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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 19, 2017 by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ) Identifier:
First received: March 20, 2009
Last updated: April 20, 2017
Last verified: April 19, 2017


  • 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.


  • 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.


  • 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.


  • 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.

Idiopathic CD4+ Lymphocytopenia
Cryptococcal Meningitis

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Estimated Enrollment: 450
Study Start Date: March 17, 2009
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/microliter 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/microliter. We propose to follow 200 ICL patients for a minimum of 4 and maximum of 14 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 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.







Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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


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 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.


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


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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00867269

Contact: Megan V Anderson, R.N. (301) 761-7323
Contact: Irini Sereti, M.D. (301) 496-5533

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 Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Principal Investigator: Irini Sereti, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID) Identifier: NCT00867269     History of Changes
Other Study ID Numbers: 090102
Study First Received: March 20, 2009
Last Updated: April 20, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Idiopathic Lymphocytopenia
Opportunistic Infection
Immunodeficiency Syndrome
Autoimmune Disease
CD4+ Lymphocytes
Idiopathic CD4 Lymphocytopenia

Additional relevant MeSH terms:
Meningitis, Cryptococcal
Central Nervous System Diseases
Nervous System Diseases
Leukocyte Disorders
Hematologic Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Meningitis, Fungal
Central Nervous System Fungal Infections
Central Nervous System Infections processed this record on May 25, 2017