Hypogammaglobulinemia
Synonyms and keywords:

# Overview
Hypogammaglobulinemia is a type of primary immune deficiency disease. "Hypogammaglobulinemia" is largely synonymous with "agammaglobulinemia". When the latter term is used (as in "X-linked agammaglobulinemia") it implies that gamma globulins are not merely reduced, but completely absent. Modern assays have allowed most agammaglobulinemias to be more precisely defined as hypogammaglobulinemias,but the distinction is not usually clinically relevant. "Hypogammaglobulinemia" is distinguished from dysgammaglobulinemia, which is a reduction in some types of gamma globulins, but not others.

# Historical Perspective
- Dr. Robert A Good and March of dimes foundation maintained a close association for a quarter century in the fight against immunodeficiency diseases.
- Immunodeficiency diseases such as ataxia telangiectasia have been described as early as 1920's, wiskott aldrich's during 1930's.
- Between 1950-1965, primary immunodeficiencies affecting all major levels of immune system were first described.
- Use of immunoglobulins for the treatment of hypogammaglobulinemia was practised as early as 1950's.
- Therapeutic results in the use of human serum gamma globulins have been published during the late 1950's. 
- Treatment of various infectious diseases with the use of gamma globulins started during the late 1950's. Whooping cough was treated with placental immunoglobulin during the year 1959.

# Classification

# Pathophysiology
- Hypogammaglobulinemia may result from lack of production, excessive loss of immunoglobulins, or both.
- Congenital disorders affecting B-cell development can result in complete or partial absence of one or more Ig isotypes. 
- The classic form of this type of disorder is Bruton agammaglobulinemia, also known as X-linked agammaglobulinemia (XLA).
- Because B, T, and natural killer (NK) cells share a common progenitor, defects occurring at early developmental stages may result in combined immunodeficiency involving all cell types, although defects further down the differentiation pathways may result in deficiencies of a single cell type only.
- The symptoms depend on the type and severity of the Ig deficiency and the presence or deficiency of cellular immunity. In general, hypogammaglobulinemia results in recurrent infections with a restricted set of microorganisms primarily localized to the upper and lower airways, although bacteremia and GI infections can also occur. Patients with associated defects in cellular immunity usually present with opportunistic viral, fungal, or parasitic infections.

# Causes
Hypogammaglobulinemia is caused by:

# Differentiating  Hypogammaglobulinemia from Other Diseases
Hypogammaglobulinemia  must be differentiated from Bronchiectasis, complement deficiencies, and cystic fibrosis

# Epidemiology and Demographics
- The incidence of primary immunodeficiency is approximately 10 per 100,000 individuals worldwide.
- In children primary immunodeficiencies are more common in boys than in girls. Male to female ratio being 5:1
- There is no racial predilection to hypogammaglobulinemia
- Hypogammaglobulinemia affects men and women equally

# Risk Factors
Common risk factors in the development of hypogammaglobulinemia include:
- Family history of a primary immune deficiency disorder
- Medical therapy with drugs such as
Rituximab
Glucocorticoids
Gold
Penicillamine
- Rituximab
- Glucocorticoids
- Gold
- Penicillamine
- Bruton's agammaglobulinemia

# Screening
There is insufficient evidence to recommend routine screening for hypogammaglobulinemia.

# Natural History, Complications, and Prognosis
Common complications of  hypogammaglobulinemia include:
- Recurrent infections
- Growth retardation (in children)
- Autoimmune disorders
- Increased risk of cancer
- Death due to serious infections

# Diagnosis

## Diagnostic Study of Choice
There is no established diagnostic study of choice for the diagnosis of hypogammaglobulinemia.

## History and Symptoms
A clinical history of the following may be present:
- Granulomatous disease, enteropathy (celiac-like/inflammatory), and autoimmune cytopenia may suggest common variable immunodeficiency (CVID).
- Infections in infancy (especially Pneumocystis jirovecii, respiratory syncytial virus, Candida, and bacteria)
- X-linked agammaglobulinemia (XLA/Bruton disease)
- Transient hypogammaglobulinemia of infancy
- Celiac disease
- Thymoma
- Recurrent infections
- Secondary causes such as nephrotic syndrome, malabsorption/gastroenteropathy (e.g., intestinal lymphangiectasia), myeloma, leukemia, lymphoma, or malnutrition
- Medication history may reveal use of rituximab, carbamazepine, phenytoin, disease-modifying antirheumatic drugs, cytotoxic drugs, or immunosuppressive drugs).
- History of radiation therapy
Symptoms may include
- Failure to thrive in children
- Recurrent infections
- Shortness of breath
- Chronic cough from bronchiectasis
- Sinus pain and nasal discharge
- Diarrhea or steatorrhea
- Complications after receiving live vaccines

## Physical Examination
Common physical examination findings of hypogammaglobulinemia include :
- Growth retardation
- Paucity of tonsillar tissue
- Skin: rash, livedo reticularis
- Splenomegaly or hypersplenism in patients with common variable immunodeficiency
- Pulmonary: Rales, rhonchi and wheezing
- Cardiovascular examination: Chronic respiratory insufficiency can result in pulmonary hypertension and right heart failure.
- Extremities: Digital clubbing

## Laboratory Findings
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)

## Electrocardiogram
There are no ECG findings associated with hypogammaglobulinemia.

## X-ray
A chest x-ray may be helpful in the diagnosis of hypogammaglobulinemia. Findings on an x-ray  may be suggestive of
- Bronchiectasis
- Atelectasis
- Lung cysts
- Mediastinal lymphadenopathy
- Features of opportunistic infection e.g., P jiroveci pneumonia, aspergillus infection and aspergilloma

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound  findings associated with hypogammaglobulinemia.

## CT scan
HRCT may show bronchial wall thickening, features of bronchiectasis, lobar and/or segmental collapse, scars, interstitial lesions and lobular air-trapping. 

## MRI
There are no MRI findings associated with hypogammaglobulinemia

## Other Imaging Findings
There are no other imaging findings associated with hypogammaglobulinemia

## Other Diagnostic Studies
Other diagnostic studies for hypogammaglobulinemia include flow cytometry which demonstrates low levels of circulating memory B cells. Molecular analysis may also be used in some cases.

# Treatment

## Medical Therapy
Immune globulin therapy is the mainstay of treatment for a variety of primary immunodeficiency states. American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly established the "Practice parameter for the diagnosis and management of primary immunodeficiency."  

## Surgery
Surgical intervention is not recommended for the management of hypogammaglobulinemia

## Primary Prevention
There are no established measures for the primary prevention of hypogammaglobulinemia

## Secondary Prevention
There are no established measures for the secondary prevention of hypogammaglobulinemia. Antibiotics and anti-inflammatory medications can help.