Caterina Bucca

Respiratory function in systemic lupus erythematosus: relation with activity and severity

OBJECTIVES To determine whether patients with primary Sjögrens syndrome (SS), diagnosed according to San Diego criteria, had improvement in their laboratory or clinical features during treatment with hydroxychloroquine (6-7 mg/kg/day) for at least two years. METHODS The study population included 50 consecutive patients with primary SS who were diagnosed according to San Diego criteria, and in whom hydroxychloroquine was suggested as treatment. This group included 10 patients who were early dropouts (side effects or desire not to take antimalarial drugs) and 40 patients who received drugs for at least two years (range 24-48 months). In a subset of SS patients, values for ESR (westergren) and quantitative immunoglobulins were available for comparison. Improvement with therapy was defined as: (a) > or = 20% improvement in variables of tear flow (Schirmers test I) or corneal integrity (rose Bengal): (b) > or = 20% salivary function (flow rate); and (c) improvement in at least two of the following measures: physicians assessment of global disease activity by > or = 20%, patient assessment of improvement in pain or fatigue by > or = 20%, and ESR improved by > or = 20 mm/hr. RESULTS In a retrospective study of SS patients who completed the trial, a significant improvement was noted in ocular symptoms (pain and dryness) in patients (55 and 57%) and improved corneal integrity (rose Bengal straining) in 53% of patients. The Schirmers test was improved by > or = 2 mm/5 minutes in 50% in patients. Improvement was noted in oral symptoms (pain and dryness) in patients (57 and 60%) and salivary flow rate was increased in 82% of patients. In a subset of SS patients evaluated, the ESR improved by > or = 20 mm/hr in 17/32 patients (53%) and quantitative IgG level by > or = 20% in 8/13 patients (61%). Physician global assessment of overall patient status and patient assessment of overall status indicated improvement in over 62% of patients. CONCLUSION In a retrospective study of patients fulfilling San Diego Criteria for SS, we found: (a) sustained improvement of local symptoms (painful eyes, painful mouth) and improvement of systemic manifestations (arthralgias and myalgias) after treatment with hydroxychloroquine 6-7 mg/kg/day over mean three-year follow-up; (b) laboratory analysis showed a significant improvement in their ESR and their quantitative IgG levels; (c) no significant late toxicity was observed in this study cohort. A prospective study of hydroxychloroquine in patients fulfilling San Diego criteria for SS is indicated.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 (PD15FEV 1), 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 μg 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 mm Hg) 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.

Exhaled Nitric Oxide and Impaired Oxygenation in Cirrhotic Patients before and after Liver Transplantation

Abnormalities of arterial oxygenation are common in patients with cirrhosis [1], and a widened alveolar-arterial oxygen gradient is reported in more than half of these patients at pretransplantation assessment of pulmonary function [2, 3]. Increasing evidence suggests that the abnormal gas exchange in cirrhotic patients is primarily due to intrapulmonary vasodilatations, which cause ventilation-perfusion mismatch and impaired diffusion [4]. Increased circulation of a pulmonary vasodilator seems to be the favored mechanism for intrapulmonary vasodilatations, and recent evidence points to nitric oxide as the most important vasodilating substance [5]. Increased nitric oxide output in exhaled air has been reported in patients with advanced cirrhosis [6], and a correlation between exhaled nitric oxide concentrations and alveolar-arterial oxygen gradient was recently shown in 45 patients with cirrhosis [7]. After successful liver transplantation, oxygenation has been reported to improve in most patients [3]. In a limited series of three patients with full-blown hepatopulmonary syndrome characterized by severe hypoxemia and evidence of intrapulmonary shunting, the increased amount of exhaled nitric oxide reportedly decreased to within the normal range in one patient after successful liver transplantation [8]. To further investigate the association between nitric oxide produced in the lung and oxygenation abnormalities in patients with cirrhosis, we sought to determine exhaled nitric oxide and oxygenation measures before and after liver transplantation in a selected group of patients with cirrhosis who did not have obvious cardiorespiratory diseases. Methods Patients Twenty patients who underwent successful orthotopic liver transplantation at our hospital from August 1995 to February 1997 were recruited for our study. These patients came from a group of 45 patients who were evaluated at the Outpatient Clinic for Liver Cirrhosis during a scheduled visit [7]. All patients gave their informed consent to participate in the study, which was approved by the ethical committee. Included patients had to have been evaluated within 8 weeks before transplantation. Exclusion criteria were respiratory and cardiovascular disease, including clinically significant pleural effusion (larger than costophrenic angle on chest radiography); tense ascites; inability to perform lung function tests; current smoking habit or a smoking history of more than 10 packs per year (1 pack per year = 20 cigarettes per day for 1 year); forced vital capacity (FVC) and FEV (1) less than 80% of predicted; FEV1/FVC 100 less than 70%; and an airway infection in the previous 4 weeks. All patients were reevaluated 3 to 12 months after transplantation. Laboratory Testing Patients underwent the following studies: pulmonary function tests, arterial blood gas analysis done while patients were breathing room air in a seated position, contrast-enhanced echocardiography, and measurement of nitric oxide in exhaled air. The hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient greater than 15 mm Hg and echocardiographic evidence of intrapulmonary vasodilatations [4]. Lung volumes and carbon monoxide diffusing capacity were obtained according to standardized procedures [9, 10]. The reference values of Quanjer were used [11]. Arterial blood gas samples were obtained by percutaneous radial artery puncture while patients were seated and breathing room air. The alveolar oxygen tension was calculated by using the ideal air Equation and assuming a respiratory exchange ratio of 0.8. The alveolar-arterial oxygen difference was then derived. A gradient less than 15 mm Hg was considered normal. Exhaled nitric oxide was measured on a chemiluminescence analyzer (Dasibi Environmental Corp., Glendale, California) that is sensitive to nitric oxide from 1 to 4000 parts per billion (ppb) by volume, adapted for on-line recording of nitric oxide concentration, at a sample gas flow of 250 mL/min according to European Respiratory Society recommendations [12]. The analyzer was calibrated daily against standard gas mixtures. While seated and wearing a noseclip, patients were asked to inhale nitric oxide-free air (<5 ppb) and to perform a slow expiratory vital capacity test over 20 to 30 seconds with a flow of 5 to 15 L/min against a low resistance (5 to 20 cm H2O). Exhaled air was sampled for nitric oxide analysis by way of a Teflon tubing side arm attached to the mouthpiece. Nitric oxide concentration, flow, and pressure were simultaneously displayed against time on a computer screen. Three successive reproducible recordings were made at 2-minute intervals, and the mean values of the plateau (the last part of expiration) of nitric oxide concentration (expressed in ppb) were recorded. Because of flow dependence of exhaled nitric oxide concentration [13], flow rates at which nitric oxide measurements were performed in each patient before and after transplantation were compared and found to not be statistically significantly different (10.2 2.37 L/min compared with 10.6 2.28 L/min). Twenty nonsmoking healthy persons (mean age, 44.6 11.2 years; 12 men) served as normal controls for exhaled nitric oxide concentrations. Saline contrast-enhanced echocardiography was done by use of a peripheral intravenous line, as reported elsewhere [14]. A positive result on contrast-enhanced echocardiography (that is, indicating intrapulmonary right-to-left shunt) was defined as the delayed appearance (three to six beats after the initial appearance of contrast in the right side of the heart) of microbubbles in the left side of the heart. Statistical Analysis The variability of the outcomes (decrease in alveolar-arterial oxygen gradient and exhaled nitric oxide concentration after transplantation) was estimated from previous studies [3, 8]. The sample size was calculated on the basis of an expected 50% decrease in the outcomes after transplantation compared with pretransplantation values, for a two-tailed value of 0.05 and a value of 0.20. Means and SDs were calculated for each variable. The Student t-test for paired data was used to compare data before and after transplantation; the McNemar test was used when appropriate. Regression analysis was performed by using the least-squares method. A P value of 0.05 or less was considered statistically significant. Role of the Funding Source Our funding source had no role in the collection, analysis, or interpretation of the data or in the submission of the paper for publication. Results Eighteen patients (mean age, 48.3 7 years; 14 men) completed the study. Two patients died after surgery (1 of pneumonia and 1 of stroke) 72 and 85 days after transplantation. Cirrhosis was alcoholic in 7 patients; viral in 8 patients; and autoimmune, cryptogenic, and associated with Wilson disease in 1 patient each. According to the Child-Pugh classification [15], 4 patients had class A cirrhosis, 4 had class B cirrhosis, and 10 had class C cirrhosis. Fifteen patients (83.3%) had esophageal varices. Patients were reevaluated 8.5 3.5 months (range, 3 to 12 months) after transplantation. Post-transplantation lung volumes and diffusion did not significantly differ from pretransplantation values: Total lung capacity increased from 95.4% 9.6% of predicted to 96.7% 10.4% of predicted, FEV1 increased from 100.3% 13.3% of predicted to 103% 13.2% of predicted, FEV1/FVC 100 decreased from 80.5% 4.5% of predicted to 79.5% 4.2% of predicted, and the diffusing capacity of the lung for carbon monoxide divided by alveolar volume decreased from 76.5% 20.9% of predicted to 71.6% 17.2% of predicted. Arterial blood gas data, exhaled nitric oxide concentrations, and findings on echocardiographic evaluation of intrapulmonary shunts before and after transplantation are given in Table 1. Before transplantation, the mean exhaled nitric oxide concentration was significantly higher in patients than in controls (13 4.9 ppb compared with 5.75 1.9 ppb; P < 0.001). Table 1. Arterial Blood Gas Analyses, Exhaled Nitric Oxide Concentrations, and Patients with the Hepatopulmonary Syndrome before and after Liver Transplantation* After transplantation, the alveolar-arterial oxygen gradient significantly decreased (from 17.3 7.1 mm Hg before transplantation 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 exhaled nitric oxide concentration after liver transplantation was significantly correlated with the decrease in alveolar-arterial oxygen gradient (r = 0.56; P = 0.014) (Figure 1). Figure 1. Correlation between the differences in alveolar-arterial oxygen gradient and exhaled nitric oxide concentrations before and after liver transplantation. Before transplantation, intrapulmonary shunts were detected by contrast-enhanced echocardiography in five patients, all of whom met the criteria for the hepatopulmonary syndrome and had an alveolar-arterial oxygen gradient greater than 15 mm Hg. In these patients, the pretransplantation exhaled nitric oxide concentration was significantly higher than that in patients without the hepatopulmonary syndrome (18 5.48 ppb compared with 11.07 3.2 ppb; P < 0.005). After transplantation, the hepatopulmonary syndrome was no longer evident; the alveolar-arterial oxygen gradient returned to normal in all affected patients, even the two patients in whom contrast-enhanced echocardiography still showed intrapulmonary vasodilatations. Discussion We found a highly significant decrease in exhaled nitric oxide concentrations after liver transplantation that was correlated with the decrease in alveolar-arterial oxygen gradient. As in other investigations [1-3], respiratory function assessment done before liver transplantation revealed a high prevalence of widened alveolar-arterial oxygen gradient in our patients with advanced liver disease. The high concentration of exhaled nitric oxide in our pati

Extrathoracic and intrathoracic airway responsiveness in sinusitis

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.

Are asthma-like symptoms due to bronchial or extrathoracic airway dysfunction?

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.

Reduction of histamine‐induced bronchoconstriction by magnesium in asthmatic subjects

The effects of inhaled MgSO4 on histamine bronchoprovocation test (BPT) were studied in nine asthmatics in clinical remission (FEV1 > 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 < 0.05. After MgSO4 the dose‐steps of histamine concentration increased two‐fold in two subjects and one‐fold in five.

Tooth loss and obstructive sleep apnoea

BackgroundComplete 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).MethodsPolysomnography 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.ResultsThe 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).ConclusionThese 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.

Effects of levetiracetam on nocturnal sleep and daytime vigilance in healthy volunteers.

Summary:   Purpose: Individuals with epilepsy commonly report daytime sleepiness, attributed to sleep disruption (frequent arousals, awakenings, and stage shifts) induced by ictal and interictal activity or antiepileptic drugs (AEDs) or both. To study the effect of levetiracetam (LEV) on sleep, at full doses but without the interference of epilepsy, we investigated the sleep architecture and daytime vigilance in healthy adults after 3 weeks of treatment.

Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms

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. FEV, 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 <8mg/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 BHRin 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 < 0.001), that of AgME to the PC20FEV1 (r = 0.78. P < 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.

Damage of the pharyngeal mucosa and hyperresponsiveness of airway in sinusitis

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.

Oral nitric oxide during plaque deposition

Background Nitric oxide (NO) is one of the most powerful antibacterial compounds. We investigated if NO oral production increases during dental plaque deposition.