Tóm tắt luận Án ta nghiên cứu Đặc Điểm lâm sàng, cận lâm sàng và nồng Độ một số cytokine huyết thanh Ở bệnh nhân hen phế quản nhiều Đợt cấp

VIETNAM MILITARY MEDICAL ACADEMYPHAM DAC THE STUDY ON CLINICAL, PARACLINICAL CHARACTERISTICS AND SERUM CYTOKINE CONCENTRATIONS IN ASTHMA PATIENTS WITH... Inour country, there have been n

VIETNAM MILITARY MEDICAL ACADEMY

PHAM DAC THE

STUDY ON CLINICAL, PARACLINICAL CHARACTERISTICS AND SERUM CYTOKINE CONCENTRATIONS IN ASTHMA PATIENTS WITH

Scientific Supervisor:

1 Assoc Prof Ph.D Nguyen Huy Luc

2 Assoc Prof Ph.D Ta Ba Thang

Opponent 1: Assoc Prof PhD Dinh Ngoc Sy

Opponent 2: Assoc Prof PhD Vu Van Giap

Opponent 3: Prof PhD Tran Huy Thinh

The thesis will be defended before the thesis evaluation board

at the university on:

Time: Date: Month: Year:

The thesis can be accessed at:

1 National Library

2 Library of the Military Medical Academy

1 Phạm Đắc Thế, Nguyễn Huy Lực, Đào Ngọc Bằng, Tạ

Bá Thắng (2024) Đặc điểm lâm sàng bệnh nhân hen phế

quản có đợt cấp thường xuyên điều trị ngoại trú tại bệnh

viện đa khoa quốc tế Hải Phòng Tạp chí Y học Việt Nam,

534: 386-390

2 Phạm Đắc Thế, Nguyễn Huy Lực, Đào Ngọc Bằng,

Tạ Bá Thắng (2024) Liên quan giữa nồng độ cytokine

huyết thanh với đặc điểm lâm sàng ở bệnh nhân hen

phế quản có đợt cấp thường xuyên Tạp chí Y học Việt Nam, 534: 402-406.

3 Pham Dac The, Nguyen Huy Luc, Dao Ngoc Bang, Ta

Ba Thang (2024) Changes in cytokines levels in asthma

patients with frequent exacerbations Journal of Military Pharmaco-medincine, Vol 49, N04 - 2024: 73-82

1 Rationale

Asthma affects public health in all aspects, regardless of race,gender, or age The burden of asthma has continued to increase overthe past 30 years Vietnam is among the countries with an increasingtrend Asthma exacerbations are an adverse event that affect theprogression of the disease, causing complications and possibly deathfor patients Asthma patients with frequent exacerbations are one of thephenotypes of uncontrolled asthma The nature of asthma withfrequent exacerbations is related to the process of diverse and unstableairway inflammatory responses: Th2 inflammatory responses and non-Th2 inflammation Assessing clinical characteristics, lung ventilationdisorders, and changes in inflammatory markers, cytokines, etc helpscontrol asthma more accurately and effectively The inflammatorymechanism plays a key role in the pathogenesis of asthma with theparticipation of many cells Cytokines play a key role in initiating,maintaining, or amplifying the inflammatory response in asthma Inour country, there have been no studies on clinical characteristics, lungventilation, or inflammatory markers, especially serum cytokineconcentrations in the frequent exacerbation asthma phenotype.Therefore, we conducted this study with two objectives:

1 Describe some clinical features, lung ventilation, inflammatory markers, and serum cytokine concentrations in asthma patients with frequent exacerbations.

2 Evaluation of the relationship between serum cytokine concentrations and some clinical characteristics, inflammatory markers, and lung ventilation in asthma patients with frequent exacerbations.

2 The new main scientific contribution of the thesis

- The results of the thesis show some distinct clinical andparaclinical characteristics and serum cytokine concentrations inasthma patients with frequent exacerbations

- Several associations between serum cytokine concentrationsand clinical features, inflammatory markers, and lung ventilationfunction have been identified

The study results contribute to determining the characteristic ofclinical phenotype and inflammatory response in asthma withfrequent exacerbations as a basis for effective control treatmentaccording to the disease phenotype

3 Thesis structure

The thesis consists of 127 pages: Problem statement 2 pages;Chapter 1 (Literature review) 33 pages; Chapter 2 (Researchmethods) 22 pages; Chapter 3 (Results) 34 pages; Chapter 4(Discussion) 33 pages; Conclusion 2 pages; Recommendations 1page, and List of published scientific articles

The thesis includes 42 tables, 5 charts, 6 figures, 164 references (6 Vietnamese documents, 158 English documents, 50% ofdocuments in the last 5 years), and Appendix of list of researchparticipants

CHAPTER 1: LITERATURE REVIEW

1.1 Asthma exacerbation and frequent exacerbation asthma 1.1.1 Asthma exacerbation

1.1.2 Frequent exacerbation asthma

1.1.2.1 Definition

Frequent exacerbation asthma, or exacerbation prone asthma, isasthma with hospitalizations ≥ 2 times/year despite standard controltreatment

1.1.2.2 Risk factors of frequent exacerbation asthma

 Early onset, allergic asthma

 Late onset eosinophilic asthma

1.2.1.2 Non Th2 – typed inflammation

1.2.2 Role of cytokines in asthma

1.2.2.1 Cytokine Th2

1.2.2.2 Cytokine non Th2

1.2.2.3 Proinflammatory and anti-inflammatory cytokine

1.3 Asthma control treatment according to inflammatory phenotype

1.3.1 Th2 – typed inflammation phenotype

1.3.2 Non Th2 – typed inflammation phenotype

1.4 Research related to the thesis

CHAPTER 2: SUBJECTS AND METHODS

2.1 Subjects

- Patient group: including 120 asthma patients with out ofexacerbation, treated as outpatients at the Asthma ManagementDepartment - Hai Phong International Hospital, from January 2020 toMay 2023 Patients were divided into 2 groups:

+ Frequent exacerbation asthma: 60 patients (Group 1).+ Few exacerbation asthma: 60 patients (Group 2)

- Healthy control group: 30 normal people were tested for serumcytokines to serve as reference values for the disease group(Group 3)

- Patients were diagnosed with asthma and had their records kept

at the hospital's asthma management department for at least 12months up to the time of collecting research indicators

- Patients were examined and treated according to the protocol

by a respiratory specialist

- Patients comply with medication use (correct dosage,proficient use of drug delivery devices), and follow-up visits

- Criteria for frequency of exacerbation: patients with fewexacerbations have 1 exacerbation/1 recent year; patients withfrequent exacerbations have ≥ 2 exacerbations/1 recent year.

- Agree to participate in the study

2.1.1.2 Healthy control group

- People who are healthy in history and currently do not haveimmunodeficiency, cancer, autoimmune diseases, or chronic diseasesand do not have acute infections

- Agree to participate in the study

2.1.2 Exclusion criteria

2.1.2.1 Patient group

- In the asthma exacerbation.

- Patients with acute respiratory infections and ACO, bronchiectasis,

and pulmonary tuberculosis

- Patients with comorbidities: uncontrolled hypertension, heart

failure, acute and chronic hepatitis, chronic glomerulonephritis,nephrotic syndrome, chronic renal failure, systemic diseases, immunediseases, malignancies in organs

- Systemic corticosteroid treatment within 2 weeks prior to study

inclusion

2.1.2.2 Healthy control group

- Acute infection within the last 2 weeks

2.2 Research content

2.2.1 Characteristics of clinical, lung ventilation, inflammatory markers, and serum cytokine levels in asthma patients with frequent exacerbations.

- Clinical characteristics: general patient characteristics, history

of allergy, age of onset, duration of illness, comorbidities, BMI,severity of illness, current symptoms, asthma control status,frequency of exacerbation

- Paraclinical characteristics: Lung ventilation, inflammatorymarkers

- Serum cytokine levels.

2.2.2 Relationship between serum cytokine concentrations and some clinical characteristics, inflammatory markers, and lung ventilation in asthma patients with frequent exacerbations.

- Relationship between serum cytokine concentrations and

gender, age group, history of allergy, age of onset, BMI, diseaseseverity, ACT

- Relationship between serum cytokine concentrations and lung

ventilation parameters

- Relationship between serum cytokine concentrations and

eosinophil count, IgE concentration, FeNO

- Correlation between non-Th2 cytokines, Th2 cytokines, and

inflammatory and anti-inflammatory cytokines

- Correlation between some clinical and paraclinical

characteristics and increased concentrations of IL-4, IL-13, IL-17,IFN-γ

2.3 Methods

2.3.1 Study design

Descriptive, cross-sectional, prospective studies

2.3.2 Location and time of research

The study was conducted at the Asthma ManagementDepartment - Hai Phong International Hospital, from January 2020 toMay 2023

2.3.3 Sample size calculation

Based on the formula for estimating an average with relativeerror:

Formula:

In which:

- n: the minimum sample size

- Z1-α/2 = 1.96 with statistical significance = 5%

- ℇ: the acceptable relative error level, choose ℇ = 0.06

- µ: is the mean value and σ: is the standard deviation of theforced vital capacity (FVC) in asthma patients with many acuteepisodes in a year, take µ = 77.45% and σ = 17.57% in the study

of author Denlinger L et al (2017)

- Substituting into the formula, we get n = 55 asthma patients withfrequent exacerbations Sample collection: convenient samplingmethod, gradually accumulated during the study period Allpatients who met the research criteria were included in the study.During the period from January 2020 to May 2023, we collected

120 patients who met the criteria, included in the analysis

2.3.4 Data collection methods

- Clinical examination

- Lung ventilation function measurement

- FeNO concentration measurement

- Blood count, IgE test

- Serum cytokine quantification

2.3.5 Treatment, control, and patient management

2.2.6 Standards for evaluating research results

2.4 Data analysis and processing

2.5 Research ethics

CHAPTER 3: RESEARCH RESULTS

3.1 Characteristics of clinical, lung ventilation, inflammatory markers and serum cytokine levels in asthma patients with frequent exacerbations

Table 3.2 Age distribution of asthma patients according to

exacerbation frequency

Asthma

Age group

Group 1 (n = 60) Group 2 (n = 60) Totall

exacerbations having a lower rate than those with few exacerbations(60% vs 65%).

Table 3.3 Patient and family history

Asthma

History

Group 1 (n = 60)

Group 2 (n = 60) p*

of allergies than those with few exacerbations (73.3% vs 36.7%); thedifference was statistically significant with p < 0.05 There was no

difference in smoking history and family allergy history between the 2groups of asthma patients with frequent and few exacerbations

Table 3.5 Distribution of age of onset according to number of

exacerbations/year and history of allergy

≤ 12 [n (%)] > 12 [n (%)] Exacerbatio

n frequency

Group 1 (n = 60) 34 (56,67) 26 (43,33)

0,26Group 2 (n = 60) 40 (66,67) 20 (33,33)

Asthma patients with frequent exacerbations had a higher rate

of onset > 12 years old than the group with few exacerbations(43.33% vs 33.33%); however, the difference was not statisticallysignificant (p = 0.26) Asthma with a history of allergy had a higherrate of onset ≤ 12 years old (early onset) than patients without ahistory of allergy (74.24% vs 46.3%), with a statistically significantdifference of p < 0.05

Table 3.7 Distribution of comorbidities with asthma

Asthma

Comorbidities

Group 1 (n = 60) Group 2 (n = 60) (n = 120) Totall p *

Sinusitis YesNo 42 (70,0)18 (30,0) 27 (45,0)33 (55,0) 69 (57,5)51 (42,5) 0,006

GERD YesNo 23 (38,33)37 (61,67) 11 (18,33) 34 (28,33)49 (81,67) 86 (71,76) 0,02OSA YesNo 20 (33,33)40 (66,67) 52 (86,67) 92 (76,67)8 (13,33) 28 (23,33) 0,01Diabetes YesNo 54 (90,0)6 (10,0) 54 (90,0)6 (10,0) 108 (90,0)12 (10,0) 1Hypertension YesNo 51 (85,0)9 (15,0) 54 (90,0)6 (10,0) 105 (87,5)15 (12,5) 0,41

*: Chi-Square Test

The asthma group with frequent exacerbations had morbidities of chronic rhinosinusitis, GERD, and OSA at rates of 70%,38.33%, and 33.33%, respectively, which were significantly higherthan those of the asthma group with few exacerbations (p < 0.05) The

co-co-morbidities of diabetes and hypertension did not differ between thetwo groups of patients (p > 0.05).

Table 3.8 Asthma control status Asthma

Control status

Group 1 (n = 60) Group 2 (n = 60) p

* : Chi-Square Test **: T - Test

The frequent exacerbation asthma had a lower mean ACT scorethan the asthma group with few exacerbations (p < 0.05) and theproportion of patients with an ACT score < 20 was higher

Figure 3.2 Distribution of asthma severity levels (n = 120)

The group with frequent exacerbations had a rate of step 5asthma of 21.67%, higher than the group with few exacerbations;however the difference was not statistically significant (p > 0.05)

Table 3.11 Inflammatory markers in patients with asthma Asthma

Inflammatory marker

Group 1 (n = 60) Group 2 (n = 60)

FeNO ≤ 50 ppb 32 (53,3) 56 (93,3) < 0,01**

> 50 ppb 28 (46,7) 4 (6,7)

Median (p25 – p75) 33,5 (19,2 -52,0)

* : Chi-Square Test **: Fisher ’ Exact Test

The group with frequent exacerbations had a higher eosinophil(Eo) count ≥ 400 cells/µl than the group with few exacerbations(45% and 28.33%, respectively); the difference was not statisticallysignificant with p > 0.05 Asthma patients had a high proportion ofIgE levels > 100 IU/ml, in which the group with frequentexacerbations (71.7%) had a higher proportion than the group withfew exacerbations (51.7%); the difference was statistically significantwith p < 0.05 There were 32/120 patients with increased FeNO > 50ppb, in which the group with frequent exacerbations had asignificantly higher number of patients with increased FeNO than thegroup with few exacerbations (28 vs 4 patients), the difference wasstatistically significant with p < 0.05

Table 3.13 Serum cytokine concentrations in response to Th2 inflammation

Group 3 (n = 30)

p *

(1; 2)

2.78 (1.47 – 9.44) 0.006 0.27 0.11

(0.40 – 1.43)

0.50 (0.40 – 1.43)

0.40 (0.40 – 0.40)

0.02

8 0.004 0.67INF-γ

6,54

(5.05 –

11.95)

5.57 (5.05 – 9.96)

5.05 (3.67 – 6.05)

0.00

5 0.007 0.63

*: Kruskal-wallis * *: Manney-White Test

Serum cytokine concentrations in patients with non-Th2inflammatory response asthma were higher than in normal subjects

In the group with frequent exacerbations, the concentrations ofcytokines INF-α, INF-γ, IL-17 were higher than in the group ofpatients with few exacerbations, however, the difference was notstatistically significant (p > 0.05)

Table 3.14 Serum cytokine concentrations in response to Th2

Group 3 (n = 30)

p *

(1; 3)

p *

(2; 3)

p *

(1; 2)

10.49 (6.69 –16.53) < 0.001 0.06

0.007IL-13 (1.73 - 13.83)9,93 (1.73 –3.95

10.52)

1.73 (1.73 –10.52)

0.001 0.29 0.01

*: Kruskal-wallis * *: Manney-White Test

Serum cytokine concentrations in patients with Th2 inflammatoryresponse asthma were higher than in normal subjects In the group withfrequent exacerbations, serum cytokine concentrations weresignificantly higher than in the group with few exacerbations; thedifference was statistically significant with p < 0.05

Table 3.15 Serum cytokine concentrations of inflammatory and

Group 3 (n = 30)

p *

(1; 3)

p *

(2; 3)

p *

(1; 2)