Page 1244 - Williams Hematology ( PDFDrive )

1218 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1219

P. jirovecii pneumonia. CMV should be treated with ganciclovir and OTHER COMBINED
adenoviral infections should be treated with cidofovir. Infants who have
received bacillus Calmette-Guérin (BCG) vaccination at birth should IMMUNODEFICIENCIES
receive isoniazid and rifampicin, regardless of the presence of overt
signs of mycobacteriosis. Administration of IVIG and antimicrobial In some cases, significant impairment of T-cell immunity is associated
prophylaxis are necessary to reduce the risk of infections. Parenteral with residual development and/or function of T lymphocytes. These
nutrition may be necessary, especially if chronic diarrhea and failure to conditions are also known as CID to distinguish them from SCID, in
thrive are present. which both T-cell development and function are abrogated. The clinical
Survival, however, is ultimately dependent on immune reconsti- features of CID overlap with SCID, but also include autoimmunity and/
tution. Allogeneic HSCT was first performed in 1968 in an infant with or inflammatory manifestations reflecting unbalanced immune homeo-
85
X-linked SCID, and is the treatment of choice. A multiinstitutional stasis. CID is caused by two main mechanisms: (1) hypomorphic muta-
analysis of outcome of HSCT for SCID performed in North America tions in SCID-causing genes that allow for some T-cell development;
in the period 2000 to 2009 demonstrates that survival following HSCT and (2) genetic defects that affect late stages in T-cell development or
from a human leukocyte antigen (HLA)-identical sibling is as high as 97 peripheral T-cell function.
86
percent. T-cell–depleted transplantation from haploidentical donors
results in a 79 percent 5-year-survival rate if no conditioning regimen is
used. Importantly, survival is as high as 94 percent, regardless of donor OMENN SYNDROME
type, if the transplant is performed within the first 3.5 months of age. Definition
86
Moreover, 90 percent survival rate has been reported for older infants Originally described in 1965, Omenn syndrome is characterized by
86
who received HSCT and did not have a prior history of infection. For severe infections, associated with early onset diffuse rash or generalized
patients who do not have a matched sibling donor, use of pretransplan- erythroderma, alopecia, eosinophilia, lymphadenopathy, hepatosple-
tation conditioning regimen increases the chance of achieving more nomegaly, hypoproteinemia with edema, and oligoclonal expansion of
robust B-cell reconstitution, but this benefit must be balanced against activated autologous T lymphocytes that infiltrate and damage target
86
toxicity of chemotherapy. By contrast, HSCT from unrelated cord tissues. 98,99
blood is associated with a lower survival rate (58 percent). 86
Failure to achieve sufficient T- and B-cell reconstitution is asso- Genetic Abnormalities
ciated with prolonged morbidity after transplantation, but most Various gene defects can cause this syndrome. Hypomorphic mutations
56
patients with SCID enjoy good quality of life after transplantation. in the RAG1 and RAG2 genes are most common, but virtually any
100
However, neurologic complications and developmental problems after gene defect that severely impairs, but does not abolish, T-cell develop-
transplantation are more common in patients with SCID associated ment may cause the disease. 101
with increased radiosensitivity and in patients with defects of purine
metabolism. 56,87–89 Pathophysiology
Enzyme replacement therapy offers rapid normalization of the Defects of immunologic tolerance have been implied in the pathophys-
toxic metabolites in ADA deficiency in those who do not have a matched iology of Omenn syndrome. Thymic expression of AIRE (autoimmune
donor, and may result in immune reconstitution and significant clinical regulator), a transcription factor involved in presentation of self-anti-
improvement in patients with ADA deficiency, although T-cell counts gens and negative selection of autoreactive thymocytes, is reduced.
102
often remain low. 45 Impaired generation of natural regulatory T cells, and homeostatic pro-
Gene therapy is an attractive form of therapy for SCID patients liferation of T lymphocytes in a lymphopenic environment, may also
who lack fully matched donors. Transplantation of gene-modified play a critical role in the pathophysiology of the disease. 103
autologous hematopoietic stem cells (aHSCs) may lead to immune
reconstitution without the risk of graft-versus-host disease. More than Laboratory Features
40 patients with ADA deficiency have received gene therapy using non- Laboratory investigations demonstrate that leukocytosis with eosin-
myeloablative conditioning regimen and transfusion of aHSCs trans- ophilia and hypogammaglobulinemia are common findings, and that
duced with ADA-encoding retroviral vectors. All of these patients are serum IgE is often elevated. The number of circulating T lymphocytes
alive, and approximately 75 percent of them have attained sufficient may vary, but they have a characteristic activated/memory (CD45R0+)
immune reconstitution. 90–92 phenotype. T cells have a restricted repertoire, and the distribution of
Twenty patients with X-linked SCID received gene therapy with CD4 and CD8 subsets is generally skewed. There is also a skewing to a
retroviral vectors in Paris and London, without conditioning regi- T-helper (Th) type 2 (Th2) profile, with increased production of IL-4
men. Seventeen of them are alive (as of this writing) with robust T-cell and IL-5. The in vitro lymphocyte response to antigens is abrogated;
immune reconstitution, but variable B-cell function. 93,94 However, five responses to mitogens are variable, but in general are reduced. 74,104 The
patients developed leukemia as the result of insertional mutagenesis. 95,96 number of circulating B and NK lymphocytes may vary, depending on
This prompted development of novel, hopefully safer, vectors. A new the nature of the underlying genetic defect. Absence of invariant NK
multiinstitutional trial of gene therapy for X-linked SCID with a self-in- T cells has been reported in RAG-deficient Omenn syndrome. 105
activating γ-retroviral vector is being conducted as of this writing. Of
nine patients treated, eight are surviving, and seven have attained good Differential Diagnosis
97
T-cell reconstitution. No leukemic proliferations have been observed. Differential diagnosis includes maternal T-cell engraftment in patients
Variable, but often poor, B-cell reconstitution has been reported after with SCID, complete atypical DiGeorge syndrome, CHARGE syn-
gene therapy for X-linked SCID without conditioning. To overcome this drome (coloboma of the eye, heart defects, atresia of the nasal choanae,
problem, a new trial based on use of a self-inactivating lentiviral trial retardation of growth and/or development, genital and/or urinary
and reduced intensity conditioning is under way at the National Insti- abnormalities, and ear abnormalities and deafness), immune dysreg-
tutes of Health as of this writing. ulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome

Kaushansky_chapter 80_p1211-1238.indd 1219 9/18/15 10:01 AM