Gordon D. Raphael

The pathophysiology of rhinitis. V. Sources of protein in allergen-induced nasal secretions.

Allergic rhinitis is characterized by a profuse rhinorrhea in addition to paroxysms of sneezing, nasal congestion, and pruritus. To define better the sources of nasal secretion produced during rhinitis, nasal allergen challenges were performed on nine atopic subjects with seasonal rhinitis. A single dose of allergen was sprayed into one side of the nose, and nasal lavages were collected bilaterally for 7 hours. Nasal lavages were assayed for protein (total protein, albumin, lactoferrin, and lysozyme) and mediator (histamine and prostaglandin D2) content. Protein concentrations increased and remained elevated above baseline levels in both ipsilateral and contralateral secretions for up to 3 hours after allergen challenge. The proportion of albumin relative to total protein (the albumin percent) increased on the ipsilateral side, whereas the relative proportions of lactoferrin and lysozyme (the lactoferrin percent and lysozyme percent) increased on the contralateral side. Prostaglandin D2, but not histamine, increased selectively on the ipsilateral side. These data suggest that the ipsilateral protein secretory response is due to allergen-induced mast cell mediator release causing increased vascular permeability, whereas the contralateral protein secretory response is primarily a reflex-induced glandular secretion.

Gustatory rhinitis: a syndrome of food-induced rhinorrhea

The consumption of certain foods causes watery rhinorrhea (gustatory rhinitis) in many individuals. To examine the underlying mechanisms responsible for this common phenomenon, 12 subjects ingested control foods and positive foods (foods that cause rhinorrhea). Nasal lavages performed 10 minutes after each food challenge were analyzed for albumin and total protein. Positive food challenge, but not control food challenge, induced rhinorrhea in all subjects. Positive food challenge increased albumin (7.8 +/- 1.9 to 24.5 +/- 7.6 mg/L; p less than 0.025) and total protein (79 +/- 9 to 258 +/- 41 mg/L; p less than 0.001) without altering the ratio of albumin to total protein (albumin percent). Nasal pretreatment with atropine clinically blocked the positive food-induced rhinorrhea and significantly inhibited secretion of both albumin and total protein, again without affecting the albumin percent. Thus, gustatory rhinitis is produced by spicy foods that stimulate atropine-inhibitable muscarinic receptors (probably on submucosal glands), and the syndrome can be treated prophylactically by use of topical atropine.

Abnormal nasal glandular secretion in recurrent sinusitis

Recurrent sinusitis (RS) is a very common clinical problem for which no underlying cause can generally be ascertained. We examined nasal mucosal responses in 14 patients with RS to determine if a relative deficiency in secretion of glandular antimicrobial factors might play a role. Twenty-four subjects with no history of sinusitis were studied concurrently as normal control (NC) subjects. RS was defined by two or more episodes of acute sinusitis per year for 2 or more years. After provocation with 25 mg of methacholine or 1 mg of histamine, nasal washings were analyzed for total proteins: the plasma protein albumin, IgG, and nonsecretory IgA (nsIgA), and the glandular proteins secretory IgA (sIgA), lactoferrin (LFN), and lysozyme (LZM). Although baseline secretions in patients with RS were relatively enriched with LFN and LZM as compared to that of secretions in NC subjects, patients with RS had a blunted cholinergic response with decreased secretion of albumin, IgG, nsIgA, sIgA, and LZM. Histamine responses were equivalent in both patients with RS and NC subjects. After 4 to 12 months of medical treatment, the abnormal cholinergic responses improved on repeat methacholine challenge in all eight subjects with RS rechallenged. Thus, patients with RS have a reversible reduction in nasal mucosal secretory responses to cholinergic stimulation. Since glandular secretions are rich in antimicrobial factors, such as LFN, LZM, and sIgA, it appears possible that the inability to secrete glandular proteins normally may predispose to recurrent infections.

Comparison of human nasal mucosal secretion in vivo and in vitro.

The secretion of proteins from the human nasal mucosa induced by histamine, alpha-adrenergic, beta-adrenergic, and cholinergic agonists was studied in vivo and in vitro. Glandular secretion of lactoferrin, lysozyme (in vivo only), and respiratory glycoconjugates (RGCs) was measured. Vascular permeability was determined in vivo by albumin secretion in relationship to the other proteins. Muscarinic stimulation by methacholine induced significant glandular secretion (lactoferrin, lysozyme and/or RCGs) both in vivo and in vitro, confirming that muscarinic receptors are stimulated directly. Histamine induced predominantly vascular permeability in vivo but caused some glandular secretion as well. However, in vitro, histamine had no effect on glandular secretion, suggesting that histamine acts predominantly on the nasal vascular bed and only affects glandular secretion through reflex actions. Phenylephrine, an alpha-adrenergic agonist, selectively stimulated lysozyme release in vivo, and both RGCs and lactoferrin release in vitro. Thus, alpha-adrenergic stimulation has some direct, albeit minimal, capacity to stimulate mucosal glands. beta-Adrenergic agonists had no effect on glandular secretion or vascular permeability either in vivo or in vitro. Therefore, glandular secretion is directly stimulated by alpha-adrenergic and cholinergic agonists, but not by beta-adrenergic agonists. The stimulation of glandular secretion by histamine is indirect and mediated through the action of neural reflexes.

The pathophysiology of rhinitis: III. The control of IgG secretion

To examine the sources of IgG in nasal secretions, nasal provocation tests with histamine (H) and methacholine (MC) were performed on 22 subjects. Nasal lavages were assayed for IgG, total protein, albumin (Alb), nonsecretory IgA (nonsIgA), and secretory IgA (sIgA). H stimulation dramatically increased the secretion of IgG, nonsIgA, and Alb and also increased the proportion of these proteins compared to total protein. H-induced protein secretion was significantly inhibited by nasal pretreatment with chlorpheniramine maleate but was unaffected by atropine sulfate. sIgA was also stimulated by H challenge, but unlike IgG and other vascular proteins, the proportion of sIgA to total protein (sIgA percent) decreased after H challenges. MC stimulation also increased secretion of IgG, Alb, nonsIgA, and sIgA but did not alter their proportions, compared to total protein. Topical atropine significantly inhibited secretion of all proteins, suggesting a mode of transportation mediated by glandular muscarinic receptor stimulation. Thus, MC can increase the amount of IgG secretion, whereas H increases both the amount and relative proportion of IgG in nasal secretions. These data suggest that pharmacologic stimulation of IgG into nasal secretions may be used as a total to modulate mucosal immunity.

Long-term safety and efficacy of intranasal ciclesonide in adult and adolescent patients with perennial allergic rhinitis

BACKGROUND Ciclesonide is a corticosteroid in development for allergic rhinitis that has been shown to be safe and effective in seasonal allergic rhinitis and perennial allergic rhinitis (PAR) trials of up to 6 weeks in duration. However, the long-term safety and efficacy of ciclesonide are unknown. OBJECTIVE To demonstrate the long-term safety of intranasal ciclesonide, 200 microg once daily, in patients with PAR. METHODS Patients (> or = 12 years old) with a 2-year or longer history of PAR were randomized in a double-blind fashion to receive ciclesonide, 200 microg, or placebo once daily in the morning for up to 52 weeks. Spontaneous and elicited adverse events were monitored throughout the study. Ear, nose, and throat examinations were performed to evaluate local tolerability. Additionally, 24-hour urinary free cortisol level, morning plasma cortisol level, intraocular pressure, and lens opacification were monitored to evaluate the systemic safety of intranasal ciclesonide. Ciclesonide efficacy was determined by measuring 24-hour reflective total nasal symptom scores. RESULTS No clinically relevant differences were observed between the ciclesonide and placebo groups in adverse events, ear, nose, and throat examinations, or 24-hour urinary free or morning plasma cortisol levels. Similarly, no clinically relevant differences were found between treatment groups in intraocular pressure, visual acuity, or lens opacification. With regard to efficacy, ciclesonide achieved a significantly greater reduction in 24-hour reflective total nasal symptom score compared with placebo over more than 52 weeks (P < .001). CONCLUSION In this study, intranasal ciclesonide, 200 microg once daily, was safe and effective for the long-term treatment of PAR, with no evidence of tachyphylaxis.

Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate-to-severe seasonal allergic rhinitis

BACKGROUND Previous studies have shown that diphenhydramine and desloratadine effectively relieve symptoms of seasonal allergic rhinitis (SAR). OBJECTIVE To compare the relative efficacy of 50 mg of diphenhydramine hydrochloride, 5 mg of desloratadine, and placebo in relieving symptoms in patients with moderate-to-severe SAR. METHODS In this 1-week, multicenter, parallel-group, randomized, double-blind, double-dummy, placebo-controlled study, 610 patients with moderate-to-severe SAR received 50 mg of diphenhydramine hydrochloride 3 times daily, 5 mg of desloratadine once daily, or placebo. Daily 24-hour reflective total nasal symptom scores (TNSSs) (primary end point), total symptom scores, and individual symptom scores were evaluated. A global evaluation of response to treatment was conducted at 2 posttreatment visits. RESULTS The mean reduction from baseline in 24-hour reflective TNSSs relative to the placebo response was 77.6% for the diphenhydramine group (P < .001) and 21.0% for the desloratadine group (P = .12). A TNSS between-treatment difference of -1.81 (46.7%; P < .001) was observed when comparing diphenhydramine with desloratadine. A similar between-treatment difference was observed for the 24-hour reflective total symptom score comparing diphenhydramine to desloratadine (-3.35; 45.5%; P < .001). Diphenhydramine provided clinically and statistically significant reductions vs placebo and desloratadine in all individual symptoms, including nasal congestion. Desloratadine had a tendency toward improvement compared with placebo for most individual symptom scores. However, a statistically significant result was reached only for sneezing (-0.27; 33.9%; P = .04). CONCLUSIONS Diphenhydramine, 50 mg, given for 1 week provided statistically significant and clinically superior improvements in symptoms compared with 5 mg of desloratadine in patients with moderate-to-severe SAR. Somnolence occurred more frequently with diphenhydramine (22.1%) compared with desloratadine (4.5%) and placebo (3.4%).

Glandular secretion of lactoferrin in a patient with neutrophil lactoferrin deficiency

Patients with specific granule deficiency (SGD) develop recurrent severe bacterial skin infections. Neutrophils from patients with SGD are deficient in lactoferrin (Lf), an antimicrobial protein commonly found in many mucosal secretions. Unstimulated and stimulated nasal secretions, saliva, and tears were collected from a patient with SGD and from normal control subjects and were analyzed for Lf. The secretions from the patient contained normal values of Lf, suggesting that the glands secrete Lf from a source other than neutrophils. Immunohistochemical staining of normal nasal mucosa demonstrated that Lf is localized within serous submucosal gland cells and that neutrophils are not normally observed in the nasal mucosa. These findings suggest that glandular tissues produce and locally secrete Lf by processes that are independent of neutrophil degranulation.

Efficacy, safety, and optimal dose selection of beclomethasone dipropionate nasal aerosol for seasonal allergic rhinitis in adolescents and adults.

Abstract Objective: Some patients with allergic rhinitis (AR) may prefer nonaqueous intranasal corticosteroid aerosols because of unwanted attributes of aqueous formulations. The mandatory removal of chlorofluorocarbon-propelled nonaqueous aerosols from the market limited available treatment options. To fulfill this unmet need, a nonaqueous, hydrofluoroalkane-propelled beclomethasone dipropionate (BDP) nasal aerosol was developed and approved for treatment of AR nasal symptoms. As part of the development program, this dose-ranging study evaluated three doses of BDP nasal aerosol to determine the optimally safe and effective dose for adolescent and adult patients (≥12 years old) with seasonal AR (SAR). Methods: After a 7 to 21 day placebo run-in period, eligible patients with SAR were randomly assigned to once-daily BDP nasal aerosol 80 µg, 160 µg, 320 µg, or placebo. The primary endpoint was the change from baseline in average a.m. and p.m. patient-reported reflective total nasal symptom scores (rTNSS) over 2 weeks. Safety and tolerability were also assessed. A potential study limitation could be lack of objective assessment of AR symptoms. Results: Significant improvements were seen in average a.m. and p.m. rTNSS (least squares [LS] mean treatment difference, −0.63; 95% CI: −1.13, −0.13; p = 0.013) as well as in average a.m. and p.m. instantaneous TNSS (iTNSS; LS mean treatment difference, −0.60; 95% CI: −1.09, −0.11; p = 0.016) with BDP nasal aerosol 320 µg/day compared with placebo. Although there were numerical improvements from baseline in patient-reported rTNSS and iTNSS with BDP nasal aerosol 80 µg and 160 µg, these doses did not achieve statistical significance compared with placebo. BDP nonaqueous nasal aerosol was well tolerated at all doses tested, with a safety profile comparable to that of placebo. Conclusions: These data indicate that 320 µg/day of BDP nasal aerosol is the optimally safe and effective dose for the treatment of SAR in adolescent and adult patients. Trial registration NCT: #NCT00854360.

Twelve- and 52-week safety of albuterol multidose dry powder inhaler in patients with persistent asthma

Abstract Objective: Evaluate the safety of albuterol multidose dry powder inhaler (MDPI), a novel, inhalation-driven device that does not require coordination of actuation with inhalation, in patients with persistent asthma. Methods: We report pooled safety data from two 12-week, multicenter, randomized, double-blind, repeat-dose, parallel-group studies and the 12-week double-blind phase of a 52-week multicenter safety study as well as safety data from the 40-week open-label phase of the 52-week safety study. In each study, eligible patients aged ≥12 years with persistent asthma received placebo MDPI or albuterol MDPI 180 µg (2 inhalations × 90 µg/inhalation) 4 times/day for 12 weeks. In the 40-week open-label phase of the 52-week safety study, patients received albuterol MDPI 180 μg (2 inhalations × 90 μg/inhalation) as needed (PRN). Results: During both 12-week studies and the 12-week double-blind phase of the 52-week study, adverse events were more common with placebo MDPI (50%; n = 333) than albuterol MDPI (40%; n = 321); most frequent were upper respiratory tract infection (placebo MDPI 11%, albuterol MDPI 10%), nasopharyngitis (6%, 5%), and headache (6%, 4%). Incidences of β2-agonist-related events (excluding headache) during the pooled 12-week dosing periods were low (≤1%) in both groups. The safety profile with albuterol MDPI PRN during the 40-week open-label phase [most frequent adverse events: nasopharyngitis (12%), sinusitis (11%), upper respiratory tract infection (9%)] was similar to that observed during the 12-week pooled analysis. Conclusions: The safety profile of albuterol MDPI 180 μg in these studies was comparable with placebo MDPI and consistent with the well-characterized profile of albuterol in patients with asthma.