key: cord-0921116-8rg2x73m
authors: Nathan, Robert A.; Eccles, Ron; Howarth, Peter H.; Steinsvåg, Sverre K.; Togias, Alkis
title: Objective monitoring of nasal patency and nasal physiology in rhinitis
date: 2005-03-02
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2004.12.015
sha: 7ef2b2ac31e6f1c498641e1b775c7120152577ff
doc_id: 921116
cord_uid: 8rg2x73m

Nasal obstruction can be monitored objectively by measurement of nasal airflow, as evaluated by nasal peak flow, or as airways resistance/conductance as evaluated by rhinomanometry. Peak flow can be measured during inspiration or expiration. Of these measurements, nasal inspiratory peak flow is the best validated technique for home monitoring in clinical trials. The equipment is portable, relatively inexpensive, and simple to use. One disadvantage, however, is that nasal inspiratory peak flow is influenced by lower airway as well as upper airway function. Rhinomanometry is a more sensitive technique that is specific for nasal measurements. The equipment, however, requires an operator, is more expensive, and is not portable. Thus, it is applicable only for clinic visit measures in clinical trials. Measurements require patient cooperation and coordination, and not all can achieve repeatable results. Thus, this objective measure is best suited to laboratory challenge studies involving smaller numbers of selected volunteers. A nonphysiological measure of nasal patency is acoustic rhinometry. This sonic echo technique measures internal nasal luminal volume and the minimum cross-sectional area. The derivation of these measures from the reflected sound waves requires complex mathematical transformation and makes several theoretical assumptions. Despite this, however, such measures correlate well with the nasal physiological measures, and the nasal volume measures have been shown to relate well to results obtained by imaging techniques such as computed tomography scanning or magnetic resonance imaging. Like rhinomanometry, acoustic rhinometry is not suitable for home monitoring and can be applied only to clinic visit measures or for laboratory nasal challenge monitoring. It has advantages in being easy to use, in requiring little patient cooperation, and in providing repeatable results. In addition to nasal obstruction, allergic rhinitis is recognized to be associated with impaired mucociliary clearance and altered nasal responsiveness. Measures exist for the monitoring of these aspects of nasal dysfunction. Although measures of mucociliary clearance are simple to perform, they have a poor record of reproducibility. Their incorporation into clinical trials is thus questionable, although positive outcomes from therapeutic intervention have been reported. Measures of nasal responsiveness are at present largely confined to research studies investigating disease mechanisms in allergic and nonallergic rhinitis. The techniques are insufficiently standardized to be applied to multicenter clinical trials but could be used in limited-center studies to gain insight into the regulatory effects of different therapeutic modalities.

Objective monitoring of nasal patency and nasal physiology in rhinitis Robert A. Nathan, MD, a Ron Eccles, PhD, DSc, b Peter H. Howarth, BSc (Hons), DM, FRCP, c Sverre K. Steinsvå g, MD, PhD, d and Alkis Togias, MD e Colorado Springs, Colo, Cardiff and Southampton, United Kingdom, Kristiansand, Norway, and Baltimore, Md Nasal obstruction can be monitored objectively by measurement of nasal airflow, as evaluated by nasal peak flow, or as airways resistance/conductance as evaluated by rhinomanometry. Peak flow can be measured during inspiration or expiration. Of these measurements, nasal inspiratory peak flow is the best validated technique for home monitoring in clinical trials. The equipment is portable, relatively inexpensive, and simple to use. One disadvantage, however, is that nasal inspiratory peak flow is influenced by lower airway as well as upper airway function. Rhinomanometry is a more sensitive technique that is specific for nasal measurements. The equipment, however, requires an operator, is more expensive, and is not portable. Thus, it is applicable only for clinic visit measures in clinical trials.

Measurements require patient cooperation and coordination, and not all can achieve repeatable results. Thus, this objective measure is best suited to laboratory challenge studies involving smaller numbers of selected volunteers. A nonphysiological measure of nasal patency is acoustic rhinometry. This sonic echo technique measures internal nasal luminal volume and the minimum cross-sectional area. The derivation of these measures from the reflected sound waves requires complex mathematical transformation and makes several theoretical assumptions. Despite this, however, such measures correlate well with the nasal physiological measures, and the nasal volume measures have been shown to relate well to results obtained by imaging techniques such as computed tomography scanning or magnetic resonance imaging. Like rhinomanometry, acoustic rhinometry is not suitable for home monitoring and can be applied only to clinic visit measures or for laboratory nasal challenge monitoring. It has advantages in being easy to use, in requiring little patient cooperation, and in providing repeatable results. In addition to nasal obstruction, allergic rhinitis is recognized to be associated with impaired mucociliary clearance and altered nasal responsiveness. Measures exist for the monitoring of these aspects of nasal dysfunction. Although measures of mucociliary clearance are simple to perform, they have a poor record of reproducibility. Their incorporation into clinical trials is thus questionable, although positive outcomes from therapeutic intervention have been reported. Measures of nasal responsiveness are at present largely confined to research studies investigating disease mechanisms in allergic and nonallergic rhinitis. The techniques are insufficiently standardized to be applied to multicenter clinical trials but could be used in limited-center studies to gain insight into the regulatory effects of different therapeutic modalities. (J Allergy Clin Immunol 2005;115:S442-59.)

Key words: Rhinitis, nasal obstruction, nasal peak flow, rhinomanometry, acoustic rhinometry, mucociliary clearance, nasal responsiveness Nasal obstruction is a common and important symptom of rhinitis. 1 Visual analogue scales or symptom rating scores may evaluate this subjectively. It is appreciated, however, that the subjective sensation of nasal obstruction can be difficult to quantify accurately, because patient perceptions of nasal obstruction vary considerably, often bearing no relationship to the actual resistance to airflow in the nose.

Consequently, objective methods have been developed to assess nasal patency quantitatively. 2 These methods include measurement of nasal peak inspiratory flow (NPIF) and nasal peak expiratory flow (NPEF), anterior and posterior rhinomanometry, acoustic rhinometry, and the peak flow nasal patency index. 3 Nasal adapters have also been fitted to spirometers to enable measurement of nasal FEV 1 , nasal forced inspiratory volume in 1 second, and nasal forced vital capacity. 4, 5 Peak flow and rhinomanometry represent physiologic measures. Rhinomanometry involves the simultaneous measurement of nasal airflow and the pressure required to achieve that flow, from which nasal airway resistance (NAR) can be calculated. Depending on the technique used, this provides either information about each nostril separately (anterior or modified posterior rhinomanometry) or an integrated measure for both nostrils together (posterior rhinomanometry). Nasal peak flow is an indirect index of nasal obstruction, because increasing nasal resistance modifies nasal airflow and hence the peak inspiratory or expiratory nasal airflow achievable. Differences exist in the cost of equipment required for these physiologic measures and their practical applicability for clinical trial purposes.

An alternative approach used to gain information of relevance to nasal obstruction is acoustic rhinomanometry. This is not a physiologic measure, because it provides no information about nasal airflow but provides information about the nasal luminal anatomic structure, either as a measure of nasal volume over a predetermined set distance into the nostril or as the minimal cross-sectional area within the nasal cavity.

Mucociliary clearance is an important upper airway defense mechanism. Defects in mucociliary clearance may promote mucus retention within the nasal cavity and indirectly reduce nasal airflow. The assessment of mucociliary function can be achieved by measures such as the saccharine test, which is in part subjective, as well as more objective tests such as the measurement of ciliary beat frequency and ciliary ultrastructure. The latter would not be applicable to clinical trials.

Another nasal physiologic parameter for which methods have been established for measurement is nasal reactivity. Tests of nasal reactivity have been used to investigate how rhinitis alters the nasal response to exogenous chemical or physical stimuli and have been primarily used as a research approach to understand the nature of altered physiology in disease. These tests may use one of the measures of nasal obstruction as an outcome parameter in association with nasal challenge, or may use an alternative outcome, such as number of sneezes or quantity of anterior rhinorrhea, depending on the nature of the challenge and the protocol involved. Some tests of nasal reactivity have shown an altered nasal responsiveness in rhinitis, which is distinct from that in the normal nose.

One of the attractions of nasal peak flow is the simplicity of the method. A mini-Wright peak flow meter, equipped with an airtight face mask instead of a mouthpiece, can be used to measure NPEF. This measure is quick, noninvasive, inexpensive, and relatively easy. The equipment is portable and useful for repeated examinations. During this procedure, patients are instructed to inspire to total lung capacity and, keeping lips tightly closed, to expire with maximal effort through the nose. 6 Maximal flow rate is read from a cursor in liters per minute. A potential drawback to the expiratory peak flow technique is the blowing of mucus into the peak flow meter. 7 Alternatively, NPIF can be measured by using a Youlten peak nasal inspiratory flow meter (an inverted mini-Wright flow meter) attached to an anesthesia mask. During this procedure, the patient places the mask over the nose and mouth, secures an airtight seal around these areas, and inspires forcefully (a vigorous sniff) through the nose, with lips tightly closed. The measurement of NPIF is associated with a small risk of nasal vestibular collapse. If the alar muscles are contracted during maximal inspiration leading to flaring of the nostrils, this counteracts the tendency for vestibular collapse. 1 In a study of patients with allergy, 2% (6 of 327) of NPIF measurements were not obtained because of total occlusion of the nose. 1 Recent mathematical modelling has indicated that nasal wall compliance, in addition to nasal patency, is an important determinant of NP1F. 8 Reproducibility and variation in nasal peak flow Reproducibility in nasal peak flow measurement is dependent on variation resulting from characteristics of the flow meter, variation related to subject technique, and variation caused by changes in airway size and shape that arise because of interindividual differences. Both the mini-Wright and Youlten flow meters are reported to offer highly reproducible results. Proper technique is more difficult with NPIF than NPEF, but most subjects still achieve reproducible values after less than 5 minutes of instruction. 9, 10 Secretions in the mini-Wright meter can influence NPEF readings. Both NPEF and NPIF are effortdependent, and variability of results might come from fatigue or subtle changes in technique. In addition, nasal patency can change quickly. Other factors that can affect NPIF measurements include severe nasal obstruction, poor coordination, alar collapse, and poor inspiratory reserve. 10 Taking the best of 3 readings with less than 10% variation is a more useful result than taking the mean of the 3 maneuvers.

For NPIF, proper fit of the mask is important-that is, the mask must be small enough to provide an airtight seal yet large enough to avoid compression of the external nares. 6 Wihl and Malm 1 reported that leakage through the mouth during NPIF and NPEF could result in false maximal values, whereas failure to relax the soft palate during maximal expiration could result in false low values. The investigators found that in patients with partially blocked noses, the eustachian tube can be pressurized during maximal expiration, causing discomfort and a decreased expiratory effort. 1

One inherent flaw of nasal peak flow is the failure of this method to account for abnormalities in pulmonary function. 11 Nasal peak flow is dependent on both nasal patency and the ventilatory capacity of the lungs. 1 Lower airway obstruction and a reduced respiratory effort can affect nasal peak flow. Findings from a study by Phagoo et al 12 demonstrated that NPIF and, to a lesser extent, NPEF were altered by changes in intrapulmonary airway dimensions. The authors stated that NPIF and NPEF may give a false impression of nasal patency when effort is submaximal, intrapulmonary dynamic resistance is increased, or nasal dynamic resistance is low. They suggested that false readings could be avoided by comparing mouth peak flow and/or mouth peak inspiratory flow with that of NPIF and NPEF. 12 Similar to peak expiratory flow rate in patients with asthma, there is a diurnal variation in nasal peak flow measurements, with readings lower in the morning and highest at dinner. There are no reported normal values for either NPEF or NPIF, and accordingly, nasal peak flow can be used only as a relative measurement in the same individual over time, although a NIPF of greater than 2.5 L/s has been proposed as being normal. 13 Some investigators have argued that NPIF should not be used to assess a very obstructed nose quantitatively. Gleeson et al 14 found that many patients with marked subjective nasal blockage were unable to obtain NPIF readings greater than 20 (on a scale from 20 to 350 units, which correspond roughly to L/min). Furthermore, a variety of stimuli can acutely influence nasal patency. Exercise and warm air increase patency. Recumbency, pain, cold air, smoking, and hypoventilation decrease patency. Hormonal factors can also influence nasal patency, although small studies in pregnancy and through the normal menstrual cycle have failed to show significant changes in NPIF. 15, 16 Nasal peak expiratory flow can be influenced by a flow meter contaminated from nasal secretions, which is common in individuals with allergy. Subjects must be instructed to evacuate secretions from the nose by sniffing or blowing before taking a measurement. False results occur if the device is not cleaned regularly.

Nasal peak flow meter portability allows measurements to be obtained during a symptomatic state to document environmentally and occupationally induced nasal obstruction. Twice-daily measurements would be adequate for determining a chronic pharmacologic effect, and measuring nasal peak flow before and 10 minutes after would examine the effects of nasal provocation. The domiciliary use of nasal peak flow meters to monitor objectively the magnitude of nasal obstruction has been found valuable, and the measures have been found to correlate significantly with the severity of symptom reporting. 17 How nasal peak flow relates to other indices of disease: Comparison with rhinomanometry and subjective measures Rhinomanometry provides a well-established, objective, quantitative measure of NAR. Several studies have compared nasal peak flow measurements with rhinomanometry and visual analogue scales in the determination of nasal obstruction with conflicting results. Gleeson et al 14 and Enberg and Ownby 9 found nasal peak flow to be an unreliable measure of nasal obstruction. Clarke et al 18 found nasal peak flow a relatively insensitive measure compared with rhinomanometry. Larsen and Kristensen 19 saw a poor intraindividual correlation. Jones et al 20 and Fairley et al 21 saw a strong correlation with subjective nasal sensation. In addition, Jones et al 20 found a high correlation between NAR, as measured by anterior rhinomanometry, and NPIF and concluded that NPIF was as good an indication of objective nasal patency as NAR measured by rhinomanometry. 20 Holmstrom et al 10 found a good correlation of NPIF with rhinomanometry, and a significant correlation has also been shown between NPIF and forced inspiratory volume in 1 second. 22 Frølund et al 6 studied the relationship between posterior rhinomanometry and NPEF in healthy subjects and patients with rhinitis. A significant correlation was found between posterior rhinomanometry and NPEF when patients were stratified by rhinitis diagnosis and height. The authors concluded that posterior rhinomanometry is an appropriate method for clinic use, and that NPEF is an easy method for measuring nasal patency and may be suitable for home use.

Marais et al 23 used nasal peak flow and acoustic rhinometry to evaluate patients undergoing septoplasty alone and septoplasty combined with trimming of the inferior turbinates. Patients who had both procedures had the greatest increase in both minimal cross-sectional areas (measured by acoustic rhinometry) and nasal peak flow fraction (the ratio of oral peak expiratory flow rate to peak nasal expiratory flow rate). Both measurements were closely correlated with patient satisfaction. The authors concluded that acoustic rhinometry and nasal peak flow fraction were accurate and easily performed perioperative measurements for patients undergoing surgery for nasal obstruction.

Gleeson et al 14 concluded that although anterior and posterior rhinomanometry have advantages for some research applications, consideration of cost and convenience makes nasal volume or NPIF measurements more practical for routine medical or surgical use.

Various opinions circulate about the role of nasal peak flow measurements in clinical practice. 24, 25 However, nasal peak flow is the only method suitable for home monitoring to investigate circadian variation, day-to-day changes, or environmental effects on nasal patency. Its portability allows objective assessment of occupationally induced nasal obstruction. Nasal peak flow can assess the acute effect on nasal blockage before and after dosing with a pharmacologic agent or with a provocative stimulus. It can also assess changes over longer periods. For example, after nasal allergen provocation, nasal peak flow measurements can assess the late phase reaction at home. This technique can establish the effect of corticosteroids on nasal polyposis and can be used for preoperative and postoperative assessment of septoplasty or turbinectomy. Nasal peak flow is also potentially useful in assessing functional nasal problems and for medical legal assessment.

Use as a measure of work-related nasal blockage Ahman 26 investigated the value of serial NPEF measurements in detecting nasal blockage in different work environments. Eleven patients who had nasal blockage caused by airway irritants were compared with 11 control subjects. Compared with the control subjects, NPEF values for patients exposed to irritants decreased gradually over the workweek, with gradual improvement during the weekend. Changes in bronchial peak expiratory flow rates were similar but less pronounced. The author concluded that NPEF was an effective means of detecting changes in the sensation of nasal blockage.

In another study, Ahman and Soderman 27 evaluated the usefulness of serial NPEF as a measure of work-related nasal obstructive symptoms in woodwork teachers and control subjects. Compared with control subjects, the teachers reported a higher level of nasal blockage (as assessed by symptom ratings). A gradual increase in nasal blockage during the week corresponded moderately with a gradual decrease in NPEF. No statistically significant difference was observed between the proportion of teachers and control subjects who had a meaningful decrease in NPEF. The authors concluded that NPEF is useful in evaluating subjects with work-related nasal obstruction, but because of its variability, a large number of subjects should be evaluated, with several measurements taken daily.

Use as an efficacy measure in clinical drug trials Nasal peak inspiratory flow has been used successfully in combination with other measures in several placebo-controlled trials to demonstrate the efficacy of steroid nasal sprays in patients with a variety of conditions. Greiff et al 28 used daily patient-assessed NPIF and nasal index scores to compare the efficacy of mometasone furoate and budesonide aqueous nasal sprays in patients with seasonal allergic rhinitis (SAR), and NPIF was also used to show improvement objectively in nasal obstruction with triamcinolone acetonide and fluticasone propionate therapy in SAR. 29 Daily NPIF (patient-assessed), in combination with other assessments, has been used to demonstrate the efficacy of fluticasone propionate nasal spray in patients with allergic rhinitis, 30 recurrent sinusitis, 31 chronic eosinophilic rhinitis, 32 and nasal polyposis. 33 NPIF has also been used in a clinical trial of an H 1 -antihistamine in combination with either a cys-leukotriene 1 receptor antagonist or pseudoephedrine to demonstrate efficacy of combination therapy on nasal obstruction. 34 In a study of patients with nasal polyps, NPIF, polyp size scores, and total symptom score were used to evaluate various doses of budesonide aqueous nasal spray as primary treatment of nasal polyps. 35 Also, NPEF measurements have been used in several placebocontrolled trials to demonstrate improvements in patients with nasal polyposis after steroid therapy. [36] [37] [38] [39] 

Rhinomanometry is the measurement of nasal pressure flow relationships during normal breathing. Rhinomanometry is generally accepted as the standard technique of measuring NAR and assessing the patency of the nose [40] [41] [42] [43] and provides a sensitive and functional measure of nasal patency during normal breathing.

In subjects free from signs of nasal disease, mean total resistance has been reported to be around 0.23 Pa cm 23 s 21 , ranging between 0.15 and 0.39 Pa cm 23 s 21 . 44 A total nasal resistance to airflow of 0.3 Pa cm 23 s 21 can be considered a reasonable upper limit of the normal range in healthy volunteers.

Nasal resistance is highest in the infant, at around 1.2 Pa cm 23 s 21 , 45,46 and declines to the adult value at around 16 to 18 years of age, showing only a slow decline with increasing age. 47 In a study in healthy volunteers, Vig and Zajac 48 reported a relationship between age and nasal resistance, with resistance declining with increasing age from 0.6 Pa cm 23 s 21 (age 5-12 years) to 0.29 Pa cm 23 s 21 (age 13-19 years), and 0.22 Pa cm 23 s 21 (age >20 years) in male subjects. The relationship between age and nasal resistance was similar in female subjects, but in general, nasal resistance was lower in female subjects than male subjects. 48 If the nose is decongested by exercise or application of a topical decongestant, then this eliminates any physiologic variation in resistance and allows investigation of the anatomical factors influencing resistance. Studies by Broms 49 have provided a table of predictive values for height and nasal resistance in the decongested nose that are useful in assessing the extent of any deviation from normality in patients with nasal skeletal stenosis.

Total nasal resistance gives an overall measure of nasal function, but it is a very crude measure because it provides no information about the separate nasal passages.

Rhinologists have a dilemma when assessing nasal function, because the nose consists of 2 separate dynamic airways. The ophthalmologist or audiologist would never consider using a bilateral measure of vision or hearing when assessing function, because this could fail to detect blindness in one eye or deafness in one ear. Similarly, the measurement of total resistance may fail to detect unilateral nasal obstruction. However, it is not very informative to quote the mean of unilateral resistance when measured over a period of several hours, because this mean value will have a large SD because of the instability of unilateral resistance. The range of unilateral NAR in a group of healthy volunteers when recorded over a period of 6 to 8 hours has been shown to vary from 0.36 to 1.36 Pa cm 23 s 21 , 50 and from 0.28 to 0.63 Pa cm 23 s 21 . 51 This indicates that there is almost a 4-fold change in unilateral resistance associated with the spontaneous natural congestion and decongestion of the nasal venous sinuses.

One way to overcome the dilemma of spontaneous changes in unilateral nasal resistance is to decongest the nose before assessment. This solution is of use to a surgeon who is interested only in assessing the extent of any nasal anatomical problem. 49 However, decongestion of the nose is of no use in studying nasal physiology and pathophysiology, because it is the spontaneous changes in unilateral resistance that are of interest to the physiologist and clinician. One solution is to quantify the extremes of unilateral resistance or the amplitude of the unilateral changes in resistance over a period of several hours. This approach has been used to determine the unilateral changes in resistance in health, 52 common cold, 50 and hay fever, 53 to assess the effects of oral decongestants, 54 and to assess the efficacy of nasal surgery. 55 The disadvantage of unilateral nasal measurements is that to assess the amplitude of changes in unilateral nasal resistance it is necessary to make measurements over several hours. The advantage of unilateral measurements is that they give a comprehensive assessment of the dynamic nose rather than the crude snapshot provided by a single measure of total resistance. In the laboratory, under conditions of bilateral nasal challenge, however, a single measurement will provide information relating to the overall effect of the provocation.

Active posterior rhinomanometry can be used to measure both unilateral and total nasal conductance. Conductance is defined as the airflow through the nose at a sample pressure of 75 Pa. Conductance is a more useful measure than resistance, because resistance measurements tend toward infinity when the nose becomes completely obstructed, whereas conductance declines toward 0.

A face mask is used to make a seal around the nose, and the patient breathes through a flow head attached to the mask. A pressure-sensing tube is held in the mouth and detects the posterior nares' pressure when the soft palate allows an airway to the mouth, as shown in Fig 1. Total nasal airflow can be measured from both nasal passages, or, by taping off one nostril, the right and left nasal air flows can be measured separately. Total nasal conductance can be determined directly from the total nasal airflow and transnasal pressure with this method. A disadvantage of this method compared with the anterior method is that not all subjects can open an airway around the soft palate into the mouth. With some training of subjects, using feedback from the pressure flow curve on the computer monitor, it is possible to obtain satisfactory results from almost all subjects, and in studies on many hundreds of subjects, very few have been unable to perform this technique.

Some centers recommend anterior rhinomanometry in preference to the posterior method. In active anterior rhinomanometry, the pressure-sensing tube is normally taped to one nasal passage. The sealed nasal passage acts as an extension of the pressure-sensing tube to measure pressure in the posterior nares. With this method, nasal airflow is measured from one nostril at a time and the pressure-sensing tube is swapped from one side to the other. Therefore, the pressure/flow curves and nasal resistance or conductance measurements are determined separately for each nasal passage and the total is then calculated. The major disadvantage of the anterior method is that it is impossible to make any measurements if one of the nasal passages is completely obstructed. This is a significant limitation of the anterior rhinomanometric method and a deciding factor in preference for posterior rhinomanometry as a standard technique, because patients with rhinitis often have obstruction of one nasal passage, and it would not be possible to include these patients in any study in which anterior rhinomanometry was the preferred measure of nasal conductance.

When making measurements of NAR, it is important to take several measurements with repositioning of the mask between measurements. This is to control for air leaks around the mask, a common source of error. A single measurement of NAR is unreliable, and a standard operating procedure should be implemented to prevent investigator bias when gathering data. The equipment should be calibrated daily.

Rhinomanometry is a relatively easy measurement when performed in a laboratory by trained personnel using a standard operating procedure. Training of subjects to perform posterior rhinomanometry and obtain the first measurement takes 10 to 15 minutes, and after this first measurement, subsequent measurements take only around 5 minutes. Measurements using anterior rhinomanometry can be made more quickly because training of subjects is not required. At present, rhinomanometers are interfaced with computers. This makes them rather expensive and not very portable for use in a clinic or hospital ward.

Nasal airflow resistance is unstable as a result of spontaneous and often reciprocal changes in resistance associated with the so-called nasal cycle. 50, 56 An example of the spontaneous changes in unilateral nasal resistance in a patient with rhinitis associated with the common cold is shown in Fig 2. Similar fluctuations in nasal resistance are associated with allergic rhinitis 57 and are also found in healthy subjects. 51 Because of the inherent instability of nasal resistance, any study on repeatability of measurements can examine only short-term comparisons made over a period of 10 to 15 minutes.

The results of a study on 21 patients (mean age, 23 years) with the common cold are illustrated in Fig 3. In this study, total NAR was measured by the technique of posterior rhinomanometry by 2 different operators using 2 different rhinomanometers. The 2 measurements of resistance were separated by no more than 6 minutes to limit the occurrence of spontaneous changes in resistance. The results show that the measurement of total resistance over this period is repeatable, although there is a tendency for more discrepancy between the 2 measurements in those patients with high nasal resistance. The mean 6 SD nasal resistance for each measurement respectively was 0.34 6 0.13 Pa cm 23 s 21 and 0.34 6 0.15 Pa cm 23 s 21 , showing that the measurements were repeatable over the 2 time points, even with different operators and separate rhinomanometers.

Although total resistance may be unstable over a period of hours because of the nasal cycle, it is possible to demonstrate the effects of medication on nasal resistance in patients with common cold 54,58 and allergic rhinitis. 59 

Some of the sources of variation have been mentioned. The spontaneous changes in nasal resistance associated with the nasal cycle are a natural source of physiologic variation, and other factors such as changes in posture, 57, 60 exercise, 61,62 cold air, 63 and ingestion of alcohol 64 also influence nasal resistance. During measurement, the main source of variation is an air leak around the face mask, which can be controlled by taking the mean of paired measurements and discounting those measurements with a high coefficient of variation. 65 

Rhinomanometry is performed more as a research measurement in the laboratory than as a standard clinical measurement, because the equipment is bulky and expensive. The spontaneous changes in nasal resistance associated with the nasal cycle and other factors described make nasal resistance relatively unstable, although it is possible to demonstrate the efficacy of medications such as nasal steroids by measuring changes in total nasal resistance. 59 The presence of mucus in the nose can confound measurements of nasal resistance, because sniffing and nose blowing will remove mucus and lower resistance (especially in patients with rhinitis). To overcome this problem, patients are asked to blow their nose gently before each measurement of nasal resistance.

Nasal obstruction is a dominant symptom associated with all types of rhinitis 66 ; it is an indirect reflection of nasal inflammation, providing that there are no significant permanent nasal anatomical abnormalities contributing to reduced nasal airflow. Any medication or disease process that causes dilation of nasal blood vessels, leading to swelling of the nasal venous sinuses, will be associated with nasal obstruction. The anti-inflammatory effects of nasal steroids account for the sustained reduction in NAR in patients with allergic rhinitis caused by treatment with intranasal steroids. 59 What is a significant alteration of disease?

Any objective reduction in nasal resistance that is also detected by the patient by the use of subjective scores could be deemed a clinically significant alteration. Objective changes in resistance, as measured by rhinomanometry, that are not detected by the patient should not be considered a significant alteration of the disease.

A major problem in this area is that the objective measures of nasal resistance do not correlate very well with subjective measurements. [67] [68] [69] This is because the nasal valve region primarily determines nasal resistance, whereas the sensation of nasal obstruction may be related to congestion in other areas of the upper airway, such as the ethmoid region. 70 If one considers the main function of the nose to be an airway to the lungs, then when the nose is obstructed, any decrease in nasal resistance brought about by treatment could be considered a significant alteration in the disease. As a general rule, one could defend a 20% reduction of total nasal resistance as being clinically significant, although this is very much a matter of opinion.

The relevance of dose timing to measurement depends on the type of medication under investigation. For treatment with topical decongestants, the maximal reduction in nasal resistance occurs as long as 45 minutes after treatment, 65 whereas the effect of treatment with nasal steroids on nasal resistance has been reported to occur only after 5 days of treatment. 59 

The power of a study is dependent on the magnitude of the change in nasal resistance expected on treatment. For studies on topical nasal decongestants in which a large reduction in nasal resistance is expected, group numbers as low as 8 will suffice. 65 For carefully controlled studies using nasal allergen challenge in patients with SAR, groups of 12 patients have been used to demonstrate significant changes in nasal resistance on treatment after 5 days' treatment with nasal steroids. 59 

In acoustic rhinometry, a sound impulse, termed the incident wave, is generated and transmitted through a tube of known dimensions into the nostrils, with analysis of the reflected echoes. The principal behind this method of measurement is that the size and pattern of the reflections are an indication of the structure and dimensions of the airways, and that the timing of the reflected wave provides information about the distance into the nostril. This method has been applied to the determination of the cross-sectional area as a function of distance into the nasal airways. The technique assumes 1-dimensional sound propagation and the lack of cross-mode waveforms. The devices and the frequency of sound used are designed to facilitate these requirements, and technologic developments in microcomputers have enabled the sampling, storage, and interpretation of the sound reflections. The conversion of the echo measurements to derive a measure of nasal volume requires complicated mathematical transformation 71 in addition to several theoretical assumptions. [71] [72] [73] [74] However, the validity of acoustic rhinometry has been proven by comparison of measures by this technique with those obtained by imaging, such as with computerized tomography (CT) or magnetic resonance imaging scanning. [74] [75] [76] Studies have indicated that measurements as far as 6 cm from the entrance to the nostril are accurate, but that beyond this distance, access of air to the maxillary sinuses through the ostiomeatal complex distorts the information from the reflected sound, at least in the decongested nose, and leads to inaccuracies in measurement. [77] [78] [79] Measures are thus usually made from 0 to 5 cm into the nostrils. In the congested nose, there is a less good correlation between CT scan evaluation of the nasal air passage dimensions and those obtained with acoustic rhinometry. 78 This is predominantly because of sound distortion in the posterior end of the nasal cavity, whereas anteriorly good agreement is evident. In addition to measuring nasal volume, for a set distance into the nostril, acoustic rhinometry standardly also provides information relating to the minimal cross-sectional area within the nose (a-min). This is usually at the level of the nasal valve, but in the congested nose, it can be at the anterior tip of the inferior turbinate.

A major advantage of acoustic rhinometry over other methods is that it is a very simple technique to use and requires minimal patient cooperation. For measurement, the patient sits in the upright position, clears their nose of secretions, and places the disposable nosepiece attached to the end of the acoustic rhinometry tube into a nostril. Different size nosepieces are available and should fit comfortably but firmly into the external nares to ensure an airtight seal. In some instances, it may be necessary to apply a proprietary soft paraffin wax to ensure an airtight seal. Measurements are made separately for each nostril. It is suggested that subjects keep their eyes focused on a point marked on a wall to keep the same head position during repeated measurements. Studies have evaluated the use of a head frame to fix the head rigidly in a set position, but this approach has not been found to provide better results 80 ; rather paradoxically, the results have been reported to be less repeatable under such circumstances. However, the angle of the rhinometry tube is important, because the axis at which the sound travels in the nasal cavity should be parallel to the nasal floor from the nasal valve, and alterations influence the measurement. 81, 82 Measurements are made during breath holding, as the area-distance function may be affected by breathing. 83 The measurements are passive and require no other cooperation from the patient.

Repeated measurements of nasal parameters by acoustic rhinometry and by rhinomanometry in 6 normal subjects over a 2-month period identified a reproducibility of 5% to 10% with acoustic rhinometry and 8% to 15% with rhinomanometry. 84 Such a measure incorporates not only machine/program variability but also subject-related variations. Studies in cadavers, which eliminate the subject variability, report a variation of less than 5% in repeated measurements of the nasal cavity volume by acoustic rhinometry. 85 

The main basis for poor repeatability of values is a nasal air leak, and it is important that the nasal nosepiece fits closely. 86 As with other measures that reflect nasal cavity volume/airflow, there is the influence of both the nasal cycle and of diurnal variations in nasal airway caliber. Thus, for repeated measures on separate days as part of a drug intervention study, measures should be undertaken at the same time of day. Because a classic nasal cycle is associated with alternating congestion/decongestion cycles matched by the opposite in the other nostril, the sum of the 2 sides is usually constant. In contrast with measures of nasal airflow, which have indicated that such reciprocating cycles occur in as many as 80% of subjects, 87 acoustic rhinometry measures of nasal volume have revealed such changes in only 25% to 50% of subjects. 75, 88, 89 In one small study of 12 subjects without allergy, repeated measurements of nasal volume, minimal cross-sectional area, and the area of the anterior end of the inferior turbinate every 15 minutes for 6 hours revealed a coefficient of variation of 9.4%, 11.3%, and 17.8%, respectively. 90 The variability was significantly larger in subjects with allergy, with a coefficient of variation for the nasal volume measurement of 14%. 90 Factors other than allergic disease that may influence intersubject variability or baseline measurements are race and height. [91] [92] [93] In a study of 106 subjects with a range of racial origins in North America, there were racial differences between white, Asian, and black noses. 92 Another study has reported no difference between Anglo-Saxon and Indian noses. 93 In a Swedish study of 334 healthy individuals, a weak correlation was found between the minimal cross-sectional area, as measured by acoustic rhinometry, and weight, height, age, and body mass index. 94 A correlation has been found between the dimensions of the external nose and the minimal crosssectional area. 95 Because acoustic rhinometry measures internal nasal cavity dimensions, any structural alterations, independent of mucosal swelling, such as those related to a deviated nasal septum, will influence nasal cavity measures. Changes resulting from mucosal swelling will be modified by a nasal decongestant, whereas those related to structural airway abnormalities will not.

During exercise, the increased sympathetic tone decongests the nasal mucosa, and measures of nasal volume by acoustic rhinometry have indicated that exercise at 75% of the maximum expected heart rate for 15 minutes has the same decongestant effect as a topical a-agonist vasoconstrictor decongestant. 71, 90 It is thus important that before any measures, subjects rest quietly for 15 minutes. It has been shown that such an acclimatization period reduces the variability in measurements. 96 

Intranasal challenge with substances such as histamine, kinins, or allergen results in a dose-related decrease in nasal volume and in a-min that correlates well with the subjective sensation of nasal obstruction. [97] [98] [99] In naturally occurring disease, there is a tendency for a smaller nasal volume and a reduced a-min, consistent with enhanced mucosal congestion. 90, 100, 101 Consistent with this, there is a greater response to nasal decongestants. 90 However, the subjective reporting of nasal obstruction in unselected clinical cases does not correlate well with acoustic rhinometry measures. 102, 103 This may well be because the sensation of nasal obstruction can also be influenced by changes in the ostiomeatal complex rather then purely reflecting nasal cavity size.

Acoustic rhinometry as a volume measurement has been compared with other imaging methods for measurement of nasal volume, such as CT and magnetic resonance imaging scanning. [74] [75] [76] [77] [78] [79] As discussed, in the decongested nose, these provide very comparable measurements, particularly within the anterior part of the nasal cavity. 77, 78 Acoustic rhinometry obviously has considerable advantage over these other methods of measurement in being considerably less expensive, easy to conduct, rapid to perform, and without radiation risk. Studies have also compared changes in acoustic rhinometry measures after intranasal challenge with measures of nasal airflow, such as rhinomanometry and nasal peak flow. 82, 97, 98, [104] [105] [106] [107] [108] Although studies have found minor variations, in general the information gained by the different techniques is very comparable, with nasal congestion leading to a decrease in nasal volume and a-min in association with a reduction in nasal inspiratory peak flow and an increase in NAR (Fig 4) . Acoustic rhinometry is noted to be user-friendly. 97, 98 Similarly, improvements can be seen with all methods of measurement with nasal decongestants that increase nasal volume and improve nasal airflow. 82, 109 One study found acoustic rhinometry to be more sensitive then rhinomanometry. 110 Theoretically, acoustic rhinomanometry and rhinomanometry may provide complimentary but slightly different information, because the resistance of a cross-sectional area may differ considerably depending on the shape, despite a constant area. 107, 111 In practice, however, under challenge situations in which large changes are induced, the methods are very comparable, and changes relate to the subjective sensation of induced nasal obstruction. 112 Under clinical circumstances, however, there is a poor correlation between the subjective scoring of nasal congestion and measures both by acoustic rhinometry and rhinomanometry. 102, 103 Changes in nasal cavity size after intranasal allergen challenge do not relate to measures of nitric oxide, and at rest, the concentration of nasal nitric oxide is independent of measures of nasal cavity volume. 113, 114 Both these findings suggest that nitric oxide per se is not a major determinant of nasal cavity dimensions. One study in patients with coronavirus-induced common cold identified a correlation between changes in olfaction and changes in nasal dimensions, as assessed by acoustic rhinometry. 115 It is probable, however, that this relationship is purely a reflection of the viral infection affecting 2 separate variables, because studies with nasal decongestants in the common cold have dissociated these measures. 116, 117 Decongestants improve nasal dimensions but have no effect on olfaction. Similarly, no significant correlation has been found between olfaction and nasal patency after nasal allergen challenge. 118 

The function of the mucociliary system relates to the characteristics and dynamics of the cilia, including the number of ciliated cells, the frequency, effectiveness, and coordination of ciliary beating, and the quantity and physiochemical composition of the secretions that coat the mucosal membrane. The overall function of the mucociliary clearance system within the nose may be measured by recording the transport rate of particles. Measurement of mucociliary clearance thus potentially provides an overall integrated measurement of cilial function and allows assessment of the net effect of disease processes, such as those associated with allergic inflammation. Important information may also be obtained by analyzing the characteristics of the cilia and the secretions. However, these additional measurements will not be further evaluated.

Traceable particles that may be soluble, such as saccharin, insoluble, such as charcoal, or radioisotopes may be placed on the surface of the inferior turbinate for measurements of mucociliary clearance within the nose. An estimate of the mucociliary activity can be obtained by recording the time until the tracer can be tasted (saccharin) or visually observed in the pharynx (charcoal). The transport rate of radioactive particles can be calculated by following them over a certain distance for a certain period. 119 The saccharin test is most frequently used for screening purposes, because it is easy to perform both for the investigated and the investigator. The radioisotopic technique gives a more exact mucociliary transport rate in millimeters per minute.

The clinical and scientific applicability of measurements of the mucociliary system is, unfortunately, considerably limited by great interindividual, intraindividual, interday, and regional variations in mucociliary transport, probably reflecting both biologic and test-related features. 119, 120 The transport rate in one nostril may differ considerably from the corresponding parameter in the other nostril at the same time, probably reflecting the nasal cycle. There may also be regional differences in clearance velocity within the same nostril. Some individuals have a rapid clearance rate, whereas others are slow clearers. Perfectly healthy individuals may not have recordable mucociliary transport. 121 Generally, it is recommended to measure the transport rate bilaterally to avoid misdiagnosis of mucociliary transport defect.

In vitro studies on cilial function have indicated that temperature, humidity, and pH are all factors that can affect performance, 119, [122] [123] [124] [125] [126] although changes in vivo in these parameters are unlikely to be very significant within the nose, because rapidly adapting changes in mucosal blood flow, glandular secretion, and nasal patency maintain homeostasis. Other endogenous confounding factors are age, 127 sex, 128 posture, 129 exercise, 130 and sleep, 131 as well as neurotransmitters and neurohormones. 122 The effect of exogenous factors on mucociliary clearance, such as environmental pollution from tobacco smoke, car exhaust fumes, and the burning of fossil fuel, have also been evaluated. The results from studies of the effect of acute exposure to tobacco smoke on the mucociliary system are inconsistent. Consequently, it appears that there are individual variations in the mucosal tolerance to toxins such as tobacco smoke. 132, 133 The functional consequences of sulfur dioxide, nitrogen dioxide, and ozone on the respiratory epithelium are controversial. Although there are reports about impairment of ciliary activity 134, 135 and mucociliary clearance, 136 other studies indicate an unchanged or enhanced transport of secretions 137 after exposure to these substances.

A diseased mucociliary apparatus is characterized by defects in the ciliary and/or secretory components of the mucociliary system that interfere with the normal mechanical, physiologic, and biologic protective functions of the airway mucosa. 138, 139 Secondary to the allergic inflammation, there are changes in the rheological properties of the respiratory secretions and in the morphology and function of cilia. Whether these alterations favor the overall mucociliary clearance is a matter for further studies. 119, 140 Influence of nasal therapy on mucociliary clearance Consistent with the variability of assessments of mucociliary clearance, there are no clear results in this outcome measure. Nasal steroids have been found to improve measures, 141 to have no effect, 142 and to be no different to antihistamines. 143 Oral and intranasal antihistamines have not been found to influence mucociliary clearance, 144, 145 and no effect has been seen with the leukotriene receptor antagonist zafirlukast, even though this treatment reduced the nasal lavage eosinophil count significantly. 146 Concern has been raised about whether mucociliary function may be adversely influenced by components of medication. Both in vitro and in vivo studies have shown that that a preservative frequently used in topical nasal drugs, benzalkonium chloride, may structurally and functionally affect both the cilia and the mucosa from which they originate. The clinical consequences of this have been a matter of debate, 147,148 although a recent review of the literature concluded that products containing the preservative benzalkonium chloride appear to be safe and well tolerated. 149 

The term nasal responsiveness refers to the functional responses of the nasal mucosa to a variety of stimuli, some of which are of physical and some of chemical nature. On the basis of convention, immunologic responses are excluded. Reactions of the nasal mucosa to such stimuli should be considered part of the protective function of the nose that is meant to benefit the entire respiratory tract. For example, cold air induces significant water loss, especially under conditions of hyperventilation. To preserve homeostasis and avoid mucosal desiccation and damage, water is being constantly replenished by passive transfer through the paracellular spaces of the nasal airway epithelium. When the water loss is excessive, hypertonicity develops and sensory nerves are activated to induce glandular secretions through a reflex mechanism. The large amounts of water in these secretions compensate for the loss. Similarly, the nose will react with sneezing, glandular secretions, and vascular engorgement (congestion) against chemical irritants or against inhaled particles. The nasal obstruction protects the nasal mucosa by limiting the access of the stimulus.

The term hyperresponsiveness refers to exaggerated protective responses. This may arise because of alterations in the normal response as a result of changes in inflammatory cell behavior, sensory neural function, central information processing and gating, efferent messaging, end-organ sensitivity, or end-organ responsiveness. Different stimuli will test different components. Altered responsiveness within the nose is described in both inflammatory (allergic) and noninflammatory (nonallergic) rhinitis.

In the clinical setting, it is believed that hyperresponsiveness manifests itself with nasal symptoms induced by various exposures or by intrinsic processes that would have gone unnoticed in the absence of this condition. For example, more than 50% of patients with allergic rhinitis complain of nasal symptoms induced by smoke, strong odors, and other irritants, with the prevalence of these complaints higher in perennial than seasonal disease. 150 Patients with some forms of nonallergic rhinopathy 151 report similar symptoms. In allergic rhinitis, hyperresponsiveness may also be involved in the phenomenon of priming to allergen, which has been described by several investigators. 152, 153 Priming can be viewed as an augmentation of the acute allergic reaction to allergen by repeated exposures. Although priming probably involves several mechanisms, it may be partly explained by allergen-induced increased responsiveness to the products of an allergic reaction, namely histamine, 154 sulfidopeptide leukotrienes, or prostaglandin D 2 .

A major misconception regarding hyperresponsiveness is that it is a phenomenon that globally affects every aspect of nasal function. It is important to realize, however, that the nasal mucosa comprises several functional elements, including sensory and effector nerves, submucosal glands, respiratory epithelium, goblet cells, subepithelial capillaries, capacitance vessels, and so forth, all of which are regulated by distinct mechanisms and have a certain degree of independence. Nasal symptoms are produced by the activity of 1 or more of these elements. For example, sneezing is produced by activation of nasal sensory nerves or by sensory nerves at a distant part of the body. Rhinorrhea, on the other hand, requires activation of the glandular apparatus, which may occur directly by a chemical stimulus or, most commonly, through cholinergic activation, via a central reflex. In the latter case, several elements of the mucosa are involved, namely sensory nerves, cholinergic effector nerves, and submucosal glands. Nasal symptoms do not always occur in concordance and, depending on the patient or the condition, different nasal symptoms may predominate. Allergic rhinitis characteristically involves sneezing and pruritus, something that is rather rare in patients with nonallergic rhinopathies. 151 Also, clinical observations have suggested that patients with rhinitis can be separated into sneezers, runners, or blockers on the basis of the predominance of the respective symptom. 155 Given this complexity, one has to attempt to define hyperresponsiveness as an attribute of a specific functional element of the nasal mucosa and not as a global condition. The terms sensorineural hyperresponsiveness, glandular hyperresponsiveness, and so forth should therefore be used. The problem arises as to which tests-that is, which stimuli-can reliably offer information on the responsiveness of specific functional elements of the nose. Unfortunately, only a few stimuli with single specificity for a particular functional element have been identified.

Methacholine. One of the most specific stimuli is methacholine. In the nasal mucosa, it induces glandular secretions by activating cholinergic receptors on the basal surface of glandular epithelial cells. 156 Methacholine does not appear to affect the nasal vasculature, although the theoretical potential for vasodilation exists. 157 Clearly, methacholine does not activate sensory nerve endings. 158 The outcome of a methacholine nasal provocation can be the amount of nasal secretions produced by the stimulus or the content of nasal secretions in biochemical markers of mucus or serous gland activation. These can include mucus glycoproteins (which are very difficult to measure), the content of fucose (a characteristic sugar of the mucus glycoproteins), lysozyme, or lactoferrin (serous cell products). 159 Is there evidence of nasal hyperresponsiveness to methacholine-that is, of nasal glandular hyperresponsiveness? Several publications support the notion that such a form of nasal hyperresponsiveness does indeed exist. [160] [161] [162] [163] [164] There is also some evidence that nasal provocation with allergen can increase nasal responsiveness to methacholine. 165 Unfortunately, not all studies reproduce these findings. One study examined the effect of methacholine applied to the septal mucosa through filter paper discs in patients with perennial allergic rhinitis who were distinguishable from healthy controls when other tests for hyperresponsiveness were applied. There was no difference between the groups, 166 and no good explanation for this discrepancy was apparent.

Capsaicin. Another stimulus with high specificity for a particular functional element of the nasal mucosa is capsaicin, the pungent component of hot peppers. Capsaicin stimulates a specific vanilloid receptor 167,168 on sensory nerve endings to induce a central reflex with its efferent arm leading to cholinergic glandular activation. 168, 169 Capsaicin induces a strong burning sensation but only induces sneezing at very low doses. In addition to the generation of neural reflexes, capsaicin can result in local release of neuropeptides by sensory nerve endings. These peptides can also stimulate glands and may induce plasma exudation from adjacent blood vessels. In the human nose, high doses of capsaicin may yield evidence of plasma exudation, but only in patients with active allergic rhinitis. 170 Despite this, it is difficult to define rhinitis by capsaicin provocation because of a considerable variability in response, and intranasal challenge cannot identify a particular type of nasal hyperresponsiveness. On the other hand, the ipsilateral and contralateral nostril secretory response to unilateral capsaicin provocation using the filter paper technique allows for a clear differentiation between healthy subjects and patients with active allergic rhinitis, with the ED 50 100-fold lower in the latter. 171 Histamine. Very little controversy exists about the ability of histamine to differentiate between active allergic rhinitis and the healthy state. 161, 163, [171] [172] [173] [174] [175] In addition, hyperresponsiveness to histamine has been convincingly demonstrated to occur after experimental nasal allergen provocation and to be inhibited by nasal corticosteroids, linking this phenomenon to allergic inflammation. 154, 172, 176, 177 Most impressively, nasal responsiveness to histamine, with symptoms as the outcome, was found to correlate moderately well with clinical indices of perennial allergic rhinitis (PAR), such as daily symptom scores and the score from the rhinitis quality of life questionnaire. 178 Histamine is by far the most commonly used stimulus in studies assessing nasal hyperresponsiveness. Histamine has multiple effects on the nasal mucosa. It induces sensory nerve activation leading to sneezing, pruritus, cholinergically mediated glandular secretions, and possibly even reflex vasodilation, which may be a cholinergic effect. In addition, histamine has a direct effect on the vasculature leading to vasodilation of the capacitance vessels and plasma exudation from the postcapillary venules of the subepithelial plexus. It is not clear whether histamine can directly activate the nasal glandular apparatus. 179 Despite the complicated effects of histamine on the nasal mucosa, the methodology of the provocation permits differentiation of various aspects of nasal hyperresponsiveness. First, histamine-induced sneezing is a quite clean outcome, reflecting sensory neural function, and can be used to assess sensorineural hyperresponsiveness. Second, evaluation of the content of histamine-induced nasal secretions in markers of plasma extravasation can be used as a measure of vascular hyperpermeability, a form of nasal hyperresponsiveness.

One can also measure changes in nasal airflow after unilateral histamine challenge and separate the ipsilateral from the contralateral to the challenge nostrils. This technique may allow an assessment of the direct effects of histamine on the capacitance vessels (by subtracting the changes in the contralateral from the ipsilateral nasal passage). Alternatively, pretreatment of the challenged nostril with a local anesthetic may reveal only the direct, as opposed to the indirect (neural), effects of histamine provocation on nasal airflow.

Bradykinin. Bradykinin is a product of allergic reactions. 180 Its most evident effect on the nasal mucosa is plasma extravasation. In this respect, bradykinin does not appear to differentiate patients with active allergic rhinitis from healthy controls. 181 However, in a study by Riccio and Proud, 181 healthy subjects or patients with SAR, when tested out of the pollen season, generate minimal secretory responses to bradykinin and no sneezing. In contrast, both ipsilateral and contralateral secretions to unilateral, localized bradykinin provocation, as well as sneezes, are induced in patients with PAR and in those with symptomatic seasonal disease. This indicates that, in the presence of active allergic disease, a sensorineural response to bradykinin is induced. However, there are some discrepancies between this study and a study reported by Baraniuk et al. 182 Thus, more work with bradykinin in the nose will be required to obtain a more concrete impression of its potential usefulness as a tool to examine specific forms of nasal hyperresponsiveness. Studies on the effects of antiinflammatory agents on hyperresponsiveness to bradykinin have not been performed. Neither do we know whether experimental allergen provocation can change as well as augment the qualitative characteristics of the responsiveness to bradykinin. However, it is worth mentioning that, in the lower airways of patients with asthma, responsiveness to bradykinin increases dramatically 24 to 48 hours after allergen inhalation challenge, much more so than the responsiveness to methacholine. 183 Inversely, bronchial responsiveness to bradykinin can be dramatically reduced with inhaled glucocorticosteroids. 184 Other pharmacologic and biochemical stimuli. Other products of the nasal allergic reaction could turn out to be useful in assessing nasal hyperresponsiveness. These include the sulfidopeptide leukotrienes, prostaglandin D 2 , platelet-activating factor, and so forth. There is very limited experience, however, with nasal provocations involving these agents. Also, other endogenous substances that are capable of inducing nasal symptoms but have not been clearly associated with allergic reactions should be considered, including serotonin, endothelin, and neuropeptides such as substance P or neurokinin A. Physical and environmental nonantigenic stimuli.

Nasal symptoms can be produced by physical stimuli. The most common and well-characterized physical stimulus is cold, dry air and, associated with that, hyperosmolar solutions. Many individuals complain of nasal symptoms on exposure to cold, windy conditions, particularly during winter skiing, a phenomenon termed skier's nose. 185 Cold, dry air nasal challenges have been performed in the laboratory, and nasal responsiveness to this stimulus has been well characterized. [186] [187] [188] [189] [190] [191] Although many individuals without allergy have a specific sensitivity to cold, dry air, which is not associated with any other kind of nasal dysfunction, patients with active allergic rhinitis respond more vigorously to this stimulus compared with healthy subjects. 189 Furthermore, patients with allergic rhinitis and asthma have stronger nasal reactivity to nasal challenge with cold, dry air compared with patients with allergic rhinitis alone. 192 Finally, nasal allergen provocation augments the nasal reaction to cold, dry air. 193 Interestingly, cold, dry air has been shown to differentiate patients with nonallergic, noninfectious perennial rhinitis from healthy subjects with higher sensitivity than histamine. 194 Although the exact mechanism through which cold, dry air induces a nasal reaction is not known, available data support the concept that this is primarily a sensorineural reaction initiated by increased tonicity (osmolarity) of the nasal surface, which is in turn induced by excessive water loss. 195 The main outcome of the reaction, however, is glandular activation. 196 In accordance with the theories regarding the mechanism of nasal reaction to cold, dry air, various forms of nasal challenges with hyperosmolar solutions have been developed. 55, 197, 198 The outcomes from these provocations support the concept that hyperosmolarity and cold, dry air share common pathways. 195 As with cold, dry air, hyperosmolar challenges reveal stronger nasal responsiveness in patients with PAR compared with healthy controls. 55 Studies in healthy volunteers have shown that intranasal hypertonic saline enhances the exudative and secretary effects of histamine and methacholine respectively. 199 Shusterman and Balmes 200 and Shusterman et al 201 have developed a methodology to stimulate the nose with chlorine gas and with carbon dioxide. These stimuli are quite relevant to daily environmental exposures, and nasal responsiveness assessed through such methodologies has direct clinical implications. These studies have so far demonstrated that patients with SAR, even when tested outside the pollen season, develop nasal airflow limitation on exposure to chlorine gas with lower threshold, compared with healthy controls.

The methodologies through which nasal provocations are performed to assess hyperresponsiveness can be largely categorized into 3 groups: whole-nose challenges, localized challenges, and environmental exposures. In the last case, provocations are performed either inside environmental chambers or with equipment designed to deliver gases into the nasal passages via face masks. 186, 201 Whole-nose challenges are usually performed with the use of a metered pump spray that delivers a known amount of stimulus into the mucosa. A large airway surface can be reached in this fashion. Objective outcomes from such provocations can be obtained with evaluations of airflow, blowing of secretions, or nasal lavage. Nasal lavage offers the advantage of collecting large volumes of secretions and performing extensive evaluations. 202 The localized provocations are performed by using filter paper discs or strips impregnated with the chemical stimulant that can be introduced into one nostril and left in contact with the septal or the inferior turbinate mucosa for a specific period. 158 Secretory outcomes can be assessed by introducing preweighed dry discs or strips, of the same size as those used for stimulation, onto the same mucosal areas. Secretions induced by the stimulus are absorbed by the filter paper, and the change in the weight of these collection discs is a reliable marker of the secretory response. Collected secretions can be eluted from the filter paper, and limited biochemical evaluations can be performed. The major advantage of the localized challenge technique is that it allows secretions to be collected from both the ipsilateral and the contralateral side to the unilateral provocation. Thus, neurally mediated outcomes involving central reflexes can be assessed.

An alternative approach to whole-nose and to localized challenges is the nasal pool device and related instruments. 203 According to this technique, a lavage is performed only in one nostril by instilling the fluid through a pump-like device (the nasal pool) and retracting it after a set period.

The major problem in efficacy trials of therapeutic modalities in allergic rhinitis is the lack of objective measures. Obviously, the importance of reported nasal symptoms should not be underestimated, because the definition and diagnosis of rhinitis is also based on symptomatology, and it is the symptoms of this ailment that drive its morbidity and its economic effect on society. Unfortunately, questions are consistently raised regarding the reliability of symptom scales or other subjective measures such as quality of life, which are associated with impressive placebo effects. From this perspective, objective measures should be sought as complementary outcomes in clinical trials to strengthen the validity of therapeutic efficacy conclusions.

Some trials have begun to use nasal peak flow measurements to provide objective measure support. The problem with this approach is that nasal airflow limitation is only 1 of several nasal symptoms, and not all patients with allergic rhinitis report congestion as a major complaint. Furthermore, nasal symptomatology is frequently episodic, and daily measurements of airflow may not track the natural presentation of the disease. By assessing nasal hyperresponsiveness, one can obtain a better picture of the propensity of a patient to develop symptoms in response to frequently encountered environmental stimuli. Most importantly, if measures of nasal hyperresponsiveness are performed by using methodologies that can dissect the various functions of the nose, as discussed, various clinical phenotypes and their response to treatment could be correlated to a particular aspect of hyperresponsiveness in a patient-tailored fashion. Unfortunately, the lack of standardization and validation of methodologies to assess nasal hyperresponsiveness means that only scattered data are available on the effects of therapeutic agents, and, even worse, none from large-scale clinical trials.

As discussed, nasal corticosteroids have been found to affect various aspects of nasal responsiveness in a limited number of short-term laboratory trials. Pretreatment with nasal corticosteroids for 1 week has been shown to reduce allergen-induced increase in some aspects of nasal responsiveness to histamine. 176, 177 It appears that this effect can be obtained even with a single dose of steroids administered 2 hours before the allergen challenge. 204 Klementsson et al, 165 using therapeutic agents other than corticosteroids, showed that pretreatment with cetirizine and terfenadine, 2 of the second-generation nonsedating antihistamines, inhibited the small increase in nasal secretory responsiveness to methacholine that was induced 24 hours after nasal allergen challenge.

The few clinical trials in which aspects of nasal responsiveness were assessed can be summarized as follows. In 1981, Malm et al 205 showed moderate reduction by a nasal corticosteroid of the secretory responsiveness to methacholine in patients with nonallergic rhinitis. In 1982, Toft et al 206 showed that sneezing induced by the spraying of beclomethasone in the nose was reduced after chronic treatment in patients with nasal polyposis. Finally, in 1991, it was reported that budesonide given nasally during the birch pollen season was able to reduce the seasonal increase in nasal secretory responsiveness to methacholine. 207 Veld et al 208 performed the only clinical trial with antihistamines that attempted to assess nasal responsiveness, in which treatment with topical levocabastine failed to reduce methacholine secretory responsiveness in patients with PAR.

Objective measures exist for the measurement of nasal patency. Nasal peak flow is an inexpensive, noninvasive, portable, and relatively simple measure that reflects changes in nasal luminal patency. Nasal peak flow is the only validated method suitable for home use, and studies have demonstrated that, when used correctly, the method is reproducible, correlates with both subjective and other objective measures, and may therefore provide a viable method for the outpatient monitoring of nasal patency. NPIF has better reproducibility than NPEF and is the best validated and studied nasal peak flow measurement. Such use would be most appropriate in persistent rather than intermittent disease, because measurement at set times of the day may not reflect episodic events. Within the laboratory, rhinomanometry is the standard technique used for the measurement of nasal resistance, and measurements are relatively easy and are reproducible. This approach is thus commonly used in nasal challenge studies. Such measures are more discerning than those of peak flow. The equipment is not portable and thus not available for home monitoring. The instability of nasal resistance means that only relatively large changes in resistance can be studied in clinical trials, when occasional clinic visit measurements are made, but despite this, such measurements have been able to demonstrate the efficacy of medications such as nasal steroids in allergic rhinitis. A nonphysiologic measure of nasal patency is acoustic rhinometry. Using sound waves and their echo reflection, this technique measures intranasal volume and a-min within the nose. This method of measurement correlates well with rhinomanometry and NPIF and is easy to undertake. Acoustic rhinometry has advantages in that it needs little patient cooperation in the measurements and is a repeatable method of measurement. Measures of nasal patency, although they provide objective outcome measures, reflect only 1 aspect of rhinitis and may thus not encompass all aspects of the disease. It is recognized that there may be altered mucociliary clearance and abnormal nasal airway reactivity in rhinitis. Measures of mucociliary clearance, although simple and easily applicable clinically, are poorly repeatable. To provide a more integrated measure of abnormal nasal airway physiology, nasal challenge testing to measure nasal reactivity has been used.

Nasal responsiveness testing theoretically reflects the propensity of a patient to develop nasal symptoms in response to exogenous or endogenous stimuli, and if this response is abnormally exaggerated, this is termed nasal hyperresponsiveness. From this perspective, evaluation of this phenomenon can potentially complement currently assessed parameters, such as symptoms, quality of life outcomes, and use of rescue medications. However, hyperresponsiveness is a very complex phenomenon that involves a range of potential abnormalities in the various functional elements of the nasal mucosa. Standardized methodologies assessing these abnormalities are not sufficiently developed, and the relationship between such abnormalities and disease presentation has not been vigorously examined. In the effort to develop objective tools to test efficacy of nasal therapeutic modalities, the area of nasal hyperresponsiveness needs to be developed.

Rhinomanometry and nasal peak expiratory and inspiratory flow rate

Evaluation of nasal patency: comparison of patient and clinician assessments with rhinomanometry

The naso-oral index: a more valid measure than peak flow rate?

Use of a portable spirometer for studies on the nasal cycle

Assessing the reproducibility of nasal spirometry parameters in the measurement of nasal patency

Comparison between different techniques for measuring nasal patency in a group of unselected patients

Measurement of nasal patency

Inspiratory flow in the nose: a model coupling flow and vasoerectile tissue distensibility

Peak nasal inspiratory flow and Wright peak flow: a comparison of their reproducibility

Assessment of nasal obstruction. A comparison between rhinomanometry and nasal inspiratory peak flow

Objective assessment of nasal obstruction

Use of nasal peak flow to assess nasal patency

Forced inspiratory nasal flow-volume curves: a simple test of nasal airflow

Assessment of nasal airway patency: a comparison of four methods

Nasal physiological changes during pregnancy

The effect of the steroid sex hormones on the nasal airway during the normal menstrual cycle

Effects of topical corticosteroid and combined mediator blockade on domiciliary and laboratory measurements of nasal function in seasonal allergic rhinitis

Peak nasal inspiratory flow-the plateau effect

The peak flow nasal patency index

The objective assessment of nasal patency

Correlation of subjective sensation of nasal patency with nasal inspiratory peak flow rate

Short-term repeatability and correlates of laboratory measures of nasal function in patients with seasonal allergic rhinitis

Minimal crosssectional areas, nasal peak flow and patients' satisfaction in septoplasty and inferior turbinectomy

The relationship of peak inspiratory airflow to subjective airflow in the nose

Peak nasal inspiratory flow measurement: an investigation in children

Nasal peak flow rate records in work related nasal blockage

Serial nasal peak expiratory flow measurements in woodwork teachers

Dose-efficacy comparison of mometasone and budesonide aqueous nasal spray in seasonal allergic rhinitis

Triamcinolone acetonide and fluticasone propionate aqueous nasal sprays significantly improve nasal airflow in patients with seasonal allergic rhinitis

Intranasal fluticasone propionate versus loratadine in the treatment of adolescent patients with seasonal allergic rhinitis

Fluticasone propionate nasal spray (FP) as adjunctive therapy to antibiotics in patients with recurrent sinusitis

Intranasal fluticasone propionate for chronic eosinophilic rhinitis in patients with aspirin-induced asthma

Fluticasone propionate aqueous nasal spray in the treatment of nasal polyposis

Comparison of the combinations of fexofenadine-pseudoephedrine and loratadine-montelukast in the treatment of seasonal allergic rhinitis

Efficacy and tolerability of budesonide aqueous nasal spray treatment in patients with nasal polyps

Double blind, placebo controlled trial of betamethasone nasal drops for nasal polyposis

Surgical versus medical treatment of nasal polyps

The effect of budesonide (Rhinocort) in the treatment of small and medium-sized nasal polyps

Efficacy of topical corticosteroid powder for nasal polyps: a double-blind, placebo-controlled study of budesonide

Assessment of the nasal passages

Rhinomanometry and diagnosis of nasal obstruction

Rhinomanometry and nasal challenge

Physiology of the nose

Relationships between vital capacity, height and nasal airway resistance in asymptomatic volunteers

The nasal resistance of newborn infants

Nasal resistance during infancy

Measurement and regulation of nasal airflow resistance in man

Age and gender effects on nasal respiratory function in normal subjects

III: procedures and criteria for distinction between skeletal stenosis and mucosal swelling

Changes in the amplitude of the nasal cycle associated with symptoms of acute upper respiratory tract infection

Spontaneous changes of unilateral nasal airflow in man: a re-examination of the ''nasal cycle

The normal range of unilateral nasal airflow in healthy human volunteers

Changes in unilateral nasal airflow in patients with seasonal allergic rhinitis measured in and out of season

Effect of pseudoephedrine on nasal airflow in patients with nasal congestion associated with common cold

Effect of submucosal diathermy to the inferior turbinates on unilateral and total nasal airflow in patients with rhinitis

The human nasal cycle

Postural variations in nasal resistance and symptomatology in allergic rhinitis

Nasal decongestant effect of oxymetazoline in the common cold: an objective dose-response study in 106 patients

The new topical steroid ciclesonide is effective in the treatment of allergic rhinitis

Posture and congestion of nasal mucosa allergic rhinitis

Exercise and nasal patency

Changes in human nasal resistance associated with exercise, hyperventilation and rebreathing

Effects of cold air and exercise on nasal patency

The effect of alcohol ingestion upon nasal airway resistance

Physiological versus pharmacological decongestion of the nose in healthy human subjects

Rhinitis mechanisms and management

Relationship between measured nasal airway resistance and the sensation of nasal airflow

Nasal airflow: resistance and sensation

Nasal resistance, sensation of obstruction, and rhinoscopic findings compared

The relationship between subjective and objective measures of nasal function

Objective measurement of nasal airway dimensions using acoustic rhinometry: methodological and clinical aspects

Airway geometry by analysis of acoustic pulse response measurements

Acoustic determinants of respiratory system properties

Acoustic rhinometry: evaluation of nasal cavity geometry by acoustic reflection

Nasal airway geometry: comparison between acoustic reflections and magnetic resonance scanning

Nasal cavity geometry measured by acoustic rhinometry and computed tomography

Acoustic rhinometry: influence of paranasal sinuses

A comparison of the nasal cross-sectional areas and volumes obtained with acoustic rhinometry and magnetic resonance imaging

Semiautomatic segmentation of computed tomographic images in volumetric estimation of nasal airway

Evaluation of the importance of head and probe stabilisation in acoustic rhinometry

Acoustic rhinometry: the bat principle of the nose

Errors arising in cross-sectional area estimation by acoustic rhinometry produced by breathing during measurement

Reproducibility of acoustic rhinometry and rhinomanometry in normal subjects

Validation of acoustic rhinometry by using the Cavalieri principle to estimate nasal cavity volume in cadavers

The magnitude of random errors in acoustic rhinometry and re-interpretation of the acoustic profile

On the nasal cycle

The role of acoustic rhinometry in studying the nasal cycle

The nasal cycle after deprivation of airflow: a study of laryngectomy patients using acoustic rhinometry

Spontaneous variations in congestion of the nasal mucosa

Racial differences in nasal fossa dimensions determined by acoustic rhinometry

Normative standards for nasal cross-sectional areas by race as measured by acoustic rhinometry

Acoustic rhinometry of the Indian and Anglo-Saxon nose

Reference values for acoustic rhinometry in subjects without nasal symptoms

External facial dimensions and minimum nasal cross-sectional area

Some fundamental studies on clinical measurement conditions in acoustic rhinometry

Acoustic rhinometry compared with posterior rhinomanometry in the measurement of histamine-and bradykinininduced changes in nasal airway patency

Nasal histamine challenge in nonallergic and allergic subjects evaluated by acoustic rhinometry

Acoustic rhinometry in nasal allergen challenge study: which dimensional measures are meaningful?

Evaluation of the nasal cavity by acoustic rhinometry in normal and allergic subjects

Decongesting effect of tramazoline on nasal airway patency and nasal symptoms as evaluated by acoustic rhinometry: an objective study in 30 allergic and six non-allergic subjects

Evaluation of acoustic rhinometry and posterior rhinomanometry as tools for inhalation challenge studies

Acoustic rhinometry, rhinomanometry, and the sensation of nasal patency: a correlative study

A comparison of the sensitivity of manometric rhinometry, acoustic rhinometry, rhinomanometry and nasal peak flow to detect the decongestant effect of xylometazoline

The role of acoustic rhinometry in nasal provocation testing

Evaluation of acoustic rhinometry in a nasal provocation test with allergen

The nasal airways response in normal subjects to oxymetazoline spray: randomized double-blind placebo-controlled trial

Evaluation of the doseresponse relationship for intra-nasal oxymetazoline hydrochloride in normal adults

Evaluation of nasal obstruction with acoustic rhinometry: a simulated study with a nasal model

Effect of terfenadine and budesonide on nasal symptoms, olfaction, and nasal airway patency following allergen challenge

Evaluating the sensation of nasal obstruction with acoustic rhinometry and rhinomanometry

Acoustic rhinometry: comparison of pre-and post-septoplasty

Nasal nitric oxide is independent of nasal cavity volume

Nasal nitric oxide does not control basal nasal patency or acute congestion following allergen challenge in allergic rhinitis

Olfactory threshold and nasal mucosal changes in experimentally induced common cold

Olfactory function in acute rhinitis

Effects of the nasal decongestant oxymetazoline on human olfactory and intranasal trigeminal function in acute rhinitis

Acoustic rhinometry in the study of the acute nasal allergic response

Mucociliary transport and its assessment: a review

Role of mucus and cilia in nasal mucociliary clearance in healthy subjects

Asymmetry in the nasal mucociliary transport rate

A perfusion system for in vitro measurement of human cilia beat frequency

Air humidity and mucociliary activity

Effects of tracheostomy on human tracheobronchial mucosa: a scanning electron microscopic study

Effect of pH, viscosity and ionic-strength changes on ciliary beating frequency of human bronchial explants

The influence of the pH and osmotic pressure upon tracheal ciliary beat frequency as determined with a new photo-electric registration device

Measurement of frequency of ciliary beats of human respiratory epithelium

No effect of gender on lung mucociliary clearance in young healthy adults

Effect of respiratory phases and gravity on mucociliary transport in the normal lungs

Effects of exercise and eucapnic hyperventilation on bronchial clearance in man

Aerosols and the lung: clinical and experimental aspects

Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis

Lung mucociliary clearance

Respiratory epithelium exposed to sulfur dioxide-functional and ultrastructural alterations

Effects of airborne pollutants on mucociliary clearance

Effects of SO2 exposure on canine pulmonary epithelial functions

Mucociliary clearance of inhaled particles measured at 2 h after ozone exposure in humans

Aerosols in medicine: principles, diagnosis and therapy

Bronchial mucus in health and disease

Ciliary responsiveness in allergic and nonallergic airways

Evaluation of the medical and surgical treatment of chronic rhinosinusitis: a prospective, randomised, controlled trial

Influence of topical beclomethasone dipropionate suspension on human nasal mucociliary activity

Local safety of intranasal triamcinolone acetonide: clinical and histological aspects of nasal mucosa in the long-term treatment of perennial allergic rhinitis

Influence of levocabastine suspension on ciliary beat frequency and mucociliary clearance

Pre and post treatment mucociliary function in allergic rhinitis in three different treatment modalities

Effects of zafirlukast on bronchial asthma and allergic rhinitis

Long-term use of preservatives on rat nasal respiratory mucosa: effects of benzalkonium chloride and potassium sorbate

The effects of topical nasal steroids on rat respiratory mucosa in vivo, with special reference to benzalkonium chloride

Safety review of benzalkonium chloride used as a preservative in intranasal solutions: an overview of conflicting data and opinions

Non-allergenic inhalant triggers in seasonal and perennial allergic rhinitis

Non-allergic rhinitis

Quantitative intranasal pollen challenges, 3: the priming effect in allergic rhinitis

Observations on the pathogenesis of nasal priming

Antigen-provoked increase in histamine reactivity: observations on mechanisms

London: Blackwell Science Ltd

Pathophysiology of rhinitis, 1: assessment of the sources of protein in methacholineinduced nasal secretions

The effects of parasympathetic nerve stimulation on the microcirculation and secretion in the nasal mucosa of the cat

Comparison of the secretory response of the nasal mucosa to methacholine and histamine

Pathophysiology of rhinitis: lactoferrin and lysozyme in nasal secretions

The role of chemical mediators and mucosal hyperreactivity in nasal hypersecretion in nasal allergy

Comparison of nasal responsiveness to histamine, methacholine and phentolamine in allergic rhinitis patients and controls

Cholinergic nasal hyperreactivity in atopic subjects

Nasal response of rhinitic and non-rhinitic subjects to histamine and methacholine: a comparative study

Nasal cholinergic hyperresponsiveness in atopic subjects studied out of season

Allergen-induced increase in nonspecific nasal reactivity is blocked by antihistamines without a clearcut relationship to eosinophil influx

Hyperosmolar saline induces reflex nasal secretions, evincing neural hyperresponsiveness in allergic rhinitis

The capsaicin receptor: a heat-activated ion channel in the pain pathway

Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons

The human nasal response to capsaicin

Dose-dependent effects of capsaicin nasal challenge: in vivo evidence of human airway neurogenic inflammation

Neural hyperresponsiveness and nerve growth factor in allergic rhinitis

Nasal histamine sensitivity in allergic rhinitis

Histamine threshold and nasal hyperreactivity in non specific allergic rhinopathy

Nasal histamine challenges in symptomatic allergic rhinitis

Evaluation of nonspecific nasal reactivity to histamine during and after natural ragweed pollen exposure

Intranasal beclomethasone inhibits antigen-induced nasal hyperresponsiveness to histamine

Allergen-induced specific and non-specific nasal reactions: reciprocal relationship and inhibition by topical glucocorticosteroids

The relationships between nasal hyperreactivity, quality of life, and nasal symptoms in patients with perennial allergic rhinitis

Characterization and autoradiographic localization of histamine H1 receptors in human nasal turbinates

Kinins are generated in vivo following nasal airway challenge of allergic individuals with allergen

Evidence that enhanced nasal reactivity to bradykinin in patients with symptomatic allergy is mediated by neural reflexes

Perennial rhinitis subjects have altered vascular, glandular, and neural responses to bradykinin nasal provocation

Allergen-induced hyperresponsiveness to bradykinin is more pronounced than that to methacholine

Airways hyper-responsiveness to bradykinin and methacholine: effects of inhaled fluticasone

The skier's nose: a model of cold-induced rhinorrhea

Nasal challenge with cold, dry air results in release of inflammatory mediators: possible mast cell involvement

Local generation of sulfidopeptide leukotrienes upon nasal provocation with cold, dry air

The osmolality of nasal secretions increases when inflammatory mediators are released in response to inhalation of cold, dry air

The relationship between atopy and the response to cold dry air CDA and histamine H challenge in perennial rhinitis PR

Hyperosmolar and histamine H nasal challenge of individuals with and without cold dry air CDA sensitivity

Reflex activation of nasal secretion by unilateral inhalation of cold dry air

Nasal cold, dry air (CDA) challenge results in stronger nasal and pulmonary responses in asthmatics compared to patients with rhinitis

Antigen AG augments the upper airway reaction to cold dry air

Intranasal cold dry air is superior to histamine challenge in determining the presence and degree of nasal hyperreactivity in nonallergic noninfectious perennial rhinitis

Dry air and hyperosmolar challenge in asthma and rhinitis

Local application of atropine attenuates the upper airway reaction to cold, dry air

In vivo release of inflammatory mediators by hyperosmolar solutions

Nasal response to allergen and hyperosmolar challenge

Hypertonic saline increases secretory and exudative responsiveness of human nasal airway in vivo

Measurement of nasal irritant sensitivity to pulsed carbon dioxide: a pilot study

Subjects with seasonal allergic rhinitis and nonrhinitic subjects react differentially to nasal provocation with chlorine gas

Mediator release during nasal provocation: a model to investigate the pathophysiology of rhinitis

The ''nasal pool'' device applies controlled concentrations of solutes on human nasal airway mucosa and samples its surface exudations/secretions

Allergen-induced changes in nasal secretory responsiveness and eosinophil granulocytes

Reduction of methacholine induced nasal secretion by treatment with a new topical steroid in perennial nonallergic rhinitis

Double-blind comparison between beclomethasone dipropionate as aerosol and as powder in patients with nasal polyposis

Eosinophils, secretory responsiveness and glucocorticoidinduced effects on the nasal mucosa during a weak pollen season

Effect of topical levocabastine on nasal response to allergen challenge and nasal hyperreactivity in perennial rhinitis