Evaluation and Follow-up of Patients With Cryptococcosis

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, 12.9-17.9% 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-CNS disease (e.g.,
pulmonary) may serve as a subset comparator to those with central nervous system (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.

- INCLUSION CRITERIA:

Patients:

Patients must:

1. Have one of the following as determined by information collected from their medical
records, telephone interviews or from a referring physician:

-cryptococcosis with unknown immune deficiencies (including idiopathic CD4+
lymphopenia ICL)

- histopathology showing cryptococci; or

- culture of Cryptococcus neoformans or Cryptococcus 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.

Blood Relatives of Patients:

Blood 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 which in the 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.

Blood Relatives of Patients:

Blood relatives will be excluded for the following:

Any condition which in the 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. 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 which in the opinion of the investigator may interfere with evaluation
of an immune system abnormality that is the subject of study under this protocol.