The Contributions of Allergic Sensitization and Respiratory Pathogens to Asthma Inception

Childhood asthma is the most common chronic disease among grade school children, and is responsible for the greatest number of school days missed.  Fortunately, there are now efficient management strategies to minimize the effect of asthma for many children, but what are the factors that lead to its development in the first place?  In this month’s issue of JACI, Jackson and colleagues discuss the risk factors that contribute to the development of asthma (J Allergy Clin Immunol 2016; 137(3): 659-665) .

As the authors explain, asthma starts long before the first wheeze.  In the first few years of life, as young immune systems encounter the environment around them, children who are more likely to eventually develop asthma tend to develop sensitization to aeroallergens and have recurrent lower respiratory infections.  This can happen alone, but new evidence suggests that they feed off each other, leading to a mix where asthma becomes a likely outcome.

Nearly all wheezing illnesses in the first few years of life are due to respiratory viruses.  New molecular techniques have shown that there is a wide variety of viruses that can cause upper and lower respiratory tract infections.  Among these, respiratory syncytial virus (RSV) and rhinoviruses (RV) are the most common pathogens.  Indeed, one third of children who have had RSV bronchiolitis develop recurring wheezing episodes, and one study showed that passively immunization against RSV led to an 80% reduction in the risk of recurrent wheezing in nonatopic children.  Rhinovirus, which was previously thought to only cause upper respiratory tract infections, is now known to cause lower respiratory tract infections too.  And, at least in one Finnish study, 60% of children with RV who wheezed in the first two years of life continued on to develop asthma five years later.  Bacteria may also play a role, but the evidence is preliminary and mixed: some bacterial infections are associated with wheezing and asthma, but exposure to other bacteria may actually be protective.

Additionally, it’s been known for some time that environmental allergies are major contributors to asthma.  In addition, they increase the chance that children will get wheezing respiratory infections.  Part of it is because allergic sensitization leads to enhanced airway responsiveness due to respiratory viral infections.  Another important factor is that allergen exposure impairs antiviral responses, such as production of Interferons I & III.  Interestingly, the use of omalizumab, a medication targeting IgE, the type of antibody responsible for allergens, also leads to a decrease in virus-induced asthma exacerbations.

Of course, there is so much more to the story.  What makes certain children more susceptible to viral infections and allergies is still unknown.  17q21, CDHR3 and IL-33 polymorphisms offer possible answers, but they are only pieces of the puzzle.  The biggest question on the horizon is can we ward off asthma by preventing allergen sensitization or avoiding  severe respiratory infections.  More research is needed, but there’s at least some glimmer of hope that we can finally stop asthma before it actually sets in.

Leveraging Gene-Environment Interactions and Endotypes for Asthma Gene Discovery

Asthma is a pressing public health problem in many developed countries.  But we don’t really know what causes asthma.  In this month’s issue of JACI, Drs. Bønnelykke and Ober talk about the genes and the gene-environment interactions that are thought to underlie susceptibility to developing asthma (J Allergy Clin Immunol 2016; 137(3): 667-679).

So far, there have been about 15 genes strongly linked to asthma, based on large genome-wide association studies (GWAS).  But each of these individual gene variants confers only a very modest increase in asthma risk.  Clearly, there remains a lot of missing information.  Although a significant portion of the risk for asthma may be attributed to environmental exposures, genetic variants may play a stronger role among subgroups of asthmatics who share similar clinical characteristics or similar exposures, as the article discusses.

To tease this apart, genome-wide interaction studies (GWIS) have been conducted to associate specific gene variants to asthma in the presence of specific environmental exposures.  Additionally, previous studies have already shown interactions between genes, early life viral wheezing illnesses, and asthma onset in childhood.  In particular, genetic variants at the 17q locus are associated with asthma among children with significant rhinovirus infections (common colds) during early childhood, but not among children who do not get very sick with rhinovirus infection.  Interestingly, these same variants at the 17q locus are associated with protection from developing asthma among children exposed to farm animals in early life.  Similarly, a variant of the CDHR3 gene, which encodes for a receptor for one type of rhinovirus, is associated with risk of severe childhood asthma.

There are several challenges to performing GWIS studies. For example, environmental exposures can be difficult to measure precisely and it is often impossible to dissect effects of a specific exposure from other related factors. An alternative approach is to study gene-environment interactions in cell models where single exposures can be studied in isolation and effects can be directly attributed to the exposure. Drs. Bønnelykke and Ober suggest that future studies using this approach will complement and guide human studies and thereby help understanding the complex mechanisms of asthma. 

    

Regardless, the roots of asthma seem to lurk at the intersections between genetic susceptibility and environmental exposures.  As Drs. Bønnelykke and Ober explain, future studies will require targeted, thoughtful research linking particular exposures in combination with genetic variants to asthma risk.

The microbial environment and its influence on asthma prevention in early life

It’s a tale of two farming communities: one run by the Amish, who retain very traditional farming practices with horses for field work, and other run by Hutterites, who have embraced modern farming technologies.  Despite coming from the same genetic background and having otherwise similar lifestyles, the Hutterites have a greater than 40% rate of allergen sensitization, while the Amish have a rate lower than 7.5%.  What can account for such a difference?  As Dr. von Mutius outlines in this month’s issue of JACI, it’s likely in the billions of bacteria that colonize the skin, gut, and respiratory passages as well as those that live all over your house, workplace, and everywhere in between (J Allergy Clin Immunol 2016; 137(3): 680-689).

Believe it or not, it’s only been within the past few years that we’ve even found out about all these bacteria.  New technology has enabled scientists to take a closer look at the microbiome, the collection of microbes that colonize virtually everything around and within us.  These microbiomes are diverse and dynamic; and can provide fingerprints about the world around us.  Cat and dog ownership can be predicted by the presence of certain bacteria.  More significantly, the presence of certain bacteria, like H. influenzae, M. catarrhalis, and S. pneumoniae in the throats of 1 month old infants, and somewhat predict the development of persistent wheeze and asthma by age 6.

This is seen in larger epidemiologic studies.  Children who enter daycare before their first birthday are at much lower risk of developing allergen sensitization compared to those who enter after their second birthday.  And, as mentioned above, upbringing on a farm with animal husbandry, especially around dairy animals, confers significant protection.  This is extended to urban environments as well, where exposure to high levels of cockroach, mouse, and cat allergens in the presence of Firmicutes and Bacteroidetes bacteria actually conferred some protection against asthma.

This field is evolving tremendously, and there are still a lot of unanswered questions.  We still don’t know which particular microbes are protective and whether increased diversity really does help to prevent sensitization to allergens.  Nevertheless, with newer, more sensitive technologies that can scan and identify bacterial and other microbial DNA, we’re on the path towards better understanding how our microbial environment shapes our susceptibility to asthma, allergies, and other immune disorders.

International consensus on allergen immunotherapy-II: Mechanisms, standardization, and pharmacoeconomics

This month, JACI presents the second portion of the comprehensive international consensus (ICON) statement on allergen immunotherapy. The ICON statement is an effort of the International Collaboration in Asthma, Allergy and Immunology (iCALL) that includes the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the World Allergy Organization (WAO). Jutel et al. review the evidence on how allergen immunotherapy (AIT) works and summarize what lies on the horizon (J Allergy Clin Immunol 2016; 137(2): 358-368).

A number of mechanisms underlie an allergic response to a substance such as grass pollen, house dust mites, or bee venom. Allergen immunotherapy involves slowly increasing exposure to an allergen over time, ideally resulting in a patient’s increased tolerance and clinical improvement. The literature indicates that administration of AIT leads to early decreases in the susceptibility of mast cells and basophils to respond to environmental proteins, even in the presence of elevated allergen-specific immunoglobulin (Ig)E. Desensitization is followed by allergen-specific T-regulatory (Treg) and B-regulatory (Breg) cell generation and regulation of allergen-specific IgE and IgG₄. In the longer term, changes in memory T- and B-cell compartments and shift in the balance of type 1 T-helper (Th1) and type 2 T-helper (Th2) cells result in sustained improvement.

There are a number of barriers to the use of AIT worldwide. One such barrier is a low awareness of its potential, in the context of patient welfare and improved pharmaco-economics. AIT is currently the only therapy with the capacity to alter the course of allergic disease. Further, standardization of the potency, consistency, and stability of allergen extracts used in AIT is essential, as is the standardization of the practices of regulatory agencies from different parts of the world. Potential facilitators for acceptance and increased use of AIT include validation and consensus on outcome measures for clinical trials; validated methods of assessing AIT’s impact; and post-marketing studies demonstrating the positive impact of AIT on the quality of life of its recipients.

Sublingual grass and ragweed immunotherapy: Clinical considerations—a PRACTALL consensus report

In early 2014, the Food and Drug Administration approved three sublingual allergen immunotherapy (SLIT) products for use in the United States: a 5-grass tablet, a timothy grass tablet, and a ragweed tablet. The approval was based on multicenter clinical trials with large patient populations and supported by decades of real-life use in Europe. Li et al. have provided a consensus report of the experts of the American Academy of Allergy, Asthma and Immunology (AAAAI) and European Academy of Allergy and Clinical Immunology (EAACI) for the prescribing clinician (J Allergy Clin Immunol 2016; 137(2): 369-376).

The decision to use SLIT depends on practical considerations, cost, convenience, and patient preference. Within the current therapeutic options for allergic rhinitis, SLIT offers a therapy that can be self-administered at home and has the potential to permanently alter the course of allergic disease. In addition to those patients who prefer a disease-modifying approach, SLIT may work well for those with disease that does not respond to standard pharmacotherapy. While preliminary studies suggest it has a beneficial effect on asthma, asthma alone is not a clinical indication.

There is currently insufficient evidence to make a meaningful comparison between SLIT and subcutaneous immunotherapy (SCIT), but the current data suggests both routes reduce symptom scores and rescue medication use. Systemic reviews and meta-analyses suggest the clinical effect size may be greater for SCIT than SLIT, but the findings are not definitive. There have also been no head-to-head comparisons of SLIT with as-needed medications such as second generation antihistamine or nasal corticosteroids, but indirect comparisons suggest SLIT’s efficacy can be as good as SCIT. An important addition is that SLIT can provide sustained benefits for up to two years after discontinuation of three years of treatment as previously observed for SCIT.

The most common adverse events associated with SLIT are local reactions, such as gastrointestinal symptoms, which affect up to 75% of patients. Most occur shortly after treatment initiation and cease without medical intervention. Patients often also experience irritation in the lips, tongue, or throat. The incidence rate of fatal and near-fatal systemic reactions is low, likely lower than that of SCIT; and severe anaphylaxis is rare. Data from three large, pivotal European trials have indicated SLIT is efficacious and safe for children. Evidence also suggests that in children with allergic rhinitis, SLIT may decrease the rate of future asthma development.

Predictive value of nonspecific bronchial responsiveness in occupational asthma

The diagnosis of occupational asthma (OA) poses challenges to the clinician and requires a stepwise approach. The American College of Chest Physicians has recently published a consensus on this approach, also providing guidelines that indicate “the absence of airway hyper-responsiveness on challenge testing has a fairly high negative predictive value (NPV) for current symptomatic asthma, and can generally be used to rule out active disease.” Pralong et al. have verified this statement, evaluating the sensitivity, specificity, and positive and negative predictive values of the methacholine challenge in the diagnosis of occupational asthma (J Allergy Clin Immunol 2016; 137(2): 412-416).

The authors used a Canadian database to review 1012 cases of workers who, between the years of 1983 and 2011, were referred for suspicion of having occupational asthma and who underwent a specific inhalation challenge (SIC). SIC is considered the gold standard for diagnosing OA. It entails a first day of testing during which a patient is exposed to a control substance followed by a methacholine challenge. The patient is then exposed to the suspected causative occupational agent and undergoes another methcholine challenge. Among the 1012 patients reviewed, the median exposure duration was seven years, the median symptom duration was one year, and the median delay between exposure cessation and testing was two months. SIC confirmed OA in 27.5% of the cases.

Results presented here are the first to confirm two current recommendations. First, a negative methacholine challenge during the time in which the patient is still working at the exposure site makes the diagnosis of OA highly unlikely, as the negative predictive value (NPV) of the test in this population while at the workplace was 95.2%. Second, the NPV rose to 97.7% when considering all patients who had undergone a methacholine challenge at least once while at work at the exposure site, and it fell to 82.2% among patients who were tested off-site. The data demonstrate the utility of the methacholine challenge and indicates that, when possible, an OA diagnostic workup is best done when the patient is still working at the location of exposure.

Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology

Mastocytosis is a condition characterized by expansion of clonal mast cells in various organ systems, often in association with activating KIT mutations. The organs most frequently affected are the skin and bone marrow. Traditionally, the disease is divided in cutaneous mastocytosis (CM) and systemic mastocytosis (SM). CM is further divided into maculopapular cutaneous mastocytosis (MPCM), also known as urticaria pigmentosa, diffuse cutaneous mastocytosis (DCM), and mastocytoma of skin. Children with mastocytosis usually have CM, whereas the majority of adults are diagnosed with SM. Both children and adults usually present with typical cutaneous (red or brown) lesions.

These cutaneous lesions are highly heterogeneous, encompassing local and disseminated forms. Overall there is a need for a better definition and a clinically meaningful classification of cutaneous lesions detectable in CM and SM. To address this need, an international task force of experts from the European Competence Network on Mastocytosis, the American Academy of Allergy, Asthma, and Immunology, and the European Academy of Allergology and Clinical Immunology met several times between 2010 and 2014. The resulting task force report published by Hartmann et al. in the current issue includes updated criteria for CM, a revised classification of cutaneous lesions, and related recommendations for daily practice (J Allergy Clin Immunol 2016; 137(1): 35-45).

Among other recommendations, the authors indicate that maculopapular cutaneous mastocytosis (urticaria pigmentosa) lesions should be subdivided into two distinct variants: a monomorphic variant characterized by small monomorphic maculopapular lesions that are typically found in adult patients, and a polymorphic variant with larger lesions of varying shape and size that are almost only detectable in children. Clinical experience suggests that the lesions of the monomorphic variant, when detected in children, always persist into adulthood, whereas the polymorphic lesions – when seen – usually fade away and disappear until puberty.

These observations highlight the prognostic value of a detailed inspection and subsequent classification of skin lesions in UP, and the related clinical implication for the management of patients in daily practice. Another recommendation of the task force group is that the Darier’s sign should be regarded as standard method for the evaluation and diagnosis of adult patients with mastocytosis with skin involvement.