Accepted Article
Article Type: Position Paper
Clinical Contraindications to Allergen Immunotherapy: an EAACI Position Paper Pitsios C1, Demoly P2, Bilò MB3, Gerth van Wijk R4, Pfaar O5, Sturm GJ6, Rodriguez del Rio P7, Tsoumani M8, Gawlik R9, Paraskevopoulos G10, Ruëff F11, Valovirta E12, Papadopoulos NG13, 14, and Calderón MA15
1
Dept. of Nutrition and Dietetics, Harokopio University, Athens, Greece
2
Département de Pneumologie et Addictologie, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, France; and Sorbonne Universités, UPMC Paris 06, UMR-S 1136, IPLESP, Equipe EPAR, 75013, Paris, France
3
Dept. of Internal Medicine, Allergy Unit, University Hospital, Ancona, Italy
4
Dept of Internal Medicine, Section of Allergology, Erasmus MC, Rotterdam, The Netherlands
5
Center for Rhinology and Allergology Wiesbaden, Germany; and Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
6
Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria
7
Allergy Section, Children’s University Hospital “Niño Jesús”, Madrid, Spain
8
Centre for Respiratory Medicine and Allergy, University Hospital of South Manchester, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/all.12638 This article is protected by copyright. All rights reserved.
Accepted Article
9
Dept. of Internal Medicine, Allergy and Clinical Immunology, Medical University of Silesia, Katowice, Poland
10
Allergy Outpatient Clinic, 401 General Military Hospital of Athens, Athens, Greece
11
Dermatology and Allergology Clinic and Policlinic, Ludwig-Maximilians University, Munich, Germany
12
Terveystalo Turku, Allergy Clinic, University of Turku, Turku, Finland
13
Allergy Dept, 2nd Pediatric Clinic, University of Athens, Athens, Greece
14
Center for Pediatrics & Child Health, Institute of Human Development, University of Manchester, UK
15
Section of Allergy and Clinical Immunology, Imperial College London, National Heart and Lung Institute and Royal Brompton Hospital NHS, London, UK
Correspondence: Dr Constantinos Pitsios. Dept. of Nutrition and Dietetics, Harokopio University, Athens, Greece. [email protected]
Short title: Contraindications to Allergen Immunotherapy
Key words: contraindications, allergen immunotherapy, asthma, autoimmune disease, neoplasias, cardiovascular, children, HIV
This article is protected by copyright. All rights reserved.
Accepted Article
ABSTRACT Clinical indications for allergen immunotherapy (AIT) in respiratory and Hymenoptera venom allergy are well established; however, clinical contraindications to AIT are not always well documented. There are some discrepancies when classifying clinical contraindications for different forms of AIT as ‘absolute’ or ‘relative’.
EAACI Task Force on ‘Contraindications to AIT’ was created in order to evaluate and review current literature on clinical contraindications, and to update recommendations for both sublingual and subcutaneous AIT for respiratory and venom immunotherapy. An extensive review of the literature was performed on the use of AIT in asthma, autoimmune disorders, malignant neoplasias, cardiovascular diseases, acquired immunodeficiencies and other chronic diseases, including mental disorders; use in patients treated with β-blockers, ACE inhibitors, or monoamine oxidase inhibitors; in children under 5 years of age; during pregnancy; in patients with poor compliance.
Each topic was addressed by the following three questions: 1) Are there any negative effects of AIT on this concomitant condition/disease?, 2) Are more frequent or more severe AITrelated side effects expected?, and 3) Is AIT expected to be less efficacious?
Evaluations of these clinical conditions as contraindications to AIT were based on insufficient evidence. Most of the conclusions were based on case-reports, and no consistency in the criteria for an absolute or relative contraindication existed.
Based on our review, we provide recommendations for each medical condition assessed. The final decision on the administration of AIT should be based on individual evaluation of any medical condition and a risk/benefit assessment for each patient.
INTRODUCTION Allergen immunotherapy (AIT) has been used worldwide for over a century, and is currently the only causative therapy for the treatment of respiratory allergies, such as rhinitis and asthma (1-3), and Hymenoptera venom allergy (4). Although clinical indications for AIT are specific and widely accepted, clinical contraindications to AIT differ between various guidelines (1, 2, 4, 5). A clinical contraindication to AIT is a situation where the allergen extract must not be given to the patient due to safety reasons (e.g., due to concomitant disease or use with another medicine) (6). Contraindications should be unambiguously, comprehensively and clearly outlined. At present, it is not generally agreed whether some concomitant diseases and situations are clinical contraindications, or whether contraindications apply to both AIT with airborne allergens and to venom immunotherapy (VIT) (4, 7-9). Clinical contraindications to
This article is protected by copyright. All rights reserved.
Accepted Article
AIT may be ‘absolute’ or ‘relative’; depending on wheather a condition/disease makes the particular use of AIT ‘absolutely’ (for absolute) or ‘potentially’ (for relative) inadvisable. Treating a patient with a relative contraindication is justified, if the expected benefit outweighs any risk of condition’s worsening. In the current published literature on AIT contraindications, the use of these two terms is inconsistent. In addition it is not well established whether the same clinical contraindication applies to both sublingual (SLIT) and subcutaneous (SCIT) AIT.
Clinical, legal and ethical issues often arise from these controversies. Therefore, the physician should explain the clinical contraindications to the patient in terms of the balance of risk versus benefit of treatment when prescribing AIT.
The aim of this EAACI Task Force (TF) was to evaluate the current published evidence on clinical contraindications to AIT for respiratory allergy (rhinitis and asthma) and to VIT. We assessed clinical recommendations based on the category of published evidence and the strength of each recommendation (7, 10).
This Position Paper is the outcome of a combined effort between the EAACI Immunotherapy and Venom Hypersensitivity Interest Groups.
METHODOLOGY The TF comprised a panel of fourteen European specialists on Allergy and Clinical Immunology. Selected panel members (CP, BMB PRR, RG, GJS, MT, GP, FR, RGW, OP, EV) performed a literature research to identify the most common and relevant clinical conditions and comorbidities that are currently considered as ‘absolute’ or ‘relative’ clinical contraindications to AIT for respiratory and venom allergies. Three other panel members (MC, PD, NGP) assessed the retrieved reports. National and International Guidelines, and direct communication with National Allergy Societies were also sought when needed.
After defining the most common clinical contraindications to AIT, nine panel members were assigned to review the literature on each topic using Medline (PubMed) search engines. Search results were compared with those of an independent librarian (JHB).
In total, 2,333 published articles were evaluated by reviewing each abstract or paper in detail. Only 150 articles provided useful information on clinical contraindications to AIT; most of these were case reports or case series.
This article is protected by copyright. All rights reserved.
Accepted Article
Based on the search results, we selected the following clinical contraindications: 1. Asthma 2. Autoimmune disorders 3. Malignant neoplasias 4. β-blockers 5. ACE inhibitors 6. Monoamine oxidase inhibitors (MAOIs) 7. Cardiovascular diseases 8. Children ( 200 cells/µL
1. Although based on limited evidence, there is no negative effect of AIT on HIV. (IV) 2. More frequent or more severe side effects are not expected, but cannot be excluded. (IV) 3. Less efficacious AIT is not expected, but cannot be excluded. (IV)
Other chronic diseases - compliance 1.
Conceptually, there are negative effects of AIT on patients immunodeficiencies, or who are in need of immunosuppressive drugs. (NR)
with
2. There is a theoretical risk of more severe side effects in such chronic diseases. (NR) 3. AIT is expected to be less efficacious in patients with issues of inadequate compliance and collaboration, or with a depleted immune system. (NR)
This article is protected by copyright. All rights reserved.
Accepted Article
Table 2: Absolute (A) and Relative (R) contraindications for AIT
Aeroallergens Medical Condition
Venom Immunotherapy
SCIT
SLIT
Asthma (partially controlled)
R
R
R
Asthma (uncontrolled)
A
A
A
Autoimmune disorders in remission
R
R
R
Autoimmune disorders in active forms (non-responding to treatment)
A
A
A
Malignant neoplasias
A
A
R
β-blockers
R
R
No
ACE inhibitors
No
No
R
MAOIs
No
No
No
Cardiovascular diseases
R
R
No
Pregnancy (initiation of AIT)
A
A
A
Pregnancy (continuation of AIT)
No
No
No
Children (200/μL)
R
R
R
AIDS
A
A
A
Psychiatric and/or mental disorders
R
R
R
Chronic infections
R
R
R
Immunodeficiencies
R
R
R
Use of immunosuppressive drugs
R
R
R
Note: SCIT= subcutaneous immunotherapy, SLIT= sublingual immunotherapy, A=Absolute contraindication, R=Relative contraindication, No= no contraindication.
This article is protected by copyright. All rights reserved.
Accepted Article
Table 3: Summary of Clinical Contraindications to AIT Asthma
•
Autoimmune disorders
• AID in remission is a relative contraindication for AIT • An absolute for active forms Strength of recommendation: D
Malignant neoplasias
β-blockers
Poorly controlled/uncontrolled asthma is an absolute (but possibly temporary) contraindication for AIT • Partially controlled asthma is a relative contraindication for AIT Strength of recommendation: A for SCIT; D for SLIT; NR for VIT
•
Malignant neoplasias are considered absolute contraindications, but VIT is a highly-advised option in case of high-risk venom-allergic patients Strength of recommendation: D •
There is no contraindication for β-blockers in VIT, and a relative contraindication for AIT with inhalant allergens • When feasible, β-blockers should be substituted with an alternative in patients undergoing AIT; if β-blockers are required and no effective substitute is available, patients should be evaluated carefully based on an individual risk-benefit assessment Strength of recommendation: C
ACE inhibitors
•
MAOIs
•
Cardiovascular Diseases
•
Children below 5 years of age
•
Pregnancy
•
There is no contraindication for ACE inhibitors for AIT with inhalant allergens • ACE inhibitors should be substituted with an alternative in patients with Hymenoptera venom allergy, if feasible Strength of recommendation: C Caution is recommended with the use of epinephrine in patients treated with MAOIs Strength of recommendation: D Cardiovascular diseases per se are not contraindications for VIT, but are a relative contraindication for AIT with inhalant allergens • The status of cardiovascular disease, its treatment, the risk of anaphylaxis, (necessitating epinephrine treatment) should be carefully evaluated, preferably with the cardiologist, before initiating AIT Strength of recommendation: D AIT is not a treatment option for infants (0–2 years of age); it is and absolute contraindication • Pre-school age (2-5 years of age) is a relative contraindication for AIT; AIT should be considered as a therapeutic option only in limited cases Strength of recommendation: C There is an absolute contraindication to initiate AIT during pregnancy
This article is protected by copyright. All rights reserved.
Accepted Article
•
It is recommended to continue a well-tolerated, on-going AIT during pregnancy, but with caution Strength of recommendation: D Acquired immunodeficiencies
•
HIV infection is a relative contraindication for AIT and can be evaluated on an individual basis Strength of recommendation: D •
Category C stage disease (CDC 1993 Classification) is considered an absolute contraindication Strength of recommendation: NR Other Chronic Diseases Compliance
•
AIT should be prescribed depending on the individual patient’s conditions, considering these entities as relative contraindications Strength of recommendation: NR
This article is protected by copyright. All rights reserved.
Article Type: Position Paper
Clinical Contraindications to Allergen Immunotherapy: an EAACI Position Paper Pitsios C1, Demoly P2, Bilò MB3, Gerth van Wijk R4, Pfaar O5, Sturm GJ6, Rodriguez del Rio P7, Tsoumani M8, Gawlik R9, Paraskevopoulos G10, Ruëff F11, Valovirta E12, Papadopoulos NG13, 14, and Calderón MA15
1
Dept. of Nutrition and Dietetics, Harokopio University, Athens, Greece
2
Département de Pneumologie et Addictologie, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, France; and Sorbonne Universités, UPMC Paris 06, UMR-S 1136, IPLESP, Equipe EPAR, 75013, Paris, France
3
Dept. of Internal Medicine, Allergy Unit, University Hospital, Ancona, Italy
4
Dept of Internal Medicine, Section of Allergology, Erasmus MC, Rotterdam, The Netherlands
5
Center for Rhinology and Allergology Wiesbaden, Germany; and Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
6
Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria
7
Allergy Section, Children’s University Hospital “Niño Jesús”, Madrid, Spain
8
Centre for Respiratory Medicine and Allergy, University Hospital of South Manchester, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/all.12638 This article is protected by copyright. All rights reserved.
Accepted Article
9
Dept. of Internal Medicine, Allergy and Clinical Immunology, Medical University of Silesia, Katowice, Poland
10
Allergy Outpatient Clinic, 401 General Military Hospital of Athens, Athens, Greece
11
Dermatology and Allergology Clinic and Policlinic, Ludwig-Maximilians University, Munich, Germany
12
Terveystalo Turku, Allergy Clinic, University of Turku, Turku, Finland
13
Allergy Dept, 2nd Pediatric Clinic, University of Athens, Athens, Greece
14
Center for Pediatrics & Child Health, Institute of Human Development, University of Manchester, UK
15
Section of Allergy and Clinical Immunology, Imperial College London, National Heart and Lung Institute and Royal Brompton Hospital NHS, London, UK
Correspondence: Dr Constantinos Pitsios. Dept. of Nutrition and Dietetics, Harokopio University, Athens, Greece. [email protected]
Short title: Contraindications to Allergen Immunotherapy
Key words: contraindications, allergen immunotherapy, asthma, autoimmune disease, neoplasias, cardiovascular, children, HIV
This article is protected by copyright. All rights reserved.
Accepted Article
ABSTRACT Clinical indications for allergen immunotherapy (AIT) in respiratory and Hymenoptera venom allergy are well established; however, clinical contraindications to AIT are not always well documented. There are some discrepancies when classifying clinical contraindications for different forms of AIT as ‘absolute’ or ‘relative’.
EAACI Task Force on ‘Contraindications to AIT’ was created in order to evaluate and review current literature on clinical contraindications, and to update recommendations for both sublingual and subcutaneous AIT for respiratory and venom immunotherapy. An extensive review of the literature was performed on the use of AIT in asthma, autoimmune disorders, malignant neoplasias, cardiovascular diseases, acquired immunodeficiencies and other chronic diseases, including mental disorders; use in patients treated with β-blockers, ACE inhibitors, or monoamine oxidase inhibitors; in children under 5 years of age; during pregnancy; in patients with poor compliance.
Each topic was addressed by the following three questions: 1) Are there any negative effects of AIT on this concomitant condition/disease?, 2) Are more frequent or more severe AITrelated side effects expected?, and 3) Is AIT expected to be less efficacious?
Evaluations of these clinical conditions as contraindications to AIT were based on insufficient evidence. Most of the conclusions were based on case-reports, and no consistency in the criteria for an absolute or relative contraindication existed.
Based on our review, we provide recommendations for each medical condition assessed. The final decision on the administration of AIT should be based on individual evaluation of any medical condition and a risk/benefit assessment for each patient.
INTRODUCTION Allergen immunotherapy (AIT) has been used worldwide for over a century, and is currently the only causative therapy for the treatment of respiratory allergies, such as rhinitis and asthma (1-3), and Hymenoptera venom allergy (4). Although clinical indications for AIT are specific and widely accepted, clinical contraindications to AIT differ between various guidelines (1, 2, 4, 5). A clinical contraindication to AIT is a situation where the allergen extract must not be given to the patient due to safety reasons (e.g., due to concomitant disease or use with another medicine) (6). Contraindications should be unambiguously, comprehensively and clearly outlined. At present, it is not generally agreed whether some concomitant diseases and situations are clinical contraindications, or whether contraindications apply to both AIT with airborne allergens and to venom immunotherapy (VIT) (4, 7-9). Clinical contraindications to
This article is protected by copyright. All rights reserved.
Accepted Article
AIT may be ‘absolute’ or ‘relative’; depending on wheather a condition/disease makes the particular use of AIT ‘absolutely’ (for absolute) or ‘potentially’ (for relative) inadvisable. Treating a patient with a relative contraindication is justified, if the expected benefit outweighs any risk of condition’s worsening. In the current published literature on AIT contraindications, the use of these two terms is inconsistent. In addition it is not well established whether the same clinical contraindication applies to both sublingual (SLIT) and subcutaneous (SCIT) AIT.
Clinical, legal and ethical issues often arise from these controversies. Therefore, the physician should explain the clinical contraindications to the patient in terms of the balance of risk versus benefit of treatment when prescribing AIT.
The aim of this EAACI Task Force (TF) was to evaluate the current published evidence on clinical contraindications to AIT for respiratory allergy (rhinitis and asthma) and to VIT. We assessed clinical recommendations based on the category of published evidence and the strength of each recommendation (7, 10).
This Position Paper is the outcome of a combined effort between the EAACI Immunotherapy and Venom Hypersensitivity Interest Groups.
METHODOLOGY The TF comprised a panel of fourteen European specialists on Allergy and Clinical Immunology. Selected panel members (CP, BMB PRR, RG, GJS, MT, GP, FR, RGW, OP, EV) performed a literature research to identify the most common and relevant clinical conditions and comorbidities that are currently considered as ‘absolute’ or ‘relative’ clinical contraindications to AIT for respiratory and venom allergies. Three other panel members (MC, PD, NGP) assessed the retrieved reports. National and International Guidelines, and direct communication with National Allergy Societies were also sought when needed.
After defining the most common clinical contraindications to AIT, nine panel members were assigned to review the literature on each topic using Medline (PubMed) search engines. Search results were compared with those of an independent librarian (JHB).
In total, 2,333 published articles were evaluated by reviewing each abstract or paper in detail. Only 150 articles provided useful information on clinical contraindications to AIT; most of these were case reports or case series.
This article is protected by copyright. All rights reserved.
Accepted Article
Based on the search results, we selected the following clinical contraindications: 1. Asthma 2. Autoimmune disorders 3. Malignant neoplasias 4. β-blockers 5. ACE inhibitors 6. Monoamine oxidase inhibitors (MAOIs) 7. Cardiovascular diseases 8. Children ( 200 cells/µL
1. Although based on limited evidence, there is no negative effect of AIT on HIV. (IV) 2. More frequent or more severe side effects are not expected, but cannot be excluded. (IV) 3. Less efficacious AIT is not expected, but cannot be excluded. (IV)
Other chronic diseases - compliance 1.
Conceptually, there are negative effects of AIT on patients immunodeficiencies, or who are in need of immunosuppressive drugs. (NR)
with
2. There is a theoretical risk of more severe side effects in such chronic diseases. (NR) 3. AIT is expected to be less efficacious in patients with issues of inadequate compliance and collaboration, or with a depleted immune system. (NR)
This article is protected by copyright. All rights reserved.
Accepted Article
Table 2: Absolute (A) and Relative (R) contraindications for AIT
Aeroallergens Medical Condition
Venom Immunotherapy
SCIT
SLIT
Asthma (partially controlled)
R
R
R
Asthma (uncontrolled)
A
A
A
Autoimmune disorders in remission
R
R
R
Autoimmune disorders in active forms (non-responding to treatment)
A
A
A
Malignant neoplasias
A
A
R
β-blockers
R
R
No
ACE inhibitors
No
No
R
MAOIs
No
No
No
Cardiovascular diseases
R
R
No
Pregnancy (initiation of AIT)
A
A
A
Pregnancy (continuation of AIT)
No
No
No
Children (200/μL)
R
R
R
AIDS
A
A
A
Psychiatric and/or mental disorders
R
R
R
Chronic infections
R
R
R
Immunodeficiencies
R
R
R
Use of immunosuppressive drugs
R
R
R
Note: SCIT= subcutaneous immunotherapy, SLIT= sublingual immunotherapy, A=Absolute contraindication, R=Relative contraindication, No= no contraindication.
This article is protected by copyright. All rights reserved.
Accepted Article
Table 3: Summary of Clinical Contraindications to AIT Asthma
•
Autoimmune disorders
• AID in remission is a relative contraindication for AIT • An absolute for active forms Strength of recommendation: D
Malignant neoplasias
β-blockers
Poorly controlled/uncontrolled asthma is an absolute (but possibly temporary) contraindication for AIT • Partially controlled asthma is a relative contraindication for AIT Strength of recommendation: A for SCIT; D for SLIT; NR for VIT
•
Malignant neoplasias are considered absolute contraindications, but VIT is a highly-advised option in case of high-risk venom-allergic patients Strength of recommendation: D •
There is no contraindication for β-blockers in VIT, and a relative contraindication for AIT with inhalant allergens • When feasible, β-blockers should be substituted with an alternative in patients undergoing AIT; if β-blockers are required and no effective substitute is available, patients should be evaluated carefully based on an individual risk-benefit assessment Strength of recommendation: C
ACE inhibitors
•
MAOIs
•
Cardiovascular Diseases
•
Children below 5 years of age
•
Pregnancy
•
There is no contraindication for ACE inhibitors for AIT with inhalant allergens • ACE inhibitors should be substituted with an alternative in patients with Hymenoptera venom allergy, if feasible Strength of recommendation: C Caution is recommended with the use of epinephrine in patients treated with MAOIs Strength of recommendation: D Cardiovascular diseases per se are not contraindications for VIT, but are a relative contraindication for AIT with inhalant allergens • The status of cardiovascular disease, its treatment, the risk of anaphylaxis, (necessitating epinephrine treatment) should be carefully evaluated, preferably with the cardiologist, before initiating AIT Strength of recommendation: D AIT is not a treatment option for infants (0–2 years of age); it is and absolute contraindication • Pre-school age (2-5 years of age) is a relative contraindication for AIT; AIT should be considered as a therapeutic option only in limited cases Strength of recommendation: C There is an absolute contraindication to initiate AIT during pregnancy
This article is protected by copyright. All rights reserved.
Accepted Article
•
It is recommended to continue a well-tolerated, on-going AIT during pregnancy, but with caution Strength of recommendation: D Acquired immunodeficiencies
•
HIV infection is a relative contraindication for AIT and can be evaluated on an individual basis Strength of recommendation: D •
Category C stage disease (CDC 1993 Classification) is considered an absolute contraindication Strength of recommendation: NR Other Chronic Diseases Compliance
•
AIT should be prescribed depending on the individual patient’s conditions, considering these entities as relative contraindications Strength of recommendation: NR
This article is protected by copyright. All rights reserved.
