Influence of allergic status and nasal polyposis on long-term Benralizumab response in eosinophilic severe asthma.

Objective: It is unclear whether Benralizumab effectiveness in severe eosinophilic asthma can be influenced by nasal polyposis (NP) or allergic status associations. We evaluated whether Benralizumab long-term efficacy in asthma outcomes could be different in subjects with atopy (SAEA) compared to the effectiveness in those without allergies (SNAEA) and in individuals with NP compared to those without NP. Methods: This observational retrospective study considered 95 consecutive patients divided into allergic (SAEA; n:65[68.4%]; skin prick tests positive [SPT] and/or IgE values ≥100 UI/mL), and non-allergic (SNAEA; n:30[31.6%], SPT negative and normal IgE levels<100 UI/mL). Overall population was also divided into two groups according to NP presence (NP+:39[41%] and NP-:56[59%]). Benralizumab treatment mean was19.7±7.2 months (range 12-35). Results: No differences in Benralizumab effectiveness were found in asthma outcomes in patients with/without NP. SNOT-22 improvement was higher in NP+ (-22±24) compared to NP- groups (6.33±15.5;p=0.055). FEV1 (16.33±19.22%), ACT(7.45±3.95) increases and frequency of SABA use (3.37±4.99) reduction were higher in SAEA compared to what obtained in non-allergic subjects (FEV1:8.15±15.6%,p=0.043; ACT:4.89±3.57,p=0.005; SABA use:-1.16±1.84;p=0.015). 93.8% of SAEA patients whereas only 72.2% of SNAEA individuals reduced OC doses at least half after Benralizumab (p=0.035). These results were partially confirmed by linear regression models showing associations between allergic status and FEV1, ACT and SABA use changes (ß=8.37;p=0.048, ß=2.056;p=0.033 and ß=-2.184;p=0.042 respectively). Conclusion: Benralizumab effectiveness in asthma appears to be independent of NP presence. The allergic eosinophilic disease, compared to just eosinophilic asthma, may be a more severe phenotype. Benralizumab may have greater efficacy in SAEA on some outcomes.

Severe asthma and long-term Benralizumab effectiveness in real-life.

OBJECTIVE: Long-term efficacy of Benralizumab in real life is not clearly known. We assessed the long-term effectiveness persistence to anti-IL-5R treatment in a group of severe eosinophilic asthmatics. PATIENTS AND METHODS: We retrospectively analyzed 95 individuals affected by severe asthma (36 males  ̶ 37.9%; mean age 58.1 ± 12.2) treated with Benralizumab (mean time 19.7 ± 7.2 months, range 12-35). Outcomes were evaluated at the beginning and at the end of patients' treatment periods. RESULTS: Mean baseline blood eosinophils were 897.5 ± 720.1 cells/µL (11 ± 5.6%) decreasing to 7.4 ± 20.6 cells/µL (0.97 ± 0.26%; p < 0.0001) after Benralizumab. FENO likewise decreased from 63.9 ± 68.4 to 28.4 ± 23.6 ppb, while FEV1% significantly improved (p < 0.0001). Mean FEF25-75 also increased from 45.8 ± 24.6% to 60.7 ± 24.6%, whereas RAW dropped from 202.15 ± 109.6% to 135.2 ± 54.75% (p < 0.0001). Also, lung volumes greatly decreased. ACT/ACQ significantly improved, while exacerbations number fell from 4.1 ± 2.4, before anti-IL-5R, to 0.33 ± 0.77, after treatment (p < 0.0001). Rhinitis severity levels and SNOT-22 also changed favorably. Patients that took long-term OCs were 71.6% before treatment, decreasing to 23.2% after Benralizumab (p < 0.0001), with an OCs dose reduction from 14.8 ± 8.9 to 1.45 ± 2.8 mg/day (p < 0.0001). 51.6% of subjects used SABA as needed before Benralizumab, falling to 4.2% after treatment. Several patients showed a reduction of ICS doses, SABA use and maintenance therapy step-down. Clinical/biological response with anti-IL-5R remained constant or even improved in terms of exacerbations or maintenance therapy reductions over time. On the contrary, FEF25-75% improvement slowed down in the long-term. No relationship was found between baseline blood eosinophil number and therapeutic response. CONCLUSIONS: Long-term Benralizumab effectiveness persistence in all outcomes in real life was confirmed.

Non-tuberculous mycobacteria: epidemiological pattern in a reference laboratory and risk factors associated with pulmonary disease.

The diseases caused by non-tuberculous mycobacteria (NTM), in both AIDS and non-AIDS populations, are increasingly recognized worldwide. Although the American Thoracic Society published the guidelines for diagnosis of NTM pulmonary disease (NTM-PD), the diagnosis is still difficult. In the first part of the study, we collected data on NTM isolates in the Mycobacteriology Laboratory of Careggi Hospital (Florence, Italy) and analysed the epidemiological data of NTM isolates. Then, to analyse the risk factors associated to NTM-PD, we studied the presence of ATS/IDSA criteria for NTM-PD in patients who had at least one positive respiratory sample for NTM and were admitted to the Infectious Disease Unit and the Section of Respiratory Medicine. We selected 88 patients with available full clinical data and, according to ATS/IDSA criteria, classified 15 patients (17%) as NTM-PD cases and 73 as colonized patients (83%). When comparing colonized and NTM-PD patients we did not find significant differences of age, gender and comorbidity. We observed that Mycobacterium avium and M. intracellulare were statistically associated with NTM-PD (P = 0·001) whereas M. xenopi was statistically associated with colonization. Although the number of studied patients is limited, our study did not identify risk factors for NTM-PD that could help clinicians to discriminate between colonization and disease. We underline the need of close monitoring of NTM-infected patients until the diagnosis is reasonably excluded. Further larger prospective studies and new biological markers are needed to identify new useful tools for the diagnosis of NTM-PD.

Whole-lung volume and density in spirometrically-gated inspiratory and expiratory CT in systemic sclerosis: correlation with static volumes at pulmonary function tests.

BACKGROUND: Spiral low-dose computed tomography (LDCT) permits to measure whole-lung volume and density in a single breath-hold. OBJECTIVE: To evaluate the agreement between static lung volumes measured with LDCT and pulmonary function test (PFT) and the correlation between the LDCT volumes and lung density in restrictive lung disease. DESIGN: Patients with Systemic Sclerosis (SSc) with (n = 24) and without (n = 16) pulmonary involvement on sequential thin-section CT and patients with chronic obstructive pulmonary disease (COPD)(n = 29) underwent spirometrically-gated LDCT at 90% and 10% of vital capacity to measure inspiratory and expiratory lung volumes and mean lung attenuation (MLA). Total lung capacity and residual volume were measured the same day of CT. RESULTS: Inspiratory [95% limits of agreement (95% LoA)--43.8% and 39.2%] and expiratory (95% LoA -45.8% and 37.1%) lung volumes measured on LDCT and PFT showed poor agreement in SSc patients with pulmonary involvement, whereas they were in substantial agreement (inspiratory 95% LoA -14.1% and 16.1%; expiratory 95% LoA -13.5% and 23%) in SSc patients without pulmonary involvement and in inspiratory scans only (95% LoA -23.1% and 20.9%) of COPD patients. Inspiratory and expiratory LDCT volumes, MLA and their deltas differentiated both SSc patients with or without pulmonary involvement from COPD patients. LDCT lung volumes and density were not correlated in SSc patients with pulmonary involvement, whereas they did correlate in SSc without pulmonary involvement and in COPD patients. CONCLUSIONS: In restrictive lung disease due to SSc there is poor agreement between static lung volumes measured using LDCT and PFT and the relationship between volume and density values on CT is altered.

Italian real-life experience of omalizumab.

Omalizumab is a humanized murine monoclonal antibody directed toward a portion of the IgE indicated in Europe for the treatment of severe persistent allergic asthma, inadequately controlled despite high-dose of ICS (mean BDP equivalent dose of inhaled corticosteroid 2224.68microg/die) in association with long-acting beta(2) agonists. Our aim was to describe the experience, efficacy and safety in a cohort of Italian patients treated with omalizumab in a real-life clinical setting. One hundred and forty two patients from 13 Italian Centers were observed and analysed. The dosage of omalizumab was established according to the labelling indication, with a median dose of IgE of 297.38IU/ml or kU/l. During the previous year, all patients experienced frequent exacerbations (mean=4.87), emergency visits (mean=4.45) and hospitalisation (mean=1.53). Following treatment with omalizumab, the annual rate of exacerbations, emergency visits and hospitalisation decreased by 79%, 88% and 95%, respectively. The proportion of patients without exacerbation, not needing emergency visits and hospitalization increased by 610%, 154% and 28%, respectively. The response to omalizumab measured with the GETE (global evaluation of treatment effectiveness) scale rated as good to excellent in 77% of patients. Overall, 9.6% (n=9) of the patients experienced one single adverse effect. Only one patient reported a serious adverse event (local reaction at the site of injection) leading to interruption of treatment. The observed reduction of asthma-related events in particularly poorly controlled patients in this Italian real-life setting is consistent with the results of other observational studies.

Induced sputum in systemic sclerosis interstitial lung disease: comparison to healthy controls and bronchoalveolar lavage.

BACKGROUND: Induced sputum (IS) is a noninvasive tool, which can be used to collect cellular and soluble materials from lung airways. OBJECTIVE: To evaluate if IS may be a useful and safe tool for the detection of airway inflammation in patients with interstitial lung disease (ILD) in systemic sclerosis (SSc). METHODS: Sixty-eight patients with SSc and ILD as well as 18 healthy individuals (controls) were selected and submitted to IS examination. In 34 of 68 patients with SSc, bronchoalveolar lavage (BAL) was also performed. Safety of IS was assessed by comparison of forced expiratory volume in the first second (FEV(1)), FEV(1)/forced vital capacity ratio and peak expiratory flow before and after the IS procedure. Cell composition in samples collected by BAL and IS was correlated, and IS total and differential cell count in SSc patients and controls were compared. RESULTS: The total number of cells was significantly higher in IS samples of SSc patients compared to those of healthy controls. Mean percentage of neutrophils was also higher in SSc patients (41.79 +/- 23.89 vs. 27.37 +/- 17.90), as well as lymphocytes (17.42 +/- 19.70 vs. 3.13 +/- 2.28) and eosinophils (2.35 +/- 4.43 vs. 0.41 +/- 0.46). On the other hand, mean percentage of macrophages was higher in healthy individuals (69.10 +/- 19.15 vs. 36.96 +/- 20.68). In fluid recovered by BAL, the most frequent cells were macrophages (67.89% +/- 17.26), while neutrophils (14.77 +/- 17.18%) and lymphocytes (15.62 +/- 13.46%) were less frequent and eosinophils (1.66 +/- 2.08%) were rare. A similar pattern of cell composition was found in IS samples (41.15 +/- 21.67% of macrophages, 39.72 +/- 23.15% of neutrophils, 15.28 +/- 19.46% of lymphocytes and 2.56 +/- 5.03% of eosinophils). Strength of correlation between BAL and IS was significant for macrophages and neutrophils. After IS procedure was performed, improvement of FEV(1) (mean value before IS was 85.09 +/- 14.44 and 88.93 +/- 16.40 after IS) and FEV(1)/forced vital capacity (mean value before IS was 98.53 +/- 12.11 and 105.22 +/- 10.78 after IS) was observed. CONCLUSION: The IS method may allow a noninvasive assessment of cell composition in airway fluid and may contribute to the better understanding of upper/medium airway inflammation in SSc. Future studies are needed to verify whether IS can replace invasive procedures for the detection and monitoring of lung inflammation in SSc.

[High resolution and spirometric synchronization computerized tomography in chronic obstructive bronchopneumopathy]. / Tomografia Computerizzata con alta risoluzione e sincronizzazione spirometrica nella broncopneumopatia cronica ostruttiva.

PURPOSE: To assess the feasibility of spirometrically gated HRCT in patients with chronic obstructive pulmonary disease and to correlate the density measures with the results of pulmonary function tests. MATERIAL AND METHODS: Pulmonary function tests and spirometrically gated HRCT were performed, on the same day, in 20 patients with chronic obstructive pulmonary disease. Spirometrically gated HRCT scans at 90 and 10% of the patient's vital capacity were acquired, at three anatomical levels (carena, carena plus 5 cm, carena minus 5 cm). In each section, lung parenchyma was isolated from the other thoracic structures and from the main bronchi and a densitometric evaluation was applied to the regions of interest. A histogram showing the distribution of the pixel frequencies versus lung densities, the mean CT number and the pixel index at -910 HU (for scans acquired at 10% of the patient's vital capacity) and at -950 HU (for scans obtained at 90% of the patient's vital capacity) were obtained. Average acquisition time for the spirometrically gated HRCt was 15-20 minutes, average data processing time was 20 minutes. RESULTS: The mean CT number and the pixel index at -910 HU obtained at 10% of the patient's vital capacity correlated with the Tiffeneau index (r = 0.85; R = 0.78 respectively). The pixel index at -910 HU correlated also with the ratio of residual volume to total lung capacity (r = 0.65). The mean CT number and the pixel index obtained at 90% of the vital capacity correlated with the lung diffusion of carbon monoxide (r = 0.64 and r = 0.79 respectively). CONCLUSIONS: In our study, we found good correlation between the densitometric values obtained with spirometrically gated HRCT and the respiratory function tests routinely employed to assess the presence and the gravity of obstructive pulmonary disease. A good reproducibility of the data is guaranteed by the spirometical gating which enables standardization of the lung acquisition volume, and by the semiautomatic contour tracing program combined with an automated densitometric evaluation. The main disadvantages of the technique are the relatively long acquisition and evaluation times. Spirometrically gated HRCT densitometry is a promising tool for longitudinal studies of diffuse lung disease (pulmonary emphysema and fibrosis).

Fog-induced respiratory responses are attenuated by nedocromil sodium in humans.

Fog inhalation induces cough and bronchoconstriction in patients with asthma, but only cough in normal subjects; whether it also influences the pattern of breathing is unclear. Nedocromil sodium (NCS) inhibits the cough response to inhalation of several pharmacological agents but its effects on fog-induced cough and changes in the pattern of breathing are unknown. We evaluated the effects of no drug, placebo, and 4- and 8-mg NCS administration on the cough threshold and changes in the pattern of breathing during fog inhalation in 14 healthy subjects. Measurements of tidal volume (VT), duration of inspiratory and expiratory times (TI and TE, respectively), total duration of the respiratory cycle (TT), mean inspiratory flow (VT/TI), duty cycle (TI/TT), respiratory frequency (f, 60/TT), and inspiratory minute ventilation (V I) were obtained by inductive plethysmography. Median cough threshold values were unaffected by placebo, but were increased (p < 0.01) by both NCS doses. In no-drug and placebo trials, inhalation of the threshold fog concentration caused increases in both VT/TI and V I (p always < 0.05) due to selective increases (p < 0.01) in VT. These changes were markedly attenuated by both NCS doses administration. Thus, fog induces coughing and increases in VT, VT/ TI, and V I in healthy subjects; NCS possesses antitussive effects and attenuates fog-induced changes in the pattern of breathing, possibly through inhibition of rapidly adapting "irritant" receptors.

Pulmonary involvement in juvenile dermatomyositis: a two-year longitudinal study.

OBJECTIVE: To investigate the prevalence and features of asymptomatic pulmonary involvement in juvenile dermatomyositis (JDM). METHODS: Twelve JDM patients underwent pulmonary function tests at baseline, 12 and 24 months. Disease activity, duration, serum lactate dehydrogenase (LDH) values and antinuclear antibody (ANA) titres were also evaluated. RESULTS: Five patients showed lung impairment at baseline and four at 12 and 24 months. Forced expiratory volume in 1s, forced vital capacity (FVC), carbon monoxide diffusing capacity (DLCO) and alveolar volume were the most frequently altered variables, indicating a restrictive pattern and impairment of diffusion. The prevalence and features of pulmonary alterations did not change during follow-up. FVC values were significantly lower in active JDM patients and were inversely related to LDH. DLCO values were significantly lower in ANA-positive patients. About half of the patients of this small case series of JDM had asymptomatic lung disease. CONCLUSIONS: We suggest that lung function should be evaluated at disease onset and regularly during follow-up, as pulmonary function tests can detect otherwise unpredictable pulmonary involvement.

Pulmonary function in children affected by juvenile spondyloarthropathy.

OBJECTIVE: Pleuropulmonary involvement in adult spondyloarthropathy (SpA) has been thoroughly investigated. SpA is usually detected by conventional radiology as fibrosis of the upper lobes in about 30% of asymptomatic patients. Pulmonary function tests (PFT) reveal decreased vital capacity and total lung capacity, as well as increased residual volume. Juvenile SpA (JSpA) is a rare clinical condition, and no extensive investigations have been carried out on pulmonary involvement in JSpA. We studied prevalence and features of PFT alterations in patients with JSpA over a 2 year followup and analyzed the relationship between PFT and disease duration, disease activity, and chest and spine mobility. METHODS: Eighteen patients with JSpA, with no clinical signs of lung disease and normal chest radiographs, underwent PFT--static and dynamic volumes, diffusing capacity for carbon monoxide (DLCO), at enrollment (T0), at 12 months (T1), and at 24 months later (T2). Disease activity was defined at each investigation by clinical and hematological data. RESULTS: Significant functional lung impairment was detected in 33% of patients (reduced forced vital capacity in 22% and DLCO in 11%). No significant change in the prevalence and features of PFT alterations was detected at T1 and T2; no relationship was found between PFT and duration, activity, and clinical scores of the disease. CONCLUSION: Thirty-three percent of JSpA patients without clinical symptoms and no radiological findings of lung involvement show PFT alterations, mainly characterized by a restrictive pattern. No progression or modification in PFT developed over 2 years. No correlation was found between PFT and disease duration, activity, and clinical scores.

Pulmonary involvement in juvenile systemic lupus erythematosus: a study on lung function in patients asymptomatic for respiratory disease.

Pleuro-pulmonary involvement has been well recognized in adults affected with systemic lupus erythematosus (SLE), but few studies have been carried out in children. A longitudinal study on a group of 15 children affected with juvenile SLE (JSLE), asymptomatic for lung disease, was performed, and the prevalence and the features of respiratory function alterations, over a period of 12 months, were analysed. Moreover, a possible correlation between any pulmonary function test (PFT) and disease duration, disease activity, visceral involvement and immunological pattern was evaluated. At baseline, a significant functional lung impairment was present in 40% of patients, with a significantly reduced FVC, VA and DLCO in 26% of them; in 60% of patients at 6 months and in 33% of patients at 12 months. At 6 and 12 months, our data did not show any significant modification in PFTs and the restrictive pattern, observed at baseline, remained unchanged. No correlation between altered PFTs and disease duration, activity and/or immunological findings was found. At baseline, the presence of neurological involvement was the only extra-pulmonary feature correlated to reduced FVC.

Effect on lung function of methotrexate and non-steroid anti-inflammatory drugs in children with juvenile rheumatoid arthritis.

We evaluated lung function in a group of patients affected by juvenile rheumatoid arthritis (JRA), without clinical and/or radiological signs of respiratory involvement. We compared the effects on pulmonary function of methotrexate (MTX) therapy combined with non-steroid anti-inflammatory drugs (NSAIDs) to those of NSAIDs alone and correlated lung function to subtype onset, disease duration and disease activity. Our patients were 27 JRA children, subdivided into two groups according to the therapy (group A = 14 patients, treated with a low dose of MTX and NSAIDs; group B = 13 patients, treated with NSAIDs alone). Clinical evaluation, haematological data and pulmonary function tests (PFTs) were obtained in each group at baseline (time 0) and at 1 year (time 1). At time 0 and time 1 PFTs were altered in 51.8% of JRA patients. The restrictive pattern (reduced forced vital capacity, FVC) was the most frequent feature, observed in 22.2% of patients. In group A the mean values of FVC, FEV1 (forced expiratory flow in 1 s), FRC (functional residual capacity), TLC (total lung capacity) and DLCO (diffusing lung capacity of carbon monoxide) were significantly lower compared to those of group B, at time 0 and at time 1. No functional parameter was correlated to subtype, duration or activity of the disease. Our study confirms that abnormalities in PFTs may be detected in JRA patients, even in the absence of clinical and/or radiological signs of lung disease; MTX in combination with NSAIDs does not seem to affect lung function at 1 year more than NSAIDs alone.

Comparison of dose-response slopes obtained by simultaneous assessment of changes in FEV1 and transcutaneous oxygen partial pressure during methacholine challenges in asthmatic patients.

We aimed to ascertain whether monitoring changes in transcutaneous (tc) oxygen partial pressure (PO2) may be used to determine the slope of the dose-response curves to inhaled methacholine. In 10 adult asthmatic patients, FEV1 and tcPO2 were simultaneously measured during inhalation of doubling methacholine concentrations. In each patient, the slopes of the methacholine dose-response curves for FEV1 and tcPO2 were similar and strongly correlated (r = 0.72; p < 0.05). The results indicate that tcPO2 monitoring represents a useful, reliable tool for analysis of the slope of dose-response curves to inhaled methacholine in asthmatic patients. It can also be used to investigate the pathophysiological implications of bronchial hyperreactivity.

Changes in transcutaneous oxygen partial pressure as an index of response to inhaled methacholine in asthmatic patients.

Bronchoconstriction and hypoxemia have been reported to occur during airway challenges, but the correlation between changes in forced expiratory volume in 1 s (FEV1) and transcutaneous oxygen partial pressure (tcPO2) during methacholine provocation tests has not yet been established (to our knowledge). In 15 symptom-free atopic asthmatic patients and 5 normal subjects, variations in tcPO2 and FEV1 were simultaneously measured during inhalation of doubling methacholine concentrations; the drug concentrations causing a 20 percent decrease in control FEV1 and tcPO2 (PC20FEV1 and PC20tcPO2, respectively) were subsequently calculated. In patients, geometric mean PC20FEV1 and PC20TcPO2 were 1.31 (range, 0.16 to 5.19) and 1.26 (range, 0.29 to 5.82) mg/ml, respectively. In addition, in six patients, methacholine-induced fall in tcPO2 was accompanied by similar changes in arterial PO2. Methacholine inhalation caused no change in tcPO2 or FEV1 in normal subjects. The independent effects of deep breath tests and bronchoconstriction on PC20tcPO2 were studied in five patients challenged on two separate occasions, with and without FEV1 assessment; in these patients, PC20tcPO2 were similar on both the study days. The results indicate that, in asthmatic patients, methacholine-induced bronchoconstriction causes parallel decreases in FEV1 and tcPO2. The tcPO2 monitoring may serve as a tool in the assessment of airway hyperreactivity when active patient's cooperation is scarce.

Clinical utility of non invasive methods in the evaluation of scleroderma lung in pediatric age.

Lung involvement in children affected with Systemic Sclerosis (SSc) has been studied. We used ventilation and perfusion scans and compared the results to those obtained with traditional pulmonary function tests. The vascular pulmonary area was examined with a gama-camera after infusion of 99mTc microspheres, while the alveolo-capillary membrane and the airways were investigated after administration of a radioaerosol, (99mTc DTPA). Pulmonary function tests revealed either alteration of the airways or a considerable involvement of the alveolo-capillary membrane in two patients. On the other hand ventilation scan showed airways alterations and a severe decrease of the alveolocapillary permeability in all patients. Our study indicates that ventilation scans may be useful in the diagnosis of early modifications of the lung function also in paediatric age and may complement the data obtained from traditional function tests.