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MINISTRY OF EDUCATION AND MINISTRY OF HEALTH NATIONAL INSTITUTE OF HYGIENE AND EPIDEMIOLOGY
NGUYEN THI UT
EPIDEMIOLOGICAL AND CLINICAL
CHARACTERISTICS AND OUTCOMES OF TREATMENT
REGIMENS FOR PEDIATRIC GASTRITIS AND PEPTIC
ULCER DISEASE CAUSED BY DRUG-RESISTANT
HELICOBACTER PYLORI AT NATIONAL PEDIATRIC
HOSPITAL
Specialty : Epidemiology
Code : 62.72.01.17
SUMMARY OF MEDICINE PHD THESIS
HANOI - 2016
This work has been completed at
the National Institute of Hygiene And Epidemiology
1. Le Thanh Hai, Associate Professor, Ph.D
2. Hoang Thi Thu Ha, Ph.D
Reviewer 1:
Hoang Huy Hau, Associate Professor, Ph.D.
Reviewer 2:
Nguyen Gia Khanh, Professor, Ph.D
Reviewer 3:
Pham Van Trong, Associate Professor, Ph.D
The Thesis will be defended at the Institute level Council for Thesis Performance Appraisal convened at the National Institute of Hygiene And Epidemiology. On: date month year 2016 The Thesis could be found at:
1. The National Library 2. The Library, National Institute of Hygiene And Epidemiology Antibiotic resistance Antimicrobial susceptibility Bismuth subsalicylate, amoxicillin, metronidazole Urease breath test CLR Clarithromycin CagA Cytotoxin-associated protein Daily doses per 1000 inhabitans per day Gastritis and peptic ulcer disease H. pylori Helicobacter pylori MTR Metronidazole Peptic ulcer disease Omeprazole, amoxicillin, clarithromycin PCR-RAPD Random amplified polymorphic PCR- RFLP Restriction fragement lenght polymorphism PPI Proton pump inhibitor PPI- clarithromycin – amoxicillin PPI- amoxicillin- nitroimidazole RUT Rapid urease test VacA Vacuolating cytotoxin A 1. INTRODUCTION
Gastritis and peptic ulcer disease (GPUD) caused by Helicobacter pylori (H. pylori) was a rather common condition among children. H. pylori had been considered a major cause of chronic gastritis (77.4 - 77.9%); duodenal ulcer (>95%) and stomach ulcer (>75%). Treatment of H. pylori induced GPUD is challenging. Outcomes of treatment regimens depend on antibiotics resistance status where high drug resistance lowers treatment effectiveness that is currently under desired levels (<80%). Thus, understanding epidemiological and clinical characteristics, and therapeutic antibiotic efficacy of H. pylori induced GPUD could help clinicians and decision-makers deal with prevention and treatment of this disease more effectively. In Vietnam, there has been a lack of studies on epidemiological, clinical and toxicological characteristics; and effectiveness of treatment for pediatric GPUD caused by drug-resistant H. pylori. Therefore, we carried out the study on "Epidemiological and clinical characteristics and outcomes of treatment regimens for pediatric gastritis and peptic ulcer disease caused by drug-resistant H. pylori at National Pediatric Hospital, October 2011 to November 2013". Specific objectives of the present study were to: 1. Describe epidemiological and clinical characteristics of pediatric peptic ulcers disease caused by drug-resistant H. pylori at National Pediatric Hospital, from October 2011 to November 2013; and 2. Determine drug resistance levels and related factors in children with GPUD; and 3. Describe drug-resistant H. pylori clearance effects of some treatment regimens for pediatric GPUD cases. 2. NEW SCIENTIFIC CONTRIBUTIONS
 This was one of comprehensive studies on epidemiology, clinical features and treatment of drug-resistant H. pylori induced GPUD in children, Vietnam, with a relatively large number of pediatric patients.  The study used molecular biology techniques, namely polychain reactions (PCR) and Random Amplified polymorphic DNA (RAPD) to identify toxic genes of bacteria, and the transmissibility in the family.  This was one of studies that simultaneously used both quadruple and triple therapy regimens to treat pediatric H. pylori GPUD.
3. PRACTICAL VALUES OF THE THESIS
- Results on epidemiological and clinical characteristics of drug-resistant
pediatric H. pylori GPUD helped physicians visualize its drug resistance. Disease related information orientated them to GPUD. - The study had also found quadruple regimen effective and safe in the treatment of drug-resistant H. pylori GPUD.
4. THESIS STRUCTURE
The thesis included 146 pages: introduction (2 pages), overview (45 pages), study subjects and methodology (20 pages), results (37 pages), discussion (39 pages), conclusion (2 pages), and recommendation (1 page), with 42 tables, 5 figures, 18 charts, and 219 reference documents including 24 Vietnamese and 195 English ones. CHAPTER 1: OVERVIEW
1.1. GPUD epidemiological and clinical characteristics, and drug-resistant
H. pylori

1.1.1. Definition:
Gastritis is a term referring to all inflammatory lesions in the
gastric mucosa, demonstrating response of the gastric mucosa to attacking
elements. Gastro-duodenal injuries when deeply impregnated through the
muscular layer of stomach or duodenal membranes would lead to ulcers.
1.1.2.Previous studies on H. pylori
In 1984, H. pylori was successfully isolated by Marshall and Warren; this finding had been official published in The Lancet (1984). Recently, the role of
H. pylori in GPUD pathogenesis, its antibiotic resistance, and treatment
regimens had been mentioned in many international and national conferences.
1.1.3. H. pylori GPUD epidemiological characteristics
1.1.3.1. Etiology and transmission sources

H. pylori is a gram-negative bacterium with spiral shape. It is a major cause of active chronic gastritis and gastric ulcers, and a risk for gastric cancer. H. pylori transmission source is mainly human being. 1.1.3.2. Modes of transmission - Mouth-to-mouth, fecal-oral, gastro-oral transmission routes. - Family transmission was found in many studies. 1.1.3.3. Susceptible population H. pylori could co-exist with the host for decades without symptoms. Once infected with H. pylori, patients may suffer from gastritis, stomach ulcers, and stomach cancer. 1.1.3.4. Disease frequency Frequency of H. pylori induced GPUD varies from country to country and from age group to the others. Generally it is observed highly in developing countries and low in developed countries. Incidence of gastroenteritis is age dependent. GPUD is a health condition occured in about 1-1.5% children; it is often primary, mostly chronic and localizes in the duodenum; its main cause is H. pylori infection (about 80%) or unknown (about 20%). About 10 to 15% people infected with H. pylori would develop PUD and 1% would develop stomach cancer. 1.1.4. Pathogenesis
In the acute phase, bacteria invade, multiply and cause mucosal inflammation. In the chronic inflammatory phase, manifestation is clear with tissue changes, peeling mucosa and multiple inflammatory cell infiltration; mucosal barrier is destroyed, leading to scratches and ulcers. 1.1.5. Immunology
After being infected with H. pylori, the host would develop a very strong local and systemic immune response. Despite of this immune response, infection may still exist throughout the life. 1.1.6. Clinical manifestations
H. pylori infection could lead to symptoms at the gastrointestinal tract or extra gastrointestinal tract. Recurrent abdominal pain is a common clinical sign – up to 87-96%; abdominal pain could be localized in the epigastric region, or persists around the navel and is associated with meals. Nausea and vomiting are two common signs in children under 3 years old. Older children often suffer from gnawing, shortness of breath, bloating and discomfort. Peptic ulcer: H. pylori infected children often have no symptom; only a small portion develops PUD. H. pylori is found in 90% of children with PUD,
and it is proved that ulcers would be healed after H. pylori clearance.
1.1.7. Methods of diagnosing H. pylori GPUD
1.1.7.1. Diagnostic methods

 Non-invasive methods + Serological test: mainly applied for epidemiological studies. + Urease Breath test (UBT): allows determining H. pylori infection based on bacterial urea hydrolysis. Carbon marking could use C13. + Stool antigen test: accuracy of the test using monoclonal antibodies is higher than of polyclonal antibodies. • Invasive methods + Endoscopy: to determine H. pylori gastritis through images - normal; inflammation; nodules with lumpy granular; new, still bleeding shallow scraped or deep ulcers; or old and scarring ulcers. + Rapid urease test (CLO test): allows determining the presence of H. + Histopathology: helps detect bacteria and evaluate peptic mucosal + Bacterial culture Culturing is considered the gold standard method with 100% specificity. Culturing verifies and identifies H. pylori antibiotic resistance. + H. pylori antibiotic susceptibility test: - Diffusion test: suspension of 108 CFU / ml bacteria cultured in the Mueller – Hinton agar media containing 10% horse blood, then put standardized antibiotic paper discs on its surface. Results are calculated following diameter of the sterile round generated. + Molecular biology methods PCR method amplifies duplicate strings, helps determine the presence of bacterial toxic genes such as cagA and vacA. RAPD – a method for multifold analysis of randomly amplified DNA. RAPD helps identify differences between different bacterial strains. Genomes of two different strains give different footages on the genes for comparison of bacteria's biodiversity. 1.1.7.2. Diagnosis of H. pylori GPUD  Criteria for H. pylori GPUD diagnosis: + Endoscopy test is used to diagnose peptic ulcer according to Sydney classification system. + Histopathological test is used to diagnose gastritis. H. pylori infection is diagnosed when present one of the following conditions:
- H. pylori (+) in histopathological and urease tests.
- H. pylori (+) in culture of gastric biopsy pieces.
1.2. Antibiotic-resistant H. pylori and risk factors of GPUD
1.2.1. Concept of antibiotic resistance
1.2.1.1. H. pylori primary antibiotic resistance
This is the status when a child has not been previously treated for clearing H.
pylori
; antibiotic resistance is the consequence of using antibiotics to treat
his/her other diseases. A small number of patients received drug-resistant
strains from others.
1.2.1.2. H. pylori secondary antibiotic resistance
This is the status when H. pylori antibiotic resistance appears in patients who
have been previously treated for H. pylori clearance.
1.2.2. Antibiotic resistance and virulence of bacteria
1.2.2.1. VacA gene related cytotoxic factors

VacA is an important toxin presented in almost all strains of H. pylori. VacA contains diverse alleles that vary from one to other H. pylori strain. VacA genotype s1/m1 is the most toxic combination, while s2/m2 and m2/s1 are nontoxic. 1.2.2.2. CagA gene related cytotoxic factors CagA is a toxic protein of H. pylori, encoded by cagA gene. CagA (+) is more often associated with peptic ulcer, atrophic hypertrophic gastritis and adenocarcinoma than strains cagA (-). Taneike had found that 68% strains contained cagA (+), metronidazole resistance rates among cagA (-) group was higher than of cagA (+) (P = 0.0089). 1.2.3. Rate of H. pylori antibiotic resistance and risk factors
-
H. pylori
antibiotic resistance is the main cause of treatment failure.
Worldwide, antibiotic resistance rate is increasing and varies from region to
region. Developing countries faces a higher antibiotic resistance rate than
developed ones. This rate of clarithromycin resistance is over 20% in the US
and other developed countries in Europe and Asia.
1.2.5.1. Clarithromycin resistance rate
Clarithromycin resistance rate among children is 50.9% in Vietnam.
1.2.5.2. Azithromycin resistance rate
Azithromycin resistance ranges is high in children; it varies from 17.9% in
Croatia to 87.7% in Beijing.
1.2.5.3. Metronidazole resistance rate
In Vietnamese children, metronidazole resistance rate is 65.3%; this is increased with age, higher in urban than in rural areas, and more common in boys. 1.2.5.4. Amoxicillin resistance rate In Europe, resistance rate is low at 0-2%. However, high rate had been seen in some countries of Africa and Asia – among children of Iran it was 59%. In Vietnam, the rate of 2006 was 0.5%. 1.2.5.5. Tetracycline resistance rate Tetracycline resistance has not been seen, or seen at very low rate in most countries (0-5%). The rate among Italian and Bulgarian children was 3%. 1.2.5.6. Quinolone resistance rate Primary resistance rate in children is low (2-7%). High resistance usually involves increased use of new quinolone generations. Ciprofloxacin primary resistance in Italian children in 2005 accounted for 6%. Levofloxacin resistance among Beijing children was rather high - 13.7%. 1.2.5.8. Resistance to two or more antibiotic classes Rate of resistance to two antibiotics classes is <10% in Europe, Asia and North America. Rate of resistance to both amoxicillin and clarithromycin
among children of Iran is 14.5%. This rate for both clarithromycin and
metronidazole among children of Vietnam is 28.8%.
1.3. Treatment of H. pylori GPUD
1.3.1. Indications for treatment

Antibiotic treatment is applied to all H. pylori (+) PUD; children with endoscopy diagnosed lesions and H. pylori (+) whose father/mother had H.
pylori
ulcers/stomach cancer; children with iron deficiency anemia who are not
successful with treatment, or with autoimmune thrombocytopenia.
1.3.2. Treatment drugs
1.3.2.1. Secrete preventing drugs
Proton pump inhibitors (PPI)
Omeprazole: Rapidly and effectively inhibits acid after an oral dose.
1.3.2.2. Antibiotics
Amoxicillin: is an antibiotic that effectively clears H. pylori by destroying
bacterial cell walls, leading to its destruction.
Metronidazole: is an osmotic drug that enters bacterial cells and causes its
DNA damage, thus destroys it.
Clarithromycin: impacts on transfer RNA and 50S ribosomal subunit,
disordering bacterial protein synthesis, thus destroys it.
Bismuth salt:
This has a direct bactericidal effect thanks to the agglomeration of crystals
inside and on the bacterial cell walls, condensing bacterial cell vacuoles.

MATERIALS AND METHODOLOGY
2.1 Study population
2.1.1 Study Subjects

Pediatric patients 2 to 16 years old diagnosed with H. pylori GPUD, examined and treated at the National Hospital of Pediatrics from October 2011
to November 2013.
2.1.2. Inclusion criteria

Patients meeting the following criteria: - Clinical: symptoms of gastroduodenal pathology, indicated for gastrointestinal endoscopy, including recurrent abdominal pain, nausea, vomiting, bloating, indigestion and epigastric burning or gastrointestinal bleeding, and unexplained anemia. - Testing: + Endoscopy: images of inflammatory lesions or peptic ulcers + Histopathology: patients with inflammatory lesions + Bacterial culture: growth and antimicrobial susceptibility obtained - Treatment: Patients who have not been treated with antibiotics, proton pump inhibitors and antacids within 1 month before being undergone endoscopy; and have no history of GPUD treatment. - Families and patients agree to participate in the study with full adherence; and to come for check ups on time.
2.1.3. Exclusion criteria
- Patients with other infections and serious illnesses. - Patients having undergone gastric operation(s) and been allergic to antibiotics.
2.2. Study sites
- Epidemiological and clinical studies performed at the Department of Gastroenterology; and Outpatient Clinics – National Pediatric Hospital. - Paraclinical studies performed at the Department of Bacteriology - National Institute of Hygiene and Epidemiology, and Departments of Endoscopy and of Pathology - National Pediatrics Hospital. 2.3. Study time
From October 2011 to November 2013. 2.4. Study Methodology
2.4.1. Design
: two designs used
- Cross-sectional descriptive study with appropriate analysis - Treatment assay without control groups, describing results of 2 treatment regimens.
2.4.2. Sample size and sampling method
2.4.2.1 Sample size and sampling method for Objectives 1 and 2
+
Sample size: total patients meeting inclusion criteria during 2 years, from
October 2011 till November 2013.
With respect to the 1st objective, 588 eligible children diagnosed with GPUD
caused by antibiotic-resistant H. pylori were enrolled in the study. For the 2nd
objective, 624 eligible children diagnosed with H. pylori GPUD were studied
on antimicrobial susceptibility (including non-resistant and resistant cases).
+ Sample selection: Children aged 2 years to 16 years, initially diagnosed with suspected GPUD, admitted to the National Pediatric Hospital, were explained about the study purpose and contents. Once families had agreed to participate, doctors asked gastroduodenal, biopsy, urease test, dyeing H. pylori shed for histopathology, and culture for H. pylori bacteria, then antimicrobial susceptibility test to determine drug resistance. Cases diagnosed with H. pylori(+) GPUD resisting to at least 1 in 8 antibiotics: amoxicillin, clarithromycin, metronidazole, ciprofloxacin, tetracycline, azithromycin, levofloxacin and cefixime had been enrolled into the study. + Other samples To determine the possibility of cross-infection within family through studying genotype of isolated H. pylori strains, we selected 17 representative households participating in the study using a convenient sample. To determine association between the antibiotic resistance and the presence of genes CagA and VacA in H. pylori strains isolated from patients infected with antibiotic-resistant H. pylori, we selected for analysis 150 H. pylori strains by sampling conveniently, of which 50 resisted to amoxicillin, 50 to clarithromycin and 50 to metronidazole. 2.4.2.2. Sample size and sampling for the 3rd objective + Sample size: based on total patients eligible for inclusion into the study during 2 years, from October 2011 until November 2013, including GPUD patients caused by H. pylori resisted to at least 1 antibiotic drug, who agreed to participate and comply with treatment regimens prescribed. 195 patients were included in the list of treatment. They were divided into 2 groups: (i) Group 1 with 97 patients, receiving 4 medicines recommended by the Association of Pediatric Gastroenterology and Hepatobiliary of Europe and North America, Maastrich IV; (ii) Group 2 included 98 patients eligible for regimen with 3 drugs following their antimicrobial susceptibility, based on the routine treatment guidelines of National Pediatric Hospital. + Sampling method: According to the convenient sampling, all subjects positive with H. pylori and resistant to antibiotics, whose families provided informed consent and committed to comply with treatment requirement were enrolled. CHAPTER 3: RESULTS
3.1. Several epidemiological and clinical characteristics of GPUD caused
by antibiotic-resistant H. pylori

3.1.1. Several epidemiological characteristics
3.1.1.1 Rate of pediatric GPUD caused by antibiotic-resistant H. pylori (A-R)

Figure 3.1. Distribution of GPUD cases with antibiotic-resistant H. pylori
at National Pediatric Hospital (n=624)
From 624 pediatric H. pylori GPUD patients examined and treated (October 2011 - November 2013), 588 found with antibiotic-resistant H. pylori (94.2%). 3.1.1.2. Distribution of antibiotic-resistant H. pylori GPUD by age group Figure 3.2. Distribution of antibiotic-resistant H. pylori GPUD by age
group (n=588)
This distribution showed that the youngest was 2 years old and the highest was 16 years old; average age was 7.29 ± 2.16; the highest proportion was in 6-
9 years group (54.9%).
3.1.1.3. Distribution of antibiotic-resistant H. pylori GPUD by sex

Figure 3.3. Distribution of antibiotic-resistant H. pylori GPUD by sex
49.5% was boys; this was equivalent to the proportion of girls, 50.5%.


3.1.1.4. Gastroduodenal disease history of patients' family Figure 3.4. Gastroduodenal disease history of patients' family (n=588)
Figure 3.5 showed that 72.3% pediatric patients came from families with Gastroduodenal disease history, and 27.7% without this history. 3.1.1.5. History of antibiotic treatment Figure 3.5 - History of antibiotic treatment for other diseases (n=588)
The result showed that proportion of patients who used antibiotic treatment for other diseases was 71.8%, and who had not used them was 28.2%. 3.1.1.6. H. pylori transmission in the family General information about study subjects In this study, we had selected 17 households with H. pylori patients. 50 H. pylori strains were isolated from patients and family members, of those 17 were from pediatric patients, 33 from family members including fathers, mothers and brothers/sisters.  Genotypic analysis of H. pylori strains isolated from patients and family All 50 H. pylori strains were analyzed by RAPD technique. Results showed that 46.1% (6/13) mothers had genotypes similar to the ones of their
children. In contrast, only 8.3% (1/12) fathers had genotypes similar to the
ones of their children. 11.8% (2/17) H. pylori strains of pediatric patients were
similar to the ones of their brothers/sisters.
3.1.2. Several clinical and paraclinical characteristics
3.1.2.1. Clinical characteristics

Figure 3.6 - Clinical characteristics of antibiotic-resistant H. pylori GPUD
Figure 3.6 showed that abdominal pain was the most common symptom, it
accounted for 96.9% cases; anorexia 59.5% was also common. Symptoms of
vomiting, belching, heartburn, bloating occupied respectively 46.9%; 29.3%;
18.7%; 19.2% and 6.1%.
3.1.2.2. Paraclinical characteristics
Gastroscopic images of injury
Figure 3.7. Gastroscopic images of injury (n=588)
Endoscopic images showed that edema and congestion were the most common phenomena, accounting for 94.2% cases; lumpy and granular lesions occupied 69.9%. PUD presented only in 5.8% patients. Figure 3.8. Locating gastroduodenal lesions by endoscopy (n = 588)
Endoscopic images showed that antral gastritis alone occupied 31.8% of 187 pediatric patients; whole gastric lesions presented in 57.1% of them. Table 3.1. Histopathological characteristics of antibiotic-resistant H. pylori
Histopathological characteristics
Number (n=588)
Proportion %
Location of lesion
Body of stomach Antrum of stomach Histopathological lesions were mainly whole stomach inflammation (92.7%), moderate and severe gastritis occupied 78.6%. 3.2. Severity of antibiotic resistance, and factors related to antibiotic
resistance in H. pylori
GPUD children
3.2.1. Antibiotic resistance of H. pylori strains
Out of 624 H. pylori strains isolated, 5.8% were sensitive, 59.8% were resisted to 2 or more antibiotics, and 215 strains (34.4%) resisted to 1 antibiotic (Figure 3.9) Figure 3.9. Severity of antibiotic resistance, H. pylori strains (n = 624)
3.2.2. General resistance of H. pylori to antibiotics
Table 3.2. Resistance of H. pylori
to each antibiotic (n=624)
Sensitive
Resistant
Antibiotic
Resistance to clarithromycin was the most serious with the highest proportion of 56.6%. Resistance to azithromycin, metronidazole, amoxicillin, and ciprofloxacin cefixime were respectively 55.8%, 29.2%, 18.3%, 11.5% and 1.8 %. 3.2.3. Isolation of multidrug resistance of H. pylori
Table 3.3. Resistance to two or more antibiotics (MDR)
Antibiotic
Number of resistant strains
Resistance to two antibiotics - azithromycin and clarithromycin - was the highest (30.6%). 9.1% H. pylori strains resisted to both amoxicillin and
clarithromycin. Resistance to triple antibiotics - azithromycin+ clarithromycin
+ metronidazole - was 6.6%. Resistance to quadruple antibiotics - azithromycin
+ clarithromycin + metronidazole + cefotaxime - was 0.6%.
3.2.4. Distribution of antibiotic resistance
Table 3.4. Distribution of antibiotic resistance by sex (n=624)
Antibiotic
Clarithromycin (n=353) Amoxicillin (n=114) Metronidazole (n=182) Ciprofloxacin (n=11) Azithromycin (n=348) Tetracycline (n=3) Levofloxacin (n=2) a. Chi-squared test b. Fisher' Exact test Resistance to clarithromycin was higher in boys (61.3%) than in girls (52%), the difference was statistically significant with P <0.05. For other
antibiotics, there was no sex difference, P > 0.05.
3.2.5. Factors associated with resistance to one antibiotic
Two groups of children with H. pylori GPUD – one was sensitive to antibiotics (36 patients) and the other was resisted to some antibiotic (215 patients) - were analyzed to determine related factors. Table 3.5 Relationship between age, sex and place of residence with
resistance to a single antibiotic
Resisted to
Sensitive to
Characteristic of
1 antibiotic
antibiotics (n=36)
subjects
0.66 (0.22-2.06) 0.95 (0.33-2.74) 1.53 (0.74-3.14) 0.73(0.35- 1.55) Results showed no (statistically significant) association between those who developed resistance to 1 antibiotic and who remained sensitive to
antibiotics regarding age, sex and place of residence.
3.2.6. Factors related to multidrug resistance
Further, comparison of two groups of children with H. pylori GPUD, one sensitive to antibiotics (36 patients) and the other resisted to 2 or more antibiotics (MDR) (373 patients) was done to identify relevant factors. Table 3.6. Relationship between age, sex and place of residence multiple-
drug resistance
Sensitive to
MDR (n=373)
antibiotics
2.20 (0.75-6.45) 1.38 (0.49-3.85) 1.55 (0.77-3.11) 0.84 (0.41-1.74) Location Other Table 3. 6 showed no statistically significant relationship between age group, sex, and geographical location with multi-antibiotic resistance.
3.2.7. Some factors associated with clarithromycin resistance

In this study, H. pylori resistance to clarithromycin was the highest (56.6%), following by metronidazole (29.2%). Both were widely used in treatment, therefore, we focused on studying factors related to H. pylori resistance to these 2 antibiotics. Table 3.7. Factors related with resistance to clarithromycin
(1.06-2.01) (1.02-1.98) Female 166 (52.0) (1.52-3.08) (1.69-3.55) (1.34-7.29) (* Not adjusted), (** Multivariate analysis, adjusted for age and sex) Note: * statistically significant (95% confidence interval did not contain the value 1) Table 3.7 showed that boys were at 1.46 time higher risk of resisting to clarithromycin than girls with 95% CI = (1.06 - 2.01). Children with a history of
clarithromycin use had the risk of resistance at 2.16 time higher; 95% CI = (1.52 -
3.08). PUD was at 3.12 time higher risk of resisting to clarithromycin with 95% CI =
(1.34 - 7.29).
3.2.8. Factors associated with resistance to metronidazole

Table 3.8. Factors associated with resistance to metronidazole
Medium and
Resisted
sensitive
1,03 (0,73-1,46) 0,71 (0,49-1,03) 0,74 (0,33-1,66) Table 3.8 showed that there was no association between metronidazole resistance and related factors such as family's GPUD history, and antibiotic use history. 3.2.9. Association between antibiotic resistance and the presence of cagA and
vacA in H. pylori antibiotic-resistant strains
150 samples of H. pylori isolated from 150 infected pediatric patients whose
antimicrobial susceptibility showed a resistance to at least 1 of 3 antibiotics -
amoxicillin, clarithromycin and metronidazole – were studied on cagA and
vacA genes.
Relationship between the presence of cagA and vacA genes and amoxicillin resistance Figure 3.10. Amoxicillin resistance by gene
There was no statistically significant difference regarding the rate of cagA and vacA between 2 groups of amoxicillin resistance and susceptibility (P>0,05). Relationship between the presence of cagA and vacA genes and clarithromycin resistance Figure 3.11. Clarithromycin resistance by gene
In the clarithromycin resistant group, 34.1% had cagA; in the other, sensitive group, this was 33.9%. There was no statistically significant difference regarding rates of cagA and vacA between 2 groups (P > 0.05). Relationship between the presence of cagA and vacA genes and metronidazole resistance Figure 3.12. Metronidazole resistance by gene
CagA positive H. pylori occupied 33.8% of the metronidazole resistant group, but no difference was detected between this and the sensitive group
(34.1%). Among 65 of metronidazole-resistant strains, vacAs1, vacAs2,
vacAm1, and vacAm2 were respectively 43.1%, 12.3%, 38.3% and 23.1%; no
statistically significant difference was detected regarding the presence of cagA
and vacA between 2 groups - resistant and sensitive to metronidazole (P>0.05).
3.3. Outcomes of several treatment regimens for GPUD caused by drug-
resistant H. pylori

3.3.1. Characteristics of patient groups

Total 195 pediatric patients with average age of 7.16 ± 2.41 were eligible and enrolled in the study on using two different treatment regimens, concretely
antimicrobial susceptibility based regimen (98 patients) and quadruple
regimen (97 patients).
3.3.2. Outcomes of quadruple regimen
Figure 3.13. H. pylori clearance with quadruple regimen (n=97)
This figure showed that quadruple regimen could clear 77.3% H. pylori; only 22.7% H. pylori could survive.
3.3.3. Outcomes of antimicrobial susceptibility based regimen
Table 3.9. H. pylori clearance by pairs of sensitive antibiotics (n=98)
Result of H. pylori clearance
Treatment regimen
Fully cleared
Not cleared
Amoxillin + klacid (n=28) Klacid + flagyl (n= 11) Amoxicillin + flagyl (n= 27) Cefixim + flagyl (n= 27) Tetracyclin + flagyl (n= 7) Tetracyclin + amoxicillin (n=9) General treatment regimen (n=98) The best clearance rate was reached by tetracycline +flagyl regimen (100%), and the worse was with amoxicillin + klacid regimen (32.1%). Table 3.10. Association between H. pylori clearance and amelioration of
general clinical symptoms
Clinical symptoms
Antimicrobial susceptibility based regimen * Statistically significant.
A. Chi-Squared test Results showed that in the UBT(-) group, absence of clinical symptoms occupied 46.9%, higher than in the UBT (+) group (26.5%), the difference was statistically significant with P = 0.002. Clinical improvement in antimicrobial susceptibility based regimen within the breath test (-) group was 3.18 time higher than within the breath test (+) group with 95% CI = (1.33 -7.58) (Table Table 3.11. Association between amelioration of clinical symptoms and H.
pylori clearance
Breath test
Breath test
Clinical
OR (95% CI)
symptoms
2.58*(1.35-4.92) 0.004*
* Statistically significant (95% confidence interval not containing the value 1)
was 2.58 time higher than in H. pylori non-cleared group; 95% CI = (1.35 - 4.92) (p < 0.01). Table 3.12. H. pylori clearance by age group
Age group
Treatment
Antimicrobial susceptibility based regimen (n=98) Absence of H. Presence of H. quadruple regimen (n=97) No H. pylori H. pylori a. Chi-Squared test * Statistically significant (95% confidence interval not containing the value 1)
The rate of H. pylori clearance of treatment regimens according to the 7-14 years old group was 3.2 time higher compared to the 3-6 years old group with 95%
CI = (1.39 - 7.33). Conversely, bacterial clearance rate of quadruple regimen is not
difference in the age group (P>0.05).
3.3.4. Side effects of medical treatments
Common side effect of treatment regimens was abdominal pain - 9.8% in quadruple regimen, and 8.1% in the antimicrobial susceptibility based regimen. Side effects of the quadruple and antimicrobial susceptibility based regimen were 16.5% and 16.3% respectively. CHAPTER 4: DISCUSSION
4.1. Epidemiological and clinical characteristics of drug-resistant H. pylori
GPUD among children treated at National Pediatric Hospital
4.1.1. Several epidemiological characteristics

This study was conducted on 588 pediatric patients with drug-resistant H. pylori GPUD whose average age was 7.29±2.16. Our study ages were lower than of some other authors; perhaps thanks to the full application of endoscopic anesthesia technique at National Pediatric Hospital, younger ages could be earlier diagnosed for GPUD. Analysis of prevalence by sex showed that boys represented in 291 (49.5%), girls in 297 (50.5%). This finding was in accordance with other authors in Vietnam and in the world. Analysis of patients with drug-resistant H. pylori GPUD showed that those who lived in Hanoi occupied a high proportion of 61.9%; other provinces occupied 38.1%. Analyzing pediatric patients history we recognized that among those infected with drug-resistant species, 72.3% had family member(s) suffered from GPUD and 27.7% had no such history. This could explain why children diagnosed with H. pylori GPUD at early age, and they could be infected with drug-resistant H. pylori strains from their family members. Our findings agreed with identification by Tong Quang Hung. Megraud and McMahon studied on relationship between H. pylori antibiotic resistance and antibiotic consumption, as well as between macrolide antibiotic use and metronidazole resistance. In our study 71.8% patients had previously used antibiotics, this explained very high rate of antibiotic resistance. When studying transmission of H. pylori within family, we had seen some relationship between bacterial strains isolated from mothers and their
children (46.1% mothers had genotypes similar to the one their children had),
this could be an evidence of mother-to-child transmission, especially at young
ages. Our study provided more evidence for proving H. pylori transmission at
molecular level within family, which was in accordance with Shiha and
Megraud.
4.1.2 Clinical symptoms

Average duration of disease among H. pylori GPUD children in this study was 6.0 month, longer than findings of some other authors; our study worked on antibiotic-resistant patients with prolonged disease duration, thus bacteria had better chance to get exposed to antibiotics, and therefore risks of drug resistance could increase. Analysis of clinical findings showed that clinical symptoms of H. pylori GPUD in children were not specific, and easy to get confused with symptoms of other diseases. Our findings showed that abdominal pain was the most common symptom, occupying 96.9%. Our findings were similar to the one of authors in and out of the country. Abdominal pain was changeable, unstable, it might appear and disappear with time; the pain could be localized or generalized, periumbilical or epigastric regions; findings also showed that pain periumbilical was the most common, occupying 75.9%; pain in the epigastric region occupied 26.9% in our study. Our findings were appropriate to Tong Quang Hung's ones. Anorexia was often met, in our study it occupied 59.5%, appropriate to the study by Le Thi Ngoc Dung. Analyzing endoscopic images showed that antral gastritis with nodules and lumpy granulars were specific only to H. pylori GPUD. Results of our study on patients infected with drug-resistant species revealed that edema and congestion were the most commonly seen, occupying 94,2%; nodules and lumpy granulars were also often met, occupying 69.9%. Our findings were in accordance with results of Nguyen Gia Khanh. Role of H. pylori in GPUD was confirmed in many studies; Malfertheiner found GPUD in H. pylori infected group was 15 times higher than in non-infected group. Successful H. pylori clearance treatment reduced ulcers. In our study this was 5.8%, appropriate to findings by Arenz and Koletzko. Discussing on locating lesions in endoscopic images for H. pylori GPUD, authors believed that H.pylori resided mainly – with the highest density - in antrum than in other regions. In our study, lower gastritis rate might due to younger ages; our findings were similar to the ones of Tong Quang Hung. 4.2. Antibiotic resistance and some related factors
4.2.1. Antibiotic resistance of H. pylori strains

When studying antibiotic resistance of H. pylori strains, our rate of resistance to 1 antibiotic was 34,4%. Our finding was similar to the one of Duck. Rat of resistance to ≥ 2 antibiotics was rather high in our study - 59.8%,
much higher than in study of Duck and Seo.
4.2.2. General antibiotic resistance of H. pylori

Based on obtained results, we had assessed antibiotic resistance of isolated H. pylori strains from patients, concretely:  Amoxicillin: According to studies of some authors worldwide, amoxicillin resistance rate varied from 0.6-59%. Our study found amoxicillin primary resistance rate 18.3%, higher than finding of Nguyen Thi Viet Ha and Boyanova.  Clarithromycin: In our study, clarithromycin resistance rate occupied 56.6%, higher than finding by Nguyen Viet Ha and Agudo.  Metronidazole: Metronidazole resistance rate in our study was 29.2%, lower than of Nguyen Thi Viet Ha, however it was similar to findings by Manfredi and Seo.  Ciprofloxacin: With the primary resistance rate of 1.8%, our finding was equivalent to findings by Agudo and Lopes.  Azithromycin: This study found azithromycin resistance rate 55.8%, lower than finding by Goudong Liu, and higher than finding by Seo.  Tetracycline: Tetracyclin resistance rate in our study was 0.5%; our finding was similar to findings by Street and Ve'csei.  Cefixime: In our study cefixim resistance rate was rather high at 11.5%, higher than finding by Samra.
4.2.3. Multidrug Resistance
In our study rate of resistance to both clarithromycin and azithromycin occupied the highest proportion of 30.6%; this was lower than the one from
study by Liu, and was equivalent to finding of Street and Peretz.
4.2.4. Antibiotic resistance by sex
Studying antibiotic resistance by sex, we found that clarithromycin resistance rate among boys significantly higher than among girls; our finding
was also similar to identification by Koletzo.
4.2.5. Epidemiological factors related to single antibiotic resistance
Relationship between age, sex and location of residence, and antibiotic history with a single antibiotic resistance was found in the study of Boyanova and Rafeey. In our study, no relationship was found between single antibiotic resistance with age, sex, and location of residence. 4.2.6. Epidemiological factors related to multidrug resistance
Risk factors of multidrug resistance included sex, age, location of residence and race were found in certain studies. In our study no relationship
was found between multidrug resistance with age, sex, location, as well as
disease status and antibiotic history.
4.2.7.
and
clarithromycin resistance
Effectiveness of regimen containing clarithromycin was reduced 55% when there was resistance (Dore). Certain studies found factors related to
clarithromycin resistance of H. pylori, including macrolide antibiotic use, age,
sex, race, disease status, cigarette smocking and residence. In our study, boys
had the risk of clarithromycin resistance at 1.46 time higher than girls, this was
appropriate to identification of Koletzo. Similarly, risk of clarithromycin
resistance among PUD group was 3.06 time higher than among non PUD
group; our study had different findings compared with the ones of Me'graud
and Kist. Among children in the community in this study, up to 71.8% had
antibiotic use history, therefore exposure to antibiotics was the chance for
developing resistance; the longer infection last, the more children exposed to
antibiotics, leading to higher resistance.
4.2.8.
and
metronidazole resistance
Many studies showed that metronidazole resistance associated with location, sex and race (Meyer), and with place of birth of children and their
mothers. Our study had not found any relationship with metronidazole resistance
regarding age, sex, location, disease status, as well as antibiotic history.
4.2.9. Relationship between antibiotic resistance and cagA and vacA genes of
H. pylori strains resistant to antibiotics

Relationship between cagA and vacA genes and amoxicillin resistance: Gene cagA (+) occupies 30.4% of the amoxicillin resistant group. Genes vacAs1, vacAs2, vacAm1, and vacAm2 of 56 amoxicillin resistant strains were correspondingly 37.5%, 17.9%, 33.9% and 28.6%, no statistically significant difference was detected on cagA and vacA between 2 groups of amoxicillin resistant and sensitive patients (P>0.05). Our findings were appropriate to identification of Gotaslou.  Relationship between cagA and vacA genes and clarithromycin resistance: Among the group of clarithromycin resistance, 34.1% had cagA (+); this of the sensitive group was 33.9%. Findings of our study were similar to the ones of Karabiber or Francesco in adults.  Relationship between cagA and vacA genes and metronidazole resistance: In our study, in metronidazole resistant group, cagA (+) was 33.8%, in other, sensitive group its was 34.1%. In the study of Taneike, metronidazole resistance rate in cagA (-) group was higher than in cagA(+) group, however our
study had not found any difference between them.
4.3. Description of H. pylori clearance by certain treatment regimens for
antibiotic-resistant H. pylori
GPUD
4.3.
1. Effectiveness of H. pylori clearance by quadruple regimen
Some studies suggested that quadruple regimen (amoxicillin + omeprazole + metronidazole + bismuth) was still effective where
metronidazole and clarithromycin resistance was high. In our study,
effectiveness of H. pylori clearance by quadruple regimen on pediatric patients
who developed antibiotic resistance reached 77.3%. Thus, with an
effectiveness of nearly 80%, quadruple regimen was one choice for clinicians
to treat pediatric patients with H. pylori GPUD when antibiotic resistance was
high.
4.3.2 Antimicrobial susceptibility based regimen
H. pylori clearance rate of common antimicrobial susceptibility based 3 drug regimens in our study (Table 3.9) was 53.1%. Our findings were lower than the ones of Faber and Yakoob. Analyzing bacterial clearance rate of sensitive antibiotic pair regimen (Table 3.9), we had seen that treatment effectiveness of our common antimicrobial susceptibility based regimens was low due to very low effectiveness (32.1%) of amoxicillin + klacid + PPI regimen. Of 28 pediatric patients who used OAC regimen, 15 were in age group of 3-6 years old, and this group' H. pylori clearance rate was 2/15 (13.3%), lower than of the 7-14 year age group (7/13=53.8%) with P=0.042; and of all these 28 children, 20 were infected with H. pylori strains that were sensitive to clarithromycin but resistant to azithromycin, besides, among them 13/20 who had azithromycin resistant strains belonged to the group of 3-6 years old. In the study of Tong Quang Hung on effectiveness of H. pylori clearance by OAC regimen, for 3-6 years group, clearance effectiveness was low either (31.6%). Inadequate drug intake and/or poor adherence among younger children was a risk factor that reduced the regimen's treatment effectiveness. Tetracyclin + flagyl regimen had full H. pylori clearance effectiveness with 7/7 pediatric patients, occupying 100%; in a study of Japan, this regimen effectiveness was 92.3% - equivalent to our finding. Effectiveness of klacid+ flagyl regimen was 72.7%, equivalent to the one of study by Casswall; however our regimen was to be used for 2 weeks. Effectiveness of H. pylori clearance by tetracyclin + amoxicillin + omeprazole regimen was 55.6%, this could be the result of combining 2 antibiotics whose bacterial clearance concentration was inadequate. Effectiveness of amoxicillin + flagyl regimen on H. pylori was 53.6%, lower than of Faber. Study of Graham showed that metronidazole's resistance in vivo and invivo was not similar; besides, metronidazole was bitter and difficult for small children to take, causing poor adherence of drug amount. Effectiveness of our cefixime + flagyl regimen on H. pylori was 8/16 (50%). Thus, bacterial clearance effectiveness was lower than in the study of
Pellicano.
4.3.3. Factors affecting effectiveness of H. pylori clearance
Our study antimicrobial susceptibility based regimen's bacterial clearance rate in 7-15 years group was 3.2 time higher with 95% CI (1.39-7.33)
compared with 3-6 years group, similar to the one of Tong Quang Hung.
Younger children faced more difficulty than elder ones in adhering to drug
amount - this was appropriate to identification by Wermeille.
4.3.4. Assessing post-treatment amelioration of clinical symptoms
Results showed that clinical symptoms' clearance in the UBT(-) group was 46.9%, this was 2.73 time higher than in the UBT(+) group, with 95% CI
= (1.44 – 5.19). Our findings were similar to the ones of Tong Quang Hung,
and lower than the ones in study of Das. We recorded a reduction of abdominal
pain at 2.58 time with 95% CI = (1.35-4.92) among the group with H. pylori
cleared than among the group still carrying H. pylori. Our study results were
also similar to the ones of Montes and Casswall.
4.3.5. Treatment side effects
Side effects of antibiotics and secrete preventing drugs recorded in our study were abdominal pain, nausea, headache, and dizziness. In fact, it was very difficult to recognize abdominal pain and vomiting as unwanted effects of drugs, or symptoms of the disease being studied. Side effects of quadruple, and antimicrobial susceptibility based regimens, occupied 16.5 and 16.3%. Our findings were in accordance with studies of Tong Quang Hung and Nguyen Thi Viet Ha. CONCLUSIONS
Studying epidemiological and clinical characteristics on 588 pediatric patients with H. pylori antibiotic-resistant GPUD, related factors on 624
pediatric patients with GPUD, and treatment outcomes on 195 pediatric
patients, we came to the following conclusions:
1. Some epidemiological and clinical characteristics of H. pylori antibiotic-
resistant GPUD

- GPUD caused by antibiotic-resistant H. pylori was present mainly in
school age children (average age 7.29±2.16). Most pediatric patients had family members with peptic pathological conditions (72.3%) and a history of antibiotic use during the last 6 months (71.8%). Mother to child transmission was rather high (46.1% children had genotype similar to their mothers). - Clinical symptoms of drug-resistant H. pylori GPUD were not specific; abdominal pain was the most frequent (96.9%), followed by anorexia 59.5%, vomiting 46.9%, belching 29.3%, and heartburn 18.%. - Endoscopic lesions: edema and mucosal congestion were the most frequent lesions (94.2%), followed by 69.9% of nodule and lumpy granular lesions. Whole stomach lesions occupied the highest proportion of 57.1%, followed by antral gastritis 31.8% and peptic ulcers 5.8%. 2. Severity and certain factors related to antibiotic resistance on pediatric
patients with H. pylori
GPUD
- Multidrug resistance occupied a significant proportion (59.8%); single
antibiotic resistance was 34,4%. (clarithromycin, metronidazole, and amoxicillin) had very high rate of resistance (correspondingly 56.6%, 55.8%, 29.2%, and 18.3%). Co-resistance to 2 antibiotics was mostly happened with azithromycin and clarithromycin (30,6%), the lower rate belonged to clarithromycin and metronidazole (9.8%). Triple resistance to azithromycin + clarithromycin + metronidazole was low - 6,6%. Quadruplet resistance to azithromycin + clarithromycin + metronidazole + cefixime occupied a very low proportion of 0.6%. - No relationship was found between antibiotic resistance with factors such as age, sex, and location of residence. - Factors related to clarithromycin resistance included boys (OR=1.42); history of antibiotic use (OR=2.45) and history of peptic ulcer (OR= 3.06). - No relationship was found between bacterial toxicity (cagA and vacA genes) and resistance to clarithromycin, metronidazole and amoxicillin.
3. H. pylori
clearance by certain treatment regimens for H. pylori
antibiotic-resistant GPUD:

- H. pylori clearance rate of quadruple regimen was rather high: 77.3%. - Bacterial clearance rate of antimicrobial susceptibility based triple regimen was lower: 53.1%; however its effectiveness depended also on combinations of sensitive antibiotics: clearing 100% by tetracyclin + flagyl regimen; and 32.1% by amoxicillin + klacid. Clearance of clinical symptoms in the UBT(-) group was 2.73 time higher than of the UBT(+) group, and 3.18 time in the UBT(-) group by antimicrobial susceptibility based regimen. Side effects of quadruple regimen occupied 16.5%, equivalent to antimicrobial susceptibility based regimen. 1. With high levels of H. pylori antibiotic resistance, it is important to pay special attention to closely indicate treatment regimen for GPUD, especially for children under 6 years old. 2. Quadruple regimen is highly effective, and it is advisably to apply to the first treatment of children with H. pylori induced GPUD in order to reduce risks of multidrug resistance by H. pylori. 3. It is not necessary to chose different treatment regimens for pediatric patients infected with antibiotic-resistant H. pylori that have cagA and vacA genes. 4. It is necessary to assess bacterial toxicity on pediatric patients with antibiotic-resistant H. pylori induced GPUD in order to orientate their follow-up and treatment. THE THESIS RELATES TO PUBLISHED TOPICS
1. Nguyen Thi Ut, Pham Dieu Quynh, Le Thanh Hai, Hoang
Thi Thu Ha (2015), "Studying CagA and vacA genes on
antibiotic resistant Helicobacter pylori strains isolated from pediatric patients, Vietnam", Journal of Medical Research, Hanoi Medical University, Vol. 96, No. 4, pp 41-50. 2. Nguyen Thi Ut, Le Thanh Hai, Hoang Thi Thu Ha (2015),
"Effectiveness of Helicobacter pylori clearance of antimicrobial susceptibility based triple therapy regimen compared with quadruple regimen for children", Journal of Preventive Medicine, Vol. XXV, No. 8 (186), pp 409-419.

Source: http://farm.vumon.vn/nihe/2016/04/15/7aab48cd-bcf3-4afe-8211-4bb0e8bf528d.pdf

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