Safety and reproducibility of nasal allergen challenge.

BACKGROUND: The nasal allergen challenge (NAC) is a useful tool for the diagnosis of allergic rhinitis (AR) and local allergic rhinitis (LAR) and might serve to design and monitor allergen immunotherapy. Nevertheless, data about its safety and reproducibility are scarce. OBJECTIVE: To investigate the safety and reproducibility of NAC in pediatric and adult rhinitis patients with/without asthmatic symptoms, and in healthy controls. METHODS: A retrospective evaluation of the NACs conducted in our Unit for 2005-2017 and monitored by acoustic rhinometry and nasal-ocular symptoms was performed to analyze the safety of two methods for allergen application (metered spray & micropipette) and NAC protocols (NAC with single or multiple allergens/session [NAC-S & NAC-M]). The adverse events (AEs), spirometry values, and rescue medication required for AE were recorded. The reproducibility was examined by a prospective analysis of three repeated NAC-S performed at 1-2-month interval in AR, LAR and nonallergic rhinitis patients, and in healthy controls. RESULTS: A total of 11 499 NACs were performed in 518 children and 5830 adults. Only four local AE occurred, and 99.97% of NACs were well tolerated. The reproducibility and positive and negative predictive values of three consecutive NAC-S performed in 710 subjects were 97.32%, 100%, and 92.91%, respectively. There were no false-positive results in the 710 analyzed subjects. Safety and reproducibility were comparable between the methods of allergen application and the rhinitis phenotypes. CONCLUSION: The NAC is a safe and highly reproducible diagnostic test ready to be used in the clinical practice in both children and adults with or without asthma.

In vivo diagnosis of allergic diseases--allergen provocation tests.

The allergen challenge test has been the mainstay of diagnosis of allergic diseases for a long time since it offers a direct proof of the clinical relevance of a particular allergen for the allergic disease symptoms and severity. Standardisation and availability for daily practice (including safety issues) are still to be refined but most of the challenge tests have safely crossed the border from research tools to diagnostic tests available for daily practice for a well trained clinical staff.

The Safety of Nasal Allergen Challenge Test Assessed in Lower Airways.

The aim of the study was to assess the safety of nasal allergen challenge, and the use of certain parameters applied in assessing the condition of the respiratory system. We enrolled 30 patients diagnosed with allergy to common environmental allergens and 30 healthy controls. The safety of nasal challenge tests with an allergen was assessed by measuring the concentration of exhaled nitric oxide from the lower respiratory tract (eNO) and forced expiratory volume in one second (FEV1) in a spirometry test. In the early phase of the allergic reaction, extra-nasal symptoms were observed, namely cough and breathlessness. These measured symptoms using the VAS scale, were far more frequent in the patients diagnosed with perennial allergic rhinitis. The eNO and FEV1 values in the spirometry test did not show any statistically significant changes. No correlation was observed between the breathlessness and cough complaints to the eNO concentration levels (cough: r=0.019, p=0.921; breathlessness: r=-0.088, p=0.644) nor the FEV1 level (cough: r=0.002, p=0.983; breathlessness: r=-0.072, p=0.751) in the spirometry test. In the early phase of the allergic reaction, nasal allergen challenge do not cause any significant changes in the lower airways, as measured with the use of certain parameters applied in assessing the function of the lower airways' function.

The value and safety of specific nasal provocation in the diagnosis of allergic rhinitis in mild persistent asthma under inhaled steroid therapy.

Although specific nasal provocation is an objective diagnostic test for allergic rhinitis, it can also increase the lower airway responsiveness in asthmatic patients. Our goal was to determine the value and safety of specific nasal provocation test for the diagnosis of allergic rhinitis in mild persistent asthmatic patients under low-dose inhaled steroid therapy. The study was performed on 32 mild persistent, stable, mite-sensitive allergic asthmatics (group 1), 9 mild persistent nonallergic asthmatics (group 2) and 9 healthy non-smokers (group 3). Nasal symptoms were noted, paranasal sinus computerized tomography (PNCT) and rhinoscopic evaluations were performed. Cases with pathologic-anatomic changes in PNCT and rhinoscopy were excluded. Symptom scoring, flow-volume, peak expiratory flow (PEF), serum and nasal lavage eosinophil cationic protein (ECP) and nasal lavage eosinophil counts were performed before mite specific nasal provocation test and at the 0th, 4th and 24th hours following the test. No adverse effects were observed in all diagnostic procedures. Total diagnostic value of nasal symptoms were found to be at 92%, while being 70% for rhinoscopy and 88% for specific nasal provocation test respectively in the diagnosis of allergic rhinitis in group 1. Statistically significant differences were found between basal nasal lavage eosinophil values (p < 0.001) and ECP levels (p < 0.05) when group 1 was compared with both group 2 and group 3. In the remaining measured values between three groups, no statistically significant differences were found. Specific nasal provocation test is a safe method for mild house dust mite allergic asthma cases under low-dose inhaled steroid therapy, but history of rhinitis might be sufficient for the diagnosis of allergic rhinitis.

Lipoxin A4 generation is decreased in aspirin-sensitive patients in lysine-aspirin nasal challenge in vivo model.

BACKGROUND: Lipoxins represent a group of lipoxygenase derived eicosanoids which, in contrast to leukotrienes, are potent anti-inflammatory mediators. The aim of our study was to determine lipoxin A(4) (LXA(4)) and leukotriene C(4) (LTC(4)) levels in nasal lavages after intranasal challenge with aspirin in aspirin intolerant (AIA) in comparison to aspirin tolerant (ATA) asthmatics and after allergen challenge in patients suffering from allergic rhinitis. METHODS: Twelve AIA, 8 ATA and 20 allergic patients were challenged with placebo, 16 mg of lysine-aspirin (Lys-ASA) or allergen (grasses). Nasal lavages were collected and eicosanoids' levels were determined using ELISA. RESULTS: Clinically positive Lys-ASA challenge in AIA resulted in influx of leukocytes (eosinophils and basophils) to nasal secretions and increase of LTC(4) to 106.82 pg/ml (P < 0.05 vs baseline (26.58 pg/ml)) on first hour after the challenge. We did not observe any differences in LTC(4) level before and after ASA challenge in ATA. In AIA group the mean level of LXA(4) was 43 +/- 21.5 pg/ml after placebo and decreased in 2 h after Lys-ASA challenge (29 +/- 17 pg/ml, P = 0.015). We found an increase in LXA(4) in ATA after ASA provocation as compared to placebo (33 +/- 16 pg/ml vs 52 +/- 31 pg/ml, P = 0.046). In atopic patients baseline level of LXA(4) was 33.49 +/- 16.95 pg/ml with no difference after the clinically positive allergen challenge (36.22 +/- 13.26 pg/ml, P = 0.23). CONCLUSIONS: Results of our study confirm that AIA have diminished LXs' biosynthesis capacities in vivo after ASA challenge. Taking into consideration anti-inflammatory properties of lipoxins this phenomenon may be partially responsible for the development of chronic inflammation in AIA patients.

Lower respiratory tract complications during nasal provocation: nonspecific stimulant or specific allergen?

BACKGROUND: Allergic rhinitis (AR) is an allergic inflammatory disease in which allergen exposure leads to the appearance of symptoms in sensitized individuals because of histamine liberation from nasal mucosal mast cells. Comorbidity of this disease with allergic asthma is common. Therefore, the one airway one disease theory has been put forward. Lower respiratory tract provocation tests with both nonspecific (methacholine) and specific stimulants (allergen) have yielded positive results in nonasthmatic patients with AR. However, not enough research is available to demonstrate whether there is a response in the lower respiratory tract during nasal provocation tests (NPTs) performed to evaluate only nasal airway in these patients. OBJECTIVES: To determine if the lower respiratory tract was affected as a result of NPTs with nonspecific and specific stimulants in nonasthmatic patients with AR and to determine the frequency of lower respiratory tract obstruction due to NPT with nonspecific and specific stimulants. METHODS: Thirty-six participants were enrolled in the study between November 2005 and January 2006 (18 AR patients and 18 healthy control subjects). Patients underwent 2 sessions of NPT. The first session was performed with nasal methacholine as a nonspecific stimulant, and the second session was performed with nasal Olea europaea extract as a specific stimulant. The control group underwent only nonspecific nasal provocation with methacholine. Basal nasal opening and nasal pressures were evaluated spirometrically by rhinomanometric measurements and basal respiratory function tests in both groups before methacholine nasal provocation. Whether or not nasal provocation was achieved, spirometric measurements were performed in all patients and controls after NPTs. RESULTS: NPTs with methacholine resulted in a similar frequency of nasal provocation in the patient and control groups (P = .63). However, the mean methacholine dose was lower in patients with AR (P = .049). There was a decrease in parameters of asthma, including the ratio of forced expiratory volume in 1 second to forced vital capacity (P = .04), peak expiratory flow (P = .01), and forced expiratory flow between 25% and 75% (P = .004), as a result of NPTs with methacholine in the patient group. However, NPTs with allergen did not cause a change in lower respiratory tract obstruction criteria. CONCLUSIONS: Lower respiratory tract obstruction can occur after NPTs with nonspecific stimulants; therefore, tests performed with specific allergens can be regarded as safer.

Nasal provocation test (NPT) with aspirin: a sensitive and safe method to diagnose aspirin-induced asthma (AIA).

BACKGROUND: We have aimed to determine the sensitivity and specificity of a simpler technique with less risk than oral provocation to diagnose aspirin-induced asthma (AIA). METHODS: We studied a group of 20 AIA patients compared to a control group with 40 aspirin-tolerant patients (confirmed by oral provocation test): 10 asthmatic patients and 30 healthy subjects. A nasal provocation test (NPT) with lysine acetylsalicylic acid (L-ASA) was carried out. Nasal and pulmonary functions were monitored with anterior active rhinomanometry (AAR) and spirometry. An L-ASA solution (900 mg/ml L-ASA, equivalent to 500 mg/ml acetylsalicylic acid) was diluted with saline solution. We administered four increasing doses: 5, 25, 50 and 100 mg/ml acetylsalicylic acid (ASA) with saline solution control. Nasal and pulmonary functions were monitored with rhinomanometry and spirometry. The patients were controlled for nasal inspiratory peak flow and expiratory peak flow. RESULTS: The results showed high sensitivity and specificity: 80% and 92.5%, respectively, with an 84.2% positive predictive value and an 89.2% negative predictive value. The patients had no bronchial or systemic symptoms, and no decreases over 20% were recorded in the FEV1. CONCLUSION: NPT has a high sensitivity and specificity in the diagnosis of AIA. An oral provocation should be performed to confirm the result whenever the clinical situation of the patient permits it.

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.

Dose-dependent effects of budesonide aqueous nasal spray on symptoms in a daily nasal allergen challenge model.

BACKGROUND: It has been difficult to demonstrate dose-dependent clinical effects of anti-allergic glucocorticosteroid drugs in allergic rhinitis. OBJECTIVE: To determine dose-dependent effects on rhinitis symptoms of clinical doses of the glucocorticosteroid budesonide in a standardized daily allergen challenge model. METHODS: Twenty-five patients with seasonal allergic rhinitis were examined outside the pollen season. The highest 256 microg once daily and lowest 64 microg once daily clinically recommended doses of budesonide aqueous nasal spray and placebo were given in a double-blind, placebo-controlled, randomized, and crossover design with 4 weeks' washout between treatments. After 1 week's treatment, the patients received individually titrated nasal allergen challenges once every morning for 8 days while treatment continued. Nasal symptoms were scored in diary cards. Nasal symptoms from the 6th to the 8th challenge days were used in the analysis. RESULTS: The provocation model produced clinically relevant, and around the clock well tolerable rhinitis symptoms, suggesting that after several days of repeated allergen challenges, a season-like, transient allergic disease condition had been established. Both 64 microg and 256 microg of budesonide aqueous nasal spray reduced nasal symptoms. Budesonide 64 microg reduced total nasal symptoms scores from 5.19 +/- 0.5 to 4.23 +/- 0.53 (P < .05), and budesonide 256 microg reduced total nasal symptoms scores to 3.41 +/- 0.51 (P < .001). A significant difference in nasal symptoms after challenge between budesonide aqueous nasal spray 64 microg and 256 microg (P = .03), indicated a dose-dependent effect. CONCLUSIONS: A dose-dependent, symptom-reducing effect of once-daily treatment with topical aqueous nasal sprays of budesonide for two weeks was demonstrated, suggesting that this model is relevant for assessments of dose-dependent effects of anti-inflammatory drugs.

Effect of pre-treatment with inhaled furosemide on allergen nasal challenge.

The inhalation of furosemide has been reported to inhibit the bronchospasm induced by several agents. In the present study, we evaluated the effect of inhaled furosemide on the specific nasal challenge test in patients with allergic rhinitis. A total of 21 consecutive patients with allergic rhinitis (positive skin test and RAST) and a positive basal nasal provocation test (NPT) with the specific allergen were investigated. In each patient, we compared the changes in nasal air-flow (anterior rhinomanometry) during NPT after inhalation of placebo and 20 mg furosemide. The previously positive NPT response to the inhalation of the specific allergen became negative after the furosemide pretreatment in 16 patients (76.2%, p < 0.001, chi-square test). The nasal air flows during NPT were significantly increased after furosemide treatment with respect to placebo inhalation (F = 17.2, d.f. = 1 and 3; p < 0.03; covariance analysis). Our results suggest that the pretreatment with inhaled furosemide in atopic subjects is able to exert a protective effect on the nasal mucosa reactivity to the specific allergen. Therefore, the anti-reactive effect of the drug on the airways is not confined to the bronchial asthmatic response.

Nasal response in subjects undergoing challenges by inhaling occupational agents causing asthma through the nose and mouth.

BACKGROUND: Subjects with occupational asthma (OA) often report nasal symptoms, but nasal reactions to inhalation challenges with occupational agents have not been well characterized. METHODS: Fifteen subjects with OA (eight due to high-molecular-weight agents--flour and guar gum--and seven due to isocyanates) underwent inhalational challenges using closed-circuit devices (dry particles for high-molecular-weight agents and gas generator for isocyanates) on two occasions, 2-4 weeks apart in a random fashion. On one occasion, they inhaled through the nose and, on another, through the mouth. The FEV1 was monitored for up to 8 h afterward, and symptoms were documented with a standardized questionnaire on nasal symptomatology, assessment of nasal resistance by rhinomanometry, and nasal lavage for the examination of cells and mediators. RESULTS: Inhaling through the mouth and through the nose: 1) yielded similar asthmatic responses (25+/-8% and 22+/-10% maximum changes in FEV1) 2) more than doubled the peak nasal symptoms and nasal resistance when the maximum daily response was compared with prechallenge results. This increase occurred on the days of inhalational challenges through the mouth and through the nose. There were some significant responses assessed by nasal lavage in terms of cells and mediators, again with no differences between the days of challenges through the mouth and through the nose. CONCLUSIONS: Inhaling occupational agents of high or low molecular weight, including isocyanates, whether through the mouth or nose: 1) results in a similar asthmatic response 2) causes a significant nasal response in terms of symptoms and an increase in nasal resistance 3) causes some significant changes in inflammatory cells and mediators.

Asthmatic reactions after nasal allergen provocation.

Three bronchoconstrictive responses associated with acute rhinitis and occurring in two patients were observed among 400 nasal allergen challenges. Causative substances were birch pollen, Dermatophagoides pteronyssinus and HSA-conjugated pyromellitic dianhydride. Both subjects showed bronchial hyperreactivity and immediate-type sensitization to these allergens. It is concluded that bronchoobstruction nearly occurs in nasal allergen challenges. The underline pathophysiological mechanism remains unclear.

Improved diagnosis and treatment of allergic rhinitis by the use of nasal provocation tests.

A simple and safe method of nasal provocation for out-patients that requires no special equipment is described. A total of 2,645 cases were tested by nasal provocation tests. Of the total, 1,175 were tested with Dermatophagoides pteronyssinus, 825 with mixed grass pollens, 352 with plantain (Plantago lanceolata), and 125 for cats and correlating nasal tests with skin tests yielded 80%, 90%, and 85%, respectively. Immunotherapy for allergic rhinitis was only considered justifiable when the nasal provocation test was positive. The nasal provocation test was repeated at the end of the normal course of injections recommended by the manufacturer. If the nasal provocation test was still positive, further injections were given until the test became negative. This method of improving diagnostic accuracy and monitoring results of immunotherapy was used with both aqueous extracts which were used for skin testing (Australian Government Commonwealth Serum Laboratories) and with Allpyral pyridine-extracted alum-precipitated extracts (Dome Laboratories, England). The number of injections of allergen required to convert a positive nasal provocation test to negative varied from 26 to 69 for mite aqueous injections with only 12 to 19 for mite suspension and 47 to 98 for grass aqueous injections compared with 12 to 36 for grass suspension. Direct provocation tests of the nose should give a more accurate diagnosis than RAST or skin tests and are required for monitoring therapy because considerable individual variations in sensitivity and response to treatment were demonstrated. Standard dosage schedules are not suitable for individual patients, who should have their immunotherapy personalized.