Clinical Features of Primary immune deficiency diseases (PIDDs)
Because IgG is actively transported across the placenta, infants born with XLA have normal levels of IgG at birth and are frequently asymptomatic for the first few months of life. Following metabolism of the maternal antibodies, affected boys begin to develop recurrent infections usually between 4 and 12 months of age. In a review of 96 XLA patients, 20 percent experienced initial clinical systems after their first birthday and approximately 10 percent after 18 months of age.3 In an Italian study of 73 patients with mutation-verified XLA, the mean age of onset of symptoms was 2 years.4 The presenting symptoms vary greatly and may be mild or severe (Table 82–1). Otitis media and chronic sinusitis, pneumonia, pyoderma, and diarrhea are frequent clinical presentations. Serious complications include septicemia, meningitis, septic arthritis, and osteomyelitis. In young children with XLA, acute infections are often associated with neutropenia. Pyogenic bacteria, such as Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus are the most common pathogens observed in XLA. Opportunistic infections such as Pneumocystis jiroveci, are rarely observed. Infections with Ureaplasma urealyticum have been reported in XLA patients with mycoplasma arthritis.5 Although resistance to viral infections is generally intact, XLA patients are unusually susceptible to enteroviruses such as echovirus, coxsackievirus, and poliovirus. Poliomyelitis after live attenuated (Sabin) poliovirus vaccine, especially if given at a time when maternal antibodies had disappeared, is associated with high morbidity and mortality.3 Before the introduction of intravenous immunoglobulin (IVIg), XLA patients frequently developed chronic, disseminated echo- and coxsackievirus infections presenting as meningoencephalitis, dermatomyositis/fasciitis, and hepatitis.6 Gastroenteritis caused by Giardia lamblia, Campylobacter species, or rotavirus is not uncommon and may be associated with malabsorption. Chronic intestinal inflammation resembling Crohn disease may develop in children and adults with XLA. Interestingly, an increased incidence of rectosigmoid cancer with high mortality has been reported.7
Table 82–1. Principal Clinical Features of Primary Immunodeficiency Disorders |
|
Neutrophils Numerical or Functional Defects |
Complement Deficiencies |
Antibody Deficiencies |
Combined Immune Deficiencies |
Severe bacterial and fungal infections |
Recurrent or severe infections sustained by encapsulated pathogens |
Recurrent infections after 4 to 6 months of age |
Early onset respiratory and gut infections |
Skin or deep bacterial and fungal abscesses |
Intestinal Giardia lamblia infection |
Opportunistic infections |
Recurrent Neisseria meningitidis infections |
Growth failure |
Infections sustained by unusual bacteria and fungi |
Enterovirus meningoencephalitis |
Persistent candidiasis |
Autoimmune manifestations (systemic lupus erythematosus-like) |
Erythroderma |
|
Atypical hemolytic-uremic syndrome |
|
|
|
Recurrent angioedema (C1-INH deficiency) |
|
|
|
|
Laboratory Features of Primary immune deficiency diseases (PIDDs)
Most patients have markedly reduced levels of all classes of immunoglobulins; 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 stage, very few B cells undergo differentiation into plasma cells. As a result lymph nodes, lymphoid follicles, germinal centers, and intestinal mucosal biopsies lack plasma cells. As expected, specific antibodies to microorganisms or vaccines are markedly reduced or undetectable (see Table 82–2).
Table 82–2. Common Primary Immunodeficiencies: Laboratory and Clinical Features* |
|
|
Lymphocytes |
Cellular Immunity |
Humoral Immunity |
Common Infections |
Serum Immunoglobulins |
Antibody Responses |
B |
T |
NK |
M |
G |
A |
E |
Predominantly antibody deficiency |
X-linked agammaglobulinemia (BTK) |
– |
+ |
+ |
+ |
|
|
|
|
– |
Bacteria, Giardia lamblia |
Autosomal recessive agammaglobulinemia |
5, Ig, Ig, or BLNK deficiency |
– |
+ |
+ |
+ |
|
|
|
|
– |
Bacteria |
Hypogammaglobulinemia (AR) ICOS, CD19, CD21, BAFF-R |
– |
+ |
+ |
+ |
|
|
|
|
– |
Bacteria |
Transient hypogammaglobulinemia of infancy |
+ |
+ |
+ |
+ |
N/ |
N/ |
N/ |
N/ |
+/– |
Bacteria |
Selective IgA deficiency |
+ |
+ |
+ |
+ |
N |
N |
|
N |
+/– |
Bacteria, G. lamblia |
Common variable immune deficiency |
+ |
+ |
+ |
+ |
N/ |
|
|
|
– |
Bacteria, G. lamblia |
IgG subclass deficiencies |
+ |
+ |
+ |
+ |
N |
N/ |
N/ |
N |
+/– |
Bacteria |
Hyper-IgM syndrome |
Activation-induced cytidine deaminase deficiency |
+ |
+ |
+ |
+ |
N/ |
|
|
|
+/– |
Bacteria |
Uracil-DNA glycosylase deficiency |
+ |
+ |
+ |
+ |
N/ |
|
|
|
+/– |
Bacteria |
X-linked CD40 ligand deficiency |
+ |
+ |
+ |
+ |
N/ |
|
N/ |
|
+/– |
Bacteria, viruses, fungi |
CD40 deficiency |
+ |
+ |
+ |
+ |
N/ |
|
N/ |
|
+/– |
Bacteria, viruses, fungi |
X-linked IKK- (NEMO) deficiency |
+ |
+ |
+ |
+ |
N/ |
|
|
|
+/– |
Bacteria, viruses, fungi |
Severe combined immunodeficiency (SCID) |
Interleukin receptor -chain deficiency (X-linked SCID) |
+ |
– |
– |
– |
N |
|
|
|
– |
Bacteria, viruses, fungi |
Janus-associated kinase 3 (JAK3) deficiency |
+ |
– |
– |
– |
N |
|
|
|
– |
Bacteria, viruses, fungi |
Interleukin-7 receptor -chain deficiency |
+ |
– |
– |
– |
N |
|
|
|
– |
Bacteria, viruses, fungi |
Zap-70 tyrosine kinase deficiency |
+ |
+/– |
+ |
– |
N |
N/ |
N/ |
N/ |
+/– |
Bacteria, viruses, fungi |
Adenosine deaminase (ADA) deficiency |
– |
– |
– |
– |
|
|
|
|
– |
Bacteria, viruses, fungi |
Purine nucleotide phosphorylase (PNP) deficiency |
+ |
– |
+ |
– |
N |
|
|
|
+/– |
Bacteria, viruses, fungi |
Recombinase activating gene (RAG 1/2) deficiency |
– |
– |
+ |
– |
|
|
|
|
– |
Bacteria, viruses, fungi |
Artemis deficiency |
– |
– |
+ |
– |
|
|
|
|
– |
Bacteria, viruses, fungi |
Reticular dysgenesis (AK2 deficiency) |
– |
– |
– |
– |
|
|
|
|
– |
Bacteria, viruses, fungi |
Primary T-cell deficiency |
Congenital thymic aplasia (DiGeorge syndrome) |
+ |
– |
+ |
– |
N |
N |
N |
N |
+/– |
Bacteria, viruses, fungi |
Major histocompatibility complex (MHC) class II deficiency |
+ |
+/– |
+ |
+ |
N |
|
|
|
+/– |
Bacteria, viruses, fungi |
Transport-associated protein (TAP)-1 or TAP-2 deficiency (MHC class I deficiency) |
+ |
+/– |
+ |
– |
N |
N |
N |
N |
+ |
Bacteria, viruses, fungi |
Th1 deficiency |
Interferon- and interferon- receptor deficiency |
+ |
+ |
+ |
+ |
N |
N |
N |
N |
+ |
Mycobacteria, Salmonella |
Interleukin-12 and interleukin-12 receptor deficiency |
+ |
+ |
+ |
+ |
N |
N |
N |
N |
+ |
Mycobacteria, Salmonella |
Other well-defined immunodeficiency syndromes |
Ataxia-telangiectasia |
+ |
+ |
+ |
+ |
N/ |
N/ |
N/ |
|
+/– |
Bacteria |
Wiskott-Aldrich syndrome |
+ |
+/– |
+ |
+/– |
|
N |
|
|
+/– |
Bacteria |
|
*Natural killer lymphocytes (NK), T cells (T), B cells (B).Normal levels (+), reduced or absent levels (–); normal (N), elevated (), or reduced ( ) serum immunoglobulins. |
BTK, a cytoplasmic protein tyrosine kinase known to interact with other cytoplasmic proteins, plays an important role in the pre–B-cell expansion and the survival of mature B cells by facilitating signaling through the B-cell antigen receptor. BTK is present in all hematopoietic cells except T cells, natural killer (NK) cells, and plasma cells. The presence of BTK in normal monocytes and platelets allows assessment of BTK in most XLA patients with low or absent BTK levels using flow cytometry, and to identify carrier females.8 Sequence analysis of the BTK gene confirms the diagnosis and allows prenatal diagnosis