Nasal responsiveness to allergen and histamine in patients with perennial rhinitis with and without a late phase response

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1 Thorax 1997;5: Nasal responsiveness to allergen and histamine in patients with perennial rhinitis with and without a late phase response C de Graaf-in t Veld, I M Garrelds, A W van Toorenenbergen, R Gerth van Wijk Abstract specific stimuli. This phenomenon has Background In the lower airways an association been described for the upper as well as for has been found between early the lower airways. 1 In the lower airways the phase reaction (EPR), late phase reaction immediate response to allergen challenge is (LPR), and bronchial hyperreactivity. often followed by a late phase response. This However, this association has not been bronchial late phase reaction is associated with shown for the upper airways in nasal pollen increased inflammation and bronchial hyperreactivity. challenge studies. A study was undertaken 5 In the upper airways late phase to determine whether the EPR, LPR, and responses have also been described. 91 Several nasal hyperreactivity are related in perennial studies have been performed to find out allergic rhinitis. whether similar associations could also be Methods Twenty four patients with rhinitis shown in patients with allergic rhinitis. How- who were allergic to house dust mite ever, no relation has been found between an (HDM) were challenged with HDM extract. increase in nasal hyperreactivity and late nasal The nasal response was monitored response, 11 between an increase in nasal hyper- by symptom scores and nasal lavages for reactivity and activation of eosinophils, 1 up to 9.5 hours after challenge and con- or between enhanced responsiveness to rechallenge centrations of albumin, tryptase, and eosinophil with allergen and late nasal recentrations cationic protein (ECP) in the sponse. 13 These studies were performed in pollen lavage fluid were measured. Thirteen sensitive patients tested outside the pollen patients (defined as dual responders) had season. increased symptom scores between 3.5 and In contrast, in a study with rhinitic patients 9.5 hours compared with the baseline allergic to house dust mite (HDM) we have score. The other 11 patients (defined as shown an association between nasal re- early responders) showed an isolated EPR sponsiveness to allergen and pre-existing nasal only. Nasal hyperreactivity was determined hyperreactivity, 1 a finding more in agreement by nasal histamine challenge with data from the lower airways. Like asth- hours later. matics, these patients also suffer from symp- Results Dual responders showed a sig- toms throughout the year. Due to this ongoing nificantly higher symptom score, albumin allergen exposure it might be expected that influx, and tryptase release during the these patients become primed more and as a EPR. During the late phase ( hours) consequence develop an increased non-specific Department of albumin influx was significantly increased hyperreactivity. We therefore wanted to in- Allergology at most time points and ECP release was vestigate further the relationship between nasal C de Graaf-in t Veld I M Garrelds significantly higher at 9.5 hours in the dual hyperreactivity and response to allergen chal- R Gerth van Wijk responder group. Dual responders showed lenge in this subgroup of patients with rhinitis. a significantly stronger response to all Patients with perennial rhinitis were chal- Laboratory of Allergology doses of histamine. The area under the lenged first with HDM and hours later with (Department of curve (AUC) of symptom scores during histamine and the clinical response, mediators, Clinical Chemistry) EPR and LPR and the AUC of the his- and nasal hyperreactivity of patients with and A W van Toorenenbergen tamine dose response were significantly without a late nasal response were compared correlated (EPR-LPR: r=.9, p<.1; to investigate whether early phase nasal reaction University Hospital EPR-histamine: r=.75, p<.1; LPR- (EPR), late phase nasal reaction (LPR), in- Rotterdam-Dijkzigt, 315 GD Rotterdam, histamine: r=., p<.1). flammation, and nasal hyperreactivity were as- The Netherlands Conclusions In patients with perennial sociated in these patients. allergic rhinitis the nasal responses to Institute of Pharmacology, allergen and histamine are associated. Methods Erasmus University Dual responders have an increased EPR, SUBJECTS Rotterdam, increased levels of mediators, and in- The Netherlands Twenty four patients (13 men) of mean age 3 I M Garrelds creased allergen-induced hyperreactivity. years (range 1 5) participated in the study. (Thorax 1997;5:13 1) Correspondence to: All were characterised by a history of perennial Dr C de Graaf-in t Veld. Keywords: allergic rhinitis, house dust mite, nasal hyper- rhinitis and an intradermal skin reaction of at Received 9 February 199 reactivity, nasal provocation. least one plus sign to 3 BU/ml HDM extract Returned to authors (ALK Benelux, Groningen, The Netherlands) 5 June 199 Revised version received according to the standardised plus sign scoring 15 July 199 In atopic patients allergen challenge gives rise to system defined by Norman. 15 Accepted for publication Patients with pol- 13 August 199 increased responsiveness to allergen and non- len allergy were tested outside the pollen sea- Thorax: first published as 1.113/thx on 1 February Downloaded from on August 1 by guest. Protected by copyright.

2 1 de Graaf-in t Veld, Garrelds, van Toorenenbergen, Gerth van Wijk son, and those with allergy to pets were only prechallenge lavages with isotonic saline solution included if they had no contact with pets. to clear the nose from secretions and to Symptomatic medication for rhinitis was obtain baseline levels of mediators. To prevent withdrawn oral corticosteroids two months nasal congestion due to allergen challenge oxy- before the start of the study, astemizole six metazoline.1% (two.15 ml puffs) was applied weeks, nasal or inhaled corticosteroids, disodium in both nostrils. Five minutes later a nasal cromoglycate and nedocromil sodium lavage was performed just before the nasal three weeks, and antihistamines three days before challenge with PBS. A nasal lavage was perpolyposis the start of the study. Patients with nasal formed 1 minutes after PBS and after each and those who had undergone nasal allergen challenge, immediately before the sub- surgery less than three months before the study sequent challenge. Subsequently, lavage fluid or who had had a nasal infection during the was obtained hourly from.5 to 9.5 hours after two weeks before the study or immunotherapy the last allergen challenge. Nasal lavages were in the past were excluded. performed with 1 ml isotonic saline solution (.9%) preheated to 37 C. In each nostril 5 ml saline was instilled with a pipette while the STUDY DESIGN subject gently flexed his/her head backwards. Patients were challenged with increasing doses After 1 seconds the lavage fluid was expelled of HDM extract. Symptom scores were recorded and collected in tubes. This procedure has been and nasal lavage fluid was obtained for shown to produce a mean (SD) recovery of 7.7 up to 9.5 hours after HDM challenge. Allergeninduced (1.) ml. 1 nasal hyperreactivity was determined by nasal histamine provocation hours later. During the study patients were not allowed SYMPTOM SCORE any medication that affected nasal function. Symptoms were recorded using a scoring sys- The study was performed during the period tem according to Lebel et al 17 at the time points from January to August; this period was chosen of lavage. Symptom scores were graded in to minimise natural exposure to HDM. points as follows: 3 sneezes =1, [5 All patients gave their written informed consneezes =3; anterior rhinorrhoea =1; posterior sent and the study was approved by the medical rhinorrhoea =1; difficult nasal breathing =1; ethics committee of the University Hospital. one nostril blocked =; both nostrils blocked =3; pruritus of the nose =1; pruritus of the palate or ear =1; and conjunctivitis = NASAL CHALLENGE WITH HDM AND HISTAMINE 1 (total score 11). In addition, the number Challenges were performed in accordance with 11 1 of sneezes and the amount of secretion were the methods described by Gerth van Wijk. noted. Before starting the nasal challenges the patients Patients were divided into two groups acwaited for 3 minutes in order to give the nasal cording to their symptom scores: those with an mucosa time to acclimatise. Each patient was early response only (defined as early rechallenged with three increasing doses of HDM sponders) and those with both early and late extract (1, 1 and 1 BU/ml; ALK phase symptoms (defined as dual responders). 1 Benelux, Groningen, The Netherlands) per- Patients whose symptom scores were above the formed at 1 minute intervals after challenge baseline level at two consecutive time points with phosphate buffered saline (PBS) conthat is, for at least one hour between 3.5 and taining human serum albumin.3% and 9.5 hours were defined as dual responders. The benzalkonium chloride.5% (ALK Benelux). others with symptom scores equal to or lower The PBS and the different doses of HDM than the baseline score at hours after extract were sprayed into each nostril by means challenge were assigned to the early responder of a nasal pump spray delivering a fixed dose group. The dual responder group included of.15 ml solution. The nasal response was patients with either a dual response or promeasured 1 minutes after each challenge, 3 longed/persistent response after challenge. The minutes after the last challenge (HDM period from 3.5 to 9.5 hours after challenge 1 BU/ml), and hourly for up to 9.5 hours was chosen because other investigators found after the last challenge. Nasal responsiveness a late phase nasal response in the same period. was monitored by the number of sneezes, the amount of secretion collected according to Borum, 1 and a symptom score according to Lebel et al. 17 MEDIATOR ASSAYS Nasal challenge with histamine phosphate Lavage fluid was stored on ice, centrifuged for (.5,.5, 1.,. and mg/ml) was per- 1 minutes at g, and the supernatant stored formed at five minute intervals after challenge at C. Histamine levels were measured with PBS. The amount of secretion, the num- with an automated fluorometric assay. 19 Tryptase ber of sneezes, and the symptom score according and eosinophil cationic protein (ECP) were to Lebel et al 17 were used as nasal determined by radioimmunoassay (RIA) according response indicators. to the manufacturer s instructions (Pharmacia, Uppsala, Sweden), and albumin was determined by automatic kinetic nephelometry NASAL LAVAGE using an Array analyser (Beckmann, Nasal lavages were performed as described by Mijdrecht, The Netherlands) according to the Naclerio et al. 1 This protocol comprises four manufacturer s instructions. Thorax: first published as 1.113/thx on 1 February Downloaded from on August 1 by guest. Protected by copyright.

3 Nasal responsiveness to allergen and histamine in patients with perennial rhinitis 15 Symptom score (pts) A b c h1 h h3 Dual group Early group Number of sneezes B c h1 h h Hours after challenge Secretion (ml) C c h1 h h Figure 1 Clinical response to house dust mite (HDM) challenge by (A) symptom score, (B) number of sneezes, and (C) volume of secretions. The nasal response of dual and early responders was measured for up to 9.5 hours after HDM challenge. b=before challenge, c=1 minutes after PBS, h1 h3=1 minutes after challenge with 1, 1 and 1 BU/ml HDM extract, respectively. pζ.5 (two sided test). Values are presented as mean (SE). Albumin (mg/l) A b c h1 h h3 Dual group Early group ECP ( g/l) B 1 1 b c h1 h h Hours after challenge Tryptase (U/l) C b c h1 h h Figure Mediators after house dust mite (HDM) challenge: (A) albumin, (B) ECP, (C) tryptase. Nasal response of dual and early responders was measured for up to 9.5 hours after HDM challenge. Abbreviations as in fig 1. p Ζ.5 (two sided test). Values are presented as mean (SE). Symptom score A 1 9 Dual group Early group PBS Number of sneezes B PBS Histamine (mg/ml). Secretion (ml) C PBS Figure 3 Responsiveness to histamine challenge measured by (A) symptom score, (B) number of sneezes, and (C) volume of secretions in dual and early responders. pζ.5 (two sided test). Values are presented as mean (SE). STATISTICAL ANALYSIS Patients were divided into the early (n=11) or dual responder group (n=13) according to their symptom scores. Differences between the groups in clinical response, mediators in lavage fluid, and histamine responsiveness were tested with the non-parametric Mann-Whitney U test. A two tailed p value of <.5 was considered significant. Mediator release/influx during the EPR and LPR was tested by the Wilcoxon test. Since the mediators decreased after the EPR, often below the baseline levels, the individual peak levels during the LPR were compared with the lowest levels after the EPR to measure recurrence of mediator influx during the LPR. A two tailed p value of <.5 was considered significant. The correlation between the area under the curve (AUC) of symptom scores during the EPR (HDM 1, 1, 1 BU/ml) and LPR ( hours) and the AUC of the histamine dose response was tested with the Spearman correlation test.. Thorax: first published as 1.113/thx on 1 February Downloaded from on August 1 by guest. Protected by copyright.

4 1 de Graaf-in t Veld, Garrelds, van Toorenenbergen, Gerth van Wijk Table 1 Profile of dual and early responders The mean symptom scores and mediator Dual responders Early responders p value release following challenge with HDM 1 BU/ml and during hours, and HDM (1 BU/ml) the mean nasal hyperreactivity (AUC of his- Symptom score (pts) 7.7 (.7). (.9). Albumin (mg/l) 97. (3.1) 17.1 (.3). tamine dose response) are shown for both Tryptase (U/l). (.9) 1. (.). groups in table 1. Dual responders showed a hours significantly stronger response to HDM AUC symptom score (pts) 1. (.5) 1. (.).1 1 BU/ml during the LPR and to his- AUC albumin (mg/l) 13. (59.) 7.7 (.).1 AUC ECP (μg/l) 1.1 (11.) 3.3 (1.).7 tamine. ECP during the LPR tended to be higher in the dual responders (p=.). Nasal hyperreactivity AUC histamine dose response (pts) 5. (.5) 13. (3.). The AUC of the symptom scores during HDM=house dust mite; AUC=area under curve; ECP=eosinophil cationic protein. EPR and LPR and the AUC of the histamine dose response curves were significantly correlated (EPR-LPR: r=.9, p<.1; EPRhistamine: r=.75, p<.1; LPR-histamine: r=., p <.1). Results Dual responders (n=13) showed a significant immediate and late nasal response while early Discussion responders (n=11) showed an immediate response A recent study of patients allergic to HDM only. The dual responder group con- revealed a relation between pre-existing nasal sisted of 1 patients with a dual response and hyperreactivity and LPR. 1 In view of this find- three patients with a prolonged response. The ing, we wanted to investigate in more detail symptom scores and, to a lesser extent, the the relation between EPR, LPR, inflammation, sneezing and secretory responses of the dual and nasal hyperreactivity in patients allergic to responder group were significantly higher at HDM. Patients were challenged with high most time points than those of the early re- doses of HDM extract in order to obtain maximal sponder group (fig 1A C). nasal response. We did not challenge each Both early and dual responders showed a patient with their individual threshold dose to significant influx of albumin following challenge induce a particular nasal response. Because with HDM 1 BU/ml and during the we were interested in a spectrum of EPRs to LPR. Albumin influx in the dual responder investigate whether the intensity of the EPR is group was significantly higher during both the related to the presence of an LPR and increased early and late phase than in the early responder hyperreactivity, each patient was challenged group (fig A). Patients in both groups showed with the same doses of HDM to obtain a range a significant increase in ECP release during of EPRs. the LPR. ECP release during the late phase To define the late phase reaction in the nose response was significantly higher at 9.5 hours is difficult. Mygind et al could not detect late and tended to be higher at.5 hours (p=.) phase reactions by means of symptom scores. in the dual responder group (fig B). During In other studies in pollen sensitive patients the EPR a significant release of tryptase was late phase reactions have been determined by detected in the dual responders only. The high measurement of nasal obstruction and analysis mean (SE) values at 1 BU/ml HDM are of nasal lavage fluid. 1 1 We assigned patients largely due to one patient. Both groups showed to an early or dual responder group according a significant increase in tryptase release during to their symptom scores during the late phase the late phase period. Since the individual period; this approach has been used in other patients showed only short and small peak 1 studies. levels during the LPR, and as the individual A comparison of the clinical responses in peak levels were distributed at variable time the two groups showed that the immediate points, these small individual tryptase peaks response was significantly higher in the dual were levelled by presenting them as mean values responder group. In addition, the AUC of the as in fig C. Dual responders showed a significantly symptom scores during the EPR and LPR were higher release of tryptase following significantly correlated, which implies that a challenge with HDM in a concentration of strong immediate response is necessary to in- 1 BU/m and at.5 hours (fig C). duce a late phase response. Small et al 3 recently Nasal responsiveness to histamine, as measured found that the amounts of LTC and PGD by the symptom score, was significantly during the EPR and LPR were correlated in a higher in the dual responder group (fig 3A). pollen challenge study, which also suggests a Although graphically the baseline scores are relation between the two phases. However, different, statistically no significant difference nasal symptoms during the EPR and LPR were was shown. When correcting for the baseline, not correlated. dual responders still showed significantly increased Albumin, being the major protein in plasma, symptom scores to all histamine doses. can be used as a marker of increased The number of sneezes of the dual responders vasopermeability. 5 Albumin influx into nasal was significantly higher at.5 mg/ml and ten- lavage fluid showed a pattern comparable with ded to be higher at.5 mg/ml (p=.9) and the symptom score: a dual response in the dual. mg/ml (p=.7; fig 3B). The secretory responder group and an immediate response response tended to be stronger at.5 mg/ml (p=.7) and was significantly stronger at the two highest histamine doses (fig 3C). only in the early responder group. However, individual early responders also had small albumin peak levels. Since these individual small Thorax: first published as 1.113/thx on 1 February Downloaded from on August 1 by guest. Protected by copyright.

5 Nasal responsiveness to allergen and histamine in patients with perennial rhinitis 17 This study was supported by Glaxo BV, Zeist, The Netherlands and by grant 9.7 of the Dutch Asthma Foundation, Leusden, The Netherlands. peaks occurred at variable time points they were levelled by using the mean values as in fig. In order to study the inflammatory response 1 Cockcroft DW, Ruffin RE, Dolovich J, Hargreave FE. Allergen-induced increase in non-allergic bronchial reactivity. we measured tryptase and ECP levels in lavage Clin Allergy 1977;7: fluid. Tryptase, a specific marker for mast cell Grønborg H, Borum P, Mygind N. Histamine and metha- choline do not increase nasal reactivity. Clin Allergy 19; activation, has proved to be a useful marker 1:597. of the immediate nasal reaction. 7 The dual 3 Andersson M, Andersson P, Pipkorn U. Allergen-induced specific and non-specific nasal reactions. Acta Otolaryngol responders showed an increase in tryptase re- 199;17:7 7. lease compared with the early responders. Dur- Connell JT. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen ing the LPR, however, both dual and early exposure, and placebo challenge on the nasal membrane. responders showed short small peaks of tryp- J Allergy 19;1: Cockroft DW. Mechanism of perennial allergic asthma. tase, suggesting some mast cell degranulation Lancet 193;ii:53. during this period. The same finding has been Cartier A, Thomson NC, Frith PA, Roberts R, Tech M, Hargreave FE. Allergen-induced increase in bronchial reported by Wang et al. The late phase re- responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber. J Allergy Clin sponse in the upper and lower airways is as- Immunol 19;7:17 7. sociated with influx of eosinophils. 79 In both 7 Monchy de JGR, Kauffman HF, Venge P, Koëter GH, groups release of ECP, a marker for activated Jansen HM, Sluiter HJ, et al. Bronchoalveolar eosinophilia during allergen-induced late asthma reactions. Am Rev eosinophils, could be detected during the late Respir Dis 195;131:373. phase period. ECP release from hours Durham SR, Craddock CF, Cookson WO, Benson MK. Increases in airway responsiveness to histamine precede (AUC) tended to be higher in the dual re- allergen-induced late asthmatic responses. J Allergy Clin sponder than in the early responder group, and Immunol 19;: Pelikan Z. Late and delayed responses of the nasal mucosa was significantly higher 9.5 hours after allergen to allergen challenge. Ann Allergy 197;1:37. 1 Ferguson H, Davies RJ. Late-phase nasal reactions rechallenge. viewed and revisited. Respir Med 1991;5:7 9. Comparing allergen induced nasal hyper- 11 Gerth van Wijk R, Zijlstra FJ, van Toorenenbergen AW, Vermeulen A, Dieges PH. An isolated early response reactivity, dual responders showed a sigafter nasal allergen challenge is sufficient to induce nasal nificantly higher clinical response at all his- hyperreactivity. Ann Allergy 199;9: Klementsson H, Andersson M, Baumgarten CR, Venge P, tamine concentrations. The AUC of the Pipkorn U. Changes in non-specific nasal reactivity and symptom scores during EPR and LPR and the eosinophil influx and activation after allergen challenge. Clin Exp Allergy 199;: AUC of the histamine dose response curve 13 Iliopoulos O, Proud D, Adkinson NF, Creticos PS, Norman were significantly correlated. This association PS, Kagey-Sobotka A, et al. Effect of immunotherapy on the early, late and rechallenge nasal reaction to provocation between nasal hyperreactivity and LPR was not with allergen-changes in inflammatory mediators and cells. found in nasal pollen challenge studies (tested J Allergy Clin Immunol 1991;7:55. 1 Gerth van Wijk R, van Toorenenbergen AW, Zijlstra FJ, outside the pollen season) The difference Jansen APH, Dieges PH. Nasal hyperreactivity and its might be explained by patients allergic to HDM effects on early and late sequelae of nasal challenge with house dust mite extract. Allergy Proc 1993;1:73 1. having more hyperreactive upper airways due 15 Norman PS. Skin testing. In: Rose NR, Friedman H, eds. to the continuous exposure to natural allergen. Manual of clinical immunology. nd edn. Washington: American Society for Microbiology, 19: The early and late phases might be influenced 1 Borum P. Nasal methacholine challenge. J Allergy Clin by the use of oxymetazoline. Svensson 3 showed Immunol 1979;3: Lebel B, Bousquet J, Morel A, Chanal I, Godard P, Michel that oxymetazoline did not influence histamine FB. Correlation between symptoms and the threshold induced plasma exudation but an effect on for release of mediators in nasal secretions during nasal challenge with grass-pollen grains. J Allergy Clin Immunol nasal patency appears probable. However, in 19;:9 77. spite of this bias we found a clearcut re- 1 Naclerio RM, Meier HL, Kagey Sobotka A, Adkinson NF Jr, Meyers DA, Norman PS, et al. Mediator release after lationship between EPR, LPR, and nasal hyper- nasal airway challenge with allergen. Am Rev Respir Dis reactivity. This systemic error, made in all 193;1: Siraganian RP, Hook WA. Histamine release and assay patients, probably did not influence this as- methods for the study of human allergy. In: Rose NR, sociation. Friedman H, eds. Manual of clinical immunology. nd edn. Washington: American Society of Microbiology, 19: Dual and early responders showed the same 1. Mygind N, Grønborg H, Bisgaard H, Romeling F. Nasal response to allergen although the intensity of late-phase response to allergen provocation: does it exist? the clinical response and the amount of me- In: Dijkman JH, van Herwaarden CLA, Hilvering Chr, Kerrebijn KF, eds. New developments in mechanisms and diator release were increased in dual retreatment of bronchial obstruction. Astra Pharmaceuticals, sponders. It seems that the more intense the 19: Naclerio RM, Proud D, Togias AG, Adkinson NF, Meyers EPR, the more mediators and chemotactic fac- DA, Kagey-Sobotka A, et al. Inflammatory mediators in tors are released. As a result, increased re- late antigen-induced rhinitis. N Engl J Med 195;313: 5 7. cruitment of inflammatory cells takes place, Pastorello EA, Galeazzo Riario Sforza G, Incorvaia C, Segala M, Fumagalli M, Gandini R. Comparison of rhinoreleasing increased amounts of mediators manometry, symptom score, and inflammatory cell counts which, at a certain threshold level, are able to in assessing the nasal late-phase reaction to allergen challenge. J Allergy Clin Immunol 199;93:5 9. induce a recurrence of symptoms. The in- 3 Small P, Biskin N, Barrett D. Effects of intensity of early creased recruitment of inflammatory cells response to allergen on the late phase of both the nose might also explain the increased nasal hyper- and skin. Ann Allergy 199;73:5. Baumgarten CR, Togias AG, Naclerio RM, Lichtenstein reactivity to histamine in the dual responder LM, Norman PS, Proud D. Influx of kininogens into nasal group. secretions after antigen challenge of allergic individuals. J Clin Invest 195;7: We conclude that, in patients with perennial 5 Svensson C, Baumgarten CR, Pipkorn U, Alkner U, Persson allergic rhinitis, the EPR, LPR and hyperduced plasma leakage in nasal airways. Thorax 199;: CGA. Reversibility and reproducibility of histamine-in- reactivity are significantly correlated just as in the lower airways. Patients with a clinical Schwartz LB. Monoclonal antibodies against human mast cell tryptase demonstrate shared antigenic sites on subunits late phase response show an increased intensity of tryptase and selective localisation of the enzyme to mast of symptoms, mediator involvement, and nasal cells. J Immunol 195;13: Rasp G, Hochstrasser K. Tryptase in nasal fluid is a useful hyperreactivity. marker of allergic rhinitis. Allergy 1993;:7. Thorax: first published as 1.113/thx on 1 February Downloaded from on August 1 by guest. Protected by copyright.

6 1 de Graaf-in t Veld, Garrelds, van Toorenenbergen, Gerth van Wijk Thorax: first published as 1.113/thx on 1 February Downloaded from Wang D, Clement P, Smitz J, De Waele M, Derde MP. gen-induced nasal hyperreactivity appears unrelated to the Correlations between complaints, inflammatory cells and size of the nasal and dermal immediate allergic reaction. mediator concentrations in nasal secretions in nasal chal- Allergy 197;:31 7. lenge and during natural allergen exposure. Int Arch Allergy 31 Small P, Biskin N, Barrett D. Relationships among ragweed Immunol 1995;1:7 5. skin tests and both allergen specific and nonspecific nasal 9 Bascom R, Pipkorn U, Lichtenstein LM, Naclerio RM. The provocation. Ann Allergy 199;5:15. influx of inflammatory cells into nasal washings during 3 Svensson C, Pipkorn U, Alkner U, Baumgarten CR, Persson the late response to allergen challenge. Am Rev Respir Dis CGA. Topical vasoconstrictor (oxymetazoline) does not 19;13: 1. affect histamine-induced mucosal exudation of plasma in 3 Andersson M, Kogerer BV, Andersson P, Pipkorn U. Aller- human nasal airways. Clin Exp Allergy 199;:11. on August 1 by guest. Protected by copyright.