Nasal nitric oxide in upper airways in children with asthma and allergic rhinitis

PurposeThe aim of this study is to compare levels of nasal nitric oxide (nNO) in pediatric patients with respiratory diseases.Materials and methodsnNO was measured by an electrochemical analyzer in 179 patients aged 7–15 with asthma, allergic rhinitis or with asthma and allergic rhinitis and in healthy children recruited from a local allergology clinic. Correlations between nNO levels and patient clinical parameters were assessed.ResultsnNO was significantly higher in patients with allergic rhinitis (2316.3 ± 442.33 ppb, p < 0.001) as well as with asthma and allergic rhinitis (2399.9 ± 446.73 ppb, p < 0.001) compared to asthmatic and healthy children (1066.4 ± 416.75; 836.2 ± 333.47 ppb, respectively). A receiver operating characteristic curve analysis revealed that a cut-off value of 1545 ppb nNO and 1459 ppb nNO has sensitivity of 100% and specificity of 100% in distinguishing allergic rhinitis and combined asthma and allergic rhinitis from healthy subjects. A positive correlation between nNO and age and height was determined only in groups of healthy controls. We found no association between nNO level and clinical parameters including percent of eosinophils and total IgE.ConclusionLevels of nNO are currently measured by different analyzers and with different methods, so assessment of nNO is in need of standardization improvement to become a more reliable tool. However, because it is cheap, painless and fast, it may be helpful in combination with recognition of clinical symptoms and typical diagnostic methods, especially in estimation of inflammation.     

Nasal nitric oxide is increased in allergic rhinitis

Background Nitric oxide (NO) plays a major role in the regulation of vascular tone and in non-specific host defence. The epithelium in the paranasal sinuses was recently identified as the major site of NO production in the upper airways. Objective To investigate NO status in allergic rhinitis, we compared the NO concentration in the nasal cavities of control subjects (n= 19) and in patients with allergic rhinitis (n= 36) with symptoms (WS, n= 17) or without symptoms (WOS, n= 19) on the day of the test. Methods NO concentration was measured using a chemiluminescent analyser aspiring from each nasal cavity at a sampling flow rate of 0.7L/min, before and 10min after administration of a nasal vasoconstrictor. Results The mean NO concentration (± se) in the control was 235 ± 11 ppb and 225 ± 9 ppb in the right and left nostrils respectively, and was decreased by 14% and 12% by the nasal vasoconstrictor (P < 0.001). The NO concentration in patients with allergic rhinitis was significantly higher in the right and left nostrils (382 × 20 ppb and 396 ± 28 respectively, P < 0.0001 versus control). All WOS patients demonstrated normal or increased NO concentrations in both nostrils, whereas two WS patients showed decreased NO concentrations in the left nostril. Inhalation of a nasal vasoconstrictor increased NO concentration by 6% and 27% in the right and left nostrils respectively in WS patients. Conclusion Nasal NO concentration is increased in patients with allergic rhinitis. Interestingly, patients without symptoms on the day of the test also showed a clear-cut increase in nasal NO production, which could reflect a permanent inflammation of the sinus mucosa.     

Nasal mucosal gene expression in patients with allergic rhinitis with and without nasal polyps

BACKGROUND: Nasal polyps are a common problem that is difficult to diagnose and treat, in part because the cause of nasal polyposis is unknown. Although information on the pathogenesis of polyposis is lacking, there are reports suggesting that a genetic predisposition underlies this disorder. OBJECTIVE: We sought to better understand the basis of nasal polyposis associated with allergic rhinitis. We hypothesize that the expression of unique genes is associated with the nasal polyposis phenotype. METHODS: We examined 12000 human genes transcribed in the nasal mucosa of patients with allergic rhinitis with and without nasal polyps. Biopsy specimens of the mucosa of patients with and without polyps were obtained after the patients refrained from the use of topical or systemic steroid therapy for 2 weeks. RESULTS: Thirty-four genes were differentially expressed between the patient groups, including those for inflammatory molecules and putative growth factors. The greatest differential expression identified by the array analysis was for a group of genes associated with neoplasia, including mammaglobin, a gene transcribed 12-fold higher in patients with polyps compared with control patients with rhinitis alone. Quantitative RT-PCR confirmed this differential expression and documented that the number of mammaglobin mRNA copies is actually 64-fold greater in tissues of patients with polyps versus control patients. The specificity of mammaglobin protein expression was evaluated by means of immunohistochemistry, which showed specific staining in nasal polyp mucosal goblet cells only in patients with polyps. CONCLUSION: These data suggest that nasal polyposis involves deregulated cell growth, using gene activation in some ways similar to a neoplasm. In addition, mammaglobin, a gene of unknown function associated with breast neoplasia, might be related to polyp growth.     

Nasal and bronchial response to exercise in patients with asthma and rhinitis: the role of nitric oxide

BACKGROUND: Physical exercise is associated with a decrease in nasal resistance in rhinitis and an increase in bronchial resistance in asthma. The objective was to evaluate the relationship between the levels of nasal nitric oxide (nNO) and exhaled bronchial nitric oxide (eNO) with bronchial responses to exercise in patients with rhinitis and asthma. METHODS: We submitted 24 subjects with asthma and rhinitis to an exercise test. A decrease in FEV(1)> or =15% was considered positive. The volume of the nasal cavity and the minimal cross-sectional area (MCA) was evaluated by means of acoustic rhinometry (AR), and nNO and eNO were evaluated by chemoluminiscence. The measurements were recorded at baseline, 15 and 50 min after the end of the exercise test. RESULTS: The exercise test was positive in 17 cases. Fifteen minutes after exercise test, the nasal volume increased by 57% (P < 0.0001) and was still increased by 30% after 50 min (P < 0.0001). There was no correlation between decrease in FEV(1) and increase in nasal volume. The baseline value of nNO was 1185 +/- 439 ppb, and the value at 15 and 50 min was 1165 +/- 413 and 1020 +/- 368 ppb, the latter value being significantly lower (P < 0.01) than the baseline. The baseline value of eNO was 21 +/- 19 ppb, with no significant differences at 15 and 50 min. There was no significant correlation between either the decrease in FEV(1) and the nasal response, or the baseline eNO and nNO values. CONCLUSIONS: The nasal and bronchial response to exercise is completely different in rhinitis and asthma; in the former, an increase in nasal volume occurs, while in the latter there is a drop in FEV(1). There is no relationship between the values of nasal or exhaled NO and the nasal and bronchial response after exercise.     

Nasal mucosal hyperpermeability to macromolecules in atopic rhinitis and extrinsic asthma

This study was designed to test the hypothesis that patients with atopic rhinitis and extrinsic asthma have a nasal mucous membrane defect that allows inhaled macromolecules access to immunocompetent cells. Three groups were studied: normal subjects, patients with extrinsic asthma, and patients with atopic rhinitis. Albumin ¹²⁵I(20 μc) was applied to the nasal mucosa and venous blood samples were drawn at set intervals up to 4 hours. Thirty-two minutes after administration, a significantly greater percentage of the dose was found in the plasma of patients with atopic rhinitis than in that of normal subjects (p < 0.001). Transport of intact albumin across the nasal mucosa was demonstrated by dialysis, gel filtration, and immunoprecipitation experiments in $\text{3}\text{9}$ normal subjects, $\text{1}\text{9}$ patients with asthma, and $\text{9}\text{10}$ patients with rhinitis (p < 0.02). These studies suggest that large, potentially antigenic molecules pass more readily across the nasal mucous membrane of patients with allergic rhinitis than that of normal subjects. No increase in nasal transport was seen in patients with extrinsic asthma. It has not been determined whether this defect is a cause or an effect of atopic rhinitis.     

Nasal nitric oxide: longitudinal reproducibility and the effects of a nasal allergen challenge in patients with allergic rhinitis

BACKGROUND: Exhaled nitric oxide (eNO) is a validated noninvasive marker of airway inflammation in asthma. In patients with allergic rhinitis (AR), increased levels of nasal nitric oxide (nNO) have also been measured. However, the applicability of nNO as a marker of upper airway inflammation awaits validation. AIM: To test the longitudinal reproducibility of standardized nNO measurements in patients with AR and the effects of nasal allergen challenge. METHODS: Twenty patients with clinically stable, untreated AR participated in a combined study design. First, reproducibility of nNO was tested over 1, 7, and 14-21 days. Subsequently, the effect of nasal allergen challenge on nNO was studied in a placebo-controlled, parallel design. Nasal NO was measured with a chemoluminescence analyzer. Ten subjects randomly underwent a standardized nasal allergen challenge; 10 subjects received placebo. Response to nasal challenge was monitored by composite symptom scores. RESULTS: There was a good reproducibility of nNO up to 7 days [coefficient of variation (CV) over 1 (16.45%) and 7 days (21.5%)], decreasing over time [CV (14-21 days): 38.3%]. As compared with placebo, allergen challenge caused a significant increase in symptom scores (P < 0.001), accompanied by a decrease in nNO at 20 min postchallenge (P = 0.001). Furthermore, there was a gradual increase in nNO at 7 h, reaching significance at 24-h postallergen (P = 0.04). CONCLUSIONS: Similar to eNO in asthma, nNO is a noninvasive marker, potentially suitable to monitor upper airway inflammation following allergen-induced late response. Present data show a good reproducibility of nNO measurements, decreasing over time, probably because of subclinical seasonal influences.     

Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma.

Experimental studies have demonstrated that induction of a nasal allergic reaction can lead to an increase in bronchial responsiveness (BR). To assess the clinical relevance of these experimental changes to chronic asthma, we sought to determine the effect of nasal beclomethasone dipropionate (Bdp) on BR in patients with seasonal allergic rhinitis and asthma. Eighteen subjects with histories of seasonal allergic rhinitis and asthma during the fall pollen season with positive skin tests to short ragweed and bronchial hyperresponsiveness to inhaled methacholine were assigned to receive either nasal Bdp (336 micrograms/day) or placebo for the entire ragweed season. Patients recorded daily nasal and chest symptoms, nasal blockage index, oral peak expiratory flow rates, and supplemental medication use. BR to methacholine was measured during the baseline period and 6 weeks into the ragweed season. Although the Bdp group did have a significant improvement in nasal blockage index, there was no improvement in daily asthma symptom scores, oral peak expiratory flow, or asthma medication use. However, subjects treated with Bdp were protected from the increase in BR seen in the placebo group (geometric mean PC20 placebo group: baseline = 0.70, week 6 = 0.29; Bdp group: baseline = 0.80, week 6 = 0.93; intergroup difference, p = 0.022). We conclude that nasal corticosteroid therapy can prevent the increase in BR associated with seasonal pollen exposure in patients with allergic rhinitis and asthma.     

Nasal mucosal expression of the leukotriene and prostanoid pathways in seasonal and perennial allergic rhinitis

Background Leukotrienes (LTs) and prostanoids are potent pro‐inflammatory and vasoactive lipid mediators implicated in airway disease, but their cellular sources in the nasal airway in naturally occurring allergic rhinitis (AR) are unclear. Objective To quantify cellular expression of enzymes of the 5‐lipoxygenase (5‐LO) and cyclooxygenase (COX) pathways by immunohistochemistry in nasal biopsies from patients with symptomatic perennial AR (PAR, n=13) and seasonal AR (SAR, n=14) and from normal subjects (n=12). Methods Enzymes of the 5‐LO pathway (5‐LO, FLAP, LT A₄ hydrolase, LTC₄ synthase) and the COX pathway (COX‐1, COX‐2, prostaglandin D₂ synthase) were immunostained in glycol methacrylate resin‐embedded inferior turbinate biopsy specimens, quantified in the lamina propria and epithelium, and co‐localized to leucocyte markers by camera lucida. Results In the lamina propria of PAR biopsies, median counts of cells expressing FLAP were fourfold higher than in normal biopsies (Mann–Whitney, P=0.014), and also tended to be higher than in SAR biopsies (P=0.06), which were not different from normal. PAR biopsies showed threefold more cells immunostaining for LTC₄ synthase compared with SAR biopsies (P=0.011) but this was not significant compared with normal biopsies (P=0.2). These changes were associated with ninefold more eosinophils (P=0.0005) with no differences in other leucocytes. There were no significant differences in the lamina propria in immunostaining for 5‐LO, LTA₄ hydrolase, COX‐1, COX‐2 or PGD₂ synthase. Within the epithelium, increased expression of COX‐1 was evident in PAR biopsies (P=0.014) and SAR biopsies (P=0.037), associated with more intra‐epithelial mast cells in both rhinitic groups (P<0.02). Conclusions In the nasal biopsies of PAR subjects, increased expression of regulatory enzymes of the cysteinyl‐LT biosynthetic pathway was associated with lamina propria infiltration by eosinophils. Seasonal rhinitis biopsies shared only some of these changes, consistent with transient disease. Increased intra‐epithelial mast cells and epithelial COX‐1 expression in both rhinitic groups may generate modulatory prostanoids.     

Nasal ocular reflexes and eye symptoms in patients with allergic rhinitis.

BACKGROUND: Allergic patients often complain of eye symptoms during the allergy season. A possible mechanism for these eye symptoms is a nasal ocular reflex. OBJECTIVE: To demonstrate eye symptoms after nasal allergen challenge. METHODS: In a double-blind, placebo-controlled, crossover, clinical trial, 20 patients with seasonal allergic rhinitis were challenged in 1 nostril with antigen, and the response was monitored in both nostrils and in both eyes. Symptoms were recorded. Filter paper disks (intranasally) and Schirmer strips (intraocularly) were used for collecting secretions, which were subsequently eluted for the measurement of histamine and albumin levels. Patients were treated once topically at the site of challenge with azelastine or placebo. RESULTS: After placebo treatment, ipsilateral nasal challenge caused nasal symptoms and an increase in secretion weights; both were blocked by treatment with azelastine. Histamine and albumin levels increased only at the site of nasal challenge. Azelastine pretreatment inhibited the increase in albumin but not histamine levels. Symptoms of itchy and watery eyes increased significantly compared with symptoms with sham challenge after nasal allergen and were blocked by azelastine use. Ocular secretion weights increased bilaterally after placebo use and were not inhibited by azelastine use. CONCLUSIONS: Nasal allergen challenge releases histamine at the site of the challenge, which probably initiates a nasonasal and a nasal ocular reflex. This reflex is reduced by an H1-receptor antagonist applied at the site of the challenge. The eye symptoms associated with allergic rhinitis probably arise, in part, from a naso-ocular reflex.     

Nasal endoscopic findings in patients with perennial allergic rhinitis

Nasal endoscopy was carried out in 83 patients with perennial allergic rhinitis to evaluate endonasal anatomic variation and to find the correlation between the symptoms of patients and the endoscopic findings. All of the patients had nasal symptoms, 7.2% of the patients were runner, 7.2% were blocker and 85.6% were both. 86.75% of the patients had allergy-related symptoms, i.e. throat symptoms (73.5%), sinus headache (50.6%), and smell disturbance (10.8%). 95.2% of patients had abnormal endoscopic findings, i.e. deviated nasal septum (72.3%), abnormal middle turbinate (49.4%), narrowing of the entrance into the frontal recess (30.1%), septal spur (25.3%), obstruction of the entrance into the frontal recess (19.3%), nasal polyps (15.7%), mucopurulent discharge (14.5%), inferior turbinate hypertrophy (10.8%), abnormal uncinate process (9.6%), abnormal ethmoid bullae (7.2%), and enlargement of aggar nasi cells (2.4%). There was no significant correlation between each symptom and each endoscopic finding. However, there was a significant correlation between sinus headache and all of the combined abnormal endoscopic findings (P<0.05). These findings suggested that variations in endonasal anatomy was not by itself a pathology or a cause of symptoms. However, a combination of these variations may narrow the cleft of the ostiomeatal unit and cause contact area or stenosis, which predisposed patients to persistent symptoms, recurrent infection or resistance to therapy in patients with perennial allergic rhinitis. The endoscope might be a very useful tool for allergists, immunologists, and rhinologists, who work in the nose to deal with these cases.     

Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Allergic rhinitis is a common problem involving activation of nasal mast cells and irritability. The hypothalamic-pituitary-adrenal (HPA) axis is stimulated in cases of emotional or environmental stress, and mast cells have been implicated in stress-induced immune responses. OBJECTIVE: To investigate whether intranasal challenge of patients allergic to a single antigen would stimulate the HPA axis. METHODS: Plasma corticotropin and cortisol levels were measured 20, 40, 60, 80, 100, and 120 minutes after intranasal antigen administration in healthy volunteers (n=3) and in patients with rhinitis who are allergic to Parietaria (n=10). RESULTS: Mean +/- SD corticotropin levels were 24.43 +/- 14.38 pg/mL in patients compared with 8.83 + 5.02 pg/mL in controls, and this increase was statistically significant (P = .049). Patient cortisol levels also increased to a mean +/- SD of 8.87 +/- 4.90 pg/mL (at 40 minutes) compared with 4.36 +/- 1.72 pg/mL in controls (P = .11 due to 1 outlier). Compared with individual patient prechallenge levels, corticotropin levels increased in 7 patients and cortisol levels increased in 5 at 40 minutes. CONCLUSION: These results suggest that allergic rhinitis may activate the HPA axis. A larger study with additional controls is required for definitive conclusions.     

Risk of childhood asthma and allergic rhinitis in relation to pregnancy complications

BACKGROUND: Events occurring during fetal life may affect the development of the immune and respiratory systems and increase the risk of asthma and allergic diseases. OBJECTIVES: We sought to elaborate the relations between the occurrence of pregnancy complications and other pregnancy-related conditions and the risk of bronchial obstruction during the first 2 years of life and the occurrence of asthma and allergic rhinitis by the age of 4 years. Pregnancy complications were considered both as predictors of the health outcomes and as possible effects caused by other prenatal factors. METHODS: A population-based, 4-year, cohort study was carried out involving 2531 children born in Oslo, Norway. We collected information on maternally related (hyperemesis, hypertension, and preeclampsia) and uterus-related complications in pregnancy (antepartum hemorrhage, preterm contractions, insufficient placenta, and restricted growth of the uterus) and the child's health and environmental exposures at birth and at 6, 12, 18, and 24 months and 4 years of age. The outcomes of interest were bronchial obstruction during the first 2 years and asthma and allergic rhinitis at the age of 4 years. RESULTS: In a logistic regression analysis adjusting for potential confounders, uterus-related, but not other pregnancy-related, complications increased the risk of bronchial obstruction (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.3-3.4), asthma (OR, 3.0; 95% CI, 1.8-5.4), and allergic rhinitis (OR, 2.9; 95% CI, 1.6-5.2). These relations were similar in children of atopic and nonatopic parents. CONCLUSIONS: Uterus-related complications in pregnancy increase the risk of having asthma and allergic rhinitis in childhood.     

Nasal eosinophilic inflammation contributes to bronchial hyperresponsiveness in patients with allergic rhinitis

There are increasing evidences that allergic rhinitis (AR) may influence the clinical course of asthma. We conducted methacholine challenge test and nasal eosinophils on nasal smear to patients with allergic rhinitis in order to investigate the mechanism of connecting upper and lower airway inflammation in 35 patients with AR during exacerbation. The methacholine concentration causing a 20% fall in FEV1 (PC20) was used as thresholds of bronchial hyperresponsiveness (BHR). Thresholds of 25 mg/dL or less were assumed to indicate BHR. All patients had normal pulmonary function. Significant differences in BHR were detected in the comparison of patients with cough or postnasal drip and without cough or postnasal drip. There were significant differences of PC20 between patients with cough or postnasal drip and those without cough or postnasal drip (3.41+/-3.59 mg/mL vs 10.2+/-1.2 mg/mL, p=0.001). The levels of total IgE were higher in patients with seasonal AR than in patients with perennial AR with exacerbation (472.5+/-132.5 IU/L vs. 389.0+/-70.9 IU/L, p<0.05). Nasal eosinophils were closely related to log PC20 (r=-0.65, p<0.01). These findings demonstrated that nasal eosinophilic inflammation might contribute to BHR in patients with AR.     

Cost-effectiveness of specific subcutaneous immunotherapy in patients with allergic rhinitis and allergic asthma

BACKGROUND: Specific immunotherapy is the only potentially curative treatment in patients with allergic rhinitis and allergic asthma. Health economic evaluations on this treatment, particularly in a German context, are sparse. OBJECTIVE: To evaluate the cost-effectiveness of specific subcutaneous immunotherapy (SCIT) in addition to symptomatic treatment (ST) compared with ST alone in a German health care setting. METHODS: The analysis was performed as a health economic model calculation based on Markov models. In addition, we performed a concomitant expert board composed of allergy experts in pediatrics, dermatology, pneumology, and otolaryngology. The primary perspective of the study was societal. Additional sensitivity analyses were performed to prove our results for robustness. RESULTS: The SCIT and ST combination was associated with annual cost savings of Euro140 per patient. After 10 years of disease duration, SCIT and ST reach the breakeven point. The overall incremental cost-effectiveness ratio (ICER) was Euro-19,787 per quality-adjusted life-year (QALY), with a range that depended on patient age (adults, Euro-22,196; adolescents, Euro-14,747; children, Euro-12,750). From a third-party payer's perspective, SCIT was associated with slightly additional costs. Thus, the resulting ICER was Euro8,308 per QALY for all patients. CONCLUSIONS: Additional SCIT was associated with improved medical outcomes and cost savings compared with symptomatic treatment alone according to a societal perspective. Taking a European accepted ICER threshold of up to Euro50,000 per QALY into account, additional SCIT is considered clearly cost-effective compared with routine care in Germany. The degree of cost-effectiveness is strongly affected by costs related to SCIT and the target population receiving such treatment.     

Effects of nitric oxide synthases in chronic allergic airway inflammation and remodeling

The precise role of each nitric oxide (NO) synthase (NOS) isoform in the pathobiology of asthma is not well established. Our objective was to investigate the contribution of constitutive NO synthase (cNOS) and inducible NOS (iNOS) isoforms to lung mechanics and inflammatory and remodeling responses in an experimental model of chronic allergic pulmonary inflammation. Guinea pigs were submitted to seven ovalbumin exposures with increasing doses (1 approximately 5 mg/ml) for 4 wk. The animals received either chronic L-NAME (N-nitro-L-arginine methyl ester, in drinking water) or 1,400 W (iNOS-specific inhibitor, intraperitoneal) treatments. At 72 h after the seventh inhalation of ovalbumin solution, animals were anesthetized, mechanically ventilated, exhaled NO was collected, and lung mechanical responses were evaluated before and after antigen challenge. Both L-NAME and 1,400 W treatments increased baseline resistance and decreased elastance of the respiratory system in nonsensitized animals. After challenge, L-NAME increased resistance of the respiratory system and collagen deposition on airways, and decreased peribronchial edema and mononuclear cell recruitment. Administration of 1,400 W reduced resistance of the respiratory system response, eosinophilic and mononuclear cell recruitment, and collagen and elastic fibers content in airways. L-NAME treatment reduced both iNOS- and neuronal NOS-positive eosinophils, and 1,400 W diminished only the number of eosinophils expressing iNOS. In this experimental model, inhibition of NOS-derived NO by L-NAME treatment amplifies bronchoconstriction and increases collagen deposition. However, blockage of only iNOS attenuates bronchoconstriction and inflammatory and remodeling processes.     

Characteristics of patients with seasonal allergic rhinitis and concomitant asthma

BACKGROUND: Allergic rhinitis and asthma often co-exist and appear to produce a continuum of airway disease, but whether the clinical characteristics of asthma in patients with seasonal rhinitis differ from those of persistent asthma has not been examined. OBJECTIVE: The aim of this retrospective study was to characterize the clinical features of patients with seasonal allergic rhinitis with concomitant asthma and to compare them with those in patients with persistent asthma. METHODS: The patient populations for this study were derived from nine prospective, placebo-controlled planned clinical trials of similar design. Six studies (958 patients) enrolled patients with seasonal allergic rhinitis and concomitant asthma; three (607 patients) involved patients with persistent asthma. In all studies, patients were excluded from oral corticosteroid therapy in the preceding 3 months, and from inhaled corticosteroids in the preceding month. RESULTS: Patients with seasonal rhinitis and asthma had a significantly (P<0.001) higher total asthma symptom score than those with persistent asthma. In particular, cough was three times more severe. The need for beta(2)-agonist as a rescue medication and the ratio of forced expiratory volume in 1 s/forced vital capacity (FVC) were similar in the two groups whereas forced expiratory fraction 25-75%/FVC was significantly (P<0.02) reduced in the persistent asthmatics. Asthma and nasal symptom severity scores were correlated in patients with seasonal rhinitis and asthma (P<0.0001). CONCLUSIONS: Patients with seasonal allergic rhinitis and concomitant asthma appear to differ from those with persistent asthma. A prospective study should be designed to discover whether patients with seasonal rhinitis and asthma may represent a distinct nosological entity, 'allergic airway disease'.     

Endothelial expression of nitric oxide synthases and nitrotyrosine in systemic sclerosis skin.

Although a multisystem disease, systemic sclerosis (SSc) most commonly affects the skin. The skin lesion is characterized by progressive changes, chief amongst which are vascular abnormalities, including endothelial cell (EC) injury and death, and dermal fibrosis. The pathogenesis of the vascular changes, and their relationship to dermal fibrosis, is poorly understood. The purpose of this study was to examine the potential role of nitric oxide (NO)-related free radical production, as part of an assessment of mechanisms leading to endothelial damage. Histologically graded skin biopsies from 33 patients with SSc (ten grade 0, ten grade 1, eight grade 2, and five grade 3) and eight healthy controls were reacted with antibodies against constitutive (eNOS) and inducible (iNOS) forms of nitric oxide synthase and nitrotyrosine. The degree of staining was assessed using a semi-quantitative system and a staining score was developed for the ECs of different vessel types in different areas of dermis at all grades. In biopsies from patients with SSc, superficial microvessel ECs showed a peak of eNOS expression in grade 1 skin which fell as the grade increased. By contrast, iNOS staining increased with the grade of skin lesion, a pattern paralleled by endothelial nitrotyrosine expression. From these findings, it is concluded that a metabolic switch occurs in dermal ECs from endothelial to cytokine inducible forms of NOS during the progression of the skin lesion of SSc. iNOS is a potent inducer of NO production which, in turn, can mediate NO free radical production. At a time of development of the SSc skin lesion when previous studies report evidence of EC damage, the cells express immunodetectable nitrotyrosine, a marker of NO-mediated free radical injury. The data suggest a role for iNOS-induced NO production in EC damage in SSc.