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Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia

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ClinicalTrials.gov Identifier: NCT00867269
Recruitment Status : Recruiting
First Posted : March 23, 2009
Last Update Posted : July 9, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:

Background:

  • Idiopathic CD4+ lymphocytopenia (ICL) is a condition in which there is a decreased level of CD4+ lymphocytes (a type of white blood cell), which can lead to opportunistic infections or autoimmune disorders and diseases.

Objectives:

  • To characterize the natural history with regard to CD4+ T cell count and onset of infection, malignancy, and autoimmunity.
  • To describe the immunological status of patients affected by ICL while providing the best possible standard therapy to eradicate opportunistic infections.
  • To establish the timeline of CD4 lymphocytopenia, with particular focus on defining subgroups of patients according to the decline, stabilization, or rise of CD4+ T cell counts over time.
  • To characterize the opportunistic infections that occur in ICL patients at microbiologic and molecular levels.
  • To characterize the immunophenotype and possible genetic immunodeficiency causes of ICL.
  • To determine whether measurable immunologic parameters correlate with the development of opportunistic infections or other comorbidities such as lymphoma in patients with ICL.
  • To determine whether there is any association between ICL and autoimmunity.
  • To determine CD4+ T cell turnover, survival, functionality, and cytokine responsiveness in ICL patients.

Eligibility:

  • Patients 2 years of age and older with an absolute CD4 count less than 300 in children 6 years or older and adults or less than 20% of T cells in children younger than 6 on two occasions at least 6 weeks apart.
  • Patients with negative results of HIV testing by ELISA, Western Blot, and viral load.
  • Patients must not have underlying immunodeficiency conditions, be receiving cytotoxic chemotherapy (anti-cancer drugs that kill cells), or have cancer.

Design:

  • At the initial visit to the National Institutes of Health, the following evaluations will be conducted:
  • Personal and family medical histories.
  • Physical examination, including rheumatology evaluation and other consultations as medically indicated (e.g., dermatology, pulmonology, ophthalmology, imaging studies).
  • Blood samples for analysis of red and white blood cell counts, liver function, immune hormones, and antibody and autoantibody levels, white blood cell growth and function, and DNA.
  • Urinalysis and urine pregnancy testing for female patients of childbearing age.
  • Evaluation and treatment of active infections as medically indicated, including biopsies, buccal swabs, pulmonary function tests, and imaging studies.
  • Follow-up visits will take place approximately every 12 months or more frequently if indicated, and will continue for a minimum of 4 years and a maximum of 10 years.
  • Evaluations at follow-up will include blood samples (i.e., CBC with differential, biochemical profile, HIV testing, etc.) and urinalysis and rheumatology consults.

Condition or disease
Idiopathic CD4+ Lymphocytopenia Cryptococcal Meningitis Warts

Detailed Description:
Idiopathic CD4+ lymphocytopenia (ICL) is a disorder characterized by decreased numbers of circulating CD4+ T lymphocytes in the absence of known causes of CD4+ lymphocytopenia. ICL is defined as an absolute CD4+ T cell count of less than 300 cells/microL in a patient with no human immunodeficiency virus infection or known immunodeficiency syndrome. The causes and frequency of the disorder remain unknown. The condition is typically diagnosed when patients present with a serious infection. In this natural history protocol, we will evaluate patients with CD4+ T cell counts below 300 cells/microL. We propose to follow 300 ICL patients for a minimum of 4 and maximum of 20 years, with a particular focus on the association between ICL and autoimmune disease. In addition to the ICL patients, we will enroll blood relatives and household contacts to better understand pathogenesis and etiologies of the syndrome. We will collect blood and other tissues for immunologic, rheumatologic, and genetic testing in an effort to identify and understand the underlying defects that cause ICL and follow its course in a cohort of patients who will receive best standard therapy for opportunistic infections.

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Study Type : Observational
Estimated Enrollment : 950 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia
Actual Study Start Date : July 13, 2009


Group/Cohort
Blood Relatives
Blood Relatives of ICL subjects
Household Contacts
Household contacts of ICL subjects
ICL Subjects
Patients with confirmed idiopathic CD4 lymphocytopenia



Primary Outcome Measures :
  1. CD4 <300/microliters or < 20% of total T cells and their blood [ Time Frame: Baseline and annually ]
    To further characterize the natural history of ICL while also investigating the genetic, environmental, and immunologic features of the condition.


Secondary Outcome Measures :
  1. Determine CD4+ T cell turnover, survival, functionality and cytokineresponsiveness in selected ICL patients. [ Time Frame: Baseline and annually ]
    Collection of research blood (PBL, serum and plasma) for storage

  2. Investigate ICL immune cell homeostasis and trafficking by immunologic studies including tissue biopsies and the utilization of ahumanized mouse model. [ Time Frame: Baseline and annually ]
    Collection of research blood (PBL, serum and plasma) for storage

  3. Establish the prognosis of CD4 lymphocytopenia, with particular focus on defining subgroups of patients according to the decline, stabilization, or rise of CD4+T cell counts over time. [ Time Frame: Baseline and annually ]
    Collection of research blood (PBL, serum and plasma) for storage

  4. Determine whether measurable immunologic parameters correlate with the development of opportunistic infections or other co-morbidities [ Time Frame: Baseline and annually ]
    Determine whether measurable immunologic parameters correlate with the development of opportunistic infections or other co-morbidities such as lymphoma in patients with ICL. Investigate the associations between idiopathic CD4+ lymphocytopenia and autoimmunity.Collection of research blood (PBL, serum and plasma) for storage

  5. Determine the relationship between ICL and the microbiome. [ Time Frame: Baseline and annually ]
    Collection of rectal swab and dietary questionnaire



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Adults with idiopathic CD4+ lymphocytopenia (ICL) who have CD4 <300/microliters or < 20% of total T cells and their blood relatives and household contacts.
Criteria
  • ICL PARTICPANT INCLUSION CRITERIA:

To be eligible for this study, patients must satisfy all of the following inclusion criteria:

  1. Age greater than or equal to 18 years
  2. Absolute CD4 count < 300 cells/microL or < 20% of total T cells on at least two occasions at least 6 weeks apart
  3. Ongoing care by a referring primary care physician
  4. Willingness to allow storage of blood and tissue samples for future analysis

ICL PARTICPANT EXCLUSION CRITERIA:

Patients will be ineligible for this study if they satisfy any of the following criteria:

  1. Known infection with HIV-1, HIV-2, or human T-cell lymphotropic viruses (HTLV-1 or HTLV-2) as demonstrated by enzyme-linked immunosorbent assay (ELISA) and western blot and/or viral load testing
  2. Known underlying immunodeficiency syndrome other than ICL
  3. Evidence of active malignancy
  4. Receipt of medications, herbal substances, or biologic agents known to diminish the CD4+ count within 30 days of when the CD4+ lymphocytopenia was detected
  5. Any condition that in the judgment of the investigators would place the subject at undue risk or compromise the results of the study.

BLOOD RELATIVE INCLUSION CRITERIA:

To be eligible for study participation as a blood relative, subjects must be greater than or equal to 18 years of age and be a blood relative of an individual who meets or has met the CDC criteria for ICL.

HOUSEHOLD CONTACT INCLUSION CRITERIA:

To be eligible for study participation as a household contact, subjects must be greater than or equal to18 years of age and live within the same household as an ICL subjects participating in this protocol. Blood relatives who are household contacts are eligible to participate.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00867269


Contacts
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Contact: Irini Sereti, M.D. (301) 496-5533 isereti@niaid.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Irini Sereti, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00867269    
Other Study ID Numbers: 090102
09-I-0102
First Posted: March 23, 2009    Key Record Dates
Last Update Posted: July 9, 2021
Last Verified: July 2, 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Opportunistic Infection
Immunodeficiency Syndrome
Autoimmune Disease
CD4+ Lymphocytes
Idiopathic CD4 Lymphocytopenia
Additional relevant MeSH terms:
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Meningitis, Cryptococcal
Meningitis
Lymphopenia
Central Nervous System Diseases
Nervous System Diseases
Meningitis, Fungal
Central Nervous System Fungal Infections
Mycoses
Cryptococcosis
Central Nervous System Infections
Leukopenia
Leukocyte Disorders
Hematologic Diseases
Immunologic Deficiency Syndromes
Immune System Diseases