EVIDENCE REVIEW:  Severe Combined Immunodeficiency (SCID)

Letter to the Committee from the Evidence Review Group-April 2009

Printer-friendly Committee Report (111 KB)

Prepared for: ADVISORY COMMITTEE ON HERITABLE DISORDERS IN NEWBORNS AND CHILDREN

Final  
01/20/2009 (revised 04/29/2009)

Authors:
Ellen Lipstein, Alixandra A. Knapp, James M. Perrin

Evidence Review Group:  Chairperson, James M. Perrin, MD
(MGH Center for Child and Adolescent Health Policy)

Committee Members:

This review was made possible by subcontract number SC-07-028 to Massachusetts General Hospital, Center for Child and Adolescent Health Policy under prime contract number HHSP23320045014XI to Altarum Institute, from the Maternal and Child Health Bureau (MCHB) (Title V, Social Security Act), Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services (DHHS).

Table of Contents                                                                                                             
i. Abbreviations Used                                                                                                            
I. Overview                                                                                                                            
II. Rationale for Review                                                                                                        
III. Objectives of Review                                                                                                      
IV. Main Questions                                                                                                               
V. Conceptual Framework                                                                                                     
VI. Methods                                                                                                                          
VII. Results                                                                                                                           
VIII. Summary                                                                                                                      
IX. References                                                                                                                       
X. Appendix A- SCID Evidence Tables                                                                               
XI. Appendix B- Conflict of Interest Form                                                                          
XII. Appendix C- Letter and Questions Sent to SCID Experts                                           
XIII. Appendix D- Letter and Questions Sent to SCID Advocacy Groups                        

i. Abbreviations used

ACHDNC                  ACTB                      ADA deficiency       BMT                        B+ SCID                  B- SCID                   CD Antigens            CI                            CIBMTR                   CMV                        DNA                        ELISA                     ERG                        ERT                        G-CSF                    GVHD                     HLA                           HSCT                         IgA                            IgG                            IgM                            IL-7                            IVIG                           JAK                           MeSH                        MMRD                       MUD                          NIAID                        NK                            PEG                          PHA                          RID                           SCID                         SCIDA                       TREC                         USIDNET                  XSCID                       c

Advisory Committee on Heritable Disorders in Newborns and Children Gene symbol for beta-actin Adenosine deaminase deficiency Bone marrow transplant Subgroup of severe combined immunodeficiency in which B lymphocytes are present Subgroup of severe combined immunodeficiency in which B lymphocytes are absent Cluster of differentiation, nomenclature of leucocyte molecules Confidence interval Center for International Blood and Marrow Transplant Research Cytomegalovirus Deoxyribonucleic acid Enzyme-Linked ImmunoSorbent Assay Evidence review group Enzyme replacement therapy Granulocyte-colony stimulating factor Graft versus host disease Human leukocyte antigen Hematopoietic stem cell transplant Immunoglobulin A Immunoglobulin G Immunoglobulin M Interleukin 7 Intravenous immunoglobulin Janus kinase National Library of Medicine medical subject heading Mismatched related donor Matched unrelated donor National Institute of Allergy and Infectious Diseases Natural killer Polyethylene glycol Phytohemagglutinin Related identical Severe Combined Immunodeficiency Severe Combined Immunodeficiency, Athabascan-type T-cell receptor excision circles United States Immunodeficiency Network X-Linked Severe Combined Immunodeficiency Common cytokine receptor chain

I.  Overview
Severe Combined Immunodeficiency (SCID) is a group of disorders characterized by the absence of both humoral and cellular immunity.  Reported incidence is approximately 1/100,000 (Chan, Puck 2005, McGhee et al. 2005). Currently at least 15 genes are known to cause SCID when mutated (Puck, SCID Newborn Screening Working Group 2007).  Although disease presentation varies (Buckley et al. 1997), as protection from maternal antibodies wanes during the first months of life, infants with SCID develop infections due to both common and opportunistic pathogens (Buckley et al. 1997).  Treatment and prevention of infections can prolong life but are not curative actions (Buckley et al. 1999).

Early receipt of hematopoietic stem cell transplant (HSCT), prior to the onset of severe infections, offers the best chance of cure (Buckley et al. 1999).  Although family history leads to early detection of some infants, the majority of infants with SCID are not detected until they develop clinical symptoms such as recurrent infections, failure to thrive and infection with opportunistic organisms (Buckley et al. 1997).  The apparent value of early HSCT has led to a search for methods for pre-symptomatic identification of infants with SCID, including possible population-based newborn screening.

II. Rationale for Review
The Advisory Committee on Heritable Disorders in Newborns and Children has directed the Evidence Review Group to produce this report for the nominated condition of SCID.  SCID has been nominated for the following reasons:

1. Without treatment, SCID leads to death in early childhood. 
2. Earlier treatment, particularly before the onset of lung infection, decreases the mortality and morbidity associated with SCID and with HSCT for SCID.
3. Methods to screen infants for SCID, using quantitative PCR for T-cell receptor excision circles (TREC), have been developed.

 III. Objectives of review 

The objective of this review is to provide information to the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) to guide recommendations regarding screening newborns for SCID.  Specifically, the Evidence Review Group’s (ERG) goal was to summarize the evidence available from published studies, as well as critical unpublished data available from key investigators in the field.

IV. Main questions

We sought to answer the following questions, with a particular emphasis on the questions related to screening and the benefits of early treatment.

1. What is the natural history of SCID and are there clinically important phenotypic or genotypic variations? 
2. What is the prevalence of SCID and its variations?
3. What methods exist to screen newborns for SCID?  How accurate are those methods?  What are their sensitivity and specificity?  What methods exist to diagnose individuals with positive screens?
4. What benefit does treatment, particularly pre-symptomatic, confer?
5. What are the potential harms or risks associated with screening, diagnosis or treatment?
6. What costs are associated with screening, diagnosis, treatment and the failure to diagnose in the newborn period?

By answering these questions we hoped to provide the ACHDNC with answers to broader questions related to SCID screening.  Specifically:

1. Do current screening tests effectively and efficiently identify cases of SCID?
2. Does pre-symptomatic or early symptomatic intervention in newborns or infants with SCID improve health outcomes?  In other words, does early identification lead to better outcomes?
3. What is the cost-effectiveness of newborn screening for SCID?
4. What critical evidence appears lacking that may inform screening recommendations for SCID?

V.  Conceptual framework
The conceptual framework illustrated below outlines the salient factors when considering newborn screening for any disorder, SCID in the case of this review.  Children will develop SCID regardless of whether or not they are screened.  The key decision points, therefore, are whether to screen newborns and what treatment to pursue for affected children.  At either decision point, children may experience benefits from the decision but also are at risk of adverse effects, including false-positive or false-negative screening results and significant treatment side-effects.  The combination of the baseline risk for SCID and the effects of the screening and treatment decisions lead to a state of health. 

Figure 1- Conceptual Framework. 

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