Hypogammaglobulinemia

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 pneumoniae and Haemophilus influenzae infections).

Essential update: Rituximab increases incidence of hypogammaglobulinemia
In a retrospective study from Memorial Sloan-Kettering Cancer Center, Casulo et al examined the relation between rituximab and hypogammaglobulinemia in 211 patients with B-cell lymphoma who were treated with rituximab and assessed with serial quantitative serum immunoglobulin (SIgG) concentrations before and after treatment.[1] Of the 211 patients, 179 (85%) had normal SIgG values before rituximab therapy; after rituximab therapy, 39% of these 179 patients had hypogammaglobulinemia. The risk was greater in patients who received maintenance rituximab.[1]

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)
See Clinical Presentation for more detail.

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, alpha1 -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)
The following biopsy procedures may also be considered:

Lymph node biopsy (for rapidly enlarging lymph nodes to rule out infection or malignancy)
Rectal biopsy (for common variable immunodeficiency [CVID] and immunoglobulin A [IgA] deficiency)
Thymus biopsy (indicated only for thymoma)
See Workup for more detail.

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[2]
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 adults[3]