage of patients with a predefined positive response to pulmonary rehabilitation (minimum clinically important difference (MCID)), as measured by improvement in exercise tolerance (6 min walking distance test (6MWD)), dyspnoea (Medical Research Council scale) and/or health related quality of life (St George's Respiratory Questionnaire (SGRQ)). RESULTS: 51% of the patients reported at least one chronic comorbidity added to COPD. Metabolic (systemic hypertension, diabetes and/or dyslipidaemia) and heart diseases (chronic heart failure and/or coronary heart disease) were the most frequently reported comorbid combinations (61% and 24%, respectively) among the overall diseases associated with COPD. The prevalence of patients with MCID was different across the comorbidity categories and outcomes. In a multiple categorical logistic regression model, the Charlson Index (OR 0.72 (96% CI 0.54 to 0.98) and 0.51 (96% CI 0.38 to 0.68) vs 6MWD and SGRQ, respectively), metabolic diseases (OR 0.57 (96% CI 0.49 to 0.67) vs 6MWD) and heart diseases (OR 0.67 (96% CI 0.55 to 0.83) vs SGRQ) reduced the probability to improve outcomes of rehabilitation. CONCLUSIONS: Most patients with COPD undergoing pulmonary rehabilitation have one or more comorbidities. Despite the fact that the presence of comorbidities does not preclude access to rehabilitation, the improvement in exercise tolerance and quality of life after rehabilitation may be reduced depending on the comorbidity.

Complex chronic comorbidities of COPD.

Chronic obstructive pulmonary disease (COPD) is defined by fixed airflow limitation associated with an abnormal pulmonary and systemic inflammatory response of the lungs to cigarette smoke. The systemic inflammation induced by smoking may also cause chronic heart failure, metabolic syndrome and other chronic diseases, which may contribute to the clinical manifestations and natural history of COPD. Thus COPD can no longer be considered a disease only of the lungs, as it is often associated with a wide variety of systemic consequences. A better understanding of the origin and consequences of systemic inflammation, and of potential therapies, will most likely lead to better care of patients with COPD. Medical textbooks and clinical guidelines still largely ignore the fact that COPD seldom occurs in isolation. As the diagnosis and assessment of severity of COPD may be greatly affected by the presence of comorbid conditions, the current authors believe that lung function measurement, noninvasive assessment of cardiovascular and metabolic functions, and circulating inflammatory markers (e.g. C-reactive protein) might help to better characterise these patients. Similarly, preventive and therapeutic interventions should address the patient in their complexity.

Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation.

Interleukin-8 (IL-8; CXCL8) is a cytokine of the CXC chemokine family that is involved in neutrophil recruitment and activation. In addition, IL-8 has been implicated in a wide variety of other processes, including angiogenesis and metastasis in lung cancer. Lung adenocarcinoma and muco-epidermoid carcinoma cells produce substantial amounts of IL-8, and express both CXCR1 and CXCR2 IL-8 receptors. We hypothesized that IL-8 stimulates proliferation of non-small cell lung cancer cells, involving transactivation of the epidermal growth factor receptor (EGFR). The EGFR plays a central role in regulating cell proliferation and it has been therefore implicated in lung cancer. Both EGFR ligands and transactivation of the receptor may lead to downstream signalling events, including mitogen-activated protein kinase (MAPK) activation. Transactivation of the EGFR has been shown to occur in response to ligands of various G-protein coupled receptors (GPCRs) and involves metalloproteinase-mediated release of membrane bound EGFR ligands. The aim of the present study was to investigate the effect of IL-8 on proliferation of lung adenocarcinoma and muco-epidermoid carcinoma cells, and to explore the mechanisms leading to this proliferation in two different non-small cell lung cancer cell lines (A549 and NCI-H292). In both NSCLC cell lines, we observed that IL-8 stimulates epithelial cell proliferation in a dose-dependent manner. The ability of IL-8 to increase cell proliferation was blocked both by an inhibitor of EGFR tyrosine kinase, by a specific anti-EGFR blocking antibody and by a panmetalloproteinase inhibitor. Similar results were obtained using the GPCR inhibitor pertussis toxin. Inhibition of the MAPK p42/44 (ERK1/2) also blocked the mitogenic effect of IL-8, while a p38 MAPK inhibitor did not affect IL-8-induced cell proliferation. These results suggest that IL-8 increases cell proliferation in NSCLC cell lines via transactivation of the EGFR and that this mechanism involves metalloproteinase activity.

Bronchial hyperresponsiveness in asthmatic adults--a long-term correlation study.

BACKGROUND: Bronchial hyper responsiveness (BHR), is a risk factor for asthma. It is a state in which excessive narrowing of the airways occurs in response to varying stimuli. BHR seems to be due to the interaction of multiple factors and its relation to asthma is complex. Asthma without BHR is unusual. Indeed, patients who show a higher degree of symptoms have higher levels of BHR. To date no study has investigated the correlation between BHR in mild persistent asthmatic adults and a long-term therapy of five years. The aim of this study is to evaluate (i) the role of BHR in the clinical evaluation of asthma, (ii) the correlation between BHR and therapy in asthma. METHODS: Seventy patients (were recruited 34 men, age 21-55 years) suffering from: (a) mild seasonal allergic asthma (17/70), (b) mild perennial allergic asthma (34/70) and (c) mild non-allergic [corrected] asthma (19/70). 14 patients from group (a) and 28 patients from group (b) were treated with inhaled beta2-agonists, beclomethasone, disodiumcromoglycate and immunotherapy. 14 patients from group (c) underwent the same treatment regimen without immunotherapy. All patients were evaluated with a metacholine challenge test. The BHR (PD20 FEV1) was calculated at baseline and after a two-year symptom free period. Fifteen pts were followed-up for five years with an evaluation every year. All other patients did not receive any treatment. The results (expressed as mean +/- SE) were evaluated. RESULTS: Fourteen pts and three pts from group (a) showed a mean BHR value of 984 +/- 3.66 and 674 +/- 2.06; 343 +/- 7.60 and 208 +/- 7.70 respectively. The results were not statistically significant Twenty-eight and six pts from group (b) showed mean values of 685 +/- 1.45 and 1405 +/- 5.65; 856 +/- 7.09 and 435 +/- 2.20 with apparent improvement for the former. Five pts and fourteen pts from group (c) showed mean value of 2682 +/- 7.85 and 2099 +/- 6.82; 816 +/- 2.53 and 877 +/- 4.78 respectively. As for the 5-yr follow up ten pts and five pts from group (b) showed mean values of 705 +/- 1.6 and 861 +/- 7.15; 911 +/- 7.3 and 457 +/- 2.3 respectively. CONCLUSIONS: Although the clinical picture improved with therapy, BHR was not significantly affected in any patient group, at two and five years of follow-up. Furthermore, no correlation was found between the clinical picture and PD20 FEV1 values. BHR seems to result from the interaction of multiple factors that are worth further investigating. BHR cannot be considered a marker of disease activity in asthma and therefore is not a useful tool for guiding asthma therapy.