Primary Immunodeficiency Diseases - Immunoglobulin Disorders

Medical Experts

Contributor

Delgado

Vice Chair and Chief of the Division of Clinical Pathology, Executive Vice President, ARUP Laboratories

Professor, University of Utah School of Medicine

Primary immunodeficiency diseases (PIDDs) result from inherited genetic defects and represent a highly heterogeneous group of disorders. PIDDs typically present with severe, repetitive infections caused by organisms of low virulence and are usually detected during childhood; however, the most common clinically significant PIDD, common variable immune deficiency (CVID), has a peak onset in the second and third decades of life. PIDDs are roughly categorized as antibody deficiencies (B cell, T cell, or combined), phagocytic defects (eg, chronic granulomatous disease [CGD]), and complement disorders. Antibody deficiencies are the most common type of PIDD and can be broadly characterized by the presence or absence of B cells. The resulting disorders range from severe forms (CVID, X-linked agammaglobulinemia) to milder forms, which are covered here.

A careful, stepwise laboratory evaluation is recommended to diagnose an underlying PIDD. After eliminating conditions that may increase susceptibility to infection (eg, adenoid hypertrophy, cystic fibrosis, immunosuppression), an initial workup may include CBC, quantitative serum immunoglobulins, IgG vaccine titers, and complement testing. These tests are often insufficient to make a definitive diagnosis, so advanced tests (eg, flow cytometric-based assays to test immune cell function, cytokine production, cellular signaling pathways, and protein expression) are often necessary. Genetic testing may also be warranted.

Quick Answers for Clinicians

When should a primary immunodeficiency disease be suspected?

According to the CDC, the average adult may have two to three colds per year, and children 2 years of age and younger average eight to 10 illnesses per year (and possibly more if attending daycare or if older children live in the house). In contrast, a primary immunodeficiency disease (PIDD) can cause numerous recurrent illnesses that are unusually severe and last longer than average. The Jeffrey Modell Foundation’s 10 Warning Signs of Primary Immunodeficiency include four or more new ear infections within a year, two or more serious sinus infections within a year, 2 or more months of antibiotic treatment with little to no effect, and two or more pneumonias within a year.

What is the general approach to investigating a suspected primary immunodeficiency disease?

First, if severe combined immunodeficiency (SCID) is suspected, laboratory testing should be expedited. Patients with SCID have a total lack of immunity, which constitutes a medical emergency. Second, all other medical conditions and anatomic abnormalities that could result in a secondary immunodeficiency, which is more common than a primary immunodeficiency disease (PIDD), should be excluded. The laboratory testing performed next depends on the clinical presentation. See Laboratory Testing for some of the more common laboratory approaches to investigate PIDDs.

Indications for Testing

Any individual with recurrent, severe infections (eg, sinopulmonary, gastrointestinal), allergic disorders, and autoimmunity may warrant testing for an immunodeficiency. Infants presenting with a recurrent, persistent, or severe bacterial, viral, or fungal infection or failure to thrive should be evaluated for severe combined immunodeficiency (SCID), a pediatric emergency.

Laboratory Testing

Suspected PIDDs should be evaluated in a stepwise fashion, with initial, nonspecific testing that includes measurement of total serum immunoglobulin and evaluation of antibody titers. Abnormal test results may suggest allergy, immunodeficiency, or chronic illness and should prompt further testing, which might include lymphocyte subset analysis by flow cytometry and IgG subclass testing. An immunologist typically performs this testing.

Initial Testing

Serum Quantitative Immunoglobulins

Immunoglobulin deficiency can be detected by determining total IgG, IgA, and IgM levels and is generally the first step in the workup of immunoglobulin disorders. Hypogammaglobulinemia is defined when the test result is <2 standard deviations below the age-adjusted norm, and agammaglobulinemia when IgG is <100 mg/dL.

Immunoglobulin results may appear normal in some individuals with PIDD because immunoglobulin levels are not sensitive indicators of specific immunity. For this reason, if strong suspicion of an immunodeficiency exists, antibody titers to previously administered vaccines should also be evaluated.

Antibody Titers

Humoral immune function is evaluated by specific antibody titers to both protein (eg, tetanus, diphtheria) and polysaccharide (eg, pneumococcus) antigens. Protein-based vaccines generate long-lasting immunity, while polysaccharide-based vaccines generate a weaker immunologic response. If any vaccination titer is below normal, revaccination and assessment of titers 4-6 weeks later (often referred to as a “vaccine challenge”) is warranted.

Secondary Testing

If initial test results are abnormal, additional testing to evaluate lymphocyte subsets and genetic testing for variants that cause humoral defects may be warranted.

Lymphocyte Subset Analysis

The investigation of a suspected PIDD requires enumeration of specific lymphocyte population subsets. Routine immunophenotyping is designed to measure qualitative and quantitative abnormalities in the major peripheral blood lymphocyte subsets and is a valuable approach to screening for several inherited immunodeficiency diseases.

IgG Subclass Testing

The measurement of IgG subclass levels is not universally recommended when evaluating antibody-mediated immunity. If testing, all four IgG subclasses should be evaluated at the same time; a single decreased level of one or more IgG subclasses is not diagnostic, and abnormal subclass concentrations must be confirmed.

Molecular Testing

Not all immunoglobulin disorders have been defined at the molecular level, but some have clear molecular associations. For example, hyper-IgM (HIGM) syndrome is associated with defects in the CD40L and CD40 genes. Hyper-IgE syndrome (HIES) is associated with defects in the STAT3 and DOCK8 genes. For these and other immunodeficiency syndromes that require genetic testing for definitive diagnosis, prognostication, and treatment, testing should be overseen by a genetic counselor.

Laboratory Findings for Select Immunoglobulin Disorders

	IgA	IgD	IgE	IgG	IgM	IgG Subclasses	Vaccine Response	Other Lab Findings
SIGAD	Low/absent	—	—	Normal	Normal	—	—	—
HIGM syndrome	Low	—	Low	Low	Elevated/normal	—	—	CD40L/CD40 deficiency
SAD	Normal	Normal	Normal	Normal	Normal	Normal	Decreased	—
THI	Normal/low	Normal/low	Normal/low	Low	Normal/low	—	Normal	—
IgG subclass deficiency	—	—	—	Normal	—	1 or more decreased levels confirmed by repeat testing	Decreased	—
HIES	—	—	Elevated	—	—	—	—	STAT3 or DOCK8 variants
SAD, specific antibody deficiency; SIGAD, selective IgA deficiency; THI, transient hypogammaglobulinemia of infancy Sources: Bonilla; Locke; Yel

Monitoring

Monitoring depends on the severity of the PIDD and the patient’s age. In young children, levels of immunoglobulins and IgG subclasses (if IgG subclass deficiency is diagnosed) should be measured yearly, and vaccine response should be reassessed. In older children and adults, immunoglobulin levels should be reevaluated annually for several years. In patients receiving immunoglobulin replacement therapy, treatment should be halted after 1-2 years for immunologic and clinical reassessment. Patients who are at risk for recurrent pneumonia or lung damage should be monitored by imaging studies, and pulmonary function should be measured serially.

Descriptions of Select Immunoglobulin Disorders

Select immunoglobulin disorders, including IgA deficiency, HIGM syndrome, HIES, IgG subclass deficiency, SAD, and THI, are discussed briefly below. For more information about other PIDDs, including SCID, agammaglobulinemia, CGD, CVID, and complement deficiency, refer to the corresponding ARUP Consult topics.

IgA Deficiency

IgA deficiency is defined as decreased or absent IgA in the presence of normal IgG and IgM in a patient older than 4 years in whom other causes of hypogammaglobulinemia have been excluded. The 4 years of age cutoff was established to prevent premature diagnosis of IgA deficiency in young children with transient deficiency due to delayed development of the IgA system after birth.

SIGAD is defined as serum IgA <7 mg/dL (generally the lowest detectable limit established by most laboratories). SIGAD is considered the most common PIDD. While there is a wide spectrum of possible clinical findings (eg, recurrent sinopulmonary and gastrointestinal infections, allergic disorders), SIGAD is asymptomatic in most individuals.

Prognosis is good for individuals with IgA deficiency if it is not associated with a significant disease, and the deficiency may even resolve over time in children. However, IgA deficiency can develop into CVID later in life, so monitoring of clinical and immunologic findings is critical.

Hyper-IgM Syndrome

HIGM syndrome is associated with defects in B-cell class switching and somatic hypermutation. The impaired specific antibody function leads to rising IgM levels with infection or immunization and limited IgG formation. The most common defect is X-linked HIGM syndrome, which is due to a deficiency of the CD40 ligand. An autosomal recessive form that is due to CD40 deficiency is also recognized.

Hyper-IgE Syndrome

HIES is characterized by recurrent sinopulmonary and skin infections, high IgE levels, eosinophilia, and eczema. Autosomal dominant or type 1 HIES is caused by STAT3 gene variants and is often referred to as Job syndrome. Variants in the DOCK8 gene are responsible for the less common autosomal recessive form, HIES type 2. STAT3 variants may lead to connective tissue, skeletal, and vascular defects, while DOCK8 variants develop cutaneous viral infections and predispose patients to malignancies at a young age. Genetic analysis is required for definitive diagnosis.

IgG Subclass Deficiency

IgG subclass deficiency is defined as the relative lack of one or more IgG subclasses with a normal or near-normal concentration of total serum IgG in a patient with recurrent severe infections. IgG subclass deficiency is a controversial diagnosis, because a deficiency in one or more subclasses may be clinically insignificant. Indeed, most individuals with low levels of IgG subclasses are asymptomatic.

Specific Antibody Deficiency

SAD is a condition defined by a nonresponse to polysaccharide antigens when all immunoglobulin isotype levels are normal. The diagnosis is made based on the level of antibodies present after receiving the 23-valent polysaccharide vaccine. A SAD diagnosis can be considered in patients older than 2 years with recurrent respiratory tract infections, normal immunoglobulin and IgG subclass levels, and impaired response to pneumococcal polysaccharide.

Transient Hypogammaglobulinemia of Infancy

Infants and young children with frequent viral and bacterial respiratory illnesses and low IgG levels with normal vaccine responses may be evaluated for THI. Infants are usually protected by transplacentally acquired maternal IgG for the first 3-6 months of life, but in some, IgG levels do not normalize until early childhood. This period of hypogammaglobulinemia may result in recurrent infections. A definitive diagnosis can be made after IgG (and in some cases IgA, IgM, or both) levels have corrected. In patients with THI, IgG levels are at least 2 standard deviations below the mean for age-matched controls, with or without diminished values of the other immunoglobulin isotypes, remain low beyond 6 months of age, and occur in the absence of other immunodeficiency conditions.