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Introduction: Many uncontrolled severe asthmatics are not on biologic therapy. We hypothesized that using a prescription database could help us identify them. Material and Methods: 3309 patients who received at least one Montelukast prescription in 2019 were extracted from our prescription database. Number of packages/year, types and dosages of ICS, LABA, ICS/LABA, LAMA and monoclonal antibodies were considered for each patient. In our analysis, for subjects that took > 7 packages of ICS/LABA + LTRA +/– LAMA (high adherent) the number of oral corticosteroids (OC) packets prescribed for each of them was also looked upon. Results: Patients that took ICS/LABA or ICS/LABA + LAMA continuously with high ICS doses were 188 (25.6%) and 117 (39.3%) respectively (total: 305 — 29.5%). Among them, 58 (30.9%) and 53 (45.3%) (total: 111 — 36.4%) were prescribed more than 2 OC packages. Whereas, 21 (11.2%) and 24 (20.5%) patients (total: 45 — 14.75%) received at least 4 OC package prescriptions. Conclusion: Approximately 36% of patients in continuous step-4/5 of GINA Guideliness treatment may have severe uncontrolled asthma (overusing OC) which needed biologic treatment. In our opinion, a prescription archiving database may be a tool that can help us identify such uncontrolled asthma patients.

Background Omalizumab therapy was found to be safe and effective as an add-on therapy for patients with poorly controlled severe asthma. Although several studies over the last decade have demonstrated its efficacy in other Immunoglobulin E related diseases, its use in such conditions is off-label. Objective This study aimed to assess the effectiveness of long-term therapy with Omalizumab in patients with persistent severe allergic rhinitis and inadequately controlled severe asthma. Methods Patients with poorly controlled severe asthma and persistent allergic rhinitis were enrolled and treated with Omalizumab for 36 months with every four-week subcutaneous administration. The efficacy assessment included the severity of AR symptoms every six months using Visual Analogue Scale, Asthma Control Test, nasal endoscopy, spirometry, and biomarkers (blood eosinophils and neutrophils, fractional exhaled nitric oxide, total IgE). Results Eleven patients aged between 26 and 70 years were enrolled, and 10 completed the study. A significant improvement of allergic rhinitis symptoms, Asthma Control Test, and lung function was observed. There was also a reduction in the status of the biomarkers at the end of the study. Conclusion Long-term therapy with Omalizumab was effective and safe in treating severe persistent allergic rhinitis and concomitant asthma.

We know that excessive short-acting β2-agonists (SABA) use in asthma may be associated to high exacerbation risks. We studied whether such excessive SABA consumption is connected with different higher oral corticosteroid (OC) prescriptions in the two sexes.In our prescribing database, we searched subjects aged 18-40 years that were prescribed at least one SABA package/year and/or at least two ICS or two ICS/LABA boxes/year to identify asthmatics. Their OC prescriptions/year were also examined. Subjects were divided into 4 groups according to SABA packages/year prescribed (0, 1-2,3-6 and ≥7), considering sexes separately.Individuals recruited were 9,102. Subjects with at least one OC prescription were higher in each group and were females (p0.001). The OC packages/year number was also more elevated in women especially those with7 SABA prescriptions/year (0.96 in males vs 2.64 in females, p0.001). 94.7%/93.6% males/females, who never used SABA, took at least one ICS/LABA (mean 5.84/5.48 packages/year), while the subject percentage adhering to ICS/LABA dropped to 28-47% (mean 0.94-3.82 packages/year) in those who used SABA (p0.001). Higher SABA prescriptions were associated with an increasing OC dispensation (β=0.057,p0.0001). We observed also a greater risk of using3 OC packages/year in subjects with 3-6 (OR:2.98[95%CI:2.19-4.06],p0.001) and ≥7 (OR:3.49[95%CI:2.39-5.10],p0.001) SABA prescriptions compared to those that never used SABA. Besides, we found that using ICS (OR:0.51[95%CI:0.35-0.75], p0.001) or ICS/LABA (OR:0.07[95%CI:0.05-0.09],p0.001) may significantly reduce SABA prescriptions.Poor adherence to maintenance treatment appears to associated with excessive SABA prescriptions that may lead to a higher OC consumption particularly noticeable in women.

Background Several immune mechanisms activate in COVID-19 pathogenesis. Usually, coronavirus infection is characterized by dysregulated host immune responses, interleukine-6 increase, hyper-activation of cytotoxic CD8 T lymphocytes. Interestingly, Vitamin D deficiency has been often associated with altered immune responses and infections. In the present study, we evaluated Vitamin D plasma levels in patients affected with different lung involvement during COVID-19 infection. Methods Lymphocyte phenotypes were assessed by flow cytometry. Thoracic CT scan involvement was obtained by an image analysis program. Results Vitamin D levels were deficient in (80%) of patients, insufficient in (6.5%) and normal in (13.5%). Patients with very low Vitamin D plasma levels had more elevated D-Dimer values, a more elevated B lymphocyte cell count, a reduction of CD8 + T lymphocytes with a low CD4/CD8 ratio, more compromised clinical findings (measured by LIPI and SOFA scores) and thoracic CT scan involvement. Conclusions Vitamin D deficiency is associated with compromised inflammatory responses and higher pulmonary involvement in COVID-19 affected patients. Vitamin D assessment, during COVID-19 infection, could be a useful analysis for possible therapeutic interventions. Trial registration: 'retrospectively registered'.

Authors present 6 cases of abdominal bleeding associated with COVID-19, representing 1.35% of all hospitalized COVID-19 patients and hypothesize that there could be, although not very frequently, a relationship between SARS-CoV2 and bleeding. They excluded a side effect of the low molecular weight heparin therapy that all patients underwent during the course of the disease or other possible causes. Alterations of the coagulation state or a weakness of the vascular wall due toa presumed endotheliitis SARS-CoV-2 infection induced, are hypothesized by the authors. Investigation and follow-up for possible hemorrhagic problems in patients with COVID-19 is recommended. In particular, clinicians should be vigilant about retroperitoneal hemorrhage in COVID-19 patients. In addition to the fact that these patients are being treated with anticoagulants, anemia and abdominal pain are the signs that should lead us to suspect this type of haemorrhage. More studies are needed to understand if COVID-19 can be directly associated with bleeding. (www.actabiomedica.it)

Background: It is not clear whether mepolizumab is differently effective in allergic and nonallergic severe eosinophilic asthmatics (SEA) in real life. Objective: We tested mepolizumab effectiveness in allergic/nonallergic SEA in real life. A strict criterion to identify the 2 phenotypes was used. Method: We retrospectively considered 134 consecutive patients divided into allergic, with a positivity to at least 1 allergen to prick tests and/or IgE values ≥100 UI/mL (severe allergic eosinophilic asthma [SAEA]; n: 97–72.4%), and nonallergic, with no prick test results and normal IgE levels n: 37–27.6%). They had taken mepolizumab for at least 6 months. Results: After 10.9 ± 3.7 months, improvements in FEV1%, FEF25–75%, exacerbation numbers, blood eosinophil (BE) counts, fractional exhaled nitric oxide (FENO) (ppb), percentages of patients that stopped/reduced short-acting β2-agonists (SABAs) or oral corticosteroid (OC), observed after treatment, were similar in both groups. Only Asthma Control Test (ACT) increases were higher in SNAEA (8 [5–9]) than in SAEA (5 [2.5–8.5]; p = 0.016). However, no differences were found after treatment in percentages of subjects with ACT ≥20, as well as with FEV1 >80%, FEF25–75 >65%, exacerbations ≤2, BE 1% (β = −0.110; p = 0.266), FEF25–75% (β = −0.228; p = 0.06), BE counts (β = −0.012; p = 0.918), FENO (β = 0.234; p = 0.085), ACT (β = 0.046; p = 0.660), and exacerbations (β = −0.070; p = 0.437). No different associations between lung function and SNAEA occurrence when compared to SAEA condition (FEV1 >80%: OR = 1.04 [95% CI: 0.43–2.55], p = 0.923; FEF25–75 >65%: OR = 0.41 [95% CI: 0.08–2.03], p = 0.272) were detected. Neither all other parameters, such as ACT >20 (OR = 0.73 [95% CI: 0.32–1.63], p = 0.440), presence of exacerbations (OR = 1.35 [95% CI: 0.55–3.27], p = 0.512), SABA discontinuation (OR = 1.16 [95% CI: 0.40–3.39], p = 0.790), and OC cessation/reduction (OR = 3.44 [95% CI: 0.40–29.27], p = 0.258), were differently associated with 1 or the other phenotype. Conclusion: Mepolizumab can be considered as a valid therapeutic choice for either allergic or nonallergic SEA in real life.

Background: Despite adding Omalizumab to conventional therapy, several severe asthmatics still show poor disease control. We investigated the factors that may affect a reduced Omalizumab response in a large population of severe asthmatics. Methods: 340 patients were retrospectively evaluated. FEV1%, FVC%, Asthma Control Test (ACT), fractional exhaled nitric oxide (FENO), possible step-downs/step-ups of concomitant therapies, exacerbations, disease control levels, ICS doses and SABA use, observed at the end of treatment, were considered as a response to Omalizumab. Results: Age was an independent risk factor for a reduced response concerning FEV1%, FVC%, ACT and for a lower asthma control. Obesity (vs normal weight) was a determinant condition for exacerbations (OR:3.114[1.509–6.424], p = 0.002), for a disease partial/no control (OR:2.665[1.064–6.680], p = 0.036), for excessive SABA use (OR:4.448[1.837–10.768], p = 0.002) and for an unchanged/increased level of concomitant asthma medications. Furthermore, obesity also reduced the response in FEV1 (β = −6.981,p = 0.04), FVC (β = −11.689,p = 0.014) and ACT (β = −2.585, p = 0.027) and was associated with a higher FENO level (β = 49.045,p = 0.040). Having at least one comorbidity was a risk factor for exacerbations (OR:1.383[1.128–1.697], p = 0.008) and for an ACT

Background Given COPD heterogeneity, we do not know if some LABA/LAMAs are more suitable for some COPD phenotypes. This real-life database study aimed to evaluate retrospectively the 4 LABA/LAMA effectiveness and highlight possible specificities that could better guide us in choosing the right LABA/LAMA to be used. Methods We searched for subjects (1,779) adherent to umeclidinium/vilanterol (UM/VI), indacaterol/glycopyrronium (IND/GLY), aclidinium/formoterol (ACLI/FOR) and tiotropium/olodaterol (TIO/OLO) treatments in our prescribing/dispensing database. Prescriptions for systemic corticosteroids (SC), antibiotics and salbutamol during one year of LABA/LAMA treatment were analyzed. Results A better adherence was found in individuals taking IND/GLY (10.42 ± 1.86 packages/year) compared with UM/VI (10.09 ± 1.9; p = 0.008), ACLI/FOR (9.8 ± 1.8; p = 0.001) and TIO/OLO (10.1 ± 2.1; p = 0.047). The number of patients that were prescribed at least one package of SC/year and their package numbers/year were similar in males/females, across age groups and in “non-frequent exacerbators” with the 4 LABA/LAMAs. More SC were taken by frequent exacerbators, whereas fewer SC/antibiotic packages were prescribed to subjects aged >80 years with all treatments. In patients treated with ACLI/FOR or TIO/OLO, lower risks to having antibiotic prescriptions were observed when UM/VI (0.698[0.516–0.945] and 0.696[0.491–0.985; p = 0.020 and p = 0.041) and IND/GLY (0.597[0.445–0.802] and 0.595[0.423–0.836]; p = 0.001 and p = 0.003) were considered as landmarks. Lower risks for salbutamol prescriptions were detected with UM/VI (0.678[0.480–0.958]; p = 0.027) and TIO/OLO (0.585[0.365–0.937]; p = 0.026) when ACLI/FOR was used as a reference. Conclusion According to our retrospective database study, each LABA/LAMA could have a specific efficacy profile in COPD that might be considered for personalized therapy. However, head-to-head targeted trials aimed to assess the impact of different LABA/LAMAs on COPD are needed to confirm/disprove such results.

Objective It is unknown whether Omalizumab effectiveness changes over the course of time. Our retrospective real-life study tried to analyze whether Omalizumab response may be influenced by treatment duration. Methods 340 severe asthmatics treated with Omalizumab for different periods of time were recruited. They were subdivided into 4 groups according to the Omalizumab treatment length: 60 months. Omalizumab treatment results (FEV1, exacerbations, ACT, SABA use, asthma control levels, medications used e and ICS doses) were compared. Results ACT, exacerbations, GINA control levels, ICS doses and SABA use were similar in all groups with different Omalizumab treatment durations. Using a linear regression model, corrected for all confounding variables, a higher significant positive increase in FEV1% in subjects treated for 12–24 (β = 9.49; p = 0.034) or 24–60 months (β = 8.56; p = 0.043) was found when compared with subjects treated for a shorter period. Treatment duration was positively associated with a step down of the other associated therapies (OR: 1.013; p = 0.019). This association was more relevant (OR: 4.167; p = 0.005) when we considered Omalizumab treatment duration >60 months compared to the shorter therapy. In particular, the percentage of subjects that were taking Montelukast, LABAs and oral corticosteroids was lower in the group treated with Omalizumab for a longer period of time. Conclusion In real-life, the positive Omalizumab response remained stable for over 60 months. Long term Omalizumab treatment may lead to a discontinuation of some associated medications and to a slowing down of FEV1decline.

Background: The avascular region of the fibrous body between the mitral and aortic valves, named mitral-aortic intervalvular fibrosa (MAIVF), is often involved in the periaortic diffusion of infective endocarditis (IE), resulting in abscess or pseudoaneurysm formation. The early recognition of these life-threatening complications is of crucial importance, as urgent surgical correction is necessary. In the first stages of the abscess formation, the only sign is an increased thickness of the MAIVF. To the best of our knowledge, normal transesophageal echocardiography (TEE) examination reference values for MAIVF thickness has not yet been established. The aim of the study was to define the normal ranges of MAIVF thickness in a population of healthy adults who underwent a TEE examination. Materials and Methods: A population of consecutive adult patients who underwent a TEE examination was enrolled in the study. Measurement was performed in short-axis (SAX) and long-axis (LAX) views. Mean-2 standard deviations (mean-2SDs) and 5%, 10%, 90%, and 95% confidence intervals were evaluated. A comparison with MAIVF thickness in patients affected by aortic IE complicated by abscess formation was performed, and receiver operating characteristic (ROC) curves were constructed to achieve the optimal cutoff value of normality. Results: A total of 477 consecutive Caucasian adult patients were enrolled (mean age: 69 years, range: 27–93 years). Mean-2SD MAIVF measurement in SAX view was 0.325 cm (95% confidence interval [CI]: 0.319–0.330 cm) and in LAX view was 0.340 cm (95% CI: 0.334–0.346 cm). Computed tomography–MAIVF mean measurement (±2SD) was 0.237 cm (95% CI: 0.110–0.340 cm). ROC curves showed that a cutoff SAX value measurement of 0.552 (area under the curve [AUC]: 95.2%) had a sensibility of 88.2% and a specificity of 92.4%; a LAX measurement value of 0.623 (AUC: 93.3%) had a sensibility of 82.7% and a specificity of 85.7%. The multivariate analysis showed no significant correlation between MAIVF thickness, age, and sex. Conclusion: In healthy patients, MAIVF thickness should not exceed 0.600 cm. Above these values, the suspicion of a periaortic abscess formation should be raised. MAIVF increased thickness may be an early sign of perivalvular diffusion requiring an urgent endocarditis team evaluation.

Today it remains unclear why children seem to be less likely to get infected by COVID-19 or why they appear to be less symptomatic after infections. All individuals, especially children, are exposed to various viruses including human coronavirus (CoVs) that can generally lead to respiratory infections. We hypothesize that recurrent CoVs exposure may induce an effective antiviral B and T-cell-mediated adaptive immune response, which could also be protective against COVID-19. Based on the high-homology between the Spike protein epitopes of taxonomically-related coronaviruses, we theorize that past/recurrent contact with CoVs might shield children also against the circulating COVID-19 through a possible neutralizing antibody response previously CoVs-induced. This would open up possible lines of research for the development of live-attenuated virus vaccines from CoVs. Future research is desirable to confirm or disprove such hypothesis.

The high spatial resolution of cardiac computed tomography (CT) and cardiac magnetic resonance (CMR) permit the diagnosis of congenital ventricular outpouchings (CVOs), including congenital ventricular diverticula (CVD), congenital ventricular aneurysms (CVA), clefts, and crypts. A unique classification has not been established, and these terms are used interchangeably with confounding terminology. Moreover, their significance is not univocal. A research was performed using PubMed on six subjects: (1) congenital left ventricular outpouchings; (2) congenital ventricular diverticulum; (3) congenital ventricular aneurysm; (4) ventricular clefts; (5) ventricular crypts; and (6) ventricular crevices. Usually, CVOs are small with a preserved contraction and in asymptomatic patients, the clinical relevance may be minimal, although electrocardiographic anomalies are often present. CVA and diverticula may carry an embolic risk and cases of arrhythmia and rupture are described. In the presence of clefts, or crypts a cardiomyopathy should be excluded. A simple classification can be proposed: CVD extend beyond the myocardial wall and fibrous type may be termed CVA, acquired forms should be kept distinct. Clefts, or crypts, are small recesses extending for more than 50% of the ventricular wall but not beyond its margin. The presence of fibrosis may be evaluated by CMR. A multicenter prospective registry would be helpful to investigate potential clinical implications and to exclude dubious forms of hypertrophic cardiomyopathy or ventricular noncompaction. In conclusion, CVOs have been described with different terminologies and classifications. Their significance needs to be interpreted in the clinical setting and with the help of a multimodality imaging, particularly of CMR.

Background. Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and comorbidities. In the present study, we focused on the effect of metronomic vinorelbine treatment in elderly patients with advanced unresectable non-small cell lung cancer (NSCLC).Methods. From January 2016 to December 2016, 44 patients affected by non-small cell lung cancer referred to our oncology day hospital were progressively analyzed. The patients were treated with oral vinorelbine 30 mg x 3/wk or 40 mg x 3/wk meaning one day on and one day off. The patients were older than 60, stage IIIB or IV, ECOG PS ≥ 1, and have at least one important comorbidity (renal, hepatic, or cardiovascular disease). The schedule was based on ECOG-PS and comorbidities. The primary endpoint was progression-free survival (PFS). PFS was used to compare patients based on different scheduled dosage (30 or 40 mg x3/weekly) and age (more or less than 75 years old) as exploratory analysis. We also evaluated as secondary endpoint toxicity according to Common Toxicity Criteria Version 2.0.Results. Vinorelbine showed a good safety profile at different doses taken orally and was effective in controlling cancer progression. The median overall survival (OS) was 12 months. The disease control rate (DCR) achieved 63%. The median PFS was 9 months. A significant difference in PFS was detected comparing patients aged below with those over 75, and the HR value was 0.72 (pConclusions.This study confirmed the safety profile of metronomic vinorelbine and its applicability for patients unfit for standard chemotherapies and adds the possibility of considering this type of schedule not only for very elderly patients.

The most important consequences of smoking are chronic obstructive pulmonary disease (COPD) and lung cancer (LC). Although the use of shocking images and warning messages on cigarette packaging is a valid tool of smoke dishabituation, unfortunately, millions of people go on smoking. Our hypotheses is that cigarette packet covers could also be used to give further messages, especially meant to spur also a screening of smoke-induced respiratory diseases. Messages on cigarette packaging suggesting smokers to perform a spirometry and a chest X-ray may persuade them not only to quit their habit but also to have a screening for COPD and LC prevention. If our hypotheses is taken into account it will have a strong worldwide impact.

Objective:The aim of this review was to understand whether FEV1 decline measured during the follow-up of asthmatic subjects (FEV1 variation between two different measurements at a distance of at least 5 years) may have a role in their management.Methods:Articles, commentaries and reviews relating to the topic were searched in PubMed.Results:Patients with an accelerated FEV1 decline (>30 ml/year) may be either steroid-resistant/difficult-to-treat asthmatics or not adequately treated because they are either under-perceivers or poorly adherent to their therapy. Sometimes they may be unable to use devices correctly. Untreated rhinitis and incorrect lifestyle (obesity status, a high-fat diet and lack of exercise) must be considered when facing a pulmonary function decline. Identifying asthmatics with an accelerated FEV1 decline, even with well controlled symptoms, may allow us to make possible treatment adjustments or to remove potentially harmful environmental exposure and suggest a correct lifestyle....

The aim was to evaluate the impact of Cupressus sempervirens (Cs) and Juniperus communis (Jc) sensitisations in "Maremma" in southern Tuscany.811 consecutive outpatients (357 F - 57.86%; age: 36.9 ± 16.6) with suspected allergic respiratory symptoms underwent skin prick tests (SPT) for common allergens and for Cs and Jc.SPT resulted negative in 295 (36.37%) subjects. A Cs/Jc sensitisation was found in 294 (36.25%): 289 (98.3%) were sensitised to Cs whereas 198 (67.34%) to Jc. There was a co-sensitisation between Cs and Jc in 193 (65.6%) subjects. Cs/Jc mono-sensitisation was found in 39 (13.6%) subjects. A higher number (p0.0001) of Cs/Jc sensitised subjects reported winter (131-44.55%) and spring (124-42.2%) symptoms compared to Cs/Jc non-sensitised and non-allergic subjects. Most Cs/Jc sensitised subjects reported rhinitis and conjunctivitis (p0.0001), whereas only few reported coughing and asthma (p0.01). The most frequent co-sensitisation was with grass, olive and other trees in Cs/Jc subjects (p0.001). Those who reported winter symptoms, likely influenced by Cupressaceae, rhinitis was the main symptom whereas asthma was less frequent. Cs/Jc sensitisation resulted to be a risk factor (OR: 1.73 [CI95% 1.18-2.55]) for rhinitis whereas the probability of being asthmatic was reduced (OR: 0.62 [CI95% 0.44-0.85]).The prevalence of Cs/Jc sensitisation is about 36% in "Maremma". However, only in 44% of the patients, Cs/Jc seem to cause typical winter symptoms. Rhinitis is the predominant symptom, whereas asthma is less frequent. Testing Cupressaceae sensitisation using Jc pollen extract, rather than Cs, may result to be less sensitive.

Background: Asthma may show an accelerated lung function decline. Asthmatics, although having FEV1 and FEV1/VC (and z-scores) higher than the lower limit of normality, may show a significant FEV1 decline when compared to previous measurements. We assessed how many asymptomatic long-standing asthmatics (LSA) with normal lung function showed a significant FEV1 decline when an older FEV1 was taken as reference point. Methods: 46 well-controlled LSA (age: 48.8±12.1; 23 females) with normal FEV1 and FEV1/VC according to GLI2012 references (FEV1: 94.8±10.1%, z-score:-0.38±0.79; FEV1/VC: 79.3±5.2, z-score:-0.15±0.77) were selected. We considered FEV1 decline, calculated by comparing the latest value to one at least five years older or to the highest predicted value measured at 21 years for females and 23 for males. A FEV1 decline >15% or 30 ml/years was regarded as pathological. Results: When comparing the latest FEV1 to an at least 5-year-older one (mean 8.1±1.4 years between 2 measurements), 14 subjects (30.4%) showed a FEV1 decline 1 5-15% change (mean: -9.2±2.5%) and 13 (28.3%) a FEV1 decrease>15% (mean: -18.3±2.4). Subjects with a FEV1 decline>30 ml/year were 28 (60.8%). When using the highest predicted FEV1 as reference point and declines were corrected by subtracting the physiological decrease, 6 (13%) patients showed a FEV1 decline higher than 15%, whereas asthmatics with a FEV1 loss>30 ml/year were 17 (37%). Conclusion: FEV1 decline calculation may show how severe asthma actually is, avoiding a bronchial obstruction underestimation and a possible under-treatment in lots of apparent “well-controlled” LSA with GLI2012-normal-range lung function values.

Objective of our study was assessing whether smoking and obesity might affect airways hyperresponsiveness (AHR) differently in younger and older subjects and whether this influence might be due to their different impacts on baseline lung function values at different ages. Methods 3,903 consecutive adult subjects with normal lung function (1,920 males; mean age 35.1±16.2; median FEV1:97.3% of predicted [interquartile range (IQR):89.7-105.2] and FEV1/FVC:84.6% of predicted [IQR:79.8-89.2]), having performed a methacholine test, were considered. They were subdivided into three groups according to age (18-39, 40-64 and ≥65 years) and into different sub-groups according to body mass index (BMI) and smoking habits, considering two AHR level cut-offs (PD20≤1600 µg and PD20≤800 µg). Results PD20 was significantly lower (p65 (OR:12.786 [IQR:1.450-112.753];p65 years) (OR:3.120 [IQR:1.144-8.509];p65 years. A small airway age-related reduction may cause the increased smoking/obesity induced AHR risk in older people.

Objective of this study was to evaluate whether outdoor temperature and humidity can influence methacholine test results in outpatients living in temperate areas. 4,723 subjects (2,391 males; age: 35.1 ± 16.15; FEV1 = 100.36 % [relative interquartile range (IQR):92.34–108.8]) that performed methacholine tests for suspected asthma between 2000 and 2010 were considered. Outdoor minimum, mean, and maximum temperature values (°C), relative humidity (%), and dew point (T dp), registered when performing the tests, were examined. Airways hyperresponsive patients, with PD20 (provocative dose to obtain a 20 % fall in FEV1)

To the Editor: We read with interest the article by Juusela et al. [1], which showed a significant risk factor for bronchial hyperresponsiveness (BHR) with a dose-dependent pattern and which underlined that BHR severity increases with increased smoking (pack-years) in an adult sample of the general population. Unfortunately, in their study the authors did not analyse a possible additional influence of overweight/obese status on BHR. In fact, several researchers have shown that the overweight/obese condition may be a risk factor for BHR (adjusted for smoking), both in healthy subjects and, in particular, in asthmatics [2–4]. A fair amount of subjects of the study of Juusela et al. [1] were most likely affected by asthma: most of them had a marked BHR, some had forced expiratory volume in 1 s (FEV1)

Anxiety 34 37 36 Headache 28 23 26 Abdominal pain 1 3 2 Weakness 13 4 9 Depression 5 0 3 Impaired sleep 4 8 7 Nicturia 7 0 5 Chest pain 11 7 9 Excitement 13 6 10 Nonlocalized pain 4 4 4 Hunger 3 4 3 Lack of appetite 5 5 5 Fever 1 3 2 Nausea 1 5 4 Urticaria 3 0 2 Palpitation 28 23 26 Heartburn 11 7 10 Generalized itching 22 30 25 Non respiratory symptoms in asthma as possible predictors of exacerbations Gennaro Liccardi, MD, Gennaro Baldi, MD, Adriano Berra, MD, Emanuela Carpentieri, MD, Marina Cutajar, MD, Maria D’Amato, MD, Mario Del Donno, MD, Bruno Del Prato, MD, Ilenia Folletti, MD, Federica Gani, MD, Domenico Gargano, MD, Domenico Giannattasio, MD, Michele Giovannini, MD, Antonio Infantino, MD, Carlo Lombardi, MD, Mario Lo Schiavo, MD, Francesco Madonna, MD, Mauro Maniscalco, MD, Antonio Meriggi, MD, Manlio Milanese, MD, Carmen Montera, MD, Antonio Pio, MD, Maria Russo, PhD, Antonello Salzillo, MD, Patrizia Scavalli, MD, Nicola Scichilone, MD, Bruno Sposato, MD, Anna Stanziola, MD, Antonio Starace, MD, Alessandro Vatrella, MD, Gennaro D’Amato, MD, and Giovanni Passalacqua, MD

Bronchial hyperresponsiveness (BHR) is a common feature in the majority of asthmatic subjects and methacholine is the most frequently used agent for the test. The influence of 3 or 5 min time intervals between doses steps in a double methacholine challenge test (MCH-3′ or MCH-5′) was investigated. Using the MCH-3′ challenge, 52 intermittent asthmatics were classified as having moderate (BHR-M; 18 subjects), mild (BHR-m; 19 subjects), or bordeline (BHR-B; 15 subjects) BHR. The cumulative dose and the PD20FEV1 were higher for MCH-5′ compared with MCH-3′ in BHR-m (p < 0.05) and BHR-B (p < 0.05) but not in the BHR-M group. Also the dose response slopes, FEV1% decline/cumulative methacholine dose, calculated for the two challenge tests were statistically different only in BHR-m (p < 0.05) and BHR-B (p < 0.01). At MCH-5′, there were 16 subjects with BHR-M, 18 with BHR-m, 12 with BHR-B and 6 subjects with normal reactivity. Results may suggest that in the group of BHR-m and BHR-B subjects, at MCH-5′ compared with MCH-3′, the cumulative effect of the administered drug, quickly metabolized by cholinesterase, is not complete, thus leading to an incorrect estimation of bronchial hyperresponsiveness degree. It is hoped that time interval between doses be standardized to ensure maximum comparability within and between subjects in challenge tests.

Neurotrophin (NT) and NT receptor expression was assessed in 12 typical (TC) and 8 atypical (AC) human pulmonary carcinoids by Western blot and immunohistochemistry. TC and AC carcinoid express to different extent NT and NT receptor proteins. Nerve growth factor (NGF) was expressed by 83% of the TC but not by the AC carcinoids. Brain derived neurotrophic factor (BDNF) was expressed by 33 and 100% of TC and AC carcinoids, respectively. NT-3 was expressed by 58% of the TC and 38% of AC carcinoids. TC carcinoids express high affinity NT receptors while 50% of the AC carcinoids express the TrkB receptor. Our results demonstrate that NGF/TrkA and BDNF/TrkB signaling need to be considered as regulatory pathways that may address survival, differentiation and/or aggressiveness of human pulmonary carcinoids. Contrarily to the BDNF/TrkB, expression of the NGF/TrkA signaling may overcome aggressiveness of carcinoid cells. NTs may be useful as markers in the clinic.

Background Epidemiological data indicate that obesity is a risk factor for asthma, but scientific literature is still debating the association between changes in body mass index (BMI) and airway hyperresponsiveness (AHR). Methods This study aimed at evaluating the influence of BMI on AHR, in outpatients with symptoms suggestive of asthma. 4,217 consecutive adult subjects (2,439 M; mean age: 38.2±14.9 yrs; median FEV1 % predicted: 100 [IQR:91.88-107.97] and FEV1/FVC % predicted: 85.77% [IQR:81.1-90.05]), performed a methacholine challenge test for suspected asthma. Subjects with PD20 < 200 or 200 < PD20 < 800 or PD20 > 800 were considered affected by severe, moderate or mild AHR, respectively. Results A total of 2,520 subjects (60% of all cases) had a PD20 < 3,200 μg, with a median PD20 of 366 μg [IQR:168–1010.5]; 759, 997 and 764 patients were affected by mild, moderate and severe AHR, respectively. BMI was not associated with increasing AHR in males. On the contrary, obese females were at risk for AHR only when those with moderate AHR were considered (OR: 1.772 [1.250-2.512], p = 0.001). A significant reduction of FEV1/FVC for unit of BMI increase was found in moderate AHR, both in males (β = −0.255; p =0.023) and in females (β = −0.451; p =0.017). Conclusions Our findings indicate that obesity influences AHR only in females with a moderate AHR level. This influence may be mediated by obesity-associated changes in baseline lung function.

Objective: This study tried to evaluate whether a methacholine test may be influenced by the seasons. Methods: We considered 4826 consecutive subjects with normal spirometry (50.53% males; age: 35.1±16.2; forced expiratory volume in one second: 99.5±13.0%) who underwent a methacholine test for suspected asthma symptoms between 2000 and 2010. They were subdivided into four groups, like the seasons, according to the test dates. Results: A total of 1981 (41%) resulted normal (no PD 20 was obtained with 2400 μg of methacholine); the others showed a mean LogPD 20 of 2.52±0.5 μg. The number of subjects with bronchial hyper-responsiveness (BHR) found in autumn (789, 62.3%) was higher than in summer (583, 56.7%; P=0.03). A higher number of females and overweight/obese subjects showed a BHR in autumn compared with the other seasons. The spring mean LogPD 20 value (2.48±0.48 μg) was lower if compared with the one measured in summer (2.59±0.49 μg; P=0.05). LogPD 20 value was lower in females and non-smokers in spring compared with summer (P

Subjects with bronchial asthmatic symptoms, forced expiratory volume in 1 second (FEV(1)) and FEV(1)/forced vital capacity [FVC]80% could show a positive reversibility test with salbutamol in about 25% of the cases. The aim of this study was to evaluate if a limit functional value for spirometry exists where a reversibility test using salbutamol, over this limit, is not necessary to confirm the diagnosis of asthma. Four hundred patients (mean age 31.12 +/- 10.99) with asthmatic symptoms and normal spirometry (mean FEV(1) 96.06 +/- 11.82%, mean FEV(1)/FVC 98.89 +/- 6.03%) were recruited. The number of subjects with reversible airflow obstruction (RAO) was evaluated using the following different criteria of reversibility: FEV(1) and FVCor= slant 12%, peak expiratory flow (PEF)or= slant 15%, FEF(25 -75)or= slant 35%, and at least one of these (ANY). In subjects with baseline FEV(1)100% (150 patients), 26 (17.3%) patients showed a FEV(1) increase12% and, among the criteria used, 45 patients (30%) showed ANY. In subjects with baseline FEV(1)/FVC100% (204 patients), 36 patients (17.6%) showed a FEV(1) increase12% and 53 patients (26.8%) showed ANY. In subjects with baseline FEF(25 -75)70% (209 patients), 26 (12.44%) and 49 (23.44%) patients, respectively, showed an increase in FEV(1)12%, and ANY. In 56 patients with baseline cut-offs (evaluated together) FEV(1)100%, FEV(1)/FVC100% and FEF(25-75)70%, 10 patients (17.85%) showed a RAO with ANY. FEV(1)121% or FEV(1)/FVC110.8% or FEF(25 -75)110% were cut-off values identified in this study where no RAO subjects were found over these limits. In conclusion, baseline FEV(1)100%, FEV(1)/FVC100% and FEF(25 -75)70% cannot be considered cut-offs where it is not necessary to perform a reversibility test with a bronchodilator over these limits. It is improbable to find a positive reversibility test using salbutamol in patients with asthmatic symptoms and FEV(1)121% or FEV(1)/FVC110.8% or FEF(25 -75)110% to confirm the diagnosis of asthma.

The protective effect of inhaled anticholinergic drugs in the methacholine-induced bronchospasm is well-known. The objective of this study was to assess if any possible differences may be found among Ipratropium (IB), Oxitropium (OXI) and Tiotropium (TIO) pre-treatments to obtain the protective effect. Forty-four patients with intermittent bronchial asthma and PD(20)FEV(1)200 microg were selected (24 M, 20 F; mean age 32 +/- 8.8). On the baseline, they had mean FEV(1)%: 98.8 +/- 8.54 of theoretical and mean PD(15)FEV(1) 111.8 +/- 61.04 microg. After 72 hours, all patients underwent a second methacholine challenge and were given Ipratropium (40 microg by MDI in 14 pts) or Oxitropium (200 microg by MDI in 14 pts) or Tiotropium (18 microg by Handihaler in 16 pts) sixty minutes before the test. Sixty minutes after the bronchodilator inhalation, the FEV(1)% increase was higher (p0.05) in OXI (6.7 +/- 4.83%) and TIO groups (6.11 +/- 2.54%) than in the IB group (3.8 +/- 1.96%). In the IB group PD(15)FEV(1) and PD(20)FEV(1) were obtained in all patients, while in the OXI group they were obtained in 12 and 5 pts respectively and in the TIO group in 14 and 5 pts respectively. Normal hyperreactivity was obtained in 2 patients, in both OXI and TIO groups. In OXI and TIO, the PD(15) obtained after drug pre-medication, was similar (respectively 1628 +/- 955.7 and 1595.5 +/- 990 microg), but higher (p0.0001) in comparison to the PD(15) measured in the IB group (532.2 +/- 434.8 microg). Also, the dose-response slope (decline percentage of FEV(1)/cumulative methacholine dose) after PD(15) was similar in both OXI and TIO groups but different in the IB group. A significant relationship (p0.01) was found between PD(15)FEV(1) (obtained in 40 pts) and the increase in FEV(1)% obtained 60 minutes after bronchodilator inhalations (r = 0.53). In conclusion, with a standard dose, both Oxitropium and Tiotropium seem to have the same protective effect in bronchial asthma but higher than Ipratropium. It's probable that the best dose of Ipratropium should be a higher one than the usual dose taken.

The protective effect of Ipratropium Bromide (IB) in the methacholine-induced bronchospasm is well known from some time. The objective of the present study was to assess whether a pretreatment with IB may influence the subsequent phase of methacholine-induced bronchospasm relief.Sixteen patients with bronchial hyper-reactivity (PD20 FEV1200 microg) were randomly assigned to three methacholine challenge tests at a 48 to 72 hours interval apart. In the first test IB was inhaled before the challenge (pre-IB), in the second IB was administered soon after the PD20 FEV1 (post-IB), and in the third no treatment was given (control).The pre-IB PD20 FEV1 (695 +/- 587.6 microg) was significantly greater (p0.0001) than that of post-IB (82.2 +/- 49.18 microg) and of control (73.9 +/- 41.8 microg). The dose response slope (DRS) (decline percentage of FEV1/cumulative methacholine dose), in pre-IB was greatly lower (p0.0001) than that in post-IB and in control. During the bronchospasm relief phase, the increase of FEV1 measured after 5, 10, 15, 30 and 60 minutes from the PD20 FEV1 was significantly greater in post-IB (p0.05) compared with the other two conditions. Conversely, the recovery slope (RS) (increase percentage of FEV1 at 60 minutes after PD20 FEV1 x cumulative methacholine dose) was significantly more efficient (p0.001) in pre-IB than in post-IB and in control.In conclusion, ipratropium bromide confirmed to have a good protective activity against methacholine-induced bronchospasm; the pre-administration of ipratropium bromide showed also a positive effect on the recovery phase.

In the early stages of bronchial asthma, it is frequent to find subjects with a positive history and an FEV1 or FEV1/FVC80% of the predicted value. This study investigated if the test of reversibility showed a reversible airway obstruction (RAO) in 291 subjects with the above clinical and functional features. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and expiratory flows (PEF, MEF50, FEF(25-75)) were registered before and 20 minutes after salbutamol administration (200 mcg by MDI). Of 291 subjects, FEV1 increased in 73 (25%) after bronchodilatoror = 12% compared to baseline; the number of subjects with aor = 35% increase in MEF50 or FEF(25-75) were similar in terms of percentage (respectively, 29.2% and 29%), whereas those with increases in FVC (or = 12%) and in PEF (or = 15%) were significantly lower (respectively, 2.7% and 12.3%). The percentage of subjects with RAO (FEV1 increase after bronchodilatoror = 12%) was lower (12%) in the subgroup (108 subjects), with an MEF50or = 70% of the value predicted at the baseline assessment, and higher (36%) in the subjects of the subgroup (183 subjects) with an MEF5070%. In conclusion, it is advisable to carry out reversibility tests in all subjects with symptoms indicative of asthma even if their functional tests are "normal" because in a considerable number of cases the RAO was found to confirm the suspected diagnosis and provided a more reliable classification of the disease.

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by intra-alveolar calcium deposits. The etiology of the disease is still unknown and many authors have supposed that an inherited local enzymatic defect is responsible for calcium deposition. The present paper aimed to study the disorder throughout the world, emphasizing the diagnostic and therapeutic views.All the papers published on this subject in the literature were reviewed.Cases studied were 576 and most of them came from Europe (42.7%) and Asia (40.6%). The countries involved were fifty-one and twelve of them were attributed with at least ten cases each (Bulgaria, France, Germany, India, Italy, Poland, Spain, Russia, Japan, Turkey, USA, ex-Yugoslavia). Symptoms were absent in more than half the patients; dyspnoea, cough and chest pain were reported in the other cases. Family history for the disease was found in one-third of the patients. Chest x-rays and computed tomography were so characteristic that they were enough to diagnose the disease even if microscopic evidence of the microliths into the alveoli was obtained in most cases (e.g. by biopsy, autopsy, bronchoalveolar lavage). Pulmonary tuberculosis or sarcoidosis were misdiagnosed in 88 cases out of the 576. The course of the disease was slow and patients usually died as a result of cardio-respiratory failure.This review of PAM has shown that the etiology of the disease is still unknown, it is widespread throughout the world and easy to diagnose; it develops slowly and therapy is ineffective except for lung transplantation.

Chronic obstructive pulmonary (COPD) patients with mild-moderate daytime hypoxia or normoxia (PaO260 mmHg) may also have transient oxygen desaturation during sleep. Revisiting literature, the authors consider various features of this condition: the prevalence, causes, diagnostic procedures, symptoms, predisposing factors, consequences and therapy. The conclusion is that isolated nocturnal oxygen desaturation in COPD patients is a pathologic condition not yet sufficiently cleared; it likely represents an intermediate step in the evolution of COPD to overt respiratory failure. Since negative outcomes are possible, nocturnal oxygen desaturation must be early put in evidence and then treated with suitable drugs, correct dietetic regimen, respiratory physiotherapy and nocturnal oxygen-therapy.

Changes in monocyte functions have been described in several human malignancies. The monocyte/macrophage system is known to play a crucial role in the rejection of tumor cells and phagocytosis represents an important defense mechanism used by these cells. This paper reports the adherence power and phagocyting ability (latex beads) of circulating monocytes in 20 patients with unresectable non-small cell lung cancer (NSCLC), stage IIIB or stage IV, before and after multiagent chemotherapy (carboplatin + etoposide + ifosfamide or cisplatinum + etoposide). We demonstrated that both monocyte adherence and phagocytosis were not affected in lung cancer patients before chemotherapy in comparison with healthy controls. After chemotherapy, a statistically significant decrease in monocyte count on day 4 (p0.05) and in their phagocyting ability on day 4 and 15 (p0.001 and p0.05 respectively) was showed. In addition, a statistically reduced monocyte adherence was found on day 4 (p0.05). The described impairment was prolonged but reversible. These changes in monocyte functions after chemotherapy could be due to a direct effect of the chemotherapy on these cells or to functionally immature cells circulating after myelodepression. The in vitro assessment of monocyte functions may be useful to better clarify mechanisms by which anti-neoplastic agents may act on immune functions and prevent adverse side effects.

Purpose Our study tried to find a relationship between baseline FEF25-75% and airway hyperresponsiveness (AHR) and whether a greater FEF25-75% impairment may be a marker of a more severe hyperresponsiveness in subjects with normal FEV1 and FEV1/FVC and suggestive asthma symptoms. Besides, we tried to asses a FEF25-75% cut-off value to identify hyper-reactive subjects. Methods 4,172 subjects (2,042 M; mean age: 38.3±14.9; mean FEV1 % predicted: 100.5±12.7 and FEV1/FVC: 85.4±6.8) were examined after performing a methacholine (Mch) test. All subjects reported a symptom onset within 3 years before the test. Subjects with PD20400 µg were arbitrarily considered affected by moderate/severe and borderline AHR, respectively. Results PD20 values were 213 (IQR:86-557), 340 (IQR:157-872) and 433 (IQR:196-1032) µg in subjects with baseline FEF25-75≤50%, FEF25-75 between 50 and 70% and FEF25-75>70% respectively (P70%. The hyperreactive subjects percentage, was higher in those with FEF25-75≤50% and lower in those with FEF25-75>70% (P70%) was a higher AHR risk factor, especially in subjects with moderate/severe AHR (OR: 2.18 [IQR:1.41-3.37]; P50 and ≤70% or FEF25-75>70% levels were similar both in normoreactive and hyperreactive subjects. Conclusions At asthma onset, reduced baseline FEF25-75 values with normal FEV1 and FEV1/FVC may predict AHR. Detectable predictive cut-off values do not exist because even normoreactive subjects can show lower FEF25-75 values. Furthermore, a greater FEF25-75 reduction may be associated to a more severe AHR, suggesting a possible FEF25-75 role in the management of asthma when FEV1 and FEV1/FVC are normal.

Forty-eight patients suffering from intermittent bronchial asthma underwent methacholine challenge test. Response was stronger in 29 patients and less pronounced in 19. The two groups had the same characteristics except for the cumulative methacholine dose which was lower in severe hyperresponsiveness. The patients were studied both in the phase of induced bronchospasm and in the subsequent phase of spontaneous recovery. Dose-response curves to methacholine were analyzed as FEV1% decline/methacholine dose for the induction phase of bronchoconstriction and as FEV1% increase*methacholine dose/time after PD20FEV1 for the recovery phase. The phase of induced bronchospasm as well as spontaneous recovery had a linear pattern in severe hyperresponsiveness; in patients with moderate response, induced bronchoconstriction had a curvilinear pattern whereas spontaneous recovery had a linear pattern. This latter group had to break down an amount of methacholine that was fivefold greater than the former, therefore the mechanism of local homeostasis recovery may be more efficient in moderate hyperresponsiveness. However, in both groups recovery after the bronchospasm was not complete after 60 min (p < 0.01 versus baseline). Furthermore, recovery was faster in the first 15 min than in the remaining time. In conclusion the behavior of methacholine-induced bronchospasm and its spontaneous recovery in both severe and moderate hyperresponsiveness seem to be different although several and not well-established mechanisms may be responsible for this phenomenon.

Mesalazine therapy for ulcerative colitis has been reported to be effective and safe. Rare cases of mesalazine-induced renal, pancreatic, myo-pericardial, pleuro-pulmonary and haematological toxicity have been described separately. We report a case characterized by the simultaneous presence of fever, pericarditis, peripheral eosinophilia, eosinophilic pneumonia, anaemia and haematuria (together with proteinuria and leukocyturia) due to mesalazine treatment in a patient with ulcerative colitis. No clinical response had been obtained with corticosteroids and various antibacterial agents. When mesalazine treatment was suspended, all symptoms rapidly and totally disappeared, confirming the direct responsibility of this drug in causing these adverse events. We conclude that mesalazine can induce multi-organ hypersensitivity, which must always be considered as a possible adverse effect during treatment with this drug. To resolve this adverse event it is essential to discontinue mesalazine treatment.