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.

Prevention of Food Allergy

Children are afraid of a lot of things: the dark, strangers, and even the bogeyman.  But for more and more kids, ordinary foods, like peanuts, eggs, and milk, are becoming sources of fear.  Food allergies are becoming increasingly common in the developed world, and we don’t have a good explanation of why.  In this month’s issue of JACI, du Toit and his colleagues talk about the factors that lead to food allergies, and what can be done to prevent children from developing food allergies (J Allergy Clin Immunol 2016; 137(4): 998-1010). It’s clear that there are some risk factors that we just can’t change: male gender, a family history of food allergies, and even race can put children at a higher risk for developing food allergies.  But there are other things that we can possibly change.  Since children with eczema (atopic dermatitis) tend to have food allergies, there have been some discussion about whether preventing and controlling eczema by regularly applying moisturizers could help prevent food allergies.  Attendant to the link between high levels of aerosolized peanut dust and the development of peanut allergies, it has been suggested that, at least for peanuts, children may become sensitized through the skin and not the gut. Thus, it is possible that by keeping the skin barrier intact, we may be able to prevent peanut allergy.  Studies are still ongoing; if successful, these would be simple ways to stop food allergies in their tracks.

Another big hope has been that we can mitigate the development of food allergy by modifying the types of food that the mother takes while pregnant or lactating.  To date, these studies have been inconclusive.  Likewise, there is not much data on the efficacy, or even safety of, dietary interventions such as fatty acids, antioxidants, pre- and probiotics and vitamin supplementation.

The one glimmer of hope is that early introduction of common food allergens during infancy may be a pro-active approach.  Two major trials, LEAP (Learning Early About Peanut Allergy), and EAT (Enquiring About Tolerance) have suggested that introducing children to peanuts during infancy does not lead to food allergy, and may actually help to prevent them.

Food allergy is an enormous problem but new research on prevention may help to bring it under control, and make sure that children can have at least one less thing to be afraid of. 

Molecular and Cellular Mechanisms of Food Allergy and Food Tolerance

One may not believe it, but there is an entire universe in one's belly.  One's guts, in and of themselves, are over 300 square meters in surface area, and are home to thousands of different species of bacteria, as well as an immune system that is exquisitely tailored towards sensing, which of the 300 kilograms of food ingredients  that we ingest each year are safe, and which are unsafe.  So in this veritable universe of bowel, it is incredibly difficult to figure out what decides whether one becomes allergic or tolerant to food.

Chintharajah et al tackle this problem in this month’s issue of JACI (J Allergy Clin Immunol 2016; 137(4): 984-997).  They begin by surveying the types of immune cells that service our gut.  They highlight the central role of a specific type of immune cell called the dendritic cell, which lives in the walls of the small intestine (among other areas), in capturing the proteins in food particles, processing them, and then presenting them to other types of immune cells.  In certain circumstances, particular food proteins, chemical messengers from the gut, and the genetic makeup of immune cells can move the immune system into a pro-allergic state.  Perhaps just as important is the role of another type of immune cell, the regulatory T-cell, which ensures the proper balance of immune responses.  When these regulatory T-cells don’t work properly, the immune system can go into overdrive and become less likely to see food proteins as safe and tolerable.

Interestingly, a lot of other surprising factors that may lead to food allergies.  The microbiome is not limited to the gut. The skin has its own microbial ecology and skin breakdown and inflammation can alter the skin microbiome and allow sensitization to aerosolized food antigens such as peanut dust.  in addition,  the gut bacteria in children with food allergies are less diverse and have different levels of different types of bacteria compared to children without food allergies. 

All of these factors need to be taken into consideration when one tries to   modify the immune system to nudge it away from producing an allergic response.  There are ongoing studies trying to figure out how to desensitize allergic individuals to certain foods.  Knowing how these approaches alter the immune system will help take those techniques out of research centers and into the allergist’s office.

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.