Symptoms of Primary immune deficiency diseases (PIDDs)

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
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