Martha V. White

The role of histamine in allergic diseases

Histamine, which is stored mainly in mast cells and basophils, is a prominent contributor to allergic disease. Elevations in plasma or tissue histamine levels have been noted during anaphylaxis and experimental allergic responses of the skin, nose, and airways. Of the four cardinal signs of asthma (bronchospasm, edema, inflammation, and mucus secretion), histamine is capable of mediating the first two through its H1 receptor and mucus secretion through its H2 receptor. Of the five cardinal signs of allergic rhinitis (pruritus, mucosal edema, sneezing, mucus secretion, and late-phase inflammatory reactions), histamine is capable of mediating the first three through its H1 receptor. In the nose, mucus secretion can be reflexively mediated by H1 and possibly also by H2 receptors. In the skin the cardinal features of urticaria (vasodilation, vascular permeability, and pruritus) can be mediated by stimulation of the H1 receptor. In anaphylaxis histamine H1-receptor stimulation can mediate vascular permeability, smooth muscle contraction, and tachycardia, whereas H2-receptor stimulation can mediate mucus secretion. Stimulation of both receptors can mediate vasodilation and reduce peripheral vascular resistance. Thus although histamine is only one of many mediators of allergic disease, it plays a primary role in allergic rhinitis, urticaria, anaphylaxis, and to a lesser degree, asthma.

Substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide increase in nasal secretions after allergen challenge in atopic patients

BACKGROUND There is suggestive evidence that neuropeptides participate in allergic reactions. Substance P (SP) and calcitonin gene-related peptide (CGRP) are released by sensory nerves, whereas vasoactive intestinal peptide (VIP) is released mainly by parasympathetic nerves. Both sets of nerves are thought to be stimulated by allergic inflammation. The aim of this study was to assess nasal secretions to determine whether SP, CGRP, and VIP were increased after allergen challenge. METHODS Eight patients with allergic rhinitis were challenged nasally with 1 mg histamine or increasing doses of allergen. Nasal lavages were collected into a cocktail of protease inhibitors in order to restrict neuropeptide degradation. Radioimmunoassay for SP, CGRP, and VIP were performed on each sample. RESULTS All patients had immediate clinical reactions to both histamine and allergen challenges, and seven patients experienced a later allergic reaction. After histamine challenge, SP and CGRP did not increase significantly above baseline in the nasal lavages, whereas VIP did (p < 0.02). In contrast, SP, CGRP, and VIP all significantly increased immediately after allergen challenge and returned to baseline within 2 hours. At the clinical peak of the late allergic reaction, SP, but not CGRP or VIP, was increased slightly but significantly (p < 0.01). CONCLUSIONS Thus SP, CGRP, and VIP are found in nasal secretions after allergen challenge, which confirms that neuropeptides are released in human beings during allergic reactions. The selective stimulation of VIP secretion by histamine challenge suggests that histamine-induced cholinergic reflexes induce the release of VIP. These data support the suggestion that neuropeptides may be partly responsible for some of the nasal symptoms of allergy.

Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma

BACKGROUND A subset of patients with asthma experience adverse nasoocular reactions after ingestion of aspirin or agents that inhibit cyclooxygenase. Recent evidence has implicated the leukotrienes in the nasoocular reaction, but the cellular sources and mechanism of activation are unknown. We used nasal lavage with and without a 5-lipoxygenase inhibitor, zileuton, to define the role of leukotrienes and to profile nasal cellular activation during this reaction. METHODS A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design. Nasal symptoms and nasal tryptase, histamine, leukotriene, and eosinophil cationic protein levels were evaluated. Serum tryptase and urinary histamine levels were also assessed. Subjects were then randomized to receive a week of treatment with zileuton or placebo, according to a double-blind, crossover design followed by aspirin challenge and measurement of the same mediators. RESULTS Aspirin ingestion produced a marked increase in nasal symptoms from a baseline symptom score of 2.1 +/- 0.7 to a maximum of 8.4 +/- 1.2 (p < 0.0007). Aspirin ingestion produced a mean maximal increase in nasal tryptase of 3.5 +/- 2.6 ng/ml, whereas placebo ingestion produced a mean maximal increase of 0.1 +/- 0.2 ng/ml (p < 0.05, aspirin vs placebo). Mean maximal nasal histamine increased 1.73 +/- 1.16 ng/ml versus 0.08 +/- 0.08 ng/ml from baseline (p < 0.05, aspirin vs placebo). Aspirin produced a mean maximal increase in nasal leukotriene value of 152 pg/ml versus a 16 pg/ml decrease after placebo ingestion (p < 0.05). Zileuton treatment blocked the increase in nasal symptoms after aspirin ingestion (maximum nasal symptom score of 1.6 +/- 0.6 with zileuton vs 5.5 +/- 0.9 with placebo [p < 0.0053]). It also blocked the rise in nasal tryptase (p = 0.011) and nasal leukotriene (p < 0.05) levels after aspirin ingestion. Zileuton treatment had no significant effect on the recovery of nasal histamine. CONCLUSION The increase in nasal symptoms in aspirin-sensitive patients with asthma after aspirin ingestion is associated with increases in nasal tryptase, histamine, and cysteinyl leukotriene levels. This mediator profile is consistent with mast cell activation during the nasal response to aspirin and suggests that 5-lipoxygenase products are essential for the nasal response to aspirin.

Mediators of inflammation and the inflammatory process

A complex interplay of inflammatory cells and chemical mediators is responsible for allergic inflammation. It is now understood that the allergic reaction consists of an early-phase response involving mast cell degranulation with the release of histamine and a late-phase response characterized by the migration of inflammatory cells. This review provides a summary of the early- and late-phase events associated with allergic inflammation and an overview of the principal chemical mediators involved in the inflammatory process.

Analysis of nasal secretions during experimental rhinovirus upper respiratory infections

BACKGROUND To determine the underlying mechanisms for rhinovirus-induced nasal secretions, nasal lavage fluids were analyzed during experimental rhinovirus infections. METHODS Twenty patients with allergic rhinitis and 18 nonallergic control subjects were inoculated with rhinovirus type 39. Nasal lavage was performed before and on days 2 through 7 after viral inoculation, and the lavage fluids were assayed for proteins and mast cell mediators. RESULTS The secretion of total protein and both plasma proteins (albumin and IgG) and glandular proteins (lactoferrin, lysozyme, and secretory IgA) increased after rhinovirus inoculation. Analysis of the specific protein constituents revealed that nasal secretions during the initial response to the rhinovirus infection were predominantly due to increased vascular permeability. Allergic subjects tended to have fewer symptoms and more vascular permeability than control subjects, and increased histamine secretion after rhinovirus inoculation was more frequently seen in the allergy group. CONCLUSION Nasal secretions found early in the course of a viral upper respiratory infection are due to increased vascular permeability, whereas glandular secretions predominate later in the infection.

Neutrophil attractant/activation protein-1 (NAP-1) causes human basophil histamine release

Basophils from five of six human donors released histamine in response to neutrophil attractant/activation protein-1 (NAP-1). Histamine release by this protein was concentration-dependent over the range of 3 x 10(-7) M to 4 x 10(-6) M. At 4 x 10(-6) M, the mean agonist-induced release was 16 +/- 3% (SEM) of total basophil histamine. For the same basophil preparations, release by anti-IgE was 35 +/- 6%. The chemotactic protein did not cause release of histamine from basophils at 0 degrees C or in the presence of 10 mM EDTA. The time-course of histamine release was rapid; release was 43% of maximal after 30 s and maximal after 1 min of incubation. Thus, in addition to its previously characterized neutrophil chemotactic and activating properties, this protein activates human basophils.

Quantitation of inflammatory cells in the nasal mucosa of patients with allergic rhinitis and normal subjects.

BACKGROUND The role of inflammatory cells at the local site of allergic inflammation in the nose is unclear. METHODS Nasal biopsy specimens were obtained from 10 patients with symptomatic seasonal allergic rhinitis and 10 normal subjects. Freeze-dried paraffin-embedded sections were stained for mononuclear cells and eosinophils. Tissues in Carnoys fixative were stained for mast cells. RESULTS T cells were much more plentiful than B cells or macrophages, and no significant differences were found between the two groups in the number of T cells, T-cell subsets, B cells, and macrophages. However, the number of CD25+ cells (lymphocyte activation markers) and the number of eosinophils were significantly higher in the allergic group than in the control group. There were no significant differences between the two groups in the total mast cell number. However, mucosal type mast cells were slightly increased, and a higher ratio of mast cells were costained for IgE in the allergic group. IgE+ cells mostly constained for mast cell tryptase and did not costain for J chain. CONCLUSIONS These data suggest that unlike granulocytes, in some mononuclear cells qualitative, not quantitative, changes may be important in allergic rhinitis and that IgE may not be locally produced in the nasal mucosa.

Sinusitis in an allergist's office: analysis of 200 consecutive cases.

Sinusitis affects up to 14% of Americans. Traditionally, most patients with sinusitis are evaluated and treated by either primary care physicians or otolaryngologists. In order to gain information regarding the characteristics at presentation and the outcome of treatment of sinusitis by an allergist, the records of 200 consecutive patients seen at the Institute for Asthma and Allergy at the Washington Hospital Center for chronic sinusitis were reviewed. The most common presenting symptoms were nasal congestion, postnasal drip, purulent rhinorrhea, headache, cough, facial pressure, anosmia or hyposmia, hypogeusia, and throat clearing. Initial abnormal physical exam findings included abnormal transillumination, purulent secretions, nasal mucosal swelling, nasal polyps, and nasal crusting. Treatment included 4 weeks of oral antibiotics, nasal corticosteroids, nasal lavage, and topical decongestants. All of the presenting symptoms (23-75% of the patients) and signs (50-84% of patients) improved with medical management. Patients have been followed for 1 to 27 months, with a mean of 6 months, and 6% have required surgery, with one complication of cerebrospinal fluid leak. These findings indicate that medical management of chronic sinusitis in an allergists office is effective.

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults.

BACKGROUND Ragweed is an important cause of allergic rhinitis with or without conjunctivitis (AR/C) in North America and elsewhere. Allergen immunotherapy enabling safe patient self-administration is considered an unmet clinical need. Allergy immunotherapy tablet (AIT) treatment has shown promising efficacy and safety for grass allergy but has not been assessed for ragweed allergy. OBJECTIVE To evaluate efficacy and safety of 2 short ragweed AIT doses in patients with AR/C. METHODS Adults with ragweed pollen-induced AR/C were randomized 1:1:1 to daily ragweed AIT (6 or 12 Amb a 1 units) or placebo before, throughout, and after ragweed season (approximately 52 weeks). Patients could use predefined allergy rescue medications in season. Efficacy end points included peak and entire season total combined score (TCS) and its components daily symptom score (DSS), and daily medication score (DMS). Safety assessments included adverse events. RESULTS A total of 565 patients were randomized. During peak season, the 6- and 12-Amb a 1 unit ragweed AIT doses showed 21% (-1.76 score) and 27% (-2.24 score) improvement in TCS vs placebo (P < .05). The 6- and 12-Amb a 1 unit AIT doses significantly improved DSS and DMS vs placebo (P < .05). Peak and entire season efficacy were comparable. The 12-Amb a 1 unit AIT dose reduced peak-season TCS vs placebo by 21% and 25% in subgroups with and without local application-site reactions, respectively. Most treatment-related adverse events were mild, oral reactions; no systemic allergic reactions were reported. One patient in the 6-Amb a 1 unit group received epinephrine at an emergency facility for sensation of localized pharyngeal edema. CONCLUSION In this trial, ragweed AIT was effective and well tolerated in ragweed-allergic North American adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00783198.

Efficacy and Safety of Fluticasone Propionate/Salmeterol HFA 134A MDI in Patients with Mild‐to‐Moderate Persistent Asthma

The objective of this study was to compare the efficacy and safety of fluticasone propionate (FP) (44 µg)/salmeterol (21 µg) delivered as two inhalations twice daily via a single hydrofluoroalkane (HFA 134a) metered dose inhaler (MDI) (FSC) with that of placebo HFA 134a (PLA), fluticasone propionate 44 µg chlorofluorocarbon (CFC) alone and salmeterol 21 µg CFC alone (S) in patients (n = 360) with persistent asthma previously treated with β2‐agonists (short‐ or long‐acting) or inhaled corticosteroids (ICS). After 12 weeks of treatment, patients treated with FSC had a significantly greater increase (p ≤ 0.006) in mean FEV1 AUC(bl) compared with PLA, FP, or S. At end point, mean change from baseline in morning predose FEV1 for FSC (0.58 L) was significantly (p ≤ 0.004) greater than PLA (0.14 L), FP (0.36 L), and S (0.25 L). Patients treated with FSC also had a significantly higher probability of remaining in the study without being withdrawn due to worsening asthma (2%) compared with those in the PLA (29%) and S (25%) groups (p < 0.001). Finally, treatment with FSC resulted in significantly (p ≤ 0.007) greater improvements in morning and evening peak expiratory flow, need for rescue albuterol, and asthma symptom scores compared with FP, S, and PLA. The safety profile of FSC was also similar to FP or S alone. Initial maintenance treatment of the two main components of asthma, inflammation, and smooth muscle dysfunction (e.g., bronchoconstriction), with FSC results in greater overall improvements in asthma control compared with treatment of either individual component alone.