Immunodeficiency

GENERAL PRINCIPLES

Definition

• Primary immunodeficiencies (PIDs) are disorders of the immune system that result in an increased susceptibility to infection.

• Secondary immunodeficiencies are also disorders of increased susceptibility to infection but are attributable to an external source.

Classification

PIDs can be organized by the defective immune components with considerable heterogeneity in each disorder.

• Predominantly antibody deficiencies: The defect is primarily in the ability to make antibodies.

î Common variable immune deficiency (CVID)

î X-linked (Bruton) agammaglobulinemia

î IgG subclass deficiency

î Specific antibody deficiency

î Hyper-IgM syndrome

î Selective IgA deficiency

• Combined immunodeficiencies and syndromes: The defect results in deficiencies in both cellular and humoral immune responses.

î Severe combined immunodeficiencies

î DiGeorge syndrome

î Hyper-IgE (Job) syndrome

• Defects of innate immunity: Defects in germline-encoded receptors and downstream signaling pathways.

î Deficiency of Toll-like receptor signaling

î Mendelian susceptibility to mycobacterial diseases (MSMD)

î Natural killer (NK) cell deficiency

î Phagocytic cell deficiencies

° Chronic granulomatous disease (CGD)

• Complement deficiencies

• Diseases of immune dysregulation: Autoimmunity and lymphoproliferation are characteristic manifestations in these disorders.

Epidemiology

• Secondary immunodeficiency syndromes, particularly HIV/AIDS, are the most common immunodeficiency disorders.

• The estimated prevalence of PIDs is approximately 1 in 1200 live births.

• Most PIDs presenting in adulthood are humoral immune defects affecting antibody production.

Etiology

• Predominantly antibody immune deficiencies are thought to be caused by defects in B-cell maturation.

• A variety of genetic mutations have been associated with specific PID syndromes.

• Secondary immunodeficiencies can be caused by medications (chemotherapy, immunomodulatory agents, corticosteroids), infectious agents (e.g., HIV), malignancy, antibody loss (e.g., nephrotic syndrome, protein losing enteropathy, or consumption during a severe underlying infection), autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis), malnutrition (vitamin D), and other underlying diseases (e.g., diabetes mellitus, cirrhosis, uremia).

DIAGNOSIS

Clinical Presentation

• The hallmark of PID is recurrent infections. Clinical suspicion should be increased by recurrent sinopulmonary infection, deep-seated infections, opportunistic infections, or disseminated infections in an otherwise healthy patient.

• Specific PIDs are often associated with particular types of pathogens (e.g., catalase-positive infections in CGD or MSMD).

• Recurrent urinary tract infections are only rarely associated with PID.

• Patients with PIDs may also present with autoimmunity, immune dysregulation, allergic diseases, and malignancies.

• Selective IgA deficiency is the most common immune deficiency, with a prevalence of 1 in 300-500 people.

î Most patients are asymptomatic. Some may present with recurrent sinus and pulmonary infections. Therapy is directed at early treatment with antibiotics because IgA replacement is not available.

î Associated autoimmune diseases are observed in 20%-30% of cases. Absolute IgA-deficient patients (i.e., B-cell numbers are often normal, but there is decreased ability to produce immunoglobulin because of the lack of isotype-switched memory B cells. Some patients may also exhibit T-cell dysfunction.

î CVID is largely idiopathic, although there are molecular defects in the B-cell signaling and development pathways (e.g., TACI, ICOS, BAFF-R, and CD19) with some forms of the disorder.

° Patients with CVID are particularly susceptible to infection with encapsulated organisms.

î Patients may have associated gastrointestinal disease or autoimmune abnormalities (most commonly autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, pernicious anemia, and rheumatoid arthritis).

î There is an increased incidence of malignancy, especially lymphoid and gastrointestinal malignancy.

° Therapy consists of IVIG or subcutaneous immunoglobulin (SCIG) replacement therapy as well as prompt treatment of infections with antibiotics.

• Specific antibody deficiency is defined as poor or absent antibody responses to polysaccharide antigens (i.e., 23-valent pneumococcal vaccine) in the setting of normal levels of immunoglobulins and IgG subclasses.

î B-cell numbers and response to protein antigens (i.e., tetanus toxoid and diphtheria toxoid) are usually normal.

î Patients have increased susceptibility to sinopulmonary infections. Allergic diseases are also common.

î Therapeutic approaches include adequate antibiotic treatment for infections, pneumococcal conjugate vaccine, and immunoglobulin replacement.

• X-linked (Bruton) agammaglobulinemia clinically manifests very similarly to severe CVID and is typically diagnosed in childhood, but can present in adulthood.

î Patients usually have low levels of all immunoglobulin types and very low levels of B cells.

î Specific genetic defect is in Bruton tyrosine kinase, which is involved in B-cell maturation.

• Subclass deficiency. Deficiencies of each of the IgG subclasses (IgG1, IgG2, IgG3, and IgG4) have been described.

î These patients present with similar complaints as the CVID patients.

î Total IgG levels may be normal. A strong association with IgA deficiency exists. There is disagreement as to whether this is a separate entity from CVID. In most cases, there is no need to evaluate IgG subclass levels.

î Isolated subclass deficiency without recurrent infections is of unknown clinical significance.

• Hyper-IgM syndrome is characterized by low IgA and IgG levels with normal or increased IgM and poor antibody function. There are several gene mutations reported, which cause defective class switching in immunoglobulins. Depending on the mutation, some patients may have poor T-cell function as well, leading to increased opportunistic infections.

• Hyper-IgE syndrome (Job syndrome) is characterized by recurrent pyogenic infections of the skin and lower respiratory tract. This syndrome can result in severe abscess and empyema formation. Some forms of the disease are associated with autosomal dominant mutation of STAT3.

î The most common organism involved is S. aureus, but other bacteria and fungi have been reported.

î Patients present with recurrent infections and have associated pruritic dermatitis, coarse (lion-like) facies, growth retardation, scoliosis, retention of primary teeth, and hyperkeratotic nails.

î Laboratory data reveal the presence of normal levels of IgG, IgA, and IgM but markedly elevated levels of IgE. A marked increase in tissue and blood eosinophils may also be observed.

• Complement deficiencies are a broad category of PID characterized by recurrent infections to a range of pathogens.

î Recurrent disseminated Neisseria infections are associated with a deficiency in the terminal complement system (C5-C9).

î Systemic lupus-like disorders and recurrent infection with encapsulated organisms have been associated with deficiencies in other components of complement.

o CH50 and AH50 are useful to screen for deficiencies of the classical pathway and alternative pathway, respectively.

• CGD is characterized by defective killing of intracellular pathogens by neutrophils.

î Patients usually present with frequent infection, often with abscesses, from S. aureus and other catalase-positive organisms. Aspergillus is a particularly troublesome pathogen for patients with CGD.

î Diagnosis is made by demonstration of defective respiratory burst with flow cytometry assay using dihydrorhodamine.

• MSMD is caused by defects in Thl immunity and is associated with mutations in genes involved in interferon-γ and IL-12 signaling. Characteristic infections include mycobacterial infections (including typical and atypical Mycobacterium) and Salmonella infections.

Diagnostic Testing

• Frequent sinopulmonary infections, recurrent and invasive infections requiring IV antimicrobial agents, infections with unusual pathogens, and family history of PID are warning signs for PIDs.

• Initial evaluation should focus on identifying possible secondary causes of recurrent infection such as allergy, medications, and anatomic abnormalities. Workup begins with a CBC with differential, HIV test, quantitative immunoglobulin levels, and complement levels. Often the evaluation will need to include enumeration of lymphocytes by flow cytometry if B-, T-, or NK-cell defects are suspected. Other specialized tests including genetic testing may be needed to make a definitive diagnosis.

• If clinical suspicion is high for an underlying antibody-predominant PID, B-cell function can be assessed by measuring immunoglobulin response to vaccinations. Preimmunization and postimmunization titers for both a protein antigen (i.e., tetanus) and a polysaccharide antigen (i.e., Pneumovax, the unconjugated 23-valent vaccine) are measured because proteins and polysaccharide antigens are handled differently by the immune system.

• Titers of specific antibodies are measured before and at 4-8 weeks after immunization.

• Genetic testing can also be performed.

TREATMENT

• Killed or subcomponent vaccines are safe for most patients with PID, although some patients may not produce full response. Live attenuated vaccines may be contraindicated in some individuals with PID and their families.

• Prophylactic antibiotics may be considered in some PID syndromes to prevent infections.

• IgA deficiency: No specific treatment is available. However, these patients should be promptly treated at the first sign of infection with an antibiotic that covers Streptococcus pneumoniae or Haemophilus influenzae.

• CVID should be treated with immunoglobulin replacement in forms of IVIG or SCIG. Numerous preparations of immunoglobulin are available, all of which undergo viral inactivation steps. Possible side effects include myalgias, vomiting, chills, and lingering headache (due to immune complex- mediated aseptic meningitis).

Referral

Patients in whom a PID is being seriously considered should undergo evaluation by an allergist/clinical immunologist with expertise in diagnosing and treating PID.