Nghiên cứu tỷ lệ nhiễm helicobacter pylori ở bệnh nhân mày đay mạn và hiệu quả điều trị bằng phác đồ ba thuốc diệt vi khuẩn tt tiếng anh

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES --- NGUYEN THI LIEN RESEARCH ON THE PREVALENCE OF HELICOBACTER PY

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE

108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

-

NGUYEN THI LIEN

RESEARCH ON THE PREVALENCE OF HELICOBACTER PYLORI INFECTION IN PATENTS WITH CHRONIC URTICARIA AND THE EFFECTIVENESS WITH BACTERIA ERADICATION

BY TRIPLE THERAPY

Speciality: Dermatology Code: 62720152

ABSTRACT OF MEDICAL PHD THESIS

Hanoi – 2019

THE THESIS WAS DONE AT 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

Supervisors:

1 Ass Prof Pham Van Linh MD, PhD

2 Ass Prof Nguyen Tien Thinh MD, PhD

Reviewers:

1 Ass Prof Pham Thi Lan MD, PhD

2 Ass Prof Tran Ngoc Tu MD, PhD

3 Ass Prof Nguyen Ngoc Thuy MD, PhD

This thesis will be presented at Institute Council at: 108 Institute of Clinical Medical and Pharmaceutical Sciences

Day Month Year

The thesis can be found at:

1 National Library of Vietnam

2 Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences

LIST OF PUBLISHED ARTICLES RELATING TO THESIS

1 Nguyen Thi Lien, Pham Van Linh, Nguyen Tien Thinh (2018), "Study of clinical characteristics in patients with chronic urticaria infected Helicobacter pylori" Journal of Clinical Medicine and Pharmacy 108, special issue, (13)

2018, 283-289

2 Nguyen Thi Lien, Pham Van Linh, Nguyen Tien Thinh (2018), "Results of treatment of chronic urticaria infected

Helicobacter pylori with bactericidal treatment" Journal of

Clinical Medicine and Pharmacy 108, special issue, (13)

2018, 296- 301

3 Nguyen Thi Lien, Pham Van Linh, Nguyen Tien Thinh (2018), "Recurrence study in patients with chronic urticaria

infected Helicobacter pylori after bacteria eradication

treatment" Journal of Clinical Medicine and Pharmacy 108, special issue, (13) 2018, 269- 276

INTRODUCTION

Chronic urticaria (CU) is a common skin disease characterized by widespread, transient wheals occurring daily or almost daily for at least 6 weeks CU may result from several causes; hidden or overt bacterial, viral, fungal, and protozoan agents have been reported as possible initiating factors

Helicobacter pylori (H pylori) is defnitely suspected in the

etiopathogenesis of gastrointestinal disorders Recent epidemiological

and experimental data have pointed to a strong relation of H pylori

infection with the development of many extragastric diseases, such as cardiovascular, immunologic, and some skin diseases Many studies

have found an etiopathogenetic link between H pylori infection and

CU and possible skin improvement after its eradication

Vietnam localized in the region with high rates of H pylori infection Based on the understanding of CU and H pylori, we conducted

this thesis “R esearch on the prevalence of Helicobacter pylori infection

in patients with chronic urticaria and the effectiveness with bacteria eradication by triple therapy” to further investigate the possible

association The existence of a correlation between H pylori and CU may

help the clinician to find more effective methods to treat people with CU

The thesis has been conducted with two following purposes:

1 Determine the prevalence of Helicobacter pylori infection in patients with chronic urticaria and clinical relevance of the disease

2 Evaluate the effectiveness of chronic urticaria treatment in patients who infected H pylori by antihistaminic H1 combined with bacteria eradication by triple therapy

Chapter 1 OVERVIEW

Urticaria is one of the most common skin diseases, and patients may present with a wide spectrum of symptoms, including sudden development of pruritic wheals or angiowheals Chronic urticaria (CU) is diagnosed when disease has been continuously or intermittently present for at least 6 weeks The chronic and acute forms of urticarial differ in etiology, pathophysiology, and underlying mechanism Chronic urticaria has a significant impact on quality-of-life due to the constant sensation of itching, regular recurrence, and unknown etiology An estimated 15% to 23% of adults have experienced at least 1 episode of acute urticaria at some time in their lives, and the prevalence of chronic urticaria in adults is estimated at 0.5% to 5% Previous studies have reported that chronic idiopathic urticaria is associated with infection, pseudo-allergy to a food, autoimmunity, and low serum level of vitamin D

As of yet, the only reliable way to assess current disease activity is the prospective determination of symptoms over several consecutive days with the Urticaria Activity Score (UAS) The UAS works as a daily diary quantifying wheals and itching To assess the quality of life of patients with CU, expert groups recommend using the only existing specifc questionnaire, the CU-Q2oL

Currently, in the process of finding out the cause of disease, international guidelines for the treatment of chronic urticarial still

choose to treat symptoms with histamine H1 receptor antagonists, the second generation is the treatment firstly Effective treatment of chronic urticaria is evaluated by the Urticaria Control Test (UCT)

Helicobacter pylori (H pylori) is a frequent gastrointestinal infectious agent having worldwide distribution It is a Gram-

negative, microaerophilic, spiral bacterium that shows particular tropism for the gastric mucosa, and induces a strong inflammatory response with release of various bacterial and host dependent cytotoxic substances Part from its well-demonstrated role in gastroduodenal diseases, some authors have suggested a potential role of H pylori infection in several extra-intestinal pathologies

including haematological, cardiovascular, autoimmune, and skin

diseases In recent studies a possible association between H pylori

infection and CU has been suggested In fact, in some studies CU patients showed regression of cutaneous signs and symptoms after H

pylori eradication treatment

Many studies on the role of H pylori in chronic urticaria

have been conducted and proposed some theories to explain the relationship between H pylori infection and chronic urticaria:

Firstly, some protein components of H pylori may play a

role in mast cell activation causing chronic urticaria

Secondly, bacteria act as full and self-allergenic antigens, causing an immune response IgG and IgA antibodies associated with

19-kDa of H pylori lipoproteins have been found to play a role in CU

Thirdly, some inflammatory mediators have been released

during the immune response to H pylori infection, which may play

an important role in the pathogenesis of urticaria, at least to create out of nonspecific hypersensitivity of skin vessels with substances that enhance vasodilation

Finally, the process of bacterial infection reduces the barrier function of the gastrointestinal mucosa, facilitating allergy food

particles into the blood H pylori may also increase the amount of

eosinophil cationic protein with a toxin secreted by eosinophilic activation that contributes to chronic urticaria

Chapter 2

SUBJECTS AND METHODS

2.1 SUBJECTS AND MATERIALS

2.1.1 SUBJECTS

* Purpose 1: 245 patients were treated chronic urticaria (CU)

in Haiphong Medical University hospital from 8/2016 to 02/2018

- Diagnostic criteria for CU: The sudden appearance of wheals and/or angiowheals A wheal consists associated itching, a fleeting nature, with the skin returning to its normal appearance, usually within 1–24 hours The symtoms are continuous or recurrent at least 6 weeks

- Diagnostic criterias for H pylori infection:

+ The concentration of H.pylori antigen ≥ 0.05 ug/ml are considered positive (CU/ H pylori+)

+ The concentration of H.pylori antigen < 0.05 ug/ml are

considered negative (CU/ H pylori-)

- Selection criteria for study patients: patients diagnosed with

chronic urticarial, agreed to participate in the study, agreed to be

tested for H.pylori infection

- Exclusive criterial: The patient used medications for

gastro-đuoenal and H.pylori eradication within 1 month before admission

Patients with mental disorders, alcoholism, drug addiction HIV, cancer, liver failure, kidney failure, heart failure Women tho pregnant

or nursing Patients who did not agree to participate in the research

* Purpose 2: 76 patients CU/ H pylori+ eradicated

- Selection criteria for study patients: patients with chronic

urticarial infected H.pylori who bactericidal treatment The patient

had not malignancy symptoms of gastrointestinal; no contraindication

to use of drug Age ≥ 18 Patients agree to participate and follow the treatment process properly

- Exclusive criterial: Patients do not qualify for selection Patients do not agree to participate in the study

2.1.2 MATERIALS

- Chemicals: HpAg kit of Dia.Pro Diagnostic, Italy

- Study devices: ELISA system, USA

- Drugs: Xyzal 5mg (Switzerland) Nexium MUPs 40mg (Sweden) Ospamox 500mg (Sandoz-Imexpharm) Klacid 500mg (Abbott)

2.2 METHODS

2.2.1 Study Design: prospective, interventional, follow-up

2.2.2 Sample size of Study

- Purpose 1: Convenient sampling From 8/2016 to 02/2018, 245

patients with chronic urticaria treated at Hai Phong Medical University Hospital, responding selection and exclusion criteria

- Purpose 2 Of 245 chronic urticarial patients, 76 patients were

2.3 Techniques and assessment standards

2.3.1 ELISA technique identified H pylori antigen in stool (Stool

antigen assay - SAT)

* Prepare specimen

1 Thaw the specimen at room temperature (4 hours)

2 Prepare 2 sets of tubes each with the ID samples

3 add 1 ml of diluent to each tube Take about 0.2 g of each sample into each tubes (weigh the tube before and after)

4 Votex for 1 minute, then centrifuge for 3000 cycles/3 minutes), transfer the solution to the second tube, centrifuge for 3000 cyclce/3 minutes then take 100µl suspension for testing

* Assay procedure

1 Place the required number of strips in the plastic holder and carefully identify the wells for calibrators and samples Leave A1+B1 wells empty for blanking purposes

2 Pipette 100 µl Calibrators in duplicate into the calibration wells (see the example of dispensation reported below)

3 Dispense then 100 µl Enzymatic Conjugate in all wells, except for A1+B1, used for blanking operations

4 Following addition of the conjugate, incubate the microplate for

7 Pipette 100 µl Sulphuric Acid into all the wells to stop the enzymatic reaction

* Calculation of results

Calculate the mean OD450nm value of the calibrators Then draw a calibration curve possibly using a 4 parameters fitting curve system Then calculate on the curve the concentration of

H.pylori antigen in the sample Samples showing a concentration of H.pylori antigen ≥ 0.05 ug/ml are considered positive

2.3.2 Evaluation criteria

- Assess the level of disease activity with UAS (urticaria

activity score) score For evaluation of symptoms of pruritus and irritation, calculate the activity score of urticaria The lowest total score is 0, the highest is 6 points

- Evaluate the effect of disease on the quality of patients' life with Chronic Urticaria Quality of Life Questionnaire/CU-Q2oL The

question set has 23 sentences with the rule of assessing the lowest point of 1 (not at all), the highest score is 5 (a lot) The minimum CU-Q2oL score is at least 23 and the maximum is 115 The higher the average score corresponds to the lower the quality of life

- Assess the level of disease control: with the Urticaria

Control Test - UCT The UCT score of 12 or greater indicates controlled disease Values of 11 and lower reflect poor control

- Evaluate H pylori infection: The concentration of H.pylori

antigen ≥ 0.05 ug/ml are considered positive (CU/ H pylori+) The

concentration of H.pylori antigen < 0.05 ug/ml are considered negative

(CU/ H pylori-)

- Assessment response to H.pylori eradication treatment:

In group CU/ H.pylori+ qualifies for bactericidal treatment,

at 4 weeks after cessation of bacteriostatic treatment, re-test for H pylori antigen in the stool Samples showing a concentration of H.pylori antigen < 0.05 ug/ml are negatives: Diagnostic CU/H.pylori+ eradicated Samples showing a concentration of H.pylori

antigen ≥ 0.05 ug/ml are positives: Diagnostic CU/H.pylori+ eradicated

not Side effects: Record whether or not side effects and assess

the level

2.4 Study procedure

2.4.1 Screening, selecting patients: Explain the objectives and procedure to conduct research with the patients if the patient agrees to sign the study agreement

2.4.2 Collecting clinical informations: Interview, examine,

clinical screening, we focus on obtaining thoroughly medical history: history of allergies, urticaria, medical history of patients The duration of disease progression, factors tringer, Clinical characteristics…

2.4.3 Blood tests: Blood formulation, urea, creatinine, GOT,

GPT

2.4.4 Stool antigen test to determine H pylori infection

Instruct patients to take stool samples, transfer to the Laboratory of Hai Phong Medical University Hospital At the Department, stool samples were stored in a negative cabinet of 40oC The specimens were collected and analyzed for analysis once a week

2.4.5 Treatment

* Drug regimens are as follows:

Group 1: CU/ H.pylori- : Xyzal 5mg take 1 table/day x 4 weeks

Group 2: CU/H.pylori+ meeting inclusion criteria

Xyzal 5mg take 1 table/day x 4 weeks

H pylori eradication treatment: use triple regimens during 10 days

Nexium 40mg x 2 tablets / day x 10 days (2 times a day, 1 capsule each time, 30 minutes before breakfast and before dinner)

Ospamox 500mg x 4 tablets / day x 10 days (2 times daily, 2 capsules, 1 hour after breakfast and 1 hour after dinner)

Klacid 500mg x 2 tablets / day x 10 days (2 times a day, 1 capsule at a time, 1 hour after breakfast and 1 hour after dinner)

* Instruct patients to take medicine, monitoring side effects

* Assessment response to H.pylori eradication treatment

2.4.6 Re-examination and evaluation

* Evaluate the effectiveness of treatment of chronic urticaria

After 2 weeks and 4 weeks of treatment, on each group, we

assesse the following criteria: Pruritus score, wheals score, UAS score; Evaluate the effect of disease on the quality of patients' life ; Side effects of drugs

* Assess the level of control of chronic urticaria after treatment

- After cesscation treatment, in each group , at 2 weeks, 1 month, 2 months, 3 months we will assessing: The score UCT; Evaluate whether the patient must re-use anti-allergy medication

- At the time after 2 weeks treatment cesscation, the patients poor control the disease, they must re-use antihistamines H1 will be used for histamine H1 resistance according to second-line regimen (increase the dose twice)

Those patients controlled disease, who do not need to take antihistamines H1 again, will continue to be monitored and re-evaluated at the time after 1 month treatment cesscation

- The evaluation and monitoring are conducted similarly as above at the time after stopping treatment for 1 month, 2 months, 3 months

2.5 DATA PROCESSMENT

The data is processed by medical statictic method with Stata 14.0

86 CU/ H pylori -

Treatment

- XYZAL x 4 weeks

245 Chonic Uticaria (CU)

Hp-Ag/Stool

76 CU/H pylori+ eradicated 31 CU/H pylori+ not-eradicated

107 CU/ H pylori +, Treatment

- XYZAL x 4 weeks

- H pylori eradication treatment: use triple regimens x 10 days

After 2 weeks, 4 weeks of treatment: Assesses

 Pruritus score, wheals score, UAS score

 Score CU-Q2oL

After cessation 2 weeks, 1 month, 2 month, 3 month: Assesses

 UCT score

 Rate of re-using antihistamin H1

After 4 weeks of H.pylori eradication treatment