Smoking habits predict adverse effects after mRNA COVID-19 vaccine: Empirical evidence from a pilot study.

OBJECTIVES: The aim of this research was to investigate the possible association between smoking habits and the incidence of adverse effects (AEs) after mRNA COVID-19 vaccine. STUDY DESIGN: A longitudinal observational study was conducted on a sample of Italian healthcare workers. METHODS: Healthcare workers who were administered the mRNA COVID-19 vaccine (either BNT162b2 or mRNA-1273) were evaluated for the occurrence of AEs after three vaccine doses. Multivariate Poisson regression analyses were fitted to predict AE risk according to smoking characteristics - such as number of tobacco cigarettes smoked per day, smoking time, and use of electronic cigarette (e-cig). RESULTS: Of 320 total participants, 72 (22.5%) smoked cigarettes, and 50 (15.6%) used e-cig, 49 of which being dual users. Tobacco smoking significantly increased the risks of muscle and joint pain during the primary COVID-19 vaccination cycle and of chills during the whole vaccination series. The number of cigarettes smoked per day and vaping variously predicted AE onset during the whole cycle, with a tendency to respectively reduce and increase their risks. Duration of smoking did not affect any AE, except for headache after the booster dose. Most results remained significant after Bonferroni adjustment of significance level. CONCLUSION: Our pilot study indicated a possible effect of smoking habits on AE onset. Our research offers evidence that helps understanding possible predictors of the interindividual variability in COVID-19 vaccine response, serving as a reference for further studies on the effect of smoking on vaccine safety and effectiveness.

Lung clearance index evaluation in detecting nocturnal hypoxemia in cystic fibrosis patients: Toward a new diagnostic tool.

BACKGROUND: Nocturnal hypoxemia adversely affects outcomes in patients with cystic fibrosis (CF). Although an early detection of this abnormality may be desirable, still its predictability remains uncertain. The Lung Clearance Index (LCI) is a measure of lung ventilation distribution obtained from a multiple-breath washout technique (MBW), recently implemented in patients with CF. This study aimed to establish whether the LCI predicts nocturnal hypoxemia in patients with stable CF, with mild to moderate disease, and normal diurnal gas exchange. METHODS: 31 stable patients (15 males, mean age 17.4 ± 5.2 years) with mild to moderate CF, normoxic when awake, were enrolled. In all patients we performed nocturnal cardio-respiratory polygraphy, lung function measurement, and MBW test to derive LCI values. RESULTS: LCI was abnormal in most of the patients and inversely correlated with mean nocturnal SpO2 (r = -0.880 p < 0.01). A receiver operating characteristic (ROC) analysis, performed to assess whether LCI predicted nocturnal hypoxemia, revealed a high predictive accuracy of LCI for nocturnal desaturation (AUC = 0.96; Youden index = 0.79). Forced expiratory volume in 1 s (FEV1) was predictive only in patients with more severe airway obstruction, with a moderate degree of accuracy (AUC 0.71). CONCLUSIONS: The LCI showed a high effectiveness in predicting nocturnal hypoxemia in stable patients with CF, particularly when compared with a traditional parameter of lung function such as FEV1.

SAFETY AND EFFICACY OF SUBLINGUAL SPECIFIC IMMUNOTHERAPY TO HOUSE DUST MITE USING A DIFFERENT DOSAGE: A PILOT STUDY.

The aim of this randomized open study was to evaluate the safety and efficacy of different dosages (2000 UI vs 4000 UI) of sublingual immunotherapy (SLIT) in patients with allergic diseases such as asthma associated to rhinitis and rhinoconjunctivitis sensitized to house dust mites. We enrolled 61 patients with a history of allergic asthma, and a positive skin prick test for Dermatophagoides (D.) pteronyssinus/farinae. Patients were randomly assigned to receiving SLIT at dosage of 2000 UI (Group A) or 4000 UI (Group B) maintenance dose. We evaluated: subjective symptoms using a Visual Analogic Scale (VAS), the amount of prescribed symptomatic drugs, bronchial reactivity to methacoline and side effects using a specific questionnaire. A significant improvement in symptoms, assessed by VAS, was observed with both SLIT doses with no significant differences between groups. The provocation dose of methacoline inducing a 20% fall of FEV1 significantly increased after 12 months only in the 4000 UI dose group. In conclusion, both monomeric allergoid dosages of SLIT (2000 UI and 4000 UI) are a safe and efficacy option to reduce symptoms in patients with allergic asthma caused by house dust mites. Moreover, both dosages are efficacious even to protect against airway reactivity but it seems that monomeric allergoid of SLIT at higher dosage (4000 UI) is better than at the lower dosage (2000 UI).

Function of the airway epithelium in asthma.

Asthma is traditionally defined as a chronic disease characterized by bronchial hyper-responsiveness and lung inflammation. The airway inflammation and remodelling together likely explain the clinical manifestations of asthma. The mechanisms by which the external environmental cues, together with the complex genetic actions, propagate the inflammatory process that characterizes asthma are beginning to be understood. There is also an evolving awareness of the active participation of structural elements, such as the airway epithelium, airway smooth muscle, and endothelium, in this process; these structural elements within the lung and the bone marrow serve as reservoirs for and the source of inflammatory cells and their precursors. Although often viewed as separate mechanistic entities, so-called innate and acquired immunity often overlap in the propagation of the asthmatic response. This review examines the newer information on the pathophysiologic characteristics of asthma and focuses on the role of airway epithelium in the exacerbation of the disease.

Hepatitis B vaccination failure in celiac disease: is there a need to reassess current immunization strategies?

Human leukocyte antigen (HLA) phenotype DQ2 is considered the most important genetic marker for un-responsiveness to hepatitis B vaccine. Since celiac disease (CD) is also strongly associated with the same haplo-type it may be hypothesized that celiac patients are less able to respond to the vaccine. We report a retrospective study on celiac patients vaccinated with three doses of 10 microg at 3, 5 and 11 months of age by an intramuscular injection of a recombinant hepatitis B vaccine (Engerix B). We found 30 of 60 celiac patients (50%) unresponsive to vaccination and a significant higher number of responders among patients younger than 18 months at the time of celiac disease diagnosis. Our study confirms that celiac patients have a lower percentage of response to hepatitis B vaccination than healthy subjects. These findings provide useful information to evaluate if current vaccine strategies should be reassessed and if revaccination should be recommended.

Emerging pathogens in cystic fibrosis: ten years of follow-up in a cohort of patients.

In patients with cystic fibrosis (CF), there is an increasing incidence of some uncommon respiratory pathogens, such as Burkholderia cepacia complex (Bcc), Stenotrophomonas maltophilia, and Achromobacter xylosoxidans. In order to evaluate the prevalence and the clinical impact of these pathogens, we retrospectively studied a total of 109 patients followed in our center from 1996 to 2006 and reviewed the results of 1,550 sputum samples. The isolation of Pseudomonas aeruginosa slightly decreased over the observed decade, whereas Staphylococcus aureus exhibited an irregular trend. Infection with Bcc reached a peak in 1998 and successively decreased to a stable 4%. S. maltophilia and A. xylosoxidans were the real emerging pathogens, since first isolation occurred in 2004; however, the percentage of infected patients remained low (7% and 3.2%, respectively) through the years. In conclusion, in our center for CF, the reduced prevalence of P. aeruginosa over the last decade has been associated with a concurrent reduction of infections by Bcc and, as compared to other centers in Italy, Europe, and the US, with a low incidence of emerging pathogens such as S. maltophilia and A. xylosoxidans.

Non-occupational malignant pleural mesothelioma due to asbestos and non-asbestos fibres.

BACKGROUND AND AIM: The occurrence of malignant pleural mesothelioma (MPM) has been reported among population groups with no documented professional exposure to asbestos fibres living in different geographic areas. This paper reviews existing data related to non occupational MPM including its occurrence in the province of Catania (Sicily, Italy). METHODS: An electronic search of literature related to non occupational MPM was performed including the year 2005. RESULTS: Non occupational MPM in subjects living in areas contaminated by a variety of asbestos and non asbestos fibres has been well documented through a number of epidemiologic studies including cases series, case-control studies, and a cohort study. In addition, the observation of familial clustering of MPM, suggests that genetic factors may play a role in the pathogenesis of this malignancy. The epidemiological evidence also suggests that MPM may occur as a result of the interaction between environmental carcinogens, genetic factors, and virus infection. CONCLUSION: It is likely that genetic predisposition and non-occupational exposure to low doses of asbestos and asbestos-like fibres may concur to the development of malignant mesothelioma. However, additional epidemiological and laboratory studies are needed to further understand the relationship between environmental exposure and individual susceptibility to this malignancy.

Effect of salbutamol on nasal symptoms and mast cell degranulation induced by adenosine 5' monophosphate nasal challenge.

BACKGROUND: In addition to its well-known functional agonism at the level of beta(2) adrenergic receptors on airways smooth muscle cells, salbutamol appears to have additional protective effects, possibly through an inhibition of mast cell activation. OBJECTIVE: The aim of this study is to provide the first evidence in vivo of inhibition of human mast cell activation by salbutamol. METHODS: Nine atopic subjects received placebo and salbutamol (5 mg/mL) 15 min before an adenosine 5' monophosphate (AMP) nasal provocation in a double-blind crossover study design. The nasal lavage was collected from these subjects prior to or 3, 5, 15 or 30 min after the AMP nasal challenge, and concentrations of histamine and tryptase in the nasal lavage were measured. RESULTS: AMP nasal provocation produced considerable sneezing and induced a transient increase in histamine and tryptase release with peak values achieved at 3 min after the challenge in all the subjects studied. Compared with placebo, salbutamol significantly attenuated the release of histamine and tryptase induced by AMP challenge (P=0.048 and 0.020, respectively). Moreover, the AMP-induced sneezing was also inhibited by pre-treatment with salbutamol (P=0.004). CONCLUSIONS: Intranasal salbutamol attenuates nasal symptoms and inhibits histamine and tryptase release caused by AMP nasal provocation thus supporting the hypothesis that salbutamol may play an additional protective role in the airways by inhibiting mast cell activation.

Cardiorespiratory interactions to external stimuli.

Respiration is a powerful modulator of heart rate variability, and of baro- or chemo-reflex sensitivity. This occurs via a mechanical effect of breathing that synchronizes all cardiovascular variables at the respiratory rhythm, particularly when this occurs at a particular slow rate coincident with the Mayer waves in arterial pressure (approximately 6 cycles/min). Recitation of the rosary prayer (or of most mantras), induces a marked enhancement of these slow rhythms, whereas random verbalization or random breathing does not. This phenomenon in turn increases baroreflex sensitivity and reduces chemoreflex sensitivity, leading to increases in parasympathetic and reductions in sympathetic activity. The opposite can be seen during either verbalization or mental stress tests. Qualitatively similar effects can be obtained even by passive listening to more or less rhythmic auditory stimuli, such as music, and the speed of the rhythm (rather than the style) appears to be one of the main determinants of the cardiovascular and respiratory responses. These findings have clinical relevance. Appropriate modulation of breathing, can improve/restore autonomic control of cardiovascular and respiratory systems in relevant diseases such as hypertension and heart failure, and might therefore help improving exercise tolerance, quality of life, and ultimately, survival.

Sleep-related hypoxaemia and excessive erythrocytosis in Andean high-altitude natives.

To determine whether nocturnal hypoxaemia contributes to the excessive erythrocytosis (EE) in Andean natives, standard polysomnographies were performed in 10 patients with EE and in 10 controls (mean haematocrit 76.6 +/- 1.3% and 5.4 +/- 0.8%, respectively) living at an altitude of 4,380 m. In addition, the effect of O2 administration for 1 h prior to sleep, and the relationship between the hypoxic/hypercapnic ventilatory response and the apnoea/hypopnoea index (AHI) during sleep were studied. Awake arterial oxygen saturation (Sa,O2) was significantly lower in patients with EE than in controls (83.7 +/- 0.3% versus 85.6 +/- 0.4%). In both groups, the mean Sa,O2 significantly decreased during sleep (to 80.0 +/- 0.8% in EE and to 82.8 +/- 0.5% in controls). The mean Sa,O2 values remained significantly lower in patients with EE than in controls at all times of the night, and patients with EE spent significantly more time than the controls with an Sa,O2 of <80%. There were no differences between the two groups in the number and duration of the apnoeas/hypopnoeas. None of these variables were affected by O2 administration. In both groups the AHI positively correlated with the hypercapnic ventilatory response. Andean natives undergo minor respiratory disorders during sleep. The reduction in oxygen saturation found in subjects with excessive erythrocytosis was small, yet consistent and potentially important, as it remained below the threshold known for the increase in erythropoietin stimulation. This may be an important factor promoting erythropoiesis, but its relevance needs to be further explored.

The effect of inhaled furosemide and acetazolamide on bronchoconstriction induced by deep inspiration in asthma.

In some asthmatics deep inspiration causes a sustained bronchoconstration, which is dependent on Ca2+ uptake. Inhaled diuretics protect against bronchoconstriction induced by a variety of indirect stimuli, by inhibiting the ionic fluxes involving Ca2+ uptake across the cell membrane of airway epithelium. The aim of this study was therefore to investigate the protective effect of inhaled furosemide on the bronchoconstriction induced by deep inspiration in asthma and to compare it with the effect of acetazolamide, an inhibitor of carbonic anhydrase devoid of effect on ion cotransport but possessing inhibitory effects on chloride ion influx and Na+/K+ exchange. The study was carried out on three different study days according to a randomized, double-blind, placebo-controlled, crossover design. Nine non smoking asthmatic subjects first performed a series of 9 controlled deep inspirations to TLC followed by forced expirations to RV within 20 min, which caused a decrease of FEV1 > 20% from baseline. Two hours later, the subjects inhaled either furosemide (40 mg), or acetazolamide (500 mg), or saline (placebo) in random order, and then two more deep-inspiration challenges were performed after 30 and 140 mins. The progressive percent decrement of FEV1 caused by deep-inspiration challenge was taken as an index of bronchoconstriction. Bronchoconstriction was significantly blunted at 30 mins, but not 140 mins, after inhaling furosemide (p < 0.01) or acetazolamide (p < 0.05) compared to control. We interpret these results as due to a modulation of ionic fluxes across the smooth muscle cell membrane afforded by inhaled furosemide and acetazolamide.

Autonomic cardiovascular function in high-altitude Andean natives with chronic mountain sickness.

We evaluated autonomic cardiovascular regulation in subjects with polycythemia and chronic mountain sickness (CMS) and tested the hypothesis that an increase in arterial oxygen saturation has a beneficial effect on arterial baroreflex sensitivity in these subjects. Ten Andean natives with a Hct >65% and 10 natives with a Hct <60%, all living permanently at an altitude of 4,300 m, were included in the study. Cardiovascular autonomic regulation was evaluated by spectral analysis of hemodynamic parameters, while subjects breathed spontaneously or frequency controlled at 0.1 and 0.25 Hz, respectively. The recordings were repeated after a 1-h administration of supplemental oxygen and after frequency-controlled breathing at 6 breaths/min for 1 h, respectively. Subjects with Hct >65% showed an increased incidence of CMS compared with subjects with Hct <60%. Spontaneous baroreflex sensitivity was significantly lower in subjects with high Hct compared with the control group. The effects of supplemental oxygen or modification of the breathing pattern on autonomic function were as follows: 1) heart rate decreased significantly after both maneuvers in both groups, and 2) spontaneous baroreflex sensitivity increased significantly in subjects with high Hct and did not differ from subjects with low Hct. Temporary slow-frequency breathing may provide a beneficial effect on the autonomic cardiovascular function in high-altitude natives with CMS.

The protective role of epithelium-derived nitric oxide in isolated bovine trachea.

Airway epithelial cells from bovine airways can release relaxant factors such as nitric oxide (NO) and prostaglandin E(2) and the removal of airway epithelium results in an increased responsiveness of smooth muscle to spasmogen stimuli. In this study, we assessed whether or not epithelial NO modulates the contractile response of bovine trachea in vitro.Cumulative concentration-response curves to acetylcholine (ACh), histamine (Hist) and 5-hydroxytryptamine (5-HT) were obtained in both intact and epithelium denuded tracheal strips in the presence of indomethacin (10 microM).In intact, but not in epithelium denuded strips, preincubation with the NO synthase inhibitor L-N((G))-Nitro-arginine methyl ester (L-NAME), but not with D-NAME, shifted to the left the concentration-response curve to ACh (pD(2) values in the absence and in the presence of L-NAME were 3.47+/-0.1 and 4.60+/-0.1, respectively; P<0.05) and to Hist (pD(2) in the absence and in the presence of L-NAME: 3.89+/-0.1 and 4.54+/-0.1, respectively; P<0.05). This effect was reversed by L-arginine (1mM), but not by D-arginine. The contractile response to 5-HT was not affected by L-NAME in either intact or epithelium denuded strips. These data suggest that NO is an epithelial relaxant factor modulating airway cholinergic and histaminergic contraction of bovine trachea and that the activation of the epithelial NO synthase is a mediator-specific process.

Future treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Theoretically, an appropriate management of the disease should be aimed to prevent and reduce symptoms, to reduce the number and the severity of exacerbations, to improve exercise tolerance and lung function and to decrease the rate of mortality. However, the rapid progress in understanding the pathophysiologic aspects of COPD has been followed by very few advances in its management and currently there is no pharmacological treatment which is able to reduce the decline in lung function that occurs in these patients or to affect mortality. Effective symptomatic relief and improvement in exercise capacity can be obtained with inhaled bronchodilators and a new long-acting (> 24 h) inhaled anticholinergic, tiotropium bromide, is now available. New pharmacological approaches for COPD include the development of drugs which should be able to control the neutrophilic, steroid-insensitive inflammation, to reassess the protease/antiprotease balance and to reduce oxidative stress in the airways. While most of these drugs are still in preclinical evaluation, some recent phase II-III clinical trials have shown the beneficial effects of a new class of anti-inflammatory compounds, the phosphodiesterase-4 (PDE-4) inhibitors, in patients with COPD. Given the relevance of mucus hypersecretion in the pathophysiology of this disease, efforts have been made also to draw definitive conclusions on the effectiveness of the available mucoactive drugs and in the development of new mucoactive molecules. Further studies are required to understand the impact of each potential therapeutic strategy in the effective control of COPD.

Slow breathing reduces chemoreflex response to hypoxia and hypercapnia, and increases baroreflex sensitivity.

OBJECTIVE: To investigate whether breathing more slowly modifies the sensitivity of the chemoreflex and baroreflex. DESIGN SETTING: University of Pavia, IRCCS Policlinico S. Matteo. PARTICIPANTS: Fifteen healthy individuals. INTERVENTIONS: Progressive isocapnic hypoxia and progressive hyperoxic hypercapnia were measured during spontaneous breathing and during a breathing rate fixed at 6 and 15 breaths per minute (b.p.m.). MAIN OUTCOME MEASURES: Variations in chemo- and baroreflex sensitivity (by monitoring ventilation, oxygen saturation, end-tidal carbon dioxide, R-R interval and blood pressure) induced by different breathing rates. RESULTS: Breathing at 6 b.p.m. depressed (P < 0.01) both hypoxic and hypercapnic chemoreflex responses, compared with spontaneous or 15 b.p.m. controlled breathing. Hypoxic and hypercapnic responses during spontaneous breathing correlated with baseline spontaneous breathing rate (r = -0.52 and r = +0.51, respectively; P = 0.05). Baroreflex sensitivity was greater (P < 0.05) during slow breathing at baseline and remained greater at end rebreathing. CONCLUSIONS: Slow breathing reduces the chemoreflex response to both hypoxia and hypercapnia. Enhanced baroreflex sensitivity might be one factor inhibiting the chemoreflex during slow breathing. A slowing breathing rate may be of benefit in conditions such as chronic heart failure that are associated with inappropriate chemoreflex activation.

Evidence that the anti-spasmogenic effect of the beta-adrenoceptor agonist, isoprenaline, on guinea-pig trachealis is not mediated by cyclic AMP-dependent protein kinase.

1. The spasmolytic and anti-spasmogenic activity of beta-adrenoceptor agonists on airways smooth muscle is thought to involve activation of the cyclic AMP/cyclic AMP-dependent protein kinase (PKA) cascade. Here we have tested the hypothesis that PKA mediates the anti-spasmogenic activity of isoprenaline and other cyclic AMP-elevating agents in guinea-pig isolated trachea by utilizing a number of cell permeant cyclic AMP analogues that act as competitive 'antagonists' of PKA. 2. Anion-exchange chromatography of guinea-pig tracheae resolved two peaks of PKA activity that corresponded to the type I ( approximately 5%) and type II ( approximately 93%) isoenzymes. 3. Pre-treatment of tracheae with zardaverine (30 microM), vasoactive intestinal peptide (VIP) (1 microM) and the non-selective activator of PKA, Sp-8-CPT-cAMPS (10 microM), produced a non-parallel rightwards shift in the concentration-response curves that described acetylcholine (ACh)-induced tension generation. The type II-selective PKA inhibitor, Rp-8-CPT-cAMPS (300 microM), abolished this effect. 4. Pre-treatment of tracheae with Sp-8-Br-PET-cGMPS (30 microM) produced a non-parallel rightwards shift of the concentration-response curves that described ACh-induced tension generation. The selective cyclic GMP-dependent protein kinase (PKG) inhibitor, Rp-8-pCPT-cGMPS (300 microM), abolished this effect. 5. Pre-treatment of tracheae with isoprenaline (1 microM) produced a 10 fold shift to the right of the ACh concentration-response curve by a mechanism that was unaffected by Rp-8-Br-cAMPS (300 microM, selective inhibitor of type I PKA), Rp-8-CPT-cAMPS (300 microM) and Rp-8-pCPT-cGMPS (300 microM). 6. We conclude that the anti-spasmogenic activity of Sp-8-CPT-cAMPS, zardaverine and VIP in guinea-pig trachea is attributable to activation of the cyclic AMP/PKA cascade whereas isoprenaline suppresses ACh-induced contractions by a mechanism(s) that is independent of PKA and PKG.