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:
- Without treatment SCID leads to death
in early childhood.
- Earlier treatment, particularly before
the onset of lung infection, decreases
the mortality and morbidity associated
with SCID and with HSCT for SCID.
- 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.
- What is the natural history of SCID
and are there clinically important phenotypic
or genotypic variations?
- What is the prevalence of SCID and
its variations?
- 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?
- What benefit does treatment, particularly
pre-symptomatic, confer?
- What are the potential harms or risks
associated with screening, diagnosis
or treatment?
- 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:
- Do current screening tests effectively
and efficiently identify cases of SCID?
- 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?
- What is the cost-effectiveness of
newborn screening for SCID?
- 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
Name |
Title
|
Completed
Written Survey |
Telephone
Interview |
Mei Baker |
Assistant Professor,
Department of Pediatrics, School
of Medicine and Public Health, Science
Advisor, Newborn Screening Program,
Wisconsin State Laboratory of Hygiene
University of Wisconsin-Madison
|
|
|
Tony (Francisco)
Bonilla |
Program Director,
Clinical Immunology Assistant in
Medicine, Assistant Professor, Harvard
Medical School and Children’s Hospital,
Boston, Mass |
*
|
|
Rebecca
Buckley |
Professor of Pediatrics,
Professor of Immunology,
Duke University Medical Center,
Durham, North Carolina |
|
|
Anne Comeau |
Deputy Director New
England Newborn Screening Program
University of Massachusetts Medical
School |
|
|
Lisa Filipovich |
Medical Director,
Hematology/Oncology Diagnostic Laboratory,
Division of Hematology/ Oncology,
Cincinnati Children's Hospital Medical
Center |
|
|
Alain Fischer |
Professor of Pediatric
Immunology and Head of the Pediatric
Immunology Department and the INSERM
Research Unit |
|
|
Alan P.
Knutsen |
Professor of Pediatrics,
Allergy and Immunology, Director
of Pediatric Clinical Immunology
Laboratory, Department of Pathology,
St Louis University Health Sciences
Center |
|
|
Ronald
Laessig |
Professor of Population
Health Sciences and Pathology at
University of Wisconsin |
|
|
Edward
McCabe |
Clinical Biochemical
Genetics, Clinical Genetics, Professor
and Executive Chair of the UCLA
Department of Pediatrics, and Physician-in-Chief
of the Mattel Children’s Hospital
at UCLA |
**
|
|
Sean McGhee |
Assistant Clinical
Professor of Pediatrics. Division
of Pediatric Immunology, Department
of Pediatrics,
David Geffen School of Medicine
at UCLA, Los Angeles, California |
|
|
Luigi Notarangelo |
Director, Research
and Molecular Diagnosis Program
on Primary Immunodeficiencies, Division
of Immunology, Children's Hospital
Boston, Mass
Professor of Pediatrics and Pathology,
Harvard Medical School |
*
|
|
Hans Ochs |
Professor of Pediatrics
and Immunology at the University
of Washington |
|
|
Sung-Yun
Pai |
Assistant Professor
in Pediatrics, Pediatric Hematology/Oncology,
Harvard Medical School and Children’s
Hospital, Boston, Mass |
*
|
|
Ken Pass
|
Senior Research Scientist,
Molecular Medicine, Wadsworth Center,
New York State Department of Health,
Albany, New York |
|
|
Jennifer
Puck |
Professor, Department
of Pediatrics and Institute for
Human Genetics University of California,
San Francisco |
|
|
Robert
Vogt |
Centers for Disease
Control and Prevention, Newborn
Screening Quality Assurance Program,
Atlanta, Georgia |
|
|
*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
Study Design |
Number
of papers |
Experimental intervention |
0 |
Cohort study |
11 |
Case-control study |
8 |
Case series total |
38 |
blank |
Sample size = 10 |
11 |
blank |
Sample size 11
to 50 |
18 |
blank |
Sample size = 51 |
9 |
Economic Evaluation |
1 |
Other design |
2* |
Total |
|
60 |
*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.
- 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
Genotype/Phenotype
Correlation |
12 |
Data from retrospective screening
studies in U.S. or similar population. |
0 |
Data from systematic studies
other than whole population screening. |
5 |
Estimated from the known clinical
features of the condition as described
for individual cases or short series. |
7 |
|
|
Incidence (cases
per 100,000), average within the
U.S. |
4 |
Data obtained from whole-population
screening or comprehensive national
surveys of clinically detected cases. |
1 |
Ia. As in I but more limited
in geographical coverage or methodology.
|
2 |
Extrapolated from class I data
for non-U.S. populations. |
0 |
Estimated from number of cases
clinically diagnosed in U.S. |
1 |
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)
Study (Author,
date) |
Population:
Size and age by subgroups
|
Study
type |
Key
findings |
Bertrand et al.
1999 |
178 children:
B+ group: 122, mean age at BMT
7 months
B- group: 56, mean age at BMT 6.5
months |
Cohort study |
- Deaths due primarily to infection.
- B- SCID had higher rates of
both early and late death
|
Bertrand et al.
2002 |
10 children: BMT
at age 0.5 to 10 months |
Case series |
- Children with reticular dysgenesis.
- Presented with infection in
first days of life.
|
Buckley et al.
1997 |
108 children: Diagnosis
at Age birth -21 months |
Case series |
- 67 (76%) of the 88 families
were white, 14 (16%) were black,
and 7 (8%) Hispanic.
- 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.
|
Buckley et al.
1999 |
89 children:
22 were <3.5 months at transplant
67 were greater than or equal to
3.5 months (0-21 months at time
of diagnosis) at transplant |
Case series |
- Mean number of T/B/NK cells
varies by genotype; all genotypes
had normal average in vitro mitogen
response after transplant.
- Poor B cell function with 45
kids requiring IVIG.
- NK activity low in c-chain
and JAK3 deficiency, otherwise
normal.
|
Cavazzana-Calvo
et al. 2007 |
31 children:
aged 1-42 months at HSCT, now 10-27
years later
|
Case series |
- 26/31 had T-cell count in normal
range for age.
- 30 had normal mitogen induced
T-cell proliferation.
- 18/31 had normal TREC counts.
- Presence of NK cells not correlated
with TREC.
- c
deficiency may be associated with
TREC detection.
- Presence of TREC/naïve T-cells
associated with significantly
higher t-cell counts and better
t-cell mitogen proliferation.
|
Gomez et al. 1995
|
9 children: Aged
0.5-5 months (mean 2.8) and had
BMT for Omenn Syndrome between 1981
and 1989 |
Case series |
- Engraftment occurred in 4/5
HLA identical transplants and
3/4 non-identical.
- Full chimerism occurred in all
but one patient of those that
engrafted.
- One patient died of CMV 50 days
post-transplant, 3 developed interstitial
pneumonia.
- Clinical manifestations of Omenn
syndrome disappeared within days
of BMT (likely due to pre-treatment
with chemo.)
- All survivors except one (who
has chronic GVHD) have normal
growth rates.
|
Laffort et al.
2004 |
41 patients, at least
10 years after HSCT for SCID
|
Case-control study |
- 9/41 developed “extensive chronic”
human papilloma virus.
- 4 had lesions typical of a rare
genodermatosis.
- All with human papilloma virus
had c/Adenylate
kinase- 3 (AK-3) deficiency, though
only 9/18 with c/JAK3
developed human papilloma virus.
- c
/AK-3 with or without human papilloma
virus showed lower NK counts than
patients with other SCID subtypes.
|
Monafo et al. 1992
|
4 children (2 sets
of siblings) aged: 20 months, 4
months, 11 months, 24 months at
the time of BMT |
Case series |
- One child did not present until
1 year of age, with a previously
undescribed phenotype.
- Presenting clinical signs of
SCID including diarrhea, poor
weight gain, oral ulcers, and
PJP pneumonia but normal lymphocyte
counts.
- CD8 cells were virtually absent
and mononuclear cells did not
proliferate normally in vitro.
|
O'Marcaigh et al.
2001 |
18 children:
Birth to 3 months at diagnosis;
mean of 17.5 months at first transplant |
Case series |
- Oral/genital ulcers associated
with SCIDA.
- SCIDA occurs with relatively
high incidence among Athabaskan-speaking
Native Americans.
|
Roberts et al.
2004 |
170 total patients:
10 with JAK3 deficiency and 160
with other types of SCID |
Case series |
- All patients had abnormal B
cell JAK3 dependent interleukin
2 induced signal transducer and
activator of transcription 5.phosphorylation.
- 9/10 patients are alive and
well 4 to 18 years after stem
cell transplant.
|
Rogers et al. 2001
|
22 children: aged
1-51 months at transplant; 0.9-18
years at follow-up;
11 ADA-deficient, 11 other SCID
types
|
Cohort study |
- No significant difference in
full scale IQ between groups (both
were below-average), ADA-deficient
2 standard deviations below zero.
- Significant behavioral differences
in ADA-deficient SCID children:
more hyperactivity, higher scores
for dysfunction in social, emotional
and behavioral domains.
- Abnormal behavior more evident
in older children.
- Gross neurologic evaluation
of motor function showed no abnormalities
in ADA-deficient group.
|
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
Overall sensitivity
and specificity of screening &
false-positive rate
|
3 |
Data obtained
from screening programs in U.S.
population or similar. |
0 |
Data from systematic
studies other than from whole population
screening. |
3 |
Estimated from
the known biochemistry of the condition.
|
0 |
|
|
Repeat
specimen rate
|
0 |
Data obtained
from screening programs in U.S.
population or similar. |
0 |
Data from systematic
studies other than whole population
screening. |
0 |
Estimated from
the known biochemistry of the condition.
|
0 |
|
|
Second-tier
testing |
1 |
Data obtained
from screening programs in US
population or similar. |
0 |
Data from systematic
studies other than whole population
screening. |
1 |
Estimated from
the known biochemistry of the condition.
|
0 |
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)
Study
(Author, Date) |
Population |
Screening
method |
Sens,
spec, PPV, NPV |
Quality
of Evidence |
Chan, Puck 2005
|
23 children
with SCID
2 children with non-SCID immunodeficiencies
242 anonymized newborn screening
cards |
DNA
amplification of TREC from dried
blood spot
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. |
*False positive
rate: 1.5% from routine nurseries;
5% from special-care nurseries.
^Sensitivity: 84%-100%
^Specificity: 97-97.1% |
Overall sensitivity
and specificity of screening &
false-positive rate
|
Hague et al. 1994
|
135
total children
45 children with SCID
90 children without SCID
matched by age and presenting symptoms
with SCID to either asymptomatic
or age and presenting symptoms |
First
available lymphocyte count with
cut-off of 2.8x109/l as indicating
SCID
Children with SCID had significantly
lower levels of lymphocytes. Unlike
the 5 control children with low
lymphocyte count, low lymphocyte
count persisted in children with
SCID |
*False-positive
rate: 8%
^Sensitivity: 86.3%, and ^Specificity:
94.4% |
Overall sensitivity
and specificity of screening &
false-positive rate |
Hennewig et al.
2007 |
36 children
with rotavirus gastroenteritis;
18 with SCID
18 without SCID |
Lymphocyte
study
SCID children were more likely
to have:
low white blood cell count:10/18
vs. 0/18,
eosinophilia: 12/18 vs. 0/18 relative
lymphopenia: 17/18 vs. 10/18
absolute lymphopenia:16/18 vs. 4/18 |
^Sensitivity: 55.6%
to 94.4% ^Specificity: 44.4% to
100%. |
Second-tier testing |
McGhee et al. 2005
|
13 children
with SCID
183 anonymized dried blood spots,
presumed to be from children without
SCID |
dried
blood spot study
Evaluated a 2-tiered screening
approach in which IL-7 is first
measured and only those with elevated
IL-7 would have TREC measured, although
for this study researchers evaluated
each test separately. |
*Combined specificity
of 100% (confidence interval, 97-100%)
*Combined sensitivity of at least
85% |
Overall sensitivity
and specificity of screening &
false-positive rate |
*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
|
Yes |
No |
Total |
SCID |
11 |
2 |
13 |
Control |
4 |
110 |
114 |
Total |
15 |
112 |
127 |
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
|
Yes |
No |
Total |
SCID |
0 |
3 |
3 |
Control |
169 |
14 |
183 |
Total |
169 |
17 |
186 |
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
Reporting Type |
Situation |
Action
Plan |
Normal |
1. TRECs
= 25 / ul in the first tier test |
None |
blank |
2.
TRECs = 25 / ul in one or both duplicates
of the second tier test |
None |
Abnormal |
TRECs
< 25 / ul and ACTB > 10,000
/ ul in full term babies |
1.Phone Primary
Care Provider and clinical consultant
2. Recommend confirmatory testing |
blank |
TRECs
< 25 / ul and ACTB > 10,000
/ ul in premature infants |
1. Phone Primary
Care Provider
2. Tracking second NBS* |
Inconclusive |
TRECs
< 25 / ul and ACTB < 10,000
/ ul in full term babies |
Recommend repeating
NBS |
blank |
TRECs
< 25 / ul and ACTB < 10,000
/ ul in premature infants |
Tracking second
NBS* |
* 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)
|
47,250
(01/01/2008-08/31/2008) |
|
20 |
|
11 (0.023%) |
|
9 (0.019%) |
|
76 |
|
57 (0.121%) |
|
19 (0.040%) |
Table 11- SCID Screening
Confirmation Results (Courtesy of Dr.
Mei Baker, presented at the Newborn Screening
Symposium, November, 2008)
Abnormal Results:
|
Inconclusive
Results: |
1 DiGeorge
Syndrome
1 Downs Syndrome with sepsis at
birth
1 Idiopathic T-cell lymphopenia
1 Leukocyte migration defect
4 normal Flow Cytometry results
9 normal results on repeated newborn
screening
2 pending cases
1 expired case |
1 DiGeorge
Syndrome
59 normal results on repeated newborn
screening
2 pending cases
14 expired cases |
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
Effectiveness
of treatment
|
47 |
I. Well-designed
RCTs. |
0 |
II-1. Well-designed
controlled trials with pseudorandomization
or no randomization. |
0 |
II-2. Well-designed
cohort studies: |
8 |
A. prospective
with concurrent controls |
0 |
B. prospective
with historical control |
1 |
C. retrospective
with concurrent controls. |
7 |
II-3. Well-designed
case-control (retrospective) studies.
|
0 |
III. Large differences
from comparisons between times and/or
places with and without intervention
|
4 |
IV. Opinions of
respected authorities based on clinical
experience, descriptive studies
and reports of expert committees.
|
35 |
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)
Study
(Author, Date) |
Population |
Key
Findings |
Quality
of Evidence |
Buckley et al.
1999*
Case series |
22 infants
transplanted prior to 3.5 months
of life
67 infants transplanted later than
3.5 months of life |
- 21/22 (95%) infants alive at
follow-up 51/67 (76%) who received
transplants at 3.5 months or older
survived to follow-up.
- Median follow-up time was 5.6
years (range 3 months -16.5 years).
|
IV |
Kane et al. 2001
case-series |
13 children
transplanted between 7 and 68 days-old |
- All patients alive and well
0.5-11.5 years post-transplant
(median 3 years).
- Concluded neonatal transplant
has better outcomes than in-utero
transplant, but provided no specific
data regarding in-utero transplant.
- 2 children with chronic GvHD
chronic.
- 3 children required more than
one transplant.
- All children achieved: neutrophil
engraftment and normal levels
of IgA.
- 7 have normal IgG.
- 12 have normal IgM.
- 10/12 maintained normal development,
of the other two: 1/12 has developmental
problems and 1/12 has motor delay.
|
IV |
Myers et al. 2002*
Cohort study |
21 children
transplanted prior to 28 days of
life (early treatment)
96 children transplanted at a median
age of 190 days (range 45-516) (late
treatment) |
- 20/21 (95%) early treatment
children survived.
- One ADA-deficient patient died
of CMV despite successful engraftment.
- 71/96 (74%) late treatment children
survived.
- Mean time to significant T-cell
function in all early treatment
was 33 days and to normal T-cell
function was 103 days.
- Mean TREC value peaked earlier
post-transplant for early treatment
recipients but the 2 groups were
indistinguishable by 5 years.
- Early transplantation did not
have an affect on B-cell function.
- 2 early treatment children had
HLA-identical donors.
|
II-2
C |
* 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)
Study
(Author, Date) |
Population |
Key
findings |
Quality
of Evidence |
Buckley et al.
1999
Case series |
89 children
treated with HSCT for SCID between
1982 and 1998 |
- 72 (81%) survived to follow-up
(median follow-up time was of
5.6 years).
- HLA-identical transplant from
a related donor: 12/12 (100%)
survived.
- T-cell depleted haplo-identical:
60/77 (78%) survived.
- Survival not statistically related
to genotype.
- Survival varied by race (white
more likely to survive) and gender
(all girls survived).
- 36 children developed GVHD.
- Most cases of GVHD required
no treatment.
|
IV |
Stephan et al.
1993*
Case series |
117
patients treated for SCID between
1970 and 1992; 85 of these children
were treated with bone marrow transplant |
- HLA-identical transplant from
a related donor 21/25 (84% survived).
- Pheno-identical transplant (HLA
genotypically haplo-identical)
from related donor 2/5 (40% survived).
- HLA haplo-identical transplant
without T-cell depletion 0/5 (0%
survived).
- T-cell depleted haplo-identical
transplant 28/50 (56% survived).
- 22 children did not receive
any type of transplant and died.
- 10 received fetal liver transplant,
9 died post transplant.
|
IV |
van Leeuwen et
al. 1994 *
Case series |
31 patients
between the ages of 1-94 months
undergoing BMT for the treatment
of SCID |
- HLA-identical related: 6/10
(60% survived).
- HLA haplo-identical related:
9/19 (47% survived).
- HLA-matched unrelated: 0/2 (0%
survived).
|
IV |
* 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)
Study
(Author, Date) |
Population
|
Key
findings |
Quality
of evidence |
1) Albuquerque
& Gaspar, 2004
Cohort study
2)
Honig et al. 2007
Case series
3)
Rogers et al. 2001
Cohort study |
ADA
deficiency
|
1)
- Compared 12 children with ADA-deficiency
to 16 children with other immunodeficiencies,
all treated with HSCT.
- 7/12 ADA-deficient children
had bilateral deafness, compared
to 1/16 in the control group.
2)
- 15 children specifically examined
for neurologic outcomes after
BMT.
- 12/15 survived.
- 6/12 have significant neurocognitive
deficits (learning disabilities,
gait problems, hearing deficit,
and/or hyperactivity).
3)
- Compared 11 children treated
with HSCT for ADA-deficiency to
matched controls treated with
HSCT for other forms of SCID.
- Significant behavioral differences
between the 2 groups with ADA-deficient
children having more hyperactivity
and higher scores for dysfunction
in social, emotional and behavioral
domains, particularly for older
children.
- ADA-deficient children had a
higher rate of deafness.
|
1)
II-B
2)
IV
3)
II-2 C |
Bertrand et al.
1999
Cohort study |
B+ SCID
vs. B- SCID |
- Disease-free survival was better
for B+ SCID (60% vs. 35% at mean
follow up of 57 and 52 months,
respectively).
- Reduced survival among children
with B- SCID was associated with
higher incidences of death from
infection and chronic GVHD, as
well as lower rates of marrow
engraftment.
- Among B- SCID cases, the method
of T-cell depletion significantly
impacted the cure rate.
- When analyzed as pre- vs. post-1991,
both groups had better survival
post-1991, but B+ SCID still did
better.
|
II-2
C |
Bertrand et al.
2002
Case series |
Reticular
Dysgenesis
|
- 3/10 patients with reticular
dysgenesis treated with HLA-non-identical
HSCT survived.
- Most deaths related to failure
of engraftment.
- Rates of engraftment appeared
to be better among children who
received conditioning chemotherapy
prior to transplant.
|
IV |
Gomez et al. 1995
Case series |
Omenn
syndrome |
- 9 children with Omenn syndrome
receiving BMT after nutritional
supplementation and immunosuppression.
- Engraftment occurred in 4/5
HLA-identical transplants and
3/4 non-identical.
- 3 children developed GVHD and
one died of CMV 50 days post-transplant.
- Clinical manifestations of Omenn
syndrome disappeared within days
after BMT.
- At follow-up, all survivors
except one with chronic GVHD have
normal growth rates.
|
IV |
O'Marcaigh et al.
2001
Case series |
SCIDA
|
- No deaths in first 100 days
after transplant for 16 SCIDA
patients.
- 15/16 achieved engraftment.
- 11/16 developed normal T cell
function.
|
IV |
Roberts et al.
2004
Case series |
Jak3
mutations |
- 9 different Jak3 mutations in
10 different SCID patients.
- 9/10 were alive and without
recurrent infections 4-18 years
after transplant.
|
IV |
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)
Study
(Author, Date) |
Population |
Key
findings |
Quality
of evidence |
Dalal et al. 2000
Case series |
16 children, 9 with
SCID, who lacked histocompatible
siblings or closely matched related
donors between 1989 and1997
|
- 12 patients survived.
- Neutrophil engraftment was achieved
in all patients at a mean of 15.4
days.
- Serum IgM and IgA normalized
in all patients within a mean
of 3.5 and 6 months.
- 2/9 (22%) SCID patients developed
GVHD and died.
|
IV |
Dal-Cortivo et
al. 2004
Case series |
25 children in which
there was no potential to exert
NK-cell
alloreactivity compared to 13
in which there was such potential
(defined by donor expression of
inhibitory killer immunoglobulin-like
receptor (KIR)), all receiving haploidentical
transplants |
- No difference in the rates of
engraftment (64% vs. 61.5%).
- Trend towards lower incidence
of grade II-IV acute GVHD in the
patients with potential NK-cell
alloreactivity (37.5% vs. 50%,
p=0.68).
- One year survival was not significantly
different between the two groups
(52% vs. 61.5%).
|
IV |
Giri et al. 1994
Case series |
11 children receiving
HLA-non-identical BMT between 1985
and 1992 |
- 9 patients engrafted.
- 5 (46%) patients survived 6-78
months post-BMT.
- 4/9 developed GVHD.
|
IV |
Grunebaum et al.
2006
Cohort study |
Compared recipient
outcomes between:
- related HLA-identical donors (RID,
n=13),
- HLA-matched unrelated donors (MUD,
n= 41)
- HLA-mismatched related donors
(MMRD, n=40). |
- Median time to transplant was
1 month for RID, 2 months for
MMRD and 4 months for MUD.
- Highest survival was RID (92.3%),
followed by MUD (80.5%) and MMRD
(52.5%).
- 0% of RID, 7.3% of MUD and 30%
of MMRD had graft failure.
- No statistical difference between
MUD and MMRD lymphocyte subsets
and lymphocyte function.
- Patient sex and presence of
B cells has no impact on survival.
- Respiratory complications occurred
in 7.3% of MUD and 35% of MMRD;
no respiratory complications in
RID children.
- GVHD most common following MUD
BMT (73.1%) or MMRD BMT (45%).
|
II-2
C |
Smogorzewska et
al. 2000
Cohort study |
11 children treated
with histocompatible transplants
from a sibling and
37 children treated with T-cell
depleted haploidentical parental
bone marrow between 1984 and 1997 |
- 100% survival in histocompatible
group.
- 46% survival in haploidentical
group.
- Mean age at transplant of children
who survived: 7.5 months.
- Mean age at transplant of children
who died: 11.4 months.
- All surviving children recovered
T-cell function.
- Recovery slower for children
receiving haploidentical transplants.
|
II-2
C |
Wijnaendts et al.
1989
Case series |
33 children who
received transplants between 1972
and 1987 and survived a minimum
of 6 months:18 HLA-identical and
15 HLA-non-identical |
- Development of immune function
occurred faster in patients with
HLA-identical transplants.
- Development of T- and B-cell
function occurred faster when
chemotherapy preceded BMT.
- Poor B-cell function was observed
more frequently when chemotherapy
was not used.
|
IV |
Table 17- Abstracted literature
pertaining to the role of myeloablation
prior to transplant (alphabetical by author)
Study
(Author, Date) |
Population |
Key
findings |
Quality
of evidence |
Amrolia et al.
2000
Case series |
Children
ineligible for conventional myeloablation
due to comorbidities; 8 patients,
including 5 with SCID |
- All treated with non-myeloablative
chemotherapy prior to transplant.
- 7/8 children survived.
- At median follow-up of 12 months:
all 7 survivors have good recovery
of T-cell numbers, 4 patients
have normal IgM levels, and 2
patients have normal IgA levels.
|
IV |
Rao et al. 2005
Cohort study |
Compared
33 children receiving reduced intensity
pre-transplant chemotherapy and
19 receiving myeloablation. |
- All children in both groups
had primary engraftment.
- Reduced intensity group: 32/33
were alive at one month and 31/33
alive at one year
- Myeloablative group: 14/19 were
alive at one month and 11/19 alive
at one year.
- At one year: all in the myeloablative
group had normal B-cell function,
5 of reduced intensity group still
required IVIG.
- GVHD incidence not different
between groups but limited chronic
was more common in myeloablative
group.
- Quality of life, as measured
by Lansky score, was similar between
the groups (97 vs. 94).
|
III |
Veys, Rao &
Amrolia 2005
Case series |
81 children
with congenital immunodeficiencies,
20 with SCID |
- All subjects underwent HSCT
with reduced-intensity conditioning.
- Survival rate of 84% (68/81).
- Authors concluded that HSCT
with reduced intensity conditioning
was well tolerated.
|
IV |
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)
Study
(Author, Date) |
Population |
Key
findings |
Quality
of evidence |
Antoine et al.
2003 *
Cohort study |
475
patients (total of 566 transplants)
from 37 European centers between
1968 and 1999 |
- Three-year survival with sustained
engraftment was 77% for HLA-identical
and 54% for HLA-non-identical
transplants.
- Survival has improved over time
for both HLA-identical and HLA-non-identical
transplant recipients.
- B- SCID (36% 3-yr survival;
CI 26-45%) had a poorer prognosis
than B+ SCID (64% 3-yr survival;
CI 57-72%).
- Myeloablation prior to HLA-nonidentical
transplant trended towards improving
survival among B- children but
not B+.
- ADA-deficiency (n=51) 3-yr-survival
was 81% for matched and 29% for
unmatched transplants.
- Reticular dysgenesis survival
(n=12) was 75% for matched and
29% for unmatched.
|
II-2
C |
Cavazzana-Calvo
et al. 2007
Case series |
31 children
10-27 years post-transplant: focus
on factors associated with long-term
T-cell reconstitution. |
- Myeloablation patients more
likely to have evidence of donor-derived
granulocytes and persistent naïve
T-cells, as measured by TREC.
- Average follow-up time in the
TREC+ group was 13 years and in
the TREC- was 16 years.
- At follow-up, 60% of TREC+ and
45% of TREC- had no clinical manifestations.
|
IV |
Fischer et al.
1990 *
Case series |
475
patients (total of 566 transplants)
gathered between 1968 and 1999 from
37 European centers
|
- Survival significantly better
for HLA-identical (76% survival)
than HLA-non-identical transplants
(56% survival).
- SCID phenotype was not associated
with difference in survival.
- Lung infection before HSCT and
absence of a protective environment
significantly affected outcome
(multivariate analysis).
- A total of 27% had acute GVHD
of grade II or higher and 25%
developed chronic GVHD.
|
IV |
Friedrich, Honig
& Muller 2007
Cohort study |
7 children
with SCID receiving HLA-identical
transplant, 25 with HLA-haploidentical
transplant, all at least 10 years
out from transplant |
- Most patients had normal and
stable T-cell numbers and functions.
- 3 patients’ T-cell numbers were
decreased.
- 4 patients’ PHA responses were
decreased (all in HLA-haploidentical
group and no chemotherapy).
- HLA-haploidentical with no conditioning
had lower levels of naïve CD4+
cells and impaired B cell functioning.
|
IV |
Gennery et al.
2001
Case series |
19 children
treated from 1987-1998 using CAMPATH-1MT
depleted BMT for SCID |
- 19/30 children survived longer
than 1 year post-BMT
- Most deaths attributed to pre-existing
infection.
- 17 had normal immune function
following transplantation.
|
IV |
Haddad et al. 1998
Case series |
193
patients from18 European centers
between 1982 and 1993: focus on
immune reconstitution |
- 116 alive with evidence of engraftment
5 months after BMT. 24 later died
(20%).
- T-cell function improved during
the 2 years after BMT and continued
to be better than B-cell function.
- Poor outcomes associated with:
absence of T-cell reconstitution,
presence chronic GVHD 6 months
after transplant, B- SCID (multivariate
analysis).
- At last follow up (median, 6
years after transplant), 93% had
normal T-cell function and 68%
had normal B-cell function.
|
IV |
Slatter et al.
2008
Cohort study |
36 children
treated with BMT with depletion
of T-cells from a non-identical
donor |
- No significant survival difference
between children receiving transplants
depleted using anti-CD52 or anti-CD34
antibodies.
- 5 patients in the anti-CD52
group and 2 in anti-CD34 group
had GvHD.
|
II-2
C |
*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)
Study
(Author, Date) |
Population |
Key
findings |
Quality
of evidence |
Borghans et al.
2006
Case control study |
19 people
treated with BMT for SCID (5-32
years earlier) compared to 173 healthy
controls. |
- Median number of T-cells was
lower in healthy matched controls:
11 SCID patients had normal T-cell
counts.
- 8 SCID patients who had low
t-cell counts at last follow-up
also had low counts early (1-4
years after BMT).
- Predictors of low T-cell count
included NK+ SCID, B- SCID, earlier
transplant.
- No significant difference in
late clinical outcomes found between
patients with and without “good”
immune reconstitution.
|
III |
Brugnoni et al.
1998
Case series |
8 childrens’
immune reconstitution and response
to PHA after BMT from unrelated
donors |
- Number of activated T-cells
decreased in the months after
BMT.
- Proliferative response to PHA
initially decreased and then increased
to normal by 8 months post-transplant.
|
IV |
Mazzolari et al.
2007
Case series |
58 children
treated with HSCT (in-utero to 34
months at time of transplant) |
- 42/58 (72.4%) survived at least
5 years (median follow-up of 132
months).
- 85% appropriately produced antibodies
to vaccines (tetanus toxoid and
hepatitis B).
- 26/28 immunized with Measles,
Mumps and Rubella vaccine had
evidence of anti-measles antibodies.
- Most children had height (77.5%)
and weight (82.5%) in the normal
range.
- At last follow-up, 24/40 required
no treatment, 6 required IVIG
and/or antibiotics, 5 are on thyroid
replacement, 3 receive anti-epileptics
and 1 is treated for portal hypertension.
|
IV |
Patel et al. 2000
Case series |
173
total patients: 83 SCID and 90 normal
Mean age of transplant was 0.5 ±0.4
years; controls ranged from <1
to 79 years |
- Non-thymus-dependent cells predominated
in the first 100 days after transplant.
- At 140-180 days after transplant
thymus-dependent cells predominated.
- After transplant thymus-dependent
cells peaked at approximately
one year but then diminished over
the next 14.
- Normal controls showed a decline
in thymus-dependent cells from
birth to age 79 years.
|
IV |
Vossen et al. 1993
Case series |
14 children
evaluated 1-23 years after BMT
|
- All children who survived greater
than 1 year had some donor T-cell
engraftment.
- Cellular immunity was quantitatively
low but mostly functionally normal.
|
IV |
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.
We found no evidence related to harms
associated with screening for SCID.
We found no evidence related to harms
associated with diagnosing SCID.
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.
Table 20- Quality Assessment
of abstracted literature pertaining to
Economic evidence
Economic
evidence |
1 |
I.
Evaluation of important alternative
interventions comparing all clinically
relevant outcomes against appropriate
cost measurement and including a
clinically sensible sensitivity
analysis. |
0 |
II.
Evaluation of important alternative
interventions comparing a limited
number of outcomes against appropriate
cost measurement, but including
a clinically sensible sensitivity
analysis. |
0 |
III.
Evaluation of important alternative
interventions comparing all clinically
relevant outcomes against inappropriate
cost measurement, but including
a clinically sensible sensitivity
analysis. |
1 |
IV.
Evaluation without a clinically
sensible sensitivity analysis |
0 |
V.
Expert opinion with no explicit
critical appraisal, based on economic
theory |
0 |
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:
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.
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.
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 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:
Marsha Browning, MD, MPH, MMSc. (Massachusetts
General Hospital)
Jennifer DeZarn, BA
(MGH Center for Child and Adolescent
Health Policy)
Nancy Green, MD
(Columbia University)
Alex R. Kemper, MD, MPH, MS
(Duke University)
Alixandra Knapp, MS
(MGH Center for Child and Adolescent
Health Policy)
Ellen Lipstein, MD
(MGH Center for Child and Adolescent
Health Policy)
Lisa Prosser, PhD
(University of Michigan)
Denise Queally, JD
(Consumer Representative)
Sienna Vorono, BA
(MGH Center for Child and Adolescent
Health Policy; Brown Medical School)
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).
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