So, my name's Vamsi Gunter. I'm a professor of clinical medicine at National Jewish Health. And my co-moderator is Dr. Shah from England, okay. India, India. Oh, India. My bad. I'm sorry. So, we have five wonderful talks on asthma, and I'm super excited to hear the data behind all of the abstracts that I had the opportunity to read beforehand, and hopefully some of you did as well. To the speakers, thank you all in advance for presenting and agreeing to present your interesting research. I'm super excited. Each presenter will have eight minutes to present, followed by two minutes of questions and comments. To the audience, please try to use the microphones that are placed in the middle of the room so that we can all hear your question, and if we can't, I can always reiterate that. So, to the speakers, you'll be given a one-minute warning. If your presentation is so engaging that I can't focus on my timer, I may be a little delayed, but I will do my best to stay on time. And so, without any further ado, let's start. So, this is an asthma and allergy symposium. I want lots of debate and lots of discussion, so I'm super excited to present our first speaker. With great pleasure, I'm going to introduce one of my colleagues, actually, Dr. Lori Manka. She'll be talking to us about Dornes' Alpha and Stable Neutrophilic Asthma. Good morning, everyone. My name's Lori Manka. I'm from National Jewish Health in Denver, and today I'll be discussing Dornes' Alpha Therapy for Neutrophilic Asthma. I have no financial disclosures to make. Let's start today by talking about neutrophilic asthma. Neutrophilic asthma is characterized by poor symptom control, chronic airflow obstruction, and corticosteroid insensitivity. It makes up about 20% of severe asthma cases and up to 50% of symptomatic asthma. Neutrophilic asthma, a subgroup of non-T2 asthma, has fewer directed therapies than T2 asthma, making it an area of significant interest for ongoing targeted therapies. When present, airway neutrophils release extracellular deoxyribonucleic acid, or DNA, into the airway, which in turn forms neutrophilic extracellular traps, or nets, and creates a scaffolding-like structure that increases sputum viscosity. We know that those with asthma have higher levels of extracellular DNA in their sputum when compared to healthy controls. Dornes alpha is a nebulized recombinant deoxyribonuclease that randomly cleaves extracellular DNA and nets, thereby reducing the viscosity of sputum. The benefits of Dornes alpha are well described in Cystic Fibrosis and include improvement in lung function and mortality outcomes. Dornes alpha may be of benefit for outpatient therapy in neutrophilic asthma, but it hasn't previously been investigated. There are a few case reports in a small case series that show clinical improvement with use of Dornes alpha in the setting of severe asthma exacerbation requiring ER visit or hospitalization. So we investigated, is Dornes alpha safe in this population? And is there improvement in, does it change lung function measured by forced expiratory volume in one second, asthma control quantified by the asthma control test, or sputum characteristics? So this was an open-label pilot study approved by our Institutional Review Board. We screened 19 adult asthma participants and enrolled 14 from February of 2020 through May of 2022. The study design consisted of three visits. At Visit 1 we confirmed a diagnosis of asthma through historical documentation of airway hyper-responsiveness. Participants then performed baseline spirometry, completed both the ACT and sputum characteristic questionnaires and produced an induced sputum sample for us. Participants with sputum neutrophilia defined as greater than or equal to 40% neutrophils on their induced sputum returned for Visits 2 and 3. At Visit 2 they received their first dose of Dornes alpha, 2.5 milligrams, and continued once-daily dosing of the study medication for approximately four weeks. Participants returned for Visit 3 with repeat spirometry, ACT, sputum induction and reported on their sputum characteristics. Fourteen participants completed the study and their data were analyzed. There were 10 neutrophilic participants and four non-neutrophilic. We're comparing them here. Age, sex, BMI and baseline spirometry were all similar. Percent sputum neutrophils were, as expected, significantly higher in the neutrophil group at about 63%. Asthma control was poor in both groups. The primary outcome of this pilot study was to determine the safety of utilizing daily Dornes alpha in an asthma population. All 10 neutrophilic participants who initiated the study medication completed four weeks of Dornes alpha. No subject withdrew from the study due to side effects of the medication. Six out of 10 did note an increased need to clear their throat, which is a known and common side effect of the medication. One out of 10 reported a side effect of chills but did not discontinue the study medication. And we had one participant who was diagnosed with an asthma exacerbation requiring intervention two days after completing four weeks of therapy. Our secondary outcomes looked at change in lung function and asthma control over the four weeks of study medication. As you can see, there's no significant change in FEV1 or ACT. There was an absolute improvement in both of them, but neither was clinically nor statistically significant, probably due to the small number of participants in the study. Regarding change in sputum characteristics, there was also no significant change in percent sputum neutrophils before and after. Interestingly, there was a small absolute change reduction in sputum eosinophils, although again not statistically significant. In addition to lung function and asthma control, we collected information regarding participant experience and perceptions of their sputum. Here's a bar graph showing participant response to the change in ease of sputum expectoration following four weeks of Dornase Alpha. On the X-axis, from left to right, is harder to markedly easier. The Y-axis is number of neutrophilic participants. As you can see, 9 out of 10 neutrophilic asthmatics noted it was easier to expectorate their sputum four weeks of Dornase Alpha, and 8 out of 10 indicated it was at least moderately easier. When we took a closer look, it turned out that the heavier participants in the study drove this effect. Of the 10 neutrophilic participants, 5 had a BMI greater than 30, and all 5 reported that it was at least moderately easier to expectorate their sputum. There was a similar pattern regarding this question on change in thickness of sputum. The X-axis goes from markedly thicker on the left to markedly thinner on the right. The Y-axis again represents number of participants. Here 8 out of 10 perceived their sputum to be thinner after four weeks of the study medication, with 6 noting that it was at least moderately thinner. And again, the heavier participants, those with a BMI greater than 30, reported greater benefit from the study medication. As is common with pilot studies, limitations were expected, but probably the biggest one for us was unexpected. The onset of the COVID-19 pandemic affected both our recruitment of participants and altered our protocol. Additionally, we did not enrich our cohort for those with chronic mucus hypersecretion. I suspect that would have magnified our outcomes had we done so. Despite these, we can conclude that DORNASE-alpha appears safe in a neutrophilic population, asthma population, at least over a four-week duration. We did not see significant change in clinical outcomes, but this pilot study did reveal a pattern of positive participant perception of improved ease of expectoration of sputum and thinning of sputum. And participants with higher BMI perceived a greater benefit. We do know that obesity can alter gut and airway microbiome, so perhaps that affects the presence and activation of airway neutrophils, driving the benefit in this subpopulation. In the future, I do look forward to more study in this area, looking specifically at those with chronic mucus hypersecretion and looking at airway neutrophilic biomarkers such as presence of nets and neutrophil elastase would be a good start. I'd like to acknowledge my co-authors on this project, including Dr. Gunter, who's here with us today. All right. Dr. Amjad Kanj, excuse me. We'll try it again and hopefully it'll work. Increased cladosporium relative abundance in lungs of patients with asthma is linked to poor asthma control. From Mayo? Is that right? Okay. Thank you. Welcome. Let me make sure it moves. It does. Okay. Well, thank you again. So my name is Amjad Kanj from Mayo Clinic, Rochester, Minnesota. My presentation is titled Increased Cladosporium Relative Abundance in Lungs of Patients with Asthma is Linked to Poor Asthma Control, and I have no disclosures. So contrary to prior beliefs, the lungs are not sterile. They host a diverse community of microorganisms, including fungi, and the particular fungal genus that we encountered in our work on the microbiome was cladosporium, depicted here in purple. So cladosporium comprises some of the most common outdoor and indoor molds. Outdoors, it's commonly found on insulation materials, stones, concrete, dead plants with peak exposure during summer and fall. Indoors, it's mostly found on surfaces, in residential buildings, museums, and libraries with exposure all year long. You can see here in this picture these colonies that cladosporium form, these olive green to black colonies here, and it's also commonly found in aerosols. So the association between cladosporium and the environment and asthma and asthma control is well-established. There have been studies showing higher concentrations of cladosporium in the homes of individuals with asthma. Other studies linking high cladosporium levels during thunderstorms towards asthma control, the so-called thunderstorm asthma. However, we were not aware of studies linking the cladosporium or the abundance of cladosporium residing in the lungs of patients with asthma to their asthma control. So we had a question. Is there a relationship between the relative abundance of cladosporium in the sputum and asthma symptom control as assessed by the asthma control test at the time of sputum collection in individuals with asthma? And just briefly here on the ACT score, so the higher the total score is, the better the asthma is controlled. So to answer this question, we collected sputum samples from 24 patients, consecutive patients from our asthma clinic. These patients also completed the ACT or the asthma control test. Their median age was 57 years, 75% were female. Their median ACT score was 17.5, and we used this score to divide them into two, this median score to divide them into two groups. So those with worse control, the ones that had ACT score lower than the median, and then those with an ACT score higher than the median, labeled them as better control or better asthma control. So we processed their sputum, we extracted the DNA, assessed its quality, and then sequenced it for fungi. We used nonparametric tests to compare between the worse and better control group. And this is what we found. So cladosporium was the third most prevalent fungal genus in the sputum of our 24 patients, with a mean prevalence of 6.9%, a median of 2.2%, with a range of 0 to 69%. Cladosporium was detected in 16 out of the 24 patients we had. So 67% of our sample had cladosporium. On the right here, this is our main finding, cladosporium being significantly more prevalent in the sputum of individuals with worse asthma control compared to those with better asthma control. So this here shows the data at the patient level. So every bar here represents one patient, and cladosporium is represented by the color green. So you can see right off the bat that cladosporium, or green color, is significantly more prevalent in the worse control group compared to the better control group. So we had eight patients with no cladosporium detected in their sputum. Out of these eight patients, seven patients were in the better control group and one patient was in the worst control group. So not only that, but these two patients here with more green in the better control group or more cladosporium were the only two patients with the ACT of 18. Now looking at baseline demographics, baseline characteristics, so age, female sex, FEV1, were not different. Total IG was slightly maybe higher in the worse control group, but that was not statistically significant because of the small sample in which it was obtained or measured. We also looked at the association between the abundance of cladosporium and glucocorticoid use in the past year and with severe exacerbations in the past year, and that was not different. We also looked at the association of cladosporium, prevalence of cladosporium, or abundance of cladosporium with the period of the year during which the sputum samples were obtained. So blue is high peak exposure, environmental exposure. So summer and fall, and then winter and spring and orange. And that was also not different. We also assessed differences and diversities of the fungal communities and those who had better asthma control compared to those who had worse asthma control. And that was also not different. Now, finally, we looked at the microbiome of the oral or the mouth of the 24 patients since, you know, sometimes the mouth is thought to be a contaminant to the sputum as well. We only had three patients who had cladosporium detected in their oral cavity out of the 24, making this unlikely cause of some of the observations at least or what we're seeing. So limitations, you know, COVID period as well that we dealt with this. Otherwise, you know, our small sample size, lack of objective measures of asthma control. And finally, in terms of clinical implications, you know, additional research is needed to establish the extent to which cladosporium contributes to uncontrolled asthma in the community. But, you know, our findings raised this question of whether there could be a subset of patients with asthma who may benefit from eliminating or reducing cladosporium in their lungs. Thank you very much. I'm happy to answer any questions. A retrospective study on the trends of the patient hospitalized for the asthma exacerbation with and without concomitant eosinophilic esophageitis in the United States. Thank you, Dr. Ko. Okay. Good morning, everyone. My presentation is entitled a retrospective study on the trends of patients hospitalized for asthma exacerbations with and without concomitant eosinophilic esophagitis in the U.S. So I'm Linda Pham. I'm a current PGY3 at Riverside Community Hospital, H.J. Riverside, and I have no financial disclosures. So the objectives of my presentation, first, are to review eosinophilic asthma as well as eosinophilic esophagitis. Second is to look at the most recent study I've done on focusing whether there's an association between these two diseases and also evaluating the trend of asthma prevalence over time. And lastly, to discuss the study's conclusions. Just so some background, there's many subtypes of asthma with different biological pathways of inflammation. And so we mainly focused on eosinophilic asthma, which is the subtype whose trademark includes an increase in eosinophils in the lung tissue, blood, and sputum. So typically, the eosinophils drive inflammation in the respiratory tract, which leads to structural changes in the bronchial wall and causes bronchial remodeling. This includes fibrosis, subepithelial collagen deposition, and metaplasia of the mucosal glands, which then increases sputum secretion and an associated cough. And so both eosinophilic asthma and eosinophilic esophagitis, also known as EOE, are both mediated by eosinophils in conjunction with the Th2 helper T cells. So typically what happens is the allergens, you know, like house mites, viruses, they're detected by the dendritic cells here, which then present the antigen to the naive Th0 helper T cell, which then becomes active. It becomes Th2 cells here, which then secrete IL-13 and IL-4, which then help with the B cell to class switch to IgE and also secretes IL-5, which is what we're mainly interested in. And so this causes the activation and recruitment of the eosinophils. So here's another representation of the same process. So here we can see the allergens activating the dendritic cells, the Th2 cell, then secretes the IL-5, which then causes eosinophil maturation, migration, and recruitment. And then EOE basically is just inflammation of the esophagus due to the hyperproliferation of eosinophils in the esophagus. And so this is typically diagnosed with upper endoscopy, and you do see the white plaques, rings, and furrows, and you see on biopsies the overabundance of eosinophils in the esophageal tissue. And there's been previous studies in children with EOE and asthma. It's shown to be about 24%. And typically these children were shown to have seromarkers of atopy, including IL-13, 5, and 4, as well as peripheral eosinophils and IgE. And so for our study, we mainly looked at the characteristics of patients with asthma and EOE. And without EOE, and general trend of asthma across time. So for our methods, we looked, we did a retrospective cross-sectional study of adults presenting to HCA hospitals across the U.S. with asthma and EOE from 2016 to 2021. There was a total of 3,678,812 patients with asthma and 5,823 with EOE. Inclusion criteria included those over 18 with a diagnosis of either asthma and or EOE. And inclusion criteria included those under 18. Moving on to the results, so the first chart looks at whether the rate of EOE and asthma is increasing over time. And so for us, the R-squared was around 0.2. There is a slightly positive correlation. However, these results were not statistically significant with a P-value of 0.678. Moving on to asthma alone, again, there is a slight correlation. However, again, the results were not statistically significant across time. And then moving on to the actual counts, there was about 2 million patients with asthma in the female population and about 1 million in males. And so mainly we're just looking at the gender differences in asthma and asthma and EOE in patients. And we did see that there was a statistically significant difference between the genders with females having about 73% and males only having about 27% of asthma cases in our study. And so looking at the mean ages of the patients, this is one of the more statistically significant results. We did see that in patients who had both EOE and asthma in male patients, they presented to the hospital around age 39. And in those only with EOE, they presented to the hospital at around age 45 with about a five-year age gap. And in females, we saw a similar result. We did see that patients who had both typically presented at age 45 or 44 and those with only EOE presented at age 49. And so moving on, we also looked at just asthma in terms of encounters. So for our study, asthma accounted for about 4% of all ED and inpatient encounters at the HA hospitals and about 18% of those patients who are admitted to the ED ended up staying overnight. For discussion, looking mainly at genders, we did see that patients with both EOE and asthma did present earlier admission than those with only asthma or EOE alone in a statistically significant manner with a p-value of less than .001. And the cause for this is not really clear. We could say it could be a result of multiple atopic processes working together to cause a stronger inflammatory response and causing patients to seek medical attention. And then also it did show that there were greater hospital encounters for females than males, about 73% versus 27%. And again, it's not clear why this is the case. There have been studies that have shown that in childhood, boys have a greater prevalence of asthma, but in adulthood, women actually have a greater prevalence, about 9% versus 6%. And actually studies have also shown that women are three times more likely to be hospitalized for asthma exacerbation. And lastly, we looked at the prevalence of EOE and asthma across time, and it looks like there's not an increase. There's been a lot of techniques to diagnose both asthma and EOE over time, but it looks like there's no upward trend. So we're thinking possibly that the treatments for these diseases are pretty efficient and have limited the amount of people that needed to seek emergent treatment for flares and exacerbations. And then for clinical implications, patients who have one atopic disease, such as asthma, may be increased risk for having other ones, including EOE. And according to this study, those with multiple conditions do present earlier to the hospital than those without, with a mean age difference of about five years in both males and females. And so we do need additional investigation to see if other atopic diseases besides EOE associated with asthma do cause patients to present earlier to the hospital. And if this is the case, this is something we need to keep in mind, as patients may be hospitalized sooner than those with just asthma alone. And so this is something we need to think about as we move on and treat our patients. Thank you. So our next presenter is Dr. Laura Huyu. And she would be presenting on the, yeah, so she would be presenting on the high burden of asthma acute care in Singapore in the next 20 years. Hello, everybody. My name is Laura. Today I'll be presenting on the high burden of asthma acute care in Singapore over the next 20 years. I'm a PhD student in health economics and outcomes research at Sausie Hawk School of Public Health, National University of Singapore. And today I'll be mainly sharing about the recent trends and the future healthcare burden of asthma in Singapore over the next 20 years. So in 2019, asthma affected 262 million people worldwide and caused 450,000 deaths. In Singapore, asthma is prevalent in 20% of children, 5% of adults, and suboptimal asthma management is an issue in Singapore because about 70% of the asthmatics are not on regular use of the recommended inhaler medication and a significant proportion are not on regular follow-ups. However, currently there is limited population level evidence of the burden of asthma in Singapore. The nationwide asthma admission rate in Singapore was last published in 2003 and the most recent economic burden study of asthma was based on a relatively small random sample of a few hundred asthmatics. And therefore, we conducted this study to look into the past trends of asthma-related healthcare burden and to project the future trends over the next, sorry, the future total burden over the next 20 years. So we obtained nationwide aggregate level data from the Singapore Ministry of Health Clinical and National Disease Registry and this data contains the annual rates of asthma admission, ED attendances, and mortality. We also obtained future population outcomes from a local study by the Institute of Policy Studies and they summarized the population growth and aging projections nicely. So we performed a longitudinal retrospective study and we included patients of all ages with asthma as the final diagnosis during any hospitalization or ED visit during this study period or who died due to asthma and identified them using these ICD codes. So in examining the past trends, we basically looked at the annual rates of asthma admission, ED attendances, mortality, and in projecting the future burden, we looked at total episodes over the next 20 years. So we first performed change point analysis, which is a method that separates trend data into time intervals within which the rate of change remains constant. So we used this to identify the latest stable trend. And then next, we did generalized linear modeling based on to fit the trend for the latest stable trend that we identified in step one. And then lastly, we developed a probabilistic model that combines the estimated rate of each outcome with population growth and aging projections that we derived from the report that was mentioned just now. So our results showed that the asthma admission rate in Singapore hovered between 70 to 80 episodes for 100,000 since 2003, whereas asthma-related ED attendance rate was generally above 400 episodes per 100,000. On the other hand, asthma mortality rate had declined from 4.02 to 0.57 per 100,000 over the past 25 years. We also noticed that in 2020, the asthma admission rate and ED attendance rate had declined by about half during the pandemic. And this pattern is consistent with the trends that we have observed during past global respiratory pandemics, such as H1N1 and SARS. Our projection results, which are based on the latest stable trend before COVID-19, so it stops until 2019, it shows that the asthma admission rate in Singapore is expected to increase by 1.7% per year. And this amounts to about 160,000 episodes over the next 20 years. The asthma-related ED attendance rate is expected to decrease over time at a rate of 3.4% per year. And this amounts to about 200,000 episodes in total over the next 20 years. On the other hand, the asthma mortality rate in Singapore is expected to remain low over time, amounting to about 600 to 700 episodes over the next 20 years. So based on our findings, currently the asthma admission rate in Singapore is about twice the OECD average and is expected to increase over time, despite globally declining trends. Our projection results are based on the latest trend before COVID-19. And we are assuming that asthma-related healthcare utilization will recover to pre-pandemic levels because such a trend has been observed in a Singapore context. Yeah. And the asthma-related ED attendance rate in Singapore is currently about 20% lower than the U.S., but it's five times that of the U.K. And it is expected to decrease over time, possibly because a significant proportion of these asthma-related ED attendances were attributed by asthmatics who are frequent attendees to the ED. And these episodes are more susceptible to the influences of previous policy interventions, changes, stuff. Yeah. On the other hand, asthma mortality rate is expected to remain low over time, and currently it has remained stable even through COVID-19, the pandemic. So, in conclusion, the burden of asthma acute care, oh, sorry, the burden of asthma acute care in Singapore is high. And, however, currently the National Asthma Program in Singapore, which is focused on shifting asthma management from tertiary to primary care settings, provides opportunities to reduce avoidable admissions as well as ED attendances. So, in the next step of our research, we will be looking into patient-level data to obtain age and sex stratified burdens of projections. And we will also account for oral cortical steroid-related comorbidities because this has a very high prevalence in severe asthma patients in Singapore. Yeah. Thank you. Thank you.

asthma

neutrophilic asthma

Dornes' Alpha therapy

sputum expectoration

Clodosporium

asthma control

hospitalization timing