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Study Description

Individuals with a past diagnosis of severe combined immune deficiency (including many cases of "leaky SCID", Omenn syndrome, and reticular dysgenesis) who have undergone blood and marrow transplant, gene therapy, or enzyme replacement in the past may be eligible for 6902. The purpose of 6902 is very similar to 6901, except 6902 is looking backwards at what has already been done in the past (compared to 6901 which is looking into the future). Over 800 patients with SCID are expected to be enrolled on 6902. This makes 6902 the largest study ever to describe outcomes for patients with SCID treated at many different hospitals around North America.

One of the most important components of the 6902 study is the "cross sectional" study. Patients who have received their treatments (BMT, gene therapy, enzyme replacement) many years ago are asked to come back to the hospital where they were treated. During this visit, additional research blood work is drawn and information is gathered regarding long-term transplant outcomes such as infections, graft-versus-host disease, autoimmune diseases, and quality of life. This will allow PIDTC researchers to better understand long-term outcomes from procedures that occurred many years ago (sometimes over 30 years ago) - something that is not possible at the present time with 6901. This will help researchers to best design new treatments and clinical trials in the future for children with SCID.

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Study Inclusion/Exclusion Criteria

Patients eligible for the retrospective analysis include all patients diagnosed to have SCID who were treated at the institutions participating in this consortium since January 1, 1968 who were not enrolled on PIDTC Protocol #6901 before starting HCT/GT/ERT. Subjects who received HCT/GT/ERT prior to enrolling with PIDTC are eligible for the retrospective study PIDTC Protocol #6902. The enrollment criteria for subjects who died prior to definitive therapy are the same as for Strata A, B and C.

Stratum A, Typical SCID
Patients who meet the following inclusion criteria and who received HCT as initial treatment are eligible for enrollment into Stratum A (Classic SCID) of the study:

  • Absence or very low number of T cells (CD3 T cells <300/microliter), AND no or very low T cell function (< 10% of lower limit of normal) as measured by response to phytohemagglutinin (PHA)
    • OR
  • T cells of maternal origin present
Note #1: If CD3 enumeration is not available, other methods of enumeration (E rosetting, staining with OKT3) are also acceptable prior to 1990. When possible the proliferation to PHA should be calculated as a percentage of the lower limit of normal controls for that laboratory. If a range is not available, patients with stimulation index (SI) < 10 or whose absolute cpms are <10% of the cpms of the normal control of the day are eligible. SI = (cpm of subject - cpm of medium) / cpm of medium.
Note #2: Acceptable methods to identify maternal T cells include demonstration of lymphocytes with an XX karyotype in a male patient, FISH for XX in a male patient, presence of maternal VNTR or STR or demonstration of maternal HLA alleles by molecular analysis in purified T cells or by flow cytometry. Prior to 1990 maternal HLA may have been identified without T cell purification and this is acceptable.
Note #3: For patients with presumed ADA SCID, T cell studies MUST be obtained prior to enzyme replacement therapy with PEG-ADA ERT or blood transfusion.

Stratum B, Leaky SCID, Omenn Syndrome, Reticular Dysgenesis.
Patients who were treated initially with HCT and who meet the following criteria are eligible for enrollment into Stratum B of the study:

Leaky SCID

  • Reduced number of CD3 T cells
    • for age up to 2 years < 1000/microliter
    • for > 2 years up to 4 years < 800/microliter
    • for > 4 years < 600/microliter
  • Absence of maternal engraftment
  • for > 30% of lower limit of normal T cell function (as measured by response to PHA)

Note: If CD3 enumeration is not available, other methods of enumeration (E rosetting, staining with OKT3) are also acceptable prior to 1990.
If maternal engraftment was not assessed or CD3 T cell numbers do not fit the above criteria, genotype may be used as supportive eligibility criteria. If maternal engraftment was not assessed and ruled out and genotype was not obtained or is not supportive, the patient is not eligible.
When possible the proliferation to PHA should be calculated as a percentage of the lower limit of normal controls for that laboratory. If a range is not T cells or by flow cytometry. Prior to 1990 maternal HLA may have been identified without T cell purification and this is acceptable.
For patients with presumed ADA SCID, T cell studies MUST be obtained prior to enzyme replacement therapy with PEG-ADA ERT or blood transfusion.

Omenn Syndrome (OS)

  • Generalized skin rash
  • Absence of maternal engraftment
  • Detectable CD3 T cells, ≥ 300/microliter
  • Absent or low (up to 30% of normal) T cell proliferation to antigens to which the patient has been exposed.
Note: If CD3 enumeration is not available, other methods of enumeration (E rosetting, staining with OKT3) are also acceptable prior to 1990.
If maternal engraftment has not been assessed or CD3 T cell numbers do not fit the above criteria, genotype may be used as supportive eligibility criteria. These patients will be considered Omenn-like.

When possible the proliferation to antigen should be calculated as a percentage of the lower limit of normal controls for that laboratory. If an arangement is not available, the lower limit of normal for that day may be used. Alternatively, patients with stimulation index (SI) ≥10 and <0 are eligible.
If the proliferation to antigen was not performed, but at least 4 of the following 10 supportive criteria, at least one of which must be among those marked with an asterisk (*) below are present, the patient is eligible:

  • Hepatomegaly
  • Splenomegaly
  • Lymphadenopathy
  • Elevated IgE
  • Elevated absolute eosinophil count
  • *Oligoclonal T cells measured by CDR3 length or flow cytometry
  • *>80% of CD3+ or CD4+ T cells are CD45RO+
  • *Proliferation to PHA is reduced <30% of lower limit of normal or SI <20
  • *Proliferative response in mixed leukocyte reaction is reduced <30% of lower limit of normal or SI <5
  • *Mutation to SCID causing gene

Reticular Dysgenesis (RD)

  • Absence or very low number of T cells (CD3 T cells <300/microliter)
  • No or very low (<10% of lower limit of normal) T cell function (as measured by response to phytohemagglutinin (PHA)
  • Severe neutropenia (absolute neutrophil count <200/microliter)
  • Sensorineural deafness and/or absence of granulopoiesis at bone marrow examination and/or a deleterious AK2 mutation

Note: If CD3 enumeration is not available, other methods of enumeration (E rosetting, staining with OKT3) are also acceptable prior to 1990.
When possible the proliferation to antigen should be calculated as a percentage of the lower limit of normal controls for that laboratory. If an arrangement is not available, patients with stimulation index (SI) <10, or whose absolute cpm are ≥10% and <30% of the cpm of the normal control of the day are eligible.
Lack of response to G-CSF, deficiency of granulocyte precursors and mutation in both alleles of AK2 are supportive but not required.

Stratum C, SCID with Non-HCT Treatments

Patients who met the following criteria and were initially treated with PEG-ADA ERT or gene therapy with autologous modified cells are eligible for enrollment into Stratum C (SCID with non-HCT treatments) of the study.

  • ADA Deficient SCID treated with PEG-ADA ERT.
  • Any SCID treated with gene therapy.

Note: For patients with presumed ADA SCID, T cell studies MUST be obtained prior to enzyme replacement therapy with PEG-ADA ERT or blood transfusion.

Participant Inclusion Criteria for Strata A, B, and C (Part 2 - Cross-Sectional Study) Patient inclusion criteria for the cross-sectional study: Eligibility for Strata A, B and C are the same as for the retrospective study except that all the patients in the cross-sectional study are currently surviving and are at least 2 years post the most recent class of therapy.

Participant Exclusion Criteria (Parts 1 and 2 - Retrospective and Cross-Sectional Studies)
Patients who meet any one or more of the following exclusion criteria are disqualified from enrollment in the study.

  • Lack of appropriate testing to rule out HIV infection after 1997 (p24 antigen or more sensitive) or other cause of secondary immunodeficiency. The PID-SCID Review Committee may consider presence of other inclusionary criteria to make a decision about entry, for subjects lacking HIV testing.
  • Presence of DiGeorge syndrome unless SCID genotype is also present.
  • Most patients with defects such as nucleoside phosphorylase, ZAP70, NEMO, RMRP (cartilage hair hypoplasia), DOCK8, MST1, ORAI1, STIM1 or CORO1A, MAGT1, IKBA, RHOH will not meet the inclusion criteria for Stratum A, B, or C above. However, a patient with one of the above may meet the inclusion criteria for Stratum A or Stratum B and if so will be included.
  • MHC Class I and MHC Class II antigen deficiency are excluded.
  • Metabolic conditions that imitate SCID or related disorders such as folate transporter deficiency, severe zinc deficiency, transcobalamin deficiency.

Study History

  • Study Activated December 17, 2010
  • First Accrual May 12, 2011

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
Authorized Data Access Requests
Study Attribution
  • Principal Investigator
    • Elie Haddad, MD, PhD. CHU Sainte-Justine, Mother and Child University Hospital Center, Montreal, Canada.
  • Co-Principal Investigators
    • Richard J. O'Reilly, MD. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    • Morton J. Cowan, MD. UCSF Department of Pediatrics, San Francisco, CA, USA.
  • Funding Sources
    • 2U54AI082973-06. National Institutes of Health, Bethesda, MD, USA.