Primary Immunodeficiency Disorders (In Adults)

Primary immunologic deficiency diseases are estimated to affect 1 in 4000 individuals; most are genetically determined and present in early childhood. Nonetheless, several important immunodeficiency disorders present in adulthood, most notably the antibody deficiency syndromes: selective IgA deficiency, common variable immunodeficiency (CVID), and specific (functional) antibody deficiency.

Antibody deficiency predisposes patients to recurrent serious bacterial infections, particularly of the respiratory tract, including refractory chronic rhinosinusitis, bronchitis, pneumonia, and bronchiectasis.

Patients are most susceptible to infections with encapsulated bacteria (eg, Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitides). However, any part of the innate or adaptive immune system can be defective, which results in infections with different spectra of organisms depending on the severity of the immune defect.

Selective IgA Deficiency

Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by undetectable serum IgA levels (< 7 mg/dL) with normal levels of IgG and IgM; its prevalence is about 1 in 500 individuals, with a higher prevalence in White persons.

Most affected individuals are asymptomatic.

A minority of patients have recurrent bacterial infections such as sinusitis, otitis, bronchitis, and GI infections.

Selective IgA deficiency can be associated with an increased incidence of atopic and autoimmune disorders, including Graves disease, SLE, juvenile rheumatoid arthritis, type 1 diabetes mellitus, and celiac disease.

Some individuals with undetectable levels of serum IgA may have high titers of anti-IgA IgG or IgE antibodies and are at risk for anaphylactic reactions to IgA following exposure through infusions of plasma (or other blood transfusions). Treatment with commercial immune globulin replacement therapy (IgG-RT) is not indicated for patients with selective IgA deficiency and may result in anaphylaxis in preparations with detectable amounts of IgA in the preparation. Notably, IgG-RT does not treat IgA deficiency since there is little IgA present in IgG-RT products.

When to Refer

• Refer patients with undetectable serum IgA and recurrent sinopulmonary infections, celiac disease, giardiasis, or a family history of immunodeficiency to an immunologist.

Common Variable Immunodeficiency (CVID)

CVID is a heterogeneous immunodeficiency disorder clinically characterized by an increased incidence of recurrent severe sinopulmonary infections with hypogammaglobulinemia.

Approximately half of CVID patients will also have autoimmune phenomena with or without neoplastic disease.

The onset is generally in adolescence or early adulthood, but it can occur at any age, mostly due to delay in diagnosis.

Most cases are sporadic; about 10–20% are familial.

Thus, routine immunoglobulin screening of family members without severe symptoms is not advised, albeit patients with CVID may have family members with a higher incidence of autoimmune disease or IgA deficiency.

Since the genetic defect is not known, patients with CVID and their offspring are not recommended to undergo genetic testing unless advised by an immunologist.

Diagnostic Essentials

• Frequent, severe sinopulmonary infections secondary to humoral immune deficiency.
• Two or more low serum immunoglobulin levels (IgG, IgA, IgM) and deficient functional antibody responses to vaccination.
• Secondary causes for hypogammaglobulinemia and recurrent sinopulmonary infections have been ruled out.

Clinical Findings

Symptoms and Signs

Increased susceptibility to serious infections, especially with encapsulated organisms, is the hallmark of the disease.

Virtually all patients suffer from recurrent bacterial sinusitis, bronchitis, and otitis, but it is the recurrent pneumonia that sets these individuals apart from patients with severe atopy.

Infections may be prolonged or associated with unusual complications such as meningitis, empyema, or sepsis.

Bronchiectasis occurs in at least 25% of patients who are not treated with IgG-RT and is a leading cause of morbidity.

Recurrent viral infections are not prototypic of the disease, albeit varicella-zoster reactivation, CMV reactivation, and increased symptomatic disease from other herpes viruses and Candida can occur in some patients.

GI infections and autoimmunity are commonly associated with CVID. Many patients will develop an inflammatory sprue-like syndrome, with diarrhea, steatorrhea, malabsorption, protein-losing enteropathy, and hepatosplenomegaly. Norovirus and Giardia can be problematic, so infectious and inflammatory etiologies should be considered.

Paradoxically, there is an increased incidence of autoimmune disease (20%) in these patients, although they often do not display the usual serologic markers as they are hypogammaglobulinemic. Autoimmune cytopenias are most common, but autoimmune endocrinopathies, seronegative rheumatic disease, and the aforementioned GI disorders are also commonly seen.

Lymph nodes may be enlarged in CVID patients, yet biopsies show marked reduction in plasma cells. Noncaseating granulomas are frequently found in the spleen, liver, lungs, or skin.

There is an increased propensity for the development of B-cell neoplasms (50- to 400-fold increased risk of lymphoma) and gastric carcinomas.

Laboratory Findings

The serum IgG level is reduced at least two standard deviations below normal in all patients. Either IgA or IgM is also reduced two standard deviations below normal; it is common that IgA is undetectable.

Demonstration of functional or quantitative defects in antibody production is essential and is typically performed by checking antibody response to polysaccharide (Pneumovax-23, H influenzae type b) and protein antigens (tetanus, diphtheria).

The diagnosis is made in patients who have reduced serum immunoglobulins and poor antibody response to vaccines, after exclusion of secondary causes as highlighted (eg, proteinuria, protein-losing enteropathy, drug effects such as rituximab and other immunosuppressants, antiepileptics, and hematologic malignancies).

The absolute B-cell count in the peripheral blood can be normal.

A subset of CVID patients have concomitant T-cell immunodeficiency with increased numbers of activated CD8 cells, splenomegaly, and decreased delayed-type hypersensitivity.

Differential Diagnosis

See secondary causes of hypogammaglobulinemia, below.

Secondary causes of recurrent sinopulmonary infections include COPD, current or past prolonged smoking, chronic sinusitis, cystic fibrosis, Kartagener syndrome, and colonization with multi-drug–resistant bacteria.

Treatment

In addition to IgG-RT, patients should be treated aggressively with antibiotics at the first sign of infection.

Since antibody deficiency predisposes patients to high-risk pyogenic infections, antibiotic coverage should cover encapsulated bacteria. Infections with other microorganisms can develop including viruses, parasites, and extracellular gram-positive or gram-negative bacteria (such as S aureus or P aeruginosa).

The current standard of care for preventive therapy is treatment with subcutaneous IgG-RT, with a typical monthly dose of 300–600 mg/kg. Subcutaneous injections of IgG offer the convenience of self-administration at home, lower incidence of adverse effects, and can be administered every 1–4 weeks. Adjustment of the dosage or infusion interval is made primarily based on clinical responses in addition to serum IgG levels. Such therapy is essential for decreasing the incidence of potentially life-threatening infections, increasing quality of life, and reducing the progression of lung disease, which can be a severe complication in patients who are not treated with IgG-RT. IgG-RT can be administered intravenously as well, but this is becoming less common due to the improved cost, ease of administration, fewer systemic side effects, and more stable IgG levels achieved with subcutaneous administration.

When to Refer

• Refer patients with low serum immunoglobulins and recurrent serious or unusual infections to a clinical immunologist with expertise in immunodeficiency.
• The presence of bronchiectasis without a known underlying cause such as cystic fibrosis or Kartagener syndrome should raise the suspicion of a primary immunodeficiency and would warrant further evaluation by a clinical immunologist.

Specific (Functional) Antibody Deficiency

Specific antibody deficiency is characterized by decreased or absent IgG antibody response to vaccines in the setting of normal or mildly decreased serum immunoglobulin levels.

The clinical spectrum can range from mild symptoms that can be managed with antibiotics and vaccination to more rarely, recurrent infections with features very similar to CVID.

Since this can be a nuanced diagnosis, recommendations are to refer to a clinical immunologist for diagnosis and treatment recommendations.

Disease	Clinical Presentation	Diagnosis1	Treatment
Complement disorders	– “Early” complement component (C1-C4) deficiencies: autoimmune diseases – “Late” complement component (C5-C8) deficiencies: recurrent meningococcal or gonococcal infections	– Screen with CH50 and AH50. Obtain individual serum complement levels if abnormal. Genetic testing if complement level absent.	– Prompt administration of antibiotics and Neisseria vaccination if C5-C8 deficient. Immune suppression if C1-C4 deficient to treat organ specific autoimmunity.
Good syndrome	– Current or past thymoma, recurrent severe sinopulmonary infections, may also have opportunistic infections	– Hypogammaglobulinemia (IgG, IgM, IgA), absent B cells on flow cytometry, may present with pure red cell aplasia or cytopenias. Chest film consistent with thymoma.	– IgG-RT (SC or IV) 300 mg-500 mg/kg/month
Hereditary angioedema	– Unpredictable swelling of face, lips, tongue, hands, feet; no urticaria; GI tract swelling causing severe abdominal pain	– Decreased C1 esterase inhibitor serum level and/or function, decreased serum C4 level.	– Prophylactic treatment: Danazol, tranexamic acid – Acute treatment: C1 esterase inhibitor product, kvllikrein inhibitor, bradykinin receptor antagonist
Granulocyte disorders	– Recurrent invasive skin and soft tissue infections, abscesses requiring incision and drainage – Common organisms are Staphylococcus aureus, gram-negative bacilli, Nocardia, Aspergillus	– CBC with differential to evaluate neutrophil count. – Dihydrorhodamine assay confirming defective oxidative burst. Genetic testing confirming diagnosis.	– Antimicrobial prophylaxis; interferon for chronic granulomatous disease

Immunoglobulin Subclass Deficiency

There are four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4.

A low level of at least one IgG subclass has been found incidentally in 2% of the population.

Thus, low or absent IgG subclass levels alone are not sufficient for a diagnosis of immunodeficiency, and IgG-RT is not clinically indicated unless other functional impairments in the immune system are identified.

Secondary Hypogammaglobulinemia

Secondary causes of hypogammaglobulinemia, rather than from a primary genetic defect, are more likely to occur in the older population due to an increase in comorbid conditions.

Some malignancies, immunosuppressants, anti-psychotic medications, chronic diarrhea, sepsis, nephrosis, and HIV have known associations with hypogammaglobulinemia.

The principle therapy of secondary hypogammaglobulinemia is treatment of the underlying condition or removal of the offending medication.

If hypogammaglobulinemia is persistent or severe with recurrent infections, consultation with an allergist immunologist is recommended to determine whether treatment should include IgG-RT, vaccination boosters, and antibiotic prophylaxis.