Research Article: Primary immunodeficiency

Date Published: November 10, 2011

Publisher: BioMed Central

Author(s): Christine McCusker, Richard Warrington.


Primary immunodeficiency disorder (PID) refers to a heterogeneous group of over 130 disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T-cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, most disorders involve at least an increased susceptibility to infection. Early diagnosis and treatment are imperative for preventing significant disease-associated morbidity and, therefore, consultation with a clinical immunologist is essential. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The heterogeneous group of disorders involving the T-cell arm of the adaptive system, such as severe combined immunodeficiency (SCID), require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides a detailed overview of the major categories of PIDs and strategies for the appropriate diagnosis and management of these rare disorders.

Partial Text

Primary immunodeficiency disorder (PID) refers to a heterogeneous group of disorders characterized by poor or absent function in one or more components of the immune system. Over 130 different disorders have been identified to date, with new disorders continually being recognized [1,2]. Most PIDs result from inherited defects in immune system development and/or function; however, acquired forms have also been described [3]. It is important to note that PIDs are distinct from secondary immunodeficiencies that may result from other causes, such as viral or bacterial infections, malnutrition, or treatment with drugs that induce immunosuppression.

PIDs are broadly classified according to the component of the immune system that is primarily disrupted: adaptive or innate immunity (see An Introduction to Immunology and Immunopathology in this supplement for more information on adaptive and innate immunity). Table 1 presents a select list of PIDs grouped according to this system [5,8].

As mentioned previously, early diagnosis of PID is critical for preventing significant disease-associated morbidity, and even mortality. However, a national survey of PID in the United States found that more than 40% of patients with these disorders were not diagnosed until adulthood (Figure 1A), despite the fact that many reported serious or chronic health conditions prior to diagnosis, such as sinusitis, bronchitis, and pneumonia (see Figure 1B) [11]. The importance of prompt recognition and management of PIDs is further highlighted by the rate of hospitalizations pre- and post diagnosis. Although 70% reported being hospitalized prior to diagnosis (Figure 1C), nearly half (48%) reported no hospitalization since diagnosis (Figure 1D).

The treatment of PIDs is complex and generally involves both supportive and definitive strategies (see Table 3). As such, therapy should be coordinated by an immunologist with expertise in the management of these disorders [5,7].

The prognosis of patients with PIDs varies depending on the etiology of the disorder. However, patient outcomes and long-term survival have improved significantly since the 1970s given our improved management of infections and early access to antibiotics, advances in BMT and HSCT techniques, and enhanced intensive care services. Furthermore, routine vaccinations provide herd immunity to those at risk, decreasing the circulation of infectious disease. Further progress in the diagnosis and management of PIDs is expected as research on the genes responsible for immunodeficiencies and the use of definitive treatments such as gene therapy continues.

PID refers to a heterogeneous group of disorders that result from defects in immune system development and/or function. Although the signs and symptoms of PIDs are highly variable, most disorders involve increased susceptibility to infection, with many leading to significant disease-associated morbidity and mortality. Given the complexity of these disorders, referral to an immunologist is required for appropriate diagnosis and management. Severe disorders such as SCID requires definitive therapy for immune reconstitution (e.g., BMT, HSCT) as soon as possible. B-cell or antibody-deficiency disorders are the most common types of PIDs. The mainstay of treatment for patients with these disorders is Ig replacement therapy. Patients with innate immunodeficiency disorders often present with unusual or difficult to eradicate infections. Treatment varies depending on the type of defect (e.g., phagocyte disorder or complement deficiency), but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and BMT.

► With the exception of IgA deficiency (prevalence = 1 in 300-500), PIDs are more frequent than previously believed, with an estimated prevalence of 1 in 1200.

Dr. Christine McCusker has been a scientific advisory board member for Baxter, CSL Behring and Talecris.




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