Meningitis in Young Infants Less than 2 Months; Its Implications and Outcome

Abstract

Meningitis, i.e., inflammation of membranes covering the brain parenchyma, is a serious problem in children especially in young infants as it is not only associated with adverse short-term outcomes but also leads to abnormal neurodevelopment including sensory neural deafness later in life. Streptococcus pneumoniae is among the leading causative organisms of meningitis in young infants. Advances in the diagnosis and management of such babies have led to decrease in the mortality from meningitis. However, certain areas such as completion of antimicrobial therapy, monitoring of these babies for complications such as post-meningitic hydrocephalus, ventriculitis, need to be addressed. With missed diagnosis, a large cohort of such babies lands up with chronic disability. There is a need to understand the management of such cases including follow-up so that they survive with good neurological outcomes.

1. Introduction

The word “meningitis” literally means “Inflammation of the meninges.” Causes can be bacterial, fungal, or protozoal infections. Children younger than 2 months old have the highest incidence of bacterial meningitis due to their immature immunity. Also, non-functional blood-brain barrier (BBB) and unimmunized state make them susceptible to infection. In neonates, meningitis can be as result of early-onset sepsis (EOS) or late-onset sepsis (LOS). The symptoms and signs of meningitis may be subtle and non-specific, and diagnosis relies mainly on high index of suspicion. The mortality rates due to neonatal meningitis from developed countries range from 3 to 13% compared with 30–40% in developing countries [1]. The most common etiological agent for meningitis among young children was Haemophilus Influenza type B. However, due to introduction of the pentavalent vaccination, the most prevalent agent now is Streptococcus Pneumoniae causing pneumococcal meningitis. Pneumonia and meningitis together account for 22.0% mortality among children aged less than 5 years [2]. This deleterious impact of meningitis is more acute and severe among children less than 5 years of age, especially in poor resource settings where vaccination for Haemophilus influenzae type b, Streptococcus pneumoniae, and N. Meningitides is either not available or not implemented in routine immunization [3]. With the advancement of neonatal units, the mortality rates due to bacterial meningitis are reduced but the long-term neurological morbidity remained unchanged with around 20–30% may have long-term neurological sequelae. Moreover, the introduction of cost-effective interventions such as vaccination for H. influenzae type b, S. pneumoniae, and N. Meningitides has significantly reduced the burden of childhood meningitis. For instance, increasing immunization rates with Pneumococcal conjugate vaccine have markedly reduced the incidence of pneumococcal meningitis [4].

2. Etiological agents

H. influenzae type b was the leading cause of acute bacterial meningitis with high mortality among confirmed cases, before the introduction of the pentavalent vaccine [5]. After the advent of the pentavalent vaccine, surveillance conducted between 2011 and 2015 documented the emergence of S. pneumoniae as the major cause of invasive bacterial diseases among children less than 5 years of age [6].

From 1998 through 2019, overall, invasive pneumococcal disease rates among children less than 5 years old decreased by 93%. (CDC) This is attributed to the fact that pneumococcal conjugate vaccine (PCV 10 or 13) is included in the routine immunization schedule of most of the countries after it was mandated by WHO and has significantly reduced the morbidity and mortality due to pneumococcal meningitis in young children.

Among neonates, Gram-negative bacteria are the most commonly reported. The variable predominance of Klebsiella pneumonia, Staphylococcus aureus, E. coli, and Pseudomonas species has been documented in various studies. Acinetobacter species and Enterococcus species have also been increasingly reported especially among hospitalized babies [7].

Age-wise organisms

Neonate (EOS)-Escherichia coli, other Gram-negative bacilli, Klebsiella pneumoniae, Streptococcus agalactiae, group B Streptococcus, and Listeria monocytogenes.

Neonate (LOS)- E. coli, K. pneumoniae, Enterobacter, Salmonella, and S. aureus.

Young infant (1–3 months)- E. coli, K. pneumoniae, Enterobacter, Salmonella, S. aureus, Strep. pneumoniae, Neisseria meningitidis, and H. influenzae type B.

Specific predisposing factors and causative organisms are given as in Table 1.

Predisposing factors	Causative organism
Cerebrospinal fluid (CSF) leak	Streptococcus pneumonia
CSF shunt, meningomyelocele, and; cranial trauma	S. aureus and Staphylococcus epidermidis
Splenic dysfunction—nephrotic; syndrome/sickle cell anemia, etc.	Strep. pneumonia, Haemophilus influenza, and; Neisseria meningitidis
Defects in the complement system	N. meningitidis
T cell defects	Listeria monocytogenes

Table 1.

Predisposing factors and causative organism of acute bacterial meningitis in young infants.

Source: IAP. Standard Treatment Guidelines 2022: Acute Bacterial Meningitis. p. 9.

2.1 Risk factors of bacterial meningitis: Neonatal period

Early-onset sepsis (EOS): It presents within 72 hours of birth [8]. The risk factors for EOS are as follows:

• Low birth weight/Prematurity

• Maternal fever (100.4 C) within 2 weeks of delivery

• Evidence of maternal chorioamnionitis – Foul smelling liquor

• Premature rupture of membranes

• Single unclean or > 3 sterile vaginal examination(s) during labor

• Prolonged labor (duration of first, second stage of labor is more than 24 hours)

• Perinatal asphyxia

Late-onset sepsis (LOS): Occurs usually after 72 hours of birth. The neonate develops septicaemia, pneumonia, or meningitis and acquires the infection either in the hospital (nosocomial) or community-acquired [9].

In neonates, the historical picture of EOS presenting as pneumonia and LOS as meningitis is found in developed nations where it is rare to find meningitis in EOS cases. In contrast, among developing world countries such as India, the proportion of babies with meningitis is similar and substantial in both EOS and LOS. Also, in India, the causative organisms of EOS, as well as LOS, are the same as EONS is caused by postnatal infections in the labor room and postnatal wards.

2.2 Risk factors beyond the neonatal period

1. Poor immunity in young infants

2. Malnutrition

3. Severe sepsis

4. Underlying immunodeficiency disorders for e.g., complement defect (C5–8) deficiency disorder can lead to recurrent meningococcal infection

5. Splenic dysfunction

6. Skull fractures, cribriform plate defects, neural tube defects, etc.

7. Otitis media, cochlear implants

8. Cerebrospinal fluid (CSF) shunt surgeries

2.3 Pathogenesis

Meningitis means inflammation of the meninges, which affects the pia, the arachnoid, and the subarachnoid space, and it continues to be a significant cause of morbidity and mortality in the pediatric age group. The infecting organism affects the pathogenesis a lot, which leads to spreading of infection. But the essential common features seen in most of the cases following bacterial invasion are as follows: [10, 11, 12]

1. Colonization of mucosa by the organism

2. Bloodstream invasion

3. Survival and multiplication

4. Resulting in high levels of bacteraemia, followed by crossing the BBB

5. Invasion of the meninges and the central nervous system

6. Subsequently, the bacteria lead to an increased permeability of the BBB

7. Pleocytosis

8. Causing edema and increased intracranial pressure

9. Release of pro-inflammatory mediators from infiltrated white blood cells and other host cells causing neuronal injury

Routes of spread across blood-brain can be:

1. Hematogenous circulation of microorganisms from a distant site

2. Nasal mucosal epithelium colonization followed by vascular and meningeal invasion

3. Infection from adjacent site such as sinusitis or mastoiditis can lead to meningitis

4. Infection can be directly in the CSF. For example, skull fractures cases or ventricular shunts. It is shown in the experimental models that Streptococcus pneumonia can enter CNS via a non-hematogenous route like in intranasal infection, otitis media [11].

As the bacteria enter the CNS through the blood, they multiply and initiate the release of pro-inflammatory and toxic substances, which in turn result in pleocytosis and enhanced BBB permeability—the characteristic feature of bacterial meningitis. A number of mediators advance to the migration of white blood cells (particularly neutrophils) across the BBB (pleocytosis) and enhanced BBB permeability during bacterial meningitis [13, 14].

3. Complications

3.1 Short term

1. Vasculitis, thrombosis of small cortical veins, occlusion of major venous sinuses due to the presence of purulent exudates of varying degrees deposited around cerebral veins

2. Cerebral infarction caused by vascular occlusion due to inflammation, vasospasm, or thrombosis

3. Inflammation of cranial, spinal nerves, and roots

4. Raised intracranial pressure, which may be due to

1. Cytotoxic cell death leading to cerebral edema

2. Cytokine-induced increased capillary permeability

3. Obstruction of reabsorption of C.S.F through the ventricular system

1. Subdural effusion – It is more common in infants compared with older children

2. Focal neurological deficits

3.2 Long term

1. Hydrocephalous – may develop at the beginning of the illness or weeks later after diagnosis with bacterial meningitis. The most common type of hydrocephalus after bacterial meningitis is communicating hydrocephalus; seen in up to 52% of cases with hydrocephalus. The most common type of hydrocephalus after bacterial meningitis is communicating hydrocephalus; seen in up to 52% of cases with hydrocephalus [15]

2. Cognitive Impairment – Due to the irreversible neuronal damage that occurs during bacterial meningitis, the risk of developing long-term cognitive deficits and learning difficulties is significant [16]

3. Seizures and Epilepsy

4. Hearing Loss – There are two ways to develop hearing. First due to direct spread of bacterial products and second by host inflammatory response. Also the labyrinthitis resulting from cochlear invasion of bacteria plays a role [17]. It is seen commonly in infections by S. pneumoniae (14–32%) as compared with N. meningitides (4–23%), H. influenzae (20%) [18].

4. Clinical features

4.1 In neonates, the various clinical features are as follows [19]

• Subtle symptoms

• Alteration in body temperature (60%)

• Lethargy, refusal to feed, and irritability (60%)

• Incessant cry, hypothermia, or occasionally irregular fever

• Altered mental status

• Persistent bulging fontanel (25%)

• Seizures (20–50%)

4.2 Older children

• headache

• nausea, vomiting,

• anorexia, restlessness

• altered state of consciousness and irritability

• refusal to feed

• seizures

• symptoms of upper respiratory tract infection, myalgia, arthralgia, tachycardia, hypotension, petechiae, purpura, and erythematous macular rash

4.3 Signs

1. Meningeal signs, which include

1. Neck rigidity

2. Kernig sign

3. Brudzinski sign

1. Focal neurological signs (10–20%) in form of cranial neuropathies

2. Papilledema – Sign may be present in complicated meningitis

   *- Meningeal signs may not be present in infants.

5. Investigations

It is challenging to diagnose meningitis in young infants. For newborns especially for preterm neonates, a high index of suspicion is required due to subtle manifestations in them. The gold standard to diagnose meningitis is positive cerebrospinal fluid culture, but the rate of CSF culture positivity is quite low as many ties the CSF examination in very sick neonates is deferred. It is seen that in NICUs only 30–50% of neonates suspected to have sepsis undergo LP and around 75% of the time it is done after starting broad-spectrum antibiotics. Therefore, any baby who is having symptoms and signs of sepsis-like lethargy, fever (100.4°C) should undergo septic evaluation including lumber puncture.

5.1 Evaluation

Any neonate suspected of sepsis should undergo sepsis screen, blood culture, and CSF examination with culture. 25–30% of neonates with septicaemia may have meningitis

Sepsis screen-.

Sepsis screen (SS) is a panel of five tests as shown below.

1. TLC < 5000/cu mm

2. Absolute neutrophil count (ANC) < 1800cu mm

3. Immature neutrophils: total neutrophil ratio (IT ratio)>0.2 (20%).

4. Micro ESR >15 mm in the first hour.

5. C-reactive protein (CRP) >10 mg/L is considered positive.

It is considered positive if any of the two parameters are positive. If the first screen is positive and there is a strong suspicion of sepsis, a repeat SS should be sent after 12 hours. The sensitivity of each of these parameters is low but when combined especially with a subsequent screen, sensitivity increases significantly. A positive screen may not be confirmatory; however, a negative sepsis screen helps to rule out sepsis.

SS is used mainly in neonates and sensitivity, specificity, positive predictive value, and negative predictive value of 93–100, 83, 27, and 100% respectively.

The most important test of SS is CRP. Recently, CRP is proved as a better marker than whole SS in newborns too. However, many cases report false-negative CRP value as the duration of its synthesis is 8–10 hours. Another promising marker is Procalcitonin, which increases within 2 hours of acquiring the infection. The sensitivity (92.6%) and specificity (97.5%) of this marker are very high, specifically drawn after the first hours of life. But the high cost of this marker makes it less practical to be used in the low-middle-income countries.

5.2 Blood culture

It is the gold standard method for diagnosing sepsis; however, many times, due to prior exposure to antibiotics, results are false negative. On the other hand, due to skin contaminants and asymptomatic bacteraemia, results can be false positive. Hence, it is advised that a blood culture should be sent before initiating antibiotic treatment. For this, collect 1–2 ml of blood in a pediatric blood culture bottle under aseptic measures. The ideal ratio for blood to the culture medium is 1:10.

Before initiating the blood collection, automated systems blood culture bottles should be kept in a fridge at a temperature of below 25°C, while the conventional broth may be kept at room temperature.

After the blood sample is inoculated in the culture bottle, it should be stored at room temperature till dispatched to the laboratory. The culture bottles should be sent to the laboratory as early as possible. It is to be noted that the Gram-negative and Gram-positive organisms begin to grow within 24 and 48 hours of incubation. Any growth that starts after 48 hours of incubation is most likely a skin contaminant. Hence, proper skin preparation is a must before sample collection.

5.3 CSF examination

Positive CSF culture is the gold standard test for diagnosing meningitis.

Lumbar puncture should be done in all symptomatic neonates with EOS as well as LOS. It may be adjourned in a neonate with RDS without any associated risk factor for sepsis and asymptomatic neonates with any risk factor for EOS. However, LP should be considered in cases where the neonate develops signs of sepsis later. LP should be done before initiation of antibiotics but should be delayed in critical babies till stable. In case of traumatic tap, it must be repeated after 12–72 hours as the presence of RBCs will complicate the interpretation. A traumatic tap increases the cell count and alters the protein levels. It is accepted that for a blood-stained CSF, the ratio of red to white cells should be more than 500:1 in uninfected CSF.

Repeat Lumbar Puncture is not recommended in babies who show signs of recovery, but it should be repeated after 48 hours, in those neonates who show no clinical recovery even after initiation of antibiotics. WBC count and sugar levels should be assessed within 30 minutes of drawing the CSF sample as these parameters fall very rapidly with passage of time.

Various studies have suggested that CSF indices are different in both term and preterm infants, and there is no single cutoff to determine abnormal CSF values especially in newborns. Table 2 depicts the normal ranges for white cell counts, protein, and glucose in the CSF sample of neonates [20, 21]. In neonates, if the polymorphonuclear count is more than 20/mm³, it should be suspected, and if more than 30, it is suggestive of bacterial meningitis. In term infants, the protein above 150 mg/dl and in preterm neonates more than 180 mg/dl are taken as meningitis. For glucose, the values less than 20 mg/dl or less than half of the simultaneous blood sugar level suggests meningitis. Beyond newborn period, the CSF findings in bacterial meningitis are the following: predominantly neutrophils in range of 10–100/mm³ to >1000/mm³, CSF protein is 50–100 to >500 mg/dL, and CSF/blood glucose ratio is less than 0.4.

Type of Infant	white cell counts (count/mm^3)	Protein (g/L)	Glucose (mmol/L)
Preterm <28 days	9(0–30)	1(0.5–2.5)	3 (1.5–5.5)
Term <28 days	6(0–210	0.6(0.3–2.0)	3(1.5–5.5)

Table 2.

Normal ranges for protein and glucose in the CSF of neonates.

All values are given as mean and ranges.

Source: Kim [12].

5.4 Neuroimaging

Diagnosis of bacterial meningitis is based specifically on clinical and CSF examination with microbiological findings. Neuroimaging in the form of CT scan, which is reserved for those neonates who do not respond to antimicrobial therapy and in whom complications such as subdural effusion, ventriculitis is suspected. For such cases, MRI is extremely useful for detecting and monitoring the complications of meningitis. Diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) are useful in differentiating abscesses from other ring-enhancing lesions [22].

6. Management

6.1 Supportive and adjunctive

• The first step of management in a sick child/neonate is supportive care

• Maintain optimum temperature, airway patency, breathing, and circulation

• Maintain oxygenation (spo2 90–95%)

• Maintain normoglycemia

• Start I. V fluids if hemodynamically unstable

• Electrolytes level should be maintained

• Anti-epileptics if needed

• Management of raised intracranial pressure with the help of cerebral dehydrates

• Elevating the head of the bed to 30 degrees

• Inducing mild hyperventilation in the intubated patient

• Adding cerebral dehydrants either 20% Mannitol at the dose of 0.25–1 g/kg or 3% hypertonic saline used as 5 ml/kg loading followed by 0.1–1 ml/kg/hour

6.2 Antibiotics

Premature infants, neonates, and infants less than 2 months of age form the highest risk group for bacterial meningitis in children. It is important to administer empirical antibiotics promptly. The antibiotic given depends on the age of the patient and local antibiotic susceptibility of the predominant organism. As the most common organisms causing meningitis are S. pneumoniae, N. meningitidis, and H. influenzae type b [23], third-generation cephalosporins, including cefotaxime and ceftriaxone, are known to possess broad-spectrum antibacterial activity against these [23].

6.3 Antibiotics in infants

Empirical antibiotics should be started as early as feasible, which can be modified according to the culture sensitivity report. Role of corticosteroids is debatable. If used better to be given within 4 hours of the first antibiotics dose and can be considered in the presence of focal neurological deficits. Antibiotics for infants beyond neonatal period and in the neonatal period are given in Tables 3 and 4, respectively.

Common organisms	Empirical antibiotics (should be given intravenously
Streptococcus pneumonia, Neisseria meningitides, Strep. agalactiae, Haemophilus influenzae, E. coli	Vancomycin (10–15 mg/kg/dose 6 hourly) plus a third-generation cephalosporin (e.g., ceftriaxone 50 mg/kg/dose 12 hourly, cefotaxime 75 mg/kg/dose 8–12 hourly)

Table 3.

Antibiotic treatment for bacterial meningitis in 1–24-month age group.

Source: IAP. Standard Treatment Guidelines 2022: Acute Bacterial Meningitis. p. 9.

Empirical Antibiotic	Each dose	Frequency	Duration
(a) Body weight < 2 kg
First line
In cefotaxime	50 mg /kg/dose	(0–7 days age) -12 hrly; (>7 days)-8 hrly	3 weeks
Inj Amikacin	15 mg/kg/day	(0–7 days age) -24 hourly; (>7 days)-24 hourly	3 weeks
Second line
Inj Meropenem	40 mg/kg/dose	8 hrly	3 weeks
Inj Amikacin	15 mg/kg/day	24 hrly	3 weeks
(b) Body wt > 2 kg
First line
Inj cefotaxime	50 mg/kg/dose	(0–7 days age) -8 hourly; (>7 days)-6 hourly	3 weeks
Inj Amikacin	15 mg/kg/day	(0–7 days age) -24 hourly; (>7 days)-24 hourly	3 weeks
Second line
Inj Meropenem	40 mg/kg/dose	8 hourly	3 weeks
Inj Amikacin	15 mg/kg/day	24 hourly	3 weeks

Table 4.

Antibiotic treatment for bacterial meningitis in neonates [24].

Source: NHM. Facility based Newborn care guidelines 2014. MOHFW.

6.4 Duration of antibiotics therapy

Unspecified bacterial meningitis: 10–14 days.

Neisseria meningitides: 5–7 days.

Haemophilus influenza: 7–10 days.

Streptococcus pneumonia: 10–14 days.

Gram-negative bacillary and pseudomonal meningitis: 21–28 days.

Ventriculitis – 4–6 weeks.

6.5 Treatment of complications

Subdural empyema- Subdural empyema occurs due to collection of pus between duramater and piamater. It presents as persistent fever despite antibiotics, altered sensorium, and convulsions. For this neurosurgical consultation should be taken. Drainage or craniotomy and washout are options. Duration of antibiotics can range from 3 to 6 weeks depending on the resolution of symptoms.

Ventriculitis- Ventriculitis means inflammation of the lining of the ventricles. It presents as fever, signs of meningial irritation, seizures, and altered sensorium. May also need neurosurgical consultation. For the management may require Ommaya reservoir placed to give intraventricular antibiotics and to drain CSF regularly. Once CSF is sterile, ventriculoperitoneal shunt insertion is done.

7. Prevention- immunization

According to an Indian study, around 27–39% of bacterial meningitis in children is caused by Pneumococci. Vaccination of children against the chief causative organisms can decrease this burden a lot. Parents should be educated regarding vaccine-preventable meningitis (H. influenzae type B, S. pneumoniae, N. meningitides, Measles, and Varicella).

The 2019 WHO position paper recommends inclusion of pneumococcal conjugate vaccine in routine childhood immunization worldwide owing to the increased morbidity and mortality caused by S. Pneumoniae either due to pneumococcal meningitis or pneumonia.

Pneumococcal vaccines are of two types – Pneumococcal Conjugate vaccine (PCV) for general population and Pneumococcal polysaccharide vaccine (PPV) for high-risk group.

7.1 Pneumococcal conjugate vaccine (PCV)

There are two types of PCV recommended by WHO, i.e., PCV10 (10 serotypes) and PCV13 (13 serotypes) [25]. The Government of India, Ministry of Health, and Family Welfare, and Gavi, the Vaccine Alliance, have included PCVs in the state immunization programs for all of India’s states and union territories [4]. The national Immunization Schedule recommends two primary doses of PCV, first at 6 weeks and second at 14 weeks, followed by a booster dose at 9 months [4]. According to Indian Academy of Pediatrics, PCV vaccination has three primary doses with a gap of at 4 weeks, followed by a booster 6 months after the third dose, preferably between 12 and 15 months of age. Rapid scale-up and widespread use of the pneumococcal conjugate vaccine and sustained use of the Hib vaccine could help accelerate achievement of child survival targets in India.

7.2 Pneumococcal polysaccharide vaccine (PPSV)

This vaccine is used in the age group 2 years and above only for the vaccination of persons with certain high-risk conditions. It is not recommended in healthy children. It should never be used alone but administered 8 weeks after the last dose of PCV to children aged 2 years or older with certain underlying medical conditions such as anatomic or functional asplenia, for example, sickle cell disease, HIV infection, cochlear implant, cerebrospinal fluid leak.

Family members should be educated about the need for prophylaxis when there is a family member with Neisseria and H. influenzae type B meningitis. All contacts should be educated about the signs and symptoms of the infection and when to return to the emergency department [26].

In India, meningococcal vaccination with MenACWY is recommended only for certain high-risk groups of children, during outbreaks and for international travelers, including students going abroad to pursue studies and travelers to the Hajj and sub-Saharan Africa regions.

8. Future perspective

Newer PCV 10 (Pneumosil) is recently endorsed by Indian academy of pediatrics for vaccination of healthy children. PCV15 has completed its trial in children, and PCV 20 vaccines are under trials for providing wider coverage of most of the invasive pneumococcal infection. Also there are investigational pneumococcal protein-based vaccines that are currently under clinical trials. Like- Protein-based, serotype-independent subunit vaccines, Combination (protein vaccine antigens plus PS-conjugates) vaccine, Pneumococcal whole-cell vaccine.

9. Conclusions

• Acute bacterial meningitis in young infants is a serious disease with high mortality and morbidity.

• Well-appearing febrile infants can become toxic quickly and are at high risk for systemic bacterial infection due to their immature immune systems.

• The lumbar puncture with a culture of the CSF continues to be the gold standard of diagnosis. CSF examination is a must in any neonate suspected of sepsis as the manifestations are usually subtle.

• In children with neurologic symptoms, consider other etiologies; however, meningitis must be ruled out, due to its high morbidity and mortality

• Delay in initiating antimicrobial, even for a few hours can be detrimental

• Neurologic sequelae that can result may require, in many cases, lifelong care. One needs to be vigilant in the follow-up of these babies to examine neurodevelopmental status carefully.

Conflict of interest

There is no conflict of interest.