Page 827 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 51 Congenital Disorders of Lymphocyte Function 713

Ultimately, infants with SCID should be evaluated for specific
Diagnostic Approach to Severe Combined Immune Deficiency
gene defects. However, definitive treatment of SCID (typically by
• SCID presents early in life with severe infections of bacterial, viral, hematopoietic cell transplantation; HCT) should not await demon-
or fungal origin. stration of a specific gene defect, as this may take some time. An
• Opportunistic infections are common in infants with SCID. exception to this general principle is ADA deficiency that can be
• Respiratory infections, protracted diarrhea, and failure to thrive easily diagnosed by measuring enzyme activity in red blood cells,
are typical signs at presentation. allowing prompt initiation of enzyme-replacement therapy (ERT),
• Lymphopenia is present in 50% to 70% of infants with SCID. which improves lymphocyte counts. Weekly intramuscular injection
Age-specific norms must be used in evaluating the ALC as infants of pegylated bovine ADA acts extracellularly to transform adenosine
and children have much higher ALCs than adults (3500–13,000 and deoxyadenosine into inosine and deoxyinosine, respectively, thus
in very young infants versus 1000–2800 in adults). preventing accumulation of toxic phosphorylated derivatives. Disad-
• T-cell lymphopenia is the hallmark of the disease; abnormalities
of the absolute count of B and NK lymphocytes are observed vantages of ERT include expense, as it must be continued indefinitely,
in some forms of SCID. However, T lymphocytes may be waning of therapeutic effect over time, and the development in some
present in SCID infants with maternal T-cell engraftment or with patients of neutralizing antibodies to PEG-ADA.
hypomorphic mutations in SCID-associated genes that allow
residual T-cell development. Thus, a normal ALC does not rule
out SCID. General Principles of Hematopoietic Cell
• Maternally engrafted T cells proliferate in the infant with Transplantation for SCID
SCID in vivo, but the vast majority do not proliferate in vitro
when stimulated with traditionally used mitogens such as HCT is the standard treatment that promotes long-term immune
concanavalin A and phytohemagglutinin, as measured by
thymidine incorporation. Thus, if SCID is suspected, but T cells reconstitution in infants with SCID. HCT for other conditions is
are detectable, maternal engraftment studies and proliferation to generally performed with chemotherapy or radiation conditioning,
mitogens must be sent. to prevent graft rejection and eliminate or reduce host hematopoietic
• Universal newborn screening has now been implemented in the stem cells (HSCs), favoring donor hematopoiesis. Because of the lack
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majority of states in the United States. The analyte is detection of of T lymphocytes, infants with SCID (especially the NK forms) are
TRECs by quantitative PCR. TRECs are high in newly generated generally considered to have an inherent inability to reject the graft,
T cells and low when T cells are absent or when maternally and may therefore receive HCT from an HLA-identical related donor
engrafted T cells are present. (sibling) without conditioning. T-cell reconstitution in this case is
• SCID is genetically heterogeneous. The most common form in generally prompt, with initial reconstitution in the first 1–3 months
+
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Western countries is inherited as an X-linked trait and is T B NK . –
• The lack of all lymphocytes (T B NK SCID) is highly suspicious mediated by expansion of mature T cells present in the donor bone
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–
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for the ADA form of SCID, in which toxic metabolites result in marrow, and later reconstitution derived from newly generated T cells
death of all lymphocytes. Testing for ADA enzyme level is critical, that mature in the thymus from donor HSC and progenitors. GVHD
because if confirmed to be absent, treatment with PEG-ADA prophylaxis is not needed. Unconditioned HCT may also be per-
can often result in sufficient reconstitution of T-cell immunity to formed from mismatched related donors (parent), with T-cell deple-
protect the baby from infection. tion of the graft to avoid fatal GVHD. Here the reconstitution is
slower, since the generation of T cells is entirely dependent on thymic
ontogeny and can take 4–6 months. Engraftment of T cells may not
always occur in this setting and up to 25% of patients may require
naive T lymphocytes that express the αβ form of the TCR. Levels of repeat transplantation. GVHD prophylaxis is not needed if the T-cell
TRECs in circulating lymphocytes are particularly high in newborns depletion is sufficiently rigorous. These approaches to HCT without
and infants, and can be detected by PCR amplification of DNA conditioning can lead to sustained T-cell immune reconstitution
extracted from the Guthrie card. Newborn screening was recom- because of the selective advantage for donor cells differentiating into
mended for addition to the standard panel in the United States in the T lineage. However, this approach rarely results in significant
2010, and in 2015 >70% of births were screened for SCID. Based donor HSC engraftment, which is generally <1%, and thus may fail
on screening of ~3,000,000 infants in the United States, the incidence to correct impairment of humoral immunity.
of SCID is now estimated to be 1 in 58,000 births, higher than with HCT from matched unrelated adult or cord blood donors has
clinical screening alone. been generally performed with myeloablative conditioning, similar to
that used for other nonmalignant disorders. As in the case of sibling
Prognosis, Therapy and Future Directions donor HCT, memory T cells present in the graft after unrelated adult
donor HCT may provide some initial protection against infection
(according to their antigen specificity). In contrast, the naive T
Supportive Management lymphocytes contained within cord blood provide little antigen-
specific immunity early after HCT. Conditioning prior to unrelated
Management of SCID includes observance of strict hygiene measures, donor HCT, or prior to mismatched related HCT, improves the rate
prevention of P. jiroveci pneumonia with TMP-SMZ, prompt inves- of HSC engraftment, but results in short-term and long-term toxicity
tigation and aggressive treatment of infections, immunoglobulin and increased risk of GVHD. Reduced-intensity conditioning regi-
replacement, and adequate support with enteral or parenteral nutri- mens have been proposed with the aim to facilitate stem cell engraft-
tion. Infections caused by cytomegalovirus (CMV; causing interstitial ment while reducing the risk of treatment-related toxicity; however,
pneumonia, hepatitis and/or gastroenteritis) and Epstein-Barr virus there is no clear evidence that such regimens are associated with better
(EBV; causing lymphoproliferative disease) require active surveillance outcome in patients with SCID treated by HCT.
and preemptive therapy. To prevent transmission of viral infection,
blood products from CMV-seronegative donors or leukofiltered
products should be used, and must be irradiated to prevent Survival and Long-Term Outcomes After
transfusion-associated GVHD. Immunosuppression with steroids HCT for SCID
and cyclosporine A may be needed to treat GVHD-like manifesta-
tions associated with Omenn syndrome or maternal T-cell engraft- While survival after HCT for SCID has improved with time due to
ment. Administration of live vaccines must be avoided in infants with advances in early diagnosis and supportive care for infants with
SCID. In spite of these measures, SCID is inevitably fatal within the SCID, donor type, the presence of infection, and subtype of SCID
first few years of life, unless immune reconstitution is achieved with remain important determinants of outcome. Studies of 10-year sur-
treatment. vival in 699 infants with SCID in Europe and 5-year survival in 240