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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From Duke University Medical Center, Durham, NC, and
the National Human Genome Research Institute, National Institutes of
Health, Bethesda, MD.
All genetic types of severe combined immunodeficiency
(SCID) can be cured by stem cell transplantation from related donors. The survival rate approaches 80%, and most deaths result from opportunistic infections acquired before transplantation. It was hypothesized that the survival rate and kinetics of immune
reconstitution would be improved for infants receiving
transplants in the neonatal period (first 28 days of life),
prior to the development of infections. A 19.2-year
retrospective/prospective analysis compared immune function in 21 SCID
infants receiving transplants in the neonatal period with that in 70 SCID infants receiving transplants later. Lymphocyte phenotypes,
proliferative responses to mitogens, immunoglobulin levels, and
T-cell antigen receptor excision circles (TRECs) were measured before
transplantation and sequentially after transplantation. Of 21 SCID
infants with transplantations in the neonatal period, 20 (95%)
survive. Neonates were lymphopenic at birth (1118 ± 128 lymphocytes
per cubic millimeter). Infants receiving transplants early developed
higher lymphocyte responses to phytohemagglutinin and higher numbers of
CD3+ and CD45RA+ T cells in the first 3 years of life than those receiving transplants late
(P < .05). TRECs peaked earlier and with higher values
(P < .01) in the neonatal transplantations (181 days to
1 year) than in the late transplantations (1 to 3 years). SCID
recipients of allogeneic, related hematopoietic stem cells in the
neonatal period had higher levels of T-cell reconstitution and thymic
output and a higher survival rate than those receiving transplants
after 28 days of life. An improved outcome for this otherwise fatal syndrome could be achieved with newborn screening for lymphopenia so
that transplantation could be performed under favorable thymopoietic conditions.
(Blood. 2002;99:872-878) Severe combined immunodeficiency (SCID) is a
rare congenital syndrome characterized by profound deficiencies of
cellular and humoral immunity.1 Recently, several
molecular defects responsible for SCID have been identified. X-linked
SCID accounts for 46% of all cases and is caused by defects in
the chain ( The mean age of diagnosis for SCID is 6.6 months, but most patients
experience recurrent infection prior to this as their transplacentally
acquired maternal antibody levels decline.1 Initial
infections may be those frequently encountered in infancy, such as oral
candidiasis, otitis media, or bronchiolitis. However, infants with SCID
have illnesses unresponsive to conventional therapies, and most
eventually develop chronic diarrhea, failure to thrive, or an
opportunistic infection that leads to their diagnosis or
demise.12 Without recognition and treatment, this syndrome is uniformly fatal, usually in the first year of life.
Bone marrow transplantation, either with HLA-identical marrow or
T-cell-depleted haploidentical parental marrow, is the standard of
care for SCID. Currently, 78% of all SCID patients and 77% of those
receiving haploidentical, T-cell-depleted bone marrow at Duke
University Medical Center (Durham, NC) survive at varying times
up to more than 19 years after transplantation.4 However, opportunistic infections and malnutrition remain major contributors to
the morbidity and mortality of these infants as well as to the health
care costs associated with thir care. It is our hypothesis that earlier
diagnosis and transplantation, before the onset of recurrent infection
and failure to thrive, could further increase survival rates and
decrease morbidity. To address this hypothesis, we performed a
retrospective/prospective study of the development of immune function
in 21 infants who were given bone marrow transplants in the first 28 days of life and compared the findings with those of 70 infants
successfully receiving transplants after that time.
Patient characteristics
None of the neonates received either pretransplantation
chemotherapeutic conditioning or posttransplantation graft-versus-host disease (GVHD) prophylaxis. The median age at transplantation was 10 days (range, 7-24 days). Two male neonates with Of the remaining 96 patients who received allogeneic bone marrow cells
after the first 28 days of life, 71 (74%) survive and are included in
this analysis. Of these, 55 were male, 16 were female, 58 were white, 7 were Hispanic, 5 were black, and 1 was Native American. The molecular
basis of SCID was Laboratory studies
Statistics The kinetics of immune reconstitution for those patients receiving transplants in the neonatal period (early) were compared with those receiving transplants after the first 28 days of life (late).4 Lymphocyte phenotype and proliferation were analyzed at the following intervals: before transplantation, 1 through 30 days, 31 through 60 days, 61 through 90 days, 91 through 120 days, 121 through 180 days, 181 through 270 days, 271 through 365 days, 1 to 2 years, 2 to 3 years, 3 to 4 years, 4 to 5 years, 5 to 6 years, 6 to 9 years, and more than 9 years after transplantation. TRECs were analyzed before transplantation, 0 through 90 days, 91 through 181 days, 181 days through 1 year, 1 to 3 years, and 3 to 7 years after transplantation. Only one measurement for each test was analyzed for an individual patient in any given interval. If more than one measurement for an individual patient was available in the same interval, then the mean of the measurements was analyzed. The Wilcoxon rank-sum test was used to compare differences in immunologic parameters between the early and late transplantations. Statistical analyses were also performed with Statistica software (StatSoft, Tulsa, OK). All ± values are reported as SEM.
Survival Of 21 patients receiving transplants in the first 28 days of life, 20 (95%) are alive (Figure 1). They range from 8 months to 19 years in age. Of the survivors, 3 are less than 1 year after transplantation; 8 are 1 to 5 years; 4 are 5 to 10 years; and 5 are 10 to 19 years. One ADA-deficient SCID patient died of CMV encephalitis at 4 months after transplantation despite successful engraftment. No other patients developed an opportunistic infection. Most have had normal growth and development and have had few, if any, restrictions placed on their activities.
Lymphocyte phenotypes at birth SCID neonates were lymphopenic at birth. The mean absolute lymphocyte count (ALC) of all neonates was 1118 ± 128/mm3, with the normal range at birth being 2000 to 11 000/mm3.15 The ADA-deficient neonates had the most profound lymphopenia, with a mean ALC of 368/mm3. One neonate with c deficiency and
one with Jak3 deficiency had ALCs that fell within the normal range,
and the cells were predominantly B lymphocytes. Neonatal lymphocyte
phenotypes varied according to genotype, as previously reported (Figure
2A).1,4 Regardless of the
genotype, all neonates had few T cells. The mean number of B cells was
normal in patients with c and Jak3 deficiency but below
normal in those with ADA deficiency and autosomal recessive SCID of
unknown molecular cause. The mean number of natural killer (NK) cells
was normal in those with autosomal recessive SCID and low in
the remaining genotypes.
Posttransplantation lymphocyte phenotypes At the most recent posttransplantation evaluation, the mean numbers of T, B, and NK cells for all neonates were within normal ranges (Figure 2B). Variations were observed according to genotype. Mean numbers of T cells were within the normal range for all genotypes. The mean number of B cells was increased in the Jak3-deficient patient and decreased in the surviving ADA-deficient patient. The mean number of NK cells was decreased in the Jak3-deficient patient.T-cell function Figure 2C shows in vitro PBMC proliferation to PHA, concanavalin A, and pokeweed mitogen before and at the latest posttransplantation evaluation as compared with healthy adults. Responses to mitogens were absent in all SCID neonates at birth. The mean counts per minute of 3Hthymidine incorporation was normal to each mitogen at the patient's most recent evaluation. Significant and normal T-cell functions were defined as in vitro stimulation indices of at least 10 and 100, respectively, to 1 or more mitogens. Mean time to significant T-cell function in all neonates was 33 ± 4 days and to normal T-cell function was 103 ± 15 days. Once normal T-cell function was achieved, no patients receiving transplants in the neonatal period developed impaired in vitro responses. Onec-deficient SCID who had GVHD required booster
peripheral blood and unfractionated bone marrow transplants from his
successfully engrafted identical twin.
Effects of age at transplantation on lymphocyte subsets and proliferation Results of studies in SCID infants receiving transplants in the first 28 days of life (early) were compared with those in patients receiving transplants after the neonatal period (late). Figure 3 shows the kinetics of proliferation to the T-cell mitogen PHA. Before transplantation, cells from neither group proliferated to PHA. Incorporation of 3Hthymidine increased in both groups at all time intervals after tranplantation. However, the mean count per minute was higher in the early group at times occurring between 91 and 270 days after transplantation (P < .05). T-cell proliferation to PHA remained stable in both groups at all time intervals greater than 1 year after transplantation. Before transplantation, the late group had a higher mean number of CD3+ cells (P < .05) (Figure 4). However, infants receiving transplants early developed higher circulating numbers of CD3+ and CD45RA+ (naive) T cells for the first 3 years after transplantation (P < .05). There were similar trends for both CD4+ and CD8+ T-cell subsets (data not shown). The numbers of CD3+ and CD45RA+ T cells gradually declined in patients given the transplants early so that they became similar to those of the late recipients by 6 years after transplantation. There were no differences in mean numbers of CD45RO+ T cells at any time interval after transplantation.
Effects of age at transplantation on thymus function TRECs are currently one of the best available measures of thymic function. They have been used to determine the kinetics of immune reconstitution and thymic output in SCID.14 In this study, TRECs were undetectable before transplantation and gradually increased by 91 through 180 days after transplantation in both groups (Figure 5). The patients receiving transplants early had higher mean TREC values at time intervals 91 through 180 days and 181 days to 1 year after transplantation (P < .01). The mean TREC value peaked earlier in those receiving transplants in the first 28 days of life than in those receiving transplants later (181 days to 1 year versus 1 to 3 years). Mean TREC values reached a plateau at 2 years after transplantation in the patients who received transplants late and gradually decreased in the patients who received transplants early so that the groups were indistinguishable by 5 years after transplantation.
While TRECs are an excellent surrogate marker for thymic function,
little direct data exist that show thymopoiesis. This is in part due to
the inappropriateness of performing a thymic biopsy in children who
have developed normal function. Since the pretransplantation SCID
thymus is vestigial, weighing less than a gram, it is difficult to find
by radiography.1,14 A computed tomography scan of the
anterior mediastinum of the Jak3-deficient SCID patient at 4 years
after transplantation shown in Figure 6
demonstrates a thymus with a transverse dimension of 3.8 cm, which is
normal for age.16 The thymus expansion seen here provides
further evidence for thymopoiesis after hematopoietic stem cell
transplantation in SCID.
B-cell function Table 1 shows the current extent of B-cell engraftment and function. Of the 20 surviving neonates, 9 have donor B-cell engraftment, defined as 5% to 100% of peripheral B cells determined to be of donor origin by karyotype analysis or restriction fragment length polymorphism. Of these 9 neonates, 7 arec-deficient; 1 is ADA-deficient; and 1 is autosomal
recessive. Forty-five percent have normal IgA concentrations for age,
and 70% have normal IgM. This is comparable to our previous report of
B-cell function in 89 SCID patients after stem cell transplantation,
where 50% and 80% had normal IgA and IgM concentrations,
respectively.4 Thirteen of the 20 (65%) surviving
neonates are receiving intravenous immunoglobulin (IVIG). The 7 remaining neonates have normal antibody-forming capacity to diphtheria
and tetanus toxoids or to bacteriophage  X-174. Donor B-cell
engraftment did not seem to correlate with B-cell function. For
instance, 2 autosomal recessive SCID neonates have only host B cells
but have normal immunoglobulin concentrations and antibody synthesis
and do not require IVIG. On the other hand, 7 of 15 c-deficient SCID patients have donor B cells, but 11 of
15 are receiving IVIG.
Graft-versus-host disease For 13 of 21 neonates, the posttransplantation period was uneventful and free of GVHD even though only 2 patients had HLA-identical donors (Table 2). The pretransplantation mixed lymphocyte reaction between donor's and recipient's mononuclear cells was positive in all of the mismatched transplants, but only 8 of 21 (38%) neonates developed GVHD and 5 of the 8 had grade 1 GVHD. Nine patients received a 2-antigen-mismatched transplant and 3, all withc deficiency, developed grade
1 GVHD. One of these patients had benign pneumatosis intestinalis,
which resolved with supportive therapy. The other 2 patients had
peripheral blood eosinophilia, which responded to corticosteroids. Nine
neonates received a 3-antigen-mismatched transplant and 5 developed
GVHD. Two of these 5 patients did not require treatment for transient
grade 1 GVHD. The identical twin c-deficient neonates
developed grade 3 GVHD, manifested by fever, rash, and severe diarrhea.
Both recovered after treatment with cyclosporine and corticosteroids.
One neonate with autosomal recessive SCID who received a
3-antigen-mismatched transplant developed grade 4 GVHD with autoimmune
hemolytic anemia, bone marrow suppression, diarrhea, and cholestatic
liver disease. He subsequently received a liver transplant from a
related living donor and remains on a low dose of tacrolimus 1.5 years
later. His mother was the donor for both the bone marrow and the liver
segment. He is a complete hematopoietic chimera and now has normal
liver function.
The studies presented here support our hypothesis that infants whose SCID is diagnosed at an early age and who receive transplants of normal related bone marrow stem cells before acquiring opportunistic infections will have a higher survival rate and lower morbidity than those whose SCID is diagnosed later when untreatable infections have developed. All but one (95%) of these SCID infants who received T-cell-depleted identical or haploidentical stem cell transplants in the first 28 days of life currently survive, with the period of survival ranging from 8 months to more than 19.2 years after transplantation. This compares favorably with a 74% survival rate of 96 infants receiving transplants after the neonatal period. In addition to having a higher survival rate, SCID patients receiving transplants in the neonatal period demonstrated increased lymphocyte proliferation to PHA and higher numbers of CD3+ and CD45RA+ T cells when compared with those receiving transplants after the first 28 days of life. Superior T-cell reconstitution was most evident from 3 months to 3 years after transplantation. This is a critical period for the development and maturation of host defenses in response to new pathogens that are frequently encountered at a young age. The observed differences in T-cell function can be attributed to higher thymic output after transplantation in the SCID neonates than in the older SCID infants. This conclusion is supported by the finding of higher TREC levels, higher numbers of circulating CD3+ T cells, higher numbers of CD45RA+(naive) T cells, and more vigorous early T-cell proliferation to mitogens in the neonates than in the older group. This supposition is also confirmed by the finding of a normal-sized thymus at 4 years after transplantation in one patient in whom computerized tomography of the thymus was obtained. In aggregate, these findings confirm our previous conclusion that the vestigial SCID thymus is able to support T-cell development from donor stem cells.14 One explanation for a favorable effect of early stem cell transplantation for SCID may be that those SCID infants receiving transplants after the neonatal period may have already suffered from recurrent or opportunistic infections, malnutrition, and failure to thrive. Stress from these comorbid factors could have had a deleterious effect on thymic function. Early transplantation does not appear to improve B-cell function. The
majority (65%) of our SCID patients receiving transplants in the
neonatal period receive monthly IVIG infusions. This percentage is
comparable to our previous report of 89 SCID patients, 63% of whom
were receiving IVIG. The high percentage of Prenatal diagnosis can identify affected fetuses in the first trimester of pregnancy if there is a family history of SCID from a known molecular defect. Prenatal diagnosis is recommended for families who are considering terminating an affected pregnancy, to alleviate anxiety, or to allow families time to plan for postnatal treatment of affected infants.17 Alternatively, all infants could be screened for SCID at birth even when there is no family history; this could be done by routine performance of a white blood cell count and a manual differential count and then flow cytometry if lymphopenia is present.1,4 Each patient in this analysis was initially evaluated for SCID because one or more family members was affected by the disease. For 9 of 21 patients, SCID was diagnosed prenatally. However, the majority of patients were identified at birth from a white blood cell count and a manual differential count that demonstrated lymphopenia. Two of our neonates had ALCs just over 2000/mm3, and the cells were predominantly B cells. Therefore, for those with a family history of SCID, lymphocyte phenotyping and T-cell functional studies should also be performed. Regardless of the genotype, nearly all SCID neonates were lymphopenic, and the lymphocyte phenotypes at birth were typical for the particular molecular defect. The ability to diagnose SCID in the first trimester of pregnancy led to attempts to treat this syndrome in utero with the hope that the infant would then be born with intact immunity. There are 4 literature reports of successful in utero bone marrow transplantation for SCID.18-24 These reports suggest that, although lymphoid reconstitution of SCID can be achieved with prenatal stem cell transplantation, T-cell development was not complete at birth. Thus, the infant may still be at risk for opportunistic infections. Our results of stem cell transplantation for SCID in the neonatal period show enhanced, stable T-cell reconstitution and 95% survival over a period of 19 years. It is difficult to justify in utero stem cell transplantation when such excellent results can be achieved by stem cell transplantation in the neonatal period. The kinetics of T-cell reconstitution with in utero transplantation demonstrate no benefit over postnatal transplantation. In addition, previous reports of prenatal stem cell transplantation for a variety of inherited diseases reveal an 18% rate of fetal demise.20 The majority of neonates in this study did not require prolonged hospitalizations. Most were admitted to the hospital for a 23-hour period of observation for the transplant procedure, discharged to local apartments, and evaluated frequently in an outpatient clinic. This method of protective isolation is preferable to reverse isolation in a hospital where nosocomial infections present great risks to the immunocompromised patient. Furthermore, outpatient care decreases the expense of caring for infants with SCID. Few neonates developed GVHD, and in most cases it was mild. Only one neonate developed an opportunistic infection. The mean time to significant T-cell function in all neonates was 33 ± 4 days and to normal T-cell function was 103 ± 15 days. Once T-cell engraftment and normal function were achieved, they were sustained. Of the 20 surviving patients, none have developed an opportunistic infection, a malignancy, or loss of T-cell immunity. The recent report of successful gene therapy for
The findings reported here suggest that the outcomes of postnatal stem cell transplantation for SCID could be further improved if routine testing for this syndrome were included in newborn screening. A cord-blood white blood cell count and a manual differential count demonstrating lymphopenia could detect nearly all infants born with SCID. This test, while relatively expensive compared with the cost of current perinatal testing for genetic defects, poses no risks to the mother or fetus. Until newborn screening becomes an accepted practice, close attention should be paid to the ALC in all infants presenting with fever, chronic diarrhea, or failure to thrive. Physicians caring for infants also need to be reminded that the lower limit of a normal ALC in the first few months of life is higher (2000 to 4500/mm3) than in older children and adults. Furthermore, an infant with a normal ALC but clinical manifestations suggestive of SCID should undergo lymphocyte phenotyping and studies of T-cell function, because transplacental transfer of maternal T cells in utero could obscure lymphopenia. In these rare cases, the T-cell number is low but not absent, and lymphocyte proliferation is profoundly depressed. Early diagnosis of SCID would allow for transplantation to be performed not only before a potentially fatal opportunistic infection develops but under conditions ideal for thymopoiesis.
The authors gratefully acknowledge the contributions of the many referring physicians, postdoctoral fellows, nurses, and other personnel who participated in the care of these infants. We thank Drs Joanne Kurtzberg, Paul Szabolcs, Paul Martin, Richard Howrey, and Timothy Driscoll and Mr Gilbert Ciocci for harvesting the marrow. We are grateful to Mrs Roberta Parrott, Mrs Carol Koch, Mrs Ruby Johnson, Ms Kim Curtis, Mrs Sherrie Schiff, and Mrs Katherine Coyne for their assistance with the T-cell depletions of donor marrow and for their expert technical assistance. We thank Ms Maria Gooding and Dr Greg Sempowski for their expert technical assistance in the TREC analyses. We thank Dr Michael Hershfield for performing adenosine deaminase and deoxyadenine nucleotide studies. We are also grateful to Genetic Counselor Joie Davis for her advice to the families of these patients.
Submitted August 2, 2001; accepted October 3, 2001.
Supported by National Institutes of Health grants AI42951, AI47604, and AI47605 and by grant MO1-RR-30 from the National Center for Research Resources, General Clinical Research Centers Program, National Institutes of Health.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Laurie A. Myers, Box 3559, Duke University Medical Center, Durham, NC 27710; e-mail: myers019{at}mc.duke.edu.
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© 2002 by The American Society of Hematology.
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  J. Chinen, J. Davis, S. S. De Ravin, B. N. Hay, A. P. Hsu, G. F. Linton, N. Naumann, E. Y. H. Nomicos, C. Silvin, J. Ulrick, et al. Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency Blood, July 1, 2007; 110(1): 67 - 73. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, CD3+ T cells; 
, CD20+ B cells;
, CD16+ NK cells. Normal range represents the 95% confidence
interval for healthy infants at birth (A) or for healthy children at 6 years of age (B). (C) The mean (± SEM) counts per minute of
3Hthymidine incorporation by proliferating PBMCs stimulated
with PHA (
)B(+)NK(+) severe combined immunodeficiency.
Nat Genet.
1998;20:394-397