Local allergic rhinitis: Allergen tolerance and immunologic changes after preseasonal immunotherapy with grass pollen

Abstract

To the Editor: Local allergic rhinitis (LAR) is a new form of localized nasal allergic disease in the absence of atopy characterized by local production of specific IgE (sIgE) antibodies and a positive response on a nasal allergen provocation test (NAPT).1Huggins K.G. Brostoff J. Local production of specific IgE antibodies in allergic-rhinitis patients with negative skin tests.Lancet. 1975; 2: 148-150Abstract PubMed Scopus (269) Google Scholar, 2Powe D.G. Jagger C. Kleinjan A. Carney A.S. Jenkins D. Jones N.S. “Entopy”: localized mucosal allergic disease in the absence of systemic responses for atopy.Clin Exp Allergy. 2003; 33: 1374-1379Crossref PubMed Scopus (175) Google Scholar, 3Rondón C. Romero J.J. López S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 4Rondón C. Doña I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (40) Google Scholar It affects more than 45% of patients previously given diagnoses of nonallergic rhinitis.3Rondón C. Romero J.J. López S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 4Rondón C. Doña I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (40) Google Scholar, 5Wedbäck A. Enbom H. Eriksson N.E. Movérare R. Malcus I. Seasonal non-allergic rhinitis (SNAR)—a new disease entity? A clinical and immunological comparison between SNAR, seasonal allergic rhinitis and persistent non-allergic rhinitis.Rhinology. 2005; 43: 86-92PubMed Google Scholar, 6Carney A.S. Powe D.G. Huskisson R.S. Jones N.S. Atypical nasal challenges in patients with idiopathic rhinitis: more evidence for the existence of allergy in the absence of atopy?.Clin Exp Allergy. 2002; 32: 1436-1440Crossref PubMed Scopus (118) Google Scholar We examined nasal tolerance and immunologic changes to specific subcutaneous immunotherapy (SCIT) in patients with LAR sensitized to grass pollen. A pilot observational study was undertaken in 20 adult patients with LAR sensitized to grass pollen who were recruited consecutively. Ten patients were treated with preseasonal grass SCIT for 6 months and rescue medication in the spring (the SCIT group), and 10 received rescue medication (the control group). The study was approved by the ethics committee, and informed consent was obtained from the participants. The primary outcomes were nasal tolerance to a grass NAPT and immunologic changes (skin prick test [SPT] responses and serum levels of grass pollen specific IgG [sIgG] and sIgE). Secondary outcomes were symptom and medication scores, medication-free days, and severity of LAR symptoms (for more information, see the Methods section in this article's Online Repository at www.jacionline.org). No significant differences were found between groups at baseline evaluation (see Table E1 and the Results section in this article's Online Repository at www.jacionline.org). For the primary outcome (Fig 1), the SCIT group showed a significant improvement in nasal tolerance compared with the control group (P = .001), with significantly higher threshold concentrations of grass pollen in NAPTs after 6 (P = .001) and 12 (P = .001) months of treatment, and 3 patients had negative NAPT responses. In the SCIT group SPT responses with grass pollen became positive in 40% of the patients with LAR after 6 months, and serum sIgG antibodies to Lolium and Phleum species increased progressively, becoming significant at 12 months (P = .026 and P = .043, respectively; see Fig E1 in this article's Online Repository at www.jacionline.org). The 4 patients with positive SPT responses at 6 months presented positive values of IgE to Lolium and Phleum species at 12 months of treatment, although no significant changes were observed in the median serum levels of sIgE antibodies (see Fig E2 in this article's Online Repository at www.jacionline.org). Although the small number of patients with newly positive SPT responses did not allow statistical analysis, it is important to mention that all these patients experienced an important increase in their nasal tolerance (2/4 had a negative NAPT response after 6 months) and reduction of symptoms, rescue medication scores, and severity of rhinitis in the following spring. No significant differences in SPT and NAPT responses or serum sIgG or sIgE levels were observed in the control subjects. In the active group patients reported a clinical improvement in the following spring, with a median reduction in average daily rhinoconjunctivitis symptom and rescue medication scores of 45% (P = .001) compared with the control subjects (Fig 2). A reduction in the severity of rhinitis was detected, decreasing from severe to moderate in 100% and from moderate to mild in 57% (P = .024; see Fig E3 in this article's Online Repository at www.jacionline.org). The median number of rescue medication–free days increased by 32% (P = .001) in the active group compared with that seen in the control group (see Table E2 in this article's Online Repository at www.jacionline.org). No systemic adverse reaction was observed in the SCIT group. No significant intragroup differences were seen in the control subjects in the severity of rhinitis or medication-free days (Fig 2 and see Table E2). SCIT with grass pollen was shown to be a safe and effective treatment in patients with LAR that significantly improved the nasal tolerance to NAPTs and the clinical response to the natural exposure to aeroallergen after 6 months of preseasonal therapy. Although a placebo effect can occur, the important increase in nasal tolerance to NAPT, an objective parameter, indicates the beneficial effect of SCIT. SCIT in patients with LAR can modify the disease course with an important reduction in severity. An important finding was the appearance of positive SPT responses and serum sIgE levels to grass pollen in 40% of the patients with LAR during immunotherapy. Although a possible adjuvant effect of the aluminum hydroxide gel used in this SCIT might lead to a TH2 response,7Ulanova M. Tarkowski A. Hahn-Zoric M. Hanson L.A. The common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin-4-dependent mechanism.Infect Immun. 2001; 69: 1151-1159Crossref PubMed Scopus (188) Google Scholar other possible reasons are that LAR might be a first step in the natural course of allergic rhinitis8Rondón C. Doña I. Torres M.J. Campo P. Blanca M. Evolution of patients with nonallergic rhinitis supports conversion to allergic rhinitis.J Allergy Clin Immunol. 2009; 123: 1098-1102Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar and/or, as occurs in classical rhinitis, that immunotherapy leads to increased sIgE levels at the beginning followed by stabilization and a further decrease after 1 year.9Creticos P.S. Reed C.E. Norman P.S. Khoury J. Adkinson Jr., N.F. Buncher C.R. et al.Ragweed immunotherapy in adult asthma.N Engl J Med. 1996; 334: 501-506Crossref PubMed Scopus (207) Google Scholar Furthermore, we can infer that the initial improvement in SCIT in these cases followed the same pattern as in classical SCIT, with the demonstration of increased tolerance to the allergen and clinical improvement shortly before the increase in serum sIgG antibodies.10Till S.J. Francis J.N. Nouri-Aria K. Durham S.R. Mechanisms of immunotherapy.J Allergy Clin Immunol. 2004; 113: 1025-1035Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar In summary, in patients with LAR to grass pollen, SCIT improves objective and subjective parameters, as well as immunologic data, indicating that patients with LAR might benefit from this approach. To provide further support for this conclusion, a double-blind, placebo-controlled study is currently underway to establish the role of immunotherapy in this type of rhinitis. We thank Ian Johnstone for help with the final English-language version of this article. Currently, the majority of patients with LAR are treated with allergen avoidance measures and symptomatic medication with intranasal corticosteroids and oral antihistamines.E1Rondón C. Romero J.J. López S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (250) Google ScholarE2Rondón C. Doña I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (134) Google Scholar Allergen avoidance is often difficult, and the resulting efficiency is controversial.E3Bousquet J. Khaltaev N. Cruz A.A. Denburg J. Fokkens W.J. Togias A. et al.Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).Allergy. 2008; 63: 8-160Crossref PubMed Scopus (3628) Google Scholar Allergen-specific immunotherapy has proved an effective and safe treatment of allergic diseases that can reduce symptoms and medication requirements.E4Bousquet J, Lockey RF, Malling HJ, editors. WHO position paper. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy 1998;44:1-42.Google Scholar, E5Walker S.M. Pajno G.B. Torres Lima M. Wilson D.R. Durham S.R. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial.J Allergy Clin Immunol. 2001; 107: 87-93Abstract Full Text PDF PubMed Scopus (262) Google Scholar, E6Frew A.J. Powell R.J. Corrigan C.J. Durham S.R. on behalf of the UK Immunotherapy Study GroupEfficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2006; 117: 319-325Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar Moreover, it is the only treatment that has the ability to modify the natural course of allergic rhinoconjunctivitis and provide efficacy in posttreatment years.E7European Medicines AgencyGuideline of the clinical on the clinical development on products for specific immunotherapy for the treatment of allergic diseases. European Medicines Agency, London2008Google Scholar This study is the first to examine the immunologic and clinical response to specific SCIT in patients with LAR sensitized to grass pollen. It confirms the clinical improvement, the immunologic modifying effect, and the safety of specific immunotherapy in these patients. Patients were recruited consecutively from the allergy unit between November 2006 and February 2007. The inclusion criteria were age 18 to 60 years and a clinical history of grass pollen–induced LAR of 2 years or more confirmed by a positive NAPT response, a positive nasal sIgE value against the grass pollen mixture (IgE CAP, ≥0.35 kU/L), or both. The exclusion criteria were sensitization to other aeroallergens that might overlap the grass pollen season, previous immunotherapy within the last 5 years, chronic rhinosinusitis with or without nasal polyps, immunologic disease, and pregnancy. In the SCIT group immunotherapy involved a 6-week up-dosing phase followed by monthly subcutaneous administrations of a standardized extract of a mixture of 6 grass pollens (Dactylis, Festuca, Lolium, Phleum, Poa, and Secale species) between September 2007 and March 2008. The immunologic response was assessed at 1, 3, 6, and 12 months after beginning SCIT based on skin test and NAPT responses and levels of grass pollen–specific IgG and IgE in serum to Lolium and Phleum species. The clinical response was evaluated by recording seasonal symptoms and medication scores from April through June 2007 (baseline evaluation) and from April through June 2008 (1 year after). Safety was explored based on adverse events. Immunotherapy was carried out with Pangramin Plus Grass mix (ALK-Abelló, Madrid, Spain), which was administered subcutaneously as an injectable solution containing allergen extract adsorbed in an aluminum hydroxide gel. Allergen extracts were standardized in mass units and labeled in specific treatment units (100 specific treatment units in vial A and 1,000 specific treatment units in vial B). Grass mix (Dactylis, Festuca, Lolium, Phleum, Poa, and Secale species) contained 2.5 μg of group 5 in the maximum-concentration vial. The primary outcome was the measure of nasal tolerance to grass pollen, as assessed based on NAPT responses to grass. Saline challenge was performed to exclude nasal hyperactivity. If results were negative, NAPTsE2Rondón C. Doña I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (134) Google Scholar were performed with freshly reconstituted grass extracts (ALK-Abelló) at increasing concentrations (0.001-0.01-0.05-0.1 mcg/mL). Before NAPTs, each 15 minutes during NAPTs, and 15 minutes and 1, 6, and 24 hours afterward, nasal obstruction, rhinorrhea, itching, sneezing, and ocular symptoms were recorded by using the visual analog scale, and the volume of the nasal cavity from 2 to 6 cm was assessed by means of acoustic rhinometry (SRE 2000 rhinometer; Rhinometrics, Lynge, Denmark).E8Hilberg O. Pedersen O.F. Acoustic rhinometry: recommendations for technical specifications and standard operating procedures.Rhinology. 2000; 16: 3-17Google Scholar A positive NAPT response was considered to be an increase of greater than 30% in the visual analog scale and a decrease of greater than 30% in the volume of the nasal cavity from 2 to 6 cm on acoustic rhinometry compared with values on the baseline test. SPTs were performed with a panel of the most prevalent aeroallergens, including house dust mite, pollens, molds, latex, and animal epithelia (ALK-Abelló).E2Rondón C. Doña I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (134) Google Scholar Serum samples were analyzed for allergen-specific IgE and IgG by means of ELISA.E9Diaz-Perales A. Blanco S. Sanchez-Monge R. Varela J. Carrillo T. Salcedo G. Analysis of avocado allergen (Pers a1) IgE-binding peptides generated by simulated gastric fluid digestion.J Allergy Clin Immunol. 2003; 112: 1002-1007Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Lolium and Phleum species extracts were tested at 20 μg/mL bound to the solid phase and each serum at 1:10 dilution for measurement of IgE and at 1:50 dilution for measurement of IgG. Specific IgE levels were considered to be positive when greater than 0.20 OD (the highest value of the mean + 3 × SD of the above-described determinations; 0.1 + 3 × 0.03 = 0.19). The clinical response was evaluated by recording the average daily rhinoconjunctivitis symptom and rescue medication scoresE10Clark J. Schall R. Assessment of combined symptom and medication scores for rhinoconjunctivitis immunotherapy clinical trials.Allergy. 2007; 62: 1023-1028Crossref PubMed Scopus (49) Google Scholar within the defined grass pollen season. Patients were instructed to keep a diary during the 2007 and 2008 grass pollen seasons for a daily evaluation of 5 rhinoconjunctivitis symptoms (sneezing, rhinorrhea, itchy nose, nasal obstruction, and ocular symptoms) according to a 4-point scoring system: 0, no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms. The maximum daily total symptom score was 15. The rescue medication score was as follows: 1 point for oral antihistamines, 2 points for intranasal corticosteroids, and 3 points for oral corticosteroids. The maximum daily total score for rescue medication was 6. The severity of LAR symptoms during spring 2007 and spring 2008 was categorized according to the modified Allergic Rhinitis and its Impact on Asthma criteriaE11Valero A. Ferrer M. Sastre J. Navarro A.M. Monclús L. Martí-Guadaño E. et al.A new criterion by which to discriminate between patients with moderate allergic rhinitis and patients with severe allergic rhinitis based on the Allergic Rhinitis and its Impact on Asthma severity items.J Allergy Clin Immunol. 2007; 120: 359-365Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar as mild, moderate, or severe. Adverse reactions were classified according to the European Academy of Allergy and Clinical Immunology's grading system.E12Alvarez-Cuesta E. Bousquet J. Canonica G.W. Durham S.R. Malling H.J. Valovirta E. EAACI, Immunotherapy Task ForceStandards for practical allergen-specific immunotherapy.Allergy. 2006; 61: 1-20Crossref PubMed Scopus (375) Google Scholar Descriptive statistics were expressed as medians and means. Intergroup comparisons were made by using the Mann-Whitney U test. Categorical data were analyzed by using the χ2 test. Comparisons at 2 different times were carried out with the Wilcoxon test for related samples. Calculations were performed with the software package SSPS for Windows 11.5.1 (SPSS Corp, Chicago, Ill). A P value of less than .05 was considered significant. No significant differences were detected between the treatment groups in the baseline demographic and clinical characteristics of the 20 patients included in the study (Table E1). At inclusion, all subjects had a history of moderate or severe LAR to grass pollen with a median duration of 5 to 6 years. In both groups there was a predominance of women and moderate nasal symptoms; conjunctivitis was the most frequently reported associated disease (50% of patients in both groups). The evolution of serum levels of allergen-specific IgG and IgE antibody to Lolium and Phleum species in the active and control groups, respectively, is described in Fig E1, Fig E2. Patients with LAR who received preseasonal SCIT reported a significant reduction in rhinoconjunctivitis symptoms in the following spring. There were no differences in the reduction in rhinoconjunctivitis symptom scores at the final evaluation in the SCIT group between patients with LAR with or without conjunctivitis (P = .343) or with or without asthma (P = 1.000). The severity of LAR after SCIT is shown in Fig E3. No systemic adverse reaction was observed in the SCIT group during the study; 1 patient had a local reaction at the injection site that did not exceed 5 cm and did not require discontinuation of treatment. Tabled 1Baseline demographic and clinical characteristics of the study groupsSCIT groupControl groupP valueSubjects (no.)1010Sex, no. (%) Male3 (30)2 (20).610 Female7 (70)8 (80)Age (y), median (range)32 (19-45)29.5 (19-43).940Disease duration (y), median (range)6 (4-7)5 (4-8).510Severity of rhinitis, no. (%) Moderate7 (70)6 (60)1.000 Severe3 (30)4 (40)1.000Comorbidity, no. (%) Asthma3 (30)2 (20)1.000 Conjunctivitis5 (50)5 (50)1.000 Open table in a new tab Tabled 1Clinical response after 6 months of preseasonal SCITSCIT group, median (mean)Control group, median (mean)P value∗Differences between groups by Mann-Whitney U test.Relative difference,†Relative difference was calculated as the absolute difference/control group. median (mean)Rhinoconjunctivitis symptoms score Baseline10.00 (11.00)11.00 (11.60).504 1 y after6.00 (6.60)11.00 (11.40).00145% (42%)Ocular symptoms score Baseline1.00 (1.10)1.00 (1.30).680 1 y after0.00 (0.60)1.00 (1.20).030100% (50%)Nasal symptoms score Itching baseline2.00 (2.40)2.00 (2.50).661 Itching 1 y after1.00 (1.20)3.00 (2.80).00167% (57%) Sneezing baseline3.00 (2.60)3.00 (2.60)1.000 Sneezing 1 y after1.00 (1.30)3.00 (2.60).00167% (50%) Rhinorrhea baseline3.00 (2.60)3.00 (2.70).648 Rhinorrhea 1 y after1.50 (1.50)2.00 (2.40).01425% (38%) Obstruction baseline2.00 (2.10)2.50 (3.00).431 Obstruction 1 y after1.00 (1.30)3.00 (2.40).00967% (46%)Rescue medication score Baseline1.95 (1.94)1.94 (1.82).475 1 y after0.96 (0.83)1.75 (1.73).00145% (52%)Rescue medication days Baseline90.00 (88.00)88.00 (85.00).155 1 y after58.00 (49.20)86.00 (85.40).00132% (42%)A total of 20 patients were analyzed at baseline (spring 2007) and 1 year after treatment (spring 2008).∗ Differences between groups by Mann-Whitney U test.† Relative difference was calculated as the absolute difference/control group. Open table in a new tab A total of 20 patients were analyzed at baseline (spring 2007) and 1 year after treatment (spring 2008).