How is meningococcal infection diagnosed?

Clinical diagnosis of isolated cases of meningococcal nasopharyngitis is unlikely due to the absence of pathognomonic symptoms and always requires bacteriological confirmation, i.e. obtaining and typing a meningococcal culture from nasopharyngeal mucus.

Clinical diagnostics of meningococcal infection and meningococcemia in typical cases is not difficult, but there may be a great deal of similarity with a number of diseases that occur with hemorrhagic rashes and CNS damage. Meningococcal meningitis is clinically difficult to distinguish from other purulent primary meningitis, so it is important to laboratory confirm the diagnosis of generalized meningococcal infection. Acute inflammatory changes in the blood are of particular importance for differential diagnostics with viral infections. Cerebrospinal fluid testing is crucial for the diagnosis of meningococcal meningitis.

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

• The use of antibiotics before collecting cerebrospinal fluid and blood reduces the seeding rate by 2-3 times.
• It is important to deliver the material to the laboratory immediately after collection (without refrigeration).
• When using high-quality nutrient media, the frequency of positive results in practice is 30-60%.

RLA, used to detect meningococcal antigen in cerebrospinal fluid, increases the frequency of positive results to 45-70%, and finally PCR allows confirming the diagnosis in more than 90% of patients, and antibiotics do not affect the frequency of positive results.

Obtaining a culture of the pathogen allows us to determine its sensitivity to antimicrobial drugs and, if necessary, correct the etiotropic therapy.

Immunological diagnostics of meningococcal infection (RPHA) is of auxiliary importance, since antibodies are detected no earlier than the 3rd-5th day of illness. The study of paired blood sera is of reliable importance, with a 4-fold increase in titers detected in 40-60% of patients, and in children under three years of age - no more than 20-30%.

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Indications for consultation with other specialists

Consultation with a neurologist - to clarify the nature of the CNS lesion, if intracranial complications are suspected, to clarify the diagnosis in questionable cases.

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

Consultation with an ophthalmologist - if there is a suspicion of damage to the visual organ or volumetric formations in the central nervous system (examination of the fundus).

Consultation with an otoneurologist - in case of damage to the auditory analyzer (neuritis of the VIII pair of cranial nerves, labyrinthitis).

Consultation with a cardiologist - if there are clinical and electrocardiographic signs of severe heart damage (endocarditis, myocarditis, pericarditis).

Consultation with a resuscitator - if there are signs of disruption of vital functions, if central vein catheterization is necessary.

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

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

Since 1966, more than twenty-five specific scoring systems have been proposed to determine the severity of meningococcal disease. All are designed to be assessed at the time of admission of a child with suspected meningococcal disease. Most have been developed and adapted for a wide range of pediatric populations. The indicators used in these scales include clinical and laboratory variables or a combination of both.

Below we present the clinical and laboratory criteria that were significantly more common in the group of deceased patients.

Clinical and physiological variables associated with mortality (Leteurtre S. et al., 2001)

Clinical characteristics	Laboratory indicators
No meningitis	BE - excess bases ↓
Age 1	C-reactive protein (CRP) ↓
Prevalence of petechiae	Platelets ↓
Interval between rash elements X	Potassium ↑
Need for mechanical ventilation	Leukocytes (4 x 10 9 /l) ↓
Cold skin	Platelet to neutrophil ratio < 40
Heart rate T	Glucose ↓
Coma (GCS < 8)	Fibrinogen (E5R) ↓
Worsening in recent hours	Lactate ↑
Oli guria	PT or APTT (> 1.5 of normal)
Refractory hypotension	Procalcitonin ↑
Cyanosis	Normal CSF values
Skin-core temperature gradient > 3°C	Interleukin-6 ↑
PRISM 2 and	PG I activator inhibitor ↑
	Creatine kinase ↑
	Troponin ↑
	Adrenocorticotropic hormone ↑

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

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Glasgow Meningococcal Septicemia Prognostic Index

Glasgow Meningococcal Septicemia Prognostic Score (GMSPS)

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

The Glasgow Meningococcal Septicemia Prognostic Score (GMSPS) can identify children with meningococcemia and a high risk of death, who require more intensive care

Indicator	Meaning	Points
Systolic blood pressure	<75 mmHg if < 4 years; <85 mmHg if > 4 years	3
	>75 mmHg if < 4 years; >85 mmHg if > 4 years	0
Skin to rectal temperature difference	>3°С	3
	<3°С	0

Indicator	Meaning	Points
Modified Coma Rating Scale	<8 or worsening >3 points per hour	3
	>8 and worsening <3 points	0
Worsening in the hour before assessment	Eat	2
	No (stable one hour before assessment)	0
Absence of meningism	Eat	2
	No (there is meningism)	0
Rash	Ascending purpura or generalized ecchymosis	1
Base deficiency (capillary or suspended)	>8	1
	<8	0

Glasgow Meningococcal Septicaemia Prognostic Score = Sum of seven parameter scores.

Modified Coma Scale

Indicator	Meaning	Points
Opening of eyes	Spontaneous	4
	To the voice	3
	For pain	2
	Absent	1
Best verbal response	Fully oriented	6
	Words	4
	Sounds	3
	Cry	2
	Absent	1
Better motor response	Executes commands	6
	Localizes pain	4
	Moves towards a painful stimulus	1
	Absent	0

Modified Coma Scale = (Eye Opening Score) + (Best Verbal Response Score) + (Best Motor Response Score)

Interpretation:

• Minimum OMBRZ indicator: 0.
• Maximum OMBRE indicator: 15.

N.B!: To predict the probability of a fatal outcome, the assessment should be carried out upon admission or during hospitalization.

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

Rotterdam Meningococcal Septic Shock Scale

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

The Rotterdam score is used to predict the likelihood of death in children with meningococcal septic shock.

Laboratory data:

1. Serum potassium.
2. Excess/deficiency of bases.
3. Platelet level.
4. C-reactive protein.

Rotterdam score = 1.01 + (1.21 x Serum Potassium, mol/L) - (0.29 x Base excess/deficit, mol/L) - (0.024 x Platelet level) - (3.75 x log10 C-reactive protein, mg/L), where

• platelet level multiplied by 109/l;
• the mentioned log does not illustrate the base 10 or natural logarithm, but the nevertheless tested information 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 survival rate 90%;
• the obtained result was recognized correctly in 86% of patients; 3.

Assessing 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 parameters. The scale helps in determining whether or not a lumbar puncture is necessary in a child.

Parameters:

• duration of complaints in days;
• vomit;
• signs of meningeal irritation;
• cyanosis;
• petechiae;
• impaired consciousness (reacts only to pain or there is no reaction at all);
• Serum C-reactive protein (CRP).

Indicator	Meaning	Points
Duration of complaints, days		Number of days; point for each
Vomit	Yes	1
	No	0
Signs of meningeal irritation	Yes	1
	No	0
Cyanosis	Yes	1
	No	0
Petechiae	Yes	1
	No	0
Impaired consciousness	Yes	1
	No	0
C-reactive protein (CRP), mg/l	0-9	0
	10-19	1
	>19	2

Notes:

• Signs of meningeal irritation in children under one year of age include a tense fontanelle, irritability on examination, positive Brudzinski and Kernig signs, tripod sign, or nuchal rigidity.
• Signs of meningeal irritation in children over one year of age include neck pain, positive Brudzinski and Kernig signs, tripod sign, and/or nuchal rigidity.

Total score = (Points for 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 petechiae) + + (8 x Points for impaired consciousness) + (Points for CRB).

Interpretation:

• Minimum score: 0.5.
• Maximum score: 31.

The risk of bacterial meningitis was considered unlikely if the score was less than 9.5, while if the score was greater than or equal to 9.5, the risk of having meningitis was 44%. The higher the score on the scale, the greater the risk of having meningitis.

Overall score	Bacterial meningitis index
<9.5	0%
9.5-14.9	15-16%
15.0-19.9	44-63%
>20	73-98%

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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 caused by severe meningococcemia.

Factors associated with increased mortality in meningococcemia include:

• Shock.
• Coma.
• Ecchymatous or necrotic purpura.
• Body temperature < 36 °C.
• Absence of meningism.
• Leukocyte count < 10,000/µl.
• Platelet count < 100,000/µL.
• Fibrinogen < 150 mg/dL.
• Potassium > 5.0 meq/L.
• The cerebrospinal fluid leukocyte level is < 20 per µl.

Since shock is one of the main prognostic factors in meningococcemia (42% of patients died with shock versus 6% in whom the disease proceeded without shock), a prognostic scale was developed for children in a state of shock, which was based on the assessment of the following parameters:

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

Indicator	Meaning	Points
Age	<1 year	1
	1-2 years	2
	>2 years	3
Potassium level	<5 mEq/L	0
	>5 mEq/L	1
Leukocyte level	>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 White blood cell count) - (1.3 x Signs of meningism) + (Platelet level) + 1.9.

Interpretation:

• 88% with a score < -1 survived.
• 75% with a score < 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 outcome of meningococcal infection in pediatrics

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

The prognostic points of Algren et al. (1993) can be used to identify children with acute meningococcal disease who are at risk for organ failure and death. The pediatric risk of mortality score (PRISM) was found to accurately predict cumulative mortality.

Patient inclusion criteria:

• Pediatric patients with acute meningococcal disease admitted to Kosair Children's Hospital in Louisville, Kentucky, over a 5-year period.
• A prospective (planned) study following a retrospective one.
• The age of the analyzed retrospective patients ranged from 1 month to 16 years, and prospective (planned) patients ranged from 3 months to 16 years.

Factors predicting organ failure:

• Circulatory failure.
• Low or normal white blood cell count (<10,000/µL).

Coagulopathy, where:

• Circulatory failure = Decreased pulse rate, capillary refill time > 3 sec, low systolic BP (< 70 mmHg or < 5th centile for age).
• Coagulopathy = PT > 150% of normal, PTT > 150% of normal, platelet count < 100,000/µL.

Organ failure:

• Cardiovascular system: persistent or recurrent hypotension requiring isotonic fluid bolus > 20 mL/kg and/or moderate to high dose inotropes or vasopressor infusion (eg, dopamine > 5 mcg/kg/min).
• Respiratory system: Pa02/Fi02 value < 200 or need for assisted ventilation for more than 24 hours.
• CNS: Glasgow score < 5.
• Hematology: WBC < 3,000/μL, hemoglobin < 5 g/dL, or DIC (PT and PTT > 150% of normal, platelets < 100,000/μL and fibrinogen breakdown products > 20 mcg/mL or positive protamine sulfate test).
• Urinary system: creatinine > 2 mg/dL or BUN > 100 mg/dL.

Circulatory failure	White blood cell count < 10,000	Coagulopathy	Probability of organ failure
No	No	No	00,001%
No	No	Eat	00,002%
No	Eat	No	25%
No	Eat	Eat	60%
Eat	No	No	99.99%
Eat	No	Eat	99.99%
Eat	Eat	No	100%
Eat	Eat	Eat	100%

Factors associated with death:

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

The Pediatric Risk of Mortality Score (PRISM) can accurately predict cumulative mortality:

• The PRISM scale requires 8-24 hours of monitoring before calculation, so it may be of little use in making initial decisions about patient management;
• if the PRISM score is > 50%, there will be no survivors;
• if the mortality risk according to PRISM is 27-49%, then the number of survivors and deaths will be proportionate;
• When using the PRISM mortality rate > 50% as an indicator of death, its sensitivity was 67% and specificity was 100%.

Other findings:

• Petechial rash present for less than 12 hours is not clinically significant.

Stepwise Logical Regression Values:

• X = 4.806 - (10.73 x Circulatory failure)

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

• circulatory failure = - 1 if present, +1 if not;
• coagulopathy = -1 if present, +1 if not;
• leukocytes < 10,000 = - 1 if yes, +1 if no.

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

• Y = (-12.73) - (6.800 (CSF leukocyte level))

(7.82 (stupor or coma)), where:

• CSF leukocyte level < 20 = - 1 if yes, +1 if no;
• stupor or coma = - 1 if present, +1 if not.

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

Differential diagnosis of meningococcal infection

Differential diagnostics of meningococcal infection is carried out based on the clinical form of the disease. Meningococcal nasopharyngitis is differentiated from acute respiratory infections, influenza, and tonsillitis. In some cases, meningococcemia must be differentiated from other infectious diseases characterized by febrile-intoxication syndrome and hemorrhagic rash (rickettsiosis, hemorrhagic fever, leptospirosis). sepsis, hemorrhagic form of influenza, toxic-allergic (drug-induced) dermatitis, hemorrhagic diathesis, and acute leukemia. The combined form of the disease is also differentiated from sepsis, leptospirosis, and rickettsiosis.

Differential diagnostics of meningococcal meningitis is carried out with other primary and secondary purulent meningitis, serous viral meningitis, tuberculous meningitis; meningism in acute febrile diseases, exogenous and endogenous intoxications, cerebrovascular accidents, and volumetric processes in the central nervous system.

The main feature of meningococcemia is the appearance of a hemorrhagic rash during the first day of the disease, while in other infections it occurs no earlier than the 2nd to 4th day of the disease. In sepsis, which is often caused by gram-negative microorganisms, the rash may be similar in appearance to coccemic rash, and infectious toxic shock may develop, but in most cases there is an entry point (for example, the genitals) and a primary lesion (urinary tract, biliary tract, etc.). Characteristic signs include an enlarged spleen, multiple organ lesions, and later onset of the rash (on the 3rd to 5th day). To this day, there are cases where the hemorrhagic form of influenza is diagnosed at the prehospital stage. It should be emphasized that a rash, including hemorrhagic, does not occur with influenza, however, small petechiae are possible in places where clothing rubs, and with a strong cough in children - hemorrhages in the sclera, eyelids, forehead, and neck.

Toxic-allergic rash may in rare cases be hemorrhagic or acquire a hemorrhagic character on the 2nd-4th day, however, there is no fever, chills and other manifestations of toxicosis. The rash is abundant, often confluent, especially in the area of joints, on the cheeks, abdomen, convex part of the buttocks. Stomatitis and glossitis are observed. Fever and intoxication are not characteristic of hemorrhagic vasculitis, the elements of the rash are located near large joints, have the appearance of plaques, papules of a regular round shape, which acquire a hemorrhagic character on the 2nd-3rd day. The fulminant form of capillary toxicosis 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, regular hemorrhages into the skin, and the absence of febrile intoxication syndrome.

In acute leukemia, a hemorrhagic rash may appear against the background of other manifestations of the disease (general weakness, nosebleeds, pale skin, necrotic tonsillitis, fever), which precede the appearance of the rash in the 2nd-3rd week and beyond.

Differential diagnostics of combined meningococcal infection with acute sepsis, most often staphylococcal, occurring with endocarditis and cerebral thromboembolism, presents great difficulties. In these cases, the rash may appear on the 2nd-3rd day of the disease, but often, along with hemorrhages, there are pustular and pustular-hemorrhagic elements. Hemorrhagic rashes in the palms, feet, and fingers are especially characteristic. Heart murmurs are often heard. In addition to meningeal symptoms, gross focal symptoms are detected. Studies of the cerebrospinal fluid reveal 2-3-digit neutrophilic or mixed pleocytosis. It should be noted that in the early stages, ultrasound of the heart does not allow detecting valve deposits.

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

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

• clinical symptoms of viral infection (catarrhal-respiratory or dyspeptic syndrome, mumps);
• the appearance of signs of meningitis on the 3rd-5th day of illness and later;
• benign picture of the disease (moderate or mild meningeal syndrome, fever within 37.5-39 °C, no disturbances of consciousness).

Certain difficulties arise when examining the cerebrospinal fluid at the early stages of the disease. In these cases, neutrophilic pleocytosis is often expressed (90% neutrophils). 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 doubtful cases, a repeat puncture should be done in 24-48 hours. If the cytosis becomes lymphocytic, then we are talking about viral meningitis, but if meningitis is bacterial, pus is found in the cerebrospinal fluid or neutrophilic cytosis persists. In recent years, due to the increase in tuberculosis, tuberculous meningitis has become more common. As a rule, the infectious disease specialist looks at patients in whom tuberculosis has not been diagnosed or meningitis is the only clinical manifestation of the disease. Characteristic features include high fever, gradual increase in headache over several days, followed by vomiting and meningeal symptoms on the 5th-7th day of illness, early cranial nerve paresis. Cerebrospinal fluid examination reveals low (up to 200-300 in 1 μl) lymphocytic or mixed pleocytosis, decreased glucose levels from the 2nd week of illness, and increased protein content. At the slightest suspicion of tuberculous etiology of meningitis, microbiological studies for Mycobacterium tuberculosis, cerebrospinal fluid examination by ELISA and PCR, X-ray examination of the lungs and examination of the fundus (miliary tuberculosis!) are necessary. If tuberculous etiology of meningitis cannot be clinically excluded, specific treatment should be started without waiting for laboratory confirmation of the diagnosis. Meningitis syndrome may develop in many febrile diseases (flu, pneumonia, salmonellosis, erysipelas, etc.). In these cases, patients should be urgently hospitalized in an infectious diseases hospital. The final diagnosis is established based on the study of cerebrospinal fluid. Meningism is possible in some poisonings (for example, alcohol substitutes), comas (diabetic, uremic, hepatic). In all these cases, there is no pronounced fever, the general cerebral syndrome dominates, and signs of the corresponding pathology are present.

In case of subarachnoid hemorrhages, aseptic meningitis often develops on the 3rd-4th day of illness, accompanied by fever and increasing meningeal symptoms. Cerebrospinal fluid obtained by spinal puncture is stained with blood, and after centrifugation, its xanthochromia is revealed. Microscopic examination reveals erythrocytes, the number of leukocytes is 100-400 in 1 μl, the protein level is significantly increased. The main difficulty is that in meningococcal meningitis, inflammation of the membranes can also be purulent-hemorrhagic. This is why anamnestic data are very important: subarachnoid hemorrhage is characterized by sudden headache ("a blow to the head"), vomiting, early appearance of meningeal symptoms. Fever joins later, on the 2nd-3rd day of illness. In doubtful cases, additional examination is necessary (echoencephalography, CT, MRI).

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