Cryptococcosis in Previously Healthy Adults

Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients and is currently responsible for an estimated 15% of all AIDS-related deaths globally. However, in developed countries, approximately one-third of cases fall outside these groups such that cryptococcal meningoencephalitis (CM) has become the most common cause of non-viral meningitis in the U.S. Within the U.S., approximately 15-20% have no readily identifiable immune defect and cryptococcal infection in these hosts has a mortality rate of 30-50% despite optimal antifungal therapy. NIH Clinical Study Protocol 93-I-0106 (NCT00001352). The objectives of this protocol can be broadly categorized as: 1) Characterize the immunologic and genetic mechanisms predisposing to disease acquisition; 2) Understand the post-infectious inflammatory response and distinguish its consequences from those directly due to fungal growth; and 3) Management of post-infectious neuro-inflammatory syndromes associated with cryptococcal meningitis (CM). This protocol recruits patients who have microbiological evidence of cryptococcal neurologic or non-CNS disease (typically pulmonary or bone). Cerebrospinal fluid (CSF) and blood samples collected during clinical care are used to measure serum and CNS cellular and soluble cytokines as well as to perform in-situ immunohistochemistry. CSF and blood samples are also collected to measure transcriptional (gene expression), proteomic (protein), and lipidomic (lipids) changes that occur throughout disease and treatment. Observational data detailing audiological, ophthalmological and neurocognitive deficits in these patients is also recorded. We have recently described a post-infectious inflammatory syndrome (PIIRS) associated with cryptococcal meningoencephalitis (CM) which can be best described as a neuro-inflammatory state during which CM patients present with altered mental status (Montreal Cognitive Assessment Score <22/30), auditory deficits and/or vision loss despite having negative CSF fungal cultures after being treated with optimal antifungal therapy. Based on findings in CSF and brain tissue samples, the underlying mechanism behind this phenomenon is related to the intrathecal expansion of both the innate and adaptive immune system, including HLA-DR+ CD4+ and CD8+ lymphocytes and NK cells. In a cohort of 15 previously healthy CM patients, we have been able to demonstrate an improvement in clinical outcomes with pulse corticosteroid therapy for patients with PIIRS and are currently exploring alternative immunomodulatory agents as steroid-sparing therapy for this indication. As part of the protocol, we treat patients for either microbiological failure or neuroinflammatory sequelae by conventional therapies utilizing FDA-approved pharmaceuticals at FDA-approved doses. To understand and identify the predominant biological pathways responsible for PIIRS neuroinflammation, we examined patient CSF at baseline (at time of PIIRS diagnosis) and post-treatment with different FDA-approved pharmaceuticals at FDA-approved doses compared to CSF from non-PIIRS donors. Upstream pathway analysis of differentially expressed genes in the CSF of PIIRS patients revealed a prominent role for the JAK/STAT pathway in the pathogenesis of PIIRS and support the use of the JAK inhibitor, ruxolinib, as a pathway-instructed therapy to treat PIIRS patients. Data available through dbGaP: single cell RNA sequencing (scRNA-seq) data from CSF cells of a patient with PIIRS at the time of diagnosis and following treatment with steroids (1g solumedrol/day) and NanoString transcriptional data from CSF cells of patients with PIIRS at the time of diagnosis compared to CSF cells from non-PIIRS donors. ]]>
INCLUSION CRITERIA: Patients must:Have cryptococcosis as determined by information collected from their medical records, telephone interviews or from a referring physician:histopathology showing cryptococci; orculture of C. neoformans or C. gattiia positive cryptococcal antigen in the serum and/or CSF, together with CSF cell count and chemistry consistent with cryptococcal meningitisBe over the age of 18 years oldHave a primary physician outside of the National Institutes of HealthAgree to undergo genetic testing that will include whole exome sequence (WES) and high density SNP arrays as appropriate for possible WES linkage studiesAllow samples to be stored for future researchPregnant patient will not be excluded; However, research procedures greater than minimal risk including bone marrow biopsy and apheresis would not be performed on pregnant subjects. Otherwise, pregnant patients with cryptococcus would be treated as per standard of care, minimizing teratogenic potential of drugs and ionizing radiation whenever possible. Genetic relatives of patients must: Be a genetic relative of a patient enrolled in this study Be over the age of 18 years old Agree to undergo genetic testing that may include WES and high density SNP analysis Allow samples to be stored for future research Healthy volunteers must:Be between the ages of 18 and 70 years old Allow samples to be stored for future research EXCLUSION CRITERIA: Patients will be excluded for any of the following: The presence of certain types of acquired abnormalities of immunity due to: HIV Cancer chemotherapeutic agent(s) An underlying malignancy could be grounds for possible exclusion of a patient if in the opinion of the investigator, the underlying disease predisposed the patient to the infection Monoclonal antibody therapy directed against a patient's immune system Any condition that in the medical opinion of the investigator may interfere with the evaluation of a co-existing abnormality of immunity that excludes patients with Cushing's disease that have very high cortisol levels at the time of diagnosis of their cryptococcosis. Genetic relatives of patients will be excluded for the following: Pregnancy Any condition that in the medical opinion of the investigator may interfere with evaluation of an immune system abnormality that is the subject of study under this protocol. Healthy volunteers will be excluded for any of the following: History of HIV or viral hepatitis (B or C) History of recurrent or severe infections History of intravenous drug use History of engaging in high risk activities for exposure to HIV Receiving chemotherapeutic agent(s), immunosuppressants or having underlying malignancy Pregnancy History of heart, lung, kidney disease, or bleeding disorders Any condition that in the medical opinion of the investigator may interfere with evaluation of an immune system abnormality that is the subject of study under this protocol.]]>