A Clinical guide to pediatric infectious disease

11

Meningitis

Meningitis is defined as inflammation of the meninges. The term meningitis denotes only the presence of inflammation and not a specific etiology. The specific etiology of meningitis is determined by clinical history, cerebrospinal fluid (CSF) profile, cultures, and specific studies of the CSF.

Bacterial Meningitis

Epidemiology

Bacterial meningitis is the most feared form of pediatric meningitis. Bacteria, which colonize the skin, nasopharynx, or both, enter the bloodstream. These bacteria then “seed” the CSF. It is for this reason that blood cultures are positive in up to 90% of children with bacterial meningitis.

Presentation

Patients with bacterial meningitis typically present with high fevers, headache, and an altered mental state. The classic clinical triad of bacterial meningitis is fever, nuchal rigidity, and a change in mental status, although only two thirds of patients with bacterial meningitis actually have all three of these symptoms. Kernig's sign is a clinical examination technique whereby 90% flexion of the hips causes subsequent painful extension of the legs. Brudzinski's sign is involuntary flexion of the knees and hips after passive flexion of the neck while supine. Although these clinical signs have traditionally been used to evaluate for bacterial meningitis, recent studies in adults have found that Kernig's and Brudzinski's signs actually have a low sensitivity for predicting the presence of bacterial meningitis. The entire clinical picture should be used in determining whether to obtain a lumbar puncture.

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Diagnosis

The major reported risk in obtaining a sample of CSF is that a preexisting intracranial mass will cause a brainstem herniation following lumbar puncture. There are also concerns that lumbar puncture could cause herniation in a child who has increased intracranial pressure secondary to severe meningitis. Many clinicians obtain a computed tomography (CT) scan of the head before obtaining a lumbar puncture, although this may delay diagnosis and optimal therapy. Although herniation remains a possibility in the setting of bacterial meningitis, it remains an uncommon occurrence, with most estimates reporting an incidence of less than 5%. Although an increase in intracranial pressure is thought to be present in virtually all cases of pediatric bacterial meningitis, it is also known that CT of the brain is normal in most cases of bacterial meningitis, including cases that had subsequent herniation following lumbar puncture. Most specialists stress the need for an accurate history and physical examination when deciding whether to obtain imaging before lumbar puncture. It is noted that a patient with a mass lesion such as an abscess or brain tumor will usually report symptoms over the preceding weeks, whereas in bacterial meningitis, there is a history ranging from hours to days. The diagnosis of impending cerebral herniation can often be made clinically from abnormalities of the neurological exam, including sixth nerve palsy, dilated or fixed pupils, and decerebrate posturing. In patients who have the clinical features of impending herniation, lumbar puncture should be deferred and diagnostic testing limited to blood cultures. Aggressive measures to reduce intracranial pressure are mandatory in such a patient.

Cerebrospinal Fluid Examination

Examination of the CSF is critical. Typically, bacterial meningitis presents with a CSF white blood cell count of several thousand white cells, most being segmented neutrophils. The mean CSF white cell count in bacterial meningitis, regardless of whether patients have been pretreated, is greater than 4,000/m3. In bacterial meningitis, the protein concentration of the CSF will be high and glucose concentration low. The probability of a positive Gram stain is dependent on the number of bacteria present in the CSF, which may be related to the timing of lumbar puncture in relation to the onset of symptoms. A positive Gram stain of the CSF in bacterial meningitis is also related to the organism causing the meningitis. Streptococcus pneumoniae has the highest rate of having a positive Gram stain (about 90%), withNeisseria meningitidis having a positive Gram stain in about 75% of cases. CSF cultures are more likely to be positive in patients who had lumbar puncture before the administration of antibiotics.

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Management

Empiric Therapy for Bacterial Meningitis

When faced with a patient with presumed bacterial meningitis, it is optimal to start appropriate antibiotics as early as possible. The “Gram stain game” can help in this decision. The following are the major pathogens of pediatric bacterial meningitis.

  1. Streptococcus agalactiaegroup B streptococcus.A gram-positive coccus, group B streptococcus is a common cause of neonatal meningitis. Up to one half of women are colonized with S. agalactiaein the genital tract; neonates become colonized at the time of delivery. A certain percentage of these neonates then become bacteremic, which can result in CSF infection. Therapy is with ampicillin and gentamicin.
  2. Streptococcus pneumoniae. Another gram-positive coccus, this is the most common cause of infant and toddler meningitis. The mechanism is similar to that of group B streptococcus, whereby colonizing bacteria entering the bloodstream with subsequent infection of the CSF.
  3. Neisseria meningitidis. A gram-negative diplococcus, this can cause rapid onset of meningitis, septic shock, and death. Septic shock associated with N. meningitidisis often associated with rapid onset of petechial and purpuric lesions. Therapy is with a third-generation cephalosporin or intravenous penicillin.
  4. Listeria monocytogenes. A gram-positive rod, this organism is ubiquitous in the environment and commonly found in unpasteurized food products. Meningitis usually occurs in the neonatal period and in immunocompromised patients. This is the one cause of bacterial meningitis not sensitive to the third-generation cephalosporins. Ampicillin is the drug of choice, used in combination with gentamycin. For patients who cannot tolerate ampicillin, intravenous trimethoprim-sulfamethoxazole is recommended as the second choice. Vancomycin may be a successful alternative antibiotic, although treatment failures have also been reported.
  5. Haemophilus influenzae(type b). Before the development of the conjugate vaccine, this gram-negative coccobacillus frequently caused invasive disease. Pediatricians rarely encounter type b H. influenzaemeningitis in unvaccinated populations. There are increasing reports of nontypeable Haemophilus causing invasive disease, including meningitis. Treatment is with a third-generation cephalosporin; ampicillin can be used if the causative bacteria are β-lactamase negative.

Pathogen

Comments

Antibiotics

Neisseria meningitidis

Gram-negative diplococcus
Associated with purpura fulminans

1.   Penicillin G, 100,000–400,000 units/kg per day in four divided doses

2.   Ceftriaxone, 100 mg/kg per day in two divided doses

3.   Cefotaxime, 200 mg/kg per day in three divided doses

Haemophilus influenzae(type b)

Gram-negative coccobacillus

1.   Third-generation cephalosporin, or ampicillin if β-lactamase negative

Listeria monocytogenes

Gram-positive rod
Occurs in neonates, immunocompromised patients

1.   Ampicillin, 200–400 mg/kg per day in four divided doses

2.   Gentamicin, 6–7.5 mg/kg per day in three divided doses

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Special Considerations: Treatment of Streptococcus pneumoniae

The most common cause of infant and toddler meningitis remains S. pneumoniae, although this may ultimately change owing to the recent addition of the conjugate vaccine to primary immunization series.

Resistance of S. pneumoniae. One of the major issues in the treatment of pneumococcal meningitis is the increasing resistance to penicillin and cephalosporins. Resistance is mediated by alterations in penicillin-binding proteins. This increases the minimal inhibitory concentration (MIC) to both these antibiotics; that is, increased concentrations of antibiotic are needed to inhibit growth of bacteria. The problem faced with treating meningitis in the context of increasing MIC is as follows:

1.   A CSF antibiotic concentration of 10 times the MIC of the infecting organism is required to ensure cure in an infection as serious as meningitis.

2.   Because of the blood–brain barrier, there is a limit to antibiotic concentration achievable in the CSF. As MIC values increase, a CSF antibiotic concentration of 10 times the MIC cannot be achieved.

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The breakpoint is the highest MIC at which an organism is defined as sensitive to a given drug. The desire to achieve a CSF concentration of 10 times the MIC explains the breakpoints for penicillin and third-generation cephalosporins for the treatment of S. pneumoniaemeningitis. The maximal concentration of penicillin obtained in the CSF is about 1.0 µg/mL. The breakpoint for the use of penicillin in pneumococcal meningitis is 0.06 µg/mL; any MIC to penicillin of an infecting pneumococcus greater than this does not guarantee a concentration 10 times the MIC. The maximal concentration for a third-generation cephalosporin in the CSF is about 5.0 µg/mL. The breakpoint for cefotaxime or ceftriaxone is 0.5 µg/mL; if the MIC is greater than 0.5, a concentration in the spinal fluid of 10 times the MIC cannot be ensured.

Rates of resistance vary from community to community. Rates of S. pneumoniae with an MIC to penicillin greater than 0.1 µg/mL can be as high as 75%. Rates of pneumococcus with an MIC to a third-generation cephalosporin greater than 0.5 µg/mL can approach 20%. These numbers may increase as antibiotic overuse persists. It is for this reason that empiric therapy for presumed pneumococcal meningitis includes vancomycin (15 mg/kg given intravenously every 6 hours) and a third-generation cephalosporin. All pneumococcal isolates from the CSF should be tested for MIC to penicillin and third-generation cephalosporins. After specific MICs are available, therapy can be tailored appropriately.

There is little experience, although justifiable concern, in the management of children with pneumococcal meningitis in which the isolated bacteria has an MIC to cefotaxime or ceftriaxone greater than 2.0 µg/mL. In those cases, treatment with both vancomycin and a third-generation cephalosporin is recommended. The addition of rifampin, 20 mg/kg in two divided doses, should also be considered.

Meropenem is a new antibiotic that has excellent gram-negative coverage and good CSF penetration. Although approved for children 3 months of age or older with penicillin-susceptible pneumococcal meningitis, there is little clinical experience with this drug in resistant pneumococcal isolates. In the coming years, more data regarding meropenem in the treatment of resistant pneumococcal meningitis will be available.

Antibiotic Therapy for Streptococcus pneumoniae Meningitis

·   Penicillin susceptible (MIC < 0.1µg/mL)
   Penicillin, 100,000–400,000 units/kg per day in four divided doses

·   Penicillin intermediate (MIC = 0.1–1.0 µg/mL)
   Cefotaxime, 200 mg/kg per day in three divided doses
   Ceftriaxone, 100 mg/kg day in two divided doses

·   Penicillin resistant (MIC > 1.0 µg/mL)
   Cefotaxime, 200 mg/kg per day in three divided doses
   Ceftriaxone, 100 mg/kg per day in two divided doses

·   Cefotaxime or ceftriaxone sensitive (MIC < 0.5 µg/mL)
   Cefotaxime, 200 mg/kg per day in three divided doses
   Ceftriaxone, 100 mg/kg per day in two divided doses

·   Cefotaxime or ceftriaxone intermediate (MIC = 0.5–2.0 µg/mL)
   Third-generation cephalosporin with vancomycin, 15 mg/kg every 6 hours

·   Cefotaxime or ceftriaxone resistant (MIC > 2.0 µg/mL)
   Third-generation cephalosporin with vancomycin, 15 mg/kg every 6 hours; consider adding rifampin, 20 mg/kg per day. Can also consider meropenem, 120 mg/kg per day in three divided doses

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Steroid Therapy for Bacterial Meningitis

During the past decade, increasing attention has been given to adjunctive treatment for bacterial meningitis. It is recognized that bacterial meningitis is a disorder of intense inflammation and that this inflammation can result in substantial morbidity, primarily in the form of hearing loss. For patients with H. influenzae type B meningitis, dexamethasone is recommended. The dose is 0.15 mg/kg of dexamethasone every 6 hours for 4 days.

The use of steroids in pneumococcal meningitis is more controversial. A major concern is a possible decrease in antibiotic concentration in the CSF when steroids are given. In animal models, vancomycin concentration was altered up to 75% when concurrent steroids were used. The few clinical trials performed have not shown CSF differences in vancomycin and cefotaxime concentrations in the presence of dexamethasone. Two retrospective studies regarding outcome in patients with resistant pneumococcal meningitis receiving dexamethasone have been published, reaching different conclusions. In a small number of children with bacterial meningitis who received both vancomycin and dexamethasone, vancomycin levels in the CSF were comparable to those measured in children who receive vancomycin without dexamethasone. At this point, the opinion of the American Academy of Pediatrics is that the clinician needs to evaluate each case individually, weighing risks and benefits of steroid use.

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Aseptic Meningitis

Etiology

The term aseptic meningitis is defined as meningitis associated with negative bacterial cultures. Most cases of aseptic meningitis are caused by viral pathogens, with enterovirus being the leading cause. Enteroviruses comprise several serotypes, including coxsackievirus, echovirus, and poliovirus. These pathogens predominate in the summer or fall months and may cause epidemics of disease.

Presentation

Patients usually present with acute onset of fever, headache, and vomiting. Clinical signs of meningeal irritation may be present. Photophobia and myalgias are common. There may be an associated gastroenteritis. Patients are typically not as acutely ill as those with bacterial meningitis.

Evaluation of Cerebrospinal Fluid

A common challenge facing the pediatrician is using the results of the CSF to determine whether the child has aseptic meningitis. Aseptic meningitis is typically characterized by a few hundred white blood cells, most of which are lymphocytes. In contrast, bacterial meningitis is characterized by thousands of white blood cells with a segmented neutrophil predominance. It also should be noted that in most cases of bacterial meningitis, there are other abnormalities seen in the CSF, such as a positive Gram stain and low glucose and high protein levels.

Standard textbooks also state that aseptic meningitis can have a predominance of polymorphonuclear cells early in the course of disease. It has long been thought that in aseptic meningitis with an early segmented neutrophil predominance, repeat lumbar puncture after 24 hours will document the typical picture of lymphocytic predominance. Recent studies have challenged this assumption; one study showed that most children with aseptic meningitis in the height of the enteroviral season actually maintained a predominance of segmented neutrophils in the CSF even after the first 24 hours of illness. These same studies also pointed out that the average number of white blood cells in patients with viral meningitis remains in the low 100s, whereas in bacterial meningitis, it is several thousand. Ultimately, the clinician evaluating the CSF from a patient will need to consider the entire clinical picture, including history, clinical exam, and abnormalities of the spinal fluid.

Diagnosis

Enterovirus can be cultured from CSF. Polymerase chain reaction (PCR) has been shown to be more sensitive than culture, and in many settings, results can be available in less than 24 hours.

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Management

Treatment is generally supportive, including hydration and pain management.

Encephalitis

Encephalitis refers to inflammation of the brain. Meningoencephalitis is a condition in which both brain and meninges are affected.

Etiology

Encephalitis can be caused by any of a long list of infectious agents. These pathogens can cause encephalitis by either direct invasion of the brain or by a postinflammatory effect. The exact mechanisms for certain agents are not well defined.

Determining the etiology of a particular encephalitis can be challenging. Brain biopsy is usually not performed. Many pathogens causing encephalitis are fastidious and are difficult to grow in standard culture. Serology has historically been a mainstay of diagnosis; recent advances in PCR technology have been employed to maximize yield in the diagnosis of encephalitis.

Presentation

Patients with encephalitis usually are sicker than those with typical aseptic meningitis because the brain itself is inflamed. Seizures are common, as are focal neurologic deficits and cognitive disturbances. CSF often shows an “aseptic” picture with several hundred white blood cells, most of which are lymphocytes.

The following is a brief discussion of the major pathogens implicated in pediatric encephalitis. In evaluating a patient with encephalitis, a complete history, particularly in regard to travel, animal exposure, concurrent immunosuppression, and geographic location, is critical.

Herpes Simplex Virus

Epidemiology and Etiology

Herpes simplex virus (HSV) is responsible for up to 30% of diagnosed adult viral encephalitis. Infection is thought to begin with colonization or infection in the nasopharynx; invasive disease can then result because HSV has an affinity for the frontal and temporal lobes of the brain.

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Presentation

The clinical spectrum of herpes simplex encephalitis has been reevaluated as diagnostic testing has become more sensitive. Once thought to be primarily a cause of acute encephalitis, it is appreciated that a more chronic course, including febrile seizures and progressive loss of higher cognitive function, is possible. The focal hemorrhagic nature of herpes encephalitis is well described. Younger patients are more likely to have characteristic lesions in areas other than the temporal lobes typically described in adults. Seizures are common, and progression to coma is frequently seen.

Diagnosis

The diagnosis of herpes simplex involves several techniques. Electroencephalography is a noninvasive technique that shows temporal lobe spikes in about 80% of cases. Viral culture of the CSF is not very sensitive, resulting in positive cultures in only 20% of cases. PCR of the spinal fluid is considered to be the new gold standard for diagnosis of herpes simplex encephalitis. Although PCR of spinal fluid offers an improvement over previous diagnostic techniques, caution should be employed. Recent studies have shown that young children may have negative PCR in CSF, especially if CSF is sampled on the first or second day of illness. It has been postulated that early in HSV encephalitis, the virus is in the brain but is absent from the CSF. Evaluation for herpes simplex encephalitis in young children should take into account the entire clinical picture, particularly if characteristic lesions are seen on neuroimaging. In certain cases in which the clinical picture is consistent with herpes simplex encephalitis, a second CSF sample should be obtained. Antiviral therapy will have little effect on the presence of HSV DNA in the CSF; prior administration of acyclovir should not preclude the continuing evaluation for herpes simplex in the CSF.

Management

HSV is one of the few treatable forms of encephalitis. Many infectious disease specialists believe that encephalitis is herpes simplex until proved otherwise. Patients with a clinical picture of meningoencephalitis should be started on acyclovir at a dose of 10 mg/kg every 8 hours.

Enteroviruses

Epidemiology and Etiology

Enteroviruses are in the family Picornaviridae, which includes poliovirus, coxsackie, and echovirus. These are a major cause of both pediatric aseptic meningitis

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and encephalitis. Epidemics of nonpolio enteroviral infections frequently occur in late summer and early fall.

Presentation

Children with enteroviral encephalitis initially may have fever, headache, and photophobia, often accompanied by symptoms of gastroenteritis. Encephalitis will then manifest with seizures, focal neurologic deficits, and altered mental status. Neonates with enteroviral disease may have a disseminated illness that closely resembles that caused by herpes simplex virus. These neonates in the first weeks of life may present with fever, liver failure, and coagulopathy.

Diagnosis

Diagnosis of enteroviral disease is as described previously. PCR can be obtained on serum and CSF and is the quickest and most sensitive diagnostic test.

Management

Treatment is generally supportive. Pleconaril is an oral antiviral agent that has been shown in compassionate use trials to be effective in some cases of severe disease, including disseminated neonatal disease.

Mycoplasma pneumoniae

Epidemiology and Etiology

  1. pneumoniaeis a common respiratory pathogen that is thought to be a major cause of pediatric encephalitis. In some series, it is the leading identifiable cause of encephalitis in children.

The organism has been isolated from brain and CSF by culture and PCR. Isolation implies direct invasion of the pathogen, although M. pneumoniae has also been implicated as a cause of immune-mediated disease, such as acute demyelinating encephalopathy, Guillain-Barré syndrome, and transverse myelitis. The mechanism of immune-mediated disease is proposed antigenic similarities between M. pneumoniaeand human neural tissue. It is speculated that patients with shorter prodromes may have a direct-invasion disease mechanism, whereas those with longer prodromes may have immune-mediated disease.

Presentation

Prodromal respiratory illness lasting days to weeks occurs in some patients, although disease has been documented without preceding respiratory symptoms. Mycoplasma

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encephalitis can be associated with focal neurologic signs thought to be the result of associated acute demyelination.

Diagnosis

The diagnosis of M. pneumoniae encephalitis is by culture, PCR of the CSF, or both. Serology can also be used, although false-negative results can occur.

Management

Treatment is supportive. A variety of treatments, including antibiotics intravenous immune globulin and corticosteroids, have been attempted, although there is no definite consensus as to their use.

Pediatric Viral Infections

A large number of common pediatric viral infections have been reportedly associated with encephalitis. These include Epstein-Barr virus, influenza virus, and cytomegalovirus. The mechanism of the encephalitis is not known, being either direct viral invasion or secondary immune response. In the setting of encephalitis, serologies for these pathogens, as well as PCR studies, can be useful in diagnoses.

Arboviruses

Arboviruses are arthropod-borne viruses spread by mosquitos, ticks, or sand flies. These pathogens cause a wide spectrum of illness ranging from self-limited febrile illnesses to aseptic meningitis to encephalitis. Certain arboviruses are present in specific regions in the United States and usually occur in late summer and early autumn.

California encephalitis (La Crosse Virus)

Etiology

La Crosse encephalitis is caused by Bunyavirus. The name is a misnomer, reflecting not geographic location but rather the initial place of discovery. The disease is actually found in the Midwestern and Eastern United States. It is often considered the most common pediatric arboviral infection in the United States.

Presentation

There is a spectrum of disease from mild febrile illness to aseptic meningitis to fatal encephalitis. There is usually a febrile prodrome, which can include headache and vomiting. La Crosse encephalitis occurs mostly in children; seizures are the

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presenting symptom in one half of cases. Focal neurologic signs, including paralysis, are seen in one fourth of cases.

Diagnosis

Diagnosis is by serologic methods, usually an immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) capture antibody.

Management

Treatment is supportive. Ribavirin has been used in clinical trials, although no definitive proof of its usefulness exists.

St. Louis Encephalitis

Etiology

St. Louis encephalitis is caused by a virus in the Flaviviridae family. This is considered an important arboviral infection due to its ability to cause epidemics of disease. A large number of cases have been reported in midwestern states as well as in Texas, Louisiana, and Florida.

Presentation

Patients with St. Louis encephalitis often present with headache and fever. Associated paralysis or weakness can occur, as can multiple cranial nerve palsies.

Diagnosis

Diagnosis is by serology, usually IgM ELISA.

Management

Treatment is supportive. No specific medical therapy is currently available.

West Nile Virus

Etiology

West Nile virus is the arbovirus most reported in the medical news. It appeared in North America in 1999 in New York City, causing 62 cases, with seven deaths. A flavivirus found commonly along major bird migration pathways, it is transmitted to birds by mosquitos, which can also infect humans. Transmission through organ transplantation, blood transfusion, and breast milk has also been reported.

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Presentation

Most infections are asymptomatic; infection can also be a self-limited febrile illness sometimes accompanied by a transient rash. Less than 1% of infections result in encephalitis. Extremes of age appear to be a risk factor for encephalitis. Patients with central nervous system involvement can exhibit encephalitis, abnormalities of movement, and ocular motor dysfunction. Examination of the CSF shows pleocytosis, with the majority of cells being mononuclear. Early signs of more severe neurologic disease include Guillain-Barré syndrome and transverse myelitis and can provide a clue to diagnosis.

Diagnosis

Diagnosis of West Nile virus is made primarily by serology. ELISA or immunofluorescent assay (IFA) are frequently used. PCR assays are also becoming available. Viremia, as detected by PCR, can be found before the onset of symptoms.

Management

There is no specific therapy for West Nile virus encephalitis. Ribavirin has been shown to inhibit the virus in neural cell cultures and has been administered to a small number of patients. There is no consensus on treatment. The major role of medical treatment remains supportive care (Table 11.1).

TABLE 11.1. Evaluation of Cerebrospinal Fluid in Pediatric Encephalitis

Pathogen

Diagnosis

1. Herpes simplex

1. CSF viral culture

2. PCR, CSF

3. EEG reveals temporal lobe spikes in 80%

2. Enteroviruses

1. Viral culture, CSF

2. Polymerase chain reaction, CSF

3. Viral culture of nasopharynx and stool (suggestive, not diagnostic)

3. Mycoplasma pneumoniae

1. Serology for mycoplasma IgM, IgG

2. PCR in cerebrospinal fluid

4. Arbovirus

1. West Nile virus

2. California equine (La Crosse)

3. St. Louis

1. Serology

CSF, cerebrospinal fluid; PCR, polymerase chain reaction; EEG, electroencephalogram; Ig, immunoglobulin.

Fungal Meningitis

Fungal meningitis is usually, but not exclusively, seen in patients with underlying immunodeficiency. The major organisms to be considered include Coccidioides immitis and Cryptococcus neoformans.

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Coccidioides immitis Infection

Etiology

This dysmorphic fungus is found in soil and infects people through inhalation of airborne spores.

Presentation

The most common manifestation in the normal host is a self-limited bronchitis. Disseminated disease occurs in less than 1% of infections, with the bones, skin, and central nervous system being common secondary sites. Severe disease is frequent in patients with underlying T-cell immunodeficiency, such as those infected with the human immunodeficiency virus (HIV). It can also be found in normal hosts, with African-American and Filipino patients at higher risk for disseminated disease.

In the immunocompetent host, the cerebrospinal profile is similar to a viral meningitis with several hundred cells, most of which are lymphocytes. In the severely immunocompromised patient, there may not be adequate functioning lymphocytes to cause an appropriate inflammatory response. In these patients, there may be a normal CSF even in the face of a severe fungal meningitis.

Diagnosis

Complement fixation antibodies in the serum and CSF are often used to make the diagnosis. Increasing antibody titers indicate progressive disease. Fungal cultures of CSF can also be used for the diagnosis.

Management

Treatment is always indicated for coccidioidomycosis meningitis. Treatment of coccidioidomycosis meningitis is usually with oral fluconazole, which achieves good levels in the CSF. Dosage is 400 mg per day, although doses as high as 1 g per day have been used. As with any granulomatous meningitis, hydrocephalus secondary to obstruction of cerebrospinal flow is always a possibility. If this complication develops, a ventriculoperitoneal shunt may be required. Therapy is typically indefinite in patients with CNS infection because withdrawing of medication often results in relapsed infection.

Cryptococcus neoformans Infection

Etiology

The etiology of C. neoformans meningitis is similar to that of coccidioidomycosis; it is found in soil contaminated with bird droppings and causes infection through inhalation of the organism.

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Presentation

In patients with HIV infection, it is one of the most common causes of central nervous system infection. These patients present with a severe headache but can also present with behavioral changes or focal neurologic signs.

Diagnosis

In patients with underlying immunodeficiency, the CSF may not contain numerous lymphocytes. Encapsulated yeast can be visualized by India ink staining of the spinal fluid. Antigen detection against the capsular polysaccharide of the organism in CSF is positive in more than 90% of patients. The organism can also be grown in fungal culture.

Management

Treatment of cryptococcal meningitis is with amphotericin B in doses of 0.5 to 0.7 mg/kg per day in combination with oral flucytosine (5-FC). When flucytosine is used, serum concentration should be monitored, as should complete blood counts. Patients should continue combination therapy for at least 2 weeks or until repeat culture of the CSF is negative. Immunocompromised patients with cryptococcal meningitis, as in patients with C. immitis meningitis, typically receive lifelong maintenance therapy with fluconazole.

Selected Readings

De Tiége X, Heron B, Lebon P, et al. Limits of early diagnosis of herpes simplex encephalitis in children: a retrospective study of 38 Cases. Clin Infect Dis 2003;36(10):1335–1339.

Glaser CA, Gilliam S, Schnurr D, et al. In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project 1998–2000. Clin Infect Dis 2003;36(6):731–742.

Greenlee JE. Approach to diagnosis of meningitis. Cerebrospinal fluid evaluation. Infect Dis Clin North Am 1990;4(4):583–598.

Oliver WJ, Shope TC, Kuhns LR. Fatal lumbar puncture: fact verus fiction. An approach to a clinical dilemma. Pediatrics 2003;112(3):3 174–176.