MENINGOCOCCAL INFECTION

Main Statements

Per one patient with manifest form of meningococcal infection there are up to 2 thousand carriers of Neisseria meningitides

Generalized forms develop in 20% of patients with meningococcal infection Meningococcal nasopharyngitis is clinically undistinguished from bacterial pharyngitis

of other etiology Main distinctions of generalized forms of meningococcal infection from other bacterial

infections are severe general condition of the child, high fever, disturbances of peripheral blood flow and hemorrhagic rash

First rash elements at meningococcemia are usually situated on lower part of the body: legs, thighs, buttocks, lower part of abdomen

At infectious toxic shock (ITSh) respiratory therapy, correction of hypovolemia, hypoglycemia and acidosis are performed urgently.

Antibiotics of choice for generalized forms are ceftriaxone and chloramphenicol In Ukraine vaccination is done by epidemiological indications, as well as to travelers to

countries with high morbidity of meningococcal infection.

Meningococcal infection is an acute infectious disease caused by meningococci

and characterized by variety of clinical forms, from nasopharyngitis and healthy

carriage till generalized (meningococcemia, meningitis and meningoencephalitis).

Etiology. The causative agent is Neisseria meningitidis (meningococcus of

Wekselbaum). This is a Gram-negative diplococcus, non-motile, without flagella or

capsule, not spore forming, aerobic. It is cultivated at media with human or animal

protein. Neisseria meningitidis is surrounded by polysaccharide capsule and has 13

serogroups. The disease is mostly caused by serogroups А, В, С, W135 and Y.

Serogroups В and С dominate currently at European countries. At the same time

meningococcal infection (MI) morbidity in Asian and African countries is associated

with serogroups А and W135. The main pathogenic factor is endotoxin which is a

protein-lypopolysaccharide complex.

Meningococcus is unstable in outer world, it is rapidly inactivated outside human

body (under the action of direct sunlight, heating, disinfecting solutions, in 70%

alcohol). In nasopharyngeal mucus it can be preserved 1-2 hours. At temperature +500С

meningococcus is inactivated in 5 minutes, at low temperatures (-7 – -100С) in 2 hours.

Epidemiology. The sources of infection at MI are sick people and carriers of

meningococcus. The most dangerous are people with localized forms and carriers of the

infection.

Mechanism of transmission is airborne. The causative agent is excreted from upper

respiratory tract at coughing, sneezing, crying of the child. Transmission is promoted by

people accumulation, close contact, high air temperature and humidity, as well as low

sanitary and cultural level of population. Infection transmission is possible during direct

contact with meningococcemia patient. At this case the bacterial transmission can occur

during 24 hours from beginning of effective antibacterial therapy.

Susceptibility to MI is high. Index of contagiosity is 10-15%. Morbidity increase is

typical in winter-spring period. Maximal amount of cases is seen in February – March.

Period of increased morbidity continues 2 – 4 years. Inter-epidemical period is 5 – 12

years.

Immunity at MI is type-specific. Natural immunity is more often formed due to an

episode of meningococcal nasopharyngitis. First months of age child can have inborn

immunity received from mother.

Children with immunodeficiencies (especially with defects of complement system

(С5-С9), properdin deficiency, with hypogammaglobulinemia, with anatomical or

functional asplenia) have high risk of invasive or recurrent forms of MI.

Pathogenesis. The entrance route for meningococcus is nasopharyngeal mucosa.

In majority of cases there are no pathological changes on the place of meningococcus

invasion (it is characterized as “carriage”). In other cases local inflammatory changes

develop (meningococcal nasopharyngitis). In some patients meningococcus penetrates

local barriers and enters blood through lymphogenic way (transitory bacteremia or

meningococcemia). At meningococcemia (meningococcal sepsis) the causative agent is

carried with blood flow to different organs and tissues. Meningococcus can penetrate

blood-brain barrier and cause damage of meninges and brain with development of

clinical picture of purulent meningitis or meningoencephalitis.

Endotoxin plays an important part in pathogenesis of generalized forms of

meningococcal infection. It is released in large amount at meningococcus destruction.

Endotoxin action on vessel endothelium causes microcirculation disturbances,

thrombohemorrhagic hemocoagulation disturbances, which lead to generalized

intravascular blood coagulation with formation of bacterial clots in small arterioles and

development of coagulopathy of consumption. It leads to massive bleedings into skin

and inner organs (suprarenal glands, kidneys, brain tissue, myocardium, etc.). The

consequences of endotoxinemia, hemodynamic and metabolic changes can be acute

brain swelling and edema.

Besides prominent bacteremia and endotoxinemia, hypersensitization and

reactivity changes of the host participate in pathogenesis of development of hypertoxic

(fulminant) form of the disease. Development of infectious-toxic shock at this form of

meningococcal infection is determined by massive endotoxinemia due to massive and

rapid breakage of microbial cells. In this case abundant hemorrhagic rash on the skin

and massive bleedings into inner organs and hemorrhages develop at the first hours of

the disease. Course of infectious-toxic shock is accompanied by prominent

hemodynamic disturbances and acute adrenal insufficiency syndrome, metabolic

changes and polyorganic insufficiency.

Clinical manifestations. Incubational period is from 1-2 till 10 days.

Meningococcal nasopharyngitis is the most frequent clinical form (up to 80%).

The disease begins acutely with moderate fever, weakness and headache. Nasal

breathing is impeded, scanty nasal discharge and throat discomfort appear. At

examination spread mucosa hyperemia and posterior pharyngeal granulation are seen.

Purulent-mucosal track on posterior pharyngeal wall is often seen. Disease symptoms

disappear in 7-10 days.

Meningococcemia is seen in 4-10% of all clinical forms of MI. The disease is

characterized by prominent intoxication syndrome and skin involvement; there can be

involvement of other organs (joints, kidneys, suprarenal glands, heart). Main clinical

distinguishes of MI from other bacterial infections are more severe general condition of

the child with high fever, hemorrhagic skin rash and disturbances of peripheral blood

flow. The first disease symptoms are often non-specific and resemble acute respiratory

viral infection. Infants present with hyperthermia, irritability, vomiting, diarrhea,

anorexia. Phase of non-specific symptoms continues approximately 4 hours in children

under 4 years of age and 6-7 hours in adolescents. Afterwards prominent paleness

develop (in 17-21% of children), cold extremities (in 35-47% of children), chills longer

than 10 minutes, extremities pain (in 31-63% of children). During the following 1-2

hours sleepiness, flaccidness, increased respiration rate, difficult respiration develop.

The disease begins acutely with fever till 39-400С and higher. Headache, malaise,

anorexia are typical; vomiting is possible. The main symptom of meningococcemia is

hemorrhagic rash. At the disease onset roseolar or papule-roseolar rash of different

diameter is seen, which disappears at pressure and is distributed all over the body.

Within several hours, more seldom on the second day of the disease, hemorrhagic rash

elements appear with cherry red color and bluish tint, which do not disappear at

pressure and are different in diameter (from petechiae till ecchymoses). These elements

elevate over the skin, are hard to palpation and in typical cases are of irregular “star-

like” form. The first rash elements are usually situated on lower parts of the body: legs,

thighs, buttocks, lower part of abdomen. At severe cases of MI they can be distributed

all over the body.

More seldom macular papular rash is seen similar to that at viral infections.

Hemorrhagic rash develops in the mean, from the disease onset:

Within 8 hours in newborns,

Within 9 hours in 1-4 years old children,

Within 14 hours in 5-14 years old children,

Within 19 hours in 15-17 years old children.

Macular papule elements disappear without residuals 1-2 days later; hemorrhagic

pigmented rash disappears during a week. In the center of large hemorrhagic elements

necroses appear; after their detachment skin defects with unhealing by secondary

intention ulcers and further hard scars formation can be seen. In especially severe cases

dry gangrene of fingers and toes, auricles, nose, etc. develops. Rash appearance within

the first hours on face, neck, upper part of the trunk has unfavorable prognosis.

Hypertoxic (fulminant) form is accompanied by ITSh. It begins acutely with

sudden fever till 39.5 - 410С, chills. Prominent intoxication in already first 6-8 hours is

accompanied by abundant hemorrhagic rash all over the body and hypostases.

Condition severity is determined by ITSh.

Main cause of death at meningococcemia is adrenal bleeding and infectious toxic

shock with multiorganic insufficiency.

Meningococcal meningitis. The disease begins acutely with fever till 380-400С,

chills, severe headache. The patients become restless, headache is increased at sound

and light stimuli, at head turning; signs of hyperparesthesias are prominent. Repeated

vomiting develops, which is not connected to meals and do not bring relief. Meningeal

signs are positive (neck stiffness, Kernig and Brudzinski signs, in first year old children

also symptom of Lessage, “suspension”), large fontanel bulging and pulsation is seen.

Patient’s face is pale, sclera vessels are widened.

Cerebral spinal fluid changes are typical: by the end of the first day it becomes

cloudy, milk-white, is leaking under increased pressure. Neutrophilic cytosis and

increased protein contain are typical. At disease onset CSF can have signs of serous

inflammation.

Mixed form of meningococcal meningitis and meningococcemia is possible.

Rare forms of MI: arthritis, endocarditis, pneumonia, iridocyclitis. These forms of

the disease do not have specific clinical symptoms and are mostly diagnosed during

outbreaks.

Diagnosis. Clinical criteria of meningococcemia:

- sudden acute beginning with fever till 380-400С;

- prominent intoxication: general weakness, headache, muscle pain, skin paleness;

- majority of patients develop macular papule rash without specific localization

several hours after disease onset. Several hours later hemorrhagic rash elements of 1-

2mm till several centimeters in diameter appear on the skin of buttocks, legs, thighs and

lower part of the trunk. Later necrosis appears in the center of the largest elements;

- sclera, oral mucosa, nasal and gastric bleeding can develop;

- at fulminate forms symptoms of infectious toxic shock rapidly increase, bluish

hypostatic spots appear on the body.

Final diagnosis is confirmed by laboratory investigations. The latter include

bacteriological, bacterioscopic, serological methods and express diagnosis (latex

agglutination, immunochromatography). Materials for bacteriologic investigation are

nasopharyngeal mucus, blood and cerebro-spinal fluid.

As a rule, meningococci can be cultivated on media in 50% of cases. However, if

patients receive antibacterial therapy before hospitalization, the efficacy of

bacteriological method is about 5%.

Microscopy of “thick blood film” with Gram’s stain in patients with

meningococcemia allows detect gram-negative diplococci inside neutrophils. At CSF

microscopy intracellular and extracellular diplococci are found. To detect

polysaccharide antigen, reaction of co-agglutination and reaction of cross-counter

immunoelectrophoresis are used.

Complete blood count shows prominent leukocytosis, young neutrophilic forms till

myelocytes, aneosinophilia and accelerated ESR.

At suspicion of meningitis, lumbar puncture (LP) is performed. If patient presents

with hemorrhagic rash, urgent lumbar puncture is not required for diagnosis as it can

delay beginning of antibiotic therapy. Lumbar puncture should also be delayed if child

shows signs of shock or prominent intracranial hypertension (fontanel bulging, edema

of ophthalmic nerve disk, decreased consciousness and focal neurological signs).

Changes of CSF at MI are those typical for purulent meningitis. Meningococci can

be seen in neutrophils and can be cultivated in 80-90% of cases.

Meningococcus can be detected in CSF by PCR.

Treatment. At meningococcal nasopharyngitis macrolides are used (erythromycin,

azythromycin, clarithromycin), chloramphenicol or rifampin during 3-5 days,

ceftriaxone during 2 days in age dosages; older age children are recommended to rinse

the mouth with warm solutions of furacilin, sodium hydrocarbonate, weak manganese

solution, etc.

Meningococcemia.

Medical help to children with meningococcemia before hospitalization:

1. Therapy with moist oxygen with O2 concentration (FiO2) 0.35-0.4.

2. If indicated, it is necessary to provide airway patency and adequate respiration

(airway tube insertion, oxygen, mask ventilation, if possible, trachea intubation and

mechanical ventilation).

3. At shock signs, it is necessary to provide reliable venous access with catheters of

type “Vasofix” or “Venflon” within 3-5 minutes and to start infusion therapy with

isotonic salt solution (0.9% normal saline or Ringer lactate) in amount 20 ml/kg during

20 minutes.

4. Antibacterial therapy with cefotaxime in single dose 75 mg/kg or ceftriaxone in

single dose 50 mg/kg parentheral, preferably by intravenous drop infusion. It is possible

to use chloramphenicol before hospitalization in single dosage 25 mg/kg intravenously

by stream injection. If it is impossible to inject antibiotics intravenously, they are

injected intramuscularly.

5. Glucocorticosteroids are injected only intravenously (prednisone,

hydrocortisone) in dosage 10 mg/kg (on prednisone).

6. Antipyretic therapy (if required): paracetamol 15 mg/kg, ibuprofen 5-10 mg/kg

orally, metamizole sodium (50%) IV 0.1 ml/year of life.

7. Anticonvulsant therapy (if required): diazepam in dosage 0.3-0.5 mg/kg once

(not more than 10 mg per injection).

Child monitoring before hospitalization:

1. Evaluation of condition severity: dynamics of pathological symptoms – skin and

mucosa color, rash, consciousness.

2. Thermometry, heart rate (HR), respiratory rate (RR), pulse oxymetry.

3. Measurement of arterial pressure.

4. Control of airway patency.

Transportation of patients with severe forms of meningococcemia must be done by

intensive care teams.

Treatment of children with meningococcemia after hospitalization:

In hospital the choices of antibiotic for children with severe forms of

meningococcemia are cefotaxime or ceftriaxone intravenously in drop infusions on

normal saline solution. Antibacterial therapy must be started if the child is infused in

amount enough to support adequate central haemodynamics. At moderate and severe

forms of MI antibiotics are started intravenously.

Mild forms of MI can be treated with penicillin G. Reserve antibiotics are

ampicillin, ceftriaxone, cefotaxime. Chloramphenicol is used at hypersensitivity to beta-

lactam antibiotics.

The goal of early infusion therapy is to eliminate hypovolemia. Solutions are

injected intravenously, by stream injection. Isotonic salt solutions are injected in dosage

20-30 ml/kg during the first 20 minutes. Colloid solutions are injected with speed 20-40

ml/kg/hour. Optimal salt solutions are normal saline, Ringer solution, Ringer lactate

solution. Optimal colloid solutions are derivatives of hydroethylstarch solutions of 3 rd

generation (HES 130/0.4). Simultaneous usage of ceftriaxone with solutions containing

calcium is contraindicated even through different IV lines. There must be not less than

48 hours after the last dosage of ceftriaxone before calcium-containing solutions.

Infusion therapy of shock must be started immediately with salt solutions in dosage

20 ml/kg during the first 20 minutes with further colloid infusion in dosage 10-20 ml/kg

the following 20 minutes. At this combination the hemodynamic effect is higher. At

fulminate forms of MI it is reasonable to combine salt and colloid solutions in ratio 2:1.

Solutions of hydroethylstarch of 1st and 2nd generation are not recommended in

children with shock due to risk of acute renal failure development and bleedings.

If injection of 60-90 ml/kg of salt solution or 20-40 ml/kg of colloids solutions

during one hour is ineffective (absence of hemodynamic stabilization), it is necessary to

evaluate haemodynamics more precisely (echocardioscopy, repeated evaluation of

central venous pressure); these evaluations must control further infusion therapy. In

these cases sympathomimetic agents or respiratory support are required.

It should be noted that glucose solutions are contraindicated at infectious toxic

shock, metabolic acidosis and brain edema. These solutions do not remain in

bloodstream and increase cellular and brain edema. The only indication for glucose

infusions in patients with shock and brain edema is hypoglycemia.

Metabolic acidosis correction is done by infusion of sodium hydrocarbonate if

blood pH is less than 7.1-7.2.

After shock relief it is necessary to continue further supportive infusion therapy.

Calculation of infusion therapy volume is done with consideration of physiological

requirements, correction of water and electrolyte deficit, pathological losses, blood

glucose level, total protein, condition of gastrointestinal system, degree of brain edema.

One of aspects of post-shock infusion therapy is enough supply of energy and feeing,

which require partial parentheral nutrition. It is based on infusion of 10-20% glucose

solution with insulin and amino acid solutions. It is recommended to support adequate

colloid-oncotic pressure and protein level not less than 40 g/l.

Inotropic drugs are used in children not responding to infusion therapy (absence of

central venous pressure increase after functional probes), low cardiac output and low

САТ. Dopamine is used as permanent infusion in dosage 10 mcg/kg/min; if no effect,

the dosage is increased till 20-30 mcg/kg/min. At decreased cardiac output dobutamine

is given in the same dosage as dopamine. Children before 12 months of age can be less

sensitive to sympathomimetic agents.

Corticosteroids are given in acute adrenal insufficiency and/or resistance to

sympathomimetic agents. Drug of choice at MI is hydrocortisone. Prednisone usage is

also possible. The drugs are injected every 6 hours. Dosage is calculated on prednisone.

Efficacy of large doses of corticosteroids has no scientific background and is not

recommended. Corticosteroids are used as an adjuvant therapy of purulent meningitis.

The drug of choice is dexamethasone 0.1-0.15 mg/kg 4 - 6 times a day during 2 -3 days.

Artificial pulmonary ventilation is done in MI at:

not stable haemodynamics

development of respiratory insufficiency, distress-syndrome

lung edema, left ventricle cardiac insufficiency

intracranial hypertension and brain edema

decreased consciousness, seizures

Prophylaxis. The most reliable prophylaxis of MI is vaccination. There are simple

capsular polysaccharide vaccines and conjugated vaccines. Simple polysaccharide

vaccines induce short-term immunity in children before 2 years of age. Repeated

injection of vaccine to children leads to decreased immune response. Considering low

efficacy of capsular polysaccharide vaccines among early age children, routine

immunization with these vaccines is not indicated. Usage of these vaccines is

recommended in people with high risk of MI (decreased spleen function, asplenia,

complement deficiency), in personnel of laboratories working with strains of Neisseria

meningitidis, in people from infection nidus caused by serogroups А and С. Preschool

children and first two classes school children, adolescents from organized institutions

and children from family dormitories should be vaccinated against MI if disease

frequency is twice as high as the previous years; if there are three and more cases of MI

in one region during less than last three months (not members of one family); when

morbidity index in the region is more than 10 per 100 thousand population.

Vaccination is also recommended to people who are going to visit endemic

countries in the nearest future: Nepal, Kenya, Saudi Arabia, countries of meningococcal

belt of Africa.

Conjugated polysaccharide vaccines are used for routine immunization against

meningococcal infection mainly in children under 2 years of age. Conjugated

polysaccharide vaccine induces stronger immune response in early age children, creates

more prolonged immune memory and is more effective in prevention of meningococcal

carriage. Conjugated polysaccharide vaccines against meningococci А and С are widely

used in Europe, against meningococci A, C, Y, W in USA.

Besides vaccination, for MI prophylaxis in infection nidus it is recommended to

use rifampin in dosage 5 mg/kg for children under 1 year of age and 10 mg/kg (maximal

dose is 600 mg) in children 1 to 12 years twice a day during 2 days or single IM

injection of ceftriaxone in dose 125 mg to children under 12 years and 250 mg to

children above 12 years after contact with patient. Chemoprophylaxis is recommended

to be accompanied by vaccination during the first 5 days after contact.

Questions for self-control

1. Name the main particularities of causative agent of meningococcal infection.2. Who can be the source of meningococcal infection?3. List the main clinical forms of meningococcal infection.4. Name the main clinical symptoms of endotoxic shock at meningococcal infection.5. Name clinical symptoms of meningococcal infection.6. Clinical particularities of meningitis diagnosis in first year old children.7. Main laboratory methods of diagnosis at generalized forms of meningococcal infection.8. Medical help to patients with severe forms of meningococcemia before and after hospitalization.9. List main principles of meningitis management.10. What are anti-epidemic measures at infection nidus?

Tests for self-control

1. What genus does the causative agent of meningococcal infection belong to:А. ListeriaВ. CorynebacteriaС. NeisseriaD. EnterobacteriaE. Yersinia2. Point out the main mechanism of meningococcal infection transmission:А. Fecal-oral В. Airborne С. Transmissible

D. Inoculation Е. Vertical 3. Which form of meningococcal infection belongs to rare forms:А. Nasopharyngitis В. Meningitis С. MeningococcemiaD. Meningoencephalitis Е. Arthritis 4. Name the most typical rash at meningococcemia:А. Roseolar В. Papules С. Hemorrhagic D. Hemorrhagic necrotic Е. Pustulous 5. What is the predominating rash localization at meningococcemia:А. Face В. Upper extremities С. Buttocks, thighs D. Back Е. Palms 6. What meningeal sign is typical for first year of age children:А. Neck stiffness В. KernigС. Brudzinki D. Lessage Е. Babinski 7. What CSF changes are typical for meningococcal meningitis:А. Decreased protein В. Increased glucose С. Increased chlorides D. Neutrophilic cytosis Е. Negative Pandi reaction 8. What method is the diagnosis of meningococcal infection confirmed with:А. Blood and CSF bacterioscopy В. Bacteriology of nasopharyngeal swab С. Bacteriology of blood and CSF D. Latex agglutination of blood and CSF Е. All the answers are correct 9. Which antibiotic should be given to a patient with meningococcemia before hospitalization:А. ErythromycinВ. Ampicillin С. Amikacin D. Cefotaxime Е. Rifampin 10. What method of meningococcal infection prophylaxis is the most effective:А. Quarantine В. Mask wearing С. Washing hands D. Immunoglobulin injection Е. Vaccination

Test answers

1-C, 2-B, 3-E, 4-D, 5-C, 6-D, 7-D, 8-E, 9-D, 10-Е.