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1212 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1213

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bacterial infections but normal BTK. Several responsible gene muta-
The clinical presentation and the results of these screening evaluations may tions have been identified, including those involving the B-cell receptor
prompt additional laboratory testing. For instance, patients with a profound complex μ heavy chain (immunoglobulin heavy constant mu [IGHM]),
hypogammaglobulinemia and a history of recurrent infections should be the surrogate light chain component λ5 (immunoglobulin lambda-like
tested for the presence of circulating B lymphocytes (CD19+ or CD20+ cells), polypeptide 1 [IGLL1]), the signal transducer complex of the pre–B-cell
which are absent or markedly reduced in X-linked agammaglobulinemia. On receptors immunoglobulin (Ig) α (CD79a), Igβ (CD79b), and mutations
the other hand, early presentation with severe and/or opportunistic infec- in the B-cell adaptor molecule BLINK, the p85α subunit of phosphat-
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tions, especially if associated with lymphopenia, should prompt enumera- idylinositol 3-kinase (PI3K) and a dominant negative E47 mutation
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causing autosomal dominant agammaglobulinemia.
tion of lymphocyte subsets. A severe reduction of circulating CD3+ T cells is
typically observed in severe combined immune deficiency, and may be asso-
ciated with defects of B and/or natural killer cells. Deep bacterial infections, Clinical Features
Because IgG is actively transported across the placenta, infants born
or infections sustained by Aspergillus, require evaluation of neutrophil count with XLA have normal levels of IgG at birth and are frequently asymp-
and function, to identify patients with congenital neutropenia and chronic tomatic for the first few months of life. Following metabolism of the
granulomatous disease, respectively. Invasive recurrent infections sustained maternal antibodies, affected boys begin to develop recurrent infections
by Neisseria species are an indication for assessing complement levels and usually between 4 and 12 months of age. In a review of 96 XLA patients,
function. The complement component deficiencies may also lead to systemic 20 percent experienced initial clinical symptoms after their first birth-
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lupus erythematosus-like features or other autoimmune disorders. Laboratory day and approximately 10 percent after 18 months of age. In an Italian
results should be compared to age-matched control values, as white blood study of 73 patients with mutation-verified XLA, the mean age of onset
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cell counts, lymphocyte subsets, complement components, immunoglobu- of symptoms was 2 years. The presenting symptoms vary greatly and
lin levels, and antibody production (especially to polysaccharide antigens) may be mild or severe (Table 80–1). Otitis media and chronic sinusitis,
undergo significant changes and progressive maturation in the first years of pneumonia, pyoderma, and diarrhea are frequent clinical presentations.
life. It is important to rule out secondary forms of immunodeficiency, such as Serious complications include septicemia, meningitis, septic arthritis, and
osteomyelitis. In young children with XLA, acute infections are often
human immunodeficiency virus infection, protein loss, and immunodeficiency associated with neutropenia. Pyogenic bacteria, such as Haemophilus
secondary to use of immunosuppressive drugs, as well as anatomical and/or influenzae, Streptococcus pneumoniae, and Staphylococcus aureus are the
functional problems (e.g., asplenia) that may lead to increased susceptibility most common pathogens observed in XLA. Opportunistic infections,
to infections. such as Pneumocystis jirovecii, are rarely observed. Infections with Ure-
Recognition of PIDDs is essential to start optimal therapies at an early aplasma urealyticum have been reported in XLA patients with myco-
age. These include immunoglobulin substitution for patients with antibody plasma arthritis. Although resistance to viral infections is generally
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deficiency; allogeneic hematopoietic stem cell transplantation for patients intact, XLA patients are unusually susceptible to enteroviruses such as
with severe combined immune deficiency; and in some cases, gene therapy echovirus, coxsackievirus, and poliovirus. Poliomyelitis after live-at-
or enzyme replacement therapy may be considered. Antimicrobial prophy- tenuated (Sabin) poliovirus vaccine, especially if given at a time when
laxis and aggressive treatment of infections is necessary in most cases of maternal antibodies had disappeared, is associated with high morbidity
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PIDD. Some patients with significant immune dysregulation may benefit from and mortality. Before the introduction of intravenous immunoglobulin
(IVIG), XLA patients frequently developed chronic, disseminated echo-
immunosuppressive therapy. virus and coxsackievirus infections presenting as meningoencephalitis,
This chapter focuses on defects that primarily affect T and B lymphocytes, dermatomyositis/fasciitis, and hepatitis. Gastroenteritis caused by
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the complement system, and innate immunity. It discusses specific immuno- Giardia lamblia, Campylobacter species, or rotavirus is not uncommon
deficiency syndromes, reviews etiology and pathogenesis, clinical and labora- and may be associated with malabsorption. Chronic intestinal inflam-
tory features, treatment, and prognosis. Chapters 65 and 66 discuss in detail mation resembling Crohn disease may develop in children and adults
disorders of neutrophil number and function. with XLA. Interestingly, an increased incidence of rectosigmoid cancer
with high mortality has been reported. Pyoderma gangrenosum-like
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ulcers of the lower extremities have been observed to be caused by
Helicobacter species. 10
Laboratory Features
PREDOMINANT ANTIBODY Most patients have markedly reduced levels of all classes of immuno-
DEFICIENCIES globulins; circulating B cells are less than 1 percent of total lymphocytes
and tonsils are absent. Because of the maturation arrest at the pre–B-cell
X-LINKED AND AUTOSOMAL RECESSIVE stage, very few B cells undergo differentiation into plasma cells. As a
AGAMMAGLOBULINEMIA result, lymph nodes, lymphoid follicles, germinal centers, and intesti-
nal mucosal biopsies lack plasma cells. As expected, specific antibodies
Definition and Genetic Features to microorganisms or vaccines are markedly reduced or undetectable
X-linked agammaglobulinemia (XLA) is the prototypic antibody defi- (Table 80–2).
ciency characterized by profound hypogammaglobulinemia caused by BTK, a cytoplasmic protein tyrosine kinase known to inter-
a maturation defect in B-cell development. XLA, originally described act with other cytoplasmic proteins, plays an important role in the
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in 1953, is one of the first primary immunodeficiencies in which the pre–B-cell expansion and the survival of mature B cells by facilitat-
underlying defect, a mutation of Bruton tyrosine kinase (BTK) was ing signaling through the B-cell antigen receptor. BTK is present in
identified. Autosomal recessive agammaglobulinemia, a variant form of all hematopoietic cells except T cells, natural killer (NK) cells, and
agammaglobulinemia, has been reported in patients with a clinical phe- plasma cells. The presence of BTK in normal monocytes and platelets
notype resembling XLA including very low B-cell numbers and severe allows assessment of BTK in most XLA patients with low or absent

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