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

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

Optical rhinometry: application on children and adolescents for nasal provocation tests.

Optical rhinometry is a new method that allows the direct, real time measurement of changes in swelling of the nasal mucosa by external measurement. The measurement is carried out with monochromatic near-infrared light. The change of intensity of the swelling is displayed and recorded. Different preceding studies on adults already showed the reliability and absence of side effects of the measuring method. With the help of a prototype of an optical rhinometer specially developed for children, 65 measurements were performed on a total of 13 children and adolescents having one-sided nasal provocation tests with histamine and allergens, negative provocation tests with control solution and decongestion with xylometazoline. The nasal provocation tests were implemented by optical rhinometry while simultaneously using the established method of active anterior rhinomanometry. We found significant differences between positive and negative provocation tests in both methods (p < 0.01). Decongestion was different from all other groups in both methods (p < 0.01). No clear connection could be made between the percentage increase of rhinometric extinction and the percentage increase of obstruction measured by anterior rhinomanometry. The evaluation of the nasal provocation test via continuous direct measurement of swelling of the nasal mucosa membrane seems feasible in children. Data which so far could not be measured, such as the beginning of swelling and the time of the maximum state of swelling, might increase the diagnostic validity of provocation tests.

Optical measurement of nasal swellings.

We introduce a new optical method to noninvasively and continuously measure the swelling process of the nasal mucosa whereby we use light of different wavelengths in the red and near-infrared range which is transilluminated through the nasal tissue and whose extinction is recorded as a function of time. From the temporal and spectral extinction data, we are able to extract characteristic parameters that describe the swelling process quantitatively by means of a regression-type parameter estimation algorithm. The method has been applied to the nasal allergen provocation test and verified on a limited number of volunteers.

[Optical Rhinometry. Continuous, direct measurement of swelling of the nasal mucosa with allergen provocation. Real-time monitoring of the nasal provocation test using optical rhinometry]. / Die optische Rhinometrie. Kontinuierliche, direkte Messung der Schwellung der Nasenschleimhaut bei Allergenprovokation.

BACKGROUND: Various methods exist for measuring swelling of the nasal mucosa. This is necessary in order to make the nasal provocation test objective. With the new method of optical rhinometry, it is possible to measure swelling of the mucosa directly from outside of the nose in real-time. The measurement is carried out with monochromatic near-infrared light of different wavelengths, the intensity change of which are recorded and displayed during the swelling. MATERIALS AND METHODS: With the help of a specially developed prototype of an optical rhinometer, we carried out measurements on 15 subjects having positive nasal provocation tests with histamine and allergens, negative provocation tests with allergens in non-allergics, negative provocation tests with control solution, and decongestion with xylometazoline. RESULTS: We found significant differences between positive and negative provocation tests ( P<0.01). Decongestion was different from all other groups ( P<0.01). Nasal congestion subjectively reported by the subject always correlated with the optical rhinometry findings. CONCLUSION: The objective assessment of nasal swelling using optical rhinometry seems reliable. The course of the endonasal swelling can thereby be monitored in real-time. The measurement is largely independent of the cooperation of the patient. The swelling is measured directly and not indirectly via air flow resistance.

Validation of an environmental exposure unit for controlled human inhalation studies with grass pollen in patients with seasonal allergic rhinitis.

BACKGROUND: There is an increasing need for allergen inhalation systems to perform basic clinical research and test anti-allergic drugs under well-controlled conditions. This requires stability of environmental conditions like temperature and humidity, as well as allergen concentration and reproducible induction of allergic symptoms. OBJECTIVE: The aim of this study was to validate an environmental exposure unit for controlled human pollen inhalation studies in participants with seasonal allergic rhinitis. METHODS: Temperature, relative humidity, and air flow rate were kept constant with an air conditioning system. Pollen atmosphere was generated using a specially designed feeding system and monitored online by laser counter and offline using rotating rod samplers. Efficacy (total nasal symptom score, nasal air flow rate, nasal secretion) and safety (lung function) parameters were evaluated at different pollen concentrations and repeated allergen challenges. RESULTS: Temperature, humidity, and air flow rate in the environmental exposure unit remained constant within a range of <2%. The spatial distribution and the temporal stability of the pollen concentration varied only slightly over 4 h (+/-10% and <4%, respectively). Dose-dependent induction of allergic rhinitis symptoms, reduction in nasal air flow rate, and increase in nasal secretion were observed over time. These effects were reproducible from day to day. Lung function remained clinically normal at all concentrations and from day to day. CONCLUSIONS: Thus, pollen exposure in the environmental exposure unit is an effective, reproducible, safe, and suitable method for single-centre clinical studies on the efficacy of anti-allergic treatment or basic clinical research.

A hooded exposure chamber method for semiquantitative latex aeroallergen challenge.

BACKGROUND: Allergen challenges are useful in adjudicating discordant clinical histories and skin test responses, serologic test responses, or both, as well as in determining the degree of allergic reactivity. Latex allergen challenges have been developed but have limitations that reduce their usefulness. OBJECTIVE: We sought to develop a novel hooded exposure chamber (HEC) system to allow safe, sensitive, and semiquantitative evaluation of respiratory latex allergy. METHODS: The HEC system uses an impinger to produce a particle cloud of cornstarch isolated from powdered latex gloves. The particles are air driven into a face shield and hood to simultaneously challenge the subject's conjunctiva, nose, and lungs during 3 minutes of normal tidal breathing. A cloud of respirable latex allergen-associated cornstarch particles (LACs) is consistently produced in the HEC during challenges. Twenty-three subjects with latex allergy (history and positive skin test response, positive serologic test response, or both) and 3 atopic control subjects not allergic to latex (history and negative skin test response, negative serologic test response, or both) were sequentially exposed to air, control cornstarch, and then progressive 2-fold increments of LACs in a single-masked fashion. A positive challenge result was defined as (1) a peak expiratory flow rate decline of 15% or greater from baseline; (2) a peak expiratory flow rate decline of 10% or greater and an increase of either the rhinoconjunctivitis or chest symptom score scale of 3 or more points from baseline; or (3) an increase of either the rhinoconjunctivitis or chest symptom score scale of 6 or more points from baseline. RESULTS: Twenty-two of the 23 subjects with latex allergy reached threshold criteria for a positive challenge at LAC titers of 1:8 or greater, giving a sensitivity of 0.96. Challenge endpoints were moderately corrected with skin test sensitivity (r (s) = -0.55, P =.01) but not with RAST reactivity. None of the 3 control subjects responded to LACs at the 1:8 dilution. No patient or control subject responded to the air or control cornstarch control exposures. All responses were confined to mild symptoms of allergic rhinoconjunctivitis, asthma, or both that either resolved spontaneously or were easily reversed with inhaled albuterol. No subject experienced a systemic or late-phase reaction. CONCLUSION: The HEC procedure is a safe, sensitive, and specific method for masked semiquantitative latex aeroallergen challenges that mimic occupational latex exposure to powdered latex gloves.

Studies of spontaneous fluctuations in congestion and nasal mucosal microcirculation and the effects of oxymetazoline using rhinostereometry and micromanipulator guided laser Doppler flowmetry.

The mucosa of the inferior turbinate was studied using rhinostereometry and micromanipulator-guided laser Doppler flowmetry in 10 healthy volunteers. First, spontaneous fluctuations were studied measuring congestion and multiple microcirculatory parameters simultaneously every 2 minutes. The subjects were then challenged with oxymetazoline using the same measuring technique studying the effects of the challenge during 12 minutes. There were spontaneous variations in congestion of up to 2.1 mm and variations in perfusion from 38% to 175% of average. There was no correlation between congestion in itself, or change in congestion, to perfusion or any other microcirculatory parameter. After challenge with oxymetazoline there was a rapid decrease in perfusion at 3 minutes after which there were no significant changes. The congestion decreased gradually throughout the procedure. Because congestion reflects the filling of the venous sinusoids and the flowmetry the state of the superficial vessels, we conclude that there are spontaneous short-term fluctuations in the sympathetic tone with independent actions on the different vessels. After challenge with a sympathomimetic drug, there was a decrease in both swelling and flow, but not synchronized. The combination of rhinostereometry and micromanipulator-guided laser Doppler flowmetry is a useful tool to study the dynamics of intranasal challenge reactions.

Nasal passage patency in patients with allergic rhinitis measured by acoustic rhinometry: nasal responses after allergen and histamine provocation.

We investigated nasal passage patency after allergen and histamine provocation in patients with allergic rhinitis by acoustic rhinometry. In total, 75 outpatients with allergic rhinitis were studied. The threshold of nasal hypersensitivity to histamine was measured by the 10 microliters instillation of serial 10-fold dilution in the ipsilateral nasal cavity. Nasal provocation testing to specific antigen was applied to the anterior part of inferior turbinate in bilateral sides in sitting position. Measurement of nasal patency by acoustic rhinometry was repeated three times in each nasal cavity. The minimal cross-sectional area and total volume of nasal cavity were measured in an individual subject. The minimal cross-sectional area and total volume in the histamine challenged-side significantly decreased on the 10(-2), 10(-1), 10(-0) of end point, and up to 30 min after challenge with the threshold dose, but not in the unchallenged side. This means acoustic reflection technique is sensitive at least 100-fold in comparison with classical method like findings by anterior rhinoscopy and symptom scores. Nasal passage patency after bilateral allergen provocation showed predominant in the unilateral side, suggesting the cross over-reflex effects. It was concluded that acoustic rhinometry is one of the highly quantitative and sensitive method which can observe the change of nasal congestion.

[Acoustic rhinometry: measuring the early and late phase of allergic immediate reaction in allergic rhinitis]. / Akustische Rhinometrie: Messung der Früh- und Spätphase der allergischen Sofortreaktion bei der allergischen Rhinitis.

Acoustic rhinometry is a method to analyse nasal airway geometry. Almost every antigen-induced allergic reaction in the nasal cavity leads to morphologic changes known as nasal obstruction. Therefore a study in 8 patients suffering from allergic rhinitis was conducted. Patients were challenged with 1,000 Biological Units (BU) of grass pollen or D. pteronyssinus extract in one nostril. Acoustic rhinometry (AR) was performed before and 10, 20, 30, 45 and 60 minutes and then 2 to 8 hours after allergen exposure. 4 of the patients developed a late phase reaction. Changes were seen in the minimal cross-sectional area (MCA) and even better in a newly induced volume parameter called volume A (V-A). Volume A is calculated by integration of the distance/area graph surrounding the anterior part of the lower turbinate. Thus we can get information on more than one point of a graph in the important region of the anterior nose. Early phase reaction leads to a decrease in both MCA and V-A from 30% to 10% of the baseline value whereas late phase reaction gives only a third of this effect. The contralateral V-A and MCA are only slightly affected in the early phase, but there is an almost symmetric reaction of both sides in the late phase reaction. All changes were more pronounced in V-A compared to MCA. Therefore we propose to add V-A to MCA in describing the results of AR. Acoustic rhinometry is a suitable method for measuring local changes following nasal allergen challenge.

Response of nasal mucosa to histamine or methacholine challenge: use of a quantitative method to examine the modulatory effects of atropine and ipratropium bromide.

We have developed a new technique for the direct local administration of test solutions to the nasal mucosa and for quantification of nasal secretory responses. This technique, a variation on several published reports of filter paper use, allows simple and rapid determination of drug effects and facilitates the analysis of ipsilateral and contralateral responses to local challenge of the nasal mucosa. We have used this technique to investigate the secretory responses of the nasal mucosa to methacholine and histamine and to determine the effects of atropine and ipratropium bromide (Atrovent nasal spray) on these secretory responses.

Nasal mucosa reaction. A model for mucosal reaction during challenge.

Rhinological symptoms in aspects of hyperreactivity and allergy are increasing problems. Previous reports on this subject are based on studies of airway obstruction (rhinomanometry), secreted substances during challenge, and symptom scores. To be able to define and evaluate the pathological reactions in nasal hyperreactivity and allergy, it is necessary to find principles to describe and standardize the reactions of the healthy nasal mucosa. The aim of this study was to examine congestion of the nasal mucosa in healthy volunteers. Existing measuring methods, in this aspect, are either indirect or not accurate enough for this purpose. With the development of rhinostereometry, an optical measuring method, it is possible to record nasal mucosa congestion with high accuracy. A nasal challenge test was made in healthy volunteers with gradually raised concentrations of a histamine solution, which was applied to the inferior concha on the right side. Recordings of the mucosal congestion were made with rhinostereometry. We found that it is possible, with statistical significance, to standardize the reactions of the healthy nasal mucosa: There is no congestion more than 0.4 mm with a histamine concentration of less than 4 mg/ml (p less than 0.05); congestion of more than 0.4 mm is present at histamine concentrations of 16 mg/ml (p less than 0.05).

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

A 'nasal pool' (NP) device, a compressible plastic container with an adapted nozzle, was used to perform a continuous 10-min nasal provocation and lavage. This novel technique brings known concentrations of agents into contact with a large and defined area of the nasal mucosal surface for extended periods of time. Simultaneously, the surface exudations/secretions of the same nasal mucosa are effectively sampled by the NP fluid. A concentration-response study of histamine (80, 400 and 2000 micrograms/ml) was performed in 12 normal subjects on three different occasions. Exudation of plasma albumin into the lavage fluid was measured to quantitate the histamine-induced airway inflammation. The effect of the dwell time on exudation was examined using histamine (400 micrograms/ml) instilled in the nasal cavity for time periods from 10 sec to 10 min. The time course of histamine-induced plasma exudation response was studied by exposing the mucosa to histamine (400 micrograms/ml) for 12 min, with the NP renewed every minute. Allergen-provocations were performed in subjects with hay fever and TAME-esterase activity in the returned lavage fluid was determined to indicate the degree of response. Histamine produced a concentration-dependent increase in albumin levels in the NP fluid; 123.3 +/- 25.6, 213.8 +/- 19.7 and 430.2 +/- 32.0 micrograms/ml (mean +/- s.e.m.), respectively. The time-course study demonstrated that plasma exudation into the lumen occurred promptly and that the exudation response reached a maximum after exposure to histamine for 6-10 min. The dwell-time experiments supported this finding. After 10 min the exudation appeared to decline despite the continued presence of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

[Rhinomanometry: indications, limitations and results]. / Rhinomanométrie: indications, limites et résultats.

The aim of this study was to present briefly the different techniques for measurement of nasal resistance and to show the importance that we attribute to this measurement. Within the framework of the allergological investigation rhinamometry is a parameter that allows evaluation of the results of allergenic nasal provocation. Nasal provocation is in the framework as a complementary examination that is often indespensable to confirm with most possible certainty the involvement of an allergen in the ORL pathology. Positive etiological diagnosis is a fundamental basis for therapeutic advice.

[A computer-assisted system for diagnosing rhinologic function]. / Computergestütztes System zur rhinologischen Funktionsdiagnostik.

We describe the new computerized rhinologic diagnostic system "CARIMA", a software-controlled system based on a measuring head and a PC. The currently available software allows active anterior rhinomanometry to be carried out with a special program for the nasal allergen test, as well as active posterior rhinomanometry and the determination of the laryngotracheal resistance in patients with an open tracheostoma. The measurement procedure is controlled by the patient by watching the screen during data collecting. The breaths are averaged after curve correction by splining, introducing a time-referred system into the computerized rhinomanometry. The advantage of the method is a detailed analysis of the increasing and decreasing part of the inspiratory and exspiratory half-wave, allowing clinical conclusions to be made about the nasal valve.

[The technic of intranasal hyposensitization and provocation with rhinomanometric control]. / Zur Technik der intranasalen Hyposensibilisierung und Provokation unter rhinomanometrischer Kontrolle.

Intranasal provocation using many related allergens over a short time with subsequent local, intranasal hyposensitization should always be used by rhinologists trained in allergy if systemic hyposensitization cannot be considered, e.g. when skin tests are negative. This is frequently the case with mold spores.

Induction of nasal late-phase reactions by insufflation of ragweed-pollen extract.

We studied changes in NAC in 17 ragweed-sensitive individuals after intranasal ragweed-challenge testing. All patients experienced immediate symptoms of sneezing, rhinorrhea, and nasal congestion that were associated with marked decreases in NAC (mean = 68%). In 10 trials patients also experienced late (greater than 0 hr) symptoms of nasal congestion with or without rhinorrhea; the mean late NAC decrease in this group was 42%. In contrast, no late symptoms were noted in nine trials, and the mean NAC decreased 5% in this group (p less than 0.003). Attempts to passively transfer immediate or late nasal sensitivity to one individual by spraying the nasal cavity with IgE antibody-containing serum, by packing the nose with cotton pledgets soaked in serum, by injecting serum directly into the inferior turbinate, and by transfusion with IgE-containing serum were not successful. We conclude that symptomatic late-phase reactions occur in the nose after intranasal challenge in about 50% of patients and that these symptomatic reactions can be confirmed objectively by rhinomanometry.

The simplified oscillation method for measuring nasal resistance during provocation with allergens.

The simplified oscillation method was adapted to register nasal resistance because complicated and difficult procedures limited other known rhinomanometric tests. An initial study of thirty-nine subjects compared the effect of different-sized masks, revealing that the smaller the face mask, the smaller the capacitance and the higher the effective resistance. After an initial measurement, a second study group of twenty healthy and twenty pollinosis patients aged from 4 to 40 years underwent nasal provocation with grass pollen extract. Both study groups showed that despite high resistance, reactances were minor. This occurs because the nose acts as an aperture and an aperture has minimal reactances. With increasing concentrations of pollen extract, the nasal resistance of pollinosis subjects increased steadily, whereas the controls showed no change. Passive anterior rhinomanometry was measured for comparison and results contrasted sharply with the oscillation method: prior to provocation, initial values of control and pollinosis groups were already significantly different; after provocation, there was a statistically significant rise in resistance amongst the control as well as the pollinosis subjects. Further, the oscillation method for measuring nasal resistance proved to be simple, effective, and suitable for children.

[A new rhinomanometer in clinical trial for nasal allergen provocation tests. (author's transl)]. / Ein neuartiges Rhinomanometriegerät im Klinischen Vergleich beim Intranasalen Provokationstest.

In 30 patients with a positive history of allergic rhinitis, positive skin tests, and a positive RAST for house dust, house dust mite, and fungi, intranasal provocation was carried out with one or several allergens. Nasal resistance was measured every 15 min for 1 h using a body plethysmograph and a new rhinomanometer (Allergopharma A440). The respective results were compared to verify the usefulness of the new rhinomanometer for ENT departments.

[Practice of intranasal allergic tests under rhinorheomanometric control (author's transl)]. / Zur Praxis der intranasalen Allergietestung unter rhinorheomanometrischer Kontrolle

The present report describes the method of rhinorheomanometry in intranasal allergic tests, how it is practised at the ENT-Clinic of Heidelberg University. In addition, we give a survey of the steps taken in order to diagnose rhinitis allergica, and explain particularly the necessity of the differentiation from non-allergical reactions as well as of histaminic control. These examinations are illustreated by describing serveral cases.