How is meningococcal disease diagnosed?

Clinical diagnosis of single cases of meningococcal nasopharyngitis is unlikely in connection with the absence of pathognomonic symptoms and always requires bacteriological confirmation, i.e. Obtaining and typing a culture of meningococcus from nasopharyngeal mucus.

Clinical diagnosis of meningococcal infection and meningococcemia in typical cases is not difficult, but there may be a lot of similarities with a number of diseases that occur with hemorrhagic eruptions and CNS damage. Meningococcal meningitis is clinically difficult to distinguish from other purulent primary meningitis, so it is important to confirm laboratory diagnosis of generalized meningococcal infection. Especially important for differential diagnosis with viral infections have acute inflammatory changes in the blood. For the diagnosis of meningococcal meningitis, the investigation of the cerebrospinal fluid is crucial.

Laboratory diagnosis of meningococcal infection is based on the use of microbiological methods, RLA and PCR. Bacterioscopically meningococcus can be found in the blood and spinal fluid, but the bacterioscopy data are approximate. Isolation of the culture of meningococcus is the most reliable method, but its results depend on many factors.

• The use of antibiotics prior to withdrawal of cerebrospinal fluid and blood reduces the frequency of seeding by 2-3 times.
• It is important to deliver the material to the laboratory immediately the fence field (without cooling).
• When using quality nutrient media, the frequency of positive results in practice is 30-60%.

RLA, used to detect the antigen of meningococcus in the spinal cord, increases the frequency of positive results to 45-70%, finally PCR allows to confirm the diagnosis in more than 90% of patients, and antibiotics do not affect the frequency of positive results.

The preparation of the pathogen culture allows one to determine its sensitivity to antimicrobial drugs and, if necessary, to correct etiotropic therapy.

Immunological diagnosis of meningococcal infection (RPHA) has an auxiliary significance, since antibodies are detected no earlier than the 3-5th day of the disease. Of definite importance is the study of paired blood sera, with a 4-fold increase in titers is detected in 40-60% of patients, av children under the age of three years - no more than 20-30%.

[1], [2], [3], [4], [5]

Indications for consultation of other specialists

Consultation of a neurologist - to clarify the nature of the CNS lesion, with suspicion of intracranial complications, to clarify the diagnosis in doubtful cases.

Consultation of a neurosurgeon - if necessary, differential diagnosis with volumetric processes of the brain (abscess, epiduritis, tumor, etc.).

Consultation of an ophthalmologist - if there is a suspicion of a lesion of the organ of vision or voluminous formations in the central nervous system (examination of the fundus).

Consultation otonevrologa - with the defeat of the auditory analyzer (neuritis VIII pair of cranial nerves, labyrinthite).

Consultation of a cardiologist - in the presence of clinical and electrocardiographic signs of severe cardiac damage (endocarditis, myocarditis, pericarditis).

Consultation of the reanimatologist - at signs of disturbance of the vital functions, if necessary catheterization of the central vein.

Diagnosis and evaluation of the severity of meningococcal infection and septic process

Among childhood infectious diseases leading to sepsis, meningococcemia stands apart. Early recognition and treatment of probable meningococcal sepsis helps to reduce mortality.

Since 1966, more than twenty-five special evaluation systems have been proposed to determine the severity of meningococcal disease. All of them are designed for evaluation at the time of receipt of a child with suspected meningococcal infection. Most of them were created and adapted for a sufficient number of different populations of the child population. The indicators used in these scales include clinical and laboratory variables or a combination thereof.

Below are the clinical and laboratory criteria that were significantly more frequent in the group of deceased patients.

Clinical and physiological variables associated with death (Leteurtre S. Et al., 2001)

Clinical characteristics	Laboratory indicators
Absence of meningitis	BE - excess of bases ↓
Age 1	C-reactive protein (CRP) ↓
Prevalence of petechiae	Platelets ↓
Interval between elements of rash X	Potassium ↑
Need for mechanical ventilation	Leukocytes (4 x 10 9 / l) ↓
Cold skin	Platelet production by neutrophils <40
Heart rate T	Glucose ↓
Coma (GCS <8)	Fibrinogen (E5Y) ↓
The deterioration in the last hours	Lactate ↑
Oli huriy	PTV or APTV (> 1.5 of the norm)
Refractory hypotension	Procalcitonin ↑
Cyanosis	Normal CSF
Gradient of skin and core temperature> 3 ° С	Interleukin-6 ↑
PRISM 2	I G type activator inhibitor ↑
	Creatine kinase ↑
	Troponin ↑
	Adrenocorticotropic hormone ↑

In a recently published comparative analysis, different scales were compared with the commonly used PRISM scale, which turned out to be the best (Leteurtre S. étal, 2001).

[6], [7], [8], [9], [10]

Prognostic index of meningococcal septicemia in Glasgow

Glasgow Meningococcal Septicemia Prognostic Score (GMSPS)

(Leclerc F. Et al., 1987, Sinclair JF, 1987, Thomson APJ, 1991)

The prognostic Glasgow scale of meningococcal septicemia (GMSPS) is able to identify children with meningococcemia and a high probability of fatal outcome. Such children require more serious intensive care

Index	Value	Points
Systolic blood pressure	<75 mm Hg. Art. At the age of <4 years; <85 mm Hg. Art. If> 4 years	3
	> 75 mm Hg. Art. At the age of <4 years; > 85 mm Hg. Art. If> 4 years	0
Cutaneous to rectal temperature difference	> 3 ° С	3
	<3 ° С	0

Index	Value	Points
Modified scale of coma evaluation	<8 or worse> 3 points per hour	3
	> 8 and deterioration <3 points	0
Deterioration per hour before evaluation	There is	2
	No (stable one hour before evaluation)	0
Absence of meningism	There is	2
	No (there is meningism)	0
Rash	Ascending purpura or common ecchymosis	1
Deficiency of bases (capillary or augmented)	> 8	1
	<8	0

Prognostic scale of meningococcal septicemia Glasgow = The sum of the seven-parameter estimates.

Modified Coma Scale

Index	Value	Points
Opening the eyes	Spontaneous	4
	To vote	3
	To the pain	2
	Absent	1
The best verbal reaction	Fully guided	6th
	The words	4
	Sounds	3
	Cry	2
	Absent	1
The best motor reaction	Executes commands	6th
	Localizes pain	4
	Moves to the pain stimulus	1
	Absent	0

Modified coma scale = (Points for eye opening) + + (Points for better verbal reaction) + (Points for better motor reaction)

Interpretation:

• Minimum OMPD indicator: 0.
• Maximum OIBFE indicator: 15.

N.B !: To predict the likelihood of a lethal outcome, the evaluation should be conducted on admission or during hospitalization.

Final score for death	Sensitivity	Specificity	Positive guessing index	Negative guess rate
> 8	100%	95%	74%	100%
9	100%	95%	74%	100%
> 10	100%	98%	88%	100%

Scale of assessment of meningococcal septic shock Rotterdam

Rotterdam Score (Meningococcal Septic Shock) (Komelisse RF et al., 1997)

The Rotterdam scale is used to predict the likelihood of a fatal outcome in children with meningococcal septic shock.

Laboratory data:

1. Potassium of serum.
2. Excess / shortage of bases.
3. Platelet level.
4. C-reactive protein.

Score on the Rotterdam scale = 1.01 + (1.21 x Potassium serum, mol / l) - (0.29 x Excess / base deficiency in mol / l) - (0.024 x Platelet level) - (3.75 x log10 C-reactive protein, mg / l), where

• the level of platelets is multiplied by 109 / l;
• The mentioned log does not illustrate the base 10 or the natural logarithm, the heme no less experienced informative set shows that the natural logarithm gives too low a value.

Probability of death = exp (Rotterdam scale) / (exp (Rotterdam scale) + 1).

Opinion:

• The predicted mortality rate was 71% and the survival rate was 90%;
• the result was correctly recognized in 86% of patients; 3.

Assessment of the risk of bacterial meningitis in children with meningeal symptoms

Bacterial Meningitis Risk Score for Children with Meningeal Signs (Oostenbrink R. Et al., 2001; Oostenbrink R. Et al., 2002)

R. Oostenbrink et al. (2001, 2002) developed a risk assessment scale for children with meningeal symptoms based on clinical and laboratory indicators. The scale helps in determining whether or not a lumbar puncture is necessary or unnecessary for a child.

Options:

• length of complaints in days;
• vomiting;
• signs of meningeal irritation;
• cyanosis;
• petechiae;
• the disturbed consciousness (reacts only to a pain or reaction is absent completely);
• C-reactive protein of serum (CRH).

Index	Value	Points
Length of complaints, days		Amount of days; score for each
Vomiting	Yes	1
	No	0
Signs of meningeal irritation	Yes	1
	No	0
Cyanosis	Yes	1
	No	0
Petechia	Yes	1
	No	0
Disturbed consciousness	Yes	1
	No	0
C-reactive protein (CRP), mg / l	0-9	0
	10-19	1
	> 19	2

Notes:

• Signs of meningeal irritation for children up to a year include a strained fontanel, irritability on examination, positive symptoms of Brudzinsky and Kernig, a tripod symptom, or stiff neck stiffness.
• Signs of meningeal irritation for children over the age of the year include neck pain, positive symptoms of Brudzinsky and Kernig, a tripod symptom and / or stiff neck stiffness.

Total score = (Points for the duration of complaints) + (2 x Points for vomiting) + (7.5 x Points for signs of meningeal irritation) + (6.5 (Points for cyanosis) + (4 x Points for petechia) + + ( 8 x Points for impaired consciousness) + (Points for CRH).

Interpretation:

• The minimum score is 0.5.
• The maximum score is 31.

The risk of bacterial meningitis is considered unlikely when assessed on a scale less than 9.5 points, while in assessing more than or equal to 9.5 points the risk of having meningitis was 44%. The higher the score, the greater the risk of having meningitis.

Total score	The index of bacterial meningitis
<9.5	0%
9.5-14.9	15-16%
15.0-19.9	44-63%
> 20	73-98%

[11], [12], [13], [14], [15], [16],

Prognostic scale for meningococcemia in children

(Prognostic Score of Leclerc et al. In Pediatric Meningococcemia) (Leclerc F. Et al., 1985)

The prognostic scale of Leclerc et al. (1985) allows predicting survival in children in septic shock due to severe meningococcemia.

The factors associated with increased mortality in meningococcemia include:

• Shock.
• Coma.
• Echimatous or necrotic purpura.
• Body temperature <36 ° C.
• Absence of meningism.
• The level of leukocytes is <10,000 per μL.
• The platelet count is <100,000 / μl.
• Fibrinogen <150 mg / dl.
• Potassium> 5.0 meq / liter.
• The level of leukocytes in the cerebrospinal fluid is <20 per μL.

Since shock is one of the main prognostic factors in meningococcemia (42% of patients who died with shock compared to 6% who had the disease without shock), a prognostic scale for children in shock was developed, which was based on the evaluation of the following parameters:

• Age.
• The level of potassium.
• The level of leukocytes in the blood.
• Clinical signs of meningism.
• Platelet level.

Index	Value	Points
Age	<1 year	1
	1-2 years	2
	> 2 years	3
Potassium level	<5 meq / liter	0
	> 5 meq / l	1
Leukocyte count	> 10,000	0
	<10,000	1
Signs of meningism	No	0
	Yes	1
Platelet level	> 100,000 / μL	0
	<100,000 / μL	1

Prognostic index for children in shock = (1.7 x Potassium level) - (Age) + (0.7 x Blood cell level) - (1.3 x Signs of meningeal disease) + (Platelet level) + 1.9.

Interpretation:

• 88% with a score of <-1 survived.
• 75% with a score of <0 survived.
• 39% with a score> 0 survived.
• 24% with a score> 1 survived.

Score	Survival
-3	100%
-2	81-100%
-1	81-86%
0	60-67%
1	19-48%
2	0-29%
3	0%

Predictors of the outcome of meningococcal infection in pediatrics

(Outcome Predictors of Algren et al. In Pediatric Meningococcal Infection) (Algren J. T., Lai S. Et al., 1993)

Prognostic moments no Algren et al. (1993) can be used to identify children with acute meningococcal infection who are at risk for organ failure and death. It was revealed that the risk of mortality in pediatrics (PRISM) can accurately predict total mortality.

Patient inclusion criteria:

• Pediatric patients with acute meningococcal infection, admitted to the Kosair Children's Hospital in Louisville, Kentucky, for 5 years.
• A prospective (planned) study, followed by a retrospective study.
• Age of analyzed retrospective patients from 1 month to 16 years and prospective (planned) from 3 months to 16 years.

Factors predictive of organ failure:

• Circulatory insufficiency.
• Low or normal leukocyte level (<10,000, μl).

Coagulopathy, where:

• Circulatory insufficiency = Decreased pulse, capillary filling time> 3 s, low systolic blood pressure (<70 mmHg or <5 centile by age).
• Coagulopathy = PT> 150% of normal, PTT> 150% of normal, platelet count <100,000 / μL.

Organ failure:

• Cardiovascular system: Persistent or recurrent hypotension, requiring the administration of isotonic fluid bolus> 20 ml / kg, and / or medium to high dose inotropes or infusion of vasopressors (eg, dopamine> 5 μg / kg / min).
• Respiratory system: value Pa02 / Fi02 <200 or the need for auxiliary ventilation for more than 24 hours.
• CNS: Score on the Glasgow scale <5.
• Hematology: leukocytes <3,000 per μL, hemoglobin <5 g / dL, or DIC (PT and PTT> 150% of normal, platelets <100,000 / μL and fibrinogen degradation products> 20 μg / ml or positive protamine sulfate test).
• The urinary system: creatinine> 2 mg / dL or BUN> 100 mg / dl.

Circulatory insufficiency	The level of leukocytes <10.000	Coagulopathy	Probability of organ failure
No	No	No	00.001%
No	No	There is	00.002%
No	There is	No	25%
No	There is	There is	60%
There is	No	No	99.99%
There is	No	There is	99.99%
There is	There is	No	100%
There is	There is	There is	100%

Factors associated with death:

• Presence of generalized organ failure.
• The level of leukocytes in the CSF is <20 / μl.
• The level of leukocytes is <10,000 / μL.
• Stupor or coma (8 points on the scale of Glasgow).
• The presence of purple.
• Metabolic acidosis (serum bicarbonate <<15 mEq / L).
• Coagulopathy.

The mortality risk in pediatrics (PRISM) can accurately predict overall mortality:

• The PRISM scale requires 8-24 hours of monitoring prior to costing, so in the initial decision making process, it may be less informative;
• when the PRISM scale is shown, there is no risk of mortality> 50% of survivors;
• if the risk of death by PRISM is 27-49%, then the number of survivors and deceased will be commensurate;
• Using the PRISM> 50% death rate as a death indicator, its sensitivity was 67%, and the specificity was 100%.

Other finds:

• The petechial rash, present for less than 12 hours, is not clinically significant.

The values of the stepwise logical regression:

• X = 4.806 - (10.73 x Circulatory insufficiency)

(0.752 x Coagulopathy) - (5.5504 x Leukocytes <10,000 / μl), where:

• circulatory insufficiency = - 1, if there is, +1, if not;
• coagulopathy = -1, if there is, +1, if not;
• leukocytes <10,000 = - 1, if so, +1, if not.

The probability of organ dysfunction = (exp (X)) / (1 + exp (X)):

• Y = (-12.73) - (6,800 (leukocyte level in the CSF))

(7.82 (stupor or coma)), where:

• level of leukocytes in CSF <20 = - 1, if yes, +1, if not;
• stupor or coma = - 1, if there is, +1, if not.

Probability of death = (exp (Y)) / (exp (Y)).

Differential diagnosis of meningococcal infection

Differential diagnosis of meningococcal infection is based on the clinical form of the disease. Meningococcal nasopharyngitis is differentiated from ARI. Flu, sore throats. Meningococcemia in a number of cases has to be differentiated from other infectious diseases, which are characterized by febrile-intoxication syndrome and hemorrhagic rash (rickettsiosis, hemorrhagic fever, leptospirosis). Sepsis, hemorrhagic form of influenza, toxic-allergic (medicamentous) dermatitis, hemorrhagic diathesis, acute leukemia. Combined form of the disease is also differentiated from sepsis, leptospirosis, rickettsiosis.

Differential diagnosis of meningococcal meningitis is carried out with other primary and secondary purulent meningitis, serous viral meningitis, tuberculosis meningitis; meningism in acute febrile illnesses, exogenous and endogenous intoxications, disorders of cerebral circulation, volumetric processes in the central nervous system.

The main feature of meningococcemia is the appearance of hemorrhagic rash during the first day of the disease, with other infections - no earlier than 2-4 days of the disease. In case of sepsis, more often caused by gram-negative microorganisms, the rash may be externally similar to cocciemic, possibly the development of an infectious-toxic shock, but in most cases there are entry gates (for example, genitals) and a primary focus (urinary, bile-excreting, etc.). Characteristic signs are an increase in the spleen, multiple organ failure, and later appearance of the rash (on the 3-5th day). Until now, there are cases when a prehospital stage is diagnosed with a hemorrhagic form of influenza. It should be emphasized that the rash, including hemorrhagic, does not occur with the flu, but small petechiae are possible in places of clothing friction, with severe coughing in children - bleeding in sclera, eyelids, forehead, neck. 

Toxico-allergic rash may rarely be hemorrhagic in nature or get hemorrhagic in nature on the 2nd-4th day, but there is no fever, chills, or other toxicosis. The rash is plentiful, often draining, especially in the area of the joints, on the cheeks, abdomen, convex part of the buttocks. There is stomatitis, glossitis. For hemorrhagic vasculitis, fever and intoxication are not characteristic, the elements of the rash are located near large joints, have the appearance of plaques, papules of regular rounded shape, which on the 2nd-3rd day acquire a hemorrhagic character. The lightning-fast form of capillarotoxicosis described in the literature does not exist; according to all clinical and laboratory criteria, it corresponds to fulminant meningococcemia. Thrombocytopenic purpura (Werlhof's disease) is characterized by increased bleeding of the mucous membranes, the correct form of hemorrhages in the skin, and the absence of febrile-intoxication syndrome.

In acute leukemia, hemorrhagic rash may appear on the background of other manifestations of the disease (general weakness, nasal bleeding, pallor of the skin, necrotic sore throat, fever) that precede the appearance of the rash in the 2-3 weeks and beyond.

The differential diagnosis of the combined form of meningococcal infection with acute sepsis, most often staphylococcal, which occurs with endocarditis and thromboembolism of the brain, presents great difficulties. In these cases, the rash may appear on the 2-3rd day of the disease, but often, along with hemorrhages, there are pustular and pustulose-hemorrhagic elements. Especially characterized by hemorrhagic eruptions in the palms, feet, on the fingers. Often heard noises in the heart. In addition to meningeal, they show a rough focal symptomatology. Studies of the cerebrospinal fluid reveal a 2-3-digit neutrophilic or mixed pleocytosis. It should be noted that in the early period of the ultrasound of the heart does not allow to detect overlaps on the valves.

It is important to emphasize that. Besides meningococcal. Primary (without the presence of a purulent-inflammatory focus) can be pneumococcal and hemophilic meningitis. Moreover, clinical differences are quantitative and do not allow differential diagnostics without bacteriological confirmation. It is important to identify pneumonia, otitis, sinusitis, characteristic of secondary pneumococcal meningitis. In addition, pneumococcal meningitis can be a manifestation of pneumococcal sepsis (pneumococcus aemia), which is characterized by a small hemorrhagic rash, localized mainly on the lateral surfaces of the chest. Secondary forms of purulent meningitis develop with a purulent focus or sepsis, so differential diagnosis is not difficult.

Differential diagnosis with serous viral meningitis is often possible at the prehospital stage on the basis of:

• clinical symptoms of viral infection (catarrhal respiratory or dyspeptic syndrome, parotitis);
• the appearance of signs of meningitis on the 3-5th days of illness and later;
• benign picture of the disease (moderately or poorly expressed meningeal syndrome, fever within 37.5-39 "C, absence of consciousness disorders).

Certain difficulties arise when examining the spinal fluid in the early stages of the disease. In these cases, neutrophilic pleocytosis (90% of neutrophils) is often expressed. In this case, as a rule, the cerebrospinal fluid is transparent, the number of cells does not exceed 200 in 1 μl, the glucose content corresponds to the upper limit of the norm or is increased. In case of doubt, repeat puncture after 24-48 hours should be done. If the cytosis becomes lymphocytic, then it is a case of viral meningitis, if the meningitis is bacterial, pus or nerve fibrosis is detected in the spinal cord. In recent years, more often, due to the increase in the incidence of tuberculosis, there is tubercular meningitis. In the field of vision infectious disease, as a rule, patients who have not been diagnosed with tuberculosis or meningitis are the only clinical manifestation of the disease. This is characterized by severe fever, a gradual increase in headache for several days, then the addition of vomiting and the appearance of meningeal symptoms on the 5th-7th day of the disease, early paresis of the cranial nerves. When studying the cerebrospinal fluid, low (up to 200-300 in 1 μl) lymphocytic or mixed pleocytosis, a decrease in the level of glucose from the 2 nd week of the disease. High protein content. At the slightest suspicion of the tuberculosis etiology of meningitis, microbiological tests for mycobacteria of tuberculosis, examination of the cerebrospinal fluid using ELISA and PCR, X-ray examination of the lungs and examination of the fundus (miliary tuberculosis!) Are necessary. If the tuberculosis etiology of meningitis can not be clinically excluded, a specific treatment should be started without waiting for a laboratory confirmation of the diagnosis. With many febrile illnesses (influenza, pneumonia, salmonellosis, erysipelas, etc.), meningeal syndrome can develop. In these cases, patients should be urgently hospitalized in an infectious inpatient facility. The final diagnosis is established on the basis of an investigation of the cerebrospinal fluid. Meningitis is possible with some poisonings (for example, surrogates of alcohol), coma (diabetic, uremic, hepatic). In all these cases, there is no pronounced fever, the general cerebral syndrome dominates, there are signs of a corresponding pathology. 

With subarachnoid hemorrhages on the 3-4th day of the disease, a picture of aseptic meningitis often develops, accompanied by fever, an increase in meningeal symptoms. Spinal-cerebral fluid obtained with spinal puncture. It is colored with blood, and after centrifugation its xanthochromy is revealed. At a microscopic examination, erythrocytes are found, the number of leukocytes is 100-400 in 1 μl, the level of protein is significantly increased. The main difficulty is that with meningococcal meningitis, the inflammation of the membranes can also be purulent-haemorrhagic. That is why the anamnestic data are very important: for subarachnoid hemorrhage, sudden headache ("blow to the head"), vomiting, early appearance of meningeal symptoms are characteristic. Fever joins later, on the 2-3rd day of the disease. In case of doubt, an additional examination is necessary (echoencephalography, CT, MRI).

[17], [18], [19], [20]