Natural History of Individuals With Immune System Problems That Lead to Fungal Infections

Study Overview
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Brief Summary
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Background: - The immune system is made up of special cells, tissues, and organs that fight infections. Problems with this system may lead to frequent, severe, or unusual fungal infections. These infections are often difficult to treat. Researchers want to collect blood and tissue samples from people who have unusual, persistent or severe fungal infections or immune problems that increase the risk of these infections. Objectives: - To collect medical information and samples for a long-term study of people with immune system problems that lead to fungal infections. Eligibility: People with a history of fungal infections caused by immune system problems. Parents, children, and siblings of this group. Healthy volunteers not related to the first two groups. Design: This long-term study may last for up to 10 years. Those in the study may need to provide new information about every 6 months. The procedures for each person may vary with the particular diagnosis and the extent of fungal infection. Healthy volunteers may have only one or two visits. At the first visit, those in the study will have a full medical history and physical exam. They will also provide blood. Research procedures may include the following: Saliva, urine or stool testing Mouthwash collection for DNA testing Collection of cheek cells, nail clippings, or vaginal fluid Tests of leftover tissue or body fluid from previous medical procedures Skin or oral mucous membrane biopsy Collection of white blood cells Followup visits will involve a physical exam and updated medical history. Blood, saliva, urine, or nail clipping samples may be taken for ongoing studies. Any additional tests or exams required by the study doctors may also be done. Participants may withdraw from the study pool at any time.

Detailed Description
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This protocol is a natural history study designed to investigate the clinical, microbiologic, genetic and immunologic correlates of primary immune deficiencies and other conditions associated with mucocutaneous and invasive fungal infections (IFIs). The hypothesis is that chronic mucocutaneous mycoses and IFIs are caused by abnormalities in immune function in these patients that can be identified using modern methods in molecular and cell biology and immunology. For inclusion, patients must have a history of or an active mucocutaneous or invasive fungal infection, but may or may not have a defined primary or acquired immunodeficiency state. Patients will undergo evaluations that include history/physical examination and blood, saliva, and possible tissue sampling for genetic and immunological testing. Patient relatives may also be screened for clinical, microbiological, genetic and/or immunological correlates of host defense abnormalities. Healthy volunteers will be enrolled as a source of control blood, saliva, and possible tissue sampling, and for genetic testing. The aim of this protocol is to use modern methods in molecular and cell biology and immunology to elucidate the immunopathogenesis of fungal disease in humans. A better understanding of primary immunodeficiency and identification of fungal and host risk factors for fungal infection may provide new insights into pathogenesis and identify targets for development of novel therapies. Enrolled subjects may be followed for up to 10 years to undergo additional clinical evaluation and sampling. Follow-up may occur every 6 months or more frequently depending on clinical course, the underlying risk factor(s), and the type of fungal infection. Under some circumstances, standard medical treatment will be provided for a fungal infection or immune deficiency.

Official Title
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The Natural History and Pathogenesis of Human Fungal Infections

Conditions
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Chronic Mucocutaneous Candidiasis, Invasive Aspergillosis, CARD9, APECED

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients: Patients with or without inherited or acquired abnormalities of immune function manifesting mucocutaneous and/or invasive fungal infections are eligible for screening and assessment under this protocol. Specifically, patients must meet all the following inclusion criteria in order to participate in this study: Adults or children (regardless of age, gender or ethnicity/race) with a known or yet uncharacterized inherited immunodeficiency and a definitively diagnosed mucocutaneous or invasive fungal infection. OR Adults or children (regardless of age, gender or ethnicity/race) with acquired immunodeficiency and a severe, unusual, persistent or treatment-refractory chronic mucocutaneous fungal infection. OR Adults or children (regardless of age, gender or ethnicity/race) with acquired immunodeficiency and a possible, probable or proven invasive fungal infection (European Organization for Research and Treatment of Cancer / Mycoses Study Group criteria). OR Adults or children (regardless of age, gender or ethnicity/race) with a well-documented prior, unusual, severe, persistent, or treatment-refractory mucocutaneous or invasive fungal infection(s), who have clinically recovered from the fungal infection. OR Adults or children (regardless of age, gender or ethnicity/race) with confirmed or suspected autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) who have not yet developed CMC. Ongoing care by a referring/primary care physician (inside or outside NIH). Willing to allow storage of blood and tissue samples for future analyses. Willing to allow genetic testing from blood, body fluids or tissue specimens. Willing to have HIV testing For Clinical Center inpatients unable to give informed consent due to an illness or cognitive incapacity, a Durable Power of Attorney (DPA) must be available to provide informed consent. No children under the age of 2 years will be seen at the Clinical Center, however they will be able to participate via mail-in specimens Patient Relatives: Individuals (regardless of age, gender or ethnicity/race) who are genetically related to the patient (e.g., mother, father, siblings, children) may be recruited to establish the genetic origin of immune defects that may be identified in the study patients at the discretion of the PI. Relatives must meet all the following inclusion criteria in order to participate in this study: Willing to allow storage of blood and tissue samples for future analyses. Willing to allow genetic testing from blood, body fluids or tissue specimens. Willing to have HIV testing Healthy Volunteers: Healthy adults regardless of gender and ethnicity/race between the ages of 18 and 85 years old may be eligible to participate in this study. Healthy volunteers must meet all the following inclusion criteria in order to participate in this study: Willing to allow storage of blood and tissue samples for future analyses. Willing to allow genetic testing from blood, body fluids or tissue specimens. Willing to have HIV testing Able to provide informed consent NIH employees are eligible EXCLUSION CRITERIA: Patients: A patient will not be eligible if he/she has any of the following: Any condition which, in the investigator s opinion, may interfere with the evaluation of a co-existing abnormality of immunity that is the subject of study under this protocol. Any condition which, in the investigator s opinion, places the patient at undue risk by participating in the study. Unwillingness to undergo testing or procedures associated with this protocol. Hemoglobin of < 7 gm/dL. If a patient is enrolled solely to obtain left-over pathology specimens, saliva, a buccal sample, skin swab, vaginal swab, or a stool sample, this exclusion criteria will not apply as there will be no blood withdrawal. Patient Relatives: A genetically related relative will not be eligible for this study if he/she has any condition which, in the investigator s opinion, may interfere with the evaluation of an immune system abnormality that is the subject of study under this protocol. Healthy Volunteers: A healthy volunteer will not be eligible if he/she has any of the following: HIV infection. History of recurrent or severe infections. History of an underlying malignancy or receipt of cancer chemotherapy within the past 5 years Receipt of systemic corticosteroids or other systemic immunosuppressants/immunomodulators within the past 30 days Pregnancy or lactating History of heart, lung, kidney disease, or bleeding disorders.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Fungal infections<br>Patients with or without inherited or acquired abnormalities of immune function manifesting mucocutaneous and/or invasive fungal infections | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological mechanisms of fungal susceptibility | Characterize and understand the immunological mechanism(s) by which inherited immunodeficiencies or acquired conditions increase susceptibility to mucocutaneous and invasive fungal infections. | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine microbiologic test usefullness | Determine the usefulness of various microbiologic tests (e.g., cultures, serology, molecular assays) for diagnosis and follow-up of the course of fungal infections. | 10 years | 
| Determine immunological profile of mucosal fungal infections | Define the transcriptional profiles and perform proteomic and microbiome analyses of skin, oral and/or vaginal mucosa, and/or other tissues, and body fluids of patients with inherited or acquired conditions predisposing them to fungal infections. | 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED), Fungal Infections, Molds, Autoimmune Polyendocrinpathy Syndrome (APS) Type 1, Natural History, Mucocutaneous Fungal Infection, Invasive Fungal Infection