From 6th to 9th November 2010, the 8th Asia Pacific Congress of Asthma, Allergy, and Clinical Immunology was held at the Suntec Singapore International Convention and Exhibition Centre, in conjunction with the 2010 Congress of the Asia Pacific Association of Paediatric Allergy, Respirology and Immunology.
New approaches to the treatment of asthma
Allergy in early life symposium
New approaches to the treatment of asthma
When asthma was first recognised as a disease entity in the late 19th century, available therapy was little more than ephedrine and Datura strammonium, an anticholinergic Indian herb which in fact remained in use until the late 1970s.
The next breakthrough came at the turn of the 20th century with adrenaline. Over the years, adrenaline underwent several refinements into the β-2 agonist salbutamol (albuterol) in 1969, the long-acting salmeterol in 1987, and, this year, the ultra-long-acting indacaterol. Even the vehicle evolved from injection to aqueous inhalation to the current powder inhalation.
“In the asthma treatment paradigm, what we’re really doing is improving the chemistry of the brain that interacts with the β-2 receptor. This is classical medicinal chemistry that could be applied to receptor pharmacology,” explained Dr Holgate, professor of immunopharmacology at the School of Medicine, Southampton General Hospital in the UK. However, he added that “of course, we recognise that ad libitum use of inhaled bronchodilators wasn’t really going to lead to the cure of asthma.”
Other innovations included preventive therapy through mast cell stabilisation with sodium cromoglycate, and the breakthrough, if serendipitous, discovery of inhaled corticosteroids. Indeed, inhaled corticosteroids with a long-acting β-2 agonist has been, for quite some time, the mainstay of asthma therapy, and only two new therapies have emerged in the last 50 years: montelukast, a cysteinyl leukotriene receptor antagonist, and omalizumab, an anti-human IgE that acts by inhibiting the allergic cascade.
“Since the discovery of omalizumab, there has been a huge amount of research focused on trying to find novel biologics that interfere with the allergic cascade,” Dr Holgate reported. This unmitigated search for newer treatment options is driven by a clear unmet need for safe and effective therapy for inadequately controlled, severe, persistent asthma. “β-agonists, inhaled corticosteroids, and leukotriene antagonists are very good for managing most types of asthma, but about 10% have severe disease,” said Dr Holgate. He added that hospital admissions and mortality due to asthma remain to be very real concerns in this population subset.
New therapeutic approaches have focused on targeting T-cell activation and their cytokines. Studies that look at targeting IL-13 and IL-4 receptors have initially shown promise in allergen challenge and have received generous support, but unfortunately failed to show efficacy in later studies. Other cytokines that initially showed potential were IL-5 and TNF-α, but further study also failed to show successful results. Other targets in the allergic cascade have also been studied, but none have managed to meet expectations in clinical trials.
“This is frankly disappointing,” Dr Holgate lamented. “Anti-IgE is of course a great innovation, but those of us who use it recognise that only about a third of the patients do really well with the treatment.” He added that of the remainder, a third get some improvement, and the remaining third hardly any at all.
Taken together, however, past studies do suggest that asthma has different subtypes. Dr Holgate therefore recommends “stratified medicine,” a movement which aims to identify the right medicine for the right patient at the right time, thus boosting improvement in patient outcomes and compliance; precision in physician prescription; outcome-driven return on investment in innovative medicines for governments and other payers; confidence in conditional licensing and interpretability of post-marketing surveillance data for regulatory bodies; and investment confidence and optimisation of innovation for pharmacologic companies. “Everyone can be a winner,” Dr Holgate enthused.
Allergy in early life
Drs Susan Prescott, Allen Liang and Stephen Holgate presented a three-pronged discussion on allergy development in one of the symposia during the second day of the Congress.
Epigenetics in the allergy epidemic
Dr Prescott opened the symposium by presenting the role of epigenetics in the allergy epidemic. She began by explaining that although humans have identical DNA, cellular diversity is achieved by genes switching different traits on and off at different times. This complex dance is controlled by what is called an epigenetic program. Dr Prescott further added that changes in gene expression or silencing are determined not by gene sequence, but by stereotypic changes in the chromatin and DNA: methylation generally results in silencing gene expression, whilst acetylation gives rise to gene activation.
Exposure to environmental factors can affect such processes as DNA methylation and acetylation. According to Dr Prescott, there is some speculation that environmental changes that increase gene methylation play a role in the development of allergic disease. Moreover, Dr Prescott illustrated how environmental exposures that modify gene expression can give rise to a genotype that can begin exerting its effects antenatally, giving rise to the emerging neonatal differences in immune response and continuing its influence after birth, ultimately exerting trans-generational effects through an evolving phenotype. Dr Prescott then further explained how environmental factors and a preset “epigenetic program” can combine to stimulate adaptive changes in gene expression in utero in preparation for the anticipated postnatal environment, resulting in presymptomatic differences in immune function at birth. Ongoing environmental modification postnatally thereafter shapes an established phenotype.
Allergen exposure in allergy prevention
Dr Liang picked up the allergy discussion from Dr Prescott by tackling the role of allergen exposure in the prevention of allergy. He acknowledged the significance of genetic predisposition to allergy, citing parental allergic history as the single most important risk factor for the development of asthma, atopic dermatitis, and allergic rhinitis in childhood. That said, Dr Liang proceeded on his lecture with a thoroughly engaging discussion of the environmental factors affecting allergic disease. After briefly discussing infant sensitivity and development of tolerance to allergens, he began presenting new challenges to popular insights on allergy development.
For instance: Does minimising exposure to allergens at an early critical period reduce or prevent allergy development? Not necessarily, if Dr Liang’s lecture is to be believed. Whilst many would answer this question with a quick and unequivocal “Yes,” Dr Liang reveals that this instinct has in fact not been proven correct in many situations. “Avoidance is not the magic wand in disease prevention,” Dr Liang declares. As more discoveries in the genesis of allergic disease are uncovered, exposure is now being seen as just one of many factors involved in allergy development.
The biggest challenge and perhaps the most controversial suggestion that Dr Liang posed to currently held beliefs was the introduction of the possibility that not only may breastfeeding not always be necessarily protective, but that it may even aggravate allergy in some infants. Dr Liang presented highlights of the Detroit Childhood Allergy Study, published by Wegienka et al in 2006, which suggested that breastfeeding without formula supplementation may be associated with an increased risk for childhood allergies (Ann Allergy Asthma Immunol 2006;97:78–83). Dr Liang followed this up later in his lecture with another novel notion proposing that early exposure to cow’s milk protein may protect against IgE-mediated cow’s milk protein allergy. He even presented data suggesting that maternal folic acid supplementation increased the risk for wheeze and respiratory tract infection in progeny up to 18 months of age.
Nevertheless, Dr Liang’s lecture was not composed entirely of maverick ideas. In its essence, Dr Liang’s lecture still supports avoidance of smoking, pollution and furry pets; breastfeeding up to 4 months of age; maternal avoidance of allergenic foods during breastfeeding; introduction of solids after 5 months of age; and probiotics, among others, as effective strategies for preventing allergy in the formative years of the child.
Viruses in asthma development – the viral march
Dr Holgate rounded out the symposium with a microbial perspective, examining the role of viruses on asthma development. Viruses have been recognised as the most frequent cause of asthma exacerbation. According to Dr Holgate, this may be related to differences in IFN-β levels between asthmatic and non asthmatic individuals.
In a non-asthmatic individual, normal levels of IFN- β lead to viral elimination through apoptosis in the event of viral infection. IFN β deficiency in asthmatic patients appears to be associated with selective infection and subsequent inflammation of the bronchial epithelium, due to failure of viral inhibition. According to a study by Murray et al, along with allergen exposure, viral infection increases the risk of asthma hospital admissions in children (Thorax 2006;61:376–82).
Interestingly, allergic sensitisation is associated with wheezing induced by rhinovirus, but not other viruses, in children (Pediatr Allergy Immunol 2010;21:1008–14). Moreover, according to a study published by Jackson et al in 2008, among viral wheezing in infancy and childhood, those caused by rhinovirus infections are the most significant predictors of subsequent development of asthma at age 6 years in a high-risk birth cohort (Am J Respir Crit Care Med 2008;178:667–72).
To conclude the symposium, Dr Holgate cited Martinez (2009) to sum up the relationship between viral infection, wheezing in early life, and asthma, which proposes, among other things, that the abnormal acute responses of asthmatic schoolchildren and adults to rhinoviruses was already present in infancy, and that this is because abnormalities in innate immune response that begin in the toddler years persist into school age, thus creating a continuum for susceptibility to asthma (Allergol Immunopathol (Madr) 2009;37:249–51).
Dr Prescott is a professor at the University of Western Australia School of Paediatrics and Child Health at Princess Margaret Hospital in Perth, Australia. Dr Liang is an honorary Senior Consultant in Pediatrics at the Auckland Children’s Hospital. Dr Holgate is a research professor of immunopharmacology at the School of Medicine, Southampton General Hospital, Southampton, UK.
