History and exam
Key diagnostic factors
common
recurrent infection
Two or more of the following clinical features: ≥8 new ear infections in 1 year; ≥2 serious sinus infections in 1 year; ≥2 deep-seated infections; persistent thrush after 1 year of age; recurrent deep skin or organ abscesses; ≥2 pneumonias within 1 year.
Infections in infancy (especially Pneumocystis jirovecii, respiratory syncytial virus, Candida, and bacteria) suggest severe combined immunodeficiency.
Patients with thymoma-associated hypogammaglobulinemia have reported recurrent bacterial, viral, fungal, and Pneumocystis infections.
infection with Streptococcus pneumoniae or Haemophilus species
Common bacterial pathogens include encapsulated bacteria (e.g., S pneumoniae, H influenzae) and nonencapsulated Haemophilus.
infection with atypical pathogens
Common atypical pathogens include mycoplasma.
repeated antibiotic use
Indicator of severity and frequency of infections.
respiratory crackles, high-pitched inspiratory squeaks, rhonchi
Lung auscultation may reveal evidence of bronchiectasis (chronic damage resulting from recurrent pulmonary infection).
Other diagnostic factors
common
absence from school/work
Indicator of severity and frequency of infections.
failure to thrive
Nonspecific indicator of possible serious illness in childhood.
diarrhea
Present with many primary immunodeficiencies, but also may occur in other bowel diseases that cause intestinal protein loss.
pallor
Anemia is common.
tympanic membrane perforation
Otoscopy may reveal chronic damage resulting from recurrent ear infection.
uncommon
illness after live vaccines
Indicator of possible immunodeficiency.
weight loss, night sweats, fevers
May indicate hematologic malignancy.
edema
Indicates protein loss (e.g., from nephrotic syndrome).
alopecia, goiter, vitiligo
May indicate presence of autoimmune disease (common in some primary immunodeficiencies such as common variable immunodeficiency and IgA deficiency).
eczema
May be seen in Wiskott-Aldrich syndrome, hyper-IgE syndrome, and some forms of severe combined immunodeficiency.
small/absent tonsils
Seen in Bruton disease (X-linked agammaglobulinemia).
lymphadenopathy and hepatosplenomegaly
Can be related to the hypogammaglobulinemia itself or to hematologic illness.
history of celiac disease or transfusion reactions
IgA deficiency is associated with increased risk of celiac disease and risk of transfusion reactions from anti-IgA antibodies.
muscle fatigability, ptosis, diplopia (if thymoma present)
Thymoma-associated hypogammaglobulinemia may present with features of myasthenia gravis.
dysmorphic features
May be seen in some rare syndromes.
neurologic involvement
May occur in ataxia-telangiectasia.
Risk factors
strong
male sex
Some primary immunodeficiencies are X-linked (e.g., X-linked agammaglobulinemia/Bruton disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome).
positive family history of primary immunodeficiency
Primary hypogammaglobulinemia usually presents in children or young adults, and rarely presents in older people. Many primary immunodeficiencies have known genetic defects, which may run in families or arise de novo. X-linked conditions may be passed on to boys from carrier mothers. IgA and IgG subclass deficiency can occur in relatives of patients with common variable immunodeficiency, but the inheritance pattern is not clearly defined. Severe combined immunodeficiency can be due to several different genetic defects and can be autosomal recessive or X-linked. Immunoglobulin class-switching disorders can be autosomal or X-linked. X-linked agammaglobulinemia often occurs in male children with a family history. Consanguinity predisposes to autosomal-recessive disorders.
severe protein-losing state
Inflammatory bowel disease, autoimmune enteropathy, and intestinal lymphangiectasia can cause hypogammaglobulinemia due to loss of protein. Renal protein loss in nephrotic syndrome can be associated with hypogammaglobulinemia and susceptibility to pneumococcal and other streptococcal infections. IgG is typically lost first (having the lowest molecular weight), and IgM is lost last (and only in extremely severe disease).
hematologic malignancy
Myeloma causes clonal proliferation of plasma cells and paraprotein formation, which leads to immunoparesis with suppression of normal immunoglobulin production. Leukemia, especially chronic lymphocytic leukemia, is associated with impaired immunoglobulin production and function. Lymphoma may be associated with hypo- or hypergammaglobulinemia; specific antibody responses may be impaired. Hypogammaglobulinemia secondary to hematologic malignancy (e.g., myeloma, chronic lymphocytic leukemia) is more common in older people (ages >50 years).
anticonvulsant and immunosuppressive drugs
Drugs associated with low immunoglobulin levels include rituximab, antimalarials, phenytoin, carbamazepine, systemic corticosteroids, and disease-modifying antirheumatic drugs (e.g., sulfasalazine, penicillamine, azathioprine, cyclophosphamide). Hypogammaglobulinemia is usually a rare consequence of these drugs, but it is increasingly being recognized as a consequence of rituximab, usually after multiple rather than single doses.[20][21][22][23]
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