nghiên cứu một số đặc điểm dịch tễ, lâm sàng viêm phổi không điển hình do vi khuẩn ở trẻ em bản tóm tắt tiếng anh

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH THE NATIONAL INSTITUTE OF HYGIENE AND EPIDEMIOLOGY PHAM THU HIEN THE STUDY OF EPIDEMIOLOGICAL CHARACTERISTICS, CLINICAL MANIFESTAT

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH

THE NATIONAL INSTITUTE OF HYGIENE AND EPIDEMIOLOGY

PHAM THU HIEN

THE STUDY OF EPIDEMIOLOGICAL

CHARACTERISTICS, CLINICAL MANIFESTATIONS

OF ATYPICAL PNEUMONIA CAUSED BY BACTERIA

IN CHILDREN

Science: Epidemiology Code: 62 72 01 17

SUMMARY OF THE DOCTORAL DISSERTATION

HA NOI - 2014

The project was completed at the National Institute of Hygiene and Epidemiology

The scientific advisors:

1 Prof Dao Minh Tuan

2 Prof Phan Le Thanh Huong

The dissertation is available at:

1 The National Library

2 The National Institute of Hygiene and Epidemiology

LIST OF THE PUBLICATIONS BY THE

AUTHORS RELATED TO THE DISSERTATION

1 Pham Thu Hien, Dao Minh Tuan, Nguyen Phong Lan,

Phan Le Thanh Huong (2011), "The role of Mycoplasma

pneumoniae, Chlamydia pneumoniae, and Legionella pneumophyla in community -acquired pneumonia in children:

preliminary results", Journal Journal preventive Medicine,

Vol XXI, No 7 ( 125 ), pp 62-69.

2 Pham Thu Hien, Dao Minh Tuan, Nguyen Phong Lan, Phan Le Thanh Huong( 2012 ) , " Causes, clinical features ,

clinical manifestations of atypical pneumonia in children " ,

Journal of Medical Research , episode 80 , No 3 A , pp

119-124

3 Pham Thu Hien, Dao Minh Tuan, Nguyen Phong Lan, Phan Le Thanh Huong (2012), "Frequency , clinical

characteristics , subclinical pneumonia caused by

Mycoplasma pneumoniae, Chlamydia pneumoniae in

children ", Journal Journal preventive Medicine, Vol XXII,

No 6 (133), tr 31 - 38.

LIST OF ABBREVIATIONS

ALT Alanine Aminotransferase

AST Aspartate Aminotransferase

BCYE buffered charcoal yeast extract

C pneumoniae Chlamydia pneumoniae Chlamydia pneumoniae

CRP C protein reactive Protein C phản ứng

ELISA enzyme-linked

immunosorbent assay

Kỹ thuật miễn dịch gắn men

IgG Immunoglubulin G Immunoglubulin GIgM Immunoglubulin M Immunoglubulin M

INF Tumor necrosis factor Yếu tố hoại tử u

L pneumophila Legionella pneumophila Legionella pneumophila

M pneumoniae Mycoplasma pneumoniae Mycoplasma

pneumoniae

PCR polymerase chain reaction Phản ứng PCR

PPLO Pleuropneumonia like

organisms

Pleuropneumonia like organisms

Real – time PCR Real –time polymerase

chain reaction

Phản ứng Real – time PCR

S pneumoniae Streptoccocus pneumoniae Streptoccocus

pneumoniae

TNF Tumor necrosis factor Yếu tố hoại tử u

VPKĐH (AP) Atypical pneumonia Viêm phổi không điển

hình

WHO World Health Organization Tổ chức y tế thế giới

ABSTRACT OF THE DISSERTATION

1.Background

Atypical pneumonia is frequent in developing countries However,the studies about these conditions in developing countries, includingVietnam are limited Forest (2007) reported that the incidence ofatypical pneumonia in the community-acquired pneumonia was 22 % inthe United States and 91% of those had been treated. In Europe, theincidence of atypical pneumonia was 28%, the rate of treatment was74%. In Latin America, the incidence of atypical pneumonia was 21%and the rate of treatment was 57%. In Asia / Africa, the incidence was20%, the rate of treatment was 10%

The diagnostic methods for atypical pneumonia include: bacterialculture in the special media, serology, and polymerase chain reactionmethod Polymerase chain reaction method (PCR) has helped confirmedand rapid diagnosis bacterial pathogens In Vietnam, PCR techniques areavailable in only few hospitals in central and major medical centers. Mosttreatments have been done with empirical therapy that may result in

increasing in antibiotic resistant, and prolonged treatment time

Little is known about the epidemiology, clinical and laboratorialmanifestations of atypical pneumonia in children, including the diagnostictechniques for bacterial causes of atypical pneumonia such as multipleprimers PCR (multiplex-PCR) and enzyme-linked immunosorbent assay

(ELISA), we conducted the study: " The study of epidemiological characteristics, clinical manifestations of atypical pneumonia caused by bacteria in children” The study objectives were:

1 To describe the epidemiological characteristics, clinical manifestations

of atypical pneumonia caused by Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila in children who were treated

at the National Hospital of Pediatrics in Hanoi, Vietnam from 07/2010

to 3/2012.

2 To identify the factors associated with the severity of atypical pneumonia in children.

2 New contribution to the science

- This project was the first study to identify the prevalence of atypicalpneumonia caused by M. pneumoniae, C. pneumoniae and L pneumophila,co-infection rate of pneumonia in hospitalized children

- The study has identified several factors associated with severity ofatypical pneumonia Co-infection with bacteria and viruses was therelated factors for severe atypical pneumonia

- This study described the clinical manifestations and laboratorialcharacteristics of atypical pneumonia, atypical pneumonia co-infection

in children

3 Practical value of the subject

- Evaluate the results of clinical manifestations and laboratorycharacteristics of atypical pneumonia to draw specific symptoms whichsuggesting early clinical diagnosis, help clinicians quickly optimaldecision the choice of antibiotic therapy and have a morecomprehensive view of the causes of pneumonia in children

- The study's results are significant in establishing the pattern ofmicroorganisms which cause respiratory infections in children, and toguide treatment and prevention strategies

- Microbiological diagnostic techniques based on molecular biology (only

in a few specialized laboratories) will be confirmed and efficient whichcan be replicated in the laboratory of clinical microbiology

4. The structure of the dissertation

The dissertation consists of 128 pages including: Background andobjectives: 2 pages; Literature review: 34 pages; Methods: 18 pages;Results: 34 pages; Discussion: 37 pages; Conclusion: 2 pages, andrecommendation: 1 page There are 29 tables and 20 figures, 228references including 22 in Vietnamese, 206 documents in foreignlanguages

Chapter 1 OVERVIEW 1.1. Introduction

Atypical pneumonia: pneumonia caused by M. pneumoniae hasbeen recognized from the dairy failed to sulfonamides or penicillin used

to treat pneumonia, help to distinguish pneumonia pathogens M pneumoniae pneumonia or pneumococcal (pneumococci). The failure

to respond to antimicrobial therapy has been thought as "atypical"(atypical). This term, along with "Walking around pneumonia" is usedbroadly to refer to respiratory disease caused by M. pneumoniae inhumans. Then other agents cause similar clinical picture was included

in the group of atypical pneumonia asC. pneumoniae, L. pneumophila

1.2. Epidemiological characteristics of atypical pneumonia caused by Mycoplasma pneumoniae, and Legionella pneumophila Chlamydia pneumoniae

1.2.1. Epidemiology characteristics of pneumonia caused by Mycoplasma pneumoniae

Disease appears in all countries, however studies about the diseasemostly have been carried out in the United States, Europe and Japan

In the U.S, infection caused byM. pneumoniaeaccounts for 15-20% ofall community-acquired pneumonia.Especially in the summer time, M.Pneumonia can reach up to 50% of all community-acquired pneumonia

During 2010 to 2012, an outbreak of M. pneumoniae infection happened in some Asian countries A multicenter study in Asia in 2005

found that M. pneumoniae was an important cause of the communityacquired pneumonia, which accounted for 22.3%

Disease occurs in people of all ages, predominant in the age groupfrom 5-9 years old

Disease can occur throughout the year, and the peak during theperiod from late summer to early fall

The bacteria can live everywhere in nature, transmitted fromperson to person via the respiratory tract The average Incubation period

is 3 weeks.After suffering from this disease, an immune survived about

4 years. Immunology temporary and recurence

1.3.2 Epidemiology characteristics of Chlamydia pneumoniae pneumonia

C. pneumoniae infection distributes over the world. A study from 10 different regions of the world showed a higher frequency intropical populations In the U.S and many other countries, the sero-prevalence ofC. pneumoniaeinfection was of 50% of total population

Estimated number of cases of pneumonia caused by C. pneumoniae inthe United States is 300,000 cases per year Globally, prevalence ofpneumonia caused by C. pneumoniae from 4337 patients was 8% inNorth America, 7% in Europe, 6% in Latin America and 5% in AsiaForest (2007).

The disease affects both genders and all age groups Diseaseoccurs throughout the year, and gets its peak during summer time.Infectious reservoir is humans, and it is transmitted throughrespiratory secretions directly exposed to coughing, sneezing Aftersuffering from this disease, patients have an immune temporarily andrecurrent frequently.Disease cycle every 4 - 8 years

1.3.3 Epidemiological characteristics of Legionella pneumophila pneumonia

Legionella disease occurs worldwide The majority of casesdisease been identified in tropical countries. In the U.S., about 8000-

18000 hospitalized cases every year In Europe, the prevalence of

Legionella infection were 5,907 cases in 2007 and 5,960 cases in 2008.Most patients exposed to L pneumophila but no symptoms. The risk increase in an older people Children after ages 4 rare occurs

pneumonia due to L pneumophila.

Legionella live everywhere, special in the aquatic environment, thedisease transmitte through tiny droplets of water vapor. Disease is nottransmitted from person to person Incubation period 2 -10 days Re-infection occurs in immunocompromised people

The common pulmonary manifestations are: eardrum inflammation,rash, urticaria, pleurisy, thrombocytopenia, meningitis, and mild anemia

The extrapulmonary manifestations are rare: hemolytic anemia,coagulation disorders, thrombosis, pulmonary abscess, pneumothorax,burnout syndrome, pericarditis, myocarditis, Stevens Johnsonsyndrome, neurological manifestations: meningitis, encephalitis,mental disorders, Guillain – Barre syndromes, cerebellar ataxia, thebrainstem, like polio.

L. pneumophila causes two distinct disease entities: pneumoniaand Pontiac fever Pontiac fever is usually mild, patients may havefever, muscle-aches, no pneumonia, no need treatment Legionella

disease may have clinical manifestations including abnormalities in thecentral nervous system (headache, mental confusion, encephalopathy,coma), cardiac abnormalities(relatively slow heart rate), gastrointestinalmanifestations (target diarrhea, abdominal pain), liver damage (liverenzymes) and kidney(microscopic hematuria, increased creatinine),electrolyte abnormalities (assuming m and decreased serum sodiumphosphate)

Extrapulmonary manifestations of Legionella can present with thedamage in spleen, liver, kidney, heart, bone and bone marrow, joints,inguinal lymph nodes, nervous and digestive tract

1.4.2. Laboratory manifestations of pneumonia caused by M.

pneumoniae, C. pneumoniae and L. pneumophila

Chest X-ray (CXR):

Radiographic manifestations of atypical pneumonia can beextremely variable and can mimic with a wide variety of lung diseases.The inflammatory response causes interstitial mononuclear cellinflammation that may be manifested radiographically as diffuse,reticular infiltrates of bronchopneumonia in the perihilar regions orlower lobes, usually with a unilateral distribution, and hilar adenopathy

Bilateral involvement may occur in about 20% of cases.

Respiratory secretions culture: by using a special medium (PPLObroth environmental bacterium M pneumoniae culture, environmentchick embryo cells or mice, Hella 229 and cultured Hep 2 find C pneumoniae;BCYE environment - Buffered Charcoal Yeast Extract Agardetect L pneumophila culture) L pneumohila usually grows after 3-5days, M pneumoniaeusually results after 7-21 days later.

(Complement Fixation - CF), immunofluorescence technique (Immuno Fluorescence Assay - IFA), Enzyme-linked immunosorbent technique

(Enzyme Immuno Assay - EIA), particle agglutination technique

(partical Agglutination - PA).

Antigen detection methods:

The tests include direct immunofluorescence, free electrolyte cellconvection, infiltration and immune enzyme immunoassay

PCR is a continuous chain reaction, including many successivecycles, each cycle consisting of three phases: denaturation phase;annealing stage; synthesis stage PCR primers to test multiple

simultaneous detection of atypical pathogens such as C. pneumoniae,

M. pneumoniae, L. pneumophila Results showed that Multiplex PCR assay is sensitive, useful, cheap and quick assay diagnosis for

children and related factors

1.5.1. Current research on atypical pneumonia in children

1.5.1.1. In the World

Worldwide, coincides water poses by M. pneumoniae, C pneumoniae encountered in the upper respiratory tract and lowerrespiratory tract, which occurs in both adults and children L pneumophila causes severe disease in adults, it occurs rarely inchildren under 4 years of age

1.5.1.2. In Vietnam

Some research interest in disease incidence and clinical features ofpneumonia caused byM. pneumoniaamong hospitalized children in someprovinces of Vietnam only. Molecular biology techniques are deployed insome centers, large hospitals nearly

1.5.2 Studies of severe atypical pneumonia and related factors

1.5.2.1 Etiological bacteria

Pneumonia caused by L.pneumophila that disease is second,

followed by pneumococcal pneumonia requiring intensive treatment.For people with normal immune systems, the mortality rate is usually inthe range of 10-15%

1.5.2.2 Coinfection status

Co-infection status was considered as aggravating factors incommunity-acquired pneumonia in adults has been demonstrated byGutiérrez: pleural effusion, atelectasis, septic shock, hypoxemiarequiring mechanical ventilation, death in patients with pneumonia due

to coinfected patients higher than agent patients (OR = 2.84, 95% CI1.24 to 6.54, p = 0,02)

1.5.2.3 Accompanying diseases

Studies in adults show that with diseases such as asthma, chronicobstructive pulmonary disease, malignancies, cardiovascular, diabetes,immunosuppression are factors that increase the severity of the disease

1.5.2.4 Specific treatment late

Specific treatment late is emphasized associated with significant

mortality in adults suffer from pneumonia caused by L pneumophila.

According to Gacouin A., duration of illness before admission to theICU for more than 5 days (OR 7:46, 95% CI 1.17 to 47.6) were risk

factors for mortality of L pneumophila pneumonia

1.5.2.5 Extrapulmonary manifestations

Atypical pneumonia with severe extrapulmonary manifestationssuch as neurologic manifestations, hemolytic, heart disease,polyarthritis, skin lesions, electrolyte disorders, multiple organ failure related to status severe, even fatal

1.5.2.6 The other factors

Concerning the situation of severe atypical pneumonia, such as the

relationship between bacterial load, drug resistance of M pneumoniae

to macrolides, leucocytosis, lung injury 2 sides, pleural effusion,increased levels of LDH, ALT, AST, and decreased blood protid;increased IL6, TNF, respiratory failure, mechanical ventilation, Lowerserum sodium <136 mEq / l, Paco 2 / FiO 2 <130 ureanemia > 30 mg /dl,albuminemia decreased, multiple organ failure, requiring mechanicalventilation, complications of lung abscess, wall chemistry, effusionrelated lung deterioration, mortality of the disease

Chapter 2 METHODS

2.1 Study subjects

- Patients with pneumonia caused by different microbial agents, agedfrom 12 months to 15 years old who were treated at the RespiratoryDepartment of the National Hospital of Paediatrics from 7/2010 to 3/2012

- Patients with atypical pneumonia due to at least one of the three

studied bacteria: M pneumoniae, C pneumoniae và L pneumophila,

aged from 12 months to 15 years old who were treated at the RespiratoryDepartment of the National Hospital of Paediatrics from 7/2010 to 3/2012,referred to “ atypical bacterial pneumonia”

- Patients with atypical pneumonia due to at least one of the three

studied bacteria: M pneumoniae, C pneumoniae và L pneumophila,

were diagnosed severe atypical pneumonia

2.2 Inclusion criteria

2.2.1 Case definition

- Pneumonia were diagnosed by using the WHO's criteria: cough, fever, tachypnea, infiltration on chest radiograph

2.2.2 Atypical bacterial pneumonia case

- Patients were diagnosed with pneumonia

-Three bacteria M pneumoniae, C pneumoniae and L pneumophila were confirmed by Multiplex PCR in bronchial secretions

or nasopharyngeal or throat swab positive for the three studiedbacterias, or ELISA: double the serum samples were positive for one ofthree studied bacterias.

2.2.3 Severe atypical pneumonia case.

Children were diagnosed with severe atypical pneumonia entitled toclassify pneumonia and WHO standards and the Association ofPediatric Infection of the America

- Patients with atypical pneumonia due to at least one of the

three studied bacteria

- The severity of pneumonia was determined by the criteria for severe pneumonia of the American Association of Pediatric Infection

a One or more major signs: required mechanical ventilation; sepsis

b Or at least two of the following signs: tachypnea, apnea,consciousness disorders; hypotension; pleural effusion, SpO2 <90%with room air and Pao 2 / FiO 2 ratio < 250; many pulmonary infiltrates

2.2.4 Exclusion criteria:

- Typical pneumonia

- Co-infection cases of pneumonia will not be considered for theclinical characteristics, laboratory manifestations

- Hospital- acquired pneumonia

- Patient s’ families without agreed to participate in the study

2 3 Methodology

2.3.1 Study Design: epidemiology descriptive case series and analysis

study

 Sample sizes for objective 1: WHO calculated by estimating the

percentage - a group

2 2

/ 1

) (

) 1 (





p

p p Z

incidence of atypical pneumonia in hospital (in this study the rate of p

= 18% = 0.18) q = 1-p = 1-.18 = 0.82; p.ε accuracy desired sample, choose

ε = 0.16 A required minimum sample size was 718 patients We did

enrolled 722 patients for this study.