Avoidance of nonsteroidal anti-inflammatory drugs after negative provocation tests in urticaria/angioedema reactions: Real-world experience.

Drug provocation tests (DPTs) are the gold standard in diagnosing nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity; however, only few data about follow-up of patients with negative DPTs are actually available. The aim of this study was to assess patients' behavior in taking NSAIDs again and to evaluate NSAID tolerability after negative allergological workup. This is a follow-up study involving patients evaluated for history of cutaneous reactions (urticaria and or angioedema) after NSAID intake and with negative DPTs with the suspected NSAID. Patients were asked during a phone interview about the intake of NSAIDs, tolerance, or reasons of avoidance. The negative predictive value (NPV) of NSAIDs DPTs was calculated. One hundred eleven of 142 patients were successfully contacted; 46/111 (41.44%) took the same NSAID previously tested with two adverse reactions reported (4.34%). Fifty-three of 111 (47.74%) patients did not take the same NSAID, but 34 of them took at least another strong cyclooxygenase (COX) 1 inhibitor, with 1 adverse reaction (2.94%) and 19 of them took only weak COX-1 inhibitors. Twelve of 111 patients (10.8%) did not take any NSAID. Reasons for drug avoidance were mainly fear of reactions (70.8%) and no need (29.2%). NPV, overall, was 96.97% (95% confidence interval, 91-99%). Although NSAID hypersensitivity diagnosis was ruled out by oral provocation test, the majority of patients with a history of urticaria/angioedema avoided the intake of the tested NSAIDs for fear of new reactions, particularly when strong COX-1 inhibitor NSAIDs were involved. The high NPV value of DPT resulting from this study should reassure NSAID intake.

Provocation tests with the offending nonsteroidal anti-inflammatory drugs in patients with urticaria/angioedema reactions.

The provocation test (PT) with the suspected drug represents the gold standard in the diagnosis of non-IgE hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, there is no consensus regarding the clinical management of suspected NSAID-sensitive patients. This study assessed if a PT with the suspected drug is a reliable and safe proceeding to confirm NSAID hypersensitivity in patients with a clinical history of urticaria/angioedema (Urt/AE). It also analyzed different patient characteristics (such as gender, age, atopy, dermographism, time interval between the last drug reaction, and number of previous NSAID reactions) in relation to PT positivity. One hundred fifty-nine patients with Urt/AE apparently related to assumption of one or more NSAIDs underwent PT with the suspected drugs. Moreover, to distinguish single/multiple NSAID reactivity in patients who did not tolerate the offending NSAID, another strong cyclooxygenase-1 inhibitor PT was performed. PT was negative in 142/159 patients (89.31%), ruling out a diagnosis of NSAIDs hypersensitivity; 17/159 patients (10.69%) experienced a reaction of Urt/AE during the PT: 8 patients were diagnosed as single reactors to NSAIDs and 4 as multiple reactors to NSAIDs. Those with a history of multiple NSAID reactions and male patients were both more likely to have a positive PT. Our results suggest that in all patients with history of NSAID cutaneous reactions, the NSAID hypersensitivity should be confirmed by an oral PT and that the diagnostic proceeding can safely start with the offending NSAID.

Innate and lymphocytic response of birch-allergic patients before and after sublingual immunotherapy.

Functional imbalance in Th1/Th2 cell response toward allergens is a recognized hallmark of allergic patients and a major role of dendritic cells (DCs) in redirecting T-cell phenotypes after specific immunotherapy has been suggested. This study investigates the proliferative and cytokine responses of T cells cocultured with monocyte-derived DCs (MoDCs) after allergen stimulation in birch-allergic patients compared with controls and investigates whether sublingual immunotherapy (SLIT) could change the DC-driven immune response. T cells were stimulated with the major birch pollen allergen (nBet v1) and MoDCs from eight birch-allergic patients with seasonal allergic rhinitis and eight nonallergic controls. Proliferation and cytokine production were measured before and after one course of SLIT with birch allergoid. Significantly lower levels of proinflammatory (IL-1beta, p = 0.027; IL-6, p = 0.030; TNF-alpha, p = 0.019) and Th1 (interferon gamma, p = 0.032; IL-12, p = 0.05) cytokines were measured in supernatants of T cells and MoDCs cultures from allergic patients compared with nonallergic controls. After SLIT, significant increase in IL-12 (p = 0.039), IL-1beta (p = 0.040), IL-6 (p = 0.041), TNF-α (p = 0.048), and IL-10 (p = 0.048) and significant decrease in IL-13 (p = 0.001) were observed. MoDCs/T-cell cocultures, pulsed with the specific allergen, produced lower quantities of proinflammatory and Th1 cytokines in allergic patients compared with healthy subjects, suggesting an allergen-specific impairment of natural immunity and Th1 immune response. A single course of SLIT was able to enhance allergen-specific innate immunity and to modify lymphocyte response, promoting Th1 and T-cell regulatory activity.

Determinants of exhaled nitric oxide in chronic rhinosinusitis.

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.

Effect of arterial hypertension on chronic urticaria duration.

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.

Nasal nitric oxide concentration in suspected chronic rhinosinusitis.

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.

Exhaled nitric oxide in a population sample of adults.

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.

Diagnostic classification of persistent rhinitis and its relationship to exhaled nitric oxide and asthma: a clinical study of a consecutive series of patients.

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.

Exhaled nitric oxide in persistent rhinitis with or without lower airway involvement: a review of the literature.

The link between upper and lower respiratory airways has been investigated in the past decade leading to the concept of united airways disease. This hypothesis was suggested by several epidemiological observations, which had shown the high prevalence of rhinitis and sinusitis in patients with asthma, and indirectly, by observing the effects of drugs used for rhinitis on asthma symptoms. A broad spectrum of airway involvement severity can be associated with rhinitis or rhinosinusitis: from a subclinical/asymptomatic inflammatory involvement with an increase in eosinophils in induced sputum cell count, to asthma-like symptoms without functional features of asthma with or without extrathoracic airway hyperresponsiveness, to respiratory symptoms with clinical and functional criteria of asthma. The aim of this paper is to review the literature about the role of breath analysis in the relationship between nose and lung, focusing on exhaled nitric oxide (FE(NO)) measurement, a non-invasive marker of inflammation, in rhinitis and in chronic rhinosinusitis in patients complaining or not of asthma symptoms.

Level of exhaled nitric oxide during human anaphylaxis.

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.

Exhaled nitric oxide as a diagnostic test for asthma in rhinitic patients with asthmatic symptoms.

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.

[Exhaled nitric oxide as a marker of diseases]. / Il ruolo della misura del monossido di azoto nell'aria espirata in patologia.

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.