Clinical Presentations

Meningococcal Infection

Epidemiology

Spread	All over the world
Dominating serotypes
А, W-135, Y В, С	China, Nepal, India, Mongolia, Africa, Saudi Arabia 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
Contagiousness	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%
Carriage rate	5-10%
Carriage rate during epidemics in closed populations	100%

• 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.

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

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

• 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

•

Development of meningococcemia:

Absence 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

↓

Capillary 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

↓

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

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. meningitides:

• 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 Generalized Rare forms
Course	Acute Subacute Fulminant Recurrent
Severity	Mild Moderate Severe

Forms of meningococcal infection:

Localized forms: Carriage Nasopharyngitis Generalized forms: Meningococcemia Meningitis Meningoencephalitis Meningococcemia with meningitis

Rare forms: Endocarditis Arthritis Iridocyclitis Pneumonia Urethritis Otitis Conjunctivitis

Meningococcemia (meningococcal sepsis):

ü Accounts for 15-20% of all invasive cases of meningococcal infection.

ü Mortality is 20 - 40%.

ü Superacute meningococcal sepsis develops in 10-20% of cases.

ü Mortality from Superacute meningococcal sepsis is over 90%.

Clinical Presentations

Main:

ü Hemorrhagic rash ü Fever, chills

Additional:

ü Pale, mottled or cyanotic skin (capillary refill >2 sec.) ü Irritation and crying or lethargy (till coma) ü Seizures ü Vomiting, nausea, diarrhea ü Feeding refusal ü Myalgias and Arthralgias ü Decreased urination

Meningococcal rash (Loclization):

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/l
5. 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 diseases
4. WBC count in peripheral blood <15х10⁹/l
5. Fever > 40°С
6. Thrombocytopenia (<100 000 /mm³)

Every index has 1 point.

≥ 4 points: case fatality rate is 100%

Criteria of severity: (Glasgow Meningococcal Septicemia Scale (1991)

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

8 points– fatality rate 73%, 10 points – 87,5%, 12 and more – 100%

Differential diagnosis:

Scarlet fever Measles Rubella Exanthema subitum Dengue Fever Gonococcal infection Influenza 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%)
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 meningococcemia:

Rare 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.

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