Jonathan Bernstein | Professor of Clinical Medicine, Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, University of Cincinnati College of Medicine, Ohio, USA
Citation: Respir AMJ. 2025; https://doi.org/10.33590/respiramj/KPEL8908
First of all, what led you down the path of asthma, allergy, and clinical immunology?
I grew up in a family of allergists and immunologists. My father was an allergist and immunologist, and past president of the American Academy of Allergy, Asthma, and Immunology (AAAAI) in 1982. So, environment was an influence, and as both a teenager and college student I had many laboratory and clinical experiences in allergy and immunology. As a medical resident, I enjoyed my allergy and immunology rotations, especially the clinical immunology aspects. I liked the broad spectrum of pathology we saw as clinicians, and that since allergy and immunology is a Conjoint Board, it afforded the opportunity to care for both children and adults.
Given your extensive experience in both clinical practice and research, how has your approach to diagnosing and managing severe asthma evolved over the years?
Major advancements in diagnosis, assessment of asthma control, and treatment outcomes with patient reported outcome measures and therapeutics have made severe cases of asthma manageable. Our biggest challenge is with patient adherence to medications and office visits. Prior to advanced therapeutics beyond inhaled corticosteroids and long-acting β2-agonists, we had oral corticosteroids or off-label use of therapies such as methotrexate or oral gold, which had marginal benefits at best. A better understanding of asthma pathogenesis has allowed the development of novel therapeutics, including anti-IL-4 receptor alpha, anti-IgE, anti-IL-5/IL-5 receptor, and anti-thymic stromal lymphopoietin agents that treat different asthma phenotypes/endotypes. Currently we will soon have available a longer acting anti-IL5 antagonist for asthma.
Your research includes the health effects of both home and occupational environmental exposures in patients with asthma. What are some of the most significant findings you’ve encountered in this area?
Our findings confirm the importance of obtaining an indoor environmental history to assess indoor air quality; specifically allergen exposures for patients with IgE-mediated asthma, but also other irritant/chemical triggers in cleaning agents, potpourris, secondary smoke exposure, mold, or other outdoor air pollutants that become indoor pollutants when windows are left open. We have looked at many environmental interventions to mitigate these exposures with success. The workplace is an extension of the home, but often more difficult to access and implement avoidance measures. For example, we demonstrated that immunosurveillance programs implemented in industries where high or low molecular weight antigen can induce asthma, are effective at preventing exposure and the development of occupational asthma and rhinitis symptoms.1 A more recent study investigating the use of an ultraviolet irradiation air cleaning device installed in the central furnace duct of asthmatic children’s homes compared to a sham unit, found significant improvement in many asthma variables for children where the home had an active unit installed after one year.2
You emphasize looking at the ‘whole patient’ rather than just the primary complaint. Can you share an example where addressing co-morbid conditions significantly improved a respiratory disorder?
We see many patients presenting with asthma who also have chronic rhinitis which is untreated. However, when you also address the upper respiratory tract, their asthma symptoms are overall better controlled. We showed that failure to treat chronic rhinitis in patients with asthma and/or chronic obstructive pulmonary disease results in increased 30-day hospital readmission rates.3
We also see many patients presenting with mast cell activation syndrome, and many of these individuals also have symptoms of dysautonomia. Treating these patients holistically improves their overall condition.4 Thus, it is essential to get a detailed history beyond the presenting problem to develop a comprehensive management plan that will improve the patient’s clinical outcomes.
Hereditary angioedema (HAE) can have significant respiratory complications. How do you differentiate between hereditary and other forms of angioedema in clinical practice, and what are the latest advancements in treatment?
HAE is due to a genetic mutation of the SERPING1 gene, resulting in its ability to produce C1INH (85% of cases [Type 1 HAE]), or a gene mutation that makes C1INH, but it doesn’t work (15% of cases; [Type 2 HAE]). The swelling episodes can involve the upper airways, tongue and lips, abdomen, genitalia, or extremities, and does not respond to H1-antihistamines or other medications used to treat mast cell mediated angioedema. These patients have a low C4 level, low C1INH functional level, and depending on the HAE subtype, a low C1INH for Type 1 HAE or a high or normal C1INH for Type 2 HAE. We now have on-demand treatments that can be used to treat an acute attack. These target kallikrein a molecule critical for regulating bradykinin production (ecallantide), bradykinin 2 receptors (icatibant) or replace C1 esterase inhibitor (Berinert or Ruconest). These all work well when used early on after the onset of an attack. For patients with more frequent attacks, involving the throat or abdomen, prophylactic treatment with a long-acting kallikrein inhibitor called lanadelumab, dosed initially every 2 weeks subcutaneously, or intravenous (Cinryze)/subcutaneous (Haegarda) C1INH replacement therapy dosed every 3–4 days can be given. These are major advances compared to what we had previously, which were androgens, fresh frozen plasma, and tranexamic acid. Newer therapies that target pre-kallikrein and kallikrein pathways that have longer half-lives, or that target feedback pathways like Factor XIIa inhibitors, have been shown to be very effective and will be available for clinical use in the near future. What is even more remarkable is that there will be oral kallikrein inhibitors for on-demand use, and oral bradykinin 2 inhibitors for on-demand use and prophylaxis in the future. Even more recently, a potential cure may be around the corner that uses CRISPR technology to edit out pre-kallikrein, so that kallikrein can be produced, preventing the over-production of bradykinin, which causes the swelling.
What role do allergic and non-allergic rhinitis play in exacerbating respiratory conditions like asthma, and how do you tailor treatments for patients dealing with both?
It is extremely important to diagnose chronic rhinitis subtypes correctly, as treatment differs. As discussed above, proper management of chronic rhinitis can significantly improve asthma control. Untreated rhinitis contributes to significant morbidity, associated with worsening asthma and recurrent sinus disease. Over 75% of patients with chronic rhinitis have a non-allergic component, or just non-allergic rhinitis. If these patients are treated like for allergic rhinitis, they will likely not realize significant clinical improvement. Therefore, proper diagnosis and management of non-allergic rhinitis is essential.
With your long-standing contributions to medical education, what key lessons do you emphasize to your students and fellows about diagnosing and managing complex respiratory disorders?
The most important lesson is to characterize the patient: what is their allergic status, what are their triggers (infectious, exercise, allergens, pollutants, etc.), and what is the nature of their environments at home, work, or school?
Confirm a diagnosis of asthma by history and objective testing with spirometry, and if available, with exhaled nitric oxide, which is a good marker for airway inflammation. Peripheral eosinophil counts and total IgE levels are also useful. Assess for chronic rhinitis subtypes and other comorbid conditions, such as gastroesophageal reflux disease, obstructive sleep apnea, chronic sinusitis, and vocal cord issues. Provide patients with a way to assess their asthma control with patient reported outcome measures. Be familiar with the American Thoracic Society (ATS) and Global Initiative for Asthma (GINA) guidelines. Start medications based on asthma severity per guidelines, and schedule follow-up visits to assess response to treatment and control; peak expiratory flow rate meter readings should be obtained at each visit, and spirometry should be obtained once the patient is stable, at least once per year thereafter. With the resources we have today to manage asthma, we should not be seeing asthma hospitalizations, emergency room visits, and certainly there should be no asthma-related deaths.
