Phenotypic heterogeneity in COPD and asthma

It has come as small comfort for pulmonary clinicians that the two most prevalent obstructive lung diseases, COPD and asthma, are being characterized as phenotypically heterogeneous.  While it sheds light on the challenging clinical management of patients with these diagnoses, it dredges up more concerns about how exactly this variability in presentation should and could be addressed to mitigate the disease-related impairment.

This month’s Clinical Review from Carolan and Sutherland [Journal of Allergy & Clinical Immunology 2013; 131(3): 627-634] compiles important advances in understanding COPD phenotypes, current knowledge of asthma phenotypes, where they overlap and the focus of therapies.  The authors cover guidelines, clinical phenotypes, exacerbations and morbidity in both diseases.  They also discuss radiologic phenotypes in COPD and the promising predictive tool, the BODE index, which applies BMI, obstruction, dypsnea, and exercise capacity to predict disease progression with greater accuracy than decline in FEV₁. 

Carolan and Sutherland note that COPD, unlike asthma, has not yet been sensitively correlated to any inflammatory biomarker, which has impaired programs for targeted drug development in COPD.  Phenotypic cluster analyses for both diseases are also covered in the authors’ review.  They comment that these efforts are creating alternative perspectives that may be useful for improving management of the variable clinical presentations.  Improved characterization of phenotype variability would permit development of personalized treatment regimens for both COPD and asthma. 

Dietary intervention for EoE remission

An article by Lucendo et al in this month’s issue [Journal of Allergy & Clinical Immunology 2013; 131(3): 797-804] provides convincing evidence supporting a drug-free therapy for eosinophilic esophagitis [EoE].  Noting that food elimination diets in children with EoE are being reported as successful for a majority of patients, the authors designed a six-food elimination diet [SFED] study involving adult EoE patients.  The six foods selected – cow’s milk, soy, cereals, eggs, nuts and legumes, and fish – were selected based on previous reports of their common association with EoE. 

Endoscopy, IgE and skin prick testing were performed to confirm diagnosis, determine EoE remission, and upon food rechallenge.  Lucendo et al report that 73% of subjects had clinical improvement and statistically significant reduction in esophageal mucosal eosinophilia.  Food challenge results showed that 1 food was the offender in approximately a third of the subjects, 2 foods in another third and 3 or more foods in the last third.  Cow’s milk was the most common food trigger affecting 62% of subjects, followed by wheat and eggs.  The authors report that among those who maintained the food avoidance at the 2 and 3 year follow up EoE remained in remission clinically and pathologically and that the subjects had not required medications for EoE during that period. 

Of particular interest, Lucendo et al report very low concordance and predictive power of IgE and skin prick testing with regard to food triggers.  They suggest that this may point to EoE as a delayed hypersensitivity response rather than an IgE-associated one. 

EoE may constitute a new, different type of food allergy, pathophysiologically closer to celiac disease than to food-triggered anaphylaxis. In fact, common IgE-based allergy tests are not sensitive in celiac patients for diagnosing the disease, even when this is also an immunologically mediated disorder. As a result, small bowel biopsies remain essential for diagnosing most patients. As in celiac disease, the mechanisms leading to EoE may be predominantly cell-mediated, but we lack specific peripheral markers that may help us in diagnosing and monitoring the disease in such as way as celiac serology does. Looking for new non-invasive markers of EoE that allow us to predict those exact food triggers and avoiding repeated endoscopies and biopsies are new challenges for EoE researchers.

The microbiota in induced sputum

Recent research has shown that the bacterial constituents of lungs from patients with asthma differ markedly from their non-asthma comparators.  Specifically, asthma lungs have increased predominance of Proteobacteria as well as higher bacterial load.  These findings came from subjects on chronic ICS therapy, which is known to be immunosuppressive.  Marri et al. in this month’s issue present important results from their investigation on lung bacteria from asthma patients not on ICS therapy (J Allergy Clin Immunol 2013; 131(2): 346-352).

The authors analyzed induced sputum from 10 asthma subjects and 10 non-asthma subjects.  Bacterial 16s rRNA was sequenced and compared to data from the Ribosomal Database Project.  All samples contained 5 phyla of bacteria, Firmicutes, Proteobacteria, Actinobacteria, Fusobacteria, and Bacteroides.  Sputum from asthma subjects had significantly higher percentages of Proteobacteria with a concordant drop in Firmicutes prevalence as compared to sputum from non-asthma subjects.  They also found increased bacterial load in the asthma subjects as well as increased bacterial diversity.   Marri et al. report a higher relative abundance of bacterial families that contain Moraxella catarrhalis and  Haemophilus influenza in asthma subjects, potentially implicating these pathogens in asthma pathogenesis.  They also note that atopic status did not influence the results.

 The authors conclude that an altered lung bacterial community in asthma patients is not attributable to ICS therapy or atopy, though further investigations are required to determine if the differential bacterial components are causal or consequential.  Antibacterial therapeutics aimed at Proteobacteria might be one of the ways to reduce the bacterial load in asthmatics.

 

Recent advancement in understanding primary immunodeficiencies

The International Union of Immunological Societies [IUIS] published an updated classification in 2011 of primary immunodeficiency diseases [PID] as part of their on-going work to collate and disseminate PID research findings reported worldwide.  This month, Parvaneh et al. provide a compendium of reports that have been published since the 2011 update (J Allergy Clin Immunol 2013; 131(2):314-323). 

Following the 2011 IUIS classification, newly published reports are summarized under combined immunodeficiences, syndromes with associated immunodeficiencies, predominant antibody defects, immune dysregulation, congenital phagocytic defects, defects of innate immunity, and autoinflammatory disorders.  Some highlights are provided below.

TCRα gene mutation/TCRαβ T cell depletion: Two patients from unrelated Pakistani families were identified after presenting with infection susceptibility, autoimmunity, T cell proliferation dysfunction, but normal antibody responses.  Both patients’ T cells were missing surface expression of TCRαβ, though CD3+ cells expressed TCRgd.  A homozygous mutation in the T cell receptor alpha constant [TRAC] gene was found in both patients.  Both patients were treated successfully with sibling bone marrow transplants. 

WIP deficiency/Wiskott-Aldrich Syndrome-like phenotype:Wiskott-Aldrich protein [WASP] binds with WASP-interacting protein [WIP] to form a stable complex.  A Morrocan infant presented with symptoms suggesting WAS, such as recurrent infections, eczema, and T cell lymphopenia.  Sequencing demonstrated normal WASP sequence and expression, though WASP was undetectable in the patient’s cells.  Additional analyses determined that WIP was absent as well and that a homozygous nonsense mutation was present in the WIPF1 gene, coding for WIP.  The patient was treated with unrelated cord blood transplantation at 4½ months and was reported to be thriving at 21 months. 

Parvaneh et al. conclude noting that reports of novel primary immunodeficiencies are increasing. There is no formal evidence that the incidence of PID has increased; however, improved treatment, allowing long-term survival may have increased the pool of mutant alleles in the general population.  The growing number of reportsofnew PIDs probably reflects several factors including:1) the increasing awareness of practicing physicians regarding the clinical and laboratory manifestations of PID; 2) improved networking (or collaboration) within the international PID community; 3) new immunological techniques to analyze leukocyte subsets and function; and finally 4) usage of next generation sequencing (whole exome sequencing) which has had a major impact on the field.  The authors emphasize the importance of this expansion in knowledge, not only to improve the patients’ outcomes, but also to contribute to the general understanding of these immune diseases.

Food tolerance and other mysteries

In a timely review and opinion article this month, Berin and Mayer take up the issue of therapeutic induction of food tolerance (J Allergy Clin Immunol 2013;131:14-22). They put to the reader the question of whether we truly understand the mechanisms that restore natural tolerance or induce tolerance in sensitized individuals, noting that without this knowledge it will not be possible to achieve tolerance through therapy in the majority of food allergic patients.

Berin and Mayer begin with a concise review of current understanding about how the human body achieves self and non-self tolerance. They cover central tolerance and peripheral tolerance induction in the thymus and gut, respectively, the development and function of natural and induced regulatory T cells, and anti-specific T-cell deletion and anergy in the context of establishing and maintaining peripheral tolerance. Immunologic profiles of critical immune cells and cytokines is also addressed.

The authors proceed with the question “is food allergy a defective T_reg response?” They review and summarize the current knowledge about T helper cell profiles in food allergic subjects and normal controls, nothing that T_reg frequencies were similar between the controls and the allergic subjects. Mouse models of food allergy are also presented.

Next, the question of whether tolerance can be induced in food allergic patients is discussed. The authors define tolerance as sustained non-responsiveness to a food allergen after therapy is discontinued, distinguishing it from desensitization that is achieved during therapy. Berin and Mayer review the research to date on immunotherapy for food allergy, noting the frequency of spontaneous tolerance. They point out that there has been little in the way of mechanistic findings that would demonstrate what immune regulatory mechanisms were operative between those who achieved desensitization and those who achieved tolerance. It remains unclear if tolerance is achieved by induction of T_reg or by decreased potency of allergic sensitization.

Berin and Mayer conclude by offering considerations for future research, such as novel routes of administration, allergen modification, the addition of adjuvants to enhance the immunotherapy, and manipulation of gut flora. Of particular importance, they press for genetic profiling of immune tolerance that develops naturally or therapeutically in order to design new methods for achieving tolerance in the majority of food allergic patients.

 

Re-equilibrating human health

Susan Prescott, PhD, MD makes a compelling case for broadly focused, interdisciplinary approaches to inflammatory non-communicable chronic diseases (iNCD) in her Current Perspectives contribution this month (JAllergy Clin Immunol 2013;131:23-30). She points to the global rise in allergies, obesity, cardiovascular disease and autoimmune diseases and their common characteristic of low grade chronic inflammation while discussing the radical and health-hostile environmental conditions that are known to influence these disease processes. Prescott states that the rise in allergic diseases specifically implicates vulnerability of the human immune system to micro- and global environmental shifts.

The author briefly discusses evidence that supports early immune dysfunction in infants and notes that environmental influences begin in utero. Thus, maternal health is a critical starting point to any preventive measures, such as dietary and nutritional support. She comments further on the need to create and sustain optimal immune development as a prerequisite to minimizing future causes of low grade chronic inflammation, which increases the risk associated with iNCD.

Prescott covers current research on important nutritional supplements known to impact immune function, such as fish oil, probiotics, and dietary soluble fiber, as well as the critical role of exposure to sunlight. She goes on to briefly discuss the roles of genetics, epigenetic modification and genetic plasticity in the context of adaptive and maladaptive evolutionary shifts.

Prescott concludes by urging interdisciplinary approaches to modifying the environment and a return to more traditional dietary and lifestyle patterns known to achieve and/or restore human health.

 

Standardizing research food challenges

A pressing need for standards of conduct for research-related double-blind, placebo-controlled, oral food challenges (OFC) provided the impetus for a consensus report by Sampson et al in this month’s issue (J Allergy Clin Immunol 2012;130:1260-1274).

After a brief review of the historical literature on diagnosing food allergy, Sampson et al present topical discussion summaries for major issues in the conduct of research OFC, noting that the guidance and recommendations apply equally to clinically performed challenges. The authors emphasize that patient/subject safety was the pre-eminent consideration. The following are highlights from their discussions:

·      Pre-challenge assessments. The authors cover important evaluations and practices prior to conducting OFC. These include case history, current food avoidance, comorbid conditions that impact safety such as atopic dermatitis and chronic disease, the utility of surrogate test results and their intrinsic problems, and the requirement for an optimal challenge setting. They also discuss the issue of differential severity of allergens as an important safety consideration prior to OFC.

·      Challenge procedures and assessments. Sampson et al discuss dosing schedules and their necessary variability tied to outcomes. General recommendations for dosing include low starting doses, separate active and placebo challenge days, dosing intervals no less than 20 minutes and appropriate, low fat matrices. Recording important, objective clinical parameters, such as respiratory symptoms and other physical reactivity symptoms, is covered. Sampson et al emphasize that scoring and stopping criteria must be pre-specified in light of the critical role of clinical judgment in OFC conduct. Delayed reaction considerations and subjective symptom issues are also reported. Tables of their recommendations are provided for reference.

·      OFC analysis and reporting. To ensure a reliable evidence base, Sampson et al provide guidance and recommendations for statistical analysis and reporting results, particularly from randomized trials.