Overview of Severe Combined Immunodeficiencies (SCID) in Plain Communities During the Era of
Newborn SCID Screening
Christine Seroogy MD Associate Professor
Department of Pediatrics Division of Allergy, Immunology & Rheumatology
Funding Source:
Objectives • Newborn Screening for SCID successfully
detects many forms of SCID • Awareness of SCID forms and T cell
lymphopenias in Plain communities and approach to evaluation (emphasis on RAG1)
• Curative treatment for SCID early and infection-free leads to better outcomes
• Ongoing challenges associated with treatment of SCID in newborns/Plain communities
Severe Combined Immunodeficiency (SCID)
CLINICAL: • Infections in first year of life • Failure to thrive
LABORATORY: • T cells markedly decreased or absent & don’t function • B cells absent or non-functional • To date, 20+ genetic mutations associated with SCID
phenotype.
Fatal without immune reconstitution in the first year of life
Common Theme in ALL forms of SCID: Impaired Thymopoiesis
T Cell Receptor Excision Circle (TREC): biomarker of thymic function
Generation of T cell receptor excision circles (TRECs) occur in >70% of all new (naïve) T
cells and can be detected by PCR Ponchel et al. BMC Biotechnology 2003
TREC Assay Platform in Newborn Screening Laboratory
Slide courtesy of Dr. Mei Baker
Population Cumulative 2008-2013 birth number SCID SCID
Prevalence
Total WI population 404,836 (average 67,473/year) 9 1 in 44,982
WI Plain Communities 5,280 (average 880/year) 5 1 in 1,056
(estimated)
Wisconsin SCID Statistics Since NBS SCID Screening
*
*
#
#
Es>mated using vital records and unique methodology, Drs. Angela Rohan and Murray Katcher, unpublished data
Includes one Amish newborn
Genetic Mutations Associated with T cell Lymphopenia & NBS SCID Screening in the Plain Communities
Immunologic Diseases Associated with T cell Lymphopenia
CSC (Lancaster Co, PA)
DDC (Northeast
OH) Indiana WI Other
Detected by NBS
SCID Screen
Plain Community
RAG1 SCID/Omenn Syndrome X X X YES Amish
ADA SCID X X YES Amish
IL7Ra SCID X X YES Mennonite
CD3delta SCID X YES Mexican/Low German-Mennonite
Cartilage Hair Hypoplasia X X X Variable Amish
ZAP70 CID X Variable Amish
Ataxia Telangiectasia X Variable Amish/Mennonite
22q11.2 microdeletion X X Variable Amish
Wiskott Aldrich Syndrome X NO Amish
RAG1 CID X Unknown Mennonite
*
* Direct experience, personal communications, expert opinion, and review of medical literature
Initial Management NBS SCID Positive Screen
• Confirmatory testing and continued diagnostic testing for SCID • Protective isolation: where is safest environment? • Antimicrobial prophylaxis • Intravenous gamma globulin • No live vaccines • Irradiated, CMV- blood products • Safety of breastfeeding? • Cure?
Railey et al J. of Ped 2009
Bone Marrow Transplant in the First 3.5 Months Of Life Has Best Outcome in SCID (Dr. Buckley’s data—no conditioning)
Overall survival 77%, survival for BMT in first 3.5 months is 94%
Primary Immunodeficiency Treatment Consortium (PIDTC, 25 centers), 240 Infants with Classical Severe Combined
Immunodeficiency Retrospective 2000-2009:
Pai S et al. N Engl J Med 2014;371:434-‐446.
Age & Infection Status at the time of Bone Marrow Transplant (BMT) Impact Survival
Primary Immunodeficiency Treatment Consortium (PIDTC, 25 centers), 240 Infants with Classical Severe Combined
Immunodeficiency Retrospective 2000-2009:
Pai S et al. N Engl J Med 2014;371:434-‐446.
Survival is Highest with Matched Sibling Donor and Reduced in Recipients with Conditioning Regimens
Conclusions
• Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection.
• All available graft sources are expected to lead to excellent survival among asymptomatic infants.
• Questions:
When does conditioning need to be used? What is the minimal amount of conditioning that is required for acceptable engraftment? Is this a one-size fits all or does SCID genotype matter?
PIDTC MultiCenter Classical SCID BMT Conclusions
• RAG (recombination-activating gene) 1/2 proteins critical for T and B cell development by initiating VDJ recombination process. This leads to a block in early thymopoiesis.
• Mutations in RAG1/2 initially associated with SCID. More recent studies have demonstrated RAG 1/2 mutations in patients with combined immune deficiencies, autoimmune disease, and granulomatous disease.
Nature Structural & Molecular Biology 2009
RAG1
J Allergy Clin Immunol. 2014 Apr;133(4):1099-‐108. doi: 10.1016/j.jaci.2013.10.007. Epub 2013 Nov 28
T-‐B-‐NK+SCID Omenn Syndrome γδ-‐T SCID Leaky SCID CID Unknown
Muta>on found
in Amish
Muta>on found in Amish
RAG Recombination Activity Tends to Correlate with Clinical Phenotype
Omenn Syndrome (OMIM no. 603554)
• Clinical features: early in life diffuse erythrodermia, hepatosplenomegaly, lymphadenopathy, alopecia, failure to thrive, recurrent infections.
• Laboratory features: Absence of circulating B cells, infiltration of skin and intestine by activated oligoclonal T lymphocytes, high serum IgE levels, peripheral blood eosinophilia, increased numbers of poorly functional activated circulating T cells.
Clinical Immunology, Volume 128, Issue 1, 2008, 31 - 38
Omenn Syndrome • To date, many SCID-associated genes have been
associated with OS. Mutations in RAG1 is the prototype and most studied.
• Some hypomorphic mutations, including RAG1, can cause either SCID or OS. Thus, suggesting other gene modifiers or environmental triggers necessary for OS phenotype.
T Cell Number & T Cell Function
Classical SCID
Leaky SCID
Omenn Syndrome
Unique Challenges in Plain Communities:
• Decreased rates of newborn screening • Increased population prevalence of
hypomorphic RAG1 mutations • Curative approaches for SCID are expensive • Opposition to chemotherapy • Opposition to prolonged hospitalizations • Poor access to tertiary care centers • Refusal of therapy for fatal, but curative
disease
General Challenges • The use of conditioning for bone marrow
transplantation in newborns (1-2 months) is an extremely difficult decision – Tandem transplant? – Antibody depleting regimens (CD45 not
readily available and anti-c-kit in development)
– Lower dose conditioning? (PIDTC trial) – Serotherapy and αβ-‐T cell depletion?
Conclusion • Newborn screening for SCID successfully
detects all forms of SCID (and other clinically actionable T cell lymphopenias).
• Early screening leads to early treatment in healthy infants resulting is better outcomes.
• All forms of SCID and some T cell lymphopenias found in Plain Communities are easily amenable to NBS SCID screening (but not all).