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Immunotherapy in asthma
PERSONAL PRACTICE
Immunotherapy in asthma
than mild local swelling at the site of the injection he suffered no adverse consequences. He subsequently reported that despite high pollen counts and less consistent use of pharmacotherapy his symptoms during the season were dramatically improved and he experienced the best spring season for many years. He is scheduled to have 3 consecutive years of pre-seasonal therapy.
J O Warner
Evidence base Historical introduction
While immunotherapy was initially developed in adults it became clear in numerous trials that the best clinical responses occurred in children particularly if the treatment was introduced early in the evolution of their allergic disease and in those with single allergies. The more persistent the disease, particularly in relation to asthma, and the wider the range of allergens involved the less likely there was to be a favourable response. Unlike any other therapy for allergic diseases it has a prolonged carry-over effect when withdrawn after 3 years of treatment. One study of grass and/or tree pollen subcutaneous immunotherapy has shown that in children with seasonal allergic rhinitis alone, the treatment will reduce the subsequent prevalence of new onset asthma compared with a contemporaneous control group not treated with immunotherapy. This effect was sustained during 3 years of injection therapy and 2 subsequent years after the treatment course had finished. Other studies have shown that giving immunotherapy to patients who only have one allergy reduces spread to new allergen sensitizations. These studies all point to the potential for allergen immunotherapy to have far greater benefits early in the evolution of allergic disease and thus firmly focused on the paediatric age group. Successive Cochrane reviews of allergen immunotherapy for asthma have shown benefits in terms of improved control of the asthma, reduced medication requirements and bronchial hyperresponsiveness. It is interesting that national and international guidelines for the management of asthma recommend allergen avoidance for which the evidence base is extremely tenuous but fail to recommend immunotherapy despite the evidence. The reason is that the size of benefit versus risk of immunotherapy compared with conventional pharmacotherapy in the management of asthma is not known. The risk of anaphylaxis is greatest in individuals with poorly controlled asthma. As a consequence the general recommendation in the UK is that this therapy should not be used in individuals with persistent asthma.
Subcutaneously injected allergen immunotherapy was first developed at St Mary’s hospital in London in 1911 with the mistaken belief that pollen produced toxin which induced hay fever (seasonal allergic rhino-conjunctivitis). It clearly had beneficial effects at a time when there was no other effective therapy. During the first half of the 20th century it was widely employed for many different allergic conditions including asthma but only in the 1950s did placebo-controlled clinical trials confirm efficacy for allergic rhinitis and asthma associated with grass pollen, tree pollen, house mite and subsequently cat and dog allergy. However, the indiscriminate use even in primary care resulted in a number of fatalities due to anaphylaxis. This led to the (then) Committee of Safety for Medicines recommending that this modality of treatment should be withdrawn with the exception of its use in patients who had anaphylaxis due to bee or wasp stings. The commonest risk factor for death was the presence of asthma. It was felt that pharmacotherapy was sufficiently efficacious and definitely safer and thus immunotherapy had no place in management protocols.
Case report James aged 15 years had a 6-year history of seasonal rhinoconjunctivitis between May and August. Despite regular antihistamines, nasal cortico-steroids, antihistamine eye drops, and beta-agonists as necessary his severe symptoms which included a degree of coughing and wheezing resulted in sleep disturbance, poor school performance and frequent absences. He and his parents were concerned about the impact on approaching GCSE exams. Allergy skin prick tests revealed a 10 mm weal to grass pollen and a weak response (3 mm) to house dust mite. Flow volume loop lung function in the winter showed a slight reduction in flow at low lung volumes. James was entered into the grass pollen immunotherapy programme and attended the day ward for each of four subcutaneous injections of Pollinex Quattro (Allergy Therapeutics Worthing UK) administered at 1 week intervals in January. This vaccine contains a chemically modified pollen extract with reduced allergenicity. Immunogenicity is increased by the presence of mono-phosphoryl lipid A, a microbial product which enhances an immunizing response. This adjuvant is also used in HPV vaccines. He had his lung function checked before each treatment and then remained under observation for a minimum of 1 h after each injection. Other
Current practice As a consequence of the safety concerns, if immunotherapy is to be considered for children with any allergic problem then this should be initiated and conducted in tertiary centres. Risk/ benefit profiles must be considered in relation to a thorough evaluation to establish the importance of allergens in contributing to the disease process. Subsequent treatment must be administered in a safe environment with the capacity to deal with any eventualities including anaphylaxis. This entails observation for at least 1 h after each subcutaneous injection. The only subcutaneous vaccines currently available on prescription in the UK are those for wasp and bee venom, tree and grass pollen. Any other allergen vaccines can only be accessed on a named patient basis. These vaccines are less modified, do not have as potent adjuvants and data of efficacy and safety are relatively limited.
J O Warner FMedSci is Professor of Paediatrics and Head of Department at Imperial College London & Director of Research, Women and Childrens Clinical Programme Group at Imperial College Healthcare NHS Trust (Academic Health Science Centre), London, UK. Conflict of interest: Paid lectures for Allergy Therapeutics and ALK-Abello. I am also in reciept of a research grant from Allergy Therapeutics.
PAEDIATRICS AND CHILD HEALTH 21:7
329
Ó 2011 Elsevier Ltd. All rights reserved.
PERSONAL PRACTICE
The other immunotherapy now available is a sublingual tablet of grass pollen (GrazaxÒ, ALK-Abello) which is administered daily (in the same dose) throughout the year including during the season. Trials have shown reasonable beneficial effects in adults and children. The first dose should be administered under supervision and if tolerated continuation can be home therapy. Transient mild oral itch after the first few doses is relatively common but the treatment is remarkably safe.
case necessitated protracted and sometimes difficult negotiation to ensure that treatment is sustained. In the 1970s I completed a trial of subcutaneous immunotherapy using a house mite vaccine in children with moderate to severe asthma. This generated very beneficial responses and in many parts of the world this form of treatment is still employed for the management of persistent asthma but not in the UK. However, developments are in progress to generate a chemically modified equivalent with the immuno-adjuvant used in the pollen vaccine. I am optimistic that this will ultimately gain a place in the therapeutic algorithm for the management of asthma but clearly not at present. There remain one or two exceptional cases where I have acquired on a named patient basis vaccines for the treatment of cat, dog and indeed also horse allergy. The latter was for one adolescent with severe asthma, growth stunted as a result of recurrent use of oral and high dose inhaled steroids, whose only ambition was to become a jockey. He insisted that he would rather die than not be allowed ride horses despite an extreme horse allergy. He underwent horse immunotherapy which at least allowed him to continue to work as a stable hand though not to achieve fame as a jockey.A
Venom There is absolutely no doubt that children with or without asthma who have had a full blown anaphylactic reaction following a wasp or bee sting should be submitted to an immunotherapy programme. The reduction in risk of anaphylaxis is very considerable. It is however important to establish that the reaction was anaphylaxis. Many children with lesser severities of reaction to wasp and bee venom do not require immunotherapy. The natural history for less severe reactions is of progressive attenuation with an 85% chance that subsequent stings will not cause a significant response. However, such patients do need to be armed with autoinjector adrenalin until it is apparent following a subsequent sting that they do not have a continuing problem.
FURTHER READING Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma (review). The Cochrane Collaboration 2003. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling H-J, Valovirta E. Standards for practical allergen-specific immunotherapy. Allergy 2006; 61(suppl 82): 1e20. Durham SR, Walker SM, Varga E-M, et al. Long-term clinical efficacy of grass pollen immunotherapy. N Engl J Med 1999; 341: 468e75. Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, et al. Five year followup on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 2006; 61: 855e9. Wahn U, Malling H-J, Kleine-Tebbe J. Sublingual immunotherapy and children e ready for prime time? Pediatr Allergy Immunol 2010; 21: 559e63. Warner JO, Price JF, Soothill JF, Hey EN. Controlled trial of hyposensitisation for Dermatophagoides pteronyssinus in children with asthma. Lancet 1978; 2: 912e5. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 2005; 60: 4e12.
Pollen With regard to inhalant allergens there should also be no hesitation about considering tree and/or grass pollen immunotherapy using the new attenuated adjuvantized vaccines in children with severe allergic rhino-conjunctivitis with or without seasonal asthma. The vaccines are administered during the winter and therefore at a time when there is no ongoing allergic inflammation in the airway. It is my practice to focus this treatment on children who have failed to be controlled on conventional pharmacotherapy and in whom there is a significant impairment of quality of life. It is very apparent that examination performance is significantly compromised by pollen allergy. Thus, studies have shown that children with seasonal rhino-conjunctivitis and/or asthma have reduced GCSE marks compared with the mock examinations while most pupils will have an increase between mock and actual exam. The GCSEs, A levels and degree exams fall firmly in the middle of the pollen season. In my service we have ever increasing numbers of older children and adolescents undergoing this programme of therapy. For those children who have significant perennial asthma superimposed on seasonal asthma the preference is for the use of the sublingual tablet, GrazaxÒ. Sadly, however, many Primary Care Trusts currently will refuse to underwrite the costs of this therapy leaving it to the hospital Trusts to decide whether they’re willing to foot the bill. In the current economic climate this is unlikely.
Practice points C
C
Other allergens In my clinical service relatively few patients are receiving immunotherapy for allergies beyond those of pollens or insect venoms. A select few children with severe persistent allergic rhinitis often associated with a degree of asthma are receiving sublingual house mite immunotherapy using aqueous extracts acquired on a named patient basis. These are administered daily with a slow build up to a maximum dose and then continued on a daily basis for a minimum of 3 years. Responses to this treatment have been favourable but there is a major funding concern which has in each
PAEDIATRICS AND CHILD HEALTH 21:7
C
C
C
330
Allergen immunotherapy is the only treatment for allergic disease which modifies the allergic march and has a prolonged carry-over effect if withdrawn after 3 years. Fatalities during subcutaneous allergen injections in patients with poorly controlled asthma have led to restricted use and absence from therapeutic algorithms for asthma. Evidence supports its safe use in specialist centres for season rhinoconjunctivitis and insect venom allergy with or without asthma. Sublingual allergen immunotherapy is a safer option for patients with persistent asthma. New vaccines are being developed with reduced allergenicity and enhanced immunogenicity which are likely to change practice in the future.
Ó 2011 Elsevier Ltd. All rights reserved.
Immunotherapy in asthma
than mild local swelling at the site of the injection he suffered no adverse consequences. He subsequently reported that despite high pollen counts and less consistent use of pharmacotherapy his symptoms during the season were dramatically improved and he experienced the best spring season for many years. He is scheduled to have 3 consecutive years of pre-seasonal therapy.
J O Warner
Evidence base Historical introduction
While immunotherapy was initially developed in adults it became clear in numerous trials that the best clinical responses occurred in children particularly if the treatment was introduced early in the evolution of their allergic disease and in those with single allergies. The more persistent the disease, particularly in relation to asthma, and the wider the range of allergens involved the less likely there was to be a favourable response. Unlike any other therapy for allergic diseases it has a prolonged carry-over effect when withdrawn after 3 years of treatment. One study of grass and/or tree pollen subcutaneous immunotherapy has shown that in children with seasonal allergic rhinitis alone, the treatment will reduce the subsequent prevalence of new onset asthma compared with a contemporaneous control group not treated with immunotherapy. This effect was sustained during 3 years of injection therapy and 2 subsequent years after the treatment course had finished. Other studies have shown that giving immunotherapy to patients who only have one allergy reduces spread to new allergen sensitizations. These studies all point to the potential for allergen immunotherapy to have far greater benefits early in the evolution of allergic disease and thus firmly focused on the paediatric age group. Successive Cochrane reviews of allergen immunotherapy for asthma have shown benefits in terms of improved control of the asthma, reduced medication requirements and bronchial hyperresponsiveness. It is interesting that national and international guidelines for the management of asthma recommend allergen avoidance for which the evidence base is extremely tenuous but fail to recommend immunotherapy despite the evidence. The reason is that the size of benefit versus risk of immunotherapy compared with conventional pharmacotherapy in the management of asthma is not known. The risk of anaphylaxis is greatest in individuals with poorly controlled asthma. As a consequence the general recommendation in the UK is that this therapy should not be used in individuals with persistent asthma.
Subcutaneously injected allergen immunotherapy was first developed at St Mary’s hospital in London in 1911 with the mistaken belief that pollen produced toxin which induced hay fever (seasonal allergic rhino-conjunctivitis). It clearly had beneficial effects at a time when there was no other effective therapy. During the first half of the 20th century it was widely employed for many different allergic conditions including asthma but only in the 1950s did placebo-controlled clinical trials confirm efficacy for allergic rhinitis and asthma associated with grass pollen, tree pollen, house mite and subsequently cat and dog allergy. However, the indiscriminate use even in primary care resulted in a number of fatalities due to anaphylaxis. This led to the (then) Committee of Safety for Medicines recommending that this modality of treatment should be withdrawn with the exception of its use in patients who had anaphylaxis due to bee or wasp stings. The commonest risk factor for death was the presence of asthma. It was felt that pharmacotherapy was sufficiently efficacious and definitely safer and thus immunotherapy had no place in management protocols.
Case report James aged 15 years had a 6-year history of seasonal rhinoconjunctivitis between May and August. Despite regular antihistamines, nasal cortico-steroids, antihistamine eye drops, and beta-agonists as necessary his severe symptoms which included a degree of coughing and wheezing resulted in sleep disturbance, poor school performance and frequent absences. He and his parents were concerned about the impact on approaching GCSE exams. Allergy skin prick tests revealed a 10 mm weal to grass pollen and a weak response (3 mm) to house dust mite. Flow volume loop lung function in the winter showed a slight reduction in flow at low lung volumes. James was entered into the grass pollen immunotherapy programme and attended the day ward for each of four subcutaneous injections of Pollinex Quattro (Allergy Therapeutics Worthing UK) administered at 1 week intervals in January. This vaccine contains a chemically modified pollen extract with reduced allergenicity. Immunogenicity is increased by the presence of mono-phosphoryl lipid A, a microbial product which enhances an immunizing response. This adjuvant is also used in HPV vaccines. He had his lung function checked before each treatment and then remained under observation for a minimum of 1 h after each injection. Other
Current practice As a consequence of the safety concerns, if immunotherapy is to be considered for children with any allergic problem then this should be initiated and conducted in tertiary centres. Risk/ benefit profiles must be considered in relation to a thorough evaluation to establish the importance of allergens in contributing to the disease process. Subsequent treatment must be administered in a safe environment with the capacity to deal with any eventualities including anaphylaxis. This entails observation for at least 1 h after each subcutaneous injection. The only subcutaneous vaccines currently available on prescription in the UK are those for wasp and bee venom, tree and grass pollen. Any other allergen vaccines can only be accessed on a named patient basis. These vaccines are less modified, do not have as potent adjuvants and data of efficacy and safety are relatively limited.
J O Warner FMedSci is Professor of Paediatrics and Head of Department at Imperial College London & Director of Research, Women and Childrens Clinical Programme Group at Imperial College Healthcare NHS Trust (Academic Health Science Centre), London, UK. Conflict of interest: Paid lectures for Allergy Therapeutics and ALK-Abello. I am also in reciept of a research grant from Allergy Therapeutics.
PAEDIATRICS AND CHILD HEALTH 21:7
329
Ó 2011 Elsevier Ltd. All rights reserved.
PERSONAL PRACTICE
The other immunotherapy now available is a sublingual tablet of grass pollen (GrazaxÒ, ALK-Abello) which is administered daily (in the same dose) throughout the year including during the season. Trials have shown reasonable beneficial effects in adults and children. The first dose should be administered under supervision and if tolerated continuation can be home therapy. Transient mild oral itch after the first few doses is relatively common but the treatment is remarkably safe.
case necessitated protracted and sometimes difficult negotiation to ensure that treatment is sustained. In the 1970s I completed a trial of subcutaneous immunotherapy using a house mite vaccine in children with moderate to severe asthma. This generated very beneficial responses and in many parts of the world this form of treatment is still employed for the management of persistent asthma but not in the UK. However, developments are in progress to generate a chemically modified equivalent with the immuno-adjuvant used in the pollen vaccine. I am optimistic that this will ultimately gain a place in the therapeutic algorithm for the management of asthma but clearly not at present. There remain one or two exceptional cases where I have acquired on a named patient basis vaccines for the treatment of cat, dog and indeed also horse allergy. The latter was for one adolescent with severe asthma, growth stunted as a result of recurrent use of oral and high dose inhaled steroids, whose only ambition was to become a jockey. He insisted that he would rather die than not be allowed ride horses despite an extreme horse allergy. He underwent horse immunotherapy which at least allowed him to continue to work as a stable hand though not to achieve fame as a jockey.A
Venom There is absolutely no doubt that children with or without asthma who have had a full blown anaphylactic reaction following a wasp or bee sting should be submitted to an immunotherapy programme. The reduction in risk of anaphylaxis is very considerable. It is however important to establish that the reaction was anaphylaxis. Many children with lesser severities of reaction to wasp and bee venom do not require immunotherapy. The natural history for less severe reactions is of progressive attenuation with an 85% chance that subsequent stings will not cause a significant response. However, such patients do need to be armed with autoinjector adrenalin until it is apparent following a subsequent sting that they do not have a continuing problem.
FURTHER READING Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma (review). The Cochrane Collaboration 2003. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling H-J, Valovirta E. Standards for practical allergen-specific immunotherapy. Allergy 2006; 61(suppl 82): 1e20. Durham SR, Walker SM, Varga E-M, et al. Long-term clinical efficacy of grass pollen immunotherapy. N Engl J Med 1999; 341: 468e75. Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, et al. Five year followup on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 2006; 61: 855e9. Wahn U, Malling H-J, Kleine-Tebbe J. Sublingual immunotherapy and children e ready for prime time? Pediatr Allergy Immunol 2010; 21: 559e63. Warner JO, Price JF, Soothill JF, Hey EN. Controlled trial of hyposensitisation for Dermatophagoides pteronyssinus in children with asthma. Lancet 1978; 2: 912e5. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 2005; 60: 4e12.
Pollen With regard to inhalant allergens there should also be no hesitation about considering tree and/or grass pollen immunotherapy using the new attenuated adjuvantized vaccines in children with severe allergic rhino-conjunctivitis with or without seasonal asthma. The vaccines are administered during the winter and therefore at a time when there is no ongoing allergic inflammation in the airway. It is my practice to focus this treatment on children who have failed to be controlled on conventional pharmacotherapy and in whom there is a significant impairment of quality of life. It is very apparent that examination performance is significantly compromised by pollen allergy. Thus, studies have shown that children with seasonal rhino-conjunctivitis and/or asthma have reduced GCSE marks compared with the mock examinations while most pupils will have an increase between mock and actual exam. The GCSEs, A levels and degree exams fall firmly in the middle of the pollen season. In my service we have ever increasing numbers of older children and adolescents undergoing this programme of therapy. For those children who have significant perennial asthma superimposed on seasonal asthma the preference is for the use of the sublingual tablet, GrazaxÒ. Sadly, however, many Primary Care Trusts currently will refuse to underwrite the costs of this therapy leaving it to the hospital Trusts to decide whether they’re willing to foot the bill. In the current economic climate this is unlikely.
Practice points C
C
Other allergens In my clinical service relatively few patients are receiving immunotherapy for allergies beyond those of pollens or insect venoms. A select few children with severe persistent allergic rhinitis often associated with a degree of asthma are receiving sublingual house mite immunotherapy using aqueous extracts acquired on a named patient basis. These are administered daily with a slow build up to a maximum dose and then continued on a daily basis for a minimum of 3 years. Responses to this treatment have been favourable but there is a major funding concern which has in each
PAEDIATRICS AND CHILD HEALTH 21:7
C
C
C
330
Allergen immunotherapy is the only treatment for allergic disease which modifies the allergic march and has a prolonged carry-over effect if withdrawn after 3 years. Fatalities during subcutaneous allergen injections in patients with poorly controlled asthma have led to restricted use and absence from therapeutic algorithms for asthma. Evidence supports its safe use in specialist centres for season rhinoconjunctivitis and insect venom allergy with or without asthma. Sublingual allergen immunotherapy is a safer option for patients with persistent asthma. New vaccines are being developed with reduced allergenicity and enhanced immunogenicity which are likely to change practice in the future.
Ó 2011 Elsevier Ltd. All rights reserved.