Idiopathic CD4+ LymphocytopeniaNCT00867269
Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia
An observational study of Idiopathic CD4+ Lymphocytopenia and Cryptococcal Meningitis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Idiopathic CD4+ Lymphocytopenia, Cryptococcal Meningitis, Warts
- How many people
- 950 participants
- Where
- 1 siteUnited States
- Study dates
- 13 Jul 2009to not given
- Phase
- Observational
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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.
- ICL PARTICPANT INCLUSION CRITERIA:
To be eligible for this study, patients must satisfy all of the following inclusion criteria:
- Age greater than or equal to 18 years
- Absolute CD4 count < 300 cells/microL or < 20% of total T cells on at least two occasions at least 6 weeks apart
- Ongoing care by a referring primary care physician
- 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:
- 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
- Known underlying immunodeficiency syndrome other than ICL
- Evidence of active malignancy
- Receipt of medications, herbal substances, or biologic agents known to diminish the CD4+ count within 30 days of when the CD4+ lymphocytopenia was detected
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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.
Read more
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.
Read the 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.
- Keywords
- Opportunistic Infection, Immunodeficiency Syndrome, Autoimmune Disease, CD4+ Lymphocytes, Natural History, Idiopathic CD4 Lymphocytopenia
- Medical subject headings
- T-Lymphocytopenia, Idiopathic CD4-Positive, Meningitis, Cryptococcal, Warts, Opportunistic Infections, Immunologic Deficiency Syndromes, Autoimmune Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Blood Relatives | Blood Relatives of ICL subjects | |
| Household Contacts | Household contacts of ICL subjects | |
| ICL Subjects | Patients with confirmed idiopathic CD4 lymphocytopenia |
What is being measured
The primary outcome is the main question the study is designed to answer.
CD4 <300/microliters or < 20% of total T cells and their blood
To further characterize the natural history of ICL while also investigating the genetic, environmental, and immunologic features of the condition.
Measured: Baseline and annually
Secondary outcomes (5)
Determine CD4+ T cell turnover, survival, functionality and cytokineresponsiveness in selected ICL patients.
Collection of research blood (PBL, serum and plasma) for storage
Measured: Baseline and annually
Investigate ICL immune cell homeostasis and trafficking by immunologic studies including tissue biopsies and the utilization of ahumanized mouse model.
Collection of research blood (PBL, serum and plasma) for storage
Measured: Baseline and annually
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.
Collection of research blood (PBL, serum and plasma) for storage
Measured: Baseline and annually
Determine whether measurable immunologic parameters correlate with the development of opportunistic infections or other co-morbidities
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
Measured: Baseline and annually
Determine the relationship between ICL and the microbiome.
Collection of rectal swab and dietary questionnaire
Measured: Baseline and annually
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Mar 2009 (estimated)
- Study start13 Jul 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Idiopathic CD4+ LymphocytopeniaStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 950 participants (estimated)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Irini Sereti, M.D., Principal investigator, National Institute of Allergy and Infectious Diseases (NIAID)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00867269
- Sponsor's protocol ID
- 090102
- Other IDs
- 09-I-0102
- Status last verified
- 8 Jan 2026
- First submitted
- 20 Mar 2009
- Last updated
- 16 Oct 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Fauci AS. CD4+ T-lymphocytopenia without HIV infection--no lights, no camera, just facts. N Engl J Med. 1993 Feb 11;328(6):429-31. doi: 10.1056/NEJM199302113280610. No abstract available.
PubMed 8093637Laurence J, Siegal FP, Schattner E, Gelman IH, Morse S. Acquired immunodeficiency without evidence of infection with human immunodeficiency virus types 1 and 2. Lancet. 1992 Aug 1;340(8814):273-4. doi: 10.1016/0140-6736(92)92359-n.
PubMed 1353194Ho DD, Cao Y, Zhu T, Farthing C, Wang N, Gu G, Schooley RT, Daar ES. Idiopathic CD4+ T-lymphocytopenia--immunodeficiency without evidence of HIV infection. N Engl J Med. 1993 Feb 11;328(6):380-5. doi: 10.1056/NEJM199302113280602.
PubMed 8093634Lisco A, Ortega-Villa AM, Mystakelis H, Anderson MV, Mateja A, Laidlaw E, Manion M, Roby G, Higgins J, Kuriakose S, Walkiewicz MA, Similuk M, Leiding JW, Freeman AF, Sheikh V, Sereti I. Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years. N Engl J Med. 2023 May 4;388(18):1680-1691. doi: 10.1056/NEJMoa2202348.
PubMed 37133586Sortino O, Dias J, Anderson M, Laidlaw E, Leeansyah E, Lisco A, Sheikh V, Sandberg JK, Sereti I. Preserved Mucosal-Associated Invariant T-Cell Numbers and Function in Idiopathic CD4 Lymphocytopenia. J Infect Dis. 2021 Aug 16;224(4):715-725. doi: 10.1093/infdis/jiaa782.
PubMed 34398238Perez-Diez A, Wong CS, Liu X, Mystakelis H, Song J, Lu Y, Sheikh V, Bourgeois JS, Lisco A, Laidlaw E, Cudrici C, Zhu C, Li QZ, Freeman AF, Williamson PR, Anderson M, Roby G, Tsang JS, Siegel R, Sereti I. Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia. J Clin Invest. 2020 Oct 1;130(10):5326-5337. doi: 10.1172/JCI136254.
PubMed 32634122