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Slide 1 – Phenotyping the Responses to Systemic Corticosteroids
Good afternoon, professors, and hi everyone. I’m very honored to be here today to
share my presentation about the paper Phenotyping the Responses to Systemic
Corticosteroids in the Management of Asthma Attacks (PRISMA) by Author Carlos et
al, published in January 2025 by the European Respiratory Journal. European
Respiratory Society Publications with an impact factor of 21.2. Before I begin, I
would like to sincerely thank my advisor, Professor Hsiao Chi Chuang, for taking the
time to review my slides and provide me with many helpful suggestions.
Slide 2 – Why this paper?
Regarding the reason for choosing the paper, I found that its content and results are
relevant to my expertise and direction, as well as my lab. Second, the study fills a
research gap in the evaluation of asthma phenotypes for oral corticosteroid
treatment options. Ultimately, the research findings are highly applicable in clinical
practice, enabling experts to accurately evaluate asthma phenotypes and make
informed treatment decisions.
Slide 3 – Outline
My presentation involves 7 main parts, including:.
Slide 4 – 4
Now we will begin the first part of today's presentation, the introduction.
Slide 5 – 1. Introduction
Asthma often involves airway inflammation and airway hyperresponsiveness, but
these problems do not always confirm the diagnosis. Groups of patients who share
similar demographic or clinical features are referred to as clinical asthma
phenotypes; however, these phenotypes often do not align well with the underlying
biological mechanisms or treatment responses. Biomarkers that show Type 2
airway inflammation are more helpful, especially when assessing and treating
difficult-to-treat asthma and severe asthma.
Slide 6 – 1. Introduction
Asthma is a major noncommunicable disease (NCD), affecting both children and
adults, and is the most common chronic disease among children. Asthma affected an
estimated 262 million people in 2019 and caused 455.000 deaths. Epidemiological
data show that although asthma prevalence is high in countries with high Social
Development Indicators (SDI), rates of severe illness, death, and Disability.
The Adjusted Life Year (DALY) is higher in low and middle-income countries due to
a lack of diagnosis and treatment, where diagnosis and under-treatment pose
significant challenges. On the chart showing prevalence and mortality estimates, we
can immediately see that in terms of prevalence rate, most developed countries
have significantly higher incidence rates than less developed countries such as the
African continent and Southeast Asia; however, in terms of mortality burden,
countries with high incidence rates but lower mortality rates than countries with
lower incidence rates.
This emphasizes that diagnostic and treatment capacity plays an important role
when less developed countries have fewer health resources; therefore, it is
necessary to identify and treat the group of seriously ill patients well through simple
but effective tests to treat them in a way that minimizes the unwanted effects of
corticosteroids.
Slide 7 – 1. Introduction
In the immune mechanism of asthma, when Environmental factors such as bacteria,
viruses, allergens, and proteases trigger the release of epithelial. derived alarmins,
which activate type 2 innate lymphoid cells (ILC2s) to release type 2 cytokines (IL-4,
IL-5, and IL-13). In parallel, dendritic cells (DCs) present allergens to T cells,
inducing the differentiation of type 2 T helper cells (Th2 cells) and the production of
type 2 cytokines, including IL-4 and IL-13. These cytokines stimulate IgE class
switching and secretion by B cells.
Additionally, IL-13 induces epithelial cells to produce nitric oxide (NO) via the
inducible isoform of nitric oxide synthase enzyme (iNOS). Eosinophil chemotaxis
from the bloodstream to the nasal mucosa is facilitated by a type 2 milieu.
Through binding to IL-5 receptors on the eosinophils, IL-5 enhances the survival,
maturation, and activation of eosinophils.
The results of this process include increased NO emissions, respiratory mucus
secretion, smooth muscle hypertrophy, airway obstruction and hypersensitivity,
airway fibrosis and remodeling.
Slide 8 – 1. Introduction
When a patient presents with chronic or recurrent respiratory symptoms, the
physician will take a detailed history and perform a physical examination to
determine if the results continue to support the diagnosis of asthma. If available,
lung function tests will be performed before and after bronchodilator use to
determine if there is a change in expiratory airflow – an important criterion for
confirming asthma. If the results are “yes”, the patient will be diagnosed with
asthma and started on ICS treatment.
If lung function cannot be measured immediately or if there is no clear evidence, the
physician may consider biomarkers and a trial of ICS treatment in the absence of
other suspected pathologies. After 1–3 months of trial treatment, the key question is
whether symptoms or lung function have improved; if the answer is “yes”, the
diagnosis of asthma is confirmed. Conversely, if the answer is “no”, the physician
needs to review the diagnosis and may refer the patient to a specialist.
Slide 9 – 1. Introduction
Normal FEV₁/FVC: In healthy people, the FEV₁/FVC ratio (forced expiratory volume
in 1 second / forced vital capacity) is usually about 0.80–0.90 in young adults and
falls with age. In asthma: Airflow is obstructed, so FEV₁ falls more than FVC →
FEV₁/FVC decreases. After a bronchodilator, an increase in FEV₁ of≥12% and ≥200
mL (in adults) indicates reversibility, supporting a diagnosis of asthma.
The ratio can be near normal between attacks, so consider combining it with
symptoms and repeat testing if needed.
Slide 10 – 1. Introduction
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GINA divides asthma treatment into two approaches: Track 1 is preferred because
ICS-formoterol is used for both maintenance and reliever, significantly reducing
exacerbations and simplifying the regimen. In steps 1–2, patients only need to use
ICS-formoterol when symptoms appear. In steps 3–4, switch to a combination of
both daily and reliever use. In step 5, add a LAMA and assess the phenotype to
choose the appropriate biologics. Track 2 is an alternative approach when Track 1 is
not feasible.
Step 1 allows for the use of SABA or ICS–SABA as needed, but if SABA is used, it must
be accompanied by an additional dose of ICS each time. Step 2 switches to low dose
daily ICS, steps 3–4 use low or medium dose ICS–LABA, and step 5 is similar to
Track 1, with the addition of LAMA and assessment of phenotype to consider
biologics.
Slide 11 – 1. Introduction
In chronic asthma, the treatment paradigm is evolving towards targeting “treatable
traits”. This framework relies on clinical characteristics that predict a higher risk
and a better treatment response. The most noteworthy application is the targeted
use of anti-inflammatory medications in asthma, characterised by a type 2 (T2)
inflammatory phenotype. This trait is identified using simple, noninvasive, and
accessible tests such as the blood eosinophil count (BEC) and fractional exhaled
nitric oxide (FENO).
Slide 12 – 1. Introduction
The questionnaire consists of 5 short questions about the patient's self. Perceived
asthma symptoms are assessed with each question having 6 answers with
corresponding scores ranging from mild to severe; the final score is the average of
the 5 questions. An ACQ score <0.75 indicates well-controlled asthma, and >1.5
indicates poorly controlled asthma. A change in ACQ score of 0.5 is considered the
minimal clinically important difference.
Slide 13 – 13
13 2. Rationale.
Slide 14 – 2. Rationale
ok
Slide 15 – 15
15 3. Hypothesis and Aim.
Slide 16 – 3. Hypothesis and Aims
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16.
Slide 17 – 17
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Slide 18 – 4. Materials & Methods
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Slide 19 – 4. Materials & Methods
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Patients were assessed before (visit 1) and after a 7-day OCS course (visit 2) with
home monitoring in between. On day 0 of the asthma attack (visit 1), patients were
reviewed for eligibility, consented and prescribed oral prednisone (40 mg for 7
days).
Evaluations in visits included clinical questionnaires, lung function, FENO and
sputum/blood samples and have been described elsewhere. On day 7 (visit 2), no
repeat of total and specific IgEs, point. of.
care multiplex PCR, and a chest X-ray, as well as additional patient satisfaction and
physician surveys. During the 7-day home monitoring period, patients record
symptom scores and measure their peak expiratory flow (PEF).
Slide 20 – 4. Materials & Methods
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Slide 21 – 4. Materials & Methods
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Slide 22 – 22
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Slide 23 – 5. Results
The study recruited and followed up a total of 59 patients with asthma who were
initially evaluated, of whom 6 were excluded due to COVID-19 infection, a negative
methacholine test, or the presence of community. acquired pneumonia on chest X-
ray, or eosinophilia.
After exclusion, 53 patients met the criteria and completed the first visit; all 53
patients also continued to complete the second visit.
Slide 24 – 5. Results
The table shows the general characteristics of the study population, we can see
some highlights that the baseline indices between the T2 groups are quite balanced,
except for the sharp increase in men at T2. High/High (p<0.001). One noticeable
factor is that the BMI ratio in all groups is high.
Slide 25 – 5. Results
Patients used ICS/LABA at similar rates and doses between groups. There was no
difference between the groups in terms of chronic sinusitis. However, in the case of
nasal polyps, the difference was statistically significant, with higher levels observed
in the more severe groups, specifically 0, 14, and 50% in the Low, Mid, and High
groups, respectively.
There was a sharp increase in the T2-High/High group, reinforcing the BEC+FENO
value, which reflects the T2 inflammatory phenotype throughout the nasal cavity.
sinus.
lung axis. This table shows that the T2-high signature in the upper respiratory tract
is very strong, while the T2-low is associated with Obstructive Sleep Apnea.
Treatment should focus on treatable traits rather than uniformly increasing ICS.
Other variables did not differ between groups.
Slide 26 – 5. Results ?????
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Slide 27 – 5. Results vẽ lại bang này???
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27.
Slide 28 – 5. Results
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Panel A shows the trend in pre. BD FEV1 improvement according to biomarker
stratification (T2-Low/Low, T2-Mid, and T2-High/High). The ANOVA trend test
revealed a significant trend in FEV1 improvement across the groups (p < 0.0001),
with a mean change of 0.0450 L in the T2-Low/Low group and 0.111 L in the T2
group. Mid, and 0.535L in T2. High/High.
The blue dotted lines indicate the minimal clinically important difference (MCID) of
0.1L. Panel B shows the trend in pre. BD FEV1 % improvement according to
biomarker stratification (T2.
Low/Low, T2. Mid, and T2. High/High).
The ANOVA trend test revealed a significant trend in FEV1 improvement across the
groups (p = 0.001), with a mean change of 2.03% in T2-Low/Low, 6.52% in T2-Mid,
and 21.4% in T2-High/High. The blue dotted lines indicate the minimal clinically
important difference (MCID). T2-Low/Low is defined as BEC < 0.15 × 10^9 cells/L
and FeNO <25 ppb, T2-Mid as not Low/Low nor High/High, and T2-High/High as
BEC ≥ 0.30 × 10^9 cells/L and FeNO ≥35 ppb. Red dots indicate patients with
sputum eosinophils ≥3%, black dots indicate patients with sputum eosinophils ≤2%,
and empty dots indicate patients for whom sputum samples were unavailable.
Blue dotted lines indicate the minimal clinically important difference (MCID) for
pre. BD FEV1 (≥0.1L and 10%). FEV1=forced expiratory volume in the first second.
Slide 29 – 5. Results
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Panel A shows the trend in post. BD FVC improvement according to biomarker
stratification (T2. Low/Low, T2.
Mid, and T2. High/High). The ANOVA trend test indicated a significant trend in post.
BD FVC improvement across the groups (p=0.03), with mean changes of . 0.0394L in
T2. Low/Low, 0.0426L in T2.
Mid, and 0.279L in T2. High/High. Panel B shows the trend in post.
BD FEV1 % improvement according to biomarker stratification (T2. Low/Low, T2.
Mid, and T2.
High/High). The ANOVA trend test indicated a non. significant trend in post.
BD FVC improvement across the groups (p=0.06), with mean changes of . 1.30% in
T2. Low/Low, 1.36% in T2.
Mid, and 6.86% in T2. High/High. T2.
Low/Low is defined as BEC <0.15×109 cells/L and FeNO <25 ppb, T2. Mid as not
Low/Low nor High/High, and T2. High/High as BEC ≥0.30×109 cells/L and FeNO
≥35 ppb.
Red dots indicate patients with sputum eosinophils ≥3%, black dots patients with
sputum eosinophils ≤2%, and empty dots indicate patients for whom sputum
samples were unavailable. FVC=forced vital capacity.
Slide 30 – 5. Results
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In graph a, we can immediately see that the change in FEV1 in the T2 low and mid
groups did not show significant improvement with the mean rate below the
significance level although some individuals showed good improvement, while the
T2 high group showed improvement beyond the clinically significant level and the
difference was statistically significant. This result also shows that T2. High is the
group with the greatest benefit after treatment.
If BEC is high and/or FENO is high → ICS intensification, consider anti. IL. 5/IL.
4R biologics in severe asthma; the possibility of achieving MCID in FEV₁/ACQ. 5 is
higher. If T2.
Low/Low → poor ICS response; need to review other factors (obesity, occupational
asthma, breathing disorders, SABA abuse, poor compliance, inhaler technique…) and
choose an alternative strategy. Monitoring efficacy: using the MCID as a benchmark
to assess whether the change is “patient. significant” (≥+0.10 L for FEV₁; ≤−0.5 for
ACQ.
5). The more pronounced the T2. high (high BEC & FENO), the greater the
improvement in FEV₁ and ACQ.
5 scores—more cases exceeding the MCID—supporting biotyping to select the right
ICS/biologic at the right time. Figure b shows the improvement in self. reported
symptoms using the ACQ.
5 questionnaire, with significant improvement in all groups and increasing in the
severe groups.
Slide 31 – 5. Results???
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31.
Slide 32 – 5. Results
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The graph helps visualize the multivariate regression model and emphasizes the
importance of type 2 inflammatory characteristics in predicting lung function
response. BEC–FENO (3. level subgroup) shows that patients with the high type 2
inflammatory phenotype (combined blood eosinophils and FENO) had a mean
improvement in FEV₁ of 0.13 L compared to the reference group.
The trend for improvement was greater in the group with lower baseline FEV₁, but
the data were not strong enough to draw firm conclusions. Gender did not influence
the improvement in FEV₁.
Slide 33 – 5. Results
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Figure 3 shows the trajectory of peak expiratory flow (PEF) and symptom/ACQ. 5
scores over 7 days, comparing three asthma groups stratified by T2 inflammation
level. In graph (a), from day 0, the T2.
High group had a higher mean PEF than the other two groups, and during the 7. day
follow. up, the PEF of this group gradually increased quite clearly, the interaction
between the T2.
High/High group and time was statistically significant (p<0.05), meaning that the
PEF improvement of the T2. High/High group was superior to that of the T2.
Low/Low (blue) and T2.
Mid (gray). The home spirometry results were slightly higher than those measured
at clinic visits, but both reflected a similar trend of PEF increase. In graph (b), all
three groups started with relatively high ACQ.
5/symptom scores (around 3–3.5 points), reflecting uncontrolled asthma, and then
the scores gradually decreased over time in all groups; however, the T2. High/High
group again stood out with the most pronounced downward slope, with the mean
score by days 6–7 approaching <1 (close to the threshold for well. controlled
asthma), while the T2.
Low/Low and T2. Mid groups remained around 1.5–2 points, meaning significant
symptoms remained. Overall, this figure shows that all patients improved in lung
function and symptoms after treatment, but patients with the T2.
High inflammatory pattern had both a higher PEF, a greater increase in PEF, and a
greater reduction in symptoms compared with the T2. Low/Low and T2. Mid
groups, supporting the finding that T2.
high asthma responds better to treatment and that stratification by BEC–FeNO is
valuable in individualizing asthma treatment.
Slide 34 – 5. Results
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This spline plot depicts the relationship between baseline peripheral blood
eosinophil count (BEC, horizontal axis, units ×10⁹ cells/L) and post. bronchodilator
FEV₁ change (vertical axis, units liters), analyzed separately for two groups
stratified by FeNO: dashed line is the group FeNO <25 ppb and solid line is the group
FeNO ≥25 ppb, the shaded areas around the graph are the 95% confidence intervals.
When BEC was low at around 0.10–0.15×10⁹/L, the improvement in FEV₁ after
bronchodilation was almost zero in both FeNO groups, but as BEC gradually
increased to 0.30×10⁹/L and especially above 0.60–1.00×10⁹/L, both curves curved
up markedly, indicating a significant increase in FEV₁, most prominent in the FeNO
≥25 ppb group with a higher curve slope and a FEV₁ difference that could reach
around 0.5–0.6 L.
The shape of the curves and the gradual separation between the two FeNO groups
showed a strong positive interaction: the higher the BEC (characteristic of
pronounced T2 inflammation), the greater the improvement in FEV₁ after
bronchodilation, and this effect was more pronounced in those with concomitant
increased FeNO, suggesting that the combination BEC and FeNO help identify
asthma subgroups that will benefit optimal respiratory function after
bronchodilator/corticoid treatment.
Slide 35 – 5. Results
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In panel A, the figure presents the odds ratios (OR) for various predictors of a
significant improvement in post. BD FEV1 ≥100 mL (MCID), as determined by a
multivariable logistic regression model. The predictors include the ordinal BEC.
FeNO 3. group status and FEV1% (per 10% decrease). The ordinal BEC.
FeNO 3. group status was the only independent predictor (odds ratio 2.50, 95%CI
1.04 to 6.67, p=0.04). Error bars represent the 95% confidence intervals (CI).
In panel B, the figure presents a receiver operating characteristic curve (ROC) for
the model predicting post. BD FEV1 improvement ≥100 mL. The area under the
curve (AUC) is 77.6% [95%CI 64.8 to 90.4%], suggesting good accuracy of the
multivariate model.
The diagonal line represents the line of no discrimination.
Slide 36 – 5. Results
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Bland. Altman Plot comparing point. of.
care (POC) blood eosinophil counts to laboratory eosinophil counts. The plot shows
the differences between POC, and laboratory eosinophil counts against the average
of the two measurements. The mean difference (bias) is represented by the solid
line, and the limits of agreement (±1.96 SD) are shown by the dashed lines.
The Intraclass Correlation Coefficient (ICC) was 0 .98 [95%CI 0.96 to 0.99],
p<0.001), indicating excellent agreement between the two measurement
techniques. This Bland–Altman plot compares blood eosinophil counts measured by
a point. of.
care (POC) device with laboratory testing, with the horizontal axis being the average
of the two measurements (POC and lab) for each patient, and the vertical axis being
the difference between POC BEC and Lab BEC. The points are mostly centered near
zero, with no clear trend toward the mean, suggesting no strong evidence of BEC.
dependent bias (e.g., POC does not increase significantly with high BEC).
There are a few outliers near the upper limit, suggesting that in some cases POC
results in significantly higher BEC values than lab, but overall the small bias and
symmetric distribution around zero suggest good agreement between POC devices
and laboratory testing, allowing POC BEC to be used as a reasonable clinical
alternative if errors within this range are acceptable.
Slide 37 – 5. Results
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The figure shows post. BD FEV1 improvement according to biomarker stratification
with sputum eosinophils, available in 48 patients. SpEos.
Low indicate patients with sputum eosinophils ≤2% (black dots); SpEos. Low
indicate patients with sputum eosinophils ≥3% (red dots). The Jonckheere.
Terpstra test indicated a significant improvement in post. BD FEV1 (p=0.005), with
mean changes of 0.0464L (0.183) in SpEos. Low group and of 0.206L (0.406) in
SPEOs.
High group.
Slide 42 – 7. Conclusion
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We found that objective improvement following OCS is confined to T2. High events.
As in chronic asthma, greater T2 burden identifies a distinct clinical and therapeutic
trajectory, whereas OCS-related adverse events are uniformly distributed.
Chúng tôi nhận thấy sự cải thiện khách quan sau khi dùng OCS chỉ giới hạn ở các
biến cố T2. cao. Giống như hen suyễn mãn tính, gánh nặng T2 lớn hơn xác định một
lộ trình điều trị và lâm sàng riêng biệt, trong khi các biến cố bất lợi liên quan đến
OCS phân bố đồng đều.
Slide 45 – Limitations
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First, being an observational study, it inherently carries the limitations of such
designs. However, by ensuring that all patients received prednisone, all groups
received active treatment. This suggests that differences between phenotypes may
be even greater in a placebo.
controlled biomarker. stratified trial, where placebo versus OCS differences would
be smaller in T2. Low/Low than in T2.
High/High events. Second, while we did not assess quality of life, we measured
symptoms. Despite being underpowered for this outcome, we observed strong
numerical trends that suggest meaningful clinical differences with greater T2
burden.
Third, adverse effects were reported by patients through a directed questionnaire,
which could have led to over. reporting and attribution bias. Fourth, we advocated
for POC BEC but failed in most of our attempts with the tested device.
Fifth, our 90. day post. attack visit was conducted virtually for people who had often
benefited from background treatment escalation, meaning that the reported
outcomes are likely confounded.
Finally, the small sample size in the T2. High/High group represents an additional
limitation that warrants caution in interpreting the findings. These limitations
should be considered in further clinical studies of asthma attacks.
Chúng tôi thừa nhận rằng nghiên cứu của chúng tôi có một số hạn chế. Thứ nhất, là
một nghiên cứu quan sát, nó vốn dĩ mang những hạn chế của những thiết kế như
vậy. Tuy nhiên, bằng cách đảm bảo tất cả bệnh nhân đều được dùng prednisone,
tất cả các nhóm đều được điều trị tích cực.
Điều này cho thấy sự khác biệt giữa các kiểu hình có thể còn lớn hơn trong một thử
nghiệm phân tầng sinh học có đối chứng giả dược, trong đó sự khác biệt giữa giả
dược và OCS sẽ nhỏ hơn ở các biến cố T2. Thấp/Thấp so với các biến cố T2.
Cao/Cao.
Thứ hai, mặc dù chúng tôi không đánh giá chất lượng cuộc sống, chúng tôi đã đo
lường các triệu chứng. Mặc dù không đủ mạnh để đưa ra kết quả này, chúng tôi đã
quan sát thấy các xu hướng số liệu mạnh mẽ cho thấy sự khác biệt có ý nghĩa về
mặt lâm sàng với gánh nặng T2 lớn hơn. Thứ ba, các tác dụng phụ được bệnh nhân
báo cáo thông qua bảng câu hỏi có hướng dẫn, điều này có thể dẫn đến báo cáo
quá mức và sai lệch quy kết.
Thứ tư, chúng tôi đã ủng hộ việc sử dụng thiết bị được thử nghiệm trên bệnh nhân
(POC BEC) nhưng đã thất bại trong hầu hết các nỗ lực của chúng tôi với thiết bị
được thử nghiệm. Thứ năm, chuyến thăm khám sau cơn đau 90 ngày của chúng tôi
được thực hiện trực tuyến cho những người thường được hưởng lợi từ việc tăng
cường điều trị nền, nghĩa là các kết quả được báo cáo có thể bị nhiễu. Cuối cùng,
quy mô mẫu nhỏ trong nhóm T2.
Cao/Cao là một hạn chế bổ sung, đòi hỏi sự thận trọng khi diễn giải các phát hiện.
Những hạn chế này cần được xem xét trong các nghiên cứu lâm sàng tiếp theo về
các cơn hen suyễn.
Slide 46 – Slide 46
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