CNS Infection prophylaxis in Immunocompromised

Central nervous system (CNS) infections are uncommon amongst the immunocompetent population. A state of immuno-incompetency increases susceptibility of the CNS to infection. CNS infections incur serious burden on the morbidity and mortality of cancer patients

 

Introduction

  • Central nervous system (CNS) infections are uncommon amongst the immunocompetent population
  • A state of immuno-incompetency increases susceptibility of the CNS to infection
  • CNS infections incur serious burden on the morbidity and mortality of cancer patients
  • Evolving drug resistance, prolonged prophylactic antimicrobial use and intense chemotherapeutic regimes have given rise to a patient group vulnerable to atypical infections e.g progressive multifocal leukoencephalopathy (PML)
  • CNS infections in the immunocompromised are, more often than not, medical emergencies

Defining Immunosuppression

Immunosuppression is defined as decreased ability of the body to mount an immune response in order to ward off disease or infection; it is determined by the interaction of several factors, these include:
  • Age (extremes of age)
  • Baseline disease : autoimmune disease, inflammatory disease, cancer
  • Comorbidities : diabetes mellitus, uremia, cirrhosis, COPD, etc.
  • Underlying immunodeficiencies : HIV, splenectomy, pregnancy, B-Lymphocyte/Immunoglobulin deficiency, T-Lymphocyte depletion, Neutropenia
  • Previous therapies : immunosuppressive therapy, biological treatments, antimicrobial therapy, chemotherapy
  • Compromise of mucocutaneous barrier : burns, indwelling catheters, surgery
  • Immunomodulating viruses : CMV, HHV-6, EBV, HBV, HCV, HIV, RsV

Epidemiology

The most common opportunistic organisms for CNS infections are: 
  • Aspergillus fumigatus
  • Cryptococcus neoformans
  • Cytomegalovirus
  • Epstein-Barr virus
  • Listeria monocytogenes
  • Mycobacterium tuberculosis
  • Toxoplasma gondii
  • Human immunodeficiency virus

Patients susceptible to opportunistic CNS infections

  • Patients with HIV
    • 40-60% of patients with HIV develop neurological complications
      • patients may present with a normal neurologic examination
  • Patients undergoing solid organ transplant (SOT)
    • up to one-thirds of patients undergoing SOT will develop neurological complications
  • Patients undergoing chemotherapy
  • Patients with hematologic disorders
    • including stem cell transplantation
    • 15% of patients undergoing allo-HSCT develop CNS infection

Clinical presentation

  • The clinical picture and prognosis of CNS infections in the immunocompromised host differ from patients with an immunocompetent status
  • Immunosuppression leads to an altered and lessened immune response, leading to less obvious symptomatology
    • Absence of typical symptoms such as fever or meningism
    • Corticosteroids blunt the immune response
    • Steroid therapy also reduces contrast enhancement on imaging
  • Presence of multiple concurrent infections
  • Heightened response to pathogens rarely seen in immunocompetent patients

Table 1 : Drugs associated with risk of specific CNS infections

Drug
CNS infection
I. Drugs approved for neurological conditions
.
Alemtuzumab
VZV, HSV, TB, PML, CMV, Listeria, Nocardia
Dimethyl fumarate
PML, VZV
Eculizumab
Neisseria meningitidis
Fingolimod
VZV, HSV, PML, Cryptococcus, Listeria
Natalizumab
PML VZV, HSV
Ocrelizumab
VZV, HSV, PML*
Teriflunomide
PML, TB
Corticosteroids (prednisone, methylprednisolone, dexamethasone)
PML, VZV, PJP, Candida
II. Drugs used off label for neurological conditions
Azathioprine
PML, CMV, EBV-associated PCNSL
Cyclophosphamide
PML, sepsis, bacterial infections (urine, lung)
Ibrutinib
Aspergillus, PML
Infliximab
VZV, TB, PML, demyelinating lesions ➔ MS
Methotrexate
Toxoplasmosis, EBV-associated lymphoproliferative disorder
Mycophenolate mofetil
PML, PCNSL
Rituximab**
Toxoplasmosis, enterovirus, Babesia, WNV, CMV, VZV, Cryptococcus, PJP, Powassan virus, PML
III. Drugs associated with CNS infections with no primary neurological indication
Adalimumab (also certolizumab, etanercept)
PML
Brentuximab
PML
Cyclosporine/tacrolimus
Fludarabine
PML, VZV, HSV, Listeria, Cryptococcus
Leflunomide
PML, TB
Ruxolitinib
PML, toxoplasmosis
*PML associated with ocrelizumab to date only seen in patients previously on natalizumab or dimethyl fumarate
**Rituximab associated with reactivation of hepatitis B virus and the unusual severity of infections with Babesia and WNV
 
Table modified from : Pruitt AA. Central Nervous System Infections in Immunocompromised Patients. Curr Neurol Neurosci Rep. 2021;21(7):37. Published 2021 May 26. doi:10.1007/s11910-021-01119-w

Table 2 : Parasitic CNS infections in immunosuppressed hosts

Parasite
Associated condition
Neuroimaging finding
Recommended testing
Note
Schistosoma species
HIV Bone marrow & liver transplant
Solitary or multiple hyperdense lesions
Serology, Stool, Urine, CSF
Larvae are detectable in esophageal and peritoneal fluid
Strongyloides stercoralis
HIV Heart & kidney transplant
Brain abscess of mycotic aneurysm
Serology, Stool, CSF
Taenia solium
HIV Kidney tranplant
Calcified or ring-enhancing lesions; large cysts; scolex on MRI
Serology, CSF
Toxoplasma Gondii
HIV Bone marrow, heart, kidney, liver & lung transplant
Solitary or multiple ring enhancing lesions; edema. MRI more sensitive.
Serology, CSF
Trophozoites can be detected in biopsy tissue specimen
Trypansoma Cruzi
HIV Heart, kidney & liver transplant
Large solitary or multiple ring enhancing lesions with surrounding edema
Serology, CSF
Table compiled and modified from : Walker M, Zunt JR. Parasitic central nervous system infections in immunocompromised hosts. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 2005;40(7):1005-1015. doi:10.1086/428621

Table 3: CNS Prophylaxis

Condition
Prophylaxis Used
HIV
Advised vaccinations, prompt management
Solid organ transplant (SOT)
Advised vaccinations before surgery, regular monitoring
Chemotherapy
Advised vaccinations before initiating therapy, regular monitoring
Hematological disorders
Permissible vaccinations, regular monitoring
💡
Vaccines recommended for immunocompromised patients
  • Inactivated influenza vaccine
  • Hepatitis A
  • Hepatitis B
  • Human Papilloma Virus
  • DTaP
  • Inactivated polio vaccine
  • Meningococcal vaccine
  • Pneumococcal vaccine
  • Rabies
  • Varicella-Zoster
  • The best form of prophylaxis and/or prevention of CNS infection in the immunocompromised is regular monitoring, testing, imaging & prompt management
  • Suspicion of CNS involvement necessitates immediate diagnostic procedures, including but not limited to :
    • CT scan
    • MRI scan
    • PET scan
    • Lumbar puncture/CSF analysis
    • blood culture
    • PCR assays
    • Histopathological workup
    • Brain biopsy
  • Although specific diagnosis is crucial, literature suggests covering the following organisms
    • Listeria (ampicillin),
    • Cryptococcus (Amphotericin B and/or fluconazole),
    • Herpes simplex virus (acyclovir or ganciclovir),
    • other common bacterial pathogens (vancomycin/linezolid, ceftriaxone)
    • broad spectrum management should be continued until a diagnosis is confirmed
  • For HIV patients : intensify antiretroviral therapy and/or increase CNS penetration
  • Always consider Mycobacterium tuberculosis in patients from developing countries and administer anti-tuberculous therapy (ATT)
  • Immunosuppression management should be tailored to the needs of the patient
  • Sudden reduction in steroid dosage may result in hydrocephalus
  • Neurosurgical intervention may be required

Further reading

  1. Dougan C, Ormerod I. A Neurologist’s Approach to the Immunosuppressed Patient. Journal of Neurology, Neurosurgery & Psychiatry. 2004;75(suppl 1):i43-i49. doi:10.1136/jnnp.2003.035071
  1. Zunt JR. CENTRAL NERVOUS SYSTEM INFECTION DURING IMMUNOSUPPRESSION. Neurologic clinics. 2002;20(1):1-v. Accessed October 12, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695971/
  1. Pruitt AA. Central Nervous System Infections in Immunocompromised Patients. Current Neurology and Neuroscience Reports. 2021;21(7). doi:10.1007/s11910-021-01119-w

Bibliography

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4. Dougan C, Ormerod I. A Neurologist’s Approach to the Immunosuppressed Patient. Journal of Neurology, Neurosurgery & Psychiatry. 2004;75(suppl 1):i43-i49. doi:10.1136/jnnp.2003.035071
5. Wright AJ, Fishman JA. Central Nervous System Syndromes in Solid Organ Transplant Recipients. Clinical Infectious Diseases. 2014;59(7):1001-1011. doi:10.1093/cid/ciu428
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7. Zunt JR. CENTRAL NERVOUS SYSTEM INFECTION DURING IMMUNOSUPPRESSION. Neurologic clinics. 2002;20(1):1-v. Accessed October 12, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695971/
8. Pruitt AA. Central Nervous System Infections in Immunocompromised Patients. Current Neurology and Neuroscience Reports. 2021;21(7). doi:10.1007/s11910-021-01119-w
9. Walker M, Zunt JR. Parasitic central nervous system infections in immunocompromised hosts. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 2005;40(7):1005-1015. doi:10.1086/428621