Variations in histamine concentration in nasal secretion in patients with allergic rhinitis

The histamine concentration and content in nasal secretion and the volume of nasal secretion in nasal washing samples were measured under different conditions in 28 patients with allergic rhinitis sensitive to birch pollen. The mean histamine concentration was significantly lower after intranasal birch pollen challenge (2.08 micrograms/ml) than in prechallenge samples (6.96 micrograms/ml), and was also significantly lower in untreated patients during the birch pollen season (2.30 micrograms/ml) than off-season (7.18 micrograms/ml). The same relationship was found between the histamine content of the secretion samples obtained on these occasions. The mean secretion volume was greater after than before challenge, but not significantly higher during the season than off-season. A partial reversion of the changes in histamine concentration and content that occurred during the season was observed during intranasal corticosteroid therapy. The concentration and content of histamine in nasal secretion from symptomatic patients after intranasal histamine challenge did not differ significantly from those in asymptomatic subjects before challenge. It was concluded that although the histamine level in nasal secretion can be used as a marker of changes in the severity of allergic rhinitis, it is not ideal for this purpose.     

Facial thermography during nasal provocation tests with histamine and allergen

Changes of skin temperature (T°) of the nose area during nasal provocation tests with histamine and allergen were followed by means of an infrared thermography camera. By a colimator system in which temperatures measured on a given surface can be integrated and averaged, thermography allows the continuous and quantitative recording of the temperature during the whole procedure in a completely noninvasive way. In 10 normal subjects, increasing doses of histamine induced a dose-dependent rise of the nose external temperature. No significant change was observed with the vehicle solution. In six subjects allergic to grass pollen, the nebulization of increasing concentrations of a pollen extract induced a dose-dependent rise in T°. The T° rise observed after histamine or allergen corresponded to a marked nasal obstruction. The nebulization of the highest dose of the pollen extract did not induce any T° rise in six nonallergic subjects. The continuous recording of the skin temperature by a noninvasive method might yield additional information on the vascular changes rapidly occurring during nasal challenges.     

Desloratadine reduces systemic allergic inflammation following nasal provocation in allergic rhinitis and asthma patients

BACKGROUND: Preclinical studies have demonstrated that some second-generation antihistamines have anti-inflammatory effects. It is not known whether these effects are also demonstrable in vivo. In this study we investigated the effect of treatment with desloratadine (DL) on systemic inflammation and on nasal and bronchial mucosal inflammation after nasal allergen provocation (NP) in subjects with grass-pollen-allergic rhinitis and asthma. METHODS: Twenty-six subjects with grass-pollen-allergic rhinitis and asthma were randomly allocated to 8 days of treatment with DL (n = 13) or placebo (n = 13) outside the grass pollen season. On day 7 they underwent nasal provocation with grass pollen allergen. Nasal and bronchial biopsies were taken for immunohistochemical evaluation, and blood samples were analysed. Rhinitis and asthma symptoms, peak nasal inspiratory flow and peak expiratory flow, were also measured at specified times. RESULTS: The number of circulating eosinophils decreased during DL treatment, and there was a reduced increase in circulating eosinophils after NP in these subjects. There was also a significant reduction in early bronchial clinical response. There was no significant lessening in the severity of the nasal symptoms. Nasal and bronchial mucosal inflammation parameters did not alter under DL treatment. CONCLUSION: These data suggest that treatment with DL reduces systemic eosinophilia and prevents the increase in circulating eosinophils after NP. DL also significantly reduces the early bronchial clinical response to NP. However, airway mucosal inflammation is not altered by 1 week of treatment.     

Effect of levocetirizine on nasal provocation testing with adenosine monophosphate compared with allergen challenge in allergic rhinitis

Background End‐organ hyperreactivity is an important feature of the allergic airway. There are no data directly comparing the responsiveness to treatment of different nasal provocation tests (NPT). Objective We compared the effect of levocetirizine on nasal adenosine 5′‐monophosphate (AMP) with specific allergen challenge in patients with intermittent and persistent allergic rhinitis (AR). Methods Patients with AR were randomized in double‐blind cross‐over fashion to receive single doses of levocetirizine 5 mg or identical placebo, with nasal challenge performed 12 h after dosing. Sixteen participants completed per protocol. Nasal AMP or allergen challenge was conducted on separate days with 1‐ and 2‐week washout periods in between, respectively. Measurements of peak nasal inspiratory flow (PNIF) were made over 60 min after each challenge. The primary end‐point was the provocative concentration of AMP or allergen causing a 20% drop in the PNIF (PC₂₀). Results The time‐profile for PNIF recovery [area under the 60 min time–response curve as % PNIF change (min)] were significantly attenuated for AMP challenge, as mean difference [95% confidence interval (CI)]: 11.57 (3.87, 19.25), P=0.005 and for allergen challenge: 17.82 (0.11, 35.53), P=0.04. A highly significant correlation was shown between methods for the area under the curve: (R=0.86, P<0.001). A statistically significant correlation was also seen for the PC₂₀: (R=0.94, P<0.001). PC₂₀ improvement amounted to a 1.26 (95% CI 0.16, 2.35) and 0.16 (95% CI ?0.41, 0.73) doubling‐dilution shifts for allergen and AMP challenges, respectively. Bland–Altman plots confirmed good agreement between methods. Conclusion A high correlation and statistical agreement has been demonstrated between AMP and allergen challenge for all outcome measures. In particular, the recovery profile after NPT is a sensitive and discriminatory measure of anti‐allergic treatment.     

Do skin prick and conjunctival provocation tests predict symptom severity in seasonal allergic rhinoconjunctivitis?

BACKGROUND: In the investigation of seasonal allergic rhinoconjunctivitis (SAR), quantitative skin and conjunctival allergen challenge tests are used to measure individual allergen sensitivity. These tests are reproducible and relate well to prevalence but their relationship to symptom severity is less well established. OBJECTIVE: We wished to determine if quantitative skin prick tests (QSPT) and conjunctival provocation tests (CPTs) using a single grass pollen allergen extract are reproducible and predict symptom severity in SAR. METHODS: We retrospectively analysed data from 91 participants in a previously published randomized placebo controlled study of low dosage allergen immunotherapy who were randomized to receive placebo treatment. We examined the relationship between pre-seasonal QSPT, CPT and SAR symptoms. RESULTS: We found a high level of reproducibility when repeated measures were compared for both the QSPT (P < 0.001) and the CPT (P < 0.001) and moderate correlation (0.49) between the standard skin prick test (SPT) and the QSPT (P < 0.001). We found weak negative correlation (-0.27) between the QSPT and the CPT (P < 0.001). We found no correlation between seasonal symptom, use of rescue medication or quality of life (QOL) scores and pre-seasonal QSPT or CPT. Conclusion In the assessment of seasonal rhinoconjunctivitis, quantitative skin and conjunctival allergen challenge tests are strongly reproducible, although there is no correlation between these tests and seasonal symptom, use of rescue medication or QOL scores.     

Modulation of neurotrophin and neurotrophin receptor expression in nasal mucosa after nasal allergen provocation in allergic rhinitis

Background: Patients with allergic rhinitis (AR) feature both allergic airway inflammation and a hyperresponsiveness to nonspecific stimuli which is partly neuronally controlled. Still, it is unclear whether or not neurotrophins are involved in airway pathophysiology of AR and in nasobronchial interaction. Methods: Nine AR patients with mono‐allergy to grass pollen and nine healthy controls underwent nasal allergen provocation (NP). Serum samples, nasal and bronchial biopsies were taken before (T₀) and 24 h after (T₂₄) NP. Pan‐neurotrophin receptor p75^NTR, tyrosine kinase A (trkA), trkB, nerve growth factor (NGF), and brain‐derived neurotrophic factor (BDNF) were assessed with immunohistochemistry, and NGF and BDNF levels with ELISA. Results: At T₂₄, BDNF and NGF were upregulated in nasal mucosa (P < 0.05) and increased in the peripheral blood of AR compared with T₀. The increase in nasal BDNF expression correlated positively with the maximum increase in total nasal symptom score in AR (P = 0.02). p75^NTR was expressed on peripheral nerves and epithelial layer, trkA on endothelial cells, and trkB on mast cells. trkB + mast cells significantly decreased after NP in AR (P < 0.01). NP did not modulate p75^NTR and trkA expression in nasal mucosa and had no effect on the expression of neurotrophins and receptors in bronchial mucosa. Conclusion: This study shows that neurotrophins and their receptors are expressed in human airways. Allergic rhinitis was characterized by a modulation of BDNF, NGF, and trkB in nasal mucosa after NP and a correlation of nasal BDNF with the maximal increase of total nasal symptom score. Therefore, our data suggest that neurotrophins participate in upper‐airway pathophysiology in AR, whereas their role in nasobronchial interaction remains unclear.     

Eosinophil cationic protein and myeloperoxidase in nasal secretion as markers of inflammation in allergic rhinitis

The inflammatory component of allergic rhinitis was studied by measuring the concentration and content of eosinophil cationic protein (ECP, specific for eosinophils) and myeloperoxidase (MPO, specific for neutrophils) in samples of nasal secretion from 20 pollen-allergic subjects. All secretion samples contained measurable concentrations of both proteins. The mean ECP concentrations on two occasions without pollen exposure were 950 and 1170 micrograms/l. The ECP concentration during the pollen season without any therapy (mean 1160 micrograms/l) did not differ significantly from the baseline values, but intranasal corticosteroid therapy resulted in a significant decrease (mean 530 micrograms/l). The concentration of MPO was about 10 times higher than that of ECP, but the changes in MPO were nonsignificant throughout the observation period. An inverse correlation was found between the threshold dose in histamine challenges and the ECP level expressed either as concentration or as content. Furthermore, the ECP concentration and content 1 day after a positive allergen challenge were both significantly correlated with the strength of the challenge reaction. Measurements of ECP in nasal secretions are useful for studying the presence and activity of eosinophils in the nasal mucosa, and may prove of value in clinical investigations on patients with allergic rhinitis.     

Immediate and dual response to nasal challenge with Dermatophagoides pteronyssinus in local allergic rhinitis

Background Local allergic rhinitis (LAR) is characterized by in situ production of specific IgE (sIgE) antibodies and a positive response to a nasal allergen provocation test (NAPT) in the absence of atopy. Objective The aim of this study was to investigate the immunological mechanisms involved in the immediate and late responses after nasal exposure to Dermatophagoides pteronyssinus (DP) in patients with LAR. Methods A total of 40 subjects with LAR to DP were studied and compared with 50 healthy controls. Immediate and late responses to NAPT‐DP were assessed using a visual analogue scale of nasal symptoms and acoustic rhinometry. Tryptase, ECP, total and sIgE‐DP were measured in the nasal lavage by immunoassay at baseline, 15 min, 1, 6 and 24 h after nasal challenge. Results NAPT‐DP was positive in all patients, with significant increases in tryptase (45%), ECP (65%) and sIgE‐DP (25%) (P<0.05). Sixty percent of the LAR patients presented an immediate response to NAPT‐DP and 40% a dual response. Immediate responders showed a fast release of tryptase with a peak at 15 min after NAPT‐DP, and a progressive increase in nasal ECP and sIgE‐DP from 1 to 24 h after challenge, with a peak at 24 h. Dual responders presented persistently higher levels of tryptase from 15 min to 6 h after challenge, and a similar pattern of nasal release of ECP and sIgE‐DP to immediate responders. There were no isolated late responders. NAPT‐DP was negative in all healthy controls, with no increases in tryptase, ECP, or total and sIgE‐DP in nasal secretions. Conclusions The results demonstrated the existence of immediate and dual responses to a NAPT with DP in LAR patients, with the local presence of sIgE and mast cell/eosinophil activation. Cite this as: S. López, C. Rondón, M. J. Torres, P. Campo, G. Canto, R. Fernandez, R. Garcia, A. Martínez‐Cañavate and M. Blanca, Clinical & Experimental Allergy, 2010 (40) 1007–1014.     

Comparison of immunologic tests in the diagnosis of occupational asthma and rhinitis

In this study, three immunologic tests, skin prick test, RAST, and basophil histamine-release test (BHRT), were compared by provocation in the diagnosis of occupational asthma and rhinitis. Twenty-three positive bronchial or nasal challenges were performed on 16 patients (six farmers, six bakery workers, and four food industry workers) and asthma or rhinitis was diagnosed as caused by cereal flour or grain, cow epithelium, storage mites, garlic, or soy dust. A control group consisted of 12 patients, of whom four (two bakery workers, one food industry worker, and one farmer) were challenge-negative, and the rest suffered from pollen allergy and seasonal rhinitis and were not challenged. The sensitivity and specificity of the prick test, RAST, BHRT, and a panel of them were as follows: 74 and 89%, 57 and 86%, 78 and 93%, and 91 and 71%, respectively. The overall concordance among these three type I allergy tests or between immunologic tests and challenge was relatively good.     

Expression of costimulatory CD80/CD86-CD28/CD152 molecules in nasal mucosa of patients with perennial allergic rhinitis

BACKGROUND: B7 molecules (CD80, CD86) and their counter-receptors, CD28 and CD152 (CTLA-4), play an important role in T cell-mediated immune responses. We previously demonstrated that B7 molecules are selectively up-regulated not only on B cells but also on T cells from the peripheral blood mononuclear cells of patients with perennial rhinitis cultured with allergen. However, the expression of CD80/CD86 molecules and their counter-receptors in nasal mucosa, the actual inflammatory site of allergic rhinitis, has not yet been clarified. PATIENTS AND METHODS: Inferior turbinates from patients with either allergy to house dust or non-allergic rhinitis were excised and immunohistologically stained. In addition, the inferior turbinates were challenged with paper discs containing extracts of house dust and subsequently excised. Samples were double stained with immunofluorescent-labelled antibody to identify cells bearing CD86. RESULTS: Without the nasal provocation, only the expression of CD86 was increased in nasal mucosa of patients with allergic rhinitis compared with those with non-allergic rhinitis. However, following the nasal provocation with house dust, not only CD86, but also CD80, CD28, and CD152 were significantly expressed in allergic patients. Immunofluorescent double staining revealed CD86 expression in CD19, CD1a, CD14 and CD3 lymphocytes. CONCLUSION: These results indicate that the expression of CD80/CD86 molecules and their counter-receptors is induced in allergic patients following nasal provocation with allergen, suggesting a local amplification of allergen-specific immune responses in perennial rhinitis.     

Antigen presenting cells in the nasal mucosa of patients with allergic rhinitis during allergen provocation

Background The role of antigen presenting cells (APC) in allergic rhinitis is underexposed. Allergen presentation to T lymphocytes is probably an important aspect of the pathophysiological mechanism of allergic rhinitis. Objectives The aim of the study was to investigate the presence and dynamics of APC with special emphasis on Langcrhans cells (LC) in the nasal mucosa of patients with an isolated grass pollen allergy during an out-of-season 2-week allergen exposure, mimicking the natural grass pollen season. Methods Seventeen patients with isolated grass pollen allergy and four control subjects were challenged daily with allergen during a 2-week period in the winter. Biopsy specimens were obtained once before, six times during and once after the provocation period. Biopsy sections were stained with monoclonal antibodies: OKT6 (CDla-Langerhans cells). Ki-M6 (CD68 macrophages), L25 (dendritic cells), anti-IgE, HLA-DR and HLA-DQ (Major Histoeompatibihty Complex Class II - antigen presenting eells), as well as staining with acid phosphatase. Results APC with different characteristics are present in the epithelium and lamina propria of the nasal mucosa. The number of LC increased significantly in epithelium and lamina propria. IgE⁺-LC were present in the nasal mucosa and increase during provocation, HLA-DR⁺ cells with dendritic and lymphocytic morphology and HLA-DQ⁺ cells were found. The number of these cells increased during provocation in epithelium and lamina propria. The number of HLA-DR⁺ epithelial cells did not change. A significant increase in the number of Ki-M6⁺ cells (macrophages) was found in the lamina propria. However, Ki-M6⁺ cells increased to the same extent in the lamina propria in the control group. Conclusion APC are influenced by allergen provocation. This study supports the hypothesis that (IgE⁺) LC are involved in allergic rhinitis. The role macrophages play remains doubtful.     

Histamine H1-receptor antagonists with immunomodulating activities: potential use for modulating T helper type 1 (Th1)/Th2 cytokine imbalance and inflammatory responses in allergic diseases

Being a first-line treatment for hypersensitivity allergic disease, histamine H1-receptor antagonists possess anti-inflammatory activity in addition to being H1-receptor antagonists. While it is not purely a histamine-related condition, hypersensitivity allergic disease is associated with an increase in the number of T helper type 2 (Th2) cells and Th2 cytokines, and a decrease in the number of Th1 cells and Th1 cytokines. Suppression of Th2-type cytokine production in addition to H1-receptor blockade may therefore represent a successful therapeutic strategy for the treatment of hypersensitivity allergic diseases. H1-receptor antagonists have been reported to modulate immune cascade at various points by acting on T cell-related inflammatory molecules, including adhesion molecules, chemokines and inflammatory cytokines. These effects of H1-receptor antagonists may be optimized for the treatment of allergic diseases. Besides their ability to regulate inflammatory molecules, some H1-receptor antagonists have been reported to down-regulate Th2 cytokine production. In particular, it has been shown that several H1-receptor antagonists specifically inhibit the production of Th2, but not Th1, cytokines. Accumulating evidence indicates a crucial role for Th1/Th2 cytokine imbalance on the development of allergic diseases. Accordingly, the use of H1-receptor antagonist with Th2 cytokine inhibitory activity to modulate Th1/Th2 cytokine imbalance might be a favourable strategy for the treatment of hypersensitivity allergic diseases. Furthermore, the identification of H1-receptor antagonists which possess immunoregulatory activities in addition to their anti-histamine activity will provide an important insight into the development of novel immunoregulatory drugs.     

Increased expression of histamine H1 receptor mRNA in allergic rhinitis

Background Histamine plays an important role in producing nasal symptoms via histamine H₁ receptor (H₁R) in allergic rhinitis. It is reported that the minimum histamine concentration that induces sneezing is lower in allergic patients than in normal control subjects. Previous studies by binding assay on H₁R gave divided results on whether the number of H₁Rs is increased in allergic rhinitis or not. Objective The objective of this study was to examine if H₁R mRNA expression is increased in patients with allergic rhinitis compared with normal healthy volunteers. Methods We extracted RNA from scrapings of inferior turbinate mucosa of 10 patients suft'ering from allergic rhinitis and 10 control subjects. As the H₁R gene lacks introns. we treated RNA pellets by DNase to distinguish RNA from contaminating genomic DNA. Since amplification of H₁R and β-actin mRNA remained in an exponential phase at 35 cycles. H₁R and β-actin mRNAs were amplified for 35 cycles by reverse transcHption-polymerase chain reaction (RT-PCR). The PCR products were hybridized with internal probes and band intensities were quantitated by a densitometer. Results The mean ± sd of H₁R/β-actin ratio was 0.88 ± 0.62 for the patients with allergic rhinitis and 0.29 ± 0.17 for the normal subjects; the difference was statistically significant (P<0.01). Conclusions These data suggest that expression of H₁R mRNA is increased in the nasal mucosa of the patients with allergic rhinitis.     

Comparative effects of desloratadine, fexofenadine, and levocetirizine on nasal adenosine monophosphate challenge in patients with perennial allergic rhinitis

Summary Background There are no data directly comparing the relative efficacy of modern H(1)-antihistamines in allergic rhinitis using nasal provocation challenge. Objective We elected to study the comparative effectiveness of usual clinically recommended doses of desloratadine (DES), fexofenadine (FEX), and levocetirizine (LEV), on nasal adenosine monophosphate (AMP) challenge in patients with perennial allergic rhinitis (PAR). Methods 16 patients with PAR were randomized in double-blind cross-over fashion to receive single doses of DES 5 mg, FEX 180 mg, LEV 5 mg, or placebo (PL), with nasal AMP challenge performed 12 h after dosing. Measurements of peak nasal inspiratory flow (PNIF) were made over 60 min after nasal AMP challenge. Results Pre-challenge values (mean+/-SEM) for PNIF (L/min) were not significantly different comparing all groups; DES (129+/-9), FEX (128+/-11), LEV (128+/-13), and PL (128+/-12). The maximum % PNIF fall from baseline over 60 min after nasal AMP challenge was significantly attenuated (P<0.05) compared to PL (50+/-4), with DES (32+/-5), FEX (36+/-4), and LEV (36+/-4). The area under the 60-min time-response curve (%.min) was also significantly attenuated (P<0.05) compared to PL (2110+/-268), with DES (1126+/-285), FEX (1225+/-255), and LEV (1261+/-194). There were no significant differences between the three H(1)-antihistamines for any outcomes. Conclusion DES, FEX, and LEV were equally effective in attenuating the response to nasal AMP challenge. However, further long-term studies will be required to study their comparative effects on nasal symptoms, quality of life, as well as on nasal inflammatory cells.     

Effects of topical treatment with H1 and H2 antagonists on clinical symptoms and nasal vascular reactions in patients with allergic rhinitis

Fifteen asymptomatic subjects with allergic rhinitis participated in a double-blind, randomized, crossover, placebo-controlled study. The subjects were pretreated intranasally with a single dose of a selective H1 receptor antagonist, levocabastine, and/or selective H2 receptor antagonist, ranitidine, prior to a nasal allergen challenge. The nasal symptoms obtained at the challenge were assessed using a scoring technique 15 min after the allergen exposure. The nasal airway resistance was determined twice prior to and once after the allergen challenge using anterior rhinomanometry. The nasal mucosal blood flow was determined before and 15 min after allergen challenge using the 133Xe wash-out technique. After pretreatment with the H1 antagonist there was a statistically significant reduction in the number of sneezes and rhinorrhea compared to pretreatment with placebo. Pretreatment with the H2 receptor significantly decreased the rhinorrhea but not the sneeze. The nasal blockage was unaffected by both the H1 and the H2 antagonists. Pretreatment with the H1 and/or the H2 antagonists inhibited the reduction in the nasal mucosal blood flow induced by the allergen challenge to a significant degree. The present findings suggest that topical treatment with the highly selective histamine antagonist, levocabastine, inhibits allergen-induced reflex-mediated symptoms. H1 and H2 receptors do not appear to be involved in the regulation of the tone of the capacitance vessels. This indicates that a more complex mechanism participates in the induction of nasal blockage than the direct effect of histamine on H1 and H2 receptors on the capacitance vessels of the nasal mucosa alone. Both H1 and H2 receptors are of importance for the regulation of nasal mucosal blood flow during the allergic reaction.