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Tuesday, December 20, 2016

Care transition interventions for children with asthma in the emergency department

Childhood asthma is a common and costly chronic medical condition, affecting 7 million children and leading to more than 50 billion dollars in direct healthcare costs every year.  It is particularly burdensome for non-Hispanic black and Puerto Rican children, who are four times as likely to visit the Emergency Department (ED) as non-Hispanic white children.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Martin and colleagues review strategies to bridge care from the ED to home and ambulatory settings, like primary care providers (J Allergy Clin Immunol 2016; 138(6): 1518-1525).   They divide these strategies into two domains: care coordination and self-management education.

Five studies were identified regarding care coordination.  Three involved improved scheduling for follow up appointments, one involved allergen skin testing in the ED, and one involved use of a template to improve adherence to guidelines in the ED.  In all five studies, there were mixed results in the improvement in asthma care.  Only one of the four interventions for self-management education showed improvement in asthma care.  An ongoing project, the CHICAGO Plan, attempts to improve asthma outcomes by taking a patient-centered approach toward asthma care coordination and self-management education in the ED.

Everyone agrees that the goal is to avoid ED visits but how exactly we can best achieve that is, as of yet, unknown. Interventions that link care coordination across the health and community sectors may be one way.  Indeed, there’s still a lot of work to be done in order to determine whether such programs are effective, but this review provides a solid basis for further progress.  

Patient-centered outcomes research to improve asthma outcomes

Asthma is a devastating chronic disease that affects up to 24 million Americans.  It is more severe and prevalent among African Americans and Hispanics, especially Puerto Ricans.  There’s a two-fold increase in asthma mortality in Hispanic children and three-fold among African Americans, compared to Whites.  The causes of these disparities are complex, but are undoubtedly worsened by the observation that they are less likely to be treated according to the National Asthma Education Prevention Program (NAEPP) guidelines, which have been widely available for the past 20 years.  To address these issues, the Patient-Centered Outcomes Research Institute (PCORI) funded 8 studies to help patients and clinicians adhere to the guidelines.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Anise and colleagues review these 8 randomized control trials (J Allergy Clin Immunol 2016; 138(6): 1503-1510).

Among the approaches being used are (1) clinician education, (2) clinical decision support, (3) patient education in the ER and clinic, (4) use of community health workers, and (5) use of long-term and quick-relief medications.    While each study has a distinct focus, all of them overlap in incorporating relevant stakeholders into the projects, and aligning local resources towards overarching, generalizable goals. 

The research projects are still underway, and results will not be available for at least two more years.  But these research projects are pioneering in the way that they are putting research in action in local communities, and embracing multi-faceted approaches with the understanding that single interventions may not be effective.

Home visits are needed to address asthma health disparities in adults

Asthma is a huge public health problem in the United States today.  But all asthmatics are not affected equally – there are a lot of disparities in asthma care.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Bryant-Stephens and colleagues describe the need for home visits to address these asthma health disparities (J Allergy Clin Immunol 2016; 138(6): 1526-1530).  They note that most of the research on asthma so far has been on patients who go to clinics.  This has meant that people who have problems getting to the clinic, like the elderly, disabled, and those with other chronic conditions are often left out.  To help prevent overlooking these blindspots, they advocate for the involvement of community health workers.  In particular, they describe the experiences of three community health workers when they visited patients.  They found that the challenges at home are often overwhelming.  Social stressors in patients’ lives can be major problems interfering with their ability to take care of their asthma and other health problems. Community health workers may be used to provide resources to overcome these barriers and to encourage patients to adopt healthier habits, such as smoking reduction, and better communication with providers.   Even though home visits are not routine in clinical practice and are only rarely used in research settings, Bryant and colleagues suggest that there may be greater room for community health workers.  They recommend examination of the costs as well as benefits, and identifying vulnerable patients who would be best managed in this way.  They conclude that there needs to be better understanding of the barriers to optimal asthma management, so that these disparities can be addressed directly.

Monday, November 28, 2016

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity

Over the past 25 years, the rates of both obesity and asthma have increased dramatically.  These are related to one another, with a 92% increased risk of asthma in people whose body mass index (BMI) exceeds 30 kg/m2. People who do lose weight through bariatric surgery or dietary restriction, tend to show improvement in their bronchial hyperresponsiveness, the major feature of asthma.  The reason for this correlation is not well understood.  IL-33, a intercellular messenger that skews helper T cells towards allergies, is produced by fat cells.  IL33 also induces type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), two more recently identified sets of immune cells in fat and the lungs. 

In this month’s issue of the Journal of Allergy and Clinical Immunology, Everaere and colleagues use mouse models to investigate the roles of innate lymphoid cells in the correlation between asthma and obesity (J Allergy Clin Immunol 2016; 138(5): 1309-1318).  The mice were given a high-fat diet to induce obesity and were then sensitized to dust mites.  Their lung secretions were isolated by bronchoaveolar lavage (BAL) and checked for various proteins, RNA, and cell types by histology and flow cytometry. 

They found that nonsensitized obese mice had increased ILC counts and tissue eosinophils, cells that mediate damage in asthma, compared to lean mice.  These mice also had high IL33 and IL-1-Beta levels.  When ILCs were depleted using an anti-CD90 antibody, there was decreased infiltration by cells that prompt allergic inflammation, such as TH2 and TH17 cells.

Altogether, these results suggest that ILC2s and ILC3s mediate and exacerbate airway inflammation in obese mice.  This opens the possibility of using anti-IL5 antibodies in treating asthma for obese patients.

Wednesday, November 23, 2016

Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice

Eosinophilic esophagitis (EoE) is an allergic disorder seen in approximately 1 out of 2000 people in the United States.  Young children often present with vomiting and failure to thrive, while older children and adults may have difficulties swallowing, food impaction, or strictures in their esophagus.  Despite increasing awareness and diagnosis, the etiology remains unclear.  Past studies support the role of a subset of Helper T-cells, called TH2 cells, which are also present in many other allergic diseases, including atopic dermatitis (AD).  In fact, approximately half of patients with EoE have AD.  But why is that so?

In this month’s issue of the Journal of Allergy and Clinical Immunology, Venturelli and colleagues investigate the role of abnormal skin barriers in the development of EoE, and, in particular, the role of IL-33, a chemical messenger whose levels are elevated in both EoE and AD (J Allergy Clin Immunol 2016; 138(5): 1367-1380).  They also investigated the role of ST2, an IL-33 receptor found on basophils using a mouse model. They applied ovalbumin to the mechanically injured skin of wild-type mice, and then to the skin of mice lacking filaggrin (ft/ft), which tend to develop AD-like skin lesions.  They then challenged both strains of mice with intra-nasal ovalbumin.  The esophagi of these mice were then examined microscopically and through advanced genetic analytic techniques. 

They found that a disrupted skin barrier (by tape stripping or a Filaggrin gene mutation) promotes the development of EoE, and that this is mediated by IL-33, ST2, and basophils.  They also reported that patients with EoE have increased ST2 in their esophagus. Their findings suggest that IL-33 could be a potential link between AD and EoE.  This is an important step in understanding how patients with AD and filaggrin deficiency tend to develop EoE.  Just as importantly, it may prompt development of new medications that block IL-33 or ST2, which could be effective targets for EoE.

Tuesday, November 22, 2016

Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania

Chronic Rhinosinusitis is a chronic disease of the sinuses that’s seen in up to 27% of adults in Europe and 14% in the United States.  Grouped in two categories, chronic rhinosinusitis with nasal polyposis (CRwNP) and chronic rhinosinusitis without nasal polyposis (CRsNP), chronic rhinosinusitis appears to be mediated by very distinct immune mechanisms.  Interestingly, there are differences in the clinical presentations between ethnic groups as well as in the types and levels of cytokines produced by immune cells. 

Wang and colleagues expand upon this prior knowledge by looking at 435 patients with chronic rhinosinusitis, and comparing them to 138 control subjects (J Allergy Clin Immunol 2016; 138(5): 1344-1353).  They were recruited from six regions covering Europe, Australia, and Asia.  They checked the levels of cytokines, inflammatory mediators and IgE, the antibody mediating allergies, from the mucosa of subjects.  The levels of these parameters were then compared among the different subjects.

They found that there was a large variety of expression of these cytokines among the different subjects in various regions.  This suggests that chronic rhinosinusitis is more of an umbrella term and that there are actually many different endotypes of patients with chronic rhinosinusitis.  

Thursday, October 13, 2016

Asthma in the inner city: Three Analyses of the APIC Study

Asthma is an incredibly variable disease with its impact on people and molecular and cellular mechanisms what it does to the lungs and rest of the body.  This month’s issue of JACI features three articles by Zoratti et al (J Allergy Clin Immunol 2016; 138(4): 1016-1029), Pongracic et al (J Allergy Clin Immunol 2016; 138(4): 1030-1041), and Liu et al (J Allergy Clin Immunol 2016; 138(4): 1042-1050), covering asthma among inner city children.  They examine factors that determine the phenotype, severity and disease control, based on data they obtained from the Asthma Phenotypes in the Inner City (APIC) study, which looked at children aged 6 to 17 years and examined them every 2 months for one year.  Even though their techniques are all slightly different, all three analyses determined that allergic inflammation was a very significant contributor to disease.  In addition to rhinitis, pulmonary physiology also influenced severity and ability to control asthma despite guideline-based therapy.  Body mass index and environmental tobacco exposure were also quite significant in explaining severity of and ability to control disease activity, respectively.  Interestingly, Vitamin D did not have a significant effect on the control of asthma.  Altogether, the results of the APIC study provide insights into what strategies can be implemented to bring asthma under better control in inner cities.  Identifying those who are most at risk through the results of these studies, and targeting allergic inflammation, both in the upper or the lower respiratory passages, may help to reduce the burden of asthma.

Wednesday, October 12, 2016

Early-life gut microbiome composition and milk allergy resolution

Allergy to cow’s milk affects roughly one in fifty children, rendering them at risk for potentially deadly allergic reactions as well as for poor nutrition that comes with avoiding cow’s milk. In this month’s issue of JACI, Bunyavanich and colleagues relay the results of their research on how gut bacteria might influence the course of this disease (J Allergy Clin Immunol 2016; 138(4): 1122-1130).  They looked at the stools of 234 milk allergic children ranging in age from 3 to 16 months. They used 16s rRNA sequencing to profile the different types of gut bacteria and followed the children up to age 8 years.

They found that among children age 3 to 6 months, bacteria in the Firmicutes phylum and Clostridia class were associated with resolution of milk allergy by age 8 years.  This is consistent with preliminary findings from mouse models that also show that Clostridia have a role in regulating sensitization to food allergens.  However, these bacteria appear to have a very short time window to exert their effect, because there was no association in children beyond 6 months of age.  It is possible that the immune systems of infants up to six months of age are easier to tolerize, or that the introduction of solid foods at around age 6 months obscures this association.

It is possible that the fatty acids produced by bacteria may have potent roles in reestablishing tolerance, but the study was not structured to answer that question.  Other questions left to answer include whether supplementation with probiotics can help reestablish tolerance and whether introducing these bacteria would be safe.

Monday, September 12, 2016

Regulation of the host immune system by helminth parasites

They may be called parasites, but we may owe helminth worms a great deal of appreciation.  At least, that’s what Dr Maizels and McSorley write in this month’s issue of the Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol 2016; 138(3): 666-675).  To those who are unaware, there are only about a dozen or so species of helminths that commonly infect human beings, but they affect more than 2 billion people worldwide.  Their wide prevalence is a testament to the fact that they can evade host defenses and establish niches from themselves within our bodies.  Learning about how they do this can provide valuable insights about how our immune system works.

They do this through many different ways.  T-cells from helminth-infected asymptomatic humans show an increase in IL-4, IL-10, and TGF-beta over IL-17 and Interferon-gamma, suggesting that parasites skew our T-cells in a way that reduces the immune system’s ability to clear helminths.  In particular, the production of IL-10 correlates with the proliferation of regulatory T-cells, which in turn drive the body to produce IgG4 instead of pro-allergic IgE antibodies.  Interestingly, when helminths are cleared away by drug treatment, IgG4 levels decrease, which suggests that it is the helminths that are driving this movement.  Very broadly, this affects a host of other cells within the body, including macrophages, dendritic cells, and B-cells, which also seem to become more tolerating of these helminths.

The end-result of these changes is a mixed bag.  Helminths prevent the body from creating polyclonal responses, leading to decreased defense against pathogens like mycobacterium tuberculosis, and compromising the effect of childhood vaccines.  They also increase the risk of developing cancer, change metabolic processes (and maybe even protect against diseases like diabetes mellitus), and alter the bacteria that make up our gut microbiome.  Not surprisingly, at least in mice, helminth infection attenuates allergic responses as well. 

These insights are incredibly important, not only because they allow us to understand the immune system in a clearer manner, but also because research in this area holds the promise of creating new therapies that mimic the parasite molecules to treat a number of inflammatory diseases.

Friday, September 9, 2016

Creation and implementation of SAMPRO™: A school-based asthma management program

Childhood asthma affects over 6 million children in the United States.  In addition to its effects on physical health, asthma has an impact on academic and personal development.  Asthma related absences lead to decreased reading proficiency and increased learning disabilities.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Lemanske and colleagues describe the creation of a central resource, termed SAMPRO (School-based Asthma Management Program). (J Allergy Clin Immunol 2016; 138(3): 711-723).

The SAMPRO workforce identified four components for development and implementation: (1) a circle of support facilitating communication, (2) asthma management plans, (3) comprehensive education plan, and (4) assessment of school environment. 

The circle of support is comprised of persons involved in taking care of children, including family, school personnel, clinicians, and community members.  School nurses in particular are pivotal in helping to ensure that children with asthma receive proper treatment.  In fact, the SAMPRO workforce strongly endorses full-time licensed registered nurses in schools (REF).

Secondly, the SAMPRO workforce strongly endorses the dissemination of asthma action plans among members of the circle of support.  Because asthma action plans have been shown to reduce deaths and emergency room visits, this is a high priority.  Electronic health information exchanges, web portals and continuity of care documents are methods that can help with this.

Thirdly, education of members within the circle of support has been highlighted, especially for school nurses.  The SAMPRO toolbox provides resources that can support nurses and others in managing chronic diseases in children.

Lastly, environmental triggers like pests, and poor indoor air quality have to be addressed.  55% of school districts require monthly campus-wide pest inspections but there remains a lot to be done.  The SAMPRO workforce recommends development of an Indoor Air Quality (IAQ) management program to help promote a healthy school environment. School staff needs to be educated in order to help empower them to make changes to the environment.

Altogether, these recommendations can help keep asthma from getting out of control enusring that children can continue to be at school, learning and growing rather than struggling with their breathing problems.

Clinical trial data access: Opening doors with TrialShare

The issue of “Data Sharing” has received considerable coverage in the medical literature and in the lay press recently.  There is a push to increase data transparency and to open such data for secondary use and analysis.  There have been different approaches to this issue with varying degrees of access. .  In this month’s issue of the Journal of Allergy and Clinical Immunology, Asare and colleagues describe their experiences with TrialShare, an online research resource providing data from the Immune Tolerance Network (ITN) of the National Institute for Allergy and Infectious Diseases (NIAID) (J Allergy Clin Immunol 2016; 138(3): 724-726).

Users of TrialShare have access to clinical trial protocols, case report forms, complete trial results, extensive de-identified participant level data, downloadable datasets for offline use, the ability to create alternate analyses, and a searchable database of ITN bio-specimen repository, among other features. 

The only requirement for registration is an e-mail address and password to establish an account.  In the 24 months since its introduction, a variety of different academic, government, nonprofit, and corporate individuals have used it to view and analyze data.

There are still many barriers preventing widespread use of data sharing software, but TrialShare is working towards breaking these down.  Unlike other data sharing projects, like the Yale Open Data Access Project and the Clinical Studies Data Access Project, there are no negotiation of data-use agreements and provisions to protect the competitive advantage of primary data generators.  Although there have been concerns that by sharing information more freely, there may be potential improper use of data, the experience of TrialShare has not demonstrated this.  And there is a vast infrastructure in the background to ensure that costs do not become burdensome for those carrying out clinical trials (about 0.5 to 2% of total costs of a clinical trial).

TrialShare is open to the biomedical community. Asare and colleagues invite us all to utilize this vital tool in order to ensure that the data being generated from immunology-related clinical trials is being analyzed in a free and open manner.

Wednesday, August 17, 2016

Cellular and molecular immunologic mechanisms in patients with atopic dermatitis

Atopic dermatitis is one of the most common chronic skin diseases among both adults and children.  Although it is often thought of as a skin disease, it also affects many organ systems. There remain a lot of gaps in our knowledge of atopic dermatitis, but researchers are developing a greater appreciation for its complexity of atopic dermatitis and introducing new treatments for this frustrating disease.

From an immunologic point of view, atopic dermatitis appears to be a collection of many different variants.  These endotypes are just recently beginning to be described, but involve the various arms of the immune system.  Defects in the innate immune system skew the skin towards inflammation; polarization of T-cells (Th2, Th17, and Th22) lead to further inflammation.  Other cell types, like dendritic cells, eosinophils, and mast cells, play important roles in the development of atopic dermatitis.  The interplay between immune cells and skin barrier proteins, like filaggrin, is also being explored.  Filaggrin influences cell differentiation, prevents water loss, and maintains the integrity of the skin barrier.  With defects in filaggrin, allergens penetrate deeper into the skin and bacteria like staphylococcus aureus are more likely to colonize the skin.

To make things even more complicated, as time progresses, so too does the disease, and patients can have an “atopic march” towards asthma, allergic rhinitis, and other allergic diseases.  Additionally, patients with atopic dermatitis have changes in the bacteria that colonize their skin and gut.  They have less microbial diversity, particularly when there is greater inflammation.  The role of these bacteria are being increasingly fleshed out with basic science and clinical research.

These insights are helping to guide new therapies.  In particular, dupilumab, an antagonist of the IL-4 receptor alpha chain, is showing promise in the treatment of atopic dermatitis.  And in those that don’t respond to dupilumab, there’s interest in other therapies like the IL-6 receptor antagonist tocilizumab.  As Werfel and colleagues note, it is difficult to find the best treatment for atopic dermatitis without knowing the pathophysiology behind the disease and its various endotypes (J Allergy Clin Immunol 2016; 138(2): 336-349).  In the future, with better knowledge, it may be possible to personalize appropriate treatment by identifying the correct endotype for each patient.

Tuesday, August 9, 2016

Multidisciplinary interventions in the management of atopic dermatitis

Atopic dermatitis is the most common skin disease in children, affecting up to 1 in 5 children in the United States.  But it doesn’t do it justice to call it just a skin disease.  The itching and scratching leads to a breakdown of the skin, disruptions in sleep, conflicts with parents, and an inability to concentrate at school.  Studies have shown that children with atopic dermatitis have a higher risk of developing mental health disorders like attention-deficit hypersensitivity disorder, anxiety, depression, conduct disorder, and autism.

Because atopic dermatitis does not have a single cause and has such far-ranging effects, management can be a challenge.  As LeBovidge and colleagues describe, multidisciplinary interventions are being investigated as a way to help these children (J Allergy Clin Immunol 2016; 138(2): 325-334).  Evaluation by an allergist or dermatologist can help to determine triggers, and education by nurses can help improve adherence and technique of applying emollients.  Psychologists can help redirect unhelpful compulsive behaviors like scratching into more helpful activities, such as re-application of moisturizers.  And nutritionists can ensure that children, especially those that have food allergies that require restriction of certain foods, receive enough Vitamin D and other nutrients.

Several institutions have embraced this multidisciplinary approach, but randomized controlled trials are limited.  Some group-based models have shown an improvement in control but others found no difference in disease severity, quality of life, or medical therapy use.  New models of collaboration between specialists and primary care providers are being developed in order to improve the quality of care.  It is hoped that improving the quality of care will decrease the economic burden of the disease.

Atopic dermatitis may be a skin disease, but its effects are felt in more than just the skin.  In order to get the disease under better control, new ways of delivering care will have to be developed.  Professionals in various fields, including allergists, dermatologists, nurses, nutritionists, and psychologists, are aligning with parents to break the itch-scratch cycle that causes such misery to the millions to have atopic dermatitis.

Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march

Some things are so evident that we take them for granted.  Take our skin for example.  We live in our skin and, for the most part, don’t give a second thought about it.  But skin is more than meets the eye.  It is vital for immunity, not only because it protects us from the outside but also because it fine tunes how our immune system responds to the various stimuli it encounters.  For those who have atopic dermatitis, a type of allergic disease that affects the skin leading it to become dry, irritated, and thickened, we see one result of a poor skin function.  In this month’s issue of JACI, Egawa and Kabashima discuss the role of skin barrier dysfunction in atopic dermatitis (J Allergy Clin Immunol 2016; 138(2): 350-358).

To understand the skin, we have to think about it in layers.  The topmost layer, called the stratum corneum, is a little like a wall, with flattened cells called corneocytes working like bricks and intercellular lipids functioning as mortar.  Together, they maintain the integrity of the skin.  But in atopic dermatitis, the wall is weakened.  Mutations in filaggrin, a protein important in making the corneocytes, have been associated with an increased risk of developing atopic dermatitis.
With the growing knowledge of genetics and immunology, there are beginning to be great insights into how atopic dermatitis starts to take hold.  In addition to filaggrin mutations, there’s a host of newer mutations that lead to the irritation, peeling, and thickening of the skin.  Mutations in genes encoding some proteins, like LEKTI and KLKs, have to do with the way that skin desquamates, or sheds, whereas others, like CLDN1, influence the tight junctions that maintain the integrity of the skin barrier.  And, in addition to these structural proteins, the immunologic messengers, particularly type 2 cytokines like IL-4, IL-13, IL-31, and IL-33, are found to be key in the development of atopic dermatitis.

As Egawa and Kabashima note, the skin is a very complex organ, and one that we are just starting to understand from an immunologic perspective.  Its importance cannot be overstated, not only because it brings us closer to figuring out what causes diseases like atopic dermatitis, but also because it opens the door towards finding new, effective medications and therapies that can target proteins like filaggrin.  In turn, this can improve the lives of the millions who live with atopic dermatitis, and the diseases that are associated with it.

Monday, July 11, 2016

Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation

You are more than just one human being.  That may sound like an inspirational quote, but it’s actually a scientific fact: there are literally millions of bacteria living on, in, and around you that play crucial roles in the ways that your body and your mind work.  And now, thanks to newer technology, we have the ability to see how these ‘old friends’ – bacteria have likely been around since the emergence of humans – interact with our own cells to change how our immune system works.
In this month’s issue of the Journal of Allergy and Clinical Immunology, Garn and colleagues provide an overview of how these microbes influence our metabolism and can lead to inflammation, based on the insights from the International von-Behring-Röntgen-Symposium (J Allergy Clin Immunol 2016; 138(1): 47-56).  While our knowledge of the microbiome keeps on growing, the fact is that there remains so much to be researched.  For example, how does our modern age of hygiene, where we have eliminated so many of the old infectious agents with which we have co-evolved, impact chronic inflammation?  How do resident microbes interact with food to cause inflammation, or resolve it?  What role does biodiversity (which plummets while on antibiotics) play in maintaining the balance between promotion and resolution of inflammation?  And how do these microbes educate our immune systems during infancy and childhood?  Unfortunately, these questions remain mostly unanswered but there are some promising leads.  For example, a study involving 560 babies of families from Baltimore, New York City, and St. Louis demonstrated that exposure to allergens in the first few months of life may be associated with a reduced risk of recurrent wheeze, while exposure to microbes may reduce both the risk of atopy and atopy plus wheeze.

Extracellular RNA, DNA, and proteins that may come from microbes have been shown to mediate inflammation.  These molecules alter the cytokines released by our own cells, and can lead to upregulation of inflammatory responses.  While research is extremely preliminary, the influence of the microbiome on allergic, autoimmune, gastrointestinal, and neuropsychiatric disease is becoming more and more appreciated, possibly opening doors to new management strategies.  So embrace your inner germs and realize that you’re more than just one, sole human being.

Friday, July 8, 2016

Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

C-O-P-D (chronic obstructive pulmonary disease) is a series of four letters that strikes terror in the hearts (and lungs) of millions throughout the world.  It’s a condition in which there is chronic inflammation within the lungs that leads to their destruction, causing problems in breathing.While the consequences of COPD have been long known, the immunology behind it is still largely unknown.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Dr. Barnes reviews the inflammatory mechanisms behind COPD (J Allergy Clin Immunol 2016; 138(1): 16-27).
As he mentions, one of the difficulties behind figuring out how immune dysfunction causes COPD is that COPD doesn’t seem to be a single disease.  Different types of immune cells and mediators seem to be involved in different ways in different patients, and our knowledge continues to grow about how we can tease apart all these endotypes and phenotypes.

However, some common themes are emerging.  Patients with COPD have lower levels of anti-oxidants, leading to excess reactive oxygen species (ROS), which, in turn, trigger the inflammatory response.   These ROS may also promote lung cancer by activating growth factors and damaging DNA directly.  The other major common theme is that there is systemic inflammation that “spills over” to cause an increased risk of heart disease, diabetes, lung cancer, and pneumonia.

Currently, we don’t have treatments to help reverse the damage from COPD, and most of our efforts remain in prevention and control of symptoms.  But with greater knowledge on the roles immune system, we may be able to help people, who have been diagnosed with COPD to regain control of their lungs, and their lives.

Thursday, July 7, 2016

Intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes

It’s not surprising that expecting mothers carry a lot of weight in their bellies.  But they also carry a lot of weight on their shoulders.  What to do, and what not to do, complicates nearly every decision when there’s a second person to think about, even the relatively minor act of using a nasal steroid spray to treat allergic rhinitis.  Fortunately for them, Dr. Berard and colleagues conducted a study to help address these concerns (J Allergy Clin Immunol 2016; 138(1): 97-104).
They looked at nearly 300,000 pregnancies in Montreal between 1998 and 2008 to find pregnant women who took intranasal triamcinolone as well as other intranasal steroids.  They then looked at the number of major abnormalities at birth, spontaneous loss of pregnancies, and underweight newborns, and compared the rates to those who did not use intranasal triamcinolone. 
For the most part, the results are comforting.  They suggest that there is no link between using intranasal triamcinolone (and, by extension, all nasal steroid sprays) and major birth abnormalities or spontaneous fetal loss.  However, out of 296 pregnancies, there were 5 cases of respiratory defects in babies born to mothers who used triamcinolone during the first trimester.  This was a statistically significant finding.  Of note, no link between respiratory defects and other nasal steroid sprays could be found.
The implications of this study are also covered in an accompanying editorial by Drs. Namazy and Schatz, who praise the importance of the study, the first of its kind trying to determine the safety of nasal steroids during pregnancy (J Allergy Clin Immunol 2016; 138(1): 105-106).  They also mention that controlling allergic rhinitis during pregnancy may be helpful in preventing snoring, which is linked to hypertension during pregnancy.Namazy and Schatz try to make sense of why triamcinolone may be correlated with respiratory defects.  It may be due to unmeasured confounders, but that is unlikely since these confounders were present in both the triamcinolone and non-exposed groups.  Or perhaps it’s a biologic effect of triamcinolone, since animal studies of intramuscular triamcinolone have shown similar defects.  Or, it may just be due to pure chance.

Regardless, the authors suggest that, to be on safe side, intranasal steroids like fluticasone or mometasone should be used instead of triamcinolone during the first trimester.  

Thursday, June 9, 2016

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.

Wednesday, May 11, 2016

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.

Friday, May 6, 2016

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.

Tuesday, April 5, 2016

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.

Saturday, March 5, 2016

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.

Tuesday, February 16, 2016

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.

Monday, February 8, 2016

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.

Tuesday, January 12, 2016

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.

Friday, January 8, 2016

Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: the spark that lights the fire in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily manifests in synovial joints, such as those in the hands and feet. It can appear at any age in life and affects up to 1% of the population. While it is classified based on the presence of articular inflammation, a growing body of evidence indicates that RA autoimmunity begins outside of the joint. Circulating rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), anti-peptidylarginine deiminases (anti-PAD4), and anti-carbamylated proteins (anti-CarP) have been detected in many people years prior to the development of joint symptoms and an RA diagnosis. Several lines of investigation have implicated mucosal tissues of the lung and oral cavity as possible sites of initial autoantibody generation and inflammation. Mikuls et al. review the recent reports of this line of investigation (J Allergy Clin Immunol 2016; 137(1): 28-34).

In addition to harboring host inflammatory cells, mucosal tissues support a rich and diverse microbiome, which is increasingly understood to contribute to host immunity and autoimmunity. Mucosal tissues provide the first line of defense against environmental challenges such as invading pathogens and cigarette smoke. Both of these have been shown to be RA risk factors. Approximately one in six new cases of RA are attributable to smoking, with the risk highest among those who carry the HLA-DRB1 shared epitope. Disease-related autoantibodies in RA include IgA isotypes; the mucosal immune system and the ectopic lymphoid tissues that can develop at mucosal surfaces show dense infiltration by IgA-producing plasma cells.

Patients with RA often have extra-articular, pulmonary complications, and a number of reports of pulmonary involvement preceding joint symptoms in seropositive patients underscore the possibility that RA may be initiated in the lung. Disease-related antibodies have been detected in sputum, and in higher levels than in sera. Those with RA are also prone to disorders characterized by chronic oral inflammation, and the authors have recently found such patients showed a 50% greater prevalence of chronic periodontitis (PD) than those with osteoarthritis. The association was strongest among patients with ACPA-positive disease. 

The evolving evidence presented here suggests the lung and periodontium can be producers or reservoirs of RA-related auto-antigens. Much remains to be elucidated. Such questions include: a) What are the mechanisms through which this autoimmunity leads to the development of an articular disease? b) Does the same occur in other mucosal surfaces? c) Might the initiating site vary across individuals? 

The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects

Autoimmunity and immunodeficiency represent two sides of the same coin. Whether the human body’s defenses attack its own healthy cells or its ability to fight off disease is compromised, both result in a dysfunctional immune system. In their review article, Grimbacher et al. discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiological pathways and clinical features of monogenic defects that result in autoimmune disease (J Allergy Clin Immunol 2016; 137(1): 3-17).

Multiple single gene defects have been shown to result in rare diseases that show features of both autoimmunity and immunodeficiency. Nearly 300 monogenic traits have been associated with various forms of primary immunodeficiency diseases and auto-inflammatory syndromes. It is likely that more common autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) result from a polygenic inheritance. Genes implicated in single gene disorders have also been linked to polygenetic disorders thus confirming the intricate connections and overlays between autoimmunity and immune deficiency,

In the case of SLE, genome-wide association studies and their follow-up studies have identified more than 50 robust loci associated with susceptibility, suggesting polygenic disease development. There are also emerging monogenic SLE disease models, as factors such as early disease onset, familial SLE, and syndromal lupus likely involve monogenic defects. The authors outline nine pathophysiological pathways, which, if impaired, inevitably lead to serious disease and ultimately to autoimmunity.

Different pathways can lead to the development of a given disease.. Autoimmunity is one of these etiopathologies, and recent and continued advancement in detection methods, in particular next generation sequencing, has led to the identification of genetic defects associated with autoimmune phenotypes. The monogenic defects explored here all interrupt the equilibrium of the immune system, and they have already begun to influence and change our patients’ management. 

This review thus emphasizes of looking at immune dysfunction as a whole rather than breaking it down into silos of immunodeficiency and autoimmunity