Fungal Infection Susceptibility

Overview

This study will follow the course of disease in previously healthy patients with cryptococcosis who developed the disease for no identifiable reason. Participants may be followed for up to 5 years.

Individuals with a positive Cryptococcus (neoformans or gattii) culture that are 18 years of age and older without HIV infection or other condition predisposing to cryptococcosis (such as high-dose corticosteroid therapy, sarcoidosis, or a blood cancer) may be eligible for this study. Genetic relatives and healthy volunteers are also eligible for this study. Candidates who test positive for HIV infection may not participate.

Study participants have the option to be completely remote through tele-health visits with cooperation from their PCP and local physicians, or participate through in-person visits at the NIH Clinical Center. Potential participants will have a physical examination, past medical and family history evaluations, routine laboratory tests, and assessment of disease activity performed during the initial screening and enrollment visit. Patients who have active cryptococcosis may also have a lumbar puncture (spinal tap), imaging, and/or additional laboratory tests performed, as clinically indicated. After the initial screening evaluation and study enrollment, patients receiving treatment for cryptococcosis can either continue to be seen remotely through tele-health visits, or they can come to the NIH Clinical Center as needed to manage their disease, typically no less than every 3 months. Other patients will be seen every 6 to 12 months. These follow-up visits may include a medical history, physical examination, routine laboratory tests, imaging, and updates to their treatment plan as indicated.

Description

Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients, particularly renal transplant recipients (1-3). However, approximately one-third of cases fall outside these groups and, overall, 12.9% to 17.9% have no readily identifiable immune defect (4, 5). The genetic factors, which may predispose to cryptococcosis and the immune response in these patients, have not been extensively studied.

This protocol is designed to examine the immune deficits that predispose to cryptococcosis as well as the clinical and immune responses among previously healthy adults. The patients included will have an unknown predisposing condition and cryptococcosis. Patients will undergo blood, saliva, and tissue sampling. Throughout the study, patients will be provided with standard medical care and will be seen as often as necessary to manage their condition. Patients in whom microbiologic control of the infection has occurred but in whom inflammation is causing neurologic damage may be treated with corticosteroids or other immunosuppressive agents. Genetically related family members of patients will also be screened for clinical, in vitro, immune, and genetic correlates of immune abnormalities. Healthy adult volunteers, as a comparison group, will be enrolled as a source of blood samples for research testing. Moreover, with respect to cryptococcosis, patients with isolated non-central nervous system (CNS) disease (e.g., pulmonary) may serve as a subset comparator to those with (CNS) involvement a major tissue tropism for Cryptococcus.

Genetic and immunologic testing will be performed on all subjects (patients, relatives, and healthy volunteers) to evaluate for possible immunogenetic factors that lead to susceptibility to cryptococcosis. Among the aims of this protocol are to better understand the pathophysiology and genetic factors that lead to defects in host defense and to use modern and evolving methods in molecular and cellular biology to elucidate the pathogenesis of this particular susceptibility. A better understanding of the underlying pathophysiology of immune defects and genetic susceptibility to fungal infections could allow for the rational development of novel therapies for such diseases and to benefit future patients.

Eligibility

• INCLUSION CRITERIA:

  Patients

Patients must:

1. Have cryptococcosis as determined by information collected from their medical records, telephone interviews or from a referring physician:
   • histopathology showing cryptococci; or
   • culture of C. neoformans or C. gattii
   • a positive cryptococcal antigen in the serum and/or CSF, together with CSF cell count and chemistry consistent with cryptococcal meningitis.
2. Be over the age of 18 years old.
3. Have a primary physician outside of the NIH.
4. Agree to undergo genetic testing that will include WES and high density SNP arrays as appropriate for possible WES linkage studies.
5. Allow samples to be stored for future research.
6. Pregnant patient willnot 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:

Genetic relatives must:

1. Be a genetic relative of a patient enrolled in this study
2. Be over the age of 18 years old
3. Agree to undergo genetic testing that may include WES and high density SNP analysis
4. Allow samples to be stored for future research

Healthy Volunteers:

Healthy volunteers must:

1. Be between the ages of 18 and 70 years old
2. Allow samples to be stored for future research

EXCLUSION CRITERIA:

Patients

Patients will be excluded for any of the following:

1. 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
2. Any condition that in the medical opinion of the investigator may interfere with the

   evaluation of a co-existing abnormality of immunity that is exclude patients with Cushing s disease that have very high cortisol levels at the time of diagnosis of their cryptococcosis.

Genetic Relatives of Patients:

Genetic relatives 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:

Healthy volunteers will be excluded for any of the following:

1. History of HIV or viral hepatitis (B or C).
2. History of recurrent or severe infections.
3. History of intravenous drug use.
4. History of engaging in high risk activities for exposure to HIV;
5. Receiving chemotherapeutic agent(s), immunosuppressants or have underlying malignancy.
6. Pregnancy.
7. Have history of heart, lung, kidney disease, or bleeding disorders.
8. 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.