EVIDENCE REVIEW:  Severe Combined Immunodeficiency (SCID)

On this page:

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         

i. ABBREVIATIONS USED

ACHDNC Advisory Committee on Heritable Disorders in Newborns and Children
ACTB  Gene symbol for beta-actin
ADA-deficiency Adenosine deaminase deficiency
BMT Bone marrow transplant
B+ SCID Subgroup of severe combined immunodeficiency in which B lymphocytes are present
B- SCID Subgroup of severe combined immunodeficiency in which B lymphocytes are absent
CD Antigens Cluster of Differentiation, nomenclature of leucocyte molecules
CI Confidence interval
CIBMTR Center for International Blood and Marrow Transplant Research
CMV Cytomegalovirus
DNA Deoxyribonucleic acid
ELISA Enzyme-Linked ImmunoSorbent Assay
ERG Evidence review group
ERT Enzyme replacement therapy
G-CSF Granulocyte-colony stimulating factor
GvHD Graft versus host disease
HLA Human leukocyte antigen
HSCT Hematopoietic stem cell transplant
IgA Immunoglobulin A
IgG  Immunoglobulin G
IgM Immunoglobulin M
IL-7 Interleukin 7
IVIG Intravenous immunoglobulin
JAK Janus kinase
MeSH National Library of Medicine medical subject heading
MMRD Mismatched Related Donor
MUD Matched Unrelated Donor
NIAID National Institute of Allergy and Infectious Diseases
NK Natural killer
PEG Polyethylene Glycol
PHA Phytohemagglutinin
RID Related Identical
SCID Severe Combined Immunodeficiency
SCIDA Severe Combined Immunodeficiency, Athabaskan-Type
TREC T-cell receptor excision circles
USIDNET United States Immunodeficiency Network
XSCID X-Linked Severe Combined Immunodeficiency
c  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.

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 identified.  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. 

VI. METHODS

This evidence review provides information from two sources: a systematic literature review and interviews with experts in the field of SCID.

A.   Literature Review
We searched MEDLINE for all relevant studies published over the 20 year period from January 1988 to October 2008.  We completed searches combining the National Library of Medicine Medical Subject Heading (MeSH) “severe combined immunodeficiency” with each of the following MeSH terms: epidemiology, incidence, prevalence, disease progression, mass screening, neonatal screening, genetic screening, diagnosis, and therapeutics.  In order to capture articles which have not yet been assigned MeSH terms, we also searched the following keywords within the OVID In-Process and Other Non-Indexed Citations database: severe combined immunodeficiency, severe immune deficiency, adenosine deaminase deficiency.  We applied human studies and English language limitations to all searches.  This search strategy resulted in a total of 725 articles.

All abstracts were reviewed by at least 2 readers (EL, JD, JP).  Articles which were non-human data, reviews, editorials or other opinion pieces, case-series of <4 patients, only contained adult subjects or did not address one or more of the key questions were eliminated.  Disagreements were resolved through discussion with emphasis on inclusion of any potentially useful data.  After this process 60 articles remained which were reviewed in detail.

Each article was evaluated, using standardized tools, for the quality of the study design (NHS Centre for Reviews and Dissemination, March 2001) and the quality of the evidence, as it relates to the category of evidence (Pandor et al. 2004, Pollitt et al. 1997).  A given article received only one rating per reader for study design, but may have received multiple quality evaluations for the type of evidence.  For example, a study that discusses prevalence and natural history would be evaluated for the quality of the evidence in each of those domains.

Data were abstracted from the articles by 2 reviewers (EL, SV).  A subset of the papers, approximately 20%, was abstracted by both reviewers in order to check for agreement.  There were no significant differences in the data extracted by the reviewers.

B.  Interviews with Experts
The ERG and the ACHDNC recognize that in a rapidly developing field, such as newborn screening for SCID, there may be crucial evidence that is either not yet ready for publication or has not been published for other reasons.  As such, using our literature search and discussions with content experts, we identified a list of key investigators.  This list was discussed among the members of the ERG, and additional names were added based on personal knowledge of the field by members of the ERG.  This list (Table 1) was approved by the ERG and the experts were contacted via e-mail.  Reminder e-mails were sent to non-responders approximately 2 weeks after the initial e-mail.

Experts were sent a letter (appendix) explaining the purpose of the review, a conflict of interest form (appendix) and an open-ended survey (appendix).  After receipt of the conflict of interest form and survey, phone interviews were scheduled between experts and members of the ERG (EL, AK, JP), when clarification of the written survey was needed.  The semi-structured phone interviews clarified information provided in the written survey.  Information from the surveys and interviews is explicitly provided in this report when such information was not available in the published literature.

Table 1- List of experts contacted and degree of participation

*Responded as a group with one combined survey
**Dr. McCabe declined to answer and referred us to Dr. McGhee

VII. RESULTS
Case definition:  For the purpose of this review, Severe Combined Immunodeficiency is defined based on the definition for the PubMed medical subheading.  SCID is a “group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. It is inherited as an X-linked or autosomal recessive defect.” (U.S. National Library of Medicine and the National Institutes of Health, 2008)   Children with SCID universally have extremely low or absent T-cells and may or may not have B-cells.  We have included some specific sub-types such as adenosine deaminase deficiency (ADA-deficiency), reticular dysgeneis and Omenn syndrome in the definition of SCID because they are characterized by absence of T-cells, but we recognize that not some groups consider these disorders distinct from SCID (WHO Scientific Group, 1995).

Table 2- Study design for abstracted articles

*Epidemiologic studies using retrospective record review (Jones et al. 1991) and telephone survey (Boyle & Buckley, 2007)

*Epidemiologic studies using retrospective record review (Jones et al. 1991) and telephone survey (Boyle & Buckley, 2007)

Evidence review:  The remainder of this section of the report is dedicated to presentation of the evidence.  Data is presented by key questions.  A table indicating the quality of the evidence for that key question leads the section, followed by data from the literature review.  Finally, any additional information learned from surveying experts is provided at the end of each section.

1. What is the natural history of SCID and are there clinically important phenotypic or genotypic variations?

Table 3- Quality Assessment of abstracted literature pertaining to Natural History
                       

Adapted from Pandor et al. 2004, Pollitt et al. 1997

The term SCID refers to a group of slightly heterogeneous disorders which are all related by the absence of T-cells in affected individuals.  Some subtypes are missing other lymphocyte subsets, such as B-cells or NK-cells, and others have associated non-immune manifestations such as neurocognitive deficits, hearing loss and skeletal abnormalities.
We describe below evidence related to the characteristic presentations of SCID, the natural history (without treatment), subtypes of SCID, and genotype/phenotype data.  The main findings are: 1) with the exception of children diagnosed early in life, typically through prenatal testing initiated because of family history, most children are diagnosed after recurrent pulmonary infections or infections with opportunistic organisms; 2) this is true of all SCID subtypes, although the exact timing may vary; and 3) without treatment of the underlying immunodeficiency, children with SCID die in early childhood from infection. 

General findings regarding natural history and associated clinical conditions -Systematic literature review
Several studies provide descriptive data regarding symptomatic presentation of children with SCID, almost all of which highlighted pulmonary and opportunistic infections, leading to early childhood death, as the key complications of untreated SCID.
A chart review (Deerojanawong et al. 1997) found that all children who did not receive prenatal diagnoses of SCID (13/15) had pulmonary symptoms at presentation.  Of 9 that died 5 were due to pulmonary disease.  Moreover, pulmonary infections, most commonly Pneumocystis jirovevi pneumonia (PJP), were the most common presenting sign of SCID, occurring in 10/15 children, at a median age of 4 months.  Another case series (Stocks et al. 1999) found 14/18 of the children, over a 20-year time period, had otolaryngological signs or symptoms (including congestion, URI, thrush, oral ulcers, cervical adenopathy, otitis media; mastoiditis) prior to diagnosis with SCID.
An institutional case-series (Stephan et al. 1993) of 117 patients treated for SCID between 1970 and 1992, found the median age at diagnosis, which did not change over the time period, was 4.6 months with an average of 2 months delay between clinical manifestations and diagnosis.  The primary clinical manifestations included oral candida, skin erythema, diarrhea with growth impairment and interstitial pneumonitis.   
Hague et al (Hague et al. 1994) found that, among 32 children with no family history of SCID, the median age of diagnosis was 7 months, despite the median age of symptom onset being 5 weeks.  In this group the median age of first hospital admission was 4 months with 22/32 presenting with respiratory infection, 9/32 with vomiting and diarrhea, 8/32 with candidal infection and 6/32 with failure to thrive. 

Two papers discussed physical signs or symptoms that may occur with high prevalence in children with SCID but are not necessarily presenting signs of the disease, including  gastroesophageal reflux (GER) (Boeck, Buckley & Schiff 1997)   and  rashes, particularly due to engraftment of maternal T lymphocytes (Denianke et al. 2001).

Table 4 - Evaluated literature pertaining to natural history of SCID (alphabetical by author)

Genotype specific findings –Systematic literature review
Although as many as 15 different genes (Puck, SCID Newborn Screening Working Group 2007) are associated with SCID, the known phenotypic variation is less extensive.  There is some phenotypic variation, as outlined below, in immunoglobulin levels, lymphocyte counts and lymphocyte function.  More striking, however, a few phenotypes appear to have distinct characteristics at presentation.  Specifically we found evidence supporting very early infections in children with reticular dysgenesis (Bertrand et al. 2002), neurologic symptoms in children with ADA-deficiency (Stephan et al. 1993, Honig et al. 2007), and oral/genital ulcers associated with a distinct form of SCID known as SCIDA occurring among Athabaskan-speaking Native Americans (O'Marcaigh et al. 2001).

A case-series (Buckley et al. 1997) of 108 infants examined the relationship between genotype and immune functional status.  These patients ranged from birth to 21 months at diagnosis and children with less severe forms of combined immunodeficiency, such as Omenn syndrome, were excluded.  The distribution of genotypes from this series is shown below in table 5.

Table 5- Relative frequencies of different SCID genotypes from Buckley et al. 1997

	SCID Infants* (n=108)		SCID families* (n=88)
Genotype	Number	Percent	Number	Percent
c deficiency	49	45.4	37	42
ADA-deficiency	16	14.8	13	15
Jak3 deficiency	8	7.4	5	6
Autosomal Recessive (not ADA or Jak3 deficiency)	21	19.4	19	22
Reticular Dysgenesis	1	0.9	1	<1
Cartilage-hair hypoplasia	1	0.9	1	<1
Unknown	12	11.1	12	14

*table depicts genotype according to the 108 individual patients in the first column, and the 88 families of origin in the second column where siblings count as one unit

The authors found abnormal serum immunoglobulin concentrations in all types of SCID.  Mean IgA levels were lowest in c-deficient, Jak3-deficient and unknown types of SCID.  Mean IgM concentrations were lowest in ADA, c and Jak3 deficient patients.  IgE was normal in all but 2 patients.
Lymphopenia was present in all categories of SCID but more severe in patients with ADA-deficient SCID.  5 infants had elevated lymphocytes, of which 4 were due to the presence of maternal cells.  Lymphocyte subpopulations varied between types of SCID.  ADA-deficient children had the lowest mean number of B-cells and c and Jak3 the highest.  Mean number of NK cells was lowest in ADA, c, and Jak3 deficient patients.  Lymphocyte response to mitogens was diminished in all patients.

B. What is the prevalence of SCID and its variations?

Most methods of determining the prevalence and incidence of a disorder depend on case ascertainment.  As in other disorders with high risk of early death, the incidence of SCID may be higher than measured via case ascertainment because some patients may die prior to having a definitive diagnosis.

Incidence and Prevalence-Systematic literature review
In a study with a primary focus on SCID screening methods, Chan and Puck (Chan, Puck 2005) estimated the annual incidence as a minimum of 1/105,000 births.  This calculation was based on assuming an annual US birthrate of 4,000,000 that all children with XSCID in the U.S. had blood samples sent to the authors’ laboratory for mutation detection (19 in one year) and that XSCID represents approximately half of all cases of SCID.  A study (Stephan et al. 1993) of French children with SCID estimated a minimum incidence of 1/100,000 births.  This estimate is based on the number of French children referred to specialized units over a 5 year time period.
Some US populations, namely the Navajo, have a higher prevalence of SCID because of a founder mutation in the Artemis gene.  The death records (Jones et al. 1991) of all Native American children in Arizona who died between 1969 and 1978 and Navajo children who died between 1969 and 1982 in Arizona and New Mexico were reviewed.  Subsequently the authors reviewed the hospital records of children who died from SCID, had signs of immunodeficiency or failure to thrive at the time of death or had unknown cause of death.  They used this information to determine who may have had SCID.  Based on this chart review the estimated prevalence of SCID is 52/100,000 live Navajo births.

Information from expert interviews
Dr. Rebecca Buckley stated that in one year in North Carolina (where the birth rate is approximately 120,000/annually) there were 3 cases of SCID, for an incidence of 1/40,000.  However, multi-year data confirming this incidence are not available.

Drs. Buckley and Notarangelo provided the distribution of genotypes among the SCID patients for which they have personally cared.  Additionally, Drs Pai, Bonilla, and Notarangelo provided subtype distribution information from both European and United States immunodeficiency collaboratives.  These data corroborated the data from the published literature portion of this evidence review. 

C. 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?

Table 6- Quality Assessment of abstracted literature pertaining to Screening Test Characteristics

            Adapted from Pandor et al. 2004, Pollitt et al. 1997

At least three different methods of screening for SCID have been proposed including 1) lymphocyte counts of whole blood, 2) quantitative polymerase chain reaction (qPCR), and 3) enzyme linked immunosorbent assay (ELISA) of dried blood spots.  This section will review the evidence regarding screening.  None of the proposed screening methods distinguish the various SCID genotypes and phenotypes.

Table 7- Evaluated literature pertaining to SCID screening studies completed (alphabetical by author)

*Calculation stated in article
^Our calculation using data provided in article

Systematic literature review
Lymphocyte studies: A case-control study (Hague et al. 1994) matched children who were both pre- and post-symptomatically diagnosed with SCID to either asymptomatic children (presenting for surgery or bilirubin screening) or children matched by age and presenting symptoms, in order to compare the earliest available lymphocyte counts. Children with SCID had significantly lower levels of lymphocytes.  Also, unlike in the 5 control children with low lymphocyte counts, in SCID children the low lymphocyte count persisted. The authors calculated a false-positive rate of 8%, positive predictive value of 86% and negative predictive value of 100% among symptomatic children, and a positive and negative predictive value of 93% for all children. As part of the evidence review, we used all data contained within this article to calculate the sensitivity, 86.3%, and specificity, 94.4%, of “first lymphocyte count” using a cut-off of 2.8x109/l as indicating SCID. 
A cohort study (Hennewig et al. 2007) that included 36 children (18 with and 18 without SCID) with rotavirus gastroenteritis, also investigated white blood cell count as a screening tool for SCID.  The researchers found that most of the children with SCID were younger than controls when rotavirus was diagnosed.  They also were more likely to have a low white blood cell count (10/18 vs. 0/18), eosinophilia (12/18 vs. 0/18) and relative lymphopenia (17/18 vs. 10/18) and absolute lymphopenia (16/18 vs. 4/18).  From these numbers we calculated sensitivities from 55.6% to 94.4% and specificities from 44.4% to 100%. 

DBS studies: Two studies published in 2005 evaluated screening methods that utilize dried blood spots. The first (McGhee et al. 2005) evaluated a 2-tiered screening approach in which IL-7 is first measured (Table 8A) and only those with elevated IL-7 would have TREC measured (Table 8B). For the study the researchers evaluated each test separately, rather than using a tiered approach. The investigators tested samples from 13 children with SCID (either dried blood spots [3] collected in immunology clinic or stored serum [10]) and 183 anonymized dried blood spots, presumed to be from children without SCID. They evaluated the levels of T-cell receptor excision circles (TREC) in both groups. However, TREC analysis cannot be done on serum, limiting that portion of the analysis to dried blood spot specimens.

Table 8A- Tier 1: Elevated IL-7 from McGhee et al. 2005

Authors calculated a specificity of 96.1% for IL-7 and a sensitivity of 85% (confidence interval, 55-98%).

Table 8B- Tier 2: Detectable TREC from McGhee et al. 2005

Authors calculated a specificity of 92.3% for TREC and a sensitivity that “approaches 100%.”

They evaluated the sensitivity and specificity of the proposed 2-tiered approach calculating a combined specificity of 100% (confidence interval, 97-100%) and combined sensitivity of at least 85%.
Among their sample of SCID patients was one child with Omenn syndrome, which is known to have detectable T-cells, and another patient with T-B- SCID of unknown cause that could theoretically have affected the IL-7 system.  This high proportion of “unusual types” of SCID led the authors to suggest that the actual sensitivity of IL-7 may be higher than shown in this study. 

In the second study (Chan, Puck 2005) investigating screening for SCID using dried blood spots, the sample included 23 children with SCID, 2 children with non-SCID immunodeficiencies, 242 anonymized newborn screening cards.
The researchers used DNA amplification as the screening method in which ß-actin served as a control, indicating that DNA could be amplified from a given specimen, i.e., that the specimen was satisfactory for analysis; and TREC amplification served as the screening test. 
Among the children known to have SCID, none had detectable levels of TREC and all had detectable ß-actin.  The 2 children with non-SCID immunodeficiency had detectable TREC. 
The researchers assumed that the anonymized newborn screening cards came from children without SCID.  In this group there were 7 (2 from routine nursery, 5 from special-care nursery) cards from which TREC could not be detected.  Cards with detectable ß-actin but not TREC were presumed to be false-positive.  They calculated a false-positive rate of 1.5% among children discharged from routine nurseries and 5% among children discharged from special-care nurseries.
We combined the results from this study, except the cards from which ß-actin could not be amplified, and calculated a sensitivity of 84% and specificity of 97.1% for undetectable TREC and sensitivity of 100% and specificity of 97% for TREC <30.

Additional data from expert interviews regarding screening:
Wisconsin implemented universal newborn screening for SCID on January 1, 2008.  Their protocol involves TREC quantification.  For samples with TREC <25/µl they repeat the testing in duplicate, two new punches from the same newborn screening sample collection card, and also assess for ß-actin.  Approximately 1.5% of samples require a second test, and approximately 0.2% requires a second newborn screen or confirmatory testing.  The table below was provided by Dr. Mei Baker as a summary of their screening reports.

Table 9- Summary of screening reports for Wisconsin’s universal newborn screening for SCID 

* The second and third NBS in premature infants is a standard practice in the Wisconsin newborn screening program, and no additional sample is requested for the SCID screening test.

As of August 31, 2008, Wisconsin had screened just over 47,250 babies, of which 76 babies had inconclusive screens and 20 had abnormal screens (Table 10 and Table 11).  To date, they have not identified any children with SCID.

Table 10- SCID Screening Results (Courtesy of Dr. Mei Baker, presented at the Newborn Screening Symposium, November, 2008)

Table 11- SCID Screening Confirmation Results (Courtesy of Dr. Mei Baker, presented at the Newborn Screening Symposium, November, 2008)

Two other investigators have definitive plans for newborn screening trials.  Dr. Anne Comeau and colleagues at the New England Newborn Screening Laboratory will soon begin a trial of universal newborn screening for SCID in Massachusetts, with a small pilot program in Texas and potential extension to other New England states. Similarly, Dr. Jennifer Puck will soon begin a screening trial at 2 hospitals on Navajo reservations in New Mexico and Arizona, a site chosen because of the high frequency of SCID in the Navajo population. 

Additionally, correspondence with topic experts indicated other screening techniques currently under consideration or evaluation. Drs. Ken Pass indicated that work is underway to develop a T-cell immunoassay that could target key T-cell antigens and serve as a quantitative assay. However, this technique is still under development and has not yet, to our knowledge, been validated. Dr. Anne Comeau indicated that her laboratory has developed a multiplex assay that ensures integral quality assurance; TRECs and RNaseP from the same aliquot of blood are measured in the same reaction.  Furthermore, the assay is amenable to measuring other markers such as key T-cell antigens and development of multi-analyte profiles for SCID.  Proof of principle for the multianlayte assay has been demonstrated; specific non-DNA markers are still in development.

Feasibility/acceptability of screening
We found no articles for inclusion in this review that evaluated the feasibility or acceptability of screening for SCID.

Diagnostic Testing
Review of the literature found no evidence that describes any specific diagnostic testing protocol for SCID.  We suspect this reflects the time-frame used in the literature search and that diagnostic testing protocols were established prior to 1988.

Articles that make reference to diagnostic testing and the experts with whom we spoke all utilize flow cytometry, which allows for the differentiation and quantification of the various sub-types of white blood cells.  As mentioned in conversation with Dr. Puck, the presence of maternal T-cells can confound standard flow cytometry results.  However, further testing for T-cell response to mitogens allows for differentiation between maternal, which do not respond to mitogens in vitro, and child cells.

Additionally, several researchers (Vogt, Puck, Buckley, Notarangelo, Pai and Bonilla) commented on gene sequencing.  The current expert opinion seems to be that knowing the specific genotype, with the exception of ADA-deficiency, has little clinical significance or implications for treatment.  However, the possibility exists that better knowledge of how children with different genotypes respond to treatment may help tailor future treatment.

• What benefit does treatment, particularly pre-symptomatic, confer?

Numerous studies document that treatment, mainly bone marrow transplant, substantially improves survival. We describe below the evidence regarding the key controversies surrounding forms of treatment and their relative efficacy. We also provide some focus on the evidence regarding early versus later treatment effects. 

Table 12- Quality Assessment of abstracted literature pertaining to Effectiveness of treatment

Adapted from Pandor et al. 2004, Pollitt et al. 1997

Over the last twenty years, three modes of treatment for SCID have been investigated: allogeneic hematopoietic stem cell transplant (HSCT), the most common subtype being bone marrow transplant (BMT), enzyme replacement therapy (ERT), and gene therapy. While HSCT is the most common treatment for SCID patients, ERT may be used for some patients with ADA-deficient SCID. Lastly, small trials of gene therapy for SCID have been conducted. This section describes the evidence for each method of treatment.

Hematopoietic stem cell transplant-Systematic literature review
HSCT has been utilized as a treatment for SCID since its initial patient application in 1968 (Buckley et al. 1999).  Since then, many researchers have investigated the efficacy, outcomes for different methods, and the long-term outcomes associated with HSCT.  This evidence review focuses on answering the questions pertaining to the benefit of treatment: overall efficacy, efficacy early in life, efficacy for different genotypes and phenotypes of SCID, efficacy based on transplant method, and long-term follow-up including survival and immune reconstitution.

HSCT in the neonatal period and/or infancy

We found 2 studies that specifically addressed HSCT in the neonatal period.  The first was a cohort study (Myers et al. 2002) and the other was a case-series (Kane et al. 2001). In addition, Buckley (Buckley et al. 1999) evaluated a group of patients receiving transplants within the first 3.5 months of life.

Table 13- Abstracted literature pertaining to HSCT in the neonatal period and/or infancy (alphabetical by author)

* Potential patient overlap of Myers et al. 2002, Buckley et al. 1999

Information from expert interviews
Dr. Buckley shared SCID treatment data with our group. They have transplanted 161 SCID infants over the past 26 years, of which 16 had an HLA-identical (genotypically HLA identical) donor. The remaining 145 patients received half-matched (HLA haplo-identical) transplants from their parents. She has documented an overall 26year survival rate of 125/161 (78%). However, her data shows there is a survival difference when the population is divided by age at transplantation. The survival rate in those transplanted before 3.5 months of age is 96%, whereas the survival rate for those transplanted after later is only 71%. All transplants performed and included in this data were done without pre-transplant chemotherapeutic conditioning or post-transplantation GVHD prophylactic immunosuppressive drugs. The Kaplan-Meier graphs from Dr. Buckley (with permission) for these data are below (Graphs 1A and 1B).

Graph 1A- Kaplan-Meier Plot of 48 Children with SCID Transplanted at Duke University Medical Center in the First 3.5 Months of Life

Graph 1B- Kaplan-Meier Plot of 113 Children with SCID Transplanted at Duke University Medical Center after the First 3.5 Months of Life

Overview of efficacy—large case-series of HSCT
We found 3 case series studies that specifically addressed the efficacy of HSCT over time.  In one series, 31 patients undergoing BMT for SCID were evaluated between 1968 and 1992 (van Leeuwen et al. 1994). In a similar large case-series (Stephan et al. 1993) 117 patients were followed from 1970 to 1992.  A single-center study (Buckley et al. 1999) followed 89 children between 1982 and 1998.

Table 14- Abstracted literature pertaining to efficacy in large case-series studies of HSCT (alphabetical by author)

* Potential patient overlap with Stephan et al. 1993 and van Leeuwen et al. 1994

HSCT efficacy in different genotypes and phenotypes of SCID
Several studies examined HSCT for patients with specific pheno- or genotypes, including: B+ SCID vs. B- SCID, SCIDA, reticular dysgenesis, ADA-deficiency, specific Jak3 mutations, and Omenn syndrome. Table 15 summarizes the results of these studies. 

Table 15-Abstracted literature pertaining to HSCT efficacy in different SCID subgroups (alphabetical by author)

HSCT variation in transplant methods

Multiple studies compare various transplant methods and their outcomes.  The main points of discussion surround the degree of matching between the donor and recipient, the extent of myeloablation prior to transplant and the method for T-cell depletion of the donor stem cells.  In addition, investigators have considered the source of stem cells and the use of “booster transplants”.

The extent of matching between the donor and recipient is only partially under the control of physicians, as many patients lack an available matched related donor. This results in recipients requiring either a haplo-identical or mismatched transplant.  Several studies have looked at the various types of transplants and their efficacy.

Table 16- Abstracted literature pertaining to HLA matching and efficacy of HSCT (alphabetical by author)

Table 17- Abstracted literature pertaining to the role of myeloablation prior to transplant (alphabetical by author)

      Other variation in treatment methods

Three studies specifically investigated stem cell sources other than bone marrow.  A small study (Knutsen, Wall 2000) which included only 8 children with SCID evaluated transplants using umbilical cord blood derived stem cells and found neutrophil recovery time was the same as that reported in BMT, while platelet recovery was delayed compared to BMT.  A study from Turkey (Arpaci et al. 2008) used peripheral stem cells mobilized by treating donors with G-CSF.  21 patients, of whom 16 had SCID, received a total of 28 haploidentical HSCT.  Median age at transplant was 12 months.  At last follow-up 8/21 children were alive with the authors believing that delay in transplantation accounted for the poor outcomes compared to other studies.  Finally, stem cells from fetal liver (Touraine et al. 2007) were used for transplants in 17 infants; in the 3 patients for whom information was available, they found normal antibody responses several years after transplant.
One study (Dror et al. 1993) reported on 24 patients who underwent a total of 36  using lectin-treated t-cell depleted haplocompatible BMT.  Of these 24 children durable T-cell engraftment was achieved in 19, although 6/19 required more than one transplant to achieve engraftment.  Pre-transplant conditioning positively affected engraftment, while cell dose, patient’s age, and donor and patient sex had no observable effect on engraftment rates

      For patients that achieve engraftment but not adequate immune function, bone marrow boosts (Kline, Stiehm & Cowan 1996), in which additional stem cells from the same donor were given without pre-treatment, led to increased absolute lymphocyte counts in 5/9, increased mean CD3, CD4 and CD8 counts and improved mean T-cell function. Mentioned prior, the long-term follow up case-series (Buckley et al. 1999) also included a total of 20/89 receiving “booster” transplants to overcome poor T/B cell function or poor engraftment. Of those who received a booster transplant, immune function improved in all but 3. 

HSCT long-term follow up, survival and immune reconstitution

Table 18- Abstracted literature pertaining to long-term follow-up and survival after HSCT (alphabetical by author)

*A subset of patients in Fischer et al. 1990 are also included in Antoine et al. 2003

Table 19- Abstracted literature pertaining to long-term immune reconstitution after HSCT (alphabetical by author)

Information from expert interviews
Consultation with experts pertaining to treatment of SCID corroborated the data from the published literature portion of this evidence review. Experts concurred that major challenges to treating SCID are due to complications prior to diagnosis and treatment (such as infections), and a lack of a uniform approach for treatment. Drs. Buckley and Notarangelo provided information on development of two SCID consortiums: United States Immunodeficiency Network (USIDNET) Registry sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and Center for International Blood and Marrow Transplant Research (CIBMTR). While USIDNET is focused on the registry of primary immune deficiencies, reporting of all BMT procedures to the CIBMTR registry has been mandatory since December. Data from these consortiums may, in the future, provide more data on treatment outcomes for patients with SCID.

At this time, Dr. Buckley reports there are fifteen major and 34 minor centers in the U.S. and Canada currently performing stem cell transplantation for SCID. Dr. Notarangelo, Bonilla and Pai stated that an informal survey performed under the auspices of the NIAID/Rare Diseases workshop identified 34 centers in the United States and Canada that currently perform HCT for SCID (unpublished data, NIAID May 12-13, 2008 HCT for Primary Immune Deficiency Diseases workshop).

Enzyme replacement therapy-Evidence Review
Enzyme replacement therapy has been a therapeutic option for patients with ADA-deficiency, a specific type of SCID.  Although multiple case studies examining the use of polyethylene glycol- adenosine deaminase (PEG-ADA) have been published, our examination of the literature found only one study meeting criteria for inclusion in this evidence review.
A long-term follow up study by Chan et al (Chan et al. 2005), evaluated outcomes in 9 children treated with PEG-ADA.  These children were diagnosed with ADA-deficiency at ages ranging from birth to 6.5 years and were followed on intramuscular PEG-ADA for 5-12 years.  Some patients also received other treatments. One child died after 9 yrs of PEG-ADA treatment and a failed bone marrow transplant.  The remaining 8 children attended school without protective precautions although 2 children have disabilities thought to be related to early, severe infections.  Lymphocyte counts (T, B and NK) and function increased significantly following initiation of PEG-ADA and peaked at 1-3 years after treatment initiation. Over time lymphocyte counts and T-cell function, as measured by PHA mitogen stimulation have diminished.

Gene therapy-Evidence Review
Gene therapy using viral vectors has been tried for the treatment of X-linked SCID and ADA-deficiency SCID. Two case-series of patients treated with gene therapy were included in this evidence review. 
In 2002, Hacein-Bey-Abina et al (Hacein-Bey-Abina et al. 2002) published a report of 5 boys with X-linked SCID due to a mutation in the common c chain gene who were treated by infusing them with their own bone marrow which had previously been extracted and transduced with a vector containing c chain derived from a defective Moloney murine leukemia virus.  4/5 had clinical improvement including resolution of infections, diarrhea and skin lesions.  At follow-up 0.7-2.5 years later those 4 were well with normal growth.  The fifth patient never had reconstitution of T-cells following gene therapy and underwent a bone marrow transplantation 8 months later.  With regards to immunologic function, 3/5 patients had normal T-cell values 3 to 4 months after gene therapy.  At last follow up, T-cells from 4/5 patients exhibited normal proliferative responses to in vitro stimulation with phytohemagglutinin and anti-CD3 antibody.   
Schmidt et al (Schmidt et al. 2005) reported on a series of 10 patients (5 of whom were included in the Hacein-Bey-Abina paper) with a focus on longer-term follow-up after gene therapy.  They found polyclonal T-cell repertoires, in the 9/10 patients who developed normal T-cell counts after treatment, indistinguishable from those of age-matched controls. In long-term follow up, 2/9 developed monoclonal lymphoproliferation 2.5 years post transplant.   Additionally, the number of circulating naïve T-cells was similar to that for age-matched controls.

• Benefits of treatment in screen positive children

We found no evidence related to the benefits of treatment in children who screen positive for SCID.  The relative outcomes for early treatment versus late treatment of children with SCID provide some evidence of improved outcomes with earlier treatment.

• Harms of SCID screening

We found no evidence related to harms associated with screening for SCID.

• Harms of SCID diagnosis

We found no evidence related to harms associated with diagnosing SCID.

• Harms of SCID treatment

We found two papers specifically focused on a harm associated with treatment of SCID. The first (Horn et al. 1999) analyzed the rates of auto-immune hemolytic anemia in children undergoing HSCT for SCID. 8/41 children developed auto-immune hemolytic anemia, 3 died from its complications. This was a higher rate of auto-immune hemolytic anemia than previously reported and higher than the rate, in the same institution, among patients undergoing HSCT for non-SCID diseases. Among several potential predictors for the development of auto-immune hemolytic anemia that were analyzed, only peripheral blood as source of stem cells was found to be related to increased risk of developing auto-immune hemolytic anemia. 
Work by Hacein-Bey-Abina et al (Hacein-Bey-Abina et al. 2008) documented a total of 4 children (of the 9/10 who had successful treatment with gene therapy) who developed leukemia between 30 and 68 months after gene therapy.  All cases were associated with vector insertion near genes associated with cancer development.  3/4 kids were successfully treated with chemotherapy and regained poly-clonal T-cell populations; the 4th child underwent 2 BMTs and ultimately died 60 months after gene therapy and 26 months after leukemia diagnosis.

• Cost-Effectiveness

Table 20- Quality Assessment of abstracted literature pertaining to Economic evidence

Adapted from NHS Centre for Reviews and Dissemination Report 4, March 2001

We found one study (McGhee, Stiehm & McCabe 2005) that addressed the cost-effectiveness of SCID screening, as it would apply to the United States population.  Using a deterministic decision-tree model, comparing universal and targeted screening approaches, the authors assessed the thresholds at which screening would be cost-effective from a health care system perspective.  They noted a significant amount of uncertainty in their model parameters due, in part, to the lack of SCID screening studies.  Additionally, utility estimates were based on information from patients receiving HSCT for oncologic processes.  The authors found that, at a threshold of $100,000 per quality adjusted life year, there is 86% likelihood of screening being cost-effective, but details of the Monte Carlo simulation used to arrive at this estimate were not provided in the paper. 

Data from experts regarding cost-effectiveness
None of the experts with whom we had contact provided any specific cost-effectiveness information.  However, several had collected some hospital cost or charge data for patients undergoing HSCT for SCID.   These costs were generally at least two to three times higher than those used by McGhee et al in their base-case analysis, suggesting that the costs used in the paper may not reflect current treatment practice.  However, the base-case analysis costs of testing are consistent with the current testing costs in the screening trials.

VIII.  SUMMARY

Key findings:

Severe Combined Immunodeficiency (SCID) affects at least 1/100,000 newborns within the United States.  However, experts believe that with systematic case-finding the prevalence may be higher (perhaps as high as 1/40,000) due to earlier diagnosis of infants who would otherwise die prior to confirming a diagnosis of SCID.  Although several population-based screening trials are underway (Wisconsin) or planned (Massachusetts, Navajo Reservation in Arizona and New Mexico), to date no population-based screening trial has been completed.

Without curative treatment, newborns with SCID develop severe, often opportunistic, infections which lead to early death.  Studies indicate that treatment, most commonly with hematopoietic stem cell transplant, is effective in decreasing both the morbidity and mortality associated with SCID.  Additionally, despite the lack of population-based screening, there is some evidence that earlier treatment may lead to better outcomes.

Regarding the key questions:

• Do current screening tests effectively and efficiently identify cases of SCID?

Various screening methods ranging from targeted use of lymphocyte counts in hospitalized children to population based newborn screening using IL-7, TREC or a combination have been studied.  Both IL-7 and TREC have been investigated using anonymized dried-blood spots.  These studies allow for estimations of sensitivity and specificity, but due to the anonymous nature there is no way to prove which test results are true.

The state of Wisconsin began a trial of population-based screening for SCID, using low TREC as the marker of SCID, in January 2008.  As of August 31 they had screened 47,250 newborns of which 76 (0.161%) had initially inconclusive results requiring a second newborn screening sample and 20 (0.042%) had abnormal results requiring either a second newborn screening sample or diagnostic testing.  The rates for both inconclusive and abnormal results are higher in premature than in full-term infants.  As of August 31, the investigators have not detected any cases of SCID.

• Does pre-symptomatic or early symptomatic intervention in newborns or infants with SCID improve health outcomes?

The most common, and well-studied, treatment modality for SCID is hematopoietic stem cell transplant which appears to be effective in significantly decreasing the morbidity and mortality associated with SCID.  Within HSCT there are numerous variables which may contribute to the effectiveness.  The most studied of these are the degree of haplotype matching between donor and recipient and the type of pre-conditioning the recipient receives.  There is no clear evidence as to the best method for HSCT.  However, despite the lack of randomized controlled trials of SCID treatment, the evidence from large case-series indicates that HSCT is effective in treating SCID. 
Furthermore, there is limited evidence, primarily from the early detection of siblings of known SCID cases, that earlier treatment may be more effective. Specifically, the existing evidence indicates that undergoing HSCT prior to the onset of lung infection is more likely to be successful.

In addition to HSCT, there is limited evidence that for children with ADA-deficiency SCID enzyme replacement may be effective in reconstituting their immune function.

• What is the cost-effectiveness of newborn screening for SCID?

The cost-effectiveness data reviewed was very limited and may not reflect current costs of treatment.

• What critical evidence appears lacking that may inform screening recommendations for SCID?

We identified several areas with deficient data:

• Prevalence of SCID

There is limited evidence regarding the true prevalence of SCID.  A systematic method of case finding is needed in order to accurately determine the prevalence.  Of note, the new consortium of treatment centers (USIDNET) that has recently been established may serve as a method of more systematic case-finding.

• Accuracy of Screening

Initial pilot screening data from Wisconsin suggests that the false-positive rate will be relatively low.  However, these data are limited at this time.  Data regarding the accuracy of other screening methods, when applied in population-based protocols, are not available.

• Feasibility of Screening

Wisconsin has been able to implement universal newborn screening for SCID, at least on a pilot basis.  Data are needed regarding the ability of other newborn screening laboratories to offer SCID screening

• Acceptability of Screening

There are no data available regarding consumer or physician acceptance of newborn screening for SCID.

• Cost-effectiveness

Cost-effectiveness analyses utilizing measured costs and utilities, as well as applicable sensitivity analyses, are needed.

• Adequacy of available treatment centers

There is no data addressing variation in treatment success between centers or the number of centers in the United States and their capacity to provide treatment for SCID.  Data from USIDNET and CIBMTR may, in the future, provide evidence on this topic.

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_________________________________________________________________________

Version:  11/12/08
Authors:
Ellen Lipstein, Alixandra Knapp, James 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).