Case Study 104 Meningitis

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CASE REPORT

Our case, a 10-day-old male patient, was born by normal spontaneous delivery at term with a weight of 3,380 g. During pregnancy, his mother was regularly followed up. The natal history was unremarkable. He was breastfed and discharged without any problems on postnatal day 2. The neonate was admitted to the neonatal intensive care unit due to fever and difficulty breathing. An initial physical examination of the patient revealed cutis marmorata. He was hypotonic in general and exhibited poor sucking. The results of cardiovascular and respiratory examinations were normal. The patient did not exhibit organomegaly or eruptions. The capillary filling time was 2 s. The patient's initial vital findings were as follows: axillary temperature, 38.8°C; heart rate, 190/min; respiratory rate, 55/min; and arterial blood pressure, 100/60 mm Hg. The admittance weight of the neonate was 3,530 ± 150 g. The results of a complete blood count and serum biochemical analysis did not reveal any abnormalities. The patient's C-reactive protein level was normal (0.2 mg/dl).

A urinalysis and chest X-ray were normal. A peripheral blood smear revealed that the immature/total neutrophil ratio was 0.3. An analysis of arterial blood gases revealed both respiratory and metabolic acidosis.

Blood and urine culture samples were obtained. The patient was diagnosed with sepsis and respiratory insufficiency based on the clinical and laboratory findings. He was intubated and given respiratory support with mechanical ventilation in SIMV (simultaneous intermittent mandatory ventilation) mode. Ampicillin (100 mg/kg of body weight/day) and cefotaxime (100 mg/kg/day) were administered. Intravenous fluid was given at an infusion rate of 150 ml/kg/day. Cranial, abdominal, and urinary ultrasound investigations done during clinical follow-up were evaluated as normal.

To rule out meningitis, a lumbar puncture was done; the cerebrospinal fluid (CSF) biochemistry did not reveal any abnormalities.

During the second hour of hospitalization in the intensive care unit, the patient's capillary filling time was found to be increased (5 s), and hypotension and bradycardia developed; thus, he was given a 10-ml/kg bolus of physiological serum twice. Because the patient's hypotension persisted, dopamine (10 μg/kg/min) and dobutamine (10 μg/kg/min) were given. However, during the fifth hour of admittance, a generalized purpuric eruption (Fig. 1) that enlarged and began to coalesce developed. Laboratory testing revealed leukopenia and thrombocytopenia, prolonged coagulation, and a rise in the C-reactive protein level (3.5 mg/dl). Vitamin K (1 mg) and fresh frozen plasma (15 ml/kg) were administered to the patient, and the antibiotic regimen was changed to vancomycin (30 mg/kg/day) and meropenem (40 mg/kg/day). A total of 1 g/kg of intravenous immunoglobulin was administered. Because the patient's hypotension persisted, the doses of dopamine and dobutamine were increased to 15 μg/kg/min. After that, noradrenalin was started at a dose of 0.1 μg/kg/min and later increased to 1 μg/kg/min. However, after 12 h, the patient exhibited severe bradycardia and cardiac arrest developed. The child did not respond to cardiac resuscitation. With consent from the patient's parents, an autopsy was performed.

FIG 1

Generalized purpuric eruption.

Neisseria meningitidis (untypeable) was isolated from blood and tissue cultures. A CSF culture was sterile.

Although N. meningitidis is a frequent cause of bacterial meningitis and sepsis (referred to as invasive meningococcal disease) during childhood and adulthood, it is rare and causes a high rate of mortality during the neonatal period (1). The incidence of invasive meningococcal disease in the general population is 0.5 to 1.1 per 100,000 (2). Although its incidence differs according to the annual epidemics and region, it is estimated that meningococcal meningitis comprises 0.54% of neonatal meningitis cases (3–4). Data from the Bacterial Core Surveillance Program indicated an annual incidence of 9 per 100,000 newborn infants (5).

After the initial presentation, which may include simple symptoms like fever, pharyngitis, and myalgia, the disease can progress to a fulminant fatal disease with disseminated intravascular coagulation, hypotension, and septic shock. Despite treatment with antibiotics and advanced intensive care support, the reported mortality in the general population is nearly 10 to 14% (2).

Here, we have described a neonate with meningococcal sepsis who was admitted to the hospital on postnatal day 10 with a fever, respiratory difficulties, and a purpuric rash appearing a few hours after hospitalization, and we discussed the clinical features of the case in relation to the literature.

Neisseria meningitidis is a Gram-negative diplococcus that can be transmitted via respiratory and vaginal secretions. The incubation time is 1 to 10 days. The most important risk factor in disease development is nasopharyngeal carriage (6). In general, the carriage rate in the respiratory tract mucosa is 5 to 20% (7–10). The carriage rate in our country is 1.23 to 28% (11–14). On the other hand, other risk factors for invasive meningococcemia are prematurity, acute viral infections, age less than 2 years, a terminal complement system (C3 and C5-9) deficiency, properdin deficiency, anatomic or functional asplenia, crowded environments, and active or passive smoking (6).

In our case, nasopharyngeal carriage among first-degree relatives and maternal vaginal carriage were found to be negative.

Neisseria meningitidis can cause meningitis in people of all ages, but the frequency is increased in childhood and adolescence; in fact, most cases occur within the first year of life and during adolescence. Nearly half of all meningococcemia cases occur in children less than 2 years of age (6).

There are rare case reports in the literature about meningococcemia during the neonatal period. However, sufficient information about the general frequency is not available. A literature search conducted using the PubMed, Google Scholar, and Scirus databases revealed 33 invasive meningococcal cases from 27 reports (15–39). Of these cases, detailed information was collected for 31 cases; the clinical and epidemiological characteristics of the patients were compared with those of our case (Table 1).

In 40% (n = 13) of cases, the disease developed during the first week. The initial symptoms of the cases were generally insignificant. After the first week, the clinical findings became distinctive (Table 2). A definitive diagnosis was successfully made after isolation from blood and CSF cultures. The microorganism was detected in 60% (n = 19) of cases by blood culture, in 72% (n = 23) of cases by CSF culture, and in 37% of cases (n = 12) by both blood and CSF cultures. Maternal vaginal colonization was detected in 6 (18.75%) cases. The most- to least-detected subgroups were as follows: untypeable (n = 14 [44%]), type B (n = 9 [28%]), type C (n = 6 [19%]), type W135 (n = 2 [6%]), and type A (n = 1 [3%]). A total of 31.25% (n = 10) of the infants were lost. Fifty percent of the deaths occurred in children who developed the disease during the first week.

A diagnosis can be made by identification of the agent in blood, CSF, or some other body fluid. Efficient supportive treatment (e.g., hemodynamic feeding and thermoregulation) is as important as antibiotic treatment (crystallized penicillin, cefotaxime, ceftriaxone, and chloramphenicol). Chemoprophylaxis should be administered to all relatives and health care workers who interact closely with the respiratory secretions of the patient. In our case, chemoprophylaxis (rifampin) was administered to both the family and health care staff.

In most cases, the initial symptoms are unclear. Shock and multiorgan failure develop within a few hours after fever. The mortality rate is 40% among patients in whom the disease develops within the first week of life. It is known that some neurodevelopmental morbidity may be observed in survivors. Hydrocephalus, subdural empyema, and the development of spinal dysfunction have been reported in four cases (15, 16, 29, 35).

In the case described by Kurlenda et al. (28), in which the patient was born prematurely (during week 31 of pregnancy) due to early membrane rupture, sepsis and meningitis developed during the first day of life; thus, the causative agent could not be isolated from CSF or blood. However, the isolation of type B N. meningitis from amniotic fluid, gastric fluid, and eye and ear swab cultures suggested intrauterine infection.

Despite the high carriage rate in the community, the reason for the rarity of these infections in neonates may be the protective effect of antibodies passed from mother to fetus during the neonatal period. These antibodies decrease until month 6 and disappear completely at 18 to 24 months. At the same time, with these antibodies, the disease can be seen as an unimportant mild viral disease, and this may make diagnosis of the illness difficult. Despite these protective antibodies and appropriate treatment, a congenital immune deficiency or deficiency in naturally acquired antibodies against N. meningitidis is a possible reason for the fatal disease (40–42).

In invasive meningococcemia, immune-based antibody-antigen reactions cause multiorgan failure via microvascular damage. However, due to the immunologic immaturity of neonates, antibody-antigen complexes and vasculitis caused by these complexes do not occur or develop during the late stages of the disease. Petechiae and purpura suggesting meningococcemia occur infrequently in neonates. These conditions can lead to treatment delays.

Despite the early initiation of antibiotic and supportive treatment, the unresponsiveness of the patient to treatment suggests an immune deficiency (e.g., complement, properdin, or protein C deficiency) that decreased the treatment response. In our case, the protein C level was lower than normal; however, the protein C levels of the mother and father were normal. In our case, the low protein C levels were attributed to consumption due to disseminated intravascular coagulation.

Conclusions.In N. meningitidis cases that are diagnosed during the first week of life, genitourinary colonization of the mother or nasopharyngeal carriage among close relatives must be evaluated. In communities with a high nasopharyngeal carriage rate, contact between neonates and crowded environments must be avoided.

During the neonatal period, in cases of sepsis/septic shock that respond poorly despite early, fast, and appropriate treatment, N. meningitidis should be considered even if there are no specific clinical findings. Additionally, the presence of an immune deficiency should be taken into account.

TABLE 1

Characteristics of neonates with invasive infection caused by Neisseria meningitidis

TABLE 2

Clinical findings according to age

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FOOTNOTES

    • Received 15 April 2014.
    • Returned for modification 9 May 2014.
    • Accepted 7 July 2014.
    • Accepted manuscript posted online 16 July 2014.
  • Address correspondence to Evrim Kiray Baş, kiray_evrim{at}hotmail.com.

REFERENCES

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Introduction:

In neonates and young infants, it can be difficult to distinguish bacterial from aseptic meningitis, especially in the setting of marked CSF (cere-brospinal fluid) pleocytosis. This case series and review of the literature explores the role of early CSF EV-PCR (enterovirus-polymerase chain reaction) in these patients' diagnostic workup, management, and overall hospital stay.

Case Series:

Patient 1 was a 30-day-old female who presented with a fever of 102°F and increased irritability for 1 day. She was admitted to the hospital for an evaluation including complete blood cell count (CBC), blood culture, urine culture, urinalysis, and lumbar puncture (LP). Ampicillin, gentamicin, and acyclovir were initiated. Admission laboratory data included peripheral white blood cell (WBC) count of 9200 cells/μL and a normal urinalysis. Cerebrospinal fluid (CSF) was remarkable for pleocytosis of 1005 cells/μL with 53% lymphocytes, 0 red blood cells (RBCs), protein of 92.8 mg/dL, and glucose of 44 mg/dL (Table 1). Gram-stain of the CSF revealed Gram-positive cocci in pairs; however, no bacteria were cultured. Results of the urine culture were negative. The blood culture grew coagulase-negative Staphylococcus, which was believed to be a contaminant. The patient continued to be febrile despite 72 hours of antibiotic therapy. Therefore, a repeat LP was performed, revealing 80 WBC/μL with 63% lymphocytes, 700 RBC/μL, protein of 138 mg/dL, and glucose of 38 mg/dL. Enterovirus-polymerase chain reaction (EV-PCR) performed on the repeat CSF was positive. Herpes simplex virus polymerase chain reaction (PCR) was negative. Antibiotic therapy was discontinued, and the patient was discharged from the hospital.

Patient 2 was a 7-day-old female who presented with fever of 104°F for 1 day and jaundice. She was transferred from a referring hospital after undergoing an evaluation that included CBC, blood culture, urine culture, urinalysis, and LP. Ampicillin, gentamicin, and acyclovir were begun before patient transfer. WBC count and urinalysis at the referring hospital were reported as normal. Total bilirubin was 9.9 mg/dL. CSF results included 2090 WBC/μL with 22% lymphocytes, 4 RBC/μL, protein of 145 mg/dL, and glucose of 40 mg/dL (Table 1). Test results for blood, urine, and CSF culture were negative. CSF herpes simplex virus PCR was negative, and CSF EV-PCR was positive. Antibiotic therapy was discontinued, and the patient was discharged from the hospital.

Patient 3 was a 6-day-old male who presented with fever to 100.8°F for 2 days. He also underwent an evaluation including CBC, blood culture, urine culture, urinalysis, and LP. Laboratory test results included 7800 WBC/μL and a normal urinalysis. CSF results included 976 WBC/μL with 94% neutrophils, 5 RBC/μL, protein of 198 mg/dL, and glucose of 28 mg/dL (Table 1). CSF Gram-stain was negative. The patient was initially started on intravenous ampicillin, cefotaxime, and acyclovir. Cefotaxime was discontinued in favor of gentamicin. Test results for blood, urine, and CSF cultures remained negative. The patient continued to have fever for 48 hours despite antibiotic and antiviral therapy. A repeat LP showed 130 WBC/μL with 85% neutrophils, 120 RBC/μL, protein of 157 mg/dL, and glucose of 36 mg/dL. Results of the Gram-stain and bacterial culture remained negative. EV-PCR of the CSF was positive. Antibiotic therapy was discontinued, and the patient was discharged from the hospital.

TABLE 1

Summary of Patient Laboratory Data

Question:

How do we currently distinguish aseptic from bacterial meningitis in patients presenting with marked CSF pleocytosis?

Discussion:

Aseptic meningitis is a common infection among children, with an estimated 75000 cases each year in the United States.1 Enteroviral infections account for up to 92% of the cases of aseptic meningitis in which an etiologic agent is identified.1 Enteroviral meningitis occurs most often during summer and early fall in temperate climates13 and usually has a benign course, although some patients develop seizures and coma.4 The most common enterovirus serotypes are Coxsackie B and echoviruses 4, 6,9, and 11.3

In enteroviral meningitis, CSF analysis shows pleocytosis with a median WBC count of 103 WBC/μL,4 although reports range from an absence of pleocytosis to >4000 WBC/μL. CSF WBC differential often shows an early dominance of neutrophils with increasing number of lymphocytes as time progresses, but this process is highly variable. CSF glucose and protein are usually in the normal range for a given age. However, hypoglycor-rhachia is seen in 5% of patients, and CSF protein is elevated in 39% to 62% of patients.57 Although bacterial meningitis is far less common than aseptic meningitis, it remains a concern in young children presenting with fever and CSF pleocytosis. In a retrospective study of neonates admitted through a pediatric emergency department, Caviness et al8 described 204 infants with fever and pleocytosis, of whom 11 (5.4%) had bacterial meningitis compared with 32 (15.7%) with non-herpes simplex viral meningitis. Ten of the 11 infants with bacterial meningitis in this group had >50% polymorphonu-clear cells on CSF evaluation. Overall, 14.9% of the 67 neonates with fever, CSF pleocytosis, and polymorphonu-clear predominance cells had bacterial meningitis.

In neonates and young infants, bacterial meningitis can be difficult to distinguish clinically from aseptic meningitis. For both entities, fever and irritability are the most common presenting signs in this age range. Signs and symptoms such as meningismus, headache, photophobia, anorexia, and altered mental status are either uncommon or impossible to elicit in neonates.4 CSF pleocytosis of >1000 cells/μL is typical in bacterial meningitis. A predominance of neutrophils, elevated CSF protein concentration, and decreased CSF glucose concentration are common.9 However, differentiation between enteroviral and bacterial meningitis based on initial CSF analysis can be difficult, with overlap in the expected ranges of WBCs, protein, and glucose in these conditions. Approximately 20% of neonates with bacterial meningitis will have pleocytosis <250 cells/μL, and up to 10% of neonates with enteroviral meningitis will show pleocytosis >1000 cells/μL.5,9

In a study of the Bacterial Meningitis Scale, Nigrovic et al9 evaluated the likelihood of bacterial meningitis based on positive CSF Gram-stain, CSF absolute neutrophil count (ANC), CSF protein, peripheral blood ANC, and history of seizures. A positive CSF Gram-stain was the most sensitive individual test, with 58% of patients with a positive test result having bacterial meningitis. Interestingly, only 9% of patients with a CSF ANC >1000 cells/μL had bacterial meningitis. CSF protein >80 mg/dL, peripheral ANC >10000 cells/ μL, and history of seizures each had a sensitivity of 2%. Taken as a group, the risk of bacterial meningitis was 0.1% if 0 risk factors were present; this risk increased to 95% if >4 risk factors were present.9 Applying this scale to our 3 patients, they would have a 27%, 27%, and 3% risk of bacterial meningitis, respectively.

Question:

Should CSF EV-PCR be used for all neonates and/or young infants presenting with fever and pleocytosis?

Discussion:

As demonstrated by this case series, CSF EV-PCR offers an additional tool in differentiating bacterial from enteroviral meningitis in neonates and young infants, particularly in the setting of marked CSF pleocytosis. The use of EV-PCR has become increasingly popular over the past decade because it provides rapid, accurate diagnosis and can reduce the use of medical resources for infected patients. EV-PCR methods can now produce results in a matter of hours with a sensitivity and specificity of virtually 100%.10 Patients with a positive EV-PCR result before hospital discharge have been shown to receive shortened courses of intravenous antibiotics and acyclo-vir, have significantly fewer ancillary tests performed, have shorter hospital stays, and have a more rapid hospital discharge than EV-PCR-negative patients.11,12

Specifically, patients with positive EV-PCR test results have had a reduction in length of stay of ∼30 hours.11 This finding correlates to a savings of ∼$1000 in hospital costs per positive test result.3 Nigrovic et al3 estimated that, given these savings, an enteroviral prevalence of disease of 5.9% in a tested population is required for EV-PCR to be a cost-effective test for utilization in all infants with fever and CSF pleocytosis. Because estimates of enteroviral meningitis in infants with fever and pleocytosis range from 66% to 90% depending on the season, EV-PCR should be cost-effective throughout the year. This efficacy increases as reporting of test results becomes more rapid. Patients with positive EV-PCR results reported <24 hours after specimen collection have had $2798 less in hospital charges than patients with positive results available in >24 hours.13

A potential concern for EV-PCR-guided management decisions is that a patient with a positive EV-PCR result may also have bacterial meningitis. We are unaware of any reports of enteroviral meningitis with associated bacterial meningitis.6,14,15 The rate of other concurrent bacterial infections in the setting of a known eneroviral infection is low, with 5.6% of neonates having a urinary tract infection and 1% having bacteremia.6 In such mixed infections, the clinical presentations are usually severe enough that positive EV-PCR detection is unlikely to deter clinicians from use of antibiotics.15 Another potential concern is that a false-positive EV-PCR result might allow a well-appearing patient with bacterial meningitis to be discharged. Current EV-PCR systems address the concern of false-positive test results by providing completely self-contained assay cartridges that perform all involved steps, including sample preparation. In evaluation of 1 such kit, 475 CSF specimens were tested, and no false-positive assay results occurred.15

Conclusions:

Year-round, routine use of CSF EV-PCR in all neonates and/or young infants with fever and pleocytosis may be warranted. Use of this technology may be particularly helpful in differentiating enteroviral from bacterial meningitis in patients with marked elevation of CSF WBC count. Justification is particularly strong in populations and seasons with a high prevalence of enteroviral disease. Early differentiation of bacterial meningitis from enteroviral meningitis may decrease iatrogenic risks associated with prolonged hospitalization, will allow decreased use of intravenous antibiotics and antiviral agents, and will produce savings for the health care system largely through decreased length of hospital stays. Positive EV-PCR results may promote earlier discharge and prevent continued evaluation in persistently febrile infants, especially those who are well appearing with a normal peripheral WBC count, normal urinalysis, lack of pretreatment, and with availability of reliable follow-up in their medical home.

Footnotes

  • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

  • FUNDING: No external funding.

ANC
absolute neutrophil count
CBC
complete blood cell count
CSF
cerobrospinal fluid
EV-PCR
enterovirus-polymerase chain reaction
LP
lumbar puncture
PCR
polymerase chain reaction
RBC
red blood cell
WBC
white blood cell

References

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  • Copyright © 2012 by the American Academy of Pediatrics

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