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Extracts from The Cochrane Library: Allergen injection immunotherapy for seasonal allergic rhinitis (review)
Otolaryngology–Head and Neck Surgery (2007) 136, 511-514
THE COCHRANE CORNER
Extracts from The Cochrane Library: Allergen injection immunotherapy for seasonal allergic rhinitis (review) Martin J. Burton, DM, FRCS, John H. Krouse, MD, PhD, and Richard M. Rosenfeld MD, MPH, Oxford, United Kingdom; Detroit, MI and Brooklyn, NY The “Cochrane Corner” is a quarterly section in the journal that highlights systematic reviews relevant to otolaryngology– head and neck surgery, with invited commentary to highlight implications for clinical decision making. This installment features a Cochrane Review entitled “Allergen injection immunotherapy for seasonal allergic rhinitis,” which shows a low risk of adverse events plus a significant reduction in symptom scores and medication use. © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
S
easonal allergic rhinitis (SAR) is a common problem treated by otolaryngologists. Among sensitized patients, exacerbations of rhinitis with pollen exposure result in nasal and nonnasal symptoms and decreased quality of life.1 Avoidance measures and pharmacotherapy often lead to satisfactory clinical improvement, but many patients require more intensive therapy. For these patients, antigen-specific immunotherapy has been a mainstay of allergy management for many decades.
the Cochrane Library should be consulted for the most recent version of the review.
Background Allergic rhinitis is the most common of the allergic diseases. Despite improved understanding of the pathophysiology of allergic rhinitis and advances in its pharmacological treatment, its prevalence has increased worldwide. For patients whose symptoms remain uncontrolled despite medical treatment, allergen injection immunotherapy is advised. An allergen-based treatment may reduce symptoms, the need for medication and modify the natural course of this disease.
Objectives To evaluate the efficacy and safety of subcutaneous specific allergen immunotherapy, compared with placebo, for reducing symptoms and medication requirements in seasonal allergic rhinitis patients.
Search Strategy
COCHRANE ABSTRACT This is an abstract of a Cochrane Review published in the Cochrane Library 2007 Issue 1 (see www.thecochranelibrary.com for information).2 Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and
We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1 2006), MEDLINE (1950 to 2006), EMBASE (1974 to 2006), Pre-MEDLINE, KOREAMED, INDMED, LILACS, PAKMEDINET, Scisearch, mRCT and the National Research Register. The date of the last search was February 2006.
Original Cochrane Review by Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S From the Department of Otolaryngology, University of Oxford and The Radcliffe Infirmary, Oxford (Dr Burton); Department of Otolaryngology, Wayne State University, Detroit, MI (Dr Krouse); and the Department of
Otolaryngology, State University of New York Downstate and The Long Island College Hospital (Dr Rosenfeld). Disclosure. Dr Krouse: Schering-Plough: shareholder, consultant, grants. ALK-Abello: consultant. Alcon: consultant, shareholder, grants. Merck: speaker.
Disclaimer
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2007.02.024
512
Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
Selection Criteria
Authors’ Conclusions
All studies identified by the searches were assessed to identify randomised controlled trials involving participants with symptoms of seasonal allergic rhinitis and proven allergen sensitivity, treated with subcutaneous allergen specific immunotherapy or corresponding placebo.
This review has shown that specific allergen injection immunotherapy in suitably selected patients with seasonal allergic rhinitis results in a significant reduction in symptom scores and medication use. Injection immunotherapy has a known and relatively low risk of severe adverse events. We found no long-term consequences from adverse events.
Data Collection and Analysis Two independent authors identified all studies reporting double-blind, placebo controlled randomised trials of specific immunotherapy in patients with seasonal allergic rhinitis due to tree, grass or weed pollens. Two authors independently performed quality assessment of studies. Data from identified studies were abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.2.8. Analysis was performed using the Standardised Mean Difference (SMD) method and a random-effects model; P values ⬍ 0.05 were considered statistically significant. The primary outcome measures were symptom scores, medication use, quality of life and adverse events.
Main Results We retrieved 1111 publications of which 51 satisfied our inclusion criteria. In total there were 2871 participants (1645 active, 1226 placebo), each receiving on average 18 injections. Duration of immunotherapy varied from three days to three years. Symptom score data from 15 trials were suitable for meta-analysis and showed an overall reduction in the immunotherapy group (SMD ⫺0.73 (95% CI ⫺0.97 to ⫺0.50, P ⬍ 0.00001)). Medication score data from 13 trials showed an overall reduction in the immunotherapy group (SMD of ⫺0.57 (95% CI ⫺0.82 to ⫺0.33, P ⬍ 0.00001)). Clinical interpretation of the effect size is difficult. Adrenaline was given in 0.13% (19 of 14085 injections) of those on active treatment and in 0.01% (1 of 8278 injections) of the placebo group for treatment of adverse events. There were no fatalities.
COMMENTS ON COCHRANE REVIEW Comments by Krouse In the present review, the authors offer convincing evidence that injection immunotherapy provides objective clinical improvement in patients with SAR. They culled the literature to select a group of 51 randomized doubleblind, placebo-controlled trials representing 2871 participants, 1645 of whom had undergone injection immunotherapy for SAR. Pooled analysis showed significant reductions in total symptom scores (Fig. 1) and use of allergy medications (Fig. 2) with immunotherapy. Significant symptomatic improvement was also noted in nasal, bronchial, and ocular symptom scores. Quality of life scores also improved. A potential barrier to the acceptance of injection immunotherapy has been the perceived potential risk of adverse systemic events and death. Among participants in the present analysis, however, only three severe systemic adverse reactions were noted: two cases of anaphylaxis and one exacerbation of asthma, all of which responded to appropriate therapy. Systemic events were treated with epinephrine after 0.13% of allergen injections and no fatalities occurred. Similarly, Hurst and colleagues3 had no fatalities in over 1.1 million immunotherapy injections given to patients with allergic rhinitis. Mortality after injection immunotherapy is very rare, usually in patients with coexisting asthma.4
Figure 1 Random-effects meta-analysis comparing allergen immunotherapy (treatment) vs. placebo (control) for difference in symptom score. Results have moderate heterogeneity (I2 63%). CI, confidence interval; Std diff, standardized difference. Data from Calderon et al.2
Burton et al
Extracts from The Cochrane Library: Allergen . . .
513
Figure 2 Random-effects meta-analysis comparing allergen immunotherapy (treatment) vs. placebo (control) for difference in medication score. Results have moderate heterogeneity (I2 64%). CI, confidence interval; Std diff, standardized difference. Data from Calderon et al.2
Two specific points should be noted in examining this review: (1) the present analysis only includes trials conducted with a single antigen or antigen class; any trials of therapy using multiple-antigen treatment vials have been excluded to eliminate possible interactive effects of disparate antigens; and (2) the current review only examines the use of immunotherapy in the treatment of SAR, not in perennial allergic rhinitis (PAR). While these research decisions allow a neater comparison across trials, they do not represent clinical practice in the United States where otolaryngic and medical allergists generally treat SAR and PAR concurrently using multiple-antigen treatment vials. These differences are primarily ones of style and convenience, and treatment outcomes in this setting would not be expected to differ from those reported by Calderon and colleagues.2 Reviews focusing on PAR and multiple-antigen immunotherapy would help establish concordance of those results with the present analysis. In summary, injection immunotherapy for SAR is safe, reduces nasal and non-nasal symptoms, decreases the need for medication, and improves disease-specific quality of life. Adverse events are rare, and can be managed effectively with prompt recognition and appropriate therapy. Allergy immunotherapy has often been relegated to a secondary role in managing SAR by many otolaryngologists. Due to skepticism or unfamiliarity, some clinicians have questioned the relevance and efficacy of allergy testing and immunotherapy. This review provides objective fodder for otolaryngologists hungry for evidence supporting allergy practice.
Comments by Burton In comparison with the United States, allergy services in the United Kingdom are poor and there will be few “otolaryngologists hungry for evidence supporting allergy practice.” There will however be many allergic patients who look enviously across the Atlantic at the well-established office-
and hospital-based practices and who are interested in the results of this review. Moises Calderon and his colleagues are to be congratulated on producing such a comprehensive and carefully considered review. Discussion of the interpretation of the results of any review is always important but particularly so here where there temptation to ‘over play’ the results must have been considerable. The authors’ caution, based on the heterogeneity of the results, is to be commended and in particular the observation that statistically detectable differences and clinically important ones are not the same thing. Their encouragement for future studies to use validated outcome measures is applauded. Systematic reviews often produce interesting ideas for future research and become as much hypothesis generating as they have been hypothesis driven. For example, these authors comment on whether immunological biomarkers may be useful as surrogate measures for, or are predictive of, clinical responses. They highlight the need for further clinical trials in this area. Good reviews also highlight important omissions or gaps in knowledge. Here the issue of cost-effectiveness has been raised along with the paucity of data on the effectiveness and safety of injection immunotherapy in children. Concerns about safety led to the almost complete abandonment of injection immunotherapy in the United Kingdom several decades ago. Readers of the review will be reassured by the safety data presented here but it is appropriate that the authors refer to the “carefully controlled circumstances” in which the trials were conducted. Finally, in their ‘implications for research’ section the authors make what is clearly a heart-felt plea for authors to report trial results according to the CONSORT statement (www.consort-statement.org). This flow chart and check-list combination optimizes the quality of reporting of randomized trials and its use is mandatory in Otolar-
514
Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
yngology – Head & Neck Surgery and other high quality journals.
REFERENCES 1. Baroody FM. Allergic rhinitis: broader disease effects and implications for management. Otolaryngol Head Neck Surg 2003;128:616 – 631.
2. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD001936. DOI: 10.1002/14651858.CD0011926.pub2. 3. Hurst DS, Gordon BR, Fornadley JA, et al. Safety of home-based and office allergy immunotherapy: A multicenter prospective study. Otolaryngol Head Neck Surg 1999;121:553–561. 4. Reid MJ, Lockey RF, Turkeltaub PC, et al. Survey of fatalities from skin testing and immunotherapy 1985-1989. J Allergy Clin Immunol 1993;92:6 –15.
THANK YOU! The people listed below served as Associate Editors of the journal during the past six years. We should have recognized them in our January issue for the contributions they have made to the journal. We apologize for the oversight, and thank them for the work they have devoted to furthering the mission of the journal and the Academy. Jeffrey M. Bumpous, MD, Case Reports, Louisville, KY Keith F. Clark, MD, PhD, Comprehensive Otolaryngology, Oklahoma City, OK Berrylin J. Ferguson, MD, Sinonasal Disorders/Allergy, Pittsburgh, PA Ellen M. Friedman, MD, Pediatrics, Houston, TX Robert Ossoff, MD, Laryngology/Neurolaryngology, Nashville, TN Michael D. Seidman, MD, Otology/Neurotology, Detroit, MI Michael Setzen, MD, Case Reports, Manhasset, NY J. Regan Thomas, MD, Facial Plastic and Reconstructive Surgery, Chicago, IL
THE COCHRANE CORNER
Extracts from The Cochrane Library: Allergen injection immunotherapy for seasonal allergic rhinitis (review) Martin J. Burton, DM, FRCS, John H. Krouse, MD, PhD, and Richard M. Rosenfeld MD, MPH, Oxford, United Kingdom; Detroit, MI and Brooklyn, NY The “Cochrane Corner” is a quarterly section in the journal that highlights systematic reviews relevant to otolaryngology– head and neck surgery, with invited commentary to highlight implications for clinical decision making. This installment features a Cochrane Review entitled “Allergen injection immunotherapy for seasonal allergic rhinitis,” which shows a low risk of adverse events plus a significant reduction in symptom scores and medication use. © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
S
easonal allergic rhinitis (SAR) is a common problem treated by otolaryngologists. Among sensitized patients, exacerbations of rhinitis with pollen exposure result in nasal and nonnasal symptoms and decreased quality of life.1 Avoidance measures and pharmacotherapy often lead to satisfactory clinical improvement, but many patients require more intensive therapy. For these patients, antigen-specific immunotherapy has been a mainstay of allergy management for many decades.
the Cochrane Library should be consulted for the most recent version of the review.
Background Allergic rhinitis is the most common of the allergic diseases. Despite improved understanding of the pathophysiology of allergic rhinitis and advances in its pharmacological treatment, its prevalence has increased worldwide. For patients whose symptoms remain uncontrolled despite medical treatment, allergen injection immunotherapy is advised. An allergen-based treatment may reduce symptoms, the need for medication and modify the natural course of this disease.
Objectives To evaluate the efficacy and safety of subcutaneous specific allergen immunotherapy, compared with placebo, for reducing symptoms and medication requirements in seasonal allergic rhinitis patients.
Search Strategy
COCHRANE ABSTRACT This is an abstract of a Cochrane Review published in the Cochrane Library 2007 Issue 1 (see www.thecochranelibrary.com for information).2 Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and
We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1 2006), MEDLINE (1950 to 2006), EMBASE (1974 to 2006), Pre-MEDLINE, KOREAMED, INDMED, LILACS, PAKMEDINET, Scisearch, mRCT and the National Research Register. The date of the last search was February 2006.
Original Cochrane Review by Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S From the Department of Otolaryngology, University of Oxford and The Radcliffe Infirmary, Oxford (Dr Burton); Department of Otolaryngology, Wayne State University, Detroit, MI (Dr Krouse); and the Department of
Otolaryngology, State University of New York Downstate and The Long Island College Hospital (Dr Rosenfeld). Disclosure. Dr Krouse: Schering-Plough: shareholder, consultant, grants. ALK-Abello: consultant. Alcon: consultant, shareholder, grants. Merck: speaker.
Disclaimer
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2007.02.024
512
Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
Selection Criteria
Authors’ Conclusions
All studies identified by the searches were assessed to identify randomised controlled trials involving participants with symptoms of seasonal allergic rhinitis and proven allergen sensitivity, treated with subcutaneous allergen specific immunotherapy or corresponding placebo.
This review has shown that specific allergen injection immunotherapy in suitably selected patients with seasonal allergic rhinitis results in a significant reduction in symptom scores and medication use. Injection immunotherapy has a known and relatively low risk of severe adverse events. We found no long-term consequences from adverse events.
Data Collection and Analysis Two independent authors identified all studies reporting double-blind, placebo controlled randomised trials of specific immunotherapy in patients with seasonal allergic rhinitis due to tree, grass or weed pollens. Two authors independently performed quality assessment of studies. Data from identified studies were abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.2.8. Analysis was performed using the Standardised Mean Difference (SMD) method and a random-effects model; P values ⬍ 0.05 were considered statistically significant. The primary outcome measures were symptom scores, medication use, quality of life and adverse events.
Main Results We retrieved 1111 publications of which 51 satisfied our inclusion criteria. In total there were 2871 participants (1645 active, 1226 placebo), each receiving on average 18 injections. Duration of immunotherapy varied from three days to three years. Symptom score data from 15 trials were suitable for meta-analysis and showed an overall reduction in the immunotherapy group (SMD ⫺0.73 (95% CI ⫺0.97 to ⫺0.50, P ⬍ 0.00001)). Medication score data from 13 trials showed an overall reduction in the immunotherapy group (SMD of ⫺0.57 (95% CI ⫺0.82 to ⫺0.33, P ⬍ 0.00001)). Clinical interpretation of the effect size is difficult. Adrenaline was given in 0.13% (19 of 14085 injections) of those on active treatment and in 0.01% (1 of 8278 injections) of the placebo group for treatment of adverse events. There were no fatalities.
COMMENTS ON COCHRANE REVIEW Comments by Krouse In the present review, the authors offer convincing evidence that injection immunotherapy provides objective clinical improvement in patients with SAR. They culled the literature to select a group of 51 randomized doubleblind, placebo-controlled trials representing 2871 participants, 1645 of whom had undergone injection immunotherapy for SAR. Pooled analysis showed significant reductions in total symptom scores (Fig. 1) and use of allergy medications (Fig. 2) with immunotherapy. Significant symptomatic improvement was also noted in nasal, bronchial, and ocular symptom scores. Quality of life scores also improved. A potential barrier to the acceptance of injection immunotherapy has been the perceived potential risk of adverse systemic events and death. Among participants in the present analysis, however, only three severe systemic adverse reactions were noted: two cases of anaphylaxis and one exacerbation of asthma, all of which responded to appropriate therapy. Systemic events were treated with epinephrine after 0.13% of allergen injections and no fatalities occurred. Similarly, Hurst and colleagues3 had no fatalities in over 1.1 million immunotherapy injections given to patients with allergic rhinitis. Mortality after injection immunotherapy is very rare, usually in patients with coexisting asthma.4
Figure 1 Random-effects meta-analysis comparing allergen immunotherapy (treatment) vs. placebo (control) for difference in symptom score. Results have moderate heterogeneity (I2 63%). CI, confidence interval; Std diff, standardized difference. Data from Calderon et al.2
Burton et al
Extracts from The Cochrane Library: Allergen . . .
513
Figure 2 Random-effects meta-analysis comparing allergen immunotherapy (treatment) vs. placebo (control) for difference in medication score. Results have moderate heterogeneity (I2 64%). CI, confidence interval; Std diff, standardized difference. Data from Calderon et al.2
Two specific points should be noted in examining this review: (1) the present analysis only includes trials conducted with a single antigen or antigen class; any trials of therapy using multiple-antigen treatment vials have been excluded to eliminate possible interactive effects of disparate antigens; and (2) the current review only examines the use of immunotherapy in the treatment of SAR, not in perennial allergic rhinitis (PAR). While these research decisions allow a neater comparison across trials, they do not represent clinical practice in the United States where otolaryngic and medical allergists generally treat SAR and PAR concurrently using multiple-antigen treatment vials. These differences are primarily ones of style and convenience, and treatment outcomes in this setting would not be expected to differ from those reported by Calderon and colleagues.2 Reviews focusing on PAR and multiple-antigen immunotherapy would help establish concordance of those results with the present analysis. In summary, injection immunotherapy for SAR is safe, reduces nasal and non-nasal symptoms, decreases the need for medication, and improves disease-specific quality of life. Adverse events are rare, and can be managed effectively with prompt recognition and appropriate therapy. Allergy immunotherapy has often been relegated to a secondary role in managing SAR by many otolaryngologists. Due to skepticism or unfamiliarity, some clinicians have questioned the relevance and efficacy of allergy testing and immunotherapy. This review provides objective fodder for otolaryngologists hungry for evidence supporting allergy practice.
Comments by Burton In comparison with the United States, allergy services in the United Kingdom are poor and there will be few “otolaryngologists hungry for evidence supporting allergy practice.” There will however be many allergic patients who look enviously across the Atlantic at the well-established office-
and hospital-based practices and who are interested in the results of this review. Moises Calderon and his colleagues are to be congratulated on producing such a comprehensive and carefully considered review. Discussion of the interpretation of the results of any review is always important but particularly so here where there temptation to ‘over play’ the results must have been considerable. The authors’ caution, based on the heterogeneity of the results, is to be commended and in particular the observation that statistically detectable differences and clinically important ones are not the same thing. Their encouragement for future studies to use validated outcome measures is applauded. Systematic reviews often produce interesting ideas for future research and become as much hypothesis generating as they have been hypothesis driven. For example, these authors comment on whether immunological biomarkers may be useful as surrogate measures for, or are predictive of, clinical responses. They highlight the need for further clinical trials in this area. Good reviews also highlight important omissions or gaps in knowledge. Here the issue of cost-effectiveness has been raised along with the paucity of data on the effectiveness and safety of injection immunotherapy in children. Concerns about safety led to the almost complete abandonment of injection immunotherapy in the United Kingdom several decades ago. Readers of the review will be reassured by the safety data presented here but it is appropriate that the authors refer to the “carefully controlled circumstances” in which the trials were conducted. Finally, in their ‘implications for research’ section the authors make what is clearly a heart-felt plea for authors to report trial results according to the CONSORT statement (www.consort-statement.org). This flow chart and check-list combination optimizes the quality of reporting of randomized trials and its use is mandatory in Otolar-
514
Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
yngology – Head & Neck Surgery and other high quality journals.
REFERENCES 1. Baroody FM. Allergic rhinitis: broader disease effects and implications for management. Otolaryngol Head Neck Surg 2003;128:616 – 631.
2. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD001936. DOI: 10.1002/14651858.CD0011926.pub2. 3. Hurst DS, Gordon BR, Fornadley JA, et al. Safety of home-based and office allergy immunotherapy: A multicenter prospective study. Otolaryngol Head Neck Surg 1999;121:553–561. 4. Reid MJ, Lockey RF, Turkeltaub PC, et al. Survey of fatalities from skin testing and immunotherapy 1985-1989. J Allergy Clin Immunol 1993;92:6 –15.
THANK YOU! The people listed below served as Associate Editors of the journal during the past six years. We should have recognized them in our January issue for the contributions they have made to the journal. We apologize for the oversight, and thank them for the work they have devoted to furthering the mission of the journal and the Academy. Jeffrey M. Bumpous, MD, Case Reports, Louisville, KY Keith F. Clark, MD, PhD, Comprehensive Otolaryngology, Oklahoma City, OK Berrylin J. Ferguson, MD, Sinonasal Disorders/Allergy, Pittsburgh, PA Ellen M. Friedman, MD, Pediatrics, Houston, TX Robert Ossoff, MD, Laryngology/Neurolaryngology, Nashville, TN Michael D. Seidman, MD, Otology/Neurotology, Detroit, MI Michael Setzen, MD, Case Reports, Manhasset, NY J. Regan Thomas, MD, Facial Plastic and Reconstructive Surgery, Chicago, IL