Allergen Immunotherapy: No Evidence of Infectious Risk

Nearly three million Americans this year will be administered subcutaneous allergen immunotherapy for a variety of different reasons, including allergic rhinitis, asthma, allergic conjunctivitis, and venom allergy.  Altogether, these are over 16 million allergy shots.  Despite low risks of a large local reaction (0.7-4%) or systematic allergic reaction (0.2%), it has been shown to be relatively safe, cost-effective disease-modifying treatment.  However, recent proposed changes by the United States Pharmacopoeia requiring that vials of allergens be mixed in a strictly sterile fashion threaten the availability of allergen immunotherapy.

To investigate whether this is a real concern, Balekian and colleagues looked through the records of over 3000 patients who collectively received more than 130,000 injections over the preceding 10 years from Massachusetts General Hospital and Brigham and Women’s Hospital (J Allergy Clin Immunol 2016; 137(6): 1887-1888).  They could not find evidence of any local or systemic bacterial infection due to allergen immunotherapy.

Their research supports the community of allergists who maintain that current practices to guarantee sterility and safety are enough to prevent bacterial infection.  They conclude that the proposed changes won’t make a difference in infection rates, but will prevent people who need allergen immunotherapy from receiving them.

Identification of Immunoglobulin E

The year is 1966: Lyndon B. Johnson is the president squaring off against the Soviet Union, the Beatles are at the height of their popularity, and Neil Armstrong is training to one day become the first man on the moon.  And, tucked away in a laboratory at the Children’s Asthma Research Institute and Hospital in Denver, Colorado, Kimishige Ishizaka and his team are busy at work isolating the antibody that mediates allergic reactions, now called immunoglobulin E.

In this month’s issue of the Journal of Allergy and Clinical Immunology, Dr. Ishizaka recounts the way in which he and his team members eventually discovered reagin, later to be called Immunoglobulin E (J Allergy Clin Immunol 2016; 137(6): 1646-1650).  Through complex purification techniques and shrewd application of scientific principles on patients with plasma cell myeloma, he was able to identify the protein that led to a local reaction to ragweed, and figured out that the binding of allergens, like ragweed, dust mites and egg, to IgE on basophils and mast cells leads to histamine release.  Even though technology has advanced considerably and certain practices, like Dr. Ishizaka’s use of himself as a test subject, have changed, the role of Immunoglobulin E remains central to the field of allergy.

Omalizumab for the treatment of chronic spontaneous urticaria: a meta-analysis of randomized clinical trials

Imagine having an itch that you just couldn’t get rid of.  Worse yet, imagine that itch was accompanied by hives and localized swelling that can’t help but consume your attention.  That’s the reality for up to 1% of the world’s population, who have a disease called chronic spontaneous urticaria (CSU, also called chronic idiopathic urticaria).  The good news is that 70% resolve within 5 years. The bad news is that the standard treatment, non-sedating anti-histamines, only works in 50% of CSU patients.  That’s where Zhao and colleagues step in, with their article in this month’s issue of the Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol 2016; 137(6): 1742-1750).

They examine the role of omalizumab, a medication that targets IgE, the human antibody which is central to the disease process of urticaria.  Omalizumab has been on the market for the treatment of urticaria since 2014.  Zhao and colleagues looked at 7 randomized controlled trials, with 1230 antihistamine- refractory CSU.  By metaanalysis, they assessed how effective and safe omalizumab is in the treatment of CSU. 

Their conclusion is that omalizumab has a safety profile comparable to placebo.  73% had an adverse effect with omalizumab, compared to 69% with placebo.  They also state that, at the dose of 300mg, omalizumab led to a complete response in 36% of patients.  Altogether, this suggests that omalizumab is a safe and effective treatment option for hard to treat chronic spontaneous urticaria.

Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers

Not all stuffy noses are alike.  That’s the conclusion of a research study by Tomassen and colleagues published this month in the Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol 2016; 137(5): 1449-1456).  Despite affecting one out of eight Americans, little is really known about chronic rhinosinusitis and treatment is often really frustrating.  To figure out more personalized approaches to tackling chronic rhinosinusitis, Tomassen’s group collected tissue samples from patients with chronic rhinosinusitis, as well as people who had no history of chronic rhinosinusitis.  They then analyzed 14 bio-markers to see if they could find groups of patients who had particular patterns of inflammation.

Ten distinct endotypes, or subgroups linked to biological pathways, that correlated to different features were identified.  The biggest differentiator was the level of IL-5.  Patients with higher levels were more likely to have polyps (outgrowths of the mucous membranes associated with more severe disease) and/or concomitant asthma.  Combined with the other markers, these findings can help identify people who would be expected to respond to different types of medications.  Since there are new medications that target individual inflammatory markers, such as IL-5, this information can provide valuable insight into personalizing an approach to reduce the frustration in treating chronic rhinosinusitis.

Toward precision medicine and health: Opportunities and challenges in allergic diseases

“Precision medicine” is a term that’s quickly gaining currency across all the different fields of medicine.  Specifically referring to the customization of healthcare in the context of each patient’s unique characteristics, including genetic and other biometric information, precision medicine seems to be on the cutting edge of healthcare.  But as Galli writes in this month’s issue, allergists have long prided themselves on a high degree of precision by testing for specific allergens and immunizing accordingly (J Allergy Clin Immunol 2016; 137(5): 1289-1300).  But now, with newer insights into genes and even the microbiome, we can take this precision medicine to another level.  Mining data from what is called the Information Commons – which includes the set of genetic and environmental factors predisposing to and/or exacerbating disease in individual patients – may help to devise approaches to more precisely and effectively diagnose and treat allergic disorders, or even to prevent these diseases.

The overarching goal is to move away from the “trial and failure” approach, where providers try therapeutics from the first-line down to the third- or fourth-line agents just to see if the approach works, towards a targeted selection of a treatment that is most likely to work.  Of course, all of this is easier said than done.  There is a lot of information about allergic disease that remains unknown and prevents us from applying precision medicine.  And even in diseases where a lot of data are available, we have yet to organize these data in a way that can move from the abstract towards a specific precise approach for a single patient.

Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among individuals with asthma

Asthma is a huge problem in the United States, and particularly among African-Americans.  Prior work has shown that African ancestry is associated with more asthma exacerbations, night-time symptoms, and worse lung function. What is it that makes African Americans so susceptible to poorly controlled asthma?  This is a question that Wells and colleagues investigate in this month’s issue of the Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol 2016; 137(5): 1364-1369).  In particular, they seek to answer if African-American ancestry is linked to a poorer response to inhaled corticosteroids (ICS), one of the first-line agents in treating persistent asthma.

To measure the response to ICS, 399 participants completed six weeks of observed ICS treatment.  242 of these were African American, compared to 97 who were European in origin.  Adherence was monitored by a special device (DOSER-CT) to make sure that participants were taking their medication; asthma response was measured by simple lung function tests, and ancestry was confirmed by genetic analysis.  After six weeks, there did not appear to be a relationship between change in lung function in response to ICS and African ancestry.

That’s not to say that African Americans don’t have particular genes that make them more or less likely to respond to inhaled corticosteroids. Rather, genetic effects are spread in such a way that, all other things held equal, there’s a similar response among African Americans and European Americans.  It’s good to know that, in tackling the epidemic of asthma in African-Americans, ICS are useful and effective.

Food Allergen Immunotherapy: Current Status and Prospects for the Future

Food allergies are a growing problem, with one in twelve children having at least one allergy, commonly peanut, eggs, milk, wheat, soy, and shellfish. Despite the enormity of this problem, allergists have so far been unable to provide any pro-active treatments, apart from advising patients to avoid those foods and to keep an epi-pen nearby in case of anaphylaxis.  But there’s now some hope.  In this month’s issue of JACI, Dr. Wood surveys a slew of new therapies that aim to modify the immune system so that children can be desensitized to the foods they are allergic to (J Allergy Clin Immunol 2016; 137(4): 973-982). 

The classic approach of desensitizing patients to environmental allergens – like pollens or dander - through shots, has been tried before with food allergies. Although this approach was somewhat successful for a few children, the risks were far too high and it has largely been avoided.  Recently, oral immunotherapy – that is, ingesting really small amounts of the food, and increasing that dose of food, over the course of weeks – is coming into fashion.  Early research results suggest that this approach is effective but it is still far from coming to the clinic.

More recently, sublingual immunotherapy has been tried: small amounts of the food is allowed to sit under the tongue for two minutes and then swallowed.  This amount is slowly increased to help children become less sensitive.  Compared to oral immunotherapy, it’s safer, but it also seems to be less effective.

This has led people to think of other ways to desensitize allergic children to their foods. One way is percutaneous immunotherapy, in which a patch with the food allergen is applied to the skin.  While research is still early, it looks promising – although a lot of side effects like local redness or eczema at the site of the patch have been reported.

A lot of unknowns remain– how long should children be on immunotherapy?  What are the long term benefits … and risks?  How do we measure success? And should we also be using ‘adjunct therapies’ like the anti-IgE antibody omalizumab while trying this immunotherapy?  Currently, we don’t have many answers but, much to the relief of the 8% of children with food allergies, cutting edge research should hopefully change that very soon.