meningococcal infection
TRANSCRIPT
Clinical forms of CNS infections
• Acute bacterial meningitis• Acute viral meningitis• Encephalitis • Local infections:
• Brain abscess • Cerebellitis • Subdural empyema • Infectious thrombophlebitis of brain
vessels
Etiology of meningitis in different age groups
Age Causative agent
0 – 3 months Listeria monocytogenes,Group B streptococci, E. Coli and other Gram- bacteria
3 – 36 months Neisseria meningitidis,Haemophilus influenzae,Streptococcus pneumoniae,Listeria monocytogenes,Enterobacteriaceae, HSV-1, 2Group B streptococci
Older than 3 years
Neisseria meningitidis,Haemophilus influenzae,Streptococcus pneumoniae,Enteroviruses
Etiotropic therapy of meningitis depending on age Under 1 month
Listeria monocytogenes,Group B streptococci, E. Coli
Ampicillin + cefotaxim (or gentamycin)
1 – 3 months
Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae,Enterobacteriaceae, HSV,Group B streptococci
Ampicillin + cefotaxim
Older 3 months
Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae,Enteroviruses
Ceftriaxon (or cefotaxim)
Bacterial causes of meningitis and encephalitis
Aerobic bacteria
Neisseria meningitidis*Haemophilus influenzae*Streptococcus pneumoniae*Streptococcus gr. "B"Streptococcus viridansStaphylococcus aureusEnterococcusEscherichia coli
Salmonella spp., S.typhi, S.enteritidisKlebsiella pneumoniaeSerratia marcescensProteus spp.Pseudomonas aeruginosaCitrobacter diversusListeria monocytogenes
Bacterial causes of meningitis and encephalitis
Anaerobic bacteria
Bacteroides fragilisBacteroides spp.PeptostreptococcusFusobacterium meningosepticum, etc.
Clinical classification of meningitis and encephalitis
Morphology Purulent Serous
Character of appearance
Primary Secondary
Etiology Bacteria Viruses
Fungi Protozoa
Mixed
Course AcuteChronic
Fulminant
Recurrent
Predominating clinics
Basal Convexital
Total Spinal
Primary purulent meningitis
• Meningococcus
• Pneumococcus (Strep. Pneumonia)
• Haemophylus Influenza type B
Primary serous meningitis
• Acute lymphocytic choriomeningitis
• Enteroviral
• Poliomyelitis
• Parotitis
Secondary purulent meningitis
Bacterial
• Staphylococcus
• Streptococcus
• E. coli
• Salmonella
• Proteus
• Klebsiella
• Pseudomonas
• Anthrax
• Listeria
• Pasterilia
• Micoplasma
• Acinetobacter
Fungi
• Candida
• Aspergillus
Protozoa
• Ameba • Toxoplasma
Ways of infection penetration into CNS
Hematogenous (systemic septicemia)
Axonal (HSV-1, 2)
Contact
(mastoiditis, epitympanitis, sinusitis)
Along perineural spaces of craniocerebral nerves (otits, mastoiditis)
Pathogenesis of viral neuroinfections – neuronal transmission (HSV, VZV)
Penetration and replication of the virus in skin
Replication in ganglia of dorsal radixes
Centrifugal migration of the virus
Transmission into spinal cord
Skin manifestations
Hematologic spread of bacteria into CNS
Primary replication in GI, respiratory tract, muscles
Secondary replication in Endothelium of vessels
Persistence of bacteria
Chorioid plexus Vascular endothelium
CSF
Aseptic meningitis
Viral meningitisFungi meningitis Bacterial meningitis (caused by bacteria
which can not be seen on Gram staining) Toxic meningitis (drugs, toxins) Meningitis at systemic diseasesMeningitis at neoplastic diseasesParameningeal processes
EpidemiologySpread All over the world Dominating
serotypes
А, W-135, Y China, Nepal, India, Mongolia, Africa, Saudi Arabia
В, С USA, Canada, Europe, Australia
Source of the infection
Symptomatic patients and carriers (up to 2000 carriers per 1 symptomatic)
Way of transmission Respiratory
Morbidity 41,19 per 100 000 (Ukraine 1998y.)
Epidemic cycle 8-30 years
Epidemiology
• Serogroups A, B, C, W135, X, Y, and Z – by capsular polysaccharide antigen.
• Most strains causing meningococcal disease have the of groups A, B, or C.
EpidemiologyContagiousness 10-15% in non-vaccinated
Seasonal morbidity
January-March
Age distribution
<2 years – 50%
15-19 years – 15%
>30 years– 25%
Mortality (Ukraine 1998y.)
In total infectious pathology - 9,1%
From meningococcemia - 20,1%
From meningococcal meningitis - 5,2%
Higher risk of meningococcal
infection • Freshmen college students,
especially living in dormitories • Viral infections (facilitate invasion) • Smoking and smoke exposure• Crowded living conditions• Underlying chronic diseases• Low socioeconomic status
Every year about 250 000 children die from meningococcal infection in the world
70% of all cases are generalized ones45% of all home-acquired sepsis cases are
caused by N. meningitidis30-40% cases of primary meningitis in children
are due to N. meningitidisAbout 86% children with invasive forms of
meningococcal infection require immediate emergency care
25% of patients are misdiagnosed primary and 70% receive inadequate emergency care
Importance
Microbiology
1. Polysaccharide capsule → resist phagocytosis
2. Lipo-oligosaccharide endotoxin → fever, shock
3. Immunoglobulin A1 protease → cleavage of lysosomal membrane glycoprotein-1 → intracellular surviving
4. Fimbria → adhesion to epithelium
N.meningitidis – Gram negative incapsulated dyplococcus
N.meningitidis
• Gram-negative • Intra- and extracellular bacteria • not stable to outer influence • Serogroups А and В typically give
generalized infections • Serogroup A is responsible for
epidemics • Can autolyse – endotoxin is released
Different Forms of Meningococcal Infection
Mucosal colonization
Carriage
Local invasion
Bacteriemia Meningococcemia (occult)
Local infection
Meningitis, pneumonia, osteomyelitis, pericarditis,
Myocarditis, Iridocyclitis
Sepsis
Meningococcemia
Chronic meningococce
mia
N.meningitidis
Exanthem Fulminant
Meningococcemia
Combined forms
Nasopharyngitis, conjunctivitis, uretritis, pneumonia, epiglottitis
Development of meningococcemiaAbsence of antimeningococcal antibody
↓Bacteriemia
↓Interaction with phagocytes + adhesion to endothelial
cells ↓
Complement system activation + attachment of white blood cells to endothelium
↓Production of multiple proinflammatory cytokines (TNFa, IL-1ß, IL-6, and IL-8) + activation of both the
extrinsic and intrinsic pathways of coagulation↓
Development of meningococcemiaCapillary leak and disseminated intravascular
coagulopathy (DIC) ↓
Leukocyte-rich fibrin clots in small vessels↓
Focal hemorrhage and necrosis in any organ system
↓Heart, CNS, skin, mucous and serous membranes,
and adrenals are affected in most fatal cases↓
Multiple organ system failure, septic shock, and sometimes death
Development of meningococcemia
Fatal cases typically have higher concentrations of TNFa and ILs
TNFa and ILs levels decrease rapidly once antibiotics are given
_______________________________Fatality risk is higher in children
capable of strong immune response
Development of meningococcemia
Meningococcal survival is enhanced by:
• Polysaccharide capsule, which helps resist phagocytic killing
• Iron scavenging system that can use host transferrin and lactoferrin
Predisposition
• Complement component deficiencies → increased susceptibility to and recurrent cases of meningococcal infections
• Immunoglobulin G2 subclass deficiency → recurrent meningococcemia
• Hereditary properdin deficiency → predisposition to meningococcal disease
Natural immunity against N. meningitidis
• After repeated colonization with different serogroups or serotypes
• From gastrointestinal colonization with enteric bacteria that express cross-reactive antigens
• Infants also have high carriage rates of the unencapsulated, nonpathogenic neisserial strain, N. lactamica → immunity against meningococci
• Protective effects of maternal IgG during only the first 3 months of life
Classification of meningococcal infection
Form Localized GeneralizedRare forms
Course AcuteSubacuteFulminantRecurrent
Severity MildModerateSevere
Forms of meningococcal infection
Localized forms: Carriage Nasopharyngitis Generalized forms: Meningococcemia Meningitis MeningoencephalitisMeningococcemia
with meningitis
Rare forms:Endocarditis Arthritis Iridocyclitis Pneumonia Urethritis Otitis Conjunctivitis
Meningococcemia (meningococcal sepsis)
Accounts for 15-20% of all invasive cases of meningococcal infection.
Mortality is 20 - 40%.Superacute meningococcal sepsis
develops in 10-20% of cases.Mortality from Superacute
meningococcal sepsis is over 90%.
Clinical PresentationsMain :Hemorrhagic rash Fever, chills
Additional:Pale, mottled or cyanotic skin (capillary refill >2 sec.)
Irritation and crying or lethargy (till coma)Seizures Vomiting, nausea, diarrheaFeeding refusal Myalgias and Arthralgias Decreased urination
Meningococcal rash
Hemorrhagic rash with uneven borders and central necrosis, first appear on lower extremities and buttocks
Waterhouse-Friderichsen syndrome
• In fulminant cases, the disease progresses rapidly over hours to septic shock characterized by hypotension, DIC, acidosis, adrenal hemorrhage, renal failure, myocardial failure, and coma.
Criteria of severity
Damroshe Scale (1966)
1. Appearance of hemorrhagic rash within 12 hours from the beginning of the diseases
2. Presence of shock (systolic pressure <70 mm.Hg.)3. Absence of meningitis (CSF cytosis <20
cells/mm3)4. WBC count in peripheral blood <10х109/l5. ESR normal or low (<10 mm/h)
Every index has 1 point. 3 points: case fatality rate is 85,7%, ≥ 4 points: 100%
Criteria of severity
Niklasson Scale (1971)
1. Absence of meningitis (CSF cytosis <100 cells/mm3)
2. Hypotension (systolic pressure <70 mm.Hg.)3. Appearance of hemorrhagic rash within 12 hours
from the beginning of the diseases4. WBC count in peripheral blood <15х109/l5. Fever > 40°С6. Thrombocytopenia (<100 000 /mm3)
Every index has 1 point. ≥ 4 points: case fatality rate is 100%
Criteria of severity
Glasgow Meningococcal Septicemia Scale (1991)
8 points– fatality rate 73%, 10 points – 87,5%, 12 and more – 100%
Systolic pressure < 75 mm.Hg. (under 4 years), < 85 mm.Hg. (older 4 years)
3 points
Gradient of skin-rectal temperature >3°С 3 points
Glasgow Coma Scale < 8 points 3 points
. “Every hour” previous worsening of condition
2 points
Absence of Meningeal signs 2 points
Spread hemorrhagic rash with large elements
1 point
Base deficit (pH>8,0) 1 point
Differential diagnosis
Scarlet fever Measles Rubella Exanthema subitum Dengue Fever Gonococcal infectionInfluenza Mycoplasma infections Rocky Mountain Spotted Fever
Streptococcal Group A & B infections Thrombocytopenic Purpura Ebola Virus Enterovirus Infective Endocarditis Malaria Drug reactions Poisonings
Diseases with hemorrhagic rash
• Neisseria meningitidis • Haemophilus influenzae • Streptococcus pneumoniae• Neisseria gonorrhoeae
Diagnosis in children with fever and hemorrhagic rash (Baker R.C. et al, Pediatrics, 1989)
Bacterial sepsis 39 (12,2%)Neisseria meningitidis 26 (8,2%)Haemophilus influenzae type b 9 (2,8%)Streptococcus pneumoniae 2 (0,6%)Staphylococcus aureus 2 (0,6%)Other bacterial infections 68 (21.3%)Bowel infection caused by Escherichia coli 3 (0,9%)Streptococcal tonsillitis 23 (7,2%)M. pneumoniae pneumonia 1 (0,3%)Pneumonia of unknown etiology 11 (3.4%)Acute otitis media 30 (9,4%)Ricketsiosis 1 (0,3%)Viral infections 195 (61,1%)Enteroviral infection 9 (2,8%)Aseptic meningitis 16 (5%)Adenoviral infection 1 (0,3%)
Diagnosis in children with fever and hemorrhagic rash –cont.
RS-infection 12 (3,8%)Human methapneumovirus 11 (3,4%)Rotavirus 1 (0,3%)
HHV-6 (exanthema subitum) 1 (0,3%)Probable viral infection 144 (45,1%)Other causes 25 (7,9%)Hemorrhagic vasculitis 2 (0,6%)Kawasaki disease 1 (0,3%)Thrombocytopenic purpura 1 (0,3%)Vaccination reaction 3 (0.9%)Acute leukemia 2 (0,6%)Febrile seizures 5 (1,6%)Partially treated meningitis 2 (0,6%)Partially treated septicemia 2 (0,6%)Exudative tonsillitis 2 (0,6%)Reaction to ampicillin 1 (0,3%)Unknown 4 (1,3%)
Occult meningococcemia
• Fever with or without associated symptoms that suggest minor viral infections
• Resolution may occur without antibiotics, but some cases will develop meningitis
Chronic meningococcemiaRare form : Intermittent Bacteriemia illness that
lasts from at least one week to as long as several months
– Intermittent fever, with afebrile periods ranging from 2-10 days, during which the patient seems entirely healthy → febrile periods occur more frequently, fever may become continuous;
– Headache, arthritis can develop;– Eventually, skin hemorrhages or signs of
meningitis appears during a febrile episode;– Blood cultures may initially be sterile.
Meningitis
Inflammation of soft meningeals of viral,
bacterial or fungi etiology or as a complication or
presentation of systemic septicemia
Current epidemiology of meningitis
• Streptococcus pneumoniae –50 %
• Neisseria meningitidis - 25 % • Group B streptococci – 15 %• Listeria monocytogenes - 10 %• Haemophilus influenzae < 10 %
(vaccination !)
Meningococcal meningitis
• Meningococcal meningitis - 50-60% of all invasive cases of meningococcal infection
• Case fatality rate is 3 - 10%• About 30% of cases are
combined with meningococcemia
Clinical Signs - main Fever Headache Positive Meningeal signs : - Neck stiffness - Brudzinski sign - Kernig sign - Lessage’s sign - Fontanel bulging
- Position of the “kicking dog” - Lobzin’s sign - Guillain’s sign - Flatau’s sign
Clinical Signs – additional Irritability Somnolence Vomiting (repeated regurgitations) Groaning crying High-pitch cry at irritation Light fear Decreased feeding Decreased consciousness Delirium Convulsions Craniocerebral nerves involvement Pain in joints and muscles
Meningeal signs – cont.
Neck stiffness Inability to touch sternum with chin
Kernig Flexed in hip and knee joints leg can not be straightened in knee joint
Brudzinski (upper)
At head bending the legs are flexed in hip and knee joints
Brudzinski (lower)
At Straightening of the flexed in hip and knee joints leg, the second leg is flexed
Lessage’s At lifting up, the infant flexes legs and remains in this position
Meningeal signsPosition of the “kicking dog”
The patient is lying on the back with thrown back head and legs flexed to the bowel
Guillain’sCompression of leg’s quadriceps causes other leg’s flexion hip and knee joints
Lobzin’s Pain increase at pressure on the eyeballs
Flatau’s Pupils’ widening at head flexion
Amoss’
Leaning on hands behind when sitting, inability to touch knee with lips
Herman’s Passive head flexion to the sternum causes extension of toes
Levinson’s Mouth opening at head flexion to the sternum
Particularities of meningitis clinics
in infants • Irritability / somnolence • Mild fever • “Brain cry” – headache equivalent • Large fontanelle bulging • Lessage’s sign• Head retroflexion • Tonic and clonic seizures• Transient diarrhea
Meningitis diagnosis
• The only way to exclude/diagnose neuroinfection is to investigate CSF
• Pleocytosis proves a CNS
infection
Differential diagnosis
Encephalitis and meningitis caused by other viruses or bacteria
Acute bowel infections Pneumonia Septic shock RhinosinusitisAcute poisoning Encephalopathies
Differential diagnosis – cont.
Acute myositis Infectious delirium Retropharyngeal abscesses Shaken baby syndrome Subdural haematoma CSF hypertension syndrome Brain blood circulation damage Hypertensive crisis
Required tests at meningitis
• CSF• CBC • Signs of brain edema:
– Eye fundus examination (edema) – CT, MRI
• Blood electrolytes• Glucose of blood and SCF• CRP
CSFIndexes Healthy
Meningitis Encephalitis
Encephalo-pathy Purulent Serous
Pressure(mm Н2О)
<150 Increased Increased Increased Increased
Cytosis <5x106
/l>1000x106/l
10-1000x106/l
10-1000x106/l
<5x106/l
Lymphocytes
60-70% 20-30% 90-100% 90-100% 60-70%
Monocytes 30-50% 10-20% 0-10% 0-10% 30-50%
Neutrophils No >60% No No No
Glucose (mmol/l)
2,8-4,4 Decreased
Normal Normal Normal
Glucose gradient (%)
>60 <60 Normal Normal Normal
Protein (g/l) <0,45 Increased Increased Increased Normal
Etiologic diagnosis Test Material Comments
Gram’s stain
CSF, aspirate from skin rash or sinovial fluid or other sterile material
Rapid test CSF Sensitivity – 65%Skin rash sensitivity - 30-70%
Culture
CSF, blood, aspirate from skin rash or sinovial fluid or any other sterile material
“Golden” standard for diagnosis
Result in 1-2 days CSF Sensitivity – 95% (without antibiotics)
Blood culture Sensitivity – 50% (without antibiotics)
Nasopharyngeal secretion
Confirms carriage
Etiologic diagnosis – cont.
Test Material Comments
PCR CSF, blood
CSF: Sensitivity - 89%, Specificity– 100%
Blood: Sensitivity – 81%, Specificity -97%
Serology Blood
Specific IgM or Ab titer increase 4 times and more (low informativity and sensitivity)
Antigen test CSF
Low sensitivity, additional test to Gram’s staining
Complications
• Disseminated intravascular coagulation • Vasomotor collapse and shock • Seizures or deafness in the acute
stages of meningitis • Ependimatitis • Postmeningitic epilepsy (rare) • Coma • Thrombocytopenia • Septic arthritis
Complications – cont.
• Herpes labialis (5-20% of patients) • Immune complex arthritis of multiple
joints • Pericarditis • Bacterial endocarditis • Myocarditis • Gangrene • Urethritis and endometritis • Osteomyelitis • Purulent conjunctivitis and sinusitis
Complications by age
Age Early Late Any Septic
shockHyponatremiaSeizures Brain edema
Subdural empyema Hyponatremia Ventriculitis Cerebral hypotension Seizures
Under 3-6 months
HypoclycemiaApnoe
Uncommon manifestations of meningococcal disease
• Endocarditis• Purulent pericarditis• Pneumonia (in 15% + pleural effusion or
empyema)• Endophthalmitis• Mesenteric lymphadenitis• Osteomyelitis• Sinusitis• Otitis media• Periorbital cellulitis• Primary purulent conjunctivitis • Urethritis, cervicitis, vulvovaginitis, proctitis
Antibiotic therapy before hospitalization for
meningococcal, pneumococcal and hemophylus infections
(Writing Group for Therapeutic Guidelines: Antibiotic 11-th edition: Therapeutic Guidelines LTd. 2000. Melbourne)
Drug Age Dosage
Ceftriaxon
Under 10 years
Older 10 years and adults
Once, IV or IM 100mg/kg (not exceed 2 g)
Once, IV or IM, 1000mg
Treatment before hospitalization at the
presence of meningitis and gemorrhagic rash
1. Dexamethazone – 4 mg IM once 2. Ceftriaxon – 100mg/kg IM once – 15’
later3. Analgin 0.1ml/year at fever > 38 C4. IV normal saline (10-20ml/kg/hour)
Etiologic treatment
• Start antibiotic – ceftriaxon (100mg/kg/d) or cefotaxim (200 mg/kg/d)
• Reserve antibiotic – meropenem (120mg/kg/d)
Length of therapy – 10-14 days, till clinics disappearance and normal cytosis of CSF (50 cells are admissible if lymphocytes)
Etiologic treatment
Proved meningococcal infection: Penicillin G – starting dose • Meningococcemia – 300 000 U/kg/d• Meningitis - 500 000 U/kg/d
Maximal allowed dose - 1 000 000 U/kg/d
Pathogenic therapy for meningitis
Septic shock
•Bolus 0.9% NaCl, start with 20ml/kg, then –10 ml/kg every hour before hematocrit → 33 %;•Cardiotonic drugs (dopamin)
Brain edema
•Osmotic dehydratation: mannitol, manit •Hyperventilation
Seizures • Barbiturates, benzodiazepins• Hyponatremic seizures: 3 % NaCl –
10-12 ml/kg/h• Hypoglycemic seizures (under 3 mo):
5-10 % glucose
Deafness prophylaxis
•Dexametazone 0,15 mg/kg every 6 h – 2 days, first dose - 15 minutes before antibiotics
Chemoprophylaxis of contacts of meningococcal, pneumococcal and
hemophylus infections (2000 Red Book: Report of the Committee on Infection Diseases 25th
Edition)Drug / age Dosage Course
Rifampicin< 1 month> 1 month and adults
Per os:5 mg/kg bid 10 mg/ kg bid(max – 600 mg)
2 days2 days
Ceftriaxon < 12 years > 12 years
Intramuscular :125 mg250 mg
Once Once
Ciprofloxacin > 16 years(not recommended for pregnant and children under 16 years)
Per os:500 mg
Once
Specific prophylaxis
Total vaccination against meningococcal infection is not performed routinely in Ukraine.
Vaccination is indicated to patients older 18 months with: Functional or anatomical aspleniaComplement components insufficiency Properdin insufficiency Factor B insufficiency People from endemic areas
Specific prophylaxis
Vaccination is indicated to patients older 18 months with (cont.):
• Hemoglobinopathies• Nephrotic syndrome• CSF shunting • Cellular and humoral
immunodeficiencies• HIV infection • Chronic diseases of cardiovascular,
respiratory systems and liver
Specific prophylaxis
Characteristics of vaccine (Meningitis Vaccine Project, 2007)
Characteristics Tetravalent polysaccharide (MPSV4)
Tetravalent conjugated (MCV4)
Composition Pure polysaccharides A,C,Y,W-135
Pure polysaccharides A,C,Y,W-135, conjugated to Diphhteria toxoid
Immunogenic in children Low High
Bactericidal activity of Аb in children Low High
Immunologic memory induction No Yes
Nasopharyngeal carriage
Transitory and incomplete
Documented decrease