Abstract: To cite this article: Heffler E, Nebiolo F, Asero R, Guida G, Badiu I, Pizzimenti S, Marchese C, Amato S, Mistrello G, Canaletti F, Rolla G. Clinical manifestations, co-sensitizations and immunoblotting profiles of buckwheat-allergic patients. Allergy 2010; DOI: 10.1111/j.1398-9995.2010.02469.x. Abstract Background: Buckwheat allergy is a rare food allergy in Europe and North America, whereas it is often described and studied in Asia. The aim of this study was to describe a series of patients with proven buckwheat allergy evaluated in an Italian allergy clinic. Co-sensitization to other food and inhalant allergens and immunoblotting profiles of buckwheat-allergic patients were studied. Methods: Patients with suspected buckwheat allergy who attended the allergy clinic between January 1, 2006, and September 30, 2008, were evaluated. All patients underwent skin prick tests for a standard panel of inhalant and food allergens, prick-by-prick with buckwheat flour, buckwheat-specific IgE determinations, and double-blind placebo-controlled food challenge (DBPCFC) with buckwheat flour. Immunoblotting with buckwheat flour extract was performed on sera from buckwheat-allergic patients. Results: Among 72 patients with suspected buckwheat allergy, 30 (41.7%) were sensitized to buckwheat and 24 had a positive DBPCFC. The mean buckwheat IgE level was 6.23 kUA/l (range, 0.16 to >100 kUA/l). Several IgE-binding proteins were identified and grouped into three patterns: a 16-kDa band in patients with predominantly gastrointestinal symptoms with grass and wheat flour co-sensitization, a 25-kDa band in patients with predominantly cutaneous symptoms and a low frequency of co-sensitization, and a 40-kDa band in patients with anaphylaxis and a low frequency of co-sensitization. Conclusions: Buckwheat allergy is an emerging food allergy in Italy. We identified three distinct patterns of clinical and laboratory characteristics, suggesting that specific allergens could be more frequently associated with clinical manifestations of different severity.
Abstract: The role of genetic and environmental factors, as well as their interaction, in the natural history of asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD) is largely unknown. This is mainly due to the lack of large-scale analytical epidemiological/genetic studies aimed at investigating these 3 respiratory conditions simultaneously. The GEIRD project is a collaborative initiative designed to collect information on biomarkers of inflammation and oxidative stress, individual and ecological exposures, diet, early-life factors, smoking habits, genetic traits and medication use in large and accurately defined series of asthma, allergic rhinitis and COPD phenotypes. It is a population-based multicase-control design, where cases and controls are identified through a 2-stage screening process (postal questionnaire and clinical examination) in pre-existing cohorts or new samples of subjects. It is aimed at elucidating the role that modifiable and genetic factors play in the occurrence, persistence, severity and control of inflammatory airway diseases, by way of the establishment of a historical multicentre standardized databank of phenotypes, contributed by and openly available to international epidemiologists. Researchers conducting population-based surveys with standardized methods may contribute to the public-domain case-control database, and use the resulting increased power to answer their own scientific questions.
Abstract: BACKGROUND: Chronic rhinosinusitis (CRS) has been reported to be associated with increased values of exhaled nitric oxide (ENO), which could not be entirely explained by the association between CRS and asthma. The aim of this study was to investigate the variables associated with increased ENO in patients with CRS. METHODS: This was a prospective cross-sectional descriptive study of 93 consecutive patients with CRS. The effect on ENO of age, gender, atopy, asthma, respiratory symptoms without bronchial hyperresponsiveness (BHR), and nasal polyps was evaluated by multiple regression analysis. RESULTS: Nasal polyps (P = .01), asthma (P < .001), and respiratory symptoms without BHR (P = .01) were the only independent variables associated with increased ENO. The prevalence of asthma was significantly higher in subjects with nasal polyps (61% vs 29.4%), P = .005, whereas the prevalence of respiratory symptoms without BHR was higher in those without nasal polyps (44.1% vs 15.3%, P = .003). Respiratory symptoms without BHR were associated with significantly higher ENO and prevalence of sputum eosinophilia (eosinophils > 3%) in patients with nasal polyps compared with those without nasal polyps (68.2 vs 24.0 ppb, P = .001; 60% vs 8.3%, P = .03, respectively). CONCLUSIONS: The presence of nasal polyps in patients with CRS was associated with increased asthma prevalence as well as increased ENO levels. Respiratory symptoms without BHR were associated with eosinophilic airway inflammation and increased ENO only in patients with nasal polyps. These findings suggest important clinical and biologic differences between the two types of CRS, with and without nasal polyps.
Abstract: BACKGROUND: Allergen exposure may increase airway oxidative stress, which causes lipid membrane peroxidation and an increased formation of 8-isoprostane. OBJECTIVE: The aim of the study was to investigate oxidative stress induced by allergen challenge in mild asthmatics, by measuring 8-isoprostane in exhaled breath condensate (EBC), and to examine their relationship with mediators derived from arachidonic acid. Methods 8-isoprostane, cysteinyl leukotrienes (cys-LTs) and prostaglandin E2 (PGE(2) ) concentrations in EBC were measured at baseline and after allergen challenge in 12 patients with mild allergic asthma sensitized to cat allergen. RESULTS: At 24 h after allergen challenge, compared with baseline values, EBC 8-isoprostane increased [48.64 pg/mL (44.14-53.61) vs. 21.56 pg/mL (19.92, 23.35), P<0.001], cys-LTs increased [27.37 pg/mL (24.09-31.10) vs. 13.28 pg/mL (11.32, 15.57), P<0.001] and PGE(2) decreased [18.69 pg/mL (12.26, 28.50) vs. 39.95 pg/mL (34.37, 46.43), P<0.001]. The trend of increasing 8-isoprostane after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.85, P<0.001) whereas the trend of decreasing PGE(2) after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.52, P=0.001). CONCLUSIONS AND CLINICAL RELEVANCE: The increase in EBC 8-isoprostane observed after allergen challenge indicates that allergen exposure increases airway oxidative stress in allergic asthma. The strict correlation between cys-LTs and 8-isoprostane underlines the relationship between allergic inflammation and oxidative stress. A shift of arachidonic acid metabolism towards lipoxygenase pathway is induced by the allergen challenge. Airway oxidative stress occurs after allergen challenge even in patients with mild intermittent allergic asthma.
Abstract: Hodgkin's disease (HD) is a malignant lymphoma with frequent mediastinal involvement, characterized by a significant inflammatory infiltration. Exhaled nitric oxide (FENO), is present in healthy humans, and has been proven to be increased in eosinophilic diseases such as allergic asthma. We investigated whether FENO is increased in mediastinal HD and whether NO is produced by lymphoma tissue. To this aim FENO was measured in 56 HD patients, 17 with and 39 without bulky mediastinal involvement, in the period from January 2007 to December 2008. Thirty-seven patients were reassessed after remission. Lymph node biopsies of 10 patients were evaluated for inducible (iNOS) and constitutive (eNOS) nitric oxide synthase expression by immunohistochemistry. FENO resulted significantly related to the mediastinal mass maximum diameter (p=0.009) and was significantly higher in patients with as compared to those without bulky mediastinal disease (38.7 ppb, CI 95% 19.3-58.0, versus 20.7 ppb, CI 95% 16.6-24.7; p=0.009). iNOS and eNOS immunoreactivity was observed in tumour and inflammatory cells (eosinophils and histiocytes). Only in patients with bulky mediastinal HD there was a significant decrease in FENO (from 50.4 ppb CI 95% 18.0-82.8 to 11.1 ppb CI 95% 4.4-17.8, p=0.011). In conclusion, high FENO and NOS expression in lymph-nodes indicate that NO is a component of the inflammatory network of HD. FENO may be proposed for the assessment and follow up of bulky mediastinal HD patients.
Abstract: BACKGROUND: Allergic asthma is consistently associated with increased FE(NO) levels whereas divergence exists regarding the use of exhaled nitric oxide (NO) as marker of inflammation in nonallergic asthma and in asthmatic smokers. The aim of this study is to analyze the effect of having allergic or nonallergic asthma on exhaled nitric oxide levels, with special regard to smoking history. METHODS: Exhaled NO measurements were performed in 695 subjects from Turin (Italy), Gothenburg and Uppsala (both Sweden). Current asthma was defined as self-reported physician-diagnosed asthma with at least one asthma symptom or attack recorded during the last year. Allergic status was defined by using measurements of specific immunoglobulin E (IgE). Smoking history was questionnaire-assessed. RESULTS: Allergic asthma was associated with 91 (60, 128) % [mean (95% CI)] increase of FE(NO) while no significant association was found for nonallergic asthma [6 (-17, 35) %] in univariate analysis, when compared to nonatopic healthy subjects. In a multivariate analysis for never-smokers, subjects with allergic asthma had 77 (27, 145) % higher FE(NO) levels than atopic healthy subjects while subjects with nonallergic asthma had 97 (46, 166) % higher FE(NO) levels than nonatopic healthy subjects. No significant asthma-related FE(NO) increases were noted for ex- and current smokers in multivariate analysis. CONCLUSIONS: Both allergic and nonallergic asthma are related to increased FE(NO) levels, but only in never-smoking subjects. The limited value of FE(NO) to detect subjects with asthma among ex- and current smokers suggests the predominance of a noneosinophilic inflammatory phenotype of asthma among ever-smokers.
Abstract: BACKGROUND: Reliable clinical or laboratory markers of chronic idiopathic urticaria (CIU) duration are not available. Angioedema, autologous serum skin test (ASST) results, and antithyroid antibodies have been inconsistently associated with longer urticaria duration. OBJECTIVE: To investigate the association of clinical and laboratory parameters with CIU duration, including systemic hypertension, because activation of the coagulation cascade pathway may contribute to the pathogenesis of CIU. METHODS: We performed a prospective study of a cohort of 228 consecutive adult patients with CIU of moderate to severe intensity referred to 2 outpatient allergy clinics and followed up for a 3- to 5-year period. The association of clinical and laboratory parameters (sex, atopy, markers of autoimmunity, antithyroid antibodies, positive ASST result, Helicobacter pylori infection, and hypertension) with urticaria duration was analyzed using semiparametric multivariable proportional hazards models (Cox regression) using remission as main outcome measure. RESULTS: Apart from systemic hypertension (hazard ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .02), none of the considered parameters influenced CIU remission of our patients; 74% and 54% of our patients with and without hypertension, respectively, still had CIU after 5 years. CONCLUSIONS: Our results show, for the first time to our knowledge, that hypertension is associated with extended duration of CIU. This observation, together with the previous findings that point to vascular and coagulation involvement in CIU, may suggest a new approach to antihistamine-refractory CIU treatment, including adequate treatment of hypertension.
Abstract: INTRODUCTION: Exhaled nitric oxide (FE(NO)) is a reliable non-invasive marker of airway inflammation. In 2003 FE(NO) chemiluminescence analyzer (NIOX; Aerocrine AB, Solna, Sweden) was approved by U.S. Food and Drug Administration for monitoring asthma therapy. Recently, the same company developed a portable device using electrochemical sensors (NIOX-MINO; Aerocrine AB). The aim of our study was to compare NIOX-MINO FE(NO) values to those obtained by NIOX and to calculate a correction equation. METHODS: Two adequate measurements obtained by NIOX and NIOX-MINO were recorded in 32 subjects (16 females, mean age 41 years). RESULTS: FE(NO) values measured by NIOX-MINO were systematically higher than those obtained by NIOX (47.1ppb, IC 95% 35.2-59.1 and 36.9ppb, IC 95% 25.0-49.0, respectively). There was a significant correlation (r=0.998, p<0.001) between FE(NO) measured by the two analyzers and the following conversion equation was calculated as: FE(NO(NIOX))=-1.656(SE=0.61)+0.808(SE=0.009)x FE(NO(NIOX-MINO)) DISCUSSION: FE(NO) values measured by the portable nitric oxide analyzer are reliable and strongly correlated with values obtained by the standard stationary device, with a systematic difference observed between the two instruments' values that can be described by the conversion equation we provided. This equation will help clinicians and researchers to compare data obtainable by the two analyzers.
Abstract: Churg Strauss Syndrome (CSS) is a systemic vasculitis in which oligoclonal T cell expansions might be involved in the pathogenesis. Combined analysis of TCR-Vbeta expression profile by flow cytometry and of TCR gene rearrangement by heteroduplex PCR was used to detect and characterize T cell expansions in 8 CSS patients, 10 asthmatics and 42 healthy subjects. In all CSS patients one or two Vbeta families were expanded among CD8+ cells, with an effector memory phenotype apt to populate tissues and inflammatory sites. Heteroduplex PCR showed the presence of one or more clonal TCR rearrangements, which reveals monoclonal or oligoclonal T cells subpopulations. After purification with a Vbeta specific monoclonal antibody, each CD8+/Vbeta+ expanded family showed a single TCR rearrangement, clearly suggestive of monoclonality. All CD8+ expansions were detectable throughout the disease course. TCR-Vbeta expanded or deleted populations were not observed in asthmatic patients. Clonal CD8+/Vbeta+ T cell expansions might be useful as a disease marker.
Abstract: BACKGROUND: The relationship between exhaled nitric oxide (FENO) and the diagnosis of asthma in the general adult population is not completely clear. OBJECTIVES: To investigate the association between FENO and asthma, after controlling for atopy and rhinitis, in a general population sample of adults (mean age 43 years). METHODS: The cohort of subjects was a sample of subjects who gave their consent to participate in the European Community Respiratory Health Survey II study. RESULTS: Atopy, rhinitis and current asthma were positively and current smoking was negatively associated with FENO. Multivariate analysis showed that asthma had a significant predictive effect on FENO (beta = 0.53; 95% CI 0.21-0.84, p = 0.001), and the increase in FENO was significantly associated with the risk of current asthma (OR = 1.07, 95% CI 1.00-1.14) by the logistic regression model. Receiver-operator characteristic curve showed that FENO >or=18.5 ppb had the best combination of sensitivity (69.2%) and specificity (71%), with a positive predictive value of 24% and a negative predictive value of 95%, for the diagnosis of asthma. CONCLUSIONS: Measuring FENO seems to be suitable as an adjunct to questionnaire in the evaluation of asthma in the general population.
Abstract: BACKGROUND: The role that nasal nitric oxide (nNO) plays in sinonasal diseases is increasingly appreciated. OBJECTIVE: To test the diagnostic value of measuring nNO levels in a symptomatic population undergoing evaluation for potential chronic rhinosinusitis (CRS). METHODS: Of the patients referred to an outpatient allergy clinic for persistent nasal symptoms, those reporting nasal blockage plus 1 or more additional symptoms (discolored discharge, anterior or postnasal drip, facial pain or pressure, and reduction or loss of smell) were categorized as having CRS according to sinus computed tomography scores, with (CRSwNP) and without (CRSsNP) nasal polyps on the basis of endoscopic signs. All the included patients underwent nNO measurement and skin prick tests for common inhalant allergens. Healthy individuals served as controls for nNO measurement. RESULTS: Levels of nNO were significantly lower in patients with CRSwNP (median, 340 ppb; 25th-75th percentile, 145-390 ppb) compared with patients with CRSsNP (762 ppb; 620-1,013 ppb), patients without CRS (917 ppb; 647-1,159 ppb), and controls (843 ppb; 762-962 ppb) (P < .001). Low values of nNO separated very well patients with CRSwNP, and the nNO cutoff value of less than 442 ppb was associated with the best combination of specificity (91%) and sensitivity (87%), resulting in a negative predictive value of 91% and a positive predictive value of 87%. A significant inverse relationship was observed between nNO level and sinus computed tomography score (r2 = -0.39, P < .001). CONCLUSION: Testing for nNO is highly predictive of CRSwNP in a selected population of patients with symptoms suggestive of CRS.
Abstract: BACKGROUND: There is no agreement about exhaled nitric oxide (FE(NO)) and its change after haemodialysis (HD) in end-stage renal disease (ESRD) patients. To comprehensively assess NO production in the respiratory system, NO metabolites in exhaled breath condensate (EBC) needs to be measured in addition to FE(NO), taking into account the influence on these markers of airway pH, which may be regulated by ammonia (NH3+), present in large amounts in the breath of ESRD patients and removed by HD. STUDY DESIGN: FE(NO) and NO metabolites (NOx, NO2-,NO3- ), pH and NH3+ in EBC were measured in 12 ESRD patients, before and after HD. Twelve healthy subjects acted as controls. RESULTS: FE(NO )values of ESRD patients were similar to normals, while EBC-NOx, NO2-, NH3+ and pH were significantly higher in ESRD patients compared to normals (EBC-NOx 12.3, range 11.1-41.9 microm vs. 9.4, range 4.6-10.9 microm, P = 0.007; NO2- 4.70, range 1.17-8.22 microm vs. 0.90, range 0.72-1.17 microm, P = 0.023; NH3+ 2340, range 1325-3922 microm vs. 660, range 406-872 microm, P < 0.001; pH 7.16, range 6.82-7.44 vs. 6.60, range 6.42-6.76, P = 0.004, respectively). HD caused a mild significant decrease of FE(NO), and normalization of NH3+, NOx, NO2- and pH. A significant positive relationship between EBC-pH and EBC-NH3+ before and after HD (r(2) = 0.65, P = 0.000) was observed, explaining higher than normal EBC-pH before HD, while no relationship was found between EBC-pH and FE(NO) or NO metabolites. CONCLUSION: Oxidative stress, and not EBC-pH, is the most probable cause of increased NO metabolites in ESRD patients before HD.
Abstract: BACKGROUND: Upper airway edema might contribute to pharyngeal collapsibility and account for the high prevalence of obstructive sleep apnea (OSA) in patients with heart disease. The aim of this study was to evaluate if intensive unloading with diuretics improves sleep-disordered breathing and increases pharyngeal caliber in patients with severe OSA and diastolic heart failure. METHODS: Fifteen patients with severe OSA, hypertension, and diastolic heart failure were hospitalized to receive IV furosemide, 20 mg, and spironolactone, 100 mg, bid for 3 days. Polysomnography was performed for assessment of apnea-hypopnea index (AHI), acoustic pharyngometry was performed for assessment of the oropharyngeal junction (OPJ) area, and forced midinspiratory flow (FIF(50)), forced midexpiratory flow (FEF(50))/FIF(50) percentage, and exhaled nitric oxide (FeNO) were measured before and after diuretic treatment. RESULTS: Diuretic treatment produced a significant decrease in body weight, BP, and AHI (from 74.89 +/- 6.95 to 57.17 +/- 5.40/h, p < 0.001), associated with an improvement in OPJ area (from 1.33 +/- 0.10 to 1.78 +/- 0.16 cm(2), p = 0.007), FIF(50) (from 3.16 +/- 0.4 to 3.94 +/- 0.4 L/s, p = 0.006), and FEF(50)/FIF(50) percentage (from 117.9 +/- 11.8 to 93.15 +/- 10.1%, p = 0.002). Weight loss was significantly related to the decrease of AHI (R = 0.602; p = 0.018), to the increase of FIF(50) (R = 0.68; p = 0.005), and to the decrease of FEF(50)/FIF(50) (R = 0.635; p = 0.011). CONCLUSIONS: These findings suggest that pharyngeal edema contributes to sleep-disordered breathing in obese patients with severe OSA, hypertension, and diastolic heart failure. Upper airway edema may contribute to the frequent occurrence of OSA in patients with heart disease.
Abstract: A 20-year-old woman developed anaphylaxis after eating pizza on 4 different occasions in 2 restaurants. Both restaurants made their pizza dough with a mixture of wheat and buckwheat flours. A prick-to-prick test with buckwheat flour was positive. Skin prick tests and specific immunoglobulin E responses to soybean and peanut were weakly positive while the response to buckwheat was negative. We ruled out a pathogenic role for peanut and soybean because the patient usually eats both with no signs of allergic reaction. Double-blind, placebo-controlled food challenges with buckwheat flour were positive after the administration of a cumulative dose of 2.3 g of the culprit flour. To our knowledge, our report describes the first case of anaphylaxis after intake of buckwheat flour as the hidden allergen in pizza dough.
Abstract: BACKGROUND: Rhinitis and asthma represent the manifestation of one syndrome. Our hypothesis is that in patients with symptoms of persistent rhinitis, lower airway inflammation, lower respiratory symptoms, and lung function abnormalities compatible with asthma are more frequently associated with the diagnosis of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) than with nonallergic rhinitis (NAR). METHODS: One hundred eight of 590 consecutive patients referred in 1 year for rhinitis were enrolled on the basis of nasal symptoms lasting > 4 weeks. Asthma was diagnosed on the basis of symptoms and a positive bronchodilation testing result and/or methacholine hyperresponsiveness. Exhaled nitric oxide (Feno) was measured with the single exhalation method at 50 mL/s. RESULTS: AR was diagnosed in 39%, NAR in 21%, and CRS in 40%. The prevalence of asthma was significantly higher in AR patients (33%) and CRS patients (42%) than in NAR patients (8.7%) [p = 0.036 and p = 0.005, respectively]. Feno was significantly higher in patients with AR and CRS compared to patients with NAR (44.3 parts per billion [ppb]; 95% confidence interval [CI], 34 to 54 ppb; and 53 ppb; 95% CI, 42 to 64 ppb; vs 22 ppb; 95% CI, 18 to 27 ppb; p = 0.002 and p = 0.001, respectively). Patients with asthma had Feno values significantly higher than patients without asthma (64 ppb; 95% CI, 51 to 77 ppb; vs 33.3 ppb; 95% CI, 28 to 39 ppb; p < 0.001). CONCLUSIONS: The diagnostic classification of persistent rhinitis helps to predict lower airway inflammation (increased Feno) and prevalence of asthma: AR and CRS are associated with higher mean Feno values and higher prevalence of asthma than NAR.
Abstract: BACKGROUND: Churg-Strauss syndrome (CSS) is a systemic vasculitis that occurs in the setting of asthma or allergic rhinitis with eosinophilia. The development of systemic manifestations in these allergic patients needs to be recognized as a likely sign of CSS. OBJECTIVE: To describe a patient with limb paresthesia and abdominal complaints related to CSS. METHODS: Blood leukocyte count, nerve conduction study, ultrasound and computed tomography of the abdomen, laparoscopic cholecystectomy and ileum resection, and histopathologic examination of ileum and gallbladder samples. RESULTS: A 55-year-old man with chronic asthma and rhinosinusitis had acute acalculous cholecystitis after he experienced lower limb paresthesia subsequently recognized as being due to mononeuritis multiplex. His eosinophil count was 1,860/microL. Three days after laparoscopic cholecystectomy the patient developed sudden severe diffuse abdominal pain with hypotension due to perforation of the ileum. The peripheral eosinophil count increased to 14,000/microL. Ileal resection was performed. Histopathologic examination showed necrotizing vasculitis with eosinophilic infiltration of the ileum and granulomatous vasculitis with eosinophilic infiltration of the gallbladder. He was treated with pulse intravenous methylprednisolone, 1 g for 3 consecutive days, followed by pulse intravenous cyclophosphamide, 750 mg/m(2), and recovered uneventfully. He received 6 additional monthly infusions of cyclophosphamide, and oral prednisone was tapered. When last seen, 2 years later, the patient was in good clinical condition, continuing alternate-day use of oral prednisone (10 mg). CONCLUSIONS: Nonrespiratory symptoms, such as paresthesia and acalculous cholecystitis, in a patient with asthma should alert the physician to consider CSS. If the neuropathic complaints had prompted the consideration of vasculitis, medical management might have avoided one or both surgical procedures.
Abstract: Since the last years the better knowledge of immunologic mechanisms underlying autoimmune phenomena and rejection of allotransplants has been accompanied by an impressive production of new drugs: new inhibitors of purine and pyrimidine synthesis, as mycophenolate mofetil and leflunomide respectively, new inhibitors of calcineurin, such as tacrolimus, and target of rapamycine, such as sirolimus. Moreover, the tremendous advance in the methodology of producing monoclonal antibodies and the genetic engineering of proteins has led to a wide variety of biological agents, many of them have been approved as important new therapies for autoimmune diseases and against graft rejection. Monoclonal antibodies targeting IL-2 cytokine receptor have been shown to be useful in decrease the incidence of rejection. Moreover, monoclonal antibodies are available which target inflammatory cytokines, such as TNFalpha and IL-1, while other monoclonal antibodies may cause immune cell depletion, such as anti CD20 rituximab, or cause disruption of co-stimuli, like CTLA4Ig abatacept in the treatment of rheumatoid arthritis and anti CD11 efalizumab in the treatment of psoriasis. The new biologic agents have induced salutary clinical effects and extended the therapeutic option of patients not responding to existing treatments. The future looks brighter than ever as the recorded success fuels efforts to optimize the use of the biologic agents and extend their use in other diseases.
Abstract: BACKGROUND: Rhinitis is a major risk factor for asthma, so that evaluation of the lower airways is recommended in patients with rhinitis. Exhaled nitric oxide (FE(NO)) is considered a marker of airway inflammation and it has been found to be useful for the screening of patients with suspected diagnosis of asthma. Our aim was to assess the validity and accuracy of FE(NO) to identify patients with asthma in 48 non-smoking patients with persistent rhinitis and asthma-like symptoms. METHODS: Asthma was diagnosed on the basis of 12% improvement in FEV1 after salbutamol or a methocholine PD(20)FEV1<800 microg. Prior to lung function FE(NO) was measured with the single exhalation method at 50 ml/s. RESULTS: The geometric mean (95% confidence interval) FE(NO) was significantly higher in the 18/48 asthmatics than in the non-asthmatic patients (60 ppb, CI 95%: 50-89, versus 30 ppb, CI 95%: 28-45, P=0.001). Receiver operating characteristic (ROC) curve for the diagnosis of asthma indicated that FE(NO) is an acceptable discriminator between patients with and without asthma (area under the ROC curve=0.78). None of the asthmatic patients had FE(NO) values<25 ppb and all the patients with FE(NO)>100 ppb (n=5) were asthmatics. The sensitivity and specificity of FE(NO) for detecting asthma, using 36 ppb as cut-off point, were 78% and 60% and the positive and negative predictive values were 54% and 82%, respectively. CONCLUSIONS: Measuring FE(NO) may be useful for the screening of rhinitic patients with asthma-like symptoms.
Abstract: BACKGROUND: Complete tooth loss (edentulism) produces anatomical changes that may impair upper airway size and function. The aim of this study was to evaluate whether edentulism favours the occurrence of obstructive sleep apnoea (OSA). METHODS: Polysomnography was performed in 48 edentulous subjects on two consecutive nights, one slept with and the other without dentures. Upper airway size was assessed by cephalometry and by recording forced mid-inspiratory airflow rate (FIF50). Exhaled nitric oxide (eNO) and oral NO (oNO), were measured as markers of airway and oropharyngeal inflammation. RESULTS: The apnoea/hypopnoea index (AHI) without dentures was significantly higher than with dentures (17.4 +/- 3.6 versus 11.0 +/- 2.3. p = 0.002), and was inversely related to FIF50 (p = 0.017) and directly related to eNO (p = 0.042). Sleeping with dentures, 23 subjects (48%) had an AHI over 5, consistent with OSA, but sleeping without dentures the number of subjects with abnormal AHI rose to 34 (71%). At cephalometry, removing dentures produced a significant decrease in retropharyngeal space (from 1.522 +/- 0.33 cm to 1.27 +/- 0.42 cm, p = 0.006). Both morning eNO and oNO were higher after the night slept without dentures (eNO 46.1 +/- 8.2 ppb versus 33.7 +/- 6.3 ppb, p = 0.035, oNO 84.6 +/- 13.7 ppb versus 59.2 +/- 17.4 ppb, p = 0.001). CONCLUSION: These findings suggest that complete tooth loss favours upper airway obstruction during sleep. This untoward effect seems to be due to decrease in retropharyngeal space and is associated with increased oral and exhaled NO concentration.
Abstract: BACKGROUND: Nitric oxide (NO) seems to play an important pathophysiologic role in modulating the systemic changes associated with anaphylaxis. Even if some effects of NO may be protective, animal models of anaphylaxis have shown that the summation effects of NO are deleterious, resulting in hypotension and loss of intravascular volume. There are no studies of NO production during anaphylaxis in humans. OBJECTIVE: To measure the level of exhaled NO during anaphylaxis induced by bee venom cluster immunotherapy in a 34-year-old beekeeper. METHODS: Exhaled NO was measured using a chemiluminescence analyzer at different flow rates, and alveolar NO concentration and airway NO production were calculated. RESULTS: We measured a high level of exhaled NO (78 ppb at 50 mL/s, with increased alveolar concentration and airway production) during anaphylaxis induced by bee venom immunotherapy in this patient. Normal values of exhaled NO were measured in the same patient 1 week later before and after a modified regimen of desensitization. CONCLUSIONS: Nitric oxide production was increased in the respiratory tract during anaphylaxis. Having excluded all the common causes of increased exhaled NO levels, these resultssupport the hypothesis that NO plays an important role in anaphylaxis.
Abstract: Recently a method to measure nitric oxide (NO) concentration in exhaled air has been developed. The method is non-invasive and easy to perform and it provides information on a fascinating molecule, with such extensive respiratory functions, ranging from bronchial and vascular dilation to ciliary motion and antibacterial defense. Nasal and sinus cavities are the site of major NO production, followed by airway and alveolar compartment. A very low nasal NO production is associated with ciliary dyskinesia, a disease characterized by severe chronic sinusitis and bronchiectasis. An increased concentration of NO in exhaled air has been reported in airway diseases, characterized by airway inflammation, such as bronchial asthma, where its concentration is related to bronchial hyperresponsiveness and sputum eosinophilia. Exhaled NO concentration in asthma is a sensitive marker of airway inflammation that reacts rapidly in response to treatment or exacerbation of disease. Clinical application of exhaled NO measurement include monitoring compliance and response to treatment, disease activity, diagnosis of asthma, and the prediction of acute exacerbations. Exhaled NO concentration may be increased also in other diseases, as COPD, bronchiectasis and some connective tissue diseases (SLE and systemic sclerosis). An increased NO production from alveolar source has been shown to be involved in oxygenation impairment of patients with liver disease, particularly in case of hepato-pulmonary syndrome.
Abstract: Hepatopulmonary syndrome is defined by oxygenation impairment due to abnormal intrapulmonary vascular dilatations in patients with liver disease. The implication of enhanced pulmonary production of nitric oxide in the pathogenesis of intrapulmonary vascular dilatations has been demonstrated both in murine models and in human hepatopulmonary syndrome. The diagnosis of hepatopulmonary syndrome in chronic liver disease is of paramount importance, considering the fact that severe hypoxemia related to hepatopulmonary syndrome may occur in patients with well compensated liver disease and that survival is reduced in patients with hepatopulmonary syndrome relative to non hepatopulmonary syndrome patients. Priority for liver transplantation, which is presently the only cure, has been recently increased in patients with advanced hepatopulmonary syndrome.
Abstract: BACKGROUND: The European tick, Argas reflexus, is an urban pest parasitizing urban pigeons and may cause a wide range of allergic reactions. METHODS: Specific IgE to A. reflexus, SDS-PAGE and IgE immunoblotting, performed with tick extract, were carried out in the sera of 6 patients who reported allergic reactions after tick bite. RESULTS: Specific IgE to A. reflexus (RAST class ranging from 1 to 3) were detected in the sera of 6 patients who reported allergic reactions (urticaria and angioedema in 2 and anaphylaxis in the other 4 patients) after tick bite. IgE reactivity to two bands of 22 and 40 kDa were identified in the patient sera. CONCLUSIONS: Allergy to A. reflexus has to be considered in allergic patients living in buildings where pigeons have their nests. The powerful sensitizing property of tick allergen is underlined by the observation that none of our patients was atopic.
Abstract: BACKGROUND: A complex relationship between arachidonic acid metabolites and nitric oxide (NO) synthesis has been reported in asthma. The effects of inhaled aspirin on fractional exhaled NO (FENO) in patients with aspirin-tolerant (ATA) and aspirin-inducible (AIA) asthma compared with normal controls have been investigated. METHODS: The FENO was measured baseline, after saline and lysine-aspirin (L-ASA) bronchial challenge in 10 patients with ATA and in 10 patients with AIA [mean (PD(20)FEV(1) L-ASA): 14.7 +/- 12.7 mg], who had comparable age and baseline FEV(1). Ten healthy subjects served as controls. Sputum eosinophils were counted after saline and after L-ASA challenge in the two groups of asthmatics. RESULTS: Asthmatic patients had baseline FENO significantly higher than controls (29.7 +/- 6.8 vs 9.8 +/- 2.05 p.p.b. respectively, P < 0.0001). No difference was observed in methacholine PD(20)FEV(1) and baseline FENO between ATA and AIA patients. After L-ASA inhalation, FENO increased significantly only in patients with AIA, reaching the peak value 4 h after bronchoconstriction (from 31.1 +/- 6 to 43 +/- 4.8 p.p.b., P < 0.001), while no change was observed in patients with ATA and in controls. Sputum eosinophils increased significantly after L-ASA inhalation only in patients with AIA (from 8.1 +/- 2.7 to 11.1 +/- 2.8%, P < 0.005) and there was a significant relationship between the increase in sputum eosinophils and the increase in FENO after ASA challenge. CONCLUSION: Exhaled NO may indicate eosinophilic airway inflammation during ASA exposure in patients with ASA inducible asthma.
Abstract: BACKGROUND: Exhaled nitric oxide (NO) levels may be elevated in patients with liver cirrhosis and autoimmune diseases. Primary biliary cirrhosis (PBC) is often associated with keratoconjunctivitis sicca (Sjogren syndrome [SS]), an extrahepatic autoimmune manifestation. The aim of this study was to evaluate the source of increased exhaled NO (ie, alveolar vs airway) in patients with PBC, whether associated with SS or not, and to evaluate its impact on oxygenation abnormalities. DESIGN: Observational controlled study. SETTING: University hospital. METHODS: The fractional alveolar NO concentration (FANO) and airway flux of NO (QbrNO) were measured by the multiple flows technique in 34 patients with PBC, 12 with associated SS, and were compared to 20 control subjects and 12 patients with primary SS. RESULTS: FANO was significantly higher in patients with PBC, associated with SS (mean [+/- SEM], 8.9 +/- 0.8 parts per billion [ppb]) or not (mean, 7.7 +/- 0.7 ppb) compared to healthy control subjects (mean, 4.6 +/- 0.5 ppb; p < 0.001) and to patients with primary SS (mean, 4.3 +/- 0.5 ppb; p < 0.001). FANO was significantly higher in cirrhotic patients with increased alveolar-arterial oxygen pressure difference (P[A-a]O(2)) compared to patients with normal P(A-a)O(2) values (9.8 +/- 0.8 vs 7.3 +/- 0.7, respectively; p = 0.018). When compared with control subjects and with patients with PBC not associated with SS, QbrNO was significantly increased in patients with both primary SS and SS associated with PBC. CONCLUSIONS: Increased exhaled NO levels found in PBC are from both alveolar and airway sources in patients with associated SS, but only FANO is associated with oxygenation impairment.
Abstract: AIM: In patients with mitral stenosis, symptoms do not always correlate with echocardiographic data. The aims of the study were to evaluate the role of cardiopulmonary exercise testing in the assessment of patients with mitral stenosis and to quantify nitric oxide production at rest and at the end of exercise. METHODS: We evaluated 43 patients with moderate to severe mitral stenosis with a discrepancy between echocardiographic data and symptoms. Nitric oxide output was calculated by measuring nitric oxide concentration in the exhaled air at rest and at the end of exercise test. RESULTS: Patients were divided in 2 groups: group 1 with a functional capacity <75% at cardiopulmonary exercise test (VO2max in % of the predicted one) and group 2 with functional capacity >75%. Transvalvular gradient and pulmonary artery pressure were significantly higher in group 1 than in group 2 (respectively 9.07 +/- 2.11 mmHg vs 6.01 +/- 1.08 mmHg, p<0.001 and 42.8 +/- 7.2 mmHg vs 33.1 +/- 4.7 mmHg, p<0.001). Patients of group 1 had a lower nitric oxide output at the end of exercise compared to group 2 (231.4 +/- 96.6 nl/min vs 326.3 +/- 74.0 ml/min, p=0.01) and to normal subjects (511.15 +/- 180.1 nl/min, p<0.001). CONCLUSION: Cardiopulmonary exercise testing provides objective non invasive information in the evaluation of patients with discrepancy between symptoms and echocardiographic data. Different levels of nitric oxide output during exercise suggest the role of nitric oxide in regulating pulmonary vascular tone.
Abstract: Hepatopulmonary syndrome--a complication of chronic liver disease-is characterised by hypoxaemia, which results from widespread intrapulmonary vascular dilatations. Amplified production of pulmonary nitric oxide is thought to be important in development of this disorder in patients with liver cirrhosis. Here, we report a 64-year-old man with hepatopulmonary syndrome associated with hepatitis-C-virus-related cirrhosis. We gave the patient nebulised N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, which enhanced oxygenation (arterial oxygen pressure increased from 6.98 to 9.45 kPa). After L-NAME, the distance the patient could walk in 6 min rose by 92 m. Administration of L-NAME by aerosol might offer a new approach to treatment of hepatopulmonary syndrome.
Abstract: BACKGROUND: Pulmonary hypertension (PH) is an important limiting factor of exercise tolerance in patients with mitral stenosis (MS). We wished to investigate the relationship between respiratory nitric oxide (NO), a potent vasodilator, and exercise tolerance in patients with moderate MS. In the same patients, we wondered whether acute change in pulmonary hemodynamics could affect respiratory NO. METHODS: Ten patients with moderate MS (valve area 1.4+/-0.2 cm(2)) were studied at rest, during incremental cycle ergometry exercise, and during dobutamine stress echocardiography (DSE). The concentration of NO in exhaled air (FE(NO)) and NO output (V'(NO)) were measured at baseline, at the end of exercise, and at the end of DSE. Eight healthy subjects served as normal controls for NO output during exercise. RESULTS: During exercise, FE(NO) decreased both in patients and in controls, while V'(NO) increased in both. At the end of exercise, both VO(2) max and V'(NO) were significantly higher in controls than in patients. The increase in V'(NO) during exercise was significantly correlated with VO(2) max, both in patients and in controls. During DSE, cardiac output (CO), pulmonary artery pressure (PAP), and mitral valve gradient increased. No changes in mean FE(NO), V'(NO), or ventilation were observed during DSE. There was a significant inverse correlation between FE(NO) and mitral valve gradient at the end of DSE. CONCLUSIONS: In patients with moderate MS, exercise performance is correlated with respiratory NO output. In the same patients, during DSE, the increase in CO, which is not accompanied by an increase in ventilation, is not associated with an increase in respiratory V'(NO).
Abstract: Primary cardiac lymphoma (PCL) is a rare and usually fatal neoplasm, which may cause syncope, arrhythmia, heart failure and pericardial effusion as presenting clinical complaints. A case of PCL in a 72-year-old man with moderate aortic stenosis is presented. The patient was investigated because of pericardial effusion and diagnosis of diffuse large B-cell lymphoma was obtained by open-chest biopsy of the heart. Fatal ventricular arrhythmia developed the day after the first course of chemotherapy. Clinical presentations and diagnostic approach of this rare tumour are discussed. While chemotherapy is the only effective treatment of PCL, early post-chemotherapy phase should be considered critical in patients with PCL, as suggested by other reported fatal complications in this period.
Abstract: The impact of denture wear in edentulous subjects while performing routine spirometric measurements has never been systematically investigated. We compared the values of FVC, FEV(1), PEFR, FEF(50%), FIV(1), and FIF(50%) recorded with and without dentures in three groups of edentulous subjects: 36 asymptomatic subjects with normal spirometry (N), 22 patients with chronic obstructive pulmonary disease (COPD), and 18 with interstitial lung disease (ILD). In 14 subjects retropharyngeal space with and without dentures was assessed by cephalometry. Subjects with N and ILD had significantly lower airflow rates without dentures, whereas subjects with COPD had no significant difference in spirometric values recorded with or without dentures. The retropharyngeal space was significantly decreased by removing dentures (from 1.52 +/- 0.07 to 1.16 +/- 0.09 cm, SEM, p < 0.0001). These findings indicate that in edentulous subjects with a normal or restrictive pattern, the recording of flow-volume curves with or without dentures produces small but significant differences. Although such differences do not appear to have clinical significance, the fact that when dentures are used some respiratory flows are higher would favor the use of dentures in edentulous subjects during spirometric evaluation.
Abstract: BACKGROUND: Nitric oxide (NO) is one of the most powerful antibacterial compounds. We investigated if NO oral production increases during dental plaque deposition. MATERIALS AND METHODS: Oral NO and salivary nitrite were measured in 31 healthy subjects - 11 smokers and 20 nonsmokers - with natural healthy teeth, in the morning after tooth cleaning (baseline), after withdrawal of oral hygiene for 24 h and again after tooth cleaning. RESULTS: NO and nitrite were significantly higher during plaque deposition than with clean teeth: mean NO values +/- SEM were 44.3 +/- 4.9 parts per billion (ppb) at baseline, 58.8 +/- 3.7 ppb with plaque and 43.6 +/- 3.7 ppb after tooth cleaning, P < 0.05; nitrite values were 32.9 +/- 5.5 microm at baseline, 66.4 +/- 8.2 with plaque and 37.5 +/- 5.5 after tooth cleaning, P < 0.01. During plaque deposition, oral NO was significantly directly related to salivary nitrite (r = 0.497, P = 0.002) and so were their respective changes after tooth cleaning (r = 0.577, P < 0.001). Smokers had significantly lower oral NO than nonsmokers, with both clean and dirty teeth (P < 0.001), and higher bacteria counts in the plaque (38.6 +/- 11.5 vs. 19.9 +/- 2.3, P = 0.046). CONCLUSIONS: Oral NO production increases during de novo deposition of dental plaque. NO might be an early host defence mechanism against bacterial proliferation in the plaque. Such a mechanism is inhibited by cigarette smoking.
Abstract: Severe hypoxemia may occur in patients with liver disease as a result of abnormal intrapulmonary vasodilatations (hepatopulmonary syndrome, HPS). Liver transplantation (LT) is the only effective treatment of HPS, with a quite variable delay of improvement of oxygenation. Smoking, by decreasing respiratory nitric oxide (NO), apparently contributed to improved oxygenation in a 44-year-old man with alcohol-induced cirrhosis, complicated by HPS, who underwent LT. The patient quit smoking just before LT, when his PaO(2) was 29 mm Hg and exhaled NO (eNO) 28 ppb, a value far above the normal limits (9.6 +/- 3.2 ppb). After LT, oxygenation remained poor and eNO remained high for more than 4 months, when the patient started to smoke again (blood HbCO going up to 5%). At that time eNO decreased to 6 ppb and PaO(2) increased to 67 mm Hg. The strict relationship between eNO and oxygenation observed in this case reinforces the hypothesis that NO is the most important vasodilating mediator in HPS. Smoking may have hastened the resolution of HPS after LT by inhibiting respiratory NO and/or through a generalized impairment of endothelium-dependent vasodilation.
Abstract: STUDY OBJECTIVES To investigate whether mantle radiotherapy (MRT) for the lung, through its proinflammatory effects, can induce an increase in airway responsiveness. DESIGN: Follow-up of the changes in lung function and methacholine responsiveness in patients 1, 6, 12, and 24 months after they underwent MRT. PATIENTS: Thirteen nonasthmatic patients with bulky Hodgkin's lymphoma who were scheduled for MRT. MEASUREMENTS AND RESULTS: Chest radiographs, lung function tests, methacholine thresholds of the bronchi (the provocative dose of methacholine causing a 10% fall in FEV(1) [PD(10)]) and central airway (the provocative dose of methacholine causing a 25% fall in the maximal mid-inspiratory flow [PD(25)MIF(50)]), and the provocative dose of methacholine causing five or more coughs (PDcough) were serially assessed. One month after patients underwent MRT, there were significant decreases in PD(10) (mean [+/- SEM], 2,583 +/- 414 microg to 1,512 +/- 422 microg, respectively; p < 0.05), PD(25)MIF(50) (mean 2,898 +/- 372 microg to 1,340 +/- 356 microg, respectively; p < 0.05), and PDcough (mean 3,127 +/- 415 microg to 1,751 +/- 447 microg; p < 0.05), which were independent of the decrease in FEV(1) and reversed within 6 months in all patients but three. Six months after undergoing MRT, four patients showed radiation-induced lung injury (RI) on chest radiographs, which subsequently evolved into fibrosis. These patients had greater decreases in vital capacity, FEV(1), MIF(50), and methacholine thresholds than those without RI, and this persisted up to 2 years after they had undergone MRT. One year after the patients underwent MRT, a close relationship was found overall between the change in FEV(1) and those in both PD(10) (r = 0.733; p = 0.004) and PD(25)MIF(50) (r = 0.712; p = 0.006). CONCLUSIONS:: MRT triggers an early transient increase in airway responsiveness, which reverses spontaneously. In patients with RI, the persistence of airway dysfunction long after undergoing MRT may depend on airway remodeling from radiation fibrosis.
Abstract: OBJECTIVE: To measure nitric oxide (NO) concentration in exhaled air of patients with systemic sclerosis (SSc) and to investigate its relationships with lung involvement, complicated or not by pulmonary hypertension (PH). METHODS: Exhaled NO was measured by chemiluminescence in 47 patients with SSc (16 with PH) and in 30 controls. All the patients underwent Doppler echocardiography to assess pulmonary artery pressure (PAP), lung function tests, and thin section computed tomographic scans of the lung to quantify the extent of fibrosing alveolitis. RESULTS: Exhaled NO levels were higher in patients with SSc (16.6 +/- 9.1 ppb), particularly those with interstitial lung disease (ILD) (18.3 +/- 10.4 ppb), compared to controls (9.9 +/- 2.9 ppb; p < 0.0001). In patients with PH, exhaled NO was less than in patients without PH (10.7 +/- 5.9 vs 19.6 +/- 9 ppb, respectively; p < 0.001), and patients with PH without ILD had even lower exhaled NO than patients with PH and ILD (6.6 +/- 1.1 vs 12.6 +/- 6.3 ppb; p = 0.004). There was an inverse correlation between PAP and exhaled NO (r = 04).53, p = 0.004). Exhaled NO was not correlated to age, disease duration, current therapy, or form of disease (limited or diffuse). CONCLUSION: The increased concentration of exhaled NO in patients with SSc may reflect respiratory tract inflammation. The relatively low value of exhaled NO in patients with PH and the negative correlation between PAP and exhaled NO suggest the important role of NO in regulating pulmonary vascular resistance in patients with SSc.
Abstract: Impaired arterial oxygenation, ranging from an increased alveolar-arterial oxygen gradient to severe hypoxaemia, is commonly reported in patients with advanced liver disease. Hepatopulmonary syndrome is defined by the clinical triad of liver disease, alveolar-arterial oxygen gradient of >15 mmHg, evidence of intrapulmonary vascular dilatations. Three methods are available for detecting intrapulmonary vascular dilatations: contrast-enhanced echocardiography, technetium 99m-labelled macroaggregated albumin scanning and pulmonary arteriography. A recent hypothesis that assigns to nitric oxide the crucial role as mediator of abnormal pulmonary vasodilatation and oxygen is discussed; the measurement of nitric oxide in the exhaled air may represent a possible marker of gas exchange abnormalities in liver disease. The therapeutic options to relieve the hepatopulmonary syndrome are discussed. While no pharmacological treatment has proved to be clinically useful, liver transplantation was reported to cure the response to transplantation is discussed. The response of hypoxaemia to 100% oxygen breathing appears to be the most important prognostic factor of perioperative death rate.
Abstract: BACKGROUND: Cough associated with gastroesophageal reflux (GER) may originate in extrathoracic airway receptors made hypersensitive by acid-induced mucosal injury. OBJECTIVE: We investigated the role of laryngeal disease and dysfunction in the pathogenesis of GER-associated cough in nonasthmatic patients. METHODS: Seven patients with GER-associated cough were compared with 7 patients with GER but no cough. The patients underwent fiberoptic endoscopy for assessment of laryngitis and esophagitis (expressed by scores); esophageal manometry; 24-hour pH monitoring; lung function tests; and histamine inhalation challenge with assessment of bronchial threshold (concentration provoking 10% fall in FEV1 [PC10]), extrathoracic airway threshold (concentration provoking 25% fall in the maximal midinspiratory flow [PC25MIF50]), and cough threshold (concentration provoking 5 or more coughs PCcough). The patients were reevaluated after 3 months of medical treatment for GER. RESULTS: Patients with cough, compared with those without cough, had significantly higher laryngitis scores (P = .002), lower esophageal sphincter pressures, longer time with pH below 4 (P = .003), greater number of episodes of reflux longer than 5 minutes (P = .016), longer esophageal clearance time (P = .048), and significantly lower PC25MIF50 (P = .005) and PCcough (P = .008) values. Laryngitis score was significantly inversely related to either PCcough (P < .001) or PC25MIF50 (P <.01) but not to PC10. Laryngitis score, PC25MIF50, and PCcough were all closely related to GER severity. After GER treatment, laryngitis, PC25MIF50, and PCcough were all significantly improved. CONCLUSIONS: These findings suggest that GER-associated cough is strongly associated with laryngeal disease and dysfunction consequent to acid reflux injury in nonasthmatic patients.
Abstract: BACKGROUND: Nitric oxide may be involved in the impaired oxygenation of cirrhotic patients, a condition that improves in most patients after liver transplantation. OBJECTIVE: To compare oxygenation and nitric oxide concentrations before and after liver transplantation. DESIGN: Before-and-after observational study. SETTING: Academic medical center. PATIENTS: 18 patients with cirrhosis and no obvious cardiopulmonary disease who underwent successful orthotopic liver transplantation. INTERVENTION: Orthotopic liver transplantation. MEASUREMENTS: Blood gas analysis, measurement of exhaled nitric oxide, contrast-enhanced echocardiography, and pulmonary function tests. RESULTS: Before transplantation, the mean (+/- SD) exhaled nitric oxide concentration was higher in patients than in normal controls (13 +/- 4.9 parts per billion [ppb] compared with 5.75 +/- 1.9 ppb; P < 0.001). After transplantation, the alveolar-arterial oxygen gradient significantly decreased (from 17.3 +/- 7.1 mm Hg to 9 +/- 5.2 mm Hg; P < 0.001), as did the exhaled nitric oxide concentration (from 13 +/- 4.9 ppb to 6.2 +/- 2.8 ppb; P < 0.001). The decrease in the exhaled nitric oxide concentration was significantly correlated with the decrease in the alveolar-arterial oxygen gradient (r = 0.56; P = 0.014). Five patients met the criteria for the diagnosis of the hepatopulmonary syndrome before transplantation; the syndrome was cured by transplantation. CONCLUSIONS: The correlation between the decrease in exhaled nitric oxide concentration after liver transplantation and the improvement in oxygenation reinforces the hypothesis that nitric oxide is an important mediator of impaired oxygenation in patients with cirrhosis.
Abstract: BACKGROUND: Inhaled endotoxin (LPS) may cause a transient increase in airway responsiveness, possibly through a cytokine-mediated airway inflammation, which is associated with an increase in nitric oxide synthesis and release. OBJECTIVE: We wondered whether pentoxifylline (PTX), which may attenuate cytokine release induced by LPS, could inhibit LPS-induced increase in airway responsiveness. METHODS: Methacholine (Mch) bronchial responsiveness was assessed 2 and 24 h after saline or LPS inhalation in eight subjects with bronchial hyperresponsiveness (PD20FEV1 610 +/- 53 micrograms), treated with iv saline or PTX, in a double-blind crossover design. Nitric oxide (NO) in the exhaled air, which was expected to increase after LPS inhalation, and PEFR values were also measured at baseline, hourly for 6 h and 24 h later. RESULTS: After LPS inhalation PEFR decreased significantly compared with placebo inhalation, reaching a maximum decrease of 11.25 +/- 1.05 and 4.5 +/- 0.84% of baseline, at 2 h, respectively during saline and PTX infusion, P < 0.001. Exhaled NO were elevated after LPS compared with placebo inhalation at 1 h (35.6 +/- 4.8 vs 18 +/- 2.8 ppb, P < 0.001), with no difference during saline or PTX infusion. Exhaled NO remained elevated until the 6th hour. PD20FEV1 2h after LPS inhalation was significantly lower than after placebo inhalation both during saline infusion (234 +/- 29 vs 625 +/- 62 micrograms, P < 0.001) and during PTX infusion (441 +/- 47 vs 616 +/- 48 micrograms, P < 0.001), the difference between saline and PTX being significant (P < 0.01). At 24 h no difference in PEFR, PD20FEV1 and exhaled NO was observed in comparison with pre-study values. CONCLUSION: PTX attenuates both the decrease in airway patency and the increase in bronchial responsiveness induced by LPS inhalation, without any significant change in exhaled NO, which is increased by LPS inhalation.
Abstract: OBJECTIVE: In experimental animals, elevated nitric oxide (NO) production has been implicated in the pathogenesis of a lupus-like syndrome. Abnormalities of lung function tests are reported in a high proportion of patients with systemic lupus erythematosus (SLE). We investigated whether NO output in exhaled air might be increased in patients with SLE and whether it is related to disease activity and to respiratory function abnormalities. METHODS: Lung volume, maximal expiratory flow at 50 and 25% of vital capacity (MEF50 and MEF25), diffusion coefficient for carbon monoxide (KCO), and NO in the exhaled air were measured in 27 outpatients with SLE (23 women, age 39.2 +/- 16.3). NO in exhaled air was also measured in 30 healthy control subjects. Disease activity was assessed by the European Consensus Lupus Activity Measurement (ECLAM) scoring system. RESULTS: Mean values of peak concentrations of NO exhaled air were 64.8 +/- 27.9 parts per billion (ppb) in patients and 31.6 +/- 7.7 ppb in controls, p < 0.001. Peak NO concentration was directly related to ECLAM activity score (p < 0.05) and inversely related to MEF25 (p < 0.05). CONCLUSION: NO in exhaled air is significantly increased and correlated with disease activity in patients with SLE. Whether increased NO output depends on respiratory tract inflammation, as the relationship with MEF25 may suggest, or on circulating cytokines produced elsewhere remains to be investigated.
Abstract: Impaired arterial oxygenation, ranging from increased alveolar-arterial oxygen gradient (AaDo2) to hypoxemia, is commonly present in patients with cirrhosis. Nitric oxide (NO), through pulmonary vasodilatation, may play a major role in the oxygen abnormalities of cirrhosis. Our aim was to study the relationship between NO production and O2 abnormalities in 45 nonsmoking patients with cirrhosis and without major cardiovascular and respiratory diseases. Intrapulmonary shunting was detected by contrast-enhanced (CE) echocardiography. Lung volumes and diffusion, arterial blood gas analysis, serum NO2-/NO3-, NO output in the exhaled air, and cardiac index by the echocardiographic method were determined in all patients. Twenty-seven (60%) patients had an abnormally increased (> 15 mm Hg) AaDo2. The mean values of exhaled NO output and serum NO2-/NO3- were significantly higher in cirrhotic patients than in controls (252 +/- 117 vs. 75.2 +/- 19 nL/min/m2, P < .0001; and 47.5 +/- 29.4 vs. 32.9 +/- 10.1 micromol/L, P < .02, respectively). In all patients, there was a significant correlation between exhaled NO and AaDo2 (r = .78, P < .0001). Twelve patients (26.6%) were found to have CE-echocardiographic evidence of intrapulmonary shunting (positive CE-echo). Nine patients were considered to have hepatopulmonary syndrome (HPS) on the basis of an AaDo2 > 15 mm Hg and positive CE-echo. These 9 patients had a mean value of exhaled NO significantly higher than patients without HPS (331 +/- 73.2 vs. 223 +/- 118.4 nL/min/m2, P < .05). In all patients, cardiac index was positively correlated with exhaled NO (r = .47, P < .001) and with serum NO2-/NO3- (r = .43, P < .01). The results suggest an important role of NO in the oxygenation and circulatory abnormalities of patients with cirrhosis.
Abstract: BACKGROUND: In sinusitis bronchoconstriction is supposed to originate from pharyngobronchial reflexes triggered by seeding of the inflammatory process into the pharynx. OBJECTIVE: Our aim was to evaluate whether in sinusitis bronchial and extrathoracic airway (EA) dysfunction correlate with morphologic abnormalities of the pharyngeal mucosa. METHODS: We performed histamine inhalation challenge, nasal lavage, and nasopharyngeal biopsies in 24 nonasthmatic patients with exacerbation of chronic sinusitis. The histamine PC20 was the threshold of bronchial responsiveness, and that causing 25% fall in maximal midinspiratory flow was the threshold of EA responsiveness (PC25MIF50). Thresholds of 8 mg/ml or less were assumed to indicate bronchial hyperresponsiveness (BHR) or EA hyperresponsiveness (EAHR). PC20 and PC25MIF50 values were related to clinical data, nasal lavage fluid eosinophils, pharyngeal epithelium and basement membrane thickness, and density of submucosal vessels and nervous fibers. RESULTS: The PC20 was closely related to PC25MIF50 (p = 0.0004). Ten patients had EAHR, 9 had combined EAHR and BHR, and 5 had neither EAHR nor BHR. EAHR was strongly associated with epithelial thinning, and BHR with long-standing sinusitis, a lower PC25MIF50, increased submucosal nerve density and increased nasal lavage fluid eosinophils. CONCLUSIONS: Our findings suggest that in nonasthmatic patients with sinusitis, pharyngeal damage may contribute to airway dysfunction by favoring the access of irritants to submucosal nerve endings, with activation of constrictive reflexes to the EA. Proliferation of sensory neurons, consequent to long-lasting pharyngeal inflammation, may cause more severe EA narrowing and activate pharyngobronchial reflexes.
Abstract: The objective of this study was to examine the relation between respiratory function tests, disease activity and disease severity in ambulatory patients with systemic lupus erythematosus (SLE) who did not present with overt respiratory problems. Lung volumes, maximal expiratory flows at 50% and 25% of vital capacity (MEF50 and MEF25), bronchial threshold to methacholine (PD15FEV1), transfer factor CO (KCO) were measured in 24 consecutive SLE outpatients (22 women, age 41 +/- 14.8 years) and in 24 healthy controls matched for age and sex. In SLE patients alveolar-arterial oxygen gradient (AaO2) was also measured. Disease activity was assessed by European Consensus Lupus Activity Measurement (ECLAM) scoring system and disease severity by Lupus Severity of Disease Index. In comparison to controls SLE patients showed a significant decrease of total lung capacity (TLC) (91.7 +/- 16.5 vs 102.7 +/- 12.9% predicted, P < 0.01), MEF25 (58.4 +/- 25.2 vs 73.5 +/- 19.5% predicted, P < 0.005) PD15FEV1 (2164 +/- 1122 vs 4230 +/- 1014 micrograms methacholine, P < 0.0001) and KCO (77.1 +/- 20.5 vs 96.3 +/- 12.4% predicted, P < 0.001). AaO2 (mean value 13.2 +/- 8.4) was abnormally high (> 20 mmHg) in 12 patients. The ECLAM score of activity was inversely related with KCO (r = 0.48, P < 0.02). The severity index was significantly related with FEV1/VC ratio (r = 0.43, P < 0.05), MEF50 (r = 0.51, P < 0.01), MEF25 (r = 0.40, P < 0.05) and PD15FEV1 (r = 0.51, P < 0.01). In eight patients, evaluated also after treatment intensification, there was a significant increase in KCO (from 71.8 +/- 24.7 to 84.9 +/- 22.3% predicted, P < 0.01) along with a decrease in ECLAM score (from 3.0 +/- 1.34 to 0.69 +/- 0.75, P < 0.01). The relation between disease activity and KCO suggests a relation between systemic and alveolar inflammation whereas the relation between severity index, airway patency and reactivity indices suggests a cumulative damage to the airways in SLE patients, even in the absence of overt respiratory manifestations.
Abstract: Severe bronchial hyperresponsiveness to methacholine developed after intravenous therapy with OK-T3 and IL-2 in a patient with multiple myeloma, in whom no factors known to be associated with bronchial hyperresponsiveness were present. A substantial increase and activation of peripheral T-lymphocytes was observed after immunotherapy. Bronchial responsiveness and lymphocyte subsets both returned to normal baseline values 2 months after the patient was shifted to subcutaneous low dose administration of IL-2. The strict association between peripheral T-lymphocytes activation and the development of bronchial hyperresponsiveness suggests a causal relationship.
Abstract: Previous studies on the bronchodilating effect of nitrates yielded conflicting results. We hypothesized that the concomitant bronchial vasodilatation induced by nitrates may limit the increase of airway patency due to bronchial smooth muscle relaxation. To test this hypothesis, we evaluated the bronchodilating effect of nebulized nitroglycerine (NTG), 0.2 mg, in 12 patients with reversible airway obstruction (FEV1 64.3 +/- 8.2% predicted, > 15% increase after salbutamol 200 micrograms by metered-dose inhaler), pretreated with aerosolized norepinephrine (NE) (0.04 mg) or placebo (PL), in a randomized double-blind crossover design, in two separate days. Baseline FEV1 values of the two test days and FEV1 after NE or PL inhalations were not significantly different. After NTG inhalation, FEV1 was 73.8 +/- 7.9% predicted, with NE pretreatment, and 70 +/- 8.2% predicted with PL pretreatment (p < 0.01). The maximal percent increases of FEV1 above baseline were 14.9 +/- 4.8% and 9.2 +/- 2.4%, respectively, after NE and PL pretreatment (p < 0.01). In conclusion, NTG produces a better bronchodilatation when the concomitant vasodilatation is attenuated by a vasocostrictive agent.
Abstract: BACKGROUND: Asthma associated with sinusitis is supposed to be sustained by bronchoconstrictive reflexes originating in extrathoracic airway (EA) receptors. OBJECTIVE: The study was designed to evaluate the relationship between EA responsiveness and bronchial responsiveness in sinusitis. METHODS: We performed histamine inhalation challenge in 106 patients with chronic sinusitis, during disease exacerbation and after treatment with antimicrobials and nasal flunisolide (100 micrograms daily) for 2 weeks. Forced expiratory volume in 1 second (FEV1) and maximal mid-inspiratory flow (MIF50) were the respective indexes of bronchial and EA narrowing; the histamine concentrations causing a 20% fall in FEV1 (PC20) and 25% drop in MIF50 (PC25MIF50) were used as thresholds of bronchial and EA responsiveness. Thresholds of 8 mg/ml or less were assumed to indicate bronchial hyperresponsiveness (B-HR) or EA hyperresponsiveness (EA-HR). RESULTS: During sinusitis exacerbation 76 patients had EA-HR, which in 46 was associated with B-HR. The values of PC20 were closely related with those of PC25MIF50 (p < 0.001). EA-HR and B-HR were strongly associated with pharyngitis. After treatment, mean PC25MIF50 and PC20 were significantly increased (p < 0.001). The improvement of PC25MIF50 was closely related to that of PC20 (p < 0.001) and to the decrease in neutrophils in nasal lavage (p < 0.05). EA-HR reversed in 58 patients and improved in 10; B-HR reversed in 29 and improved in 12. CONCLUSIONS: Our findings suggest that in sinusitis, B-HR may be sustained by constrictive reflexes originating in pharyngeal receptors, made hypersensitive by seeding of the inflammatory process.
Abstract: The current treatment of airway obstruction using beta-agonists and theophylline is designed to increase intracellular level of cAMP. Experimental data show that cGMP and cAMP induce functionally additive relaxation of airways. Nitrates relax smooth muscle through the activation of guanylate cyclase. We wondered whether an additive effect of nitroglycerin (NTG) on beta2-agonist-induced bronchodilatation was present in asthmatic patients. To this aim we evaluated the acute bronchodilating effect of inhaled salbutamol (200 mu g MDI) in 10 asthmatics, pre-treated with inhaled NTG or placebo, in a double-blind cross-over design. FEV1 after NTG was higher than that obtained after placebo (2197 +/- 175 vs. 1981 +/- 155 ml, P <0.001). Mean FEV1 obtained 5 min after salbutamol was higher when patients were pre-treated with NTG than placebo (2694 +/- 217 vs 2440 +/- 228 ml respectively, P <0.001). The bronchodilatation due to salbutamol was identical whether NTG or placebo was inhaled first, respectively at 458 +/- 68 and 497 +/- 44 ml after 5 min. After 15 min FEV1 was higher than baseline, but no significant difference was still present between the value observed after pre-treatment with NTG or placebo (2554 +/- 235 and 2551 +/- 205 ml respectively). In conclusion, in asthmatics nebulized NTG produces a moderate and short-lasting bronchodilatation, which is additive with that produced by salbutamol.
Abstract: Patients with asthma-like symptoms may not have asthma but obstruction of the extrathoracic airway (EA). To evaluate if dysfunction of the EA causes asthma-like symptoms, we assessed bronchial and EA responsiveness to inhaled histamine in 441 patients who presented with at least one of three key symptoms--cough, wheeze, dyspnoea--but had neither documented asthma nor bronchial obstruction. The histamine concentrations causing a 20% fall in forced expiratory volume in 1 s (PC20FEV1) and a 25% fall in maximal mid-inspiratory flow (PC25MIF50) were used as respective thresholds of bronchial and EA responsiveness. Values 8 mg/mL or less indicated bronchial (B-HR) or EA hyper-responsiveness (EA-HR). The influence of concurrent upper respiratory tract diseases, such as post-nasal drip (PND), pharyngitis, laryngitis and sinusitis, was also assessed. We found four response patterns to the histamine challenge: EA-HR in 26.5% of the patients, B-HR in 11.1%, combined EA-HR and B-HR in 40.6%, and no-HR in 21.8%. Cough was reported by 79% of the patients, wheeze by 53%, and dyspnoea by 40%. Patients with cough as the sole presenting symptom (34.2%), as compared with those with wheeze and/or dyspnoea (20%), had significantly greater probability of having EA-HR (OR 5.35, 95% CI 3.25-8.82) and lower probability of having B-HR (OR 0.45, CI 0.28-0.70); patients with cough plus wheeze and/or dyspnoea (45.8%) had significantly greater probability of having both EA-HR and B-HR than either those with cough alone (OR 2.48, CI 1.49-4.13), or those with wheeze and/or dyspnoea but not cough (OR 1.74, CI 1.36-2.22). EA-HR alone or combined with B-HR was strongly associated with EA diseases, particularly pharyngitis and PND. Cough was significantly associated with PND, either when it was the sole symptom (OR 2.16, CI 1.14-4.09) or when it was combined with wheeze and/or dyspnoea (OR 3.53, CI 1.97-6.33). Our results suggest that extrathoracic airway dysfunction may account for asthma-like symptoms, particularly chronic cough. This abnormality seems to be sustained by chronic diseases of the upper respiratory tract.
Abstract: In vitro experimental data show that magnesium increases beta-receptor affinity to agonists. We studied the effect of a mild increase in serum magnesium level on the bronchial dose-response curve to salbutamol in six patients with asthma (age 54 +/- 3.6 years, FEV1 49.2 +/- 4.9 per cent of predicted), with a normal serum magnesium level, in a double blind placebo-controlled design. The salbutamol dose-response curve was obtained on two separate days, starting 30 min after an intravenous infusion of saline or MgSO4 (20 mg/kg over 10 min, followed by 10 mg/kg/h). The baseline FEV1 values and the values after 30 min infusion on the two test days were not significantly different. During MgSO4 infusion, the serum magnesium level increased significantly from 0.86 +/- 0.01 to 1.31 +/- 0.19 mmol/litre after 30 min and 1.29 +/- 0.17 mmol/litre at the end of the study. FEV1 values after salbutamol were significantly higher during MgSO4 than during saline infusion at the low doses of salbutamol: 1480 +/- 253 vs. 1368 +/- 212 ml, P < 0.05, after 5 micrograms, and 1596 +/- 585 vs. 1378 +/- 532 ml, P < 0.01, after 10 micrograms of salbutamol. The maximum increase in FEV1 obtained after the maximum dose of salbutamol (400 micrograms) was not significantly different during saline and MgSO4 infusion. In conclusion, a mild sustained increase in serum magnesium level increases the bronchodilating effect of low doses of salbutamol, possibly through an increased beta-receptor affinity. There was no effect on the maximum bronchodilating effect of salbutamol.
Abstract: To examine the role of adhesion molecules in T cell recruitment and activation during allergen-induced late asthmatic response (LAR), we evaluated the expression of lymphocyte function-associated antigen-1 alpha (LFA-1 alpha) and intercellular adhesion molecule-1 (ICAM-1) on peripheral blood T lymphocyte subsets from atopic asthmatic patients and their changes following allergen inhalation challenge. 12 atopic asthmatic patients were studied. Six patients showed only a single early response after allergen challenge, and six developed a dual response. At baseline, dual responders (DR) had a significantly higher expression of ICAM-1 on CD4+ and CD8+ T lymphocytes as compared with both single early responders (P < 0.005 and P < 0.02, respectively) and controls (P < 0.001, both comparisons). Allergen challenge was followed by a decrease of CD8+ ICAM-1+ T lymphocytes in all DR (P < 0.05) and of CD4+ ICAM-1+ T lymphocytes in four out of six DR, at the time of the LAR. At the same time, a significant rise in serum levels of the soluble form of ICAM-1 was observed in DR. These results suggest that peripheral blood immunoregulatory T lymphocytes are in a higher state of activation in DR as compared with early responders. The upregulation of ICAM-1 on these cells may be important in enhancing airway inflammation in patients with LAR.
Abstract: Coronary artery by-pass grafting with internal mammary artery (IMA) has become the graft conduit of choice, due to improved survival and its long term patency rate. However, some studies have shown that, in comparison with saphenous vein grafts, after IMA grafting, there is increased postoperative impairment of pulmonary function, possibly due to the frequent performance of pleurotomy. In 57 consecutive patients, admitted for elective CABG with IMA, we prospectively evaluated the early (2nd and 6th day) postoperative chest X-ray complications and the late (2 months) respiratory function tests changes. Thirty-two patients had been subjected to pleurotomy (group 1) and 25 not (group 2). The incidence of pulmonary atelectasis and pleural effusion in 2nd and in 6th postoperative days was not different in the two groups: 22 vs. 19%, 74 vs. 52% in 2nd, and 29 vs. 19%, 48 vs. 38% in 6th postoperative day respectively. The incidence of elevated hemidiaphragm in 6th postoperative day was not different in the two groups (18.5 vs. 14%). Two months after surgery the mean values of spirometric tests were significantly lower than the preoperative values: VC from 88.5 +/- 1.26 to 80 +/- 1.65% of predicted, P < 0.001, FEV1 from 96.1 +/- 1.27 to 84.7 +/- 1.73% of predicted, P < 0.001, MEF50 from 84.9 +/- 3.14 to 69.2 +/- 3.18% of predicted, P < 0.001. No significant changes were detected in RV and in AaPO2.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Atrial natriuretic peptide (ANP) has been reported to have protective effects against methacholine-induced bronchoconstriction in asthmatics. The aim of the study was to evaluate the relationship between plasma ANP levels and bronchial responsiveness to methacholine in patients with mitral stenosis. In 12 patients with moderate mitral stenosis, age 35-58 years, 9 female, 8 in NYHA class 2, 4 in NYHA class 3 for symptoms, plasma ANP and bronchial threshold to methacholine (PD20FEV1) were determined. The same measurements were performed in 10 asthmatic patients, hyperresponsive to methacholine, and in 10 normal subjects, nonresponsive to methacholine. Mean +/- SE plasma ANP levels were significantly higher in patients with mitral stenosis in comparison with asthmatics and normals (159 +/- 41.8, 7.3 +/- 0.98, 7.6 +/- 1.3, respectively, p < 0.01). In patients with mitral stenosis there was a significant relationship between plasma ANP and PD20FEV1 (r = 0.81, p < 0.01). No relationship was found between ANP and PD20FEV1 in asthmatics. In conclusion, in patients with mitral stenosis ANP seems to play a protective role against bronchial hyperresponsiveness to methacholine.
Abstract: To better characterize airway hyperresponsiveness reported in cardiac patients questionnaire-recorded symptoms, bronchial responsiveness to methacholine (Mch) and to ultrasonically nebulized distilled water (UNDW), diurnal oscillations of peak expiratory flow (PEF) rate were evaluated in 32 patients with moderate mitral stenosis. Twenty patients were responsive to Mch (defined as provocative dose producing a 20% fall in forced expiratory volume in one second (PD20 FEV1) less than 3.2 mg) (geometric mean PD20 FEV1 851 +/- 154 micrograms SE). Only two patients showed a fall in FEV1 greater than 20% after UNDW challenge. Patients responsive to Mch challenge had lower FEV1 as percentage of vital capacity (FEV1/VC) (80 +/- 4.8 vs 83 +/- 3.8%, p less than 0.05), higher coefficient of variation of PEF (CV-PEF) (7.1 +/- 2.8 vs 5 +/- 2.4, p less than 0.05) and higher prevalence of wheeze (70 vs 25%, p less than 0.05) in comparison with patients non-responsive to Mch challenge. CV-PEF was significantly related to FEV1 (r = 0.347, p less than 0.05) and maximal expiratory flow at 50% expired volume (MEF50) (r = 0.405, p less than 0.05). The probability of responding to Mch bronchial challenge increased proportionally with the increase in CV-PEF and the decrease in FEV1, FEV1/VC and MEF50. Airway hyperresponsiveness of patients with mitral stenosis seems to be more similar to that reported in bronchitic than in asthmatic patients.
Abstract: Sixteen patients with mitral valve disease, in whom bronchial hyperresponsiveness to methacholine had been detected shortly before mitral valve replacement (MVR), were reevaluated 35 +/- 1.5 months after MVR. In 9/16 patients there was a significant (greater than 1.5 fold) increase in bronchial provocation dose of methacholine (PD20FEV1) after MVR. In the same patients there was a significant increase in vital capacity (from 69.6 +/- 5 to 75.8 +/- 5.2% of predicted, p less than 0.01), a significant decrease in cardiothoracic ratio and in radiologic score for lung edema (from 64.3 +/- 2.9 to 56 +/- 2.1, p less than 0.01 and from 38 +/- 4.5 to 14.6 +/- 2, p less than 0.001, respectively). In all the patients the increase in PD20FEV1 was not related to any change in spirometric values but it was related to the decrease in cardiothoracic index (r = 0.72, p less than 0.01) and in radiologic score for lung edema (r = 0.61, p less than 0.05) observed after cardiosurgery.
Abstract: Functional abnormalities of the extrathoracic airway (EA) may produce symptoms mimicking bronchial asthma. We assessed the bronchial (B) and EA responsiveness to inhaled histamine in 40 patients with asthmatic symptoms and in nine asymptomatic controls. FEV1 and maximal mid-inspiratory flow (MIF50) were used as index of bronchial and EA narrowing. Hyperresponsiveness of the intra-(BHR) or extra-(EA-HR) thoracic airway was diagnosed when the provocative concentrations of histamine (PC20FEV1 or PC25MIF50) were less than 8 mg/ml. Fiberoptic laryngoscopy was performed in nine patients and three controls. The glottal region was measured at mid-volume of maximal inspiration (AgMI) and expiration (AgME) before and after histamine. Predominant EA-HR was found in 13 patients, predominant BHR in 12, equivalent BHR and EA-HR in another 12; no significant airway narrowing was observed in three patients and in the nine controls. EA-HR was significantly associated with female sex, sinusitis, post-nasal drip, dysphonia; BHR with atopy, wheezing and lower MEF50. The percent change in AgMI after histamine was closely related to the PC25MIF50 (r = 0.87, P less than 0.001), that of AgME to the PC20FEV1 (r = 0.78, P less than 0.01). These findings suggest that the assessment of EA responsiveness may be useful in the evaluation of asthmatic symptoms, especially in patients with no BHR.
Abstract: Bronchial responsiveness has been evaluated in patients with chronic lung congestion secondary to mitral valve disease. Methacholine bronchial challenge was performed by intermittent aerosol generation in 31 patients with mitral valve disease, 18 in New York Heart Association (NYHA) Class II and 13 in NYHA Class III, non-atopic and with baseline forced expiratory volume in one second/vital capacity (FEV1/VC) greater than 85% of predicted and in 30 normal controls. Haemodynamic data were available in 17 patients. The methacholine bronchial provocation dose causing a 35% fall of airway conductance (PD35sGaw) was significantly lower in patients (507 +/- C.I. 205 micrograms) than in normals (2779 +/- C.I. 358 micrograms), (p less than 0.001). In patients log PD35sGaw was significantly correlated with mean pulmonary artery pressure (r = 0.53, p less than 0.05), mean pulmonary capillary wedge pressure (r = 0.67, p less than 0.01), but not with any spirometric parameters. Bronchial hyperresponsiveness seems to be common in patients with mitral valve disease and evidence of lung congestion.
Abstract: In 95 patients with severe chronic airway obstruction (FEV1 33.2 +/- 12% of predicted; mean +/- SE), we investigated whether drug therapy had any influence on serum Mg levels. 11/95 patients had a serum Mg less than 1.45 mEq/l (lower normal limit). Multiple-regression analysis showed that the use of diuretics was associated with a significantly lower serum Mg level (1.59 +/- CI 0.06 mEq/l vs. an adjusted mean of 1.71 mEq/l; F = 11, 2, p less than 0.001). There was a significant negative correlation between serum Mg and the length of oral steroid therapy (1.64 +/- CI 0.02 mEq/l for less than 24 months of therapy vs. 1.52 +/- CI 0.06 mEq/l for greater than 24 months of therapy; F = 7, 3, p less than 0.005). No effect of theophylline, inhaled steroids or beta 2-agonists on serum Mg was observed. Because of potential negative effects of hypomagnesemia on respiratory function, routine serum magnesium determination is recommended in patients with chronic obstructive lung disease taking diuretic drugs or corticosteroids.
Abstract: The effect of acute oral administration of 2 g vitamin C on bronchial responsiveness to inhaled histamine in 16 patients with allergic rhinitis was compared with placebo on two consecutive days in a double-blind, crossover design. The PC15FEV1 was significantly increased one hour after treatment with vitamin C but not after placebo.
Abstract: It has been suggested that cough from captopril may originate from an increased sensitivity of receptors in the extrathoracic airway (EA). To explore this hypothesis, we assessed the responsiveness of EA and bronchi and the cough sensitivity to inhaled histamine in nine hypertensive patients with captopril-induced cough (group 1) during treatment and one month after withdrawal of the drug treatment. Nine patients who were asymptomatic while receiving captopril (group 2) and nine patients receiving no current treatment (group 3) served as controls. The EA responsiveness was assessed by using the maximal midinspiratory flow (MIF50) as an arbitrary index of EA constriction and was expressed as the histamine concentration causing a 25 percent decrease in MIF50 (PC25MIF50). PC15FEV1 was the index of bronchial responsiveness and PCcough (dose causing five or more coughs) was that of cough sensitivity. Airway hyperresponsiveness (EA-HR or BHR) was diagnosed when PC25MIF50 or PC15FEV1 were 8 mg/ml or lower. Patients with captopril-cough, as compared with controls, had significantly lower values of PC25MIF50, PC15FEV1, and PCcough; EA-HR and BHR were found, respectively, in seven and three of these patients and in none of the control subjects. In all the patients of group 1, cough and EA-HR resolved after withdrawal of captopril treatment, while BHR persisted in one. PC25MIF50, PC15FEV1, and PCcough were all significantly improved. Our findings suggest that cough during captopril therapy may originate from receptors in the EA.
Abstract: The effect of lung surgery on respiratory function has been investigated in 40 patients considering separately the three main procedures (pneumonectomy, lobectomy and thoracotomy alone) to ascertain if the resected lung and the volume removal can influence this function in the immediate postoperative period. The patients were submitted to spirometry and arterial gas analysis preoperatively and during 9 days postoperation; the tests controlled were VC, FEV1, TV and RR. No significant difference has been noticed among various surgical procedures.
Abstract: We investigated the acute effect of ascorbic acid on histamine bronchial responsiveness (PC 20: concentration causing a 20% fall in FEV1) in 9 hospital staff members with upper respiratory tract infection (URI) and cough. Subjects were examined within 5 days from the start of illness and 6 weeks after. On day 1, the reproducibility of PC20 was assessed by 2 consecutive inhalation challenges 1 h apart; the two values were closely related (r = 0.96, p less than 0.001). Five subjects had bronchial hyperresponsiveness (PC20 less than 8 mg/ml histamine). On the following day, PC20 was measured before and 1 h after oral intake of 2 g ascorbic acid. Vitamin C produced a significant increase in average PC20 (p less than 0.01) from 7.8 +/- (SE) 1.2 to 25.1 +/- (SE) 1.2 mg/ml. None had airway hyperresponsiveness after treatment. Six weeks after the onset of URI, bronchial responsiveness was normal in all the subjects but one. The mean PC20 was 15.5 +/- (SE) 1.25 mg/ml, significantly higher than during URI (p less than 0.05); after ascorbic acid it increased nonsignificantly to 25.7 +/- (SE) 1.35 mg/ml. Our results indicate that vitamin C inhibits the transient increase in bronchial responsiveness occurring in otherwise normal subjects during URI.
Abstract: Mucosal oedema and airway hyperreactivity are common features of asthma, in which they seem to share a common pathogenesis, i.e. airway inflammation. The relationship between oedema and hyperreactivity has not yet been properly investigated. Some speculations are advanced, based on the available experimental evidence. Mucosal oedema may amplify bronchial responsiveness by increasing epithelial permeability, by altering airway mechanics, or by stimulating neural pathways. On the other hand, bronchoconstriction may contribute to oedema by increasing hydrostatic pressure in postcapillary venules.
Abstract: Histamine bronchial threshold, the provocation concentration of histamine causing a 25% fall in maximal expiratory flow at 50% of forced vital capacity from the control value (PC25MEF50), was measured in seven heavy smokers and in seven sex- and age-matched nonsmokers before and one hour after ingestion, double-blind, of vitamin C (2 g) or placebo. Smokers had significantly lower baseline values of serum ascorbate, maximal expiratory flow at 50% of forced vital capacity (MEF50) and PC25MEF50: the latter was negatively related to serum ascorbate (r = -0.85; p less than 0.001). Acute treatment with vitamin C produced a significant decrease in PC25MEF50 in smokers (95% confidence limit (CL) from 4.87-3.36 to 2.91-2.01 mg.ml-1; p = 0.017), whilst it had no effect in nonsmokers. A preliminary open study on the effect of prolonged administration of vitamin C (1 g daily) was performed in smokers. One week of treatment produced a further significant decrease in PC25MEF50 (p less than 0.0001). Our results suggest that in heavy smokers histamine bronchial responsiveness may be attenuated by chronic ascorbate deficiency. In these circumstances, acute and short-term treatment with vitamin C may increase the bronchoconstrictive response to inhaled histamine.
Abstract: In a 37-year-old woman, a heavy smoker and an alcoholic, bronchial hyperreactivity to histamine (PC20 FEV1 0.8 mg/ml) was related to hypomagnesemia (0.55 mmol/l). After acute magnesium repletion (24 h i.v. infusion MgSO4 6 g, serum magnesium 1.05 mmol/l), histamine PC20 FEV1 increased up to 9.8 mg/ml. The role of magnesium in modulating smooth muscle contractility is discussed and the importance of checking serum magnesium in patients with airway obstruction is suggested.
Abstract: The effects of various doses of inhaled MgSO4 on the histamine bronchoprovocation test were studied in nine asthmatics in clinical remission (FEV1 greater than 80% of predicted). The minimal effective dose of MgSO4 was 0.20 mmol, which increased the dose of histamine which produced a 20% decrease in control FEV1 (PD20) from 2.88 +/- 1.4 to 5.62 +/- 1.38 mumol, p less than 0.05. A greater increase of histamine PD20 was observed after inhalation of MgSO4 at 0.40 mmol (6.90 +/- 1.6 mumol of histamine, p less than 0.05 in comparison with baseline PD20). The decrease in bronchial hyper-reactivity produced by MgSO4 suggests that it influences smooth muscle contractility and may prove to be clinically important in the treatment of asthma.
Abstract: Tight junctions (TJ) play a major role in maintaining the integrity of epithelia. Damage of conducting airway surface epithelium is commonly observed in asthma, and recent data suggest that epithelial cells modulate airway smooth muscle tone by the production of relaxant factor(s). To evaluate the ultrastructure of tight junctions (TJ) in human bronchial epithelium of normal and diseased lung, biopsy samples were obtained by fiberoptic bronchoscopy in three normal healthy subjects, four asthmatic patients with bronchial hyperreactivity to methacholine and one heavy smoker with chronic bronchitis. Specimens were examined by electron microscopy, using both thin sections and freeze-fracture techniques. In normal subjects two types of TJ were identified, based on 27 type I, 23 type II junctional areas. Epithelium from the patient with chronic bronchitis showed extensive mucous metaplasia and only junctions of the second type. Extensive epithelial damage was detected in asthmatic subjects, so that a few TJ could be found. Varying degrees of TJ abnormalities were observed and the possible role of such ultrastructural derangements was discussed.
Abstract: The bronchodilating effect of magnesium sulfate (MgSO4) was studied in ten asthmatic patients with moderate to severe airway obstruction. Two grams of MgSO4 or saline in double-blind crossover design was administered IV for 20 minutes (0.40 mmol/min) and forced expiratory capacity and forced expiratory volume in one second (FEV1) were studied at intervals. Only at the end of MgSO4 infusion did FEV1 increase significantly (109% of initial values). The bronchodilating effect was short lasting and far less than that observed after salbutamol.
Abstract: The effects of inhaled MgSO4 on methacholine bronchoprovocation test (BPT) were studied in 16 asthmatics in clinical remission (FEV1 greater than 80% of predicted). The patients performed methacholine BPT on two separate days, one day after saline, the other day after MgSO4 inhalation, in double-blind cross-over design. Spirometry was recorded on each test day before and 5 min after NaCl or MgSO4. Neither NaCl nor MgSO4 was found to have a significant effect on spirometric measurements. A significant inhibition of reactivity to methacholine was observed with an increase in log PD20 FEV1 from 1.31 +/- 0.11 inhalation units after NaCl to 1.56 +/- 0.11 inhalation units after MgSO4 (p less than 0.01). The most attractive hypothesis to explain the latter, is that Mg2+ might interfere with Ca2+ handling in the bronchial smooth muscle cells similar to that shown for other types of smooth muscle.
Abstract: The acute effects of the intravenous administration of 10 mg verapamil on pulmonary function changes induced by rapid saline infusion were studied in six normal subjects. Rapid intravenous fluid overloading caused on increase of closing volume (from 6.55 +/- 1.74 to 9.53 +/- 1.77%, p less than 0.05). After verapamil, the closing volume did not increase after infusion in three subjects and the mean increase was not significant (7.08 +/- 1.82 to 8.43 +/- 1.86%). These results suggest that the rapid administration of intravenous verapamil blunts respiratory function abnormalities caused by overhydration interstitial lung oedema.
Abstract: The effects of inhaled MgSO4 on histamine bronchoprovocation test (BPT) were studied in nine asthmatics in clinical remission (FEV1 greater than 80% of predicted). Patients performed histamine BPT on 2 separate days, one day after saline and the other after MgSO4 inhalation, in a randomized double-blind design. Spirometry and flow/volume curve were recorded on each test day before and 5 min after NaCl or MgSO4. No significant difference was observed in lung function measurements 2 days before and after either NaCl or MgSO4. The dose of histamine which produced a 20% decrease in control FEV1 (PD20FEV1) was significantly increased by aerosolized MgSO4 (from 0.177 +/- 0.036 mg after NaCl to 0.350 +/- 0.085 after MgSO4, P less than 0.05. After MgSO4 the dose-steps of histamine concentration increased two-fold in two subjects and one-fold in five.
Abstract: A retrospective study of 561 patients with silicosis and 234 with asbestosis was performed to assess whether lung function decline in five years is related to the type (restrictive or obstructive) and/or to the degree of initial damage. Based on lung function tests, three groups of patients were identified: NC with normal lung function tests, CR with restrictive impairment and CO with airway obstruction. The degree of impairment was classified as mild, moderate and severe. Patients were considered worse if five years later they presented a higher degree of impairment. The prevalence of CR was significantly higher in asbestosis, that of NC and CO in silicosis (p less than 0.01). Among subjects with normal starting lung function, 9% only developed CR or CO 5 years later. The prevalence of subjects with worsened lung function in the CR groups was significantly higher (p less than 0.001) in asbestotics (36%) than in silicotics (14%) and was closely related to starting functional impairment. In the CO group the prevalence of worsened subjects was significantly higher than in CR (p less than 0.001), similar in the two diseases and independent of starting lung impairment.
Abstract: Five healthy subjects were challenged with methacholine on 2 different days, 1 week apart, the second day after acute intravenous 30 ml/kg 0.9% saline infusion. After infusion, we observed a significant reduction in vital capacity (VC), maximal expiratory volume in 1 s (FEV1), provocation dose producing a 35% fall in SGaw (PD35SGaw) and in 25% of maximal expiratory flow (MEF25), and an increase in the slopes of log dose-response curves. Our results suggest an increased bronchial reactivity in acute minimal interstitial lung edema.
Abstract: The effects of the combination of oral nifedipine (20 mg) and inhaled salbutamol (400 mcg) were studied in ten stable patients with chronic partially reversible airway obstruction in a double-blind crossover design. Specific airway conductance (SGaw), forced expiratory volume in 1 second (FEV1), heart rate and blood pressure were recorded before and 30 min after administration of nifedipine or a placebo and 30, 60, 90, 150, 210 and 270 min after salbutamol inhalation. The mean value of FEV1 30 min after nifedipine was significantly (p less than 0.05) higher than after the placebo. The increase of SGaw and FEV1 produced by salbutamol was not significantly affected by pretreatment with nifedipine at any time. Nifedipine produced a significant increase of the heart rate which persisted throughout the study, but it did not influence blood pressure. No untoward effect was noticed during the study.
Abstract: Aims of our study were: to evaluate small airway function of subjects with past or present silica dust exposure and normal spirometric values; to investigate whether small airway disease is related to radiographic signs of silicosis, to cumulative dust exposure (ES) and to cigarette smoking. Maximal expiratory flow at 50% (MEF50) and 25% (MEF25) of forced expired vital capacity were measured in 112 subjects, 69 with radiographic signs of silicosis, group I, and the remaining 43 with normal chest X-rays. Even if age and ES were significantly higher in group I, no significant difference in respiratory function tests and in prevalence of small airway disease was found between the two groups. In both groups small airway function was significantly negatively related to smoking habits, while it was independent of the other variables considered. Multiple regression analysis with MEF50 and MEF25 as dependent variables did not show any significant relationship. We conclude that small airway disease due to encroachment of bronchiolar walls by SiO2 deposition is masqued by the damage produced by cigarette smoking, even in the presence of radiographic signs of silicosis.
Abstract: This study was undertaken to assess the validity of cluster analysis for stratifying patients with severe COLD into homogenous subgroups in view of further prospective studies. To this aim, physiological measurements and questionnaire data were obtained from 532 outpatients with severe COLD (e.g. a 1 sec forced expiratory volume (FEV1) below 1.5-1/sec). The model variables selected for the partition in cluster were FEV1, PaO2, response to bronchodilators and heart rate. Two subgroups of patients were identified by the analysis: cluster I with significantly greater physiological impairment than cluster II. The comparison of the prevalences of the variables outside the model between the 2 clusters showed, in fact, that cluster I had a significantly higher prevalence of subjects with heavy smoking (p less than 0.01), prolonged occupational exposure (p less than 0.05), low body weight (p less than 0.05), recent hospitalizations for respiratory troubles (p less than 0.02) and emphysema (p less than 0.01). In conclusion, cluster analysis based on few physiological variables was able to identify, among patients with severe COLD, those with poorer general conditions and higher exposure to specific risk factors, for whom a worse prognosis of life can be expected. The advantages of cluster analysis in comparison to other techniques of classification in this kind of patient is discussed.
Abstract: Circulating Angiotensin Converting Enzyme (ACE) level, chest X-rays and respiratory function tests were determined in 76 male patients with silicosis. Mean serum ACE in the patients was significantly higher than in 30 healthy controls (129.8 +/- 4 U/ml and 92.4 +/- 22.7 respectively), although individual values were in the normal range in about half of the patients. Enzyme levels were independent of silica dust exposure, X-ray changes, functional lung impairment, age, smoking habits, and presence of chronic obstructive pulmonary disease. However, patients with more severe radiological changes tended to have lower ACE values. Our data confirm that serum ACE level is frequently raised in silicosis, but does not give further information in the evaluation of the disease.
Abstract: Static and dynamic lung volumes, flow-volume curve in air and after He-O2 were carried out in 5 normal subjects baseline, immediately after rapid infusion of 2 litres of normal saline, and then 15, 30 and 60 min after. At the end of the infusion, a marked reduction of delta MEF50, FVC, FEV1, MEF50, MEF25 and an increase of Viso V and CV/VC were observed in all the subjects. The poor response to He-O2 suggests a predominant increase of small airway resistance after rapid infusion. In the recovery phase, He-O2 tests promptly returned to control values, while an increased CV/VC was detectable until 30 min after the infusion.
Abstract: Two groups of 10 patients with systemic arterial hypertension were studied by respiratory function tests before and after acute administration of diazoxide or furosemide. Small airways obstruction was present in a high percentage of patients and was partially reversed after the acute administration either of diazoxide or of furosemide. Systemic arterial hypertension seems to influence small airways caliber, through pulmonary vascular distension and/or pulmonary interstitial edema.
