Etiologies, clinical presentation and hospital outcome of bacterial meningitis in children at the pediatric unit of the Yaounde -gyneco- obstetric and pediatric hospital

JULY, 2019

THE UNIVERSITY OF BAMENDA

FACULTY OF HEALTH SCIENCES

DEPARTMENT OF CLINICAL SCIENCES

ETIOLOGIES, CLINICAL PRESENTATION AND HOSPITAL
OUTCOME OF BACTERIAL MENINGITIS IN CHILDREN
AT THE PEDIATRIC UNIT OF THE YAOUNDE -GYNECO -
OBSTETRIC AND PEDIATRIC HOSPITAL

A Dissertation submitted to the Department of Clinical Sciences in the Faculty of Health
Sciences in partial fulfilment of the requirements for the award of a Postgraduate
Diploma (DM) in Clinical Sciences.

By

MAURANE EMMA NDJOCK MBEA
Registration Number: UBa12H034

SUPERVISOR CO-SUPERVISOR

Prof. CHIABI ANDREAS Prof. ATANGA MARY

(c) Copyright by Maurane Emma Ndjock Mbea, 2019 All Rights Reserved

1

DECLARATION

I, Nlaurane Emma Ndjock Mbea, Registration N° UBaI2HO34, Department of Clinical Sciences in the Faculty of Health Sciences, University of Bamenda, hereby declare that, this work titled: "Etiologies, Clinical Presentation And Hospital Outcome Of Bacterial Meningitis In Children At The Pediatric Unit Of The Yaounde --Gyneco -- Obstetric And Pediatric Hospital" is my original work. It has not been presented in any application for a degree or any academic pursuit. 1 have sincerely acknowledged all borrowed ideas nationally and internationally through citations.

Date 4 (t'A f q-cac)
	Signature ~~ j

ii

iii

DEDICATION
TO MY PARENTS
CHANTAL BAYEGUI Epse NDJOCK MBEA
AND
EMMANUEL NDJOCK MBEA
TO MY SISTER
FINKE FICTIME YAN NDJOCK MBEA

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ACKNOWLEDGEMENT

I am most grateful to:

Thesis supervisor Prof CHIABI Andreas for his outstanding teaching received during the course of the work. Professor, your rigor and constant devotion for a work perfectly done forces our admiration.

Thesis co directors Prof NGUEFACK Seraphin and Prof ATANGA Mary for their acceptance given to us in agreeing to guide us in this work. Thank you once more for your availability and dynamism.

Dean of the Faculty of Health Sciences of the University of Bamenda for her constant advice and support given to us at any given circumstances to all her students.

Pediatric Department of YGOPH for their welcome and help during our study.

Formal Dean of the Faculty of Health Sciences for his rigorous training he has given to us.

My parents Mr and Mrs Ndjock Mbea for their love, moral and financial support they have been given me throughout the realization of this work.

My family members: Mrs Finke Fictime Marie Louise for her moral and financial support, my sisters Finke yan and Bayegui Marie Louise for their prayers and moral support.

Second batch of Faculty of Health Sciences of the University of Bamenda and my friend Ngo Linwa Esther for the exceptional 7 years they have made me gone through, together in struggle and brighter days, thanks.

To all whose names are not cited, I say my most gratitude towards any form of help from you, thanks.

GOD Almighty for the inspiration, mental and physical strength and protection he gave me to be able to go through this work successfully.

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ABSTRACT

INTRODUCTION AND OBJECTIVES:

Meningitis is a term that describes the inflammation of membranes (meninges) and/or cerebrospinal fluid that surrounds and protects the brain and spinal cord. Bacterial meningitis remains a serious global health problem, with World Health Organization estimating over 1.2 million of cases worldwide each year. It still affects mostly children with significant morbidity and mortality despite the presence of vaccins. Many studies have been conducted out of Africa, in Africa and in Cameroon with an incidence of 1.54 in 2014, all emphasizing the continuous rising incidence, thus our main aim being to: determine incidence, etiologies, clinical presentations, and describe the hospital outcome of bacterial meningitis in children.

MATERIALS AND METHODS:

This was a retrospective cross sectional descriptive study done at the pediatric unit of the Yaoundé Gyneco-Obstetric and Pediatric hospital. Those included in the study were children admitted for meningitis from the 1^st of January 2014 till the 31^st of December 2018 and aged from 1 month to 15 years. The sample size of 23 was calculated from the Cochrane's formula, and there was consecutive search of files in the archives for the following information: pathogens isolated and clinical manifestation and hospital outcome of children with the disease. The data were recorded using CS PRO 7.2(census and survey processing system) soft ware and analysed using IBM SPSS 23.0(statistical package for the social sciences)

RESULTS:

The incidence of bacterial meningitis in children at the Yaoundé Gyneco -Obstetric Hospital was 0.3% and the female sex was predominant at 56% in the admissions. Streptococcus pneumoniae and Neisseria meningitidis were the most common pathogens isolated; 63% and 25% respectively. Children within the age group of < 12 months were the most affected. Fever (95.3 %) and convulsion (60.5%) were the most common presentations of meningitis at time of admission, while neck stiffness and meningeal signs (Kerning and Brudzinski's signs) were present on clinical examination at 20.9% and16.3% respectively. A mortality rate of 2.4% was recorded against cure rate of 97.6%.

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CONCLUSION AND RECOMMENDATION:

The incidence of bacterial meningitis was 0.3% with streptococcus pneumoniae being the most common pathogen identified, and fever and convulsion as the most common presentations of meningitis. Neck stiffness and meningeal signs were the most common signs on clinical examination. There was a low mortality rate of 2.4 %.

Following our conclusions ,the ministry of public health is recommended to look into vaccination campaigns in children all over the country against infectious diseases especially meningitis. This could be done through re-enforcement of information, education and communication of vaccination in children.

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RESUME

INTRODUCTION ET OBJECTIFS:

La méningite est un terme qui décrit l'inflammation des meninges et /ou le liquide céphalo-rachidien qui entoure et protège le cerveau et la moelle épinière. La méningite bactérienne reste un problème de santé publique sérieuse, avec l'Organisation Mondiale de la Santé l'estimant à plus de 1,2 million de cas dans le monde entier chaque année. Elle affecte toujours les enfants, avec une morbidité et une mortalité significative malgré la présence des vaccins. Plusieurs études ont été faites hors d'Afrique, en Afrique en général et au Cameroun avec une incidence à 1,54 en 2014, toutes mettant l'accent sur la monté des incidences d'où le but de cette étude qui et de : déterminer l'incidence, les étiologies, la présentation clinique, et le devenir hospitalier de la méningite bactérienne chez les enfants.

METHODOLOGIE:

Cette étude était rétrospective-descriptive et a été faite à l'Hôpital Gynéco-Obstétrique et Pédiatrique de Yaoundé. Ceux inclus dans l'étude étaient les enfants admis pour la méningite du 1^er Janvier 2014 au 31 Décembre 2018 et âgés de 1 mois à 15 ans. La taille d'échantillon était de 23 a partir de la formule de Cochrane et y'avait une fouille consécutive de dossiers aux archives pour recueillir les informations suivantes : germes isolées, présentation clinique et devenir hospitalier chez l'enfant atteint de la maladie. Les données ont été saisis a l'aide du logiciel CS PRO 7 .2 et analysées avec le logiciel IBM SPSS 23.0

RESULTATS:

L'incidence de la méningite bactérienne était de 0.3% à l'Hôpital Gynéco-Obstétrique et Pédiatrique de Yaoundé avec une prédominance de genre féminin à 56% à l'hospitalisation. Streprococcus pneumoniae et Neisseria meningitidis étaient les germes les plus isolés à 63 % et 25 % respectivement .Les enfants âgés de < 12 mois étaient les plus affectés. La fièvre et la convulsion étaient des présentations les plus communes a la consultation, pendant que la raideur de la nuque (20.9%) et les signes méningés(Signes de Kerning et de Brudzinski) (16.3%) étaient les plus retrouvés comme signes à l'examen clinique. Un taux de 2.4 % de mortalité était enregistré contre un taux de 97.6% de guérison.

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CONCLUSION ET RECOMMANDATION:

L'incidence de la méningite était de 0.3 % avec le Streptococcocus pneumoniae comme germe le plus isolé et la fièvre et la convulsion étaient les présentations les plus communes de la méningite. La raideur de la nuque et les signes méninges comme signes les plus communs à l'examen clinique. Il y'avait un taux bas de mortalité à 2.4%

Compte tenue de ces conclusions, le ministère de la santé publique est recommandé de mettre un regard sur les campagnes de vaccination des enfants dans tout l'étendu du territoire contre les maladies infectieuses surtout sur la méningite. Le renforcement de l'information, l'éducation et la communication des vaccinations chez les enfants est nécessaire.

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TABLE OF CONTENTS

DECLARATION i

CERTIFICATION ii

DEDICATION iii

ACKNOWLEDGEMENT iv

ABSTRACT v

RESUME vii

TABLE OF CONTENTS ix

LIST OF TABLES xii

LIST OF FIGURES xiii

LIST OF ABBREVIATIONS AND SYMBOLS xiv

HIPPOCRATIC OATH xx

CHAPITRE ONE 1

INTRODUCTION 1

I.1) Background 1

I.2) Rationale And Justification 2

I.3 ) Main Objectives 2

I .3.1) Specific Objectives 2

I.5) Research Question 3

I.6 Conceptual Framework 3

CHAPTER TWO 4

LITERATURE REVIEW 4

Ii.1) General Overview 4

Ii.4) Pathophysiology Of Bacterial Meningitis 12

Ii.4.1) Bacterial Invasion 12

Ii.4.2) Inflammatory Response 14

Ii.4.3) Raised Intracranial Pressure 14

Ii.4.4) Neuronal Damage 15

Ii.5) Diagnosis Of Meningitis In Children 16

Ii.5.1) Clinical Diagnosis Of Meningitis In Children 16

Ii.5.2) Paraclinical Diagnosis Of Bacterial Meningitis 17

Ii.5.2.1) Lumbar Pucture And Csf Analysis 17

Ii.5.2.2) Complications Of Lumbar Puncture 19

Ii.5.3) Other Laboratory Investigations 19

Ii.6)

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Current Treatment On Bacterial Meningitis In Children 21

Ii.6.1) Antibiotic Treatment 21

Ii.6.2) Adjuvant Therapy And Supportive Therapy 22

Ii.6.3) Fluid Restriction 22

Ii.7.2) Chemoprophylaxis 24

Ii.7) Complications Of Bacterial Meningitis In Children 24

Ii.8) Publications On Meningitis 26

CHAPTER THREE 29

MATERIALS AND METHODS 29

Iii.1) Study Design 29

Iii.2) Duration Of The Study 29

Iii.3) Study Setting 29

Iii.4) Sampling 29

Iii.5) Study Population 29

Iii.5.1) Inclusion Criteria 29

Iii.5.2) Exclusion Criteria 30

Iii.6) Sample Size 30

Iii.7) Materials 30

Iii.8) Methods 31

Iii.8.1) Administrative Authorizations And Ethical Clearance 31

Iii.8.2) Patient Recruitment 31

Iii.8.3) Data Management 33

Iii.8.3.1) Ethical Considerations 33

Iii.9.1) Human Resources 33

CHAPITRE FOUR 34

RESULTS 34

Iv.1) Incidence 34

Iv.2.3) Type Of Admissions 35

V.2.4) Distribution Of Patients According To Year Of Admission 36

Iv.3) Clinical Presentation Of Bacterial Meningitis 37

Iv.5) Etiologies Of Bacterial Meningitis 41

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CHAPITRE FIVE 47

DISCUSSION 47

V.1) Incidence 47

V.2) Clinical Presentation Of Patients 48

V.3) Hospital Outcome Of Bacterial Meningitis In Children 50

Conclusion 51

Recommendations 51

REFERENCES 53

APPENDICES

xii

LIST OF TABLES

Table I: Distribution of patients according to gender 35

Table 2: Distribution of clinical presentation according to symptoms. 37

Table 3: Distribution of neurological clinical presentation according to signs 38

Table 4: Biochemical and cytological aspect of csf analysis of patients at admission 39

Table 5: Biochemical and cytologic aspect of csf analysis of patients at admission 40

Table 6: Distribution of pathogens according to age 42

Table 7: Distribution of complications found during admission 43

Table 8: Distribution of patients according to outcome during admission 44

Table 9: Distribution of patients according to sequelae at time of discharge 45

Table 10: Distribution of patients according to treatment recieved for sequalae 46

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LIST OF FIGURES

Figure 1: Meningitis Belt in West Africa [14] 4

Figure 2: Countries trained to conduct surveillance for the Pediatric Bacterial Meningitis Surveillance Network, by performance level* --- World Health

Organization African Region, 2008 [16] 5
Figure 3: Causes of confirmed bacterial meningitis from eleven years of active

surveillance in a Mexican hospital, 2005 -2016. [18] 6

Figure 4 : Pathogenesis of bacterial meningitis [38] 15

Figure 5: Lumbar spine anatomy[41]. 17

Figure 6 : Distribution of patients according to age groups 34

Figure 7: Distribution of patients according to the type of admission. 35

Figure 8: Flow chart illustrating the incidence per year at YGOPH. 36

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LIST OF ABBREVIATIONS AND SYMBOLS

C D14 : Cluster of differentiation 14

CbpA : Choline binding protein A

CSF : Cerebro spinal fluid

E.coli : Escherichia coli

H.influenzae : Haemophilus influenzae

Hib : Haemophilus influenzae type b

Ibe A : Invasion of brain endothelium protein A

Ibe B : Invasion of brain endothelium protein

N.meningitidis : Neisseria meningitidis

OmpA : Outer membrane protein A

S .pneumoniae : Streptococcus pneumoniae

SDG : Sustainable development Goal

WHO : World's Health Organisation

YGOPH : Yaoundé-Gynaeco-Obstetric and Pediatric Hospital

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THE ADMINISTRATIVE STAFF OF THE UNIVERSITY OF BAMENDA

Prof Sammy Beban Chumbaw Pro-Chancellor

Prof Theresia Akenji Vice-Chancellor

Prof Suh Cheo Emmanuel Deputy Vice-Chancellor in

charge of Teaching,

Professionalization and
Development of Information

and Communication
Technologies

Prof Agwara Moise Ondoh Deputy Vice-Chancellor in

charge of Internal Control and Evaluation

Prof Roselyn Jua Deputy Vice-Chancellor in

charge of Research,
Cooperation and relationship with the Business world

Prof Banlilon Victor Tani Registrar

Prof Ghogomu Julius Numbonui Director of Academic Affairs

Dr Mbifi Richard Director of Administrative

Affairs

Prof Anong Damian Nota Director Students' Affairs

MrGiyohYerima Peter Director of Finance

MmeBongnda Winifred B. Beriliy Director of Library

xvii

THE ADMINISTRATIVE AND TEACHING STAFF OF THE FACULTY OF HEALTH SCIENCES (FHS), THE UNIVERSITY OF BAMENDA

2018/2019 Academic Year

1. Administrative staff

Prof Dora Mbanya Dean

Prof Christopher TangnyinPisoh Vice-Dean in charge of Academic

Affairs

Prof Helen KuokuoKimbi Vice-Dean in charge of Admissions

and

Records

Prof Henri Lucien F.Kamga Vice-Dean in charge of Research

and Cooperation

MrJacobTitafanVoma Faculty Officer

Dr Gerald Ngo Teke Chief of service,programmes,

Teaching

And research

Dr Moses Samje Chief of Service, Administration

and

Personnel

Mr Zaccheus Aweneg Chief of Service, Finance

Mr Humphrey Njoamomoh Chief of Service, Admissions and

Records

Mr Leonard Peyechu Chief of Service, Materials And

Maintenance

Dr Mary Garba Chief of Service, Internships

xviii

Mr Cyprien Bongwong Stores Accountant

2. Heads of Departments

Prof Frederic Agem kechia Biomedical Sciences

Prof Christopher Tangnyin Pisoh Clinical Sciences

Prof Bih Suh Mary Atanga Nursing/Midwifery

Dr Esther Etengeneng Agbor Medical Laboratory

Sciences

Teaching staff

a) Professors

1.	Christopher Kuaban		Internal Medicine/Chest Medicine	2.
Helen Kuokuo kimbi	Medical Parasitology		3.
Dora Mbanya	Haematology

b) AssociateProfessors

1.	BihSuh Mary Atanga		Nursing/Midwifery	2.
Henri Lucien F. Kamga	Medical Parasitology		3.
Frederic Agem Kechia	Medical Mycology		4.
Christopher Tangnyin Pisoh	General Surgery

c) Senior Lecturers

1.	Esther EtengenengAgbor		Nutritional Biochemistry	2.
Marie Ebob Bissong	Medical Microbiology		3.
Flore Ngoufo Nguemaim	Medical Parasitology		4.
Gerald Ngo Teke	Pharmacology		5.
Omarine Nfor Njimanted	Medical Parasitology

6.

xix

Moses Samje Biochemistry

7. William AkoTakang Obstetrics/Gynaecology

d) Assistant Lecturer

Jacob TitafanVoma Physics

e) Instructors

1. Kwende Odelia Nursing

2. Foba Marcelline Nursing

xx

HIPPOCRATIC OATH

« I solemnly pledge to dedicate my life to the service of humanity;

The health and well being of my patient will be my first consideration ;

I will respect the automomy and dignity of my patient ; I will maintain the utmost respect for human life ;

I will not permit considerations of age , disease or disability , creed , ethnic origin , gender , nationality , political affiliation , race , sexual orientation , social standing , or any factor to intervene between my duty and my patient ;

I will respect the secrets that are confided in me , even after the patient has died ;

I will practise my profession with conscience and dignity and in accordance with good medical practice ;

I will foster the honour and noble traditions of the medical profession ;

I will give to my teachers , colleagues , and students the respect and gratitude that is their due ;

I will share my medical knowlegde for the benefit of the patient and the advancement of health care ;

I will attend to my own health , well being ,and abilities in order to provide care of the highest standard ;

I will not use my medical knowledge to violate human rights and civil liberties, even under threat ;

I make these pomises solemnly , freely , and upon my honour. »

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CHAPITRE ONE
INTRODUCTION

I.1) BACKGROUND

Bacterial meningitis is an infectious disease characterized by infection and inflammation of the meninges due to the penetration and multiplication of the bacterium in the cerebrospinal fluid. It results in significant morbidity and mortality globally [1][2], and is estimated to be fatal in 50% of cases with affecting approximately 1.2 million people each year with two thirds occurring under 5 years of age [2].

In USA, bacterial meningitis was responsible for an estimated 4100 cases and 500 deaths annually between 2003 and 2007, while in 2012, in Africa World Health Organization identified 22000 meningitis cases in 14 countries in the meningitis belt [1][ 3].

Meningitis can be difficult to diagnose clinically particularly in young infants who do not seem to reliably display the classic features of the disease [4], where symptoms observed vary from the bulging fontanel in neonates to frank meningeal signs in older children, thus high index of suspicion is needed [5].Sequelae vary based primarily on the etiologic agent [6] where higher mortality rates tend to be associated with Haemophilus influenza type b meningitis, pneumococcal meningitis and meningococcal meningitis [7].

The different etiologies of bacterial meningitis in children were observed in various studies where Anouk et al demonstrated in 2018 that in Northern America Streptococcus pneumoniae was the most common pathogen with weighted mean 43.1% [1].

Touré et al also showed in 2017 in Ivory Coast in a study that Streptococcus pneumoniae and Neisseria meningitidis were the commonest incriminated pathogens [8]. In Cameroon in a study in 2014, it was seen that the incidence of bacterial meningitis still remained high despite the introduction of vaccins against the three most incriminated bacteria, notably Haemophilus influenzae which was the most common pathogens constituting 39.2%, followed Streptococcus pneumoniae with 31.6% and Neisseria meningitidis 10.5% [3].

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I.2) RATIONALE AND JUSTIFICATION

Bacterial meningitis is a serious often disabling and fatal infection which causes 170,000 deaths worldwide each year [5]. On a review on meningococcal meningitis particularly, it was demonstrated that the rate of 15 cases per 100,000 per week for two weeks provokes vaccination of children aged greater than 2 years with one injection of group A and C polysaccharide. Even still only about 50 % of cases of meningitis are preventable[9].

Despite the development of vaccines, ad useful tools of rapid identification of pathogens and potential antibiotherapy, bacterial meningitis still remains a significant cause of preventable childhood deaths and a major cause of neurological deficits and physical handicaps in children [5][ 10], especially in sub-Saharan Africa where populations seem to be more exposed to the different causative agents than any other part of the world.

Though many reviews, above 100, have been conducted on bacterial meningitis, especially in Cameroon, we can agree from those reviews that this disease still makes one to ask question on the control and prevention of the disease, through the implementation and correct dispensing of the three main vaccins against the three major causative agents which are;Haemophilus influenzae typeb ,Neisseria meningitidis and Streptococcus pneumoniae.

Therefore, the purpose of this study is in line with the goal 3.2 of Sustainable Development Goal (SDG) which has as objective to ensure by 2030 a decrease, of avoidable death of newborns and children of less than 5 years [11], to determine the new incidence, etiologic agents, clinical manifestations and hospital outcome of bacterial meningitis in children.

I.3 ) MAIN OBJECTIVES

To identify the common pathogens responsible for bacterial meningitis and to describe the hospital outcome in children with bacterial meningitis.

I .3.1) SPECIFIC OBJECTIVES

1) To determine the incidence of bacterial meningitis in children in the pediatric unit at the YGOPH.

2) To identify the common pathogens responsible for bacterial meningitis in children at YGOPH.

3) To describe the different clinical manifestations of bacterial meningitis in children at YGOPH and the evolution.

4) To describe the hospital outcome in children with bacterial meningitis I.5) RESEARCH QUESTION

1) What are the incidence, etiologies, clinical presentation and hospital outcome of bacterial meningitis in children at the YGOPH?

I.6 CONCEPTUAL FRAMEWORK

Sociodemograp hic

Characteristics

- Age

- Gender

- Vaccinati

on status - Immune

status

BACTERIAL VIRAL

ETIOLOGIES

-S. pneumoniae

-N.meningitidis

-H.influenzae

CHILDHOOD MENINGITIS

CLINICAL PRESENTATION

TREATMENT

HOSPITAL OUTCOME

? Mortalit y

? Cure

? Disabilit y

3

4

CHAPTER TWO

LITERATURE REVIEW

II.1) GENERAL OVERVIEW

The World Health Organization (WHO) recognizes Neisseria meningitidis, in most countries to be the leading cause of meningitis and fulminant septicemia and is also recognized to be a significant public health problem [12] However, large recurring epidemics affect an extensive region of sub-Saharan Africa known as the « THE MENINGITIS BELT » (Figure 1) which comprises of 26 countries from Senegal in the West to Ethiopia in the East [13].

Figure 1: Meningitis Belt in West Africa [14]

Most meningitis cases and out breaks in the African meningitis belt occur during the epidemic season which tend to extend from November to June depending on the region [13], with sub-Saharan region having the world's greatest disease burdens of Haemophilus influenzae type b streptococcus pneumoniae, and Neisseria meningitides [15]. An enhanced meningitis surveillance regional network is also available where the 23 countries participating (Figure 2) reported in 2017 a total of 29827 of suspected cases of meningitis including 2276 deaths [13]. This was said to represent an increased

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number of cases compared with 2016 of 18178 suspected cases resulting also in an increased number of epidemic districts from 42 in 2016 to 57 in 2017[13]

Figure 2: Countries trained to conduct surveillance for the Pediatric Bacterial Meningitis Surveillance Network, by performance level* --- World Health Organization African Region, 2008 [16]

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II.2) ETIOLOGIES AND RISK FACTORS OF BACTERIAL MENINGITIS IN CHILDREN

In 2000, Hib and S. pneumoniae infections are accountered for approximately 500,000 deaths in the sub-Saharan region.N. meningitidis has been responsible for recurring epidemics resulting in 700,000 cases of meningitis [17]

Figure 3: Causes of confirmed bacterial meningitis from eleven years of active surveillance in a Mexican hospital, 2005 -2016. [18]

? STREPTOCOCCUS PNEUMONIAE

Streptococcus pneumoniae is one of the main causing agents responsible for meningitis in newborns, in young children and teenagers with higher rates of lethality and morbidity [19] [20]. Streptococcus pneumoniae is a Gram - positive, encapsulated bacterium often found as a normal commensal in the nasopharynx of healthy children [20].Streptococcus pneumoniae was the commonest cause of bacterial meningitis in US and Europe, and tends to occur mostly among children older than 5 years of age [10]. However, the highest risk of bacterial meningitis caused by Streptococcus pneumoniae

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is in children greater than 2 years [21]. The bacterium can become pathogenic, with invasive disease, greatest in patients who develop meningitis.

? VIRULENCE FACTOR AND PATHOGENESIS

The bacterium is spread by the respiratory fluids from the infected person when they cough or sneeze, the bacterium then finds its way in the system where it escapes to the local host defenses and phagocytic mechanisms, then penetrates the CSF either through choroid plexus / subarachnoid space originating from bacteremia or via direct extension from local respiratory system infections [20]. It is able to escape into the central nervous system easily with the aid of pneumococcal proteins which include [22]:

> Pneumococcal surface protein A (PspA) :It is located in the cell wall of the bacterium and acts as a protective antigen against the host complement system.[22]

> Hyaluronate lyase (Hyl) :This enzyme mediates facilitation of tissue invasion by breaking down the extracellular matrix component of the host cell ,thereby increasing tissue permeability.This factor aids in the pathogenesis of wound infection, meningitis and even pneumonia[22].

> Autolysin (LytA) :These enzymes are located in the cell envelope and has a very important role in cell wall degradation which leads to cell death .They degrade the peptidoglycan backbone of bacterial organisms , which leads to cell lysis[22].

> Pneumococcal surface antigen A (PsaA) : This protein is thought to have protective properties and is anchored to S.pneumoniae through bacterial cell membrane[22].

> Choline binding protein A (CbpA) : It serves as an anchoring device to pneumococci lipoteichoic C acid structures present on the surface of the bacterium.Thus aids in the adherence and host tissue colonization[22].

> Neuraminidase: They enhance colonization due to their action on gylcans where , they cleave terminal sialic acid from cell surface gylcans such as mucin, glycolipids and glycoproteins which is probably responsible for damage to host cell gylcan[22].

Children with basilar skull fractures with CSF leak, asplenism and HIV infection are at particular risk of developing pneumococcal meningitis [23], pneumococcal conjugate vaccines have been implemented in many countries, and immunization with the heptavalent pneumococcal vaccins PCV7 has decreased incidence by incriminating

8

pathogen by greater than 90% [24]. Meanwhile pneumococcal population undergoes temporal changes in clonal distributions in the absence of pressure from a vaccine [24].

? HAEMOPHILUS INFLUENZAE

Haemophilus influenzae is Gram-negative coccobacilli capable of causing serious invasive disease in the child of less than 5 years of age (Figure 3). Haemophilus influenzae encapsulated serotypes are: a, b, c, d, e, and f which facilitates its penetration in the blood with the serotype b being the most virulent of all. The pathogen does not stay alive for a long time in the environment, it thus has a 12 hours' survival on plastic objects [25].Haemophilus influenzae type b was the most common cause of life threatening infection in children in industrialized countries until universal immunization, where children of less than 5 year of age, were the primary host with 39% of nasopharynx colonization, but nowadays, it is instead older children and adults that are considered to be more susceptible carriers shifting them to primary host[26][25].

? VIRULENCE FACTOR AND PATHOGENESIS

The transmission of the pathogen is done through droplets from the respiratory airways, through cough, sneezing, speaking from colonized person, through saliva, and contaminated objects from respiratory secretions. Sodium hypochlorite at 1%, ethanol at 70%, formaldehyde, glutaraldehyde has good efficacy against Haemophilus influenzae [25].However Hib , though not known to produce toxins, it has the capacity to invade the host system using the following defense methods[27] :

? Polysaccharide capsule : It is a very important virulence factor of encapsulated strains of Haemophilus influenza strains and it protects the bacterium from host immune functions[27].

? Lipooligosaccaharide (LOS) : A major component of the outer leaflet of the Gram -negative bacteria outer membrane , which mediates interactions between bacteria and the host immune system[27].

Hib apart from using the above defense mechanism also uses , particular processes to escape from complement systems such as;

- Phase variation which is a immune evasion strategy during infection where the outer surface of the bacterium is modified to adapt to changes in the host environment[27].

9

- Binding of host complement regulatory factors which is important during colonization and infaction, where these factors block activity at various step of the complement pathway[27].

Globally, Hib accounts for approxi mately 8-13 million serious illness annually, including 173.000 cases of meningitis causing 78.000 deaths [28]. The incidence of bacterial meningitis due to the pathogen has been experiencing a drop in its incidence in developed countries[8], in Belgium it was at 0,04/100,000 inhabitants in 2012 and even in developing countries where there is implementation of the vaccin against the Haemophilus influenza type b, less prevalence was noticed compare to previous years[25]. Despite its reduction in the cause of meningitis, its identification and prompt treatment are essential because of the short incubation period which is 2 - 4 days [25].World Health Organization recommended the addition of Hib vaccine to immunization programs , according to national capacities and priorities, however, uptake in developing countries has remained slow[26].This is partly due to the uncertainty about the true disease burden[26].

? NEISSERIA MENINGITIDIS

Meningococcal infections occur worldwide as endemic disease(Figure 3)[29], and it appears that the occurrence of invasive meningococcal disease is not solely determined by the introduction of a new virulent bacterial strain but also by other risk factors determining the transmission of the pathogens [29][19]. Meningococcal meningitis occurs when Neisseria meningitidis multiplies on the meninges and in the CSF [30]. Early recognition of this type of meningitis is important than in any of the acute infectious diseases [31].

Neisseria meningitidis is a Gram -negative diplococci which has 13 serogroups defined by specific polysaccharide designated A, B,C,H, I, K, L, M,X,Y,Z, 29E, and W135(serogroup D is no longer recognized),but is A, B,C, W135, X, and Y account for most disease where group A is mostly found in Sub-Saharan Africa, group B found in the temperate climates and group C occurs mostly as outbreaks [29][32].

Neisseria meningitidis is found in the oropharynx of 10 % of the population with an annual number of invasive disease cases worldwide estimated to be atleast 1,2 million with 135,000 deaths related to invasive meningococcal disease and WHO categorizes countries by risk of meningococcal disease as follows [32];

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? High risk: countries with greater than 10 cases /100,000 and /or =1 epidemic Over last 20 years

? Moderate risk: Countries with 2-10 cases /100,000 population per year

? Low risk: Countries with less than 2 cases /100.000 populations per year.

The proportion of cases caused by each serogroup varies by age group also geographic distribution and epidemic potential differ according to serogroup.Neisseria meningitidis ends to be present particularly in children less than 5 years old with estimated 500,000 cases and 50,000 deaths globally each year [29].The largest burden of meningococcal disease occurs in the sub-Saharan Africa during dry season with the presence of dust , winds , cold nights with the upper respiratory tract infections combine to damage the nasopharyngeal mucosa increasing the risk of the disease which is transmitted through droplets of respiratory secretions while Invasive disease developing in a small percentage of carriers is regarded as emergency[32][33].

? VIRULENCE FACTOR AND PATHOGENESIS

Neisseria meningitidis is a fastidious, encapsulated aerobic bacterium that colonises host mucosal surface using multiple factors such as[34] :

> Capsule : It is present in strains that cause invasive disease ,since it provides resistance to antibody and complement -mediated killing and inhibits phagocytosis[34].

> Lipolysaccharide (LPS) : Induces the release of chemokines , reactive oxygen speies and nitric oxide and has a role in resistnce to other host defense[34].

> Adhesins pili : Initiate binding to epithelial cells,and facilitate passage through the epithelial mucus layer and movement over the epithelial surfaces .They also facilitates the uptake of DNA by meningococci and enable adherence to endothelial cells and erythrocytes[34].

> Opacity proteins : Opa and Opc (only expressed in Neisseria meningitidis) while Opa is expressed by both meningococci and gonococci.They have potential roles in pathogenesis that is not well understood[34].

> Porins : Por A and Por B are porins through which small nutrients diffuse to the bacterium and they are also involved in host cell interactions and they are targets for bactericidal antibodies.Por A is the main component of vesicle based vaccines and a target for bactericidal antibodies while Por B insert in membranes and induce Ca 2+ influx and activates TLR2 causing cell death[34].

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? Iron binding proteins: They enable the meningococci to acquire iron which is an important growth factor during colonization and disease[34].

World's Health Organization policy's of epidemic containments prevents at best 50% of cases, therefore for an effective prevention of meningococcal meningitis in sub Saharan Africa, there should be a strict and effective follow up of universal vaccination recommendation, but still more than half of cases among infants less than 1 year are caused by serogroup B meningococci for which no vaccins is available. Also serogroup X, previously a rare cause of sporadic meningitis, has been responsible for outbreaks between 2006 and 2010 in Kenya, Niger, Togo, Uganda, and Burkina Faso, the latter with 1,300 cases among the 6, 732 reported annual cases [9][ 32].

II.3) RISK FACTORS ASSOCIATED WITH THE OCCURENCE OF BACTERIAL MENINGITIS IN CHILDREN

The human infection with meningitis has seasonal variation and this differs from one country to another [33]. Worldwide meningitis was estimated to cause 1.73.000 deaths in 2002, most children from the developing countries [35]. Bacterial meningitis as any other disease has factors that may be associated to its development, and they can be preventable or not as follows;

? AGE: The first age group (less than 1year) occupies the highest number of incidence of the disease which tends to be higher in developing countries than developed countries. The cause might be due to the immaturity of immune system, lack in the pre-exposure of the body to the most incriminated organisms which enhances the memory of the immune system to fight against the invaders[33].

? GEOGRAPHIC ZONE AND CLIMATE: Bacterial meningitis is endemic in the sub-Saharan region of Africa, especially in those countries that are included in the «Meningitis Belt» which is made up of 26 countries from the Senegal to the West to Ethiopia to the East. Meningitis in tropical areas occurs in dry season and decrease in periods of rains, while in temperate regions, the epidemics usually occur during winter and spring seasons [13][ 33].

? SEX: The male sex has been observed in various studies to be a risk factor for bacterial meningitis. It is not yet well understood why males will be more susceptible to getting the disease than female sex [33].

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? LOW SOCIOECONOMIC STATE AND CROWDING LIVING CONDITIONS: These are factors that are mostly seen in developing countries.Crowdness encourage development of meningitis since most of the detected pathogens are air transmissible [33][35].

? PASSIVE SMOKING: Children exposed to smoking are found to get meningitis because, passive smokers tends to harbor a greater number of bacteria in their throat and nasal passage. Also smoking plays an important role in diminishing the capacity of epithelial cells covering the respiratory tract for prevention of acquiring infection in addition to the prevalence of healthy carrier of pathogens [33][ 35].

? RECENT UPPER RESPIRATORY TRACT INFECTION: This can easily be explained by the route of entrance of the microorganisms to the brain and those important routes of infection are: Otitis media, mastoiditis, sinusitis and pneumoniae [33].

? HISTORY OF HEAD INJURY AND BRAIN SURGERY: It is considered an important risk for development of bacterial meningitis, because of the proximity of the injury with the central nervous system [33].

? MALNUTRITION: Malnutrition is a complex disease that if not well controlled affects every system of the body including the hematopoietic system, and most of the time complicates with anemia. Anemic patients are highly susceptible to serious infections such as bacterial meningitis and can be caused by different etiologies [35]. OTHER FACTORS ASSOCIATED WITH THE DEVELOPMENT OF BACTERIAL MENINGITIS:

? Bottle feeding[33]

? Compromised immune system[33]

? Splenectomy[33]

? Sickle cell disease[33]

? Inherited family tendency for meningitis[33]

II.4) PATHOPHYSIOLOGY OF BACTERIAL MENINGITIS There are conditions required to cause invasive diseases such as : II.4.1) BACTERIAL INVASION

Bacteria reach the central nervous system either by hematogenous spread or by contiguity like in the case of neonates and children where pathogens are acquired from

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non-sterile maternal genital secretions and from organisms that colonize the upper respiratory tract respectively[29]

Successful colonization of the nasopharyngeal mucosa depends on the ability of bacteria to evade host defenses including secretory Ig A and ciliary clearance mechanisms, and to adhere to mucosal epithelium[29]. Microbial virulence factors include the Ig A protease secreted by Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae that cleave Ig A to an active form. Notably meningococus depends on the binding of fimbriae on the bacterial cell surface to adhere on epithelial cells, and non-encapsulated strains of meningococci adhere better than capsulated strains. As the mucosa has been breached and the intravascular space has been entered, the pathogen must survive in the circulation in order to penetrate the blood brain barrier[36]. The principal host defense mechanism is complement although neutrophil and antibodies are also important(Figure 4). The meningeal pathogens are all capsulated and this virulence factor of theirs enables them to evade phagocytosis and bactericidal activity of the complement system. In Streptococcus pneumoniae infection, the alternative complement pathway is activated by pneumococcal capsular polysaccharides, where there is direct cleavage of the C3 which generates C3b which opsonizes the organism, enhancing phagocytic clearance from the circulation[37]. The C3b then binds to Factor B on the pneumococcal capsular surface offering resistance to opsonisation. Therefore, it is understandable why individuals with impaired complement systems are at high risk of getting all the manifestations of invasive pneumococcal disease.

Neisseria meningitidis, has its capsular sialic acids which facilitates binding to the C3b to the complement regulatory protein Factor H, thus blocking activation of the alternative pathway by presenting the binding of C3b to factor B[36].

In order to cross the blood brain barrier and to overcome structures such as tight junctions, meningeal pathogens carry effective molecular tools. They cross the blood brain barrier to enter the subarachnoid space and are aided with the presence of specific surface bacterial proteins like E. coli proteins IbeA,IbeB and ompA, Streptococcal proteins such as CbpA which interacts with glycoconjugate receptor of phosphorlcholine with platelet activating factor (PAF) on the eukaryotic cells and promotes endocytosis and crossing the blood brain barrier.N. meningitidis proteins Opc,

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Opa, PilC, and a Pili protein[36]. Bacteria causing meningitis in newborns, most importantly group B streptococcal and Escherichia coli are also well equipped with adhesive proteins allowing them to invade the central nervous system[37].

II.4.2) INFLAMMATORY RESPONSE

The lack of host defenses in the CSF allows rapid multiplication of bacterial pathogens resulting in the release of microbial products such as lipopolysaccharide[36]. The hall mark of bacterial meningitis is recruitments of neutrophils into the cerebo spinal fluid(Figure 4)[37]. Neutrophil extravasation to any site of inflammation depends on the coordinated sequential expression at the cell surface of specific adhesion molecule, notably L-selectin (CD62l) is expressed at the cell surface and allows the neutrophil to «roll» along the endothelium.For extravasation to proceed L-selectin must be removed from the surface of neutrophil and expression of the B2 integrin CD11b /CD18 must be upregulated[36].

Neutrophil adherence to endothelium occurs through the interaction of neutrophil CD11b/CD18 and diapedesis and migration of neutrophil along a chemotactic gradient to focus of inflammation that follows. The removal of L-selectin and integrin upregulation are achieved by neutrophil activation which occurs when the cell encounters activated endothelium (IL-8 and PAF are typical activators of endothelium)[36].

II.4.3) RAISED INTRACRANIAL PRESSURE

Intracranial pressure often rises in meningitis and can lead to life threatening cerebral herniation. Three pathophysiologic mechanisms contribute to the development of cerebral oedema[37]. They are;Vasogenic, Cytotoxic and Interstitialoedema. Vasogenicoedema occurs directly as a result of the increased permeability of the blood brain barrier[37]. Cytotoxic oedema is the rise in intracellular water due to loss of cellular homeostatic mechanism and cell membranes function, attributed to the release of toxins from neutrophil or organisms. Anti-diuretic hormone (ADH) release leads to hypotonicity of cerebral extracellular fluid and increase the permeability of the brain to water. Interstitial oedema is the result of an imbalance between cerebo spinal production and resorption, and occurs when blood flow or cerebo spinal resorption is impaired[37].

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Figure 4 : Pathogenesis of bacterial meningitis [38]

II.4.4) NEURONAL DAMAGE

Bacterial meninges causes disabling neuropsychological deficits in up to 50 % of its survivors with the hippocampus most affected and vulnerable area of the brain. The extracellular fluid around the brain cell is contiguous with the cerebo spinal fluid and the proximity to the ventricular system allows diffusion between those compartments around could deliver soluble bacterial and inflammatory toxic mediators[37].

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Neuronal damage in meninges involve bacterial toxins, cytotoxic products of immune competent cells and indirect pathology secondary to intracranial complications(Figure 4)[38]. In the case of Streptococcus pneumoniae is associated with the highest frequency of neuronal damage, produce two major toxins identified; H2O2 and Pneumolysin a pore forming cytolysin[37]. They cause programmed death of neurons and microglia by inducing rapid mitochondrial damage. Pneumolysin translocate to mitochondria and induce pore formation in mitochondrial membranes. Release of apoptosis inducing factor (AIF) from damaged mitochondria leads to fragmentation of DNA and apoptosis like cell death[37]. The cell death is executed in the Caspase-independent manner, where cells exposed to live Pneumolysin cannot be rescued by caspase inhibitors but somehow any intervention from those inhibitors, z-VAD-fmk there is a 50% chance to avoid neuronal damage[37].

II.5) DIAGNOSIS OF MENINGITIS IN CHILDREN

II.5.1) CLINICAL DIAGNOSIS OF MENINGITIS IN CHILDREN

The clinical symptoms and signs of bacterial meningitis in children vary depending on the age of the child and duration of disease. The classic symptoms of meningitis are fever, headache, photophobia and neck stiffness. However, in the early stages of meningitis, and particularly in young children, the symptoms of meningitis can be variable or nonspecific and the classic symptoms may be absent, making meningitis difficult to diagnose. Nonspecific signs include abnormal vital signs such as tachycardia and fever, poor feeding, irritability, lethargy, and vomiting [23][ 39].

Children may have fever and vomiting associated with irritability, drowsiness and confusion. They may become suddenly ill with fever and rigors, which can be mistaken for seizures. Also muscle and joint aches can occur which can be responsible for children being restless and miserable. Vomiting, nausea and poor appetite are common while abdominal pain and diarrhea are less common. Meningitis causes a rise in intracranial pressure [39 ]. It presents in babies and in young children as a bulging or full fontanel. In children without an open fontanel, raised intracranial pressure is seen as other features like systemic hypertension with bradycardia. Children may have an abnormal tone, jerky movements or be floppy [39][40].

Other children are more likely to have the classic features of meningitis, fever, vomiting and headache, stiff neck and photophobia.

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Rashes may be present, most commonly when the causative organism is Neisseria meningitidis, but more likely to be absent, atypical, scarce or petechial in character than those seen in meningococcal septicemia [41].

II.5.2) PARACLINICAL DIAGNOSIS OF BACTERIAL MENINGITIS II.5.2.1) LUMBAR PUCTURE AND CSF ANALYSIS

A lumbar puncture and CSF analysis is the gold standard and definitive diagnosis of bacterial meningitis. It is done in either sitting or lateral decubitus position and is important to monitor the patient visually and with a pulse oximetry for any signs of respiratory difficulties as a result of the assumed position.

The subarachnoid space should be entered below the level of spinal cord termination (Figure 5), and any of the interspace between L3 -L4 and L5 -S1 in children

Analysis of CSF should include: Gram stain and cultures; white blood cell (WBC) count and differential; Glucose and protein concentrations; Cytocentrifugation of the CSF enhancing the ability to detect bacteria and perform a more accurate determination of the WBC differential [23].

Figure 5: Lumbar spine anatomy[41].

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Typically, the CSF white cell count (wcc) is >1000 cells/mm3 although it may not be elevated in the early phase of the infection and the majority of white cells are polymorph nuclear (PMNs). CSF protein is typically elevated (100-200 mg/dL) and glucose low (CSF to serum ratio <0.4) [23]

A reduced absolute CSF concentration of glucose is as sensitive as the CSF-to serum glucose ratio in the diagnosis of bacterial meningitis [21]

The Gram-stained smear of CSF has a lower limit of detection of about 105 colony-forming units/mL. Of patients with untreated bacterial meningitis, 80% to 90% have a positive CSF Gram stain. Unless unusual pathogens, such as anaerobes, are suspected, agar plate cultures of CSF are preferred to liquid media [21][ 23].Pleocytosis is a typical finding in bacterial meningitis, the WBC count usually greater than 1000 cells/mm3, and there is a predominance of polymorphornuclear leukocytes.

The lumbar puncture for the cerebro spinal analysis should be performed once the diagnosis of meningitis is suspected and after the patient is stabilised. However, there can be reasons to delay lumbar puncture which include the following

+ Local site for lumbar puncture: Skin infection at site of lumbar puncture, and

anatomical abnormality at the site of lumbar puncture site[42]

+ Patient instability: Respiratory or cardiovascular compromise, and continuing

seizure activity[42]

+ Suspicion of space occupying lesion [42]

+ Raised intracranial pressure[42]

+ Focal seizures[42]

+ Focal neurological signs[42]

+ Reduced conscious state of GCS less than 8 and especially if patient is comatose[42]

+ Decerebrate or decorticate posturing[42]

+ Fixed dilated or unequal pupils[42]

+ Absent dolls eye movement[42]

+ Papilledema [42]

+ Hypertension or bradycardia[42]

+ Irregular respirations[42]

+ Anticoagulations and bleeding disorders[42]

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II.5.2.2) COMPLICATIONS OF LUMBAR PUNCTURE

As in any other procedure, there might be complications after, and in lumbar puncture some complications have being observed such as;

1. Postural puncture headache (PDPH): It is usually self-limiting, but when serious, supportive treatment for the PDPH and its accompanying symptoms include: bed rest, analgesics, hydration, corticosteroids, and anti-emetic medications [43]. Also in case of severe and persistent headaches, injecting saline into the epidural space may be therapeutic [43].

2. Local back pain [43]

3. Infection[43]

4. Spinal hematoma[43]

5. Subarachnoid epidermal cyst[43]

6. Apnea[43]

7. Herniation (post procedural cerebral herniation): Herniation can be the direct cause of death in around 30% of such children. Therefore, it is practical to perform cranial CT imaging to evaluate any such abnormalities before performing an LP [41][ 43].

8. Transient limp or paresthesia[43]

9. Transient ocular palsy[43]

10. Cerebral Herniation[43]

II.5.3) OTHER LABORATORY INVESTIGATIONS

Despite the fact that CSF analysis from lumbar puncture is the gold standard in the diagnosis of meningitis , some other tests could be performed like the following:

? C-REACTIVE PROTEIN (CRP) : Clinically it is not easy to differentiate between bacterial and viral etiologies in patients with suspected meningitis, and due to the high mortality rate and potential neurological sequelae in survivors, there is an urgent need for rapid diagnosis with a near 100 % sensitivity. CRP was used and is still used as the biomarker for inflammation and tends to be elevated in both viral and bacterial infections, limiting its ability to discriminate between bacterial and viral etiologies of meningitis [44].

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? PROCALCITONIN :Procalcitonin (PCT) is now considered to be the best candidate to replace CRP due to its high diagnostic accuracy in various infectious pathologies, including sepsis, acute infections, endocarditis, and pancreatitis. Normal PCT levels of healthy individuals are less than 0.1ng/ml and level increase drastically in response to bacterial infections, unlike CRP, PCT has not been reported to the elevated in viral infections, thus conferring it to the important ability to distinguish easily between bacterial and viral etiologies [44].

- PCT also shows utility in the early diagnosis of meningitis by rising after 4h, peaking at 6h and remaining elevated over 24 h. This is in contrast to CRP, which rises over 6-12h and peaks at 24 -48 h. This delay in diagnosis combined with the traditional 72h wait for results of Gram stains, often results in patients receiving empiric antibiotics [44].

? Full blood count, Serum electrolytes and Coagulation studies: Normally these investigations are required initially before thinking about lumbar puncture, in order to assess for sepsis complications [21].

? Serum Glucose: This test must be measured routinely in a child having meningitis, since in a state of hypoglycaemia (low glucose in blood) seizure might occur and it can be the cause of convulsion in children apart from the presence of uncontrolled fever [21].

? Blood Cultures: Cultures are also important in the diagnosis of the disease especially in those patients having contraindications towards lumbar puncture [21].

? Normally all the above usually changes in a declining pattern after the introduction of antibiotics , but some authors propose Latex agglutination , as a reliable test to detect bacterial capsular antigens in patients with suspected bacterial meningitis and have been receiving antibiotics all the time lumbar puncture was performed and it is also estimated that in the future a more sensitive technique like 16rRNA gene by polymerase chain reaction might help in the diagnosis of bacterial meningitis in patients already on antibiotics[23].

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II.5.3.1) IMAGING TECHNIQUES

? COMPUTED TOPOGRAPHIC SCAN (CT SCAN): This should normally be done before lumbar puncture in order to rule out any presence of raised intracranial pressure in order to avoid brain herniation during a lumbar puncture performance. Now it should be noted that, CT SCAN is not sensitive at 100%, because a normal SCAN does not absolutely exclude subsequent risk of herniation[21].

? MAGNETIC RESONANCE IMAGING (MRI): It is also useful in the diagnosis meningitis and is more sensitive than the SCAN with the fact that, it is able to show extensive inflammatory tissue destruction of the meninges in their different spaces, also detects pus and thus can be used when the others are not available or feasible[45].

II.6) CURRENT TREATMENT ON BACTERIAL MENINGITIS IN CHILDREN

The three major aspects of treatment of bacterial meningitis include (1) antibiotic therapy (2) fluid restriction (3) adjunctive therapy [21].

II.6.1) ANTIBIOTIC TREATMENT

Most treatment guidelines recommend the use of a third-generation cephalosporin (such as ceftriaxone or cefotaxime) in conjunction with vancomycin as initial antibiotic therapy. Cefotaxime and ceftriaxone have excellent activity against all Hib and N. meningitidis strains [46].

Increasing resistance of S. pneumoniae to penicillins has been reported, and although cefotaxime and ceftriaxone remain active against many penicillin-resistant pneumococcal strains, treatment failure has been reported, hence the addition of empirical vancomycin [46].

In resource limited settings the treatment of paediatric BM generally has two protocols based on age (under 2 months and above 2 months of age).Accordingly, for neonates and young infants (under 2 months of age) the first-line antibiotics are Ampicillin and Gentamicin and alternatives, a third-generation cephalosporin, such as Ceftriaxone or Cefotaxime plus Gentamycin.For infants and children (above 2 months of age) the first line is the combination of Penicillin G and Chloramphenicol and the alternative is Ceftriaxone, or Cefotaxime [2].

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II.6.2) ADJUVANT THERAPY AND SUPPORTIVE THERAPY

Recommended dexamethasone dosing regimens range from 0.6 to 0.8 mg/kg daily in two or three divided doses for 2 days to 1 mg/kg in four divided doses for 2 to 4 days [47][48].

For optimal results, the first dose of dexamethasone could be administered before, but due to its side effects in children like duodenal perforation, it is better to administered it,concomitant with the first parenteral antibiotic dose, since in either way the efficacy of the corticosteroid still remains the same.

Control and prevention of seizures can be attained with anticonvulsant medications; benzodiazepines, phenytoin, and phenobarbital are commonly used for this purpose [21].

II.6.3) FLUID RESTRICTION

In general, it is a common practice to restrict fluids to two thirds or three quarters of the daily maintenance during the management of childhood meningitis. The basis for this practice is the need to reduce the likelihood of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH is characterized by hyponatraemia, fluid retention and a tendency to worsen cerebral oedema in meningitis. Therefore, practitioners reduce fluid therapy in children with meningitis in the hope of preventing SIADH [21].

II.7 PREVENTION OF BACTERIAL MENINGITIS IN CHILDREN II.7.1) VACCINATION

Vaccination is the immunisation of someone against an infectious disease through the administration of a vaccine. These vaccins act by stimulating the immune system, thereby protecting from infection and / or disease (WHO)[49]. Bacterial meningitis even though still an aggressive infection, is preventable with the use of vaccines against its different etiologies introduced and served mostly in children with less than 2 years of age. This is because these children are more susceptible to infection with encapsulated bacteria because of their immature immune system to respond against the bacterium polysaccharide antigens[50].

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Approximately 3/4 of deaths due to meningitis are prevented with Hib and pneumococcal conjugate vaccines,which reduce nasopharyngeal carriage of these organisms in the host and induce immunity[51].

Pneumococcal vaccins are available in two forms [52]:

Pneumococcal conjugate vaccine which is served in children with less than 2 years of age and protects them against severe forms of pneumococcal disease like; pneumoniae, meningitis and bacteremia.Two conjugates are used PCV 13 with 13 serotypes and PCV 10 with 10 serotypes which are relatively well tolerated. WHO recommends three primary doses starting as early as 6 weeks of age or as an alternative, two primary doses could be given at the age of 6 months plus a booster dose at 9- 15 months of age[53].

Pneumococcal polysaccharide vaccine which is served in adults of greater than or equal to 65 years of age[53].

The different meningococcal polysaccharide vaccines include:

Bivalent(A and C)

Trivalent (A,C and W135)

Tetravalent (A,C,Y and W135)[54]

The Group A and C vaccines have a short term immunisation effects in older children and adults and it should be noted that group C only does not prevent disease in children with less than 2 years of age. Meanwhile polysaccharide Y and W135 are efficient in children greater than 2 years of age.Tetravalent vaccines are administered in single dose and in children as from 1 year.These vaccines have as role to induce T cell 6 dependent immune response and to reduce the nasopharyngeal carriage of meningococci[54].

The anti-Hib vaccine is mixed with a set of four other vaccines (Pentavalent vaccine) which are vaccines against; diphtheria, hepatitis B, tetanus and pertussis.Normally three doses are to be administered for a good immunity, and the first dose is served as from 6 weeks. It can be administered to 18 months maximum with atleast four weeks spacing in between the doses[55].

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II.7.2) CHEMOPROPHYLAXIS

Close contacts of all children with meningococcal meningitis should receive chemoprophylaxis (ceftriaxone, rifampin, or ciprofloxacin), and contacts of those with Hib should receive ceftriaxone or rifampin[21].

Rifampin is administered 10 mg /Kg of body weight every 12 hours for children greater than or equal to 1 month of age, and 5 mg /Kg every 12 hours for infants less than 1 month of age. Rifampin is effective in the eradication of nasopharyngeal carriage of Neisseria meningitidis. In addition to rifampin, other antimicrobials are effective in the reduction of nasopharyngeal carriage of meningococcal pathogens, like ciprofloxacin but generally not recommended for persons less than 18 years of age because of its destructive effect on cartilage. Whereas ceftriaxone administered in a single dose of 125 mg in children is also effective [55].

Unvaccinated children less than 5 years of age should also be vaccinated against H. influenzae as soon as possible. Patients should be kept in respiratory isolation for at least the first 24 hours after commencing antibiotic therapy [21].

II.7) COMPLICATIONS OF BACTERIAL MENINGITIS IN CHILDREN

Meningococcal disease remains a major cause of morbidity and mortality in childhood. Neurological disorders in children are common occurrences in clinical practice. The disorder accounts for more than 170.000 deaths worldwide each year with majority of people affected living in Africa [56][ 57].

Young children are particularly vulnerable to bacterial meningitis, and when exposed poor outcomes may occur due to the immaturity of their immune systems [57]. Two thirds of meningitis deaths in low income countries occur among children less than 15 years of age. These complications could be classified as [57]; short term, middle term and long term.

SHORT TERM

- Brain edema is an early life threatening complication, in which brain structure changes is not usually found in 80%, but the residual stage of bacterial meningitis is characterised by cerebral destructive /proliferative or atrophic changes of different severity [58].

-

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MID TERM

- Seizure could be placed in this term. Most children present with recurrent seizure disorder.Seizures that occur early in the course of bacterial meningitis are easily controlled and are rarely associated with permanent or long term neurologic complications. In contrast, seizures that are prolonged, difficult to control, or begin more than 72 hours after hospitalization are more likely to be associated with neurologic sequelae, suggesting that a cerebrovascular complication may have occurred [57].

- Paresis: It is usually present but resolve with time, which typically resolves from and intracranial abnormality suh as; cortical vein, sagittal vein thrombosis, central artery spasm, subdural effusion or empyema and cerebral infarct [57].

LONG TERM

The incidence , type and severity of sequelae is influenced by infecting organisms, age of child and severity of acute illness , but it can be difficult to predict with children.The potential impact of the illness is further complicated by the fact that some of these sequelae may not become apparent until months or years after the acute illness.These long term complications include ;Visual loss ,Cognitive delay, Speech/language disorders[,Behavioral problems,motor delay/impairment and attention deficit hyperactivity[57].

- Hearing loss: It might be transient or permanent. Transient hearing loss may be secondary to a conductive disturbance affecting many patients. Permanent damage results from damage to the eighth cranial nerves, bacterial invasion, cochlea or labyrinth induced by direct bacterial invasion and /or inflammatory response elicited by the infection [57].

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II.8) PUBLICATIONS ON MENINGITIS OUT OF AFRICA

· Almuneef et al in 1998 analysed bacterial etiologies and outcome of childhood meningitis in Saudi Arabia and in his study there was a predominance of female sex, also the most affected age being from 3 months of age to 5 years. The presenting complaints in his study appearing in order of decreasing frequency were; fever 86 %, vomiting 29 %, poor feeding 19 %, seizure 14 % and lethargy 14 %[59]

· Franco -Paredes et al reviewed acute bacterial meningitis cases in 2008, in Mexican patients aged from 1 month of age to 18 years, recorded the most affected group by bacterial meningitis to be between 1-6 months, with Hib being the common pathogen found in 50% of cases. Incidence proven to have declined significantly after the introduction of appropriate vaccins [60].

· Nicole Le Saux in 2014 reviewed the current epidemiology of bacterial meningitis in children beyond the neonatal period in Canada, and came to the conclusion that the incidence of bacterial meningitis in infants and children has decrease since the routine use of conjugated vaccines targeting Hib, Streptococcus pneumoniae, and Neisseria meningitidis [61]

· Polkowska et al presented in Finland Streptococcus pneumoniae and Neisseria meningitidis to be the most common pathogens with an incidence drop from 1.88 to 0.70 in 2014[62].

· Incidence of bacterial meningitis dropped in Japan from the records of Shingoh in 2015 of 1.19 in 2009-2010 to 0.37 in 2013 -2015, confirming the efficacy of the Hib and PCV introduction [63].

IN AFRICA

· In Niamey, in Niger in 1999, using a retrospective surveillance on cases of laboratory diagnosed bacterial meningitis from 1981-1996 showed that the majority of cases were caused by Neisseria meningitidisat 57 %, and there was a predominance of meningitis in males occurring the dry season[64]

· Koko in Libreville, Gabon had predominance in the female sex among the admissions of children with bacterial meningitis in 2000, he also noted the highest mortality in children with less than 1 year of age[65]

·

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Mullan et al in 2011, evaluating records of cerebrospinal fluid samples between 2000 to 2008 at Princess Marina hospital in Gabonone, Botswana, reported Streptococcuspneumoniae(n=125) and Haemophilusinfluenzae(n=60) to be the most common bacteria cultured, present in less than or equal to 12 years old and less than 5 years respectively. The author also reported the climatic tendency of the pathogens, where Haemophilus influenza was mostly common between April and September, while Streptococcus pneumoniae most common between May and October[66]

· In Nigeria , Frank - Briggs in a study followed patients post meningitis to assess outcome post admissions in 2013 , and had 94 cases with neurological sequelae, notably recurrent seizures being the most common complication[57].

· Touré et al recorded a total number of 31 cases out of 833 CSF specimens analysed and had Streptococcus pneumoniae, followed by Neisseria meningitidis being the most common pathogens [8].

IN CAMEROON

· Sile et al in a study done in Garoua Provincial Hospital in the North region of Cameroon in 1999, reported bacterial meningitis to be responsible for 5 % of consultations and 9 % of hospitalisation. Children less than 5 years affected at 41 % [67].

· Fonkoua et al conducted a study in 2001 at Centre Louis Pasteur in Yaoundé, demonstrated that the main etiological agents detected in samples of cerebrospinal fluid sent to this laboratory, were Streptococcus pneumoniae at 56%, followed by Haemophilus influenzae 18%, also noting that, the 4 strains of Neisseria meningitidis of serotypes W135 were found isolated[68]

· Gervaix et al reported in 2012 in a study that only 62 % of theStreptococcuspneumoniaetype in Cameroon are covered by vaccins, bringing out the question on the certainty of the vaccination against bacterial meningitis and its impact in this country[69]

· Nguefack et al demonstrated in 2014 in a retrospective study conducted at YGOPH that the incidence of bacterial meningitis was high in Cameroon with Haemophilus influenzae being the most common pathogen responsible of bacterial meningitis in children with 39.2%, followed by Streptococcus pneumoniae with 31.6% and

28

Neisseria meningitidis least with 10.5%.There was a high mortality observed with poor prognostic factors as ; age, attitude in treatment , pathogen incriminated (for this particular study pneumococcal meningitis) and emphasis was done on the strengthening of routine immunization on vaccines preventable diseases of infants and children[3]

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CHAPTER THREE

MATERIALS AND METHODS

III.1) STUDY DESIGN

This was a retrospective- descriptive cross sectional study. III.2) DURATION OF THE STUDY

The study went on from the 1^st December 2018 till the 31^st May 2019, a period of 6 months.

III.3) STUDY SETTING

This study was carried out at the Yaoundé Gyneco-Obstetric and Pediatric hospital (YGOPH) at the pediatric unit. This unit is composed of 3 sub units which are; Hospitalisation 1 and 2 of infants and young children; External consultation with vaccination; and Neonatalogy.Hospitalisation 1 has 6 rooms and hospitalisation 2 has 7 rooms with one isolation room for contagious diseases. The unit is also made up of instruments such as oxygen extractors (4), aspirators (2) and resuscitators (2).

The service has an administration made of (1) head of service and (2) deputy head of services ; medical doctors (12) that is paediatricians (9) and general practitioners (3); State nurses (20) ; assistant nurses , and cleaners.

III.4) SAMPLING

There was recruitment of files from a period of 1^st of January 2014 to the 31^st of December 2018 of children admitted at YGOPH who fulfilled the inclusion criteria.

III.5) STUDY POPULATION

Children from 1 month of age to 15 years admitted at the paediatric unit of YGOPH within the study period.

III.5.1) INCLUSION CRITERIA

- Patients from 1 month of age to 15 years admitted for bacterial meningitis at YGOPH

- Patients who had bacterial examination of CSF with identification of the pathogen by culture or soluble antigen

- Patients who had their WBC above 10 cells/mm3.

30

III.5.2) EXCLUSION CRITERIA

- Patients in whom bacterial meningitis has not been confirmed through examination of csf by culture or soluble antigen

- Any file with incomplete information III.6) SAMPLE SIZE

N=

d²

The sample size will be calculated using the Cochran's formula: (??1-??:??)^??P(1-P)

Where:

- Z1 - á: 2= is the standard normal variate at 5% type I error (p<0,005),

- P= expected proportion in the population based on previous studies or pilot studies, for this study, the proportion from NGUEFACK of 1.54%, 2014 was used [3].

-d= Absolute error or precision.

For our study the numerical application of the above formula was used:

Z1 - á: 2=1.96; P=0.0514%; d=5%. Then N=1.96*1.96*0.0154(1-

0.0154)/0.05*0.05=23.29

After plugging in all the information in the equation, we get a minimum of 23files to collect and use.

III.7) MATERIALS

? Materials of data collection and analysis

o Registered files from the paediatric unit

o A laptop

o Microsoft^® Office Excel 2016 and CS PRO 7.2 software for data analysis and Microsoft^® Office Word 2016 to keyboard the thesis.

o A 8 GB flash disk

o A 4 GB flash disk

o

31

Office equipment

o Questionnaire for data collection

o Ballpoint ink-pens, pencils, correction fluid and eraser. ? Human resources:

o The investigator

o Supervisor and co supervisors

o Collaborators (service of archives, paramedical and medical personnel)

III.8) METHODS

III.8.1) ADMINISTRATIVE AUTHORIZATIONS AND ETHICAL CLEARANCE

Ethical clearance was obtained from the Ethical Committee of the Faculty of Health Sciences of the University of Bamenda. Authorization to carry-out the study at the YGOPH was obtained from the Director General of YGOPH.

The recruited information's from the questionnaires was held secret by the investigator in order to maintain data confidentiality taken throughout the study, and was definitely destroyed through burning after the data was analyzed and results confirmed.

III.8.2) PATIENT RECRUITMENT

After the approval of the research protocol and the research authorizations from the different authorities, the personnel in charge of archives in the pediatric unit were approached. An exhaustive census of all the children admitted at the pediatric unit with bacterial meningitis within the study period was done with their admission dates. Then, with information obtained from the files selection was done according to inclusion criteria. The children not corresponding to the inclusion criteria were excluded from the study. The next step was that information from the different files or medical books was filled into the pre-prepared questionnaires and was kept strictly confidential.

32

The following information was sought:

- Age

- Gender

- Weight of the child

- Origin (Geographical)

- Class level in school

- Rank among the siblings

- Past history (Immunization calendar, p24 status, underlying disease, any

contact with someone with meningitis)

- Information on the mother /guardian (age, profession, level of education,

matrimonial status)

- Manifestation of the disease in the child (convulsions, fever, kerning,

Brudzinski's, nuchal rigidity, lethargy) and physical examination

- Laboratory findings on CSF (Isolation of bacterium either by culture ,

soluble antigens and /or Gram stain)

- Treatment (antibiotherapy proposed)

- Evolution throughout the admission (cured, death)

- Any preventive measure proposed (either on the education on vaccination

programme which is to be respected as directed or education on chemoprophylaxis with the rest of the individuals at high risk in the entourage).

The studied variables included:

? Dependent variables: childhood bacterial meningitis

? Independent variables:

- socio- demographic,

- intervening factors such as immune status

33

III.8.3) DATA MANAGEMENT

The data were collected and recorded on the pre-prepared questionnaire, where the data in a form designed and coded for study. Pass word were employed on the PC in order to ensure security and confidentiality of data.The data were analysed using Microsoft Excel 2016 and CS PRO 7.2 software. The data were analysed following the analyses plan set by the investigator; and the results were recorded then discussed accordingly. Evolution was grouped into three categories: Cured and death.

III.8.3.1) ETHICAL CONSIDERATIONS

The data collected during the study process was kept and treated confidential, and the prepared questionnaires used to collect the data were destroyed after the analyses finished. The study was not used for any personal profit, but for benefits to the general population and also to health care givers which will use the information for the amelioration of care in our various health centers and hospitals.

III.9 MANAGERIAL ASPECTS III.9.1) HUMAN RESOURCES

o Supervisor: 01

o Co-supervisors: 02

o Principal Investigator: MAURANE EMMA NDJOCK MBEA

o Collaborators (medical and paramedical personnel)

o A statistician

34

CHAPITRE FOUR
RESULTS

IV.1) INCIDENCE

A total number of 14868 were admitted in the general pediatric unit of the YGOPH within the studied period, among which 43 cases of bacterial meningitis were admitted with biological evidence of either leucocytes count >10 cells /mm3 or positive bacteria culture or soluble antigen, (from which bacteria were isolated in 16 cases) giving an incidence of 0.3%.

IV.2) SOCIODEMOGRAPHIC CHARACTERISTICS OF PATIENTS

Age groups

14(32.6%)

16

14

12

10

4

8

6

0

2

13(30.2%)

8(18.6%)

2(4.7%)

6(14.0%)

[1-3mths[ [3mths-1yr [ [1yr-3yrs [ [3yrs-5yrs] >5yrs

Figure 6 : Distribution of patients according to age groups

The age range of 3months - 1year had the highest percentage of 32.6 %, out of the total number of patients admitted for bacterial meningitis. The mean age of patients admitted was 22.4 months (ranging from 1 - 60 months).

35

Table I: Distribution of patients according to gender

Sex Number Percentage(%)

Male 19 44.2

Female 24 55.8

Total 43 100

The female sex is noted to have the highest admission with 24 patients among the 43 cases with a sex ratio of 0.8.

IV.2.3) Type of admissions

Type of admission

26(60.5%)

30

25

20

15

10

5

0

17(39.5%)

YGOPH Referral

Figure 7: Distribution of patients according to the type of admission.

Most of the patients (60.5 %) consulted directly and 39. 5 % were referred.

36

V.2.4) Distribution of patients according to year of admission

0.5 0.45 0.4 0.35 0.3 incidence per year 0.25 0.2 0.15 0.1 0.05 0 Year

0.46

0.37

0.3

0.26

0.07
2014	2015	2016	2017	2018
0.37	0.46	0.07	0.3	0.26

Figure 8: Flow chart illustrating the incidence per year at YGOPH.

From the year 2014 there was an increase in incidence of 0.37 %, with a total number of 8 cases confirmed with meningitis, to 2015 with an incidence of 0.46 % with a total number of 12 confirmed cases. Then came a sudden drop of incidence in 2016 with 0.07% with a number of 2 cases, then increased as from 2017 with 0.3% with a number of 11 cases and slightly dropped in 2018 with 0.26 % with 10 confirmed cases.

37

IV.3) CLINICAL PRESENTATION OF BACTERIAL MENINGITIS Table 2: Distribution of clinical presentation according to symptoms.

Symptoms Number Percentage(%)

Neurologic

- Convulsion 26 60.5

- Cevical pain 2 4.7

Digestive

Respiratory

Behavioural

Thermal

Total 41 95.3

otl

Total 23 53.6

Total 8 18.6

Total 31 72.2

Total 10 23.3

- Loss of

consciousness

- Headache

- Diarrhea 10 23.3

- Feeding problems - Vomiting

- Irritability 10 23.3

- Respiratory distress 8 18.6

- Fever 41 95.3

2

7

6

1

4.7

2.3

16.3

14.0

Most patients presented with fever (95.3) % and convulsion (60.5) % at admission.

38

Table 3: Distribution of neurological clinical presentation according to signs

Clinical signs Number Percentage(%)

Neck stiffness 9 20.9

Meningeal signs 7 16.3

Bulging fontanella 4 9.3

*Among patients with meningeal signs 7 had both Kernig and Brudzinski sign.

The clinical sign most found was neck stiffness with 20.9 % of the total patients admitted, followed by meningeal signs at 16.3 % where both Kernig and Brudzinski's signs were present in all patients who presented with meningeal signs that is 100 %.

39

IV.4) PARACLINICAL INVESTIGATION

Table 4: Biochemical and cytological aspect of csf analysis of patients at admission
	Mean#177;SD	Min - max
WBC/????^??	1181.2#177;6379.0	11 - 42000
Protein g/dL	1.30#177;1.15	0.1 - 5.1
Glucose g/L	0.49#177;0.21	0.16 - 1.10
RBC	1665.8#177;6646.5	1 - 36000

The means of the WBC were 1181.2#177;6379.0 cells/mm3 with the minimum being 11 cells /mm3and the maximum 42000 cells /mm3. Proteins had a mean of 1.30 #177; 1.15g/L with the minimum at 0.1 and maximum at 5.1 g/L.Glucose was 0.49#177;0.21 g/L with the minimum at 0.16 to 1.10 g/L.RBC had a mean 1665.8#177; 6646.5 cells/mm3 with the minimum at 1 and maximum at 36000 cells/mm3.

40

Table 5: Biochemical and cytologic aspect of csf analysis of patients at admission

Variable	Number	Percentage (%)
White blood cells /mm3
- [100-1000[	22	51.2
- [10-100[	19	44.2
- [1000-10000[	1	2.3
- =10000	1	2.3
-
Proteins (g/L) N=22
- <0.40	6	14.0
- 0.40 - 0.79	2	4.7
- 0.80 - 0.99	1	2.3
- =1	13	30.2
Glucose (g /L) N=22
- <0.4	9	20.9
- 0.4-0.6	8	18.6
	5	11.6
- >0.6

*N=number of patients who had CSF analysis done for both biochemistry and cytology.

The biochemical and cytologic aspects of the CSF analysis showed in this study that most of the patients that were confirmed with meningitis had the WBC from 101000 cells /mm3 at 95.4 %.

Then 22 patients had their CSF biochemistry done and, among them 13 had proteins =1 g/L at 30.2 % and 9 patients had glucose <0.4 g/L with a high percentage of 20.9 %.

41

IV.5) ETIOLOGIES OF BACTERIAL MENINGITIS

N. meningitidis

4 (25%)

Group B Strep

1 (6%)

Salmonella

1 (6%)

S. pneumoniae

10 (63%)

*Culture = 6 patients

* Soluble antigen = 7 patients * Gram stain = 10 patients

*It is seen that the means of identification of bacterium indicates more than 16 patients but it is due to the fact that a bacterium was identified by both Gram stain and soluble antigen.

Streptococcus pneumoniae was the most predominant bacterium isolated with 56 %, followed by Neisseria meningitidis at 33 %. Other bacteria found were Salmonella and Group-B streptococcus each at a lower percentage of 6 %.

42

Table 6: Distribution of pathogens according to age

GERM	[1 - 3[ month s N (%)	[3 - 12[ months N (%)	[12 -36[ months N (%)	[36-60[ months N (%)	=60 months N(%)	Total
	2	5	2	0	1	10
S.pneumoniae	(15.4)	(35.7)	(25.0)	(0.0)	(16.7)	(23.3)
	0	1	0	0	0	1
	(0.0)	(7.1)	(0.0)	(0.0)	(0.0)	(2.3)
GBS
N.meningitidi	1	1	0	1	1	4
s	(7.7)	7(.1)	(0.0)	(50.0)	(16.7)	(9.3)
Salmonella	0	1	0	0	0	1
	(0.0)	(7.1)	(0.0)	(0.0)	(0.0)	(2.3)
No culture nor soluble antigen done	1 (7.7)	2 (14.3)	3 (37.5)	0 (0.0)	1 (16.7)	7 (16.3)
Sterile	9	4	3	1	3	20
	(69.2)	(28.6)	(37.5)	(50.0)	(50.0)	(46.5)
	13	14	8	2	6	43
TOTAL	(100.	(100.0	(100.0	(100.0	(100.0	(100.0
	0)	)	)	)	)	)

It is seen that among the 43 cases of bacterial meningitis, bacteria were isolated in 16 cases with a total percentage of 37.2% of patients who did either the culture or soluble antigen for the diagnosis of bacterial meningitis. From the 16 cases, we had Strep pneumoniae which was higher present at 23.3 % at age range 3months to 12 months more affected. Neisseriameningitidis follows with 9.3% and evenly distributed amongst the age group. It should also be noted that 46.5 % of the cases had sterile CSF.

43

IV.6) HOSPITAL OUTCOME

Table 7: Distribution of complications found during admission

Complication		Number	Percentage(%)
Respiratorydistress		9	20.9
Anemia		7	16.3
Brain abcess		6	14.0
Status epilepticus		5	11.6
Dehydration		5	11.6
Motor deficit		4	9.3
Intracranial hypertension		4	9.3
Hydrocephalus Others (strabismus, retardation)	psychomotor	4 2	9.3 4.7
Cerebral empyema		2	4.7

Most of the patients with bacterial meningitis developed respiratory distress in the course of admission with a percentage of 20.9 %, followed by anemia with a percentage of 16.3 %. Brainabscess also being an important complication in meningitis was present at 14.0%.

44

Table 8: Distribution of patients according to outcome during admission

Outcome Number Percentage(%)

Cured 41 97.6

Death 1 2.4

Total 42 100

Most patients admitted for meningitis 41 were cured at 95.3 % and among those, 25 had complications at 61.0 %.

We recorded 1 death, and 1 patient went against medical advice.

45

Table 9: Distribution of patients according to sequelae at time of discharge

Sequelae Number Percentage(%)

Hydrocephalus 4 9.3

Tetraparesis 2 4.3

Hemiparesis 1 2.3

Facial paralysis 1 2.3

Psychomotorregression 1 2.3

Hydrocephalus was the most frequent sequelae at time of discharged at 9.3 % of all the complications found.

46

Table 10: Distribution of patients according to treatment recieved for sequalae

Sequelae	N(%)	Treatment	N
Hydrocephalus	4(9.3)	Neurosurgery	2
Tetraparesis	2(4.3)	Physiotherapy	1
Hemiparesis	1(2.3)	-
Facial paralysis	1(2.3)	-
Psychomotorregression	1(2.3)	Physiotherapy	1

Among the patients withsequelae, 2 undergone surgery and 2 undergone physiotherapy.

47

CHAPITRE FIVE
DISCUSSION

Our main objective was to identify the common pathogens that cause bacterial meningitis in children at the Pediatric unit in YGOPH and to describe their hospital outcome. At the end of our study, we were able to identify these pathogens causing bacterial meningitis in children and described the hospital outcome.

V.1) INCIDENCE

A total number of 43 patients were admitted at the general pediatric unit for bacterial meningitis with biological confirmation from the 1st of January 2014 till the 31st of December 2018 giving an incidence of 0.3 %. This incidence is similar to that of Shingoh et al in Japan that had an incidence of 0.37 %[63] .Our incidence for bacterial meningitis is far lower than what Nguefack et al had in 2014 in YGOPH where bacterial meningitis was 1.54 % of the total admissions in the general pediatric unit[3].This large difference could be explained first by the problem of lost files from the archives .Secondly , the difference could be explained by the vaccination programme in Cameroon which was introduced since 1976, became operational in all the regions in 1982 and covers children from 0-11 months of age against infectious diseases[73] . In that same line, in a study done at YGOPH in 2016, there was vaccination completeness in children aged from 0-11 months at 96.3 % [73]. Koko et al in Libreville, Gabon also had a higher incidence of 1.2 % [65], thus our incidence tends to be much lower than most incidences of bacterial meningitis in Africa and even for those in developed countries; 0.70% in Finland in 2014[62].

V.2) SOCIODEMOGRAPHIC CHARACTERISTICS

The average age in our study was 22.4 months, with most patients admitted for bacterial meningitis being less than 12 months of age. These are similar to Nguefack et al who had more patients with 2 months - 1 year of age [3]. Similar results were observed with Mohammed in Al-Ramadi with more patients being less than 1 year of age, but our results are contradictory to those of Campagne who had instead less patients of bacterial meningitis with less than 1 year of age [33][ 64].Fayyaz also had less patients of less than 1 year of age [70].

48

The sex ratio was 0.79 in our study. There was a predominance of female sex admissions of 56 %.This result is similar to that of Almuneef et al in Saudi Arabia which had 36 females over 34 males[59].Contradictory result is gotten from Sile et al who had a sex ratio of 1.65 with a predominance in male sex in Garoua Provincial hospital[67] , also with Franck - Briggs who had male predominance of 58 in Nigeria[57].Otero et al had in Columbia a predominance in the male sex of 61.4 %[72] .Thus any predominance of either sex varies with each study.

There was more direct entry in YGOPH than referral in our study with 60.5 %. This result can be explained by the fact that YGOPH is a tertiary and a reference hospital which has the capacity to take care of emergencies.Therefore, patients will prefer to start consultations directly in such settings especially as they consider some symptoms as a sign of fatality.

V.3) CLINICAL PRESENTATION OF PATIENTS

The presentations in our study were divided into two; symptoms and signs. The most predominant symptom presented in children with bacterial meningitis was fever at 95.3%, and is similar to that of Nguefack et al who had fever as the main symptom at 98.8 % at YGOPH [3]. This result is similar to that of Almuneef et al who had fever as the main symptom at 86 % [59]. This result is also the same as the one from Heydari who had fever as the most common symptom at 94.44 % [48]. The high appearance of fever may be explained by the fact that most infectious diseases start manifesting with high temperature before any other symptom, and the knowledge on the fatality of fever on children prompts consultation with this earliest sign. Zewdie in Ethiopia instead had feeding intolerance at 76.6 % as the main symptom in neonates [5].Diarrhea was present in our study at 23.3 % as a digestive manifestation which is rare in meningitis, but in this setting the bacterium causing gastro enteritis is very common and could easily find its way into the central nervous system through hematogenous route.

The most present sign was neck stiffness with 20.9 % which is contrary to that of Heydari who had fever as the main sign at 94.44 % [48]. The result is also contradictory to that of Johnson who had drowsiness/coma at 50.0 % as the predominant clinical sign [10].

49

V.4) PARACLINICAL INVESTIGATIONS

The biochemical and hematologic analyses of cerebrospinal fluid in our study are suggestive of bacterial meningitis, with the WBC mean of 1181.2 which is similar to the results gotten from Heydari who had high WBC count [48]. This mean result of WBC could be explained by the fact that most of the patients received antibiotic treatments before the lumbar puncture was performed.

The proteins found in our study were high that is,=1 g/L predominantly at 30.2 % which is similar to Heydari that had >0.4g/L at 47.2% [48], confirming the presence of bacterial meningitis ,where it is known that proteins tend to increase.

The glucose of <0.4g/L was most present at 20.9 % in our study and is similar to that obtained with Heydari who had the same quantity at a higher percentage of 75%, proving the diagnosis of bacterial meningitis [48].

From our study Streptococcus pneumoniae was the pathogen mostly found at 63 %, followed by Neisseria meningitidis at 25.0%. These results are contradictory with that of Nguefack et al at YGOPH in 2014 that had Haemophilus influenzae as the predominant pathogen at 39.2 %, followed by Streptococcus pneumoniae at 31.6 % [3]. Nevertheless, our results are similar to that of Fonkoua et al who had Streptococcus pneumoniae at centre Pasteur in Yaoundé at 56 % [68]. There is also a similarity with that of Mullan et al in Botswana that found Streptococcus pneumoniae predominantly with n =125[66].Touré et al in Bouaké had the same results as ours with Streptococcus pneumoniae at 48.4 % as predominant followed by Neisseria meningitidis 16.1 %[8].Otero in Columbia also had Streptococcus pneumoniae as the predominant pathogen with a percentage of 11.4 %[72].These discrepancies in results are justified by the fact that each setting in which the study was done had a well-planned vaccination programme , which is probably implemented correctly especially for the Hib vaccine which is proven to be efficient.

The age group of 3 months to 12 months has the highest percentage of bacterial meningitis caused by Streptococcus pneumoniae at 35.7 %. This is different to that of Nguefack et al at YGOPH who had most patients from 2 months - 1 year affected with Haemophilus influenzae n= 43[3].Touré et al had S. pneumonia predominance in a higher age group that is 13 - 60 months in Bouaké[8].These results could be explained

50

by the fact that vaccination completeness in YGOPH was high for the vaccines at 97.1%[73]explaining the absence of Haemophilus influenzae in our study , with the introduction of the Haemophilus vaccine into the PEV in 2009 and the pneumococcal vaccin in 2010 , in Cameroon[73].

V.5) HOSPITAL OUTCOME OF BACTERIAL MENINGITIS IN CHILDREN

We recorded in our study 1 death representing 2.4 % of all the children admitted for bacterial meningitis. This is very low compared to that of Nguefack et al at YGOPH in 2014 with 17 deaths that is 53.1 % [3]. Koko in Gabon had much higher with 62 % [65]. However, our result had similarities with that of Wee LY et al in Singapore who recorded 6 % of death cases [71]. Chandran had a much lower percentage of 0.4% [6]. This low record of ours is probable due to the early death of patients that were suspected of having meningitis at entry, who died before any confirmatory examination notably lumbar puncture could be performed probably because they presented with contraindications.

We found that respiratory distress was the most common complication of bacterial meningitis during hospitalization at 20.9 % at the general pediatric unit at the YGOPH, followed by anemia with 16.3 %. We also noted dehydration and status epilepticus as complications of meningitis both at 11.6 %. It is different from what Franco-Paredes and Nguefack had both with seizure disorders and status epileticus as their main complication of bacterial meningitis at 37 % and 54.7 % respectively[3][60].This result can be explained by the fact that Streptococcus pneumoniae was the predominant pathogen found , thus it is obvious for these patients to have respiratory problems. The anemia can be justified by the fact that there must have been an associated disease like malaria which is known to cause anemia .Dehydration being present as a complication can be explained by the symptom of fever, where fluid tends to be lost through sweat.

Hydrocephalus was the most common sequelae in the study at 9.3 % which is contradictory to that of Nguefack et al who had psychomotor regression as the highest sequelae at 2.9 %3]. Sile had at the Garoua provincial hospital 1 case of paraplegia [67].

Among the 4 patients that had hydrocephalus from our study, 2 had neurosurgery as treatment. This is probably due to poor financial conditions that disabled the 2 others from benefiting from the treatment.Among patients who had psychomotor regression (1)

51

and tetra paresis (2), 2 had physiotherapy done for their rehabilitation, explained by probable poor financial conditions for the one that could not afford for the service.

? LIMITATIONS OF THE STUDY

We encountered various difficulties of which some are naturally found in every retrospective study that is: files with incomplete information, files that were not exploitable, and many files were lost from the archives because most of these files didn't return when they left this service for another unit in the hospital. There was a problem of uniformity among the health personnel too in taking clinical observations notably for the diagnosis.

Also considering the fact that there were a limited number of pathogens available, the antibiogramme sensitivity analysis could not be done.

CONCLUSION

At the end of this study, the different specific objectives have been attained. We can therefore come to the conclusion that:

> The incidence of bacterial meningitis in children at the YGOPH is 0.3%.

> The most common etiologies responsible for bacterial meningitis in YGOPH are Streptococcus pneumoniae at 63% and Neisseria meningitidis at 25 % and presented more in children <12 months of age .

> Most children presented at the consultation with fever as the predominant symptom at 95.3%, followed by convulsions at 60.5 %.On clinical examination, neck stiffness was the most common sign at 20.9%, followed by meningeal signs at 16.3%.

> The mortality was 2.4 %, and 97.6 % of patients left the hospital alive .Among the 97.6 % patients that left the hospital alive, 61.5% had neurological complications.

RECOMMENDATIONS

Our conclusions above enable us to do the following recommendations;

? TO THE MINISTRY OF PUBLIC HEALTH

- Re-enforce vaccination campaigns in children all over the country.

52

? YAOUNDE GYNECO-OBSTETRIC AND PEDIATRIC HOSPITAL

- Re-enforce information towards infectious diseases especially on meningitis.

- Re-enforce information, education and communication on vaccinations of children.

53

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60

APPENDIX A : AUTORISATION OF THE YGOPH

APPENDIX B : QUESTIONNAIRE

A. IDENTIFICATION OF THE CHILD

Questionnaire N° File N°

Date of admission Weight

Date of birth Age

Sex M F

School level: pre-school primary secondary High school

Origin
Type of admission:CME/FCB Referred

Reason for admission

B. PAST HISTORY OF THE CHILD

1) Immunization calendar up to date yes No

i) If No, which vaccines lacks?

2) P24 statusyes No

i)If yes on treatment

3) Underlying disease yes No

i) If yes what disease

ii) Undergoing treatment for the

disease

4) Any contact with someone with meningitis before admission? Yes No

C. INFORMATION ON THE PARENT / GUARDIAN i)MOTHER

Age (years):<20 (20-34) >34

Profession: Liberal Non-liberal Student or pupil Not employed

Level of education: primary secondary higher education illiterate

Matrimonial status: married single

Past medical history Region of

origin ..
ii)FATHER

Age (years):<20 (20-34) >34

Profession: Liberal Non-liberal Student or pupil Not employed

Level of education: primary secondary higher education illiterate

Matrimonial status: married single

Past medical history Region of

origin ..

D. MANIFESTATION OF THE DISEASE ON THE CHILD

Convulsion yes No

Fever yes No

Kerning sign yes No

Brudzinski'ssign yes No

Nuchal rigidity yes No

Lethargy yes No

Bulging fontanelle yes No
Feeding problems yes No

Behavioural changes yes No

Respiratory manifestations yes No

i) If Yes which one
Digestive manifestations yes No

Others

E. LABORATORY FINDINGS ON CSF

1) Macroscopic examination of the

CSF/Appearance ..

2) CSF Biochemistry characteristics

Proteins g/dl

Glucose mmol/L

3) Cytology aspect of the CSF

WBC count cells/ml

RBC count cells/ml

4) Gram stain, bacteria isolated yes No

i) If yes what findings

5) Any CSF culture done yes No

If yes which growth was obtained

6)Soluble Antigens yes No

i)If Yes

F. OUTCOME DURING ADMISSION

Any complications yes No

i) If any, which one(s)

ii) Treatment received for the

complications

ii) Mortality yes No

Comorbidities: yes No .If yes which one(s)

G. EVOLUTION

cured Died Discharged against medical advice

H. TREATMENT RECEIVED i) Antibiotherapy

cephalosporins .Others
ii)Adjuvant therapy

Steroids anticonvulsant antipyretics

Iii) Fluid

I. PREVENTIVE MEARSURE

Preventive measures proposed? Yes No
i) If yes, which one?

Education on vaccination chemoprophylaxis of child at risk