A tender sinus does not always mean rhinosinusitis.

BACKGROUND: Sinus tenderness has not been quantitatively assessed. OBJECTIVE: We sought to compare sinus and systemic tenderness in rhinosinusitis, allergic rhinitis, and chronic fatigue syndrome (CFS), and healthy (non-CFS) groups. METHODS: Cutaneous pressures (kg/cm(2)) causing pain at 5 sinus and 18 systemic sites were measured in acute and chronic rhinosinusitis, active allergic rhinitis, healthy non-CFS/no rhinosinusitis, and CFS subjects. RESULTS: Sinus thresholds differed significantly (P

Hypertonic saline nasal provocation and acoustic rhinometry.

BACKGROUND: Hypertonic saline (HTS) acts as an airway irritant in human nasal mucosa by stimulating nociceptive nerves and glandular secretion. HTS does not change vascular permeability. In asthma, HTS causes airflow obstruction. OBJECTIVE: To determine the effect of HTS on mucosal swelling using acoustic rhinometry (AcRh). Potential vasodilator effects were controlled by maximally constricting mucosal vessels with oxymetazoline (Oxy). METHOD: Normal subjects had AcRh before and 30 min after either 0.05% Oxy or saline (0.9% NaCl) nasal treatments. Nasal provocations followed immediately with five step-wise incremental escalating doses of HTS administered at 6-min intervals. AcRh was performed 1, 3 and 5 min after each HTS administration, and then after blowing the nose at 5 min. The minimum cross-sectional area (Amin), volume of the anterior 6 cm of nasal cavity (V6) and incremental changes from pre-drug treatment baseline levels (delta, mean +/- SEM) were calculated. RESULTS: Oxy increased Amin by 46% (delta = 0.48 +/- 0.07 cm2, P = 0.0001) and V6 by 53% (Delta = 9.9 +/- 1.5 mL, P < 1 x 10-7) during the first 30 min. Saline (vehicle) treatment had no effect. The maximum HTS dose had no effect after 1 or 3 min. However, in the 4th and 5th minutes there were reductions in Amin (delta = 0.07 +/- 0.03 cm2, P = 0.035) and V6 (delta = 1.57 +/- 0.42 mL, P = 0.004) with an increase in the weight of secretions (delta = 700 +/- 100 mg, P < 0.05). Blowing the nose returned Amin and V6 towards baseline. Oxy had no effect on HTS-induced changes in Amin, V6, pain, rhinorrhea or weight of secretions. CONCLUSION: HTS induced nociceptive nerve stimulation and mucus secretion, and reduced V6 and Amin. Oxy caused vasoconstriction but did not alter HTS-induced effects. HTS may stimulate neurogenic axon response-mediated glandular secretion that contributes to perceptions of nasal obstruction in normal subjects.

Nasal lavage concentrations of free hemoglobin as a marker of microepistaxis during nasal provocation testing.

BACKGROUND: The constituents of nasal mucus may be contaminated by plasma if there is epistaxis. Gross epistaxis is apparent as a red lavage fluid, while microepistaxis may yield a clear fluid. If gross or microepistaxis are present, it will be difficult to decide whether plasma protein concentrations are elevated because of plasma exudation or bleeding. In order to discriminate between these two possibilities, we measured erythrocyte-derived free hemoglobin (fHb) in nasal lavage fluids. METHODS: Single-blinded subjects underwent standard hypertonic saline nasal provocation. Unilateral hypertonic nasal provocation was performed in normal, allergic rhinitis (AR) and nonallergic rhinitis (NAR) subjects (total of 1316 specimens). fHb was measured using the Sigma-Aldrich kit (St. Louis, MO). Grossly bloody specimens were analyzed separately from the remainder. Statistical analysis defined the means and 95th percentiles for fHb and albumin in the nonbloody normal group. RESULTS: fHb concentrations ranged from below the limits of detection (< 1 microg/ml) to > 164 microg/ml fHb was 79.3 microg/ml +/- 4.7 (mean +/- SEM) in four normal, 31 AR and 25 NAR grossly bloody specimens. The 95th percentile of fHb in the nonbloody normal samples (n = 68 subjects, n = 681 specimens) was 16.5 microg/ml. This value was defined as the threshold to detect potential microepistaxis, and corresponded to approximately 245 000 erythrocytes per ml of lavage fluid. Total protein (P < 0.05) and albumin (P < 0.001), but not markers of glandular secretion, were significantly increased in samples with fHb > 16.5 microg/ml compared to those < or = 16.5 microg/ml. Elevations of fHb without changes in albumin were more prevalent in nonallergic rhinitis. CONCLUSIONS: Significant bleeding into nasal lavage samples can contaminate the specimens and increase the concentrations of both fHb and plasma proteins. Increased albumin alone would indicate increased vascular permeability. The mechanism(s) leading to elevated fHb without increased plasma proteins require further investigation.

IgE levels are the same in chronic fatigue syndrome (CFS) and control subjects when stratified by allergy skin test results and rhinitis types.

BACKGROUND: Chronic fatigue syndrome (CFS) has an uncertain pathogenesis. Allergies have been suggested as one cause. OBJECTIVE: The aim of this study was to compare serum immunoglobulin (Ig)E in CFS and control subjects to determine whether IgE levels were elevated in CFS. This would be suggestive of increased atopy in CFS. METHODS: IgE was measured by quantitative ELISA (sandwich) immunoassay in 95 CFS and 109 non-CFS control subjects. Subjects were classified by positive or negative allergy skin tests (AST) and rhinitis questionnaires (rhinitis score, RhSc) into four rhinitis types: nonallergic rhinitis (NAR with positive RhSc and negative AST); allergic rhinitis (AR with positive AST and RhSc); atopic/no rhinitis (AST positive/RhSc negative); and nonatopic/no rhinitis (both AST and RhSc negative) subjects. RESULTS: IgE was not significantly different between control (128 +/- 18 IU/mL, mean +/- SEM) and CFS (133 +/- 43 IU/mL) groups, or between control and CFS groups classified into the four rhinitis types. IgE was significantly higher in subjects with positive AST whether or not they had positive RhSc or CFS symptoms. CONCLUSIONS: Elevated IgE and positive AST indicate allergen sensitization, but are not necessarily indicators of symptomatic allergic diseases. There was no association between IgE levels and CFS, indicating that atopy was probably not more prevalent in CFS. Therefore, TH2-lymphocyte and IgE-mast cell mechanisms are unlikely causes of CFS.

The linear relationship between changes in childhood growth velocity and topical glucocorticoid dose.

The concept of therapeutic indices for glucocorticoid treatment of rhinitis and asthma requires demonstration of the dose dependency of benefits and side effects. Therefore, we examined the relationship between glucocorticoid dose and changes in growth velocity (delta GV). The literature was reviewed for articles where the net delta GV could be calculated among steroid and parallel placebo, active treatment, or baseline run-in periods. Steroid dose and delta GV were analyzed by linear regression for 5 rhinitis and 19 asthma studies using topical budesonide, beclomethasone, fluticasone and mometasone, parenteral steroids, and nonsteroid comparitors. Dose dependency was established between 0 and the equivalent of 2000 micrograms/day of beclomethasone (r2 = 0.60). delta GV was not significantly affected by 200 micrograms/day of BDP or less. Nasal and bronchial administrations appeared to give equivalent responses. Growth suppression occurred within 2 weeks, and may be linked to a delay in the onset of puberty. The physiology of these effects was discussed.

Nasal provocation testing: a review.

OBJECTIVE: This review focuses on the uses of nasal provocation testing (NPT) for scientific investigations of the mechanisms of allergic and nonallergic rhinitis. It also describes the use of NPT as a diagnostic tool in clinical practice. The indications, contraindications, advantages, and limitations of different techniques for evaluation of nasal responses are reviewed. The paper familiarizes investigators with particulars of different nasal delivery systems, provocation agents, nasal patency measurements, secretion collection, and nasal lavage techniques. DATA SOURCES: Relevant publications obtained from a literature review. STUDY SELECTION: Relevant publications on the topics of NPT, allergic, and nonallergic rhinitis were critically evaluated. RESULTS AND CONCLUSIONS: To date, NPT has been used primarily as a research tool for the investigation of allergic and nonallergic rhinitis with a wide variety of techniques depending on the specific scientific purposes. NPT will continue to provide useful information about the pathogenesis of airway diseases. Standardized nasal provocation testing has the potential to become a more frequently used clinical test in the diagnosis of allergic and occupational rhinitis and for determination of the appropriate and focused therapy.

Mechanisms of allergic rhinitis.

The pathogenesis of allergic rhinitis can be better appreciated by understanding the numerous protective mechanisms available for mucosal defense. The system of TH2 lymphocytes, IgE production, mast cell degranulation, eosinophil infiltration, and resident cell responses are central to our understanding and treatment of allergic rhinitis. Histamine remains preeminent in causing the cardinal symptoms of the immediate allergic reaction: itching, watery discharge, and nasal swelling. Recruitment and activation mechanisms responsible for the late-phase allergic response are also reviewed.

Neurogenic mechanisms in rhinosinusitis.

Nasal sensory nerve stimulation leads to sensations of pain and congestion and nociceptive nerve axon response-mediated release of substance P that stimulates glandular secretion as an immediate-acting protective mucosal defense. Recruited parasympathetic reflexes cause submucosal gland secretion via muscarinic M3 receptors. Parasympathetic reflexes, sneezing, and other avoidance behaviors rapidly clear the upper airway of offending agents while protecting the lower airways. Dysfunction contributes to allergic, infectious, and other nonallergic rhinitides and possibly sinusitis. Sympathetic arterial vasoconstriction reduces mucosal blood flow, sinusoidal filling, and mucosal thickness, restoring nasal patency. Loss of sympathetic tone may contribute to some chronic, nonallergic rhinopathies.

Hypertonic saline nasal provocation stimulates nociceptive nerves, substance P release, and glandular mucous exocytosis in normal humans.

Hypertonic saline (HTS) induces bronchoconstriction. Potential mechanisms were evaluated in a human nasal provocation model. Aliquots of normal saline (1 x NS, 100 microliters) and higher concentrations (3 x NS, 6 x NS, 12 x NS, 24 x NS) were sprayed into one nostril at 5-min intervals. Lavage fluids were collected from the ipsilateral and contralateral sides to determine the concentrations of specific mucus constituents. Nasal cavity air-space volume was assessed by acoustic rhinometry (AcRh). The distribution of substance-P-preferring neurokinin-1 (NK-1) receptor mRNA was assessed by in situ reverse transcriptase-polymerase chain reaction. Unilateral HTS induced unilateral dose-dependent increases in sensations of pain, blockage, and rhinorrhea, the weights of recovered lavage fluids, and concentrations of total protein, lactoferrin, mucoglycoprotein markers, and substance P. Contralateral, reflex-mediated effects were minor. There were no changes in IgG or AcRh measurements. NK-1 receptor mRNA was localized to submucosal glands. HTS caused pain with unilateral substance P release. The presumed nociceptive nerve efferent axon response led to glandular exocytosis, presumably through actions on submucosal gland NK-1 receptors. Vascular processes, including plasma exudation, filling of venous sinusoids, and mucosal edema were not induced in these normal subjects.

Item responsiveness of a rhinitis and asthma symptom score during a pollen season.

Twenty-one asthma patients with allergic rhinitis completed a series of self-administered questionnaires (21-item symptom score for rhinosinusitis and asthma, bother scale, McMaster Asthma Quality of Life Questionnaire [MAQOL] and Euroqol) at 2-week intervals from August to November 1994. Relative responsiveness of the instruments was assessed in reference to the maximum and minimum average scores for MAQOL, with area under the curve (AUC) and correlation coefficients between the different instruments. Symptom score, MAQOL, and bother scale provided similar results for both extreme values and AUC, whereas Euroqol utilities were less responsive. These results suggest that the symptom scores and bother scales are responsive and valid, and might prove valuable in everyday practice, clinical trials, and quality assurance programs.

Direct expenditures for the treatment of allergic rhinoconjunctivitis in 1996, including the contributions of related airway illnesses.

BACKGROUND: Previous estimates of the national economic burden of allergic rhinoconjunctivitis (AR/AC) have relied on data analyses in which AR/AC was the primary International Classification of Diseases-ninth revision-Clinical Modification (ICD-9-CM)-coded diagnosis. These studies ignore the costs when AR/AC was a secondary diagnosis to other disorders such as asthma and sinusitis. OBJECTIVE: We sought to determine the national direct cost of illness for AR/AC. METHODS: An expert panel used the Delphi technique to estimate the proportion of visits coded by other primary ICD-9-CM diagnoses in which AR/AC was a significant secondary comorbid condition. The costs of this proportion were deemed to be "attributable" to AR/AC and were added to the costs when allergic rhinitis and allergic conjunctivitis were the primary diagnoses. RESULTS: The cost when AR/AC was the primary diagnosis was $1.9 billion (in 1996 dollars). The cost when AR/AC was a secondary diagnosis was estimated at $4.0 billion, giving an estimate of $5.9 billion for the overall direct medical expenditures attributable to AR/AC. Outpatient services (63%, $3.7 billion), medications (25%, $1.5 billion), and inpatient services (12%, $0.7 billion) accounted for the expenditures. Children 12 years and younger accounted for $2.3 billion (38.0%). CONCLUSION: Upper airway allergy is an expensive disease process because of its readily apparent manifestations as AR/AC and its contribution to other airway disorders.

Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders.

BACKGROUND: There have been no recent assessments of the economic burden of sinusitis in the peer-reviewed literature. OBJECTIVE: We sought to estimate the 1996 total direct health care expenditures for the treatment of sinusitis. METHODS: This study determined (1) direct expenditures of medical and surgical encounters in which sinusitis was the primary diagnosis and (2) attributable expenditures when related airway diseases were the primary diagnosis and sinusitis was a comorbid condition. An expert panel used the Delphi consensus-building technique to determine the proportions for the latter. RESULTS: Overall health care expenditures attributable to sinusitis in 1996 were estimated at $5.8 billion, of which $1.8 billion (30.6%) was for children 12 years or younger. A primary diagnosis of acute or chronic sinusitis accounted for 58.7% of all expenditures ($3.5 billion). About 12% each of the costs for asthma and chronic otitis media and eustachian tube disorders were attributed to diagnosis and treatment of comorbid sinusitis. Nearly 90% of all expenditures ($5.1 billion) were associated with ambulatory or emergency department services. CONCLUSION: The economic burden of sinusitis in the United States is significant. However, the limitations of this type of evaluation suggest the $5.8 billion amount may be an underestimate of the true direct costs.

Glucocorticoids decrease c-fos expression in human nasal polyps in vivo.

BACKGROUND: Activated c-fos binds to jun proteins to form the activation protein 1 (AP-1) transcription factor that regulates cytokine and other proinflammatory genes. c-Fos may play a key role in nasal polyp formation. Glucocorticoids may exert their anti-inflammatory effects through an interaction of glucocorticoid receptors with AP-1 that leads to mutual inactivation of both factors, and a "default" termination of AP-1 mediated gene activation. This may explain the beneficial effects of glucocorticoids in the treatment of nasal polyps. METHODS: To test this hypothesis in humans in vivo the immunohistochemical expression of c-fos-immunoreactive material (c-fos-irm) was assessed in nasal polyps from eight steroid naive subjects, polyps from eight subjects treated with topical beclomethasone dipropionate (BDP), and normal inferior turbinate nasal mucosa (n = 6). RESULTS: mRNA for c-fos was detected in all nasal polyps and normal mucosa. In contrast, c-fos-irm was present in all steroid naive subjects but in only two of the eight subjects treated with BDP (p = 0.007, two-tailed Fisher's exact test). c-Fos-irm was expressed solely in epithelial cells and glandular structures; it was expressed in normal epithelium and glands, but the staining intensity was low. CONCLUSION: Glucocorticoids appear to modulate expression of c-fos-irm and possibly AP-1 in human airway epithelial cells in vivo.

Aminopeptidase activity in human nasal mucosa.

BACKGROUND: Aminopeptidases activate bradykinin and degrade many inflammatory peptides. OBJECTIVE: The objective of this study was to identify the types of aminopeptidase activities in human nasal mucosa. METHODS: Human nasal mucosa was homogenized (n = 12), and cytoplasmic (S2) and membrane-rich (P2) fractions were obtained. Several aminopeptidase (Ap) activities were defined by (1) substrate specificity with leucine-enkephalin (leu-Ap) and alanine-nitroanilide (ala-Ap), (2) inhibitor studies with puromycin and bestatin, (3) enzyme activity histochemistry (zymography), (4) immunohistochemistry, and (5) gel electrophoresis. Human volunteers had methacholine, histamine, and allergen nasal provocations to determine the mechanisms controlling nasal aminopeptidase secretion in vivo. RESULTS: P2 was the largest reservoir of puromycin-resistant aminopeptidase activity (630 pmol leu-enk/min/mg protein). S2 contained 32 pmol leu-enk/min/mg activity, with 80% representing puromycin-resistant activity and 20% puromycin-sensitive aminopeptidase (PS-Ap). Ala-Ap was detected in both P2 and S2 fractions and was localized by zymography to epithelial and gland cells. Anti-rat brain-soluble PS-Ap IgG detected immunoreactive material in epithelium, glands, and endothelium. In nasal provocation studies, leu-AP correlated with glandular exocytosis but not vascular leak. CONCLUSIONS: The predominant aminopeptidase in human nasal epithelial and submucosal gland cells was membrane-bound puromycin-resistant aminopeptidase. A novel soluble puromycin-resistant aminopeptidase and lower amounts of soluble PS-Ap were also detected.

Rhinitis symptoms in chronic fatigue syndrome.

BACKGROUND: Atopy and allergic rhinitis are thought to be increased in prevalence in chronic fatigue syndrome (CFS). METHODS: To investigate this hypothesis, 51 CFS (CFS), 34 normal (N), 27 allergic rhinitis (AR), and 17 patients with other rheumatologic diseases filled out an Airway Symptom Severity self-report questionnaire to determine the frequencies of nasal, sinus, and chest symptoms, and a Systemic Complaints self-report questionnaire to determine the frequencies of complaints referable to neurologic, rheumatologic, gastrointestinal, and other systems. All subjects received a standard set of allergy skin tests, and were subdivided into those with positive and negative results. RESULTS: Allergy skin tests were positive in 35% of CFS and 44% of N subjects (difference not significant by Chi2). Significant rhinitis complaints were present in 83% of skin test positive CFS, 76% of skin test negative CFS, 74% of AR, and 23% of N subjects. Systemic Complaints scores were significantly elevated in skin test positive (94%) and negative (94%) CFS groups compared with AR (35%) and N (6%) groups. This score could significantly discriminate between CFS and N subjects. CONCLUSIONS: These data indicate that in this CFS population, 24% had no significant rhinitis complaints, 30% had positive skin tests suggesting the potential for allergic rhinitis complaints, and 46% had nonallergic rhinitis. The mechanism of the nonallergic component may offer insights into the pathogenesis of CFS.

Rhinovirus infection induces mucus hypersecretion.

Rhinorrhea is a prominent symptom of the common cold. Although increases in vascular permeability and serous cell secretion have been demonstrated in human nasal mucus during active rhinovirus infections, changes in mucin constituents have not been quantified. Nonallergic (n = 48) and asymptomatic allergic rhinitis (n = 32) subjects were inoculated with rhinovirus type hanks before the spring allergy season. Nasal lavages were performed before inoculation (day 0), then daily for 5 days afterward. The subjects were divided into infected and noninfected groups on the basis of evidence of successful rhinovirus infection (nasal shedding of virus or fourfold increases in specific serum antibodies). Concentrations of interleukin (IL)-8, markers of vascular leak (IgG), seromucous cells (lysozyme), and mucoglycoprotein exocytosis [7F10-immunoreactive mucin (7F10-irm) and Alcian blue staining of acidic mucoglycoproteins] were measured in lavage fluids. The infected subgroup had maximal increases in nasal lavage fluid concentrations of IL-8 (sevenfold), IgG (fourfold), total protein (twofold), and gel-phase 7F10-irm (twofold) on day 3. There were no differences between infected allergic and nonallergic subjects. IL-8 and gel-phase 7F10-irm were significantly higher in infected than in noninfected subjects. In addition to promoting plasma exudation, rhinovirus hanks infection increases IL-8 and gel-phase mucin secretion. These processes may contribute to a progression from watery rhinorrhea to mucoid discharge, with mild neutrophilic infiltration during the common cold.

Anticholinergic properties of brompheniramine, chlorpheniramine, and atropine in human nasal mucosa in vitro.

Brompheniramine and chlorpheniramine have anticholinergic activities, but the relative potency of these effects has not been well defined. The anticholinergic properties of brompheniramine, chlorpheniramine, and atropine were assessed in an in vitro model of human nasal mucosal glandular secretion. Methacholine was used as a cholinergic agonist to stimulate glandular secretion of 7F10-mucin. These drugs (0.01-1000 microM) or vehicle (saline) were added to explant cultures with and without 100 microM methacholine. 7F10-mucin concentrations were measured in culture supernatants after 2-hour incubations. The effective dose reducing methacholine-induced secretion (ED50) was determined. ED50 was 0.25 microM for atropine, 4.10 microM for brompheniramine, and 4.63 microM for chlorpheniramine. None of the anticholinergic drugs changed spontaneous glandular exocytosis. Brompheniramine and chlorpheniramine are equipotent anticholinergic agents in human nasal mucosa in vitro. Atropine was 16 to 19 times more potent.

Enhancement of histamine--induced vascular permeability in guinea pigs infected with Bordetella bronchiseptica.

In the nasal mucosa, histamine induces vascular permeability, stimulates nociceptive nerves, and recruits parasympathetic reflexes that regulate glandular exocytosis. Unilateral histamine nasal provocations were performed in a group of guinea pigs in the prodromal stage of undiagnosed Bordetella bronchiseptica infection. Vascular permeability in the histamine challenged nostrils was increased approximately 2- to 4-fold compared to healthy animals (p < 0.001). The duration of significant vascular leak was prolonged from 10 to 30 minutes. In the contralateral, nonchallenged nostrils, secretion of total protein and albumin, but not exudation of intravenously infected 125I-bovine serum albumin, was increased, suggesting an augmentation of parasympathetic reflexes without changes in contralateral vascular leak. These observations suggest that Bordetella bronchiseptica infection leads to hyperresponsiveness to histamine in the nasal mucosa with increased vascular permeability and recruitment of nociceptive nerve-parasympathetic reflexes.

Neuropeptides.

Sensory, parasympathetic, and sympathetic nerves innervate many structures in airways. The anatomy, histology, and function of these nerves and their varied neurotransmitters will be reviewed. Changes that may contribute to the pathophysiology of allergic, viral, and nonallergic rhinitis will be described.