Central Nervous System Infections in the Immunocompromised Adult Presenting to the Emergency Department

Over the past 2 decades, the population of immunocompromised patients has increased dramatically in the United States. These patients are at elevated risk for both community-acquired and opportunistic central nervous system infections. We review the most common and serious central nervous system pathogens affecting these patients and outline a diagnostic and therapeutic approach to their management in the emergency department. We recommend a broad diagnostic evaluation, including neuroimaging and cerebrospinal fluid studies where appropriate, empiric antimicrobial therapy, and early involvement of subspecialists to provide comprehensive care for these complex patients.

Key points

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Emergency physicians should maintain a high index of suspicion for central nervous system infection in immunocompromised patients.
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The diagnostic approach to central nervous system infection in immunocompromised patients should include neuroimaging, lumbar puncture for cerebrospinal fluid sampling when appropriate, and pathogen-directed testing based on the differential diagnosis.
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Early empiric antimicrobial therapy should include coverage for community-acquired bacteria (eg, Streptococcus pneumoniae ), Listeria monocytogenes , and herpes simplex virus.
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Infectious disease, oncology, hematology, transplant, and other subspecialists should be consulted early in the management of immunocompromised patients with central nervous system infection.

The population of immunocompromised patients in the United States is increasing. More than 650,000 patients with cancer receive cytotoxic chemotherapy annually and this population is expected to rise in the coming years. In 2012, more than 90,000 patients with cancer were hospitalized for neutropenic fever owing to chemotherapy and subsequent immunosuppression. The number of solid organ transplants (SOT) performed annually has more than tripled since the Organ Procurement and Transplant Network began data collection in 1987 as advances in immunosuppression to prevent rejection have improved long-term survival. More than 20,000 hematopoietic stem cell transplants (HSCT) are performed annually in the United States, and it is estimated there will be more than 500,000 HSCT survivors by 2030, many of whom will require immunosuppression to prevent graft-versus-host disease. More than 37,000 cases of human immunodeficiency virus (HIV) infection were newly diagnosed in the United States every year from 2013 to 2018 and there are more than 1 million people living with HIV infection in the United States today. ^, The advent of novel immunomodulating drugs such as complement and check point inhibitors have also contributed to the expanding population of immunocompromised patients presenting for acute care in the emergency department (ED). ^, Although antimicrobial prophylaxis has greatly decreased the risk of opportunistic infection, immunocompromised patients remain significantly more vulnerable to infection compared to the general population.

Central nervous system (CNS) infections are relatively rare in the developed world. Meningitis accounts only for 66,000 ED visits each year in the United States. However, the risk for CNS infections is high among the immunocompromised, ranging from an 8-fold increase in HIV to a 30-fold increase in risk in allogenic HSCT recipients. In an early case series from San Francisco from the 1980s, up to 60% of patients with AIDS developed a CNS infection, often diagnosed on initial presentation to care. In another series, 3% of cardiac transplant patients developed a CNS infection within the first 4 years after transplant. Among allogenic HSCT, 4% had a CNS infection during the first year and this factor was significantly associated with mortality. Immunocompromised patients are more likely to present atypically with subtle signs and symptoms. A high index of suspicion is necessary to avoid missing a diagnosis of a CNS infection in this challenging patient population.

In this review, we discuss an approach to CNS infections in immunocompromised patients. We address common pathogens, clinical presentations, laboratory findings, and imaging correlates, and provide a basic framework for the initial evaluation and empiric management of suspected CNS infection in immunocompromised patients presenting to the ED.

Common clinical syndromes

Inflammation of the meninges, termed meningitis, can be bacterial, viral, fungal, or parasitic in etiology. Classically, these patients present with altered mental status, nuchal rigidity, and fever, but this triad is seen in only a minority of patients. Other symptoms may include rash, headache, cranial nerve abnormalities, nausea, emesis, and seizures. Clinical examination is not sensitive and cannot be used to exclude meningitis.

Parenchymal inflammation of the brain constitutes encephalitis. As with meningitis, patients with encephalitis may present with headache and fever but are more likely to have focal neurologic deficits and seizures. Deficits will correspond to the region of inflammation. Herpes simplex virus (HSV) encephalitis, for example, classically affects the temporal lobes, resulting in disinhibition and psychotic behavior, and is often confused with acute psychiatric illness.

Brain abscesses, collections of purulent material in the brain parenchyma, are commonly caused by hematogenous or contiguous spread of a bacterial infection. Although rare in the general population, brain abscesses are more common among the immunocompromised. Clinical presentations are variable and often subacute in nature. Although new-onset seizures are a relatively common presenting symptom, fever occurs in less than one-half of patients. More subtle signs include ataxia and cranial nerve palsies. Other associated symptoms such as nausea and headache can arise from mass effect and increased intracranial pressure.

CNS infections in the immunocompromised can result in the development of inflammatory or malignant space-occupying intracranial lesions. As with brain abscesses, presentations may vary based on the location and size of the lesion and may reflect signs of increased intracranial pressure. Symptoms can be subacute because these lesions are often slow growing.

Approach to central nervous system infection in the emergency department

Initial evaluation with neuroimaging in the ED helps to inform decision making regarding the safety of lumbar puncture (LP) in cases of suspected meningitis or encephalitis through exclusion of intracranial mass lesions with the potential to promote intracranial herniation. ^, In the case of a brain abscess, neuroimaging helps establish the diagnosis. Given the time-sensitive nature of many CNS infections, computed tomography (CT) scan of the brain with and without contrast is the preferred initial imaging modality in the ED. MRI is time consuming but more sensitive than a CT scan in its ability to differentiate multiple lesions. The presence of an intracranial mass lesion with evidence of mass effect and/or herniation on neuroimaging necessitates emergent neurosurgical consultation.

LP to obtain cerebrospinal fluid (CSF) for diagnostic testing is warranted if there is clinical suspicion of meningitis or encephalitis. Adherence to aseptic technique is important, both for patient safety and to avoid specimen contamination. Because this procedure can be technically complicated in some patients, it is vital to collect adequate volumes of CSF to evaluate for a wide range of probable and serious pathogens. The International Encephalitis Consortium recommends that at least 20 mL of CSF be collected in adults; any unused CSF should be saved for future testing. At a minimum, CSF studies should include measuring an opening pressure and obtaining CSF glucose, protein, white blood cell count with differential, and bacterial culture. Additional CSF testing should hinge on an assessment of the patient’s immunocompromised state and further consideration of the differential diagnosis of CNS infections possible.

Time-to-antibiotics remains one of the most important predictors of outcome in CNS infection. Therefore, neuroimaging and LP, if indicated, should take high priority with the objective of initiating empiric broad-spectrum antibiotic therapy within the first 2 hours of ED presentation. ^, However, if the patient is clinically unstable or delays in obtaining these studies are anticipated, it is reasonable to start empiric antibiotics immediately. Although data are limited to the immunocompetent pediatric population, time to sterilization of the CSF by antibiotics occurs within hours and, in some cases, in as little as 15 minutes. There is evidence to suggest that Neisseria meningiditis present in CSF is likely to be killed within 2 hours of antibiotic treatment, whereas Streptococcus pneumoniae may require more than 4 hours. Empiric antibiotics should be held until after LP whenever safe and feasible to maximize the yield of CSF cultures. Our recommended diagnostic and treatment approach to CNS infection in the immunocompromised is outlined in Fig. 1 .

Early involvement of an infectious disease specialist can aid in diagnostic planning and has been associated with improved patient outcomes. Consultation with members of the patient’s care team (eg, oncologists, hematologists, transplant specialists) familiar with their history and immunosuppression regimen also promotes high-quality, patient-centered care in the ED.

A differential diagnosis of a central nervous system infection in immunocompromised patients

Immunocompromised states owing to cancer-related chemotherapy, immunosuppression to prevent rejection after SOT or HSCT, HIV infection, and immunomodulatory therapies render patients susceptible to distinct spectrums of CNS infection.

Among patients who have recently undergone cytotoxic chemotherapy, the degree and duration of neutropenia are important to know. Neutrophils play an integral role in the immune response to infection owing to bacteria and fungi, particularly at mucosal surfaces. Classically, the nadir of neutropenia occurs 7 to 12 days after chemotherapy, but may vary by regimen. Neutropenia can still be present even after patients receive recombinant granulocyte colony-stimulating factors. Patients receiving chemotherapy should be considered neutropenic until their absolute neutrophil count can be determined.

In patients receiving maintenance immunosuppression after SOT or HSCT, the risk for and spectrum of CNS infection is determined by a patient’s net state of immunosuppression. Dose, duration, and combination of immunosuppressants are key determinants. Immunosuppression is driven by lymphocyte dysfunction; therefore, fungi and viruses are predominant pathogens. Time from initiation of post-transplantation immunosuppression is also an important factor. In the month immediately after transplantation, immunosuppression has not yet fully taken effect; therefore, most infections are associated with health care (eg, surgery, hospitalization) and opportunistic infections are rare. The highest risk period for opportunistic infection owing to fungi and viruses is between 1 and 6 months after transplantation. After 6 months, community-acquired pathogens become more common as immunosuppression is tapered. Regardless of the time after transplant, most patients remain at substantially higher risk of CNS infection compared with the general population.

HIV primarily targets CD4 T lymphocytes, leading to immunosuppression and impaired cell-mediated immunity. Consequently, opportunistic viruses and fungi are common causes of CNS infection in patients with AIDS. In persons living with HIV, the CD4 count is an important predictor of which pathogens should be considered in the differential diagnosis for CNS infection. Unless laboratory data are available from the past 3 months, a CD4 count and HIV viral load should be obtained in all patients with HIV presenting to the ED the for evaluation of CNS infection.

Novel immunotherapies used in the treatment of hematologic malignancies, including check point inhibitors and chimeric antigen receptor T-cell therapy, do not behave like typical immunosuppressive chemotherapy agents. Patients receiving these therapies will not usually present with neutropenia. The most serious side effects of these drugs are often autoimmune or cytokine mediated. Neurotoxicity is among the most common adverse effects of chimeric antigen receptor T-cell therapy and serious neurologic adverse events such as encephalitis, seizures, and altered mental status occur, albeit rarely. These adverse reactions are indistinguishable from an infectious process. However, neurologic symptoms should not be attributed to an adverse drug reaction until a CNS infection has been ruled out.

The complement system plays a vital role in the immune response to encapsulated organisms, in particular N meningiditis . Patients with complement deficiencies are at marked increased risk of developing N meningiditis infection. Recently, the complement-inhibiting drugs ravulizumab and eculizumab have been used to treat atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Despite meningococcal vaccination, patients receiving these drugs remain at an increased risk of developing meningococcal disease.

Additional considerations

Immunocompromised patients engaged in care are frequently prescribed antimicrobial prophylaxis to prevent opportunistic infections. An accurate medication list and history regarding compliance are important in informing the differential diagnosis of CNS infection. Prophylaxis against cytomegalovirus (CMV) infection significantly reduces the risk of reactivation with CMV, but also with HSV and varicella zoster virus (VZV). ^, Yet, antimicrobial dosing for prophylaxis against some infections may not be adequate to prevent others. For example, Pneumocystis jirovecii prophylaxis dosing for trimethoprim-sulfamethoxazole (TMP-SMX) adequately prevents toxoplasmosis, but not nocardiosis. ^, Furthermore, although prophylactic antimicrobials decrease the risk of opportunistic infections, clinically significant “breakthrough” infections can still occur. Current prophylactic antimicrobial use should be elicited for each patient, but this information should not obviate a diagnostic workup or the initiation of empiric antimicrobial treatment if clinical suspicion for an opportunistic infection remains high.

Immunization has proven vital in preventing bacterial meningitis among immunocompromised patients. Vaccination against Haemophilus influenzae, S pneumoniae, and N meningiditis have decreased the rates of bacterial meningitis in the United States, but mortality among those infected remains stubbornly unchanged. ^, Meningococcal meningitis rates have dropped so precipitously that they now match rates of nosocomial CNS infections owing to Staphylococcus spp and Gram-negative bacilli. Immunization can be less protective in the immunocompromised. Although immunization against H influenzae , S pneumoniae , and N meningiditis may render these pathogens lower on the differential diagnosis for CNS infection, empiric antimicrobial coverage including these organisms is still recommended until an alternative etiology has been identified, given the devastating nature of these infections.

Recent neurosurgical procedures (eg, shunt placement, intrathecal chemotherapy) are also vital pieces of the history that can guide diagnostic evaluation and empiric antibiotic therapy for CNS infection. Postsurgical patients are at increased risk of CNS infection secondary to skin flora such as coagulase-negative Staphylococci , Staphylococcus aureus , and Gram-negative bacilli. Early neurosurgical consultation is advised in these instances.

Bacterial central nervous system infections

Bacterial pathogens frequently associated with CNS infection in the immunocompromised are summarized in Table 1 .

Table 1

Bacterial pathogens implicated in CNS disease in immunocompromised patients and associated clinical findings

Pathogen	Typical CNS Syndrome	Typical Computed Tomographic Findings	Typical/Important CSF Findings
S pneumonia	Meningitis	Unremarkable	Protein high, glucose low Neutrophilic pleocytosis Gram stain can be informative ( S pneumoniae / H influenzae/N meningiditis )
H influenzae
N meningiditis
L monocytogenes	Meningoencephalitis	Unremarkable	Protein high, glucose low Lymphocytic pleocytosis Gram stain may be negative
Nocardia spp.	Brain abscess	May show abscess	Protein high, glucose low Neutrophilic pleocytosis
M tuberculosis	Three phases: 1. Subacute mental status change 2. Meningitis 3. Paralytic	Variable	Protein high, glucose low Lymphocytic pleocytosis Acid-fast stain and mycobacterial culture poorly sensitive Multiple cultures often necessary

Common Acquired Bacteria

Bacteria can gain entry to the CNS through contiguous spread from sinus or dental infections or hematogenous seeding. Rarely, neurosurgical procedures or traumatic communication with the subarachnoid space can also inoculate the CNS with bacteria. S pneumoniae , H influenzae , and N meningiditis remain the most common pathogens associated with bacterial meningitis. Morbidity and mortality rates are especially high among immunocompromised patients. ^, Less common, pyogenic brain abscesses are often polymicrobial or owing to Streptococcus or Staphylococcus species; gram-negative bacteria are implicated in up to 15% of cases.

CSF findings of elevated protein, decreased glucose, and increased white blood cell (WBC) count with neutrophilic predominance are typical of bacterial meningitis, although up to 10% of cases may have a WBC count with lymphocytic predominance. The diagnostic yield of a Gram stain is highest for S pneumoniae and H influenzae . Nucleic acid amplification tests are not routinely used for bacterial pathogens owing to the high combined diagnostic yield of Gram stain and bacterial culture, although this is standard of care in the United Kingdom. ^,

Third- and fourth-generation cephalosporins (eg, ceftriaxone, cefepime) are generally recommended for the treatment of community-acquired bacterial meningitis. In countries including the United States, where penicillin-resistant strains of S pneumoniae are prevalent, vancomycin should be empirically added pending CSF culture and antibiotic susceptibility testing. Adjunctive dexamethasone has been supported to decreased mortality associated with bacterial meningitis, with a benefit demonstrated in the setting of infection owing to S pneumoniae . Corticosteroid therapy for meningitis in immunosuppressed patients has not been subjected to rigorous investigation.

Listeria

Listeria monocytogenes can be a serious CNS pathogen in the immunocompromised. Almost 90% of neurolisteriosis cases are associated with immunosuppression, with solid organ malignancy being the most common comorbidity. Active cancer and monocytopenias are significantly associated with mortality. The mortality rate for neurolisteriosis is nearly 30%; only 40% of survivors make a full recovery and one-half experience long-term neurologic sequelae.

Meningoencephalitis is the most common presentation, although isolated meningitis and encephalitis can also occur. Encephalitis is an independent risk factor for death. Rhomboencephalitis (brainstem or cerebellar involvement) comprises less than 20% of cases, manifesting with headache, fever, and vomiting, but also brainstem-specific symptoms such as cranial nerve palsies, cerebellar dysfunction, and motor and sensory deficits. Brain abscess is a rare complication marked by focal neurologic deficits determined by the location of the abscess. Fever is present in approximately 90% of patients with neurolisteriosis and most patients have altered mental status.

CSF findings in neurolisteriosis are variable. L monocytogenes is one of the few bacteria that can present with lymphocytic predominance on CSF WBC count. Gram stain is positive in only one-third of cases, although CSF culture is usually positive. ^, Neuroimaging may show abscess, small intracranial hemorrhage, or periventricular enhancement, none of which is specific.

Cephalosporins commonly used to cover typical community-acquired bacteria associated with CNS infection are ineffective against neurolisteriosis. Failure to initiate appropriate empiric antibiotic therapy is associated with significantly worse outcome. ^, Aminopenicillins (eg, ampicillin) are first-line agents for neurolisteriosis; meropenem and TMP-SMX can also be used. A secondary analysis of data demonstrated a trend toward improved outcomes with the addition of an aminoglycoside, but was not statistically significant. Finally, corticosteroid therapy may significantly worsen survival, although confounding by indication was possible in a subgroup analysis.

Nocardia

Infection with Nocardia spp. is rare, even among immunocompromised patients. ^, In a series of 1050 cases of nocardiosis, CNS involvement was present in 22% and systemic infection in 44%. Glucocorticoid and calcineurin inhibitor use are among the most important risk factors for developing nocardiosis. In a series of patients with HIV/AIDS with nocardiosis, all had a CD4 count of less than 200 cells/μL and a 75% had a CD4 count of less than 100 cells/μL. CNS nocardiosis can manifest as a single or multiple brain abscesses, with symptoms ranging from acute focal neurologic deficits to altered mental status.

Nocardia will grow in aerobic bacterial culture media, as well as fungal and acid-fast bacilli media. There are no widely available serologic or molecular testing methods. Several case reports of CNS nocardiosis demonstrate CSF with neutrophilic pleocytosis, elevated protein, and decreased glucose levels consistent with bacterial meningitis, although this remains poorly characterized in the literature.

CNS nocardiosis is treated with either a sulfonamide (most commonly high-dose TMP-SMX) or amikacin in combination with imipenem. Sulfonamides should be considered even in patients with known intolerance or allergy provided appropriate desensitization can be achieved. Resistance to TMP-SMX is rare. It is important to note that typical doses of TMP-SMX used for P jirovecii prophylaxis do not prevent Nocardia infection. ^,

Empiric Antibacterial Therapy for Central Nervous System Infection in the Immunocompromised Patient

Initial empiric antibiotic therapy for immunocompromised patients presenting to the ED with suspected CNS infection should include coverage of community-acquired bacteria (namely, S pneumoniae ) and L monocytogenes . Expanded gram-negative coverage for Pseudomonas aeruginosa is also generally recommended in immunocompromised patients presenting with severe infection. Given these considerations, broad-spectrum antibacterial coverage for CNS infection in the ED can be achieved with a combination of vancomycin, cefepime, and ampicillin. Empiric therapy for CNS nocardiosis is seldom indicated in the ED, but may be considered in consultation with an infectious disease specialist in the appropriate clinical context.

Viral infection

Viral pathogens often implicated in CNS infection in the immunocompromised are summarized in Table 2 .

Table 2

Viral pathogens implicated in CNS disease in immunocompromised patients and associated clinical findings

Viral Pathogens	Typical CNS Syndrome	Typical Computed Tomographic Findings	Typical/Important CSF Findings
HSV	HSV-1: encephalitis HSV-2: meningitis	Unremarkable May have subtle changes in temporal lobe	Protein high, glucose normal Lymphocytic pleocytosis May have RBCs HSV PCR positive
VZV	Encephalitis	Unremarkable	Protein high, glucose normal Lymphocytic pleocytosis VZV PCR positive
CMV	Encephalitis Ventriculoencephalitis	Unremarkable Periventricular enhancement may be seen in ventriculoencephalitis	Protein high, glucose normal Lymphocytic pleocytosis CMV PCR positive
Epstein–Barr virus	PCNSL Focal neurologic deficits	Solitary contrast-enhancing hyperdensity	Unremarkable Epstein–Barr virus PCR may be positive.