Medical Journal Review
WAO Reviews – Editors’ Choice
Articles are selected for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases by Juan Carlos Ivancevich, MD, WAO Web Editor-in-Chief, and John J. Oppenheimer, MD - FACAAI - FAAAAI, WAO Reviews Editor.
1. A switch in regulatory T cells through farm-exposure during immune maturation in childhood
Schröder PC, Illi S, Casaca VI, Lluis A, Böck A et al. A switch in regulatory T cells through farm-exposure during immune maturation in childhood. Allergy 2016; published online ahead of print, October 12. (doi:10.1111/all.13069)
Recent studies have demonstrated in replicate that farm milk exposure protects against the development of allergies early in life and this appears at least partially mediated by regulatory T-cells (Tregs). Thus, the aim of this study by Schröder and colleagues was to investigate the critical time window of the “asthma-protective” farm effect via Tregs during childhood immune maturation. Tregs were assessed longitudinally at 4.5 and 6 years in 111 children participating in the PASTURE/EFRAIM birth cohort. Peripheral-Blood-Mononuclear-Cells were cultured unstimulated (U), with phorbol-12-myristate-13- acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+CD25highFOXP3upper20%). mRNA-expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo and suppressive capacity of Tregs on effector cells and cytokines was also assessed.
They found that Treg percentage before and after stimulation and FOXP3 mRNA-expression ex vivo decreased from age 4.5 to 6 years (p(U,LPS)<0.001;p(PI)=0.051; p(FOXP3)<0.001). Furthermore, high vs low farm milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (p(LPS)=0.045). As would be expected, elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR=11.29, CI:0.96-132.28, p=0.053)., and Tregs from asthmatics vs nonasthmatics suppressed IFN-γ (p=0.015) and IL-9 (p=0.023) less efficiently. From the standpoint of the timeline, mRNA-expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 to 6 years (p<0.001). Overall, this indicates that there is an immunological switch that defines a critical “time-window” for Treg-mediated asthma protection via environmental exposure before age 6 years.
2. Antibodies and superantibodies in patients with chronic rhinosinusitis with nasal polyps
Chen JB, James LK, Davies AM, Wu YCB, Rimmer J et al. Antibodies and superantibodies in patients with chronic rhinosinusitis with nasal polyps. Journal of Allergy and Clinical Immunology 2016; published online ahead of print, September 19. (doi: 10.1016/j.jaci.2016.06.066)
Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with local immunoglobulin hyperproduction and the presence of IgE antibodies against Staphylococcus aureus enterotoxins (SAEs). In this study, Chen and colleagues examined antibodies reactive to SAEs to determine whether they recognize SAEs through their complementarity-determining regions (CDRs) or framework regions (FRs). To do so, they isolated single SAE-specific B cells from the nasal polyps of three aspirin-exacerbated respiratory disease (AERD) patients by FACS. They utilized patients with AERD, as almost all express anti-SAEsRecombinant antibodies. “Matched” heavy- and light-chains were then cloned as IgG1, and those of high-affinity for specific SAEs, assayed by ELISA and surface plasmon resonance (SPR), were re-cloned as IgE and Fab. The activities of the IgEs were then tested in basophil degranulation assays. They were able to isolate 37 SAE-specific, IgG or IgA-expressing B cells which yielded six anti-SAE clones, two each for SEA, SED, and SEE. Competition binding assays revealed that the anti-SEE antibodies recognize non-overlapping epitopes in SEE. The authors note that surprisingly, each anti-SEE mediated SEE-induced basophil degranulation and IgG1 or Fab of each anti-SEE enhanced degranulation by the other anti-SEE.
They conclude that SEE may activate basophils by simultaneously binding as antigens in both the conventional manner to CDRs as well as superantigens to FRs of anti-SEE IgE in anti-SEE IgE-FcεRI complexes.
3. POINT: Will new anti-eosinophilic drugs be useful in asthma management: Yes. COUNTERPOINT: Will new anti-eosinophilic drugs be useful in asthma management: No.
O’Byrne PM. POINT: Will New Anti-eosinophilic Drugs Be Useful in Asthma Management: Yes. Chest 2016; published online ahead of print, October 13. (doi:10.1016/j.chest.2016.09.021)
Barnes PJ. COUNTERPOINT: Will New Anti-eosinophilic Drugs Be Useful in Asthma Management: No. Chest 2016; published online ahead of print, October 13. (doi:10.1016/j.chest.2016.09.023)
This is a very interesting pro/con debate regarding the utility of new anti-eosinophilic drugs in asthma management. The Pro argument is presented by Dr. O’Byrne, who highlights that there are many impediments to asthma care, including lack of adherence to maintenance medicines, co-morbidities that can impede asthma control (rhino-sinusitis, allergic bronchopulmonary aspergillosis, gastroesophageal reflux, obesity, bronchiectasis, vocal cord dysfunction, smoking, psychopathology, persistent allergen/occupational exposure) as well as incorrect diagnosis. Even with optimization of these issues, 5-8% of asthmatics remain poorly controlled. It is this group of patients that go on to have the greatest risk of severe asthma exacerbations which ultimately translates to patient anxiety, and financial stress to the healthcare system, beyond the obvious patient morbidity and potential mortality. Research indicates that up to 50% of this severe/refractory group continue to have elevated sputum eosinophils despite the use of inhaled corticosteroids. Thus, explaining a rationale for the development of biologic agents that target control of eosinophilic inflammation within the airways, despite the use of standard controller medicines. Presently, anti-IgE (Omalizumab), and anti-IL5 (Mepolizumab and Reslizumab) therapies are available. Ongoing studies are also examining another IL-5 receptor antagonist, Benzralizumab, several IL13 antagonists (Lebrikizumab and Tralokinumab), as well as Dupilumab which binds to the common subunit of the IL-4 and IL-13 receptor. Studies have demonstrated that several of these agents can reduce severe asthma exacerbations by as much as 50% or more. Thus, Dr. O’Byrne concludes that although these agents are expensive, when appropriately used their added expense can be “easily justified” by a reduction in direct and indirect cost savings associated with exacerbation reduction.
For the Con argument, Dr. Barnes argues that the vast majority of patients with severe/recalcitrant asthma are suffering from disease lability as a consequence of their non-adherence and that the subgroup that is truly recalcitrant are not the eosinophil upregulated phenotype, but those with neutrophil or a pauci-cellular makeup. In his argument he notes that society cannot afford these expensive biologic agents as a solution for non-adherence and further points out that in the UK the National Institute for Health and Care Excellence has not approved Mepolizumab on cost-effectiveness grounds He further suggests that we should find innovative ways to improve adherence, such as utilizing the maintenance and reliever approach or implement electronic surveillance devices and direct our exploration of new therapies towards the non-eosinophilic phenotype of recalcitrant asthma.
This debate certainly was a clash of titans and is very much worth reading in its entirety.
4. Effectiveness of air purifier on health outcomes and indoor particles in homes of children with allergic diseases in Fresno: a pilot study
Park HK, Cheng KC, Tetteh AO, Hildemann LM, Nadeau KC. Effectiveness of Air Purifier on Health Outcomes and Indoor Particles in Homes of Children with Allergic Diseases in Fresno: A Pilot Study. Journal of Asthma 2016; published online ahead of print, October 10. (doi:10.1080/02770903.2016.1218011)
We have all seen the epidemiologic studies demonstrating that indoor air pollution is correlated with increased morbidity of allergic disease. In this study by Park et al, the authors evaluated the effectiveness of aggressive use of air purifiers (living room and bedroom) for 12 weeks in a group of children with asthma and/or allergic rhinitis in Fresno, California. They were very clearly able to show a reduction in the PM2.5 concentrations (43%) in the active group. This was accompanied by a significant reduction in total and daytime nasal symptoms scores (P=0.001 and p=0.011, respectively). Also, at week 12, there was a trend towards improvement in childhood asthma control test scores and mean evening peak flow rates in the active group. Certainly, this data is encouraging and requires longer duration of study with larger numbers.
5. New pharmaceutical approaches for the treatment of food allergies
Brotons-Canto A, Martin-Arbella N, Gamazo C, Irache JM. New pharmaceutical approaches for the treatment of food allergies. Expert Opinion on Drug Delivery 2016; published online ahead of print, October 27. (doi:10.1080/17425247.2016.1247805)
Up until now, those allergic to food had no options but to avoid the allergenic food and when a reaction did occur, to use an auto-injectable epinephrine and seek emergency room care. As noted in this review by Brotons-Canto et al. there is hope on the horizon for our food allergic patients. This includes the use of nanoparticles as an allergen delivery system for mucosal immunotherapy as well as monoclonal antibody therapy targeting IgE or specific cytokines, such as IL-5. In this article, they detail both the science and potential clinical implementation of these therapies.