CNS Infection prophylaxis in Immunocompromised

Primary Category

Neurocritical Care

P-Category

Secondary Category

Neuroinfectious

S-Category

Authors:

Zaitoon Zafar MBBS,
Ayaz Khawaja MD

Contents

Introduction Defining Immunosuppression Epidemiology Patients susceptible to opportunistic CNS infections Clinical presentation Table 1 : Drugs associated with risk of specific CNS infections Table 2 : Parasitic CNS infections in immunosuppressed hosts Table 3: CNS Prophylaxis Further reading Bibliography

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	ㅤ
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	ㅤ
Adalimumab (also certolizumab, etanercept)	PML
Brentuximab	PML
Cyclosporine/tacrolimus	ㅤ
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	ㅤ
Taenia solium	HIV Kidney tranplant	Calcified or ring-enhancing lesions; large cysts; scolex on MRI	Serology, CSF	ㅤ
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	ㅤ

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
ㅤ	ㅤ

💡

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

Bibliography

1. Rm L, De B, Ml R. Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. Journal of neurosurgery. 1985;62(4). doi:10.3171/jns.1985.62.4.0475

2. Levin SN, Lyons JL. Infections of the Nervous System. The American Journal of Medicine. 2018;131(1):25-32. doi:10.1016/j.amjmed.2017.08.020

3. Castro I, Ruiz J, Tasias M, Montero M, Salavert M. Central nervous system infections in immunocompromised patients. Revista Española de Quimioterapia. 2018;31(Suppl 1):56-61. Accessed October 12, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459576/

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

6. Pruitt AA, Graus F, Rosenfeld MR. Neurological Complications of Transplantation. The Neurohospitalist. 2013;3(1):24-38. doi:10.1177/1941874412455338

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