Primary immune deficiency diseases (PIDDs) are characterized
by increased susceptibility to infections, often associated with
autoimmunity and inflammation and an increased risk of malignancies because
of impaired immune homeostasis and surveillance. Depending on the
nature of the immune defect, the clinical presentation of PIDD may
vary and may include recurrence of upper and lower respiratory tract
infections, invasive bacterial infections, purulent lymphadenitis,
skin or deep abscesses, infections sustained by poorly virulent
or opportunistic pathogens (Pneumocystis jiroveci,
cytomegalovirus, environmental mycobacteria, Cryptosporidium, Giardia
lamblia), persistent or recurrent candidiasis, autoimmunity, increased
susceptibility to malignancies, and association with typical signs
of specific immunodeficiency syndromes.
With the exception of immunoglobulin (Ig) A deficiency, PIDDs
are generally rare, with a prevalence of approximately 1:10,000
to 1:50,000. However, prompt recognition of PIDD is of importance,
because diagnostic delay is associated with increased risk of death
and of irreversible complications. Most forms of PIDD follow mendelian
inheritance; however, some, for example, common variable immunodeficiency
(CVID), have a multifactorial origin. In most cases, PIDDs present
in childhood, but late presentations may occur or even predominate
in some forms, such as CVID.
The diagnostic approach to PIDD is based on a detailed family
and clinical history, physical examination and appropriate laboratory
tests. Lymphopenia is characteristic of severe combined immune deficiency.
Abnormalities of the neutrophil count can be observed in patients
with disorders of neutrophil production (e.g., congenital neutropenia)
or function (e.g., chronic granulomatous disease), respectively. Evaluation
of serum immunoglobulin levels and of antibody responses to immunization
antigens is important for patients with a history of recurrent infections.
The clinical presentation and the results of these preliminary evaluations
may prompt additional laboratory testing. For instance, patients
with a profound hypogammaglobulinemia and a history of recurrent infections
should be tested for the presence of circulating B lymphocytes (CD19+ or
CD20+ cells), which are absent or markedly reduced in X-linked
agammaglobulinemia. On the other hand, early presentation with severe
and/or opportunistic infections, especially if associated
with lymphopenia, should prompt enumeration of lymphocyte subsets.
A severe reduction of circulating CD3+ T cells is typically
observed in severe combined immune deficiency, and may be associated
with defects of B and/or natural killer cells. Deep bacterial
infections, or infections sustained by Aspergillus,
require evaluation of neutrophil count and function, to identify
patients with congenital neutropenia and chronic granulomatous disease,
respectively. Invasive recurrent infections sustained by Neisseria species
are an indication for assessing complement levels and function.
On the other hand, complement component deficiencies may also lead
to systemic lupus erythematosus-like features or to autoimmune disorders.
Laboratory results should be compared to age-matched control values,
as white blood cell counts, lymphocyte subsets, complement components and
immunoglobulin levels, and antibody production (especially to polysaccharide
antigens) undergo significant changes and progressive maturation
in the first years of life. It is important to rule out secondary forms
of immunodeficiency, such as human immunodeficiency virus infection,
protein loss, immunodeficiency secondary to use of immunosuppressive
drugs, as ...