Hypogammaglobulinemia refers to a set of clinicolaboratory entities with varied causes and manifestations. The common clinical feature of hypogammaglobulinemia relates to a predisposition toward infections that normally are defended against by antibody responses (including Streptococcus pneumoniaeand Haemophilus influenzae infections).

Signs and symptoms

Most patients with hypogammaglobulinemia present with a history of recurrent infections. A detailed clinical history should emphasize the following:

• Family history
• Age of onset
• Site of infections
• Type of microorganisms
• Blood product reactions
• Recurrent infections
• Gastrointestinal symptoms
• Musculoskeletal symptoms
• Autoimmune and collagen vascular diseases

Physical findings may include the following:

• Growth retardation
• Abnormalities of lymphoid tissue and organs (eg, a paucity of tonsillar tissue, adenoids, and peripheral lymph nodes)
• Developmental abnormalities (eg, of skeleton or chest wall)
• Abnormalities of skin and mucous membranes (eg, scars, rash, or livedo reticularis)
• Ear, nose, and throat abnormalities (eg, tympanic membrane perforation, purulent nasal discharge, cobblestone pattern of pharyngeal mucosa, and nasal exudate)
• Pulmonary abnormalities (eg, bronchiectasis and lung fibrosis with rales, rhonchi, and wheezing)
• Cardiovascular abnormalities (eg, a loud pulmonic heart sound, right ventricular heave, and tricuspid regurgitation murmur suggesting pulmonary hypertension; jugular venous distention, tender hepatomegaly, and lower-extremity edema suggesting cor pulmonale)
• Neurologic abnormalities (eg, paralytic poliomyelitis or deep sensory loss with decreased vibratory and position sense of limb segments)

Diagnosis

Laboratory studies that may be helpful include the following:

• Serum immunoglobulin
• Antibody response after immunization
• Isohemagglutinins
• Peripheral blood lymphocyte immunophenotyping
• Evaluation of cellular immunity (cutaneous delayed-type hypersensitivity)
• Complete blood count
• Renal studies
• GI studies (eg, alpha ₁ -antitrypsin)

Imaging studies that may be useful include the following:

• Chest radiography
• High-resolution computed tomography (HRCT) and nuclear scanning

The following tests may be considered as circumstances warrant:

• Adenosine deaminase (ADA) levels and mutations in purine nucleoside phosphorylase
• Flow cytometry or Western blotting
• Restriction fragment length polymorphism (RFLP

Management

Replacement therapy with immunoglobulin G (IgG), administered intravenously (IVIG) or subcutaneously (SCIG), is the treatment of choice for most primary immunodeficiency syndromes, including the following:

• X-linked agammaglobulinemia (Bruton disease; XLA)
• CVID
• Severe combined immunodeficiency (SCID)
• Hyper-IgM
• ADA deficiency
• Wiskott-Aldrich syndrome (WAS)

Treatment of secondary hypogammaglobulinemia is directed at the underlying cause, as follows:

• IVIG is not indicated for lymphoproliferative disorders unless immunoglobulin levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions that may accompany these disorders
• Live vaccines should not be given to patients with T-cell disorders, XLA, or other severe B-cell disorders or to the family members of such patients
• High doses of IVIG or intrathecal immunoglobulin may be beneficial in patients with XLA who have enteroviral meningoencephalitis
• Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for SCID and, if a matched donor is available, for ADA deficiency ^[1]
• Enzyme replacement with polyethylene glycol-ADA (PEG-ADA) may be an effective alternative for patients with ADA deficiency who lack an HLA-identical sibling
• Tumor necrosis factor (TNF) inhibitors have been used to treat granulomatous diseases in patients with CVID
• Gene therapy has been shown to be successful in reconstituting immune function in infants with X-linked SCID, but efficacy is less proven in older children and young adult