History and exam
Key diagnostic factors
common
presence of risk factors
Primary disease commonly occurs in young people and secondary disease commonly occurs in older people. X-linked primary immunodeficiencies affect males. Many primary immunodeficiencies have known genetic defects, which may run in families or arise de novo. History of severe protein-losing state, haematological malignancy, or use of anticonvulsant/immunosuppressive drugs may result in hypogammaglobulinaemia.
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 hypogammaglobulinaemia 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 non-encapsulated 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
Non-specific indicator of possible serious illness in childhood.
diarrhoea
Present with many primary immunodeficiencies, but also may occur in other bowel diseases that cause intestinal protein loss.
pallor
Anaemia 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 haematological malignancy.
oedema
Indicates protein loss (e.g., from nephrotic syndrome).
alopecia, goitre, 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's disease (X-linked agammaglobulinaemia).
lymphadenopathy and hepatosplenomegaly
Can be related to the hypogammaglobulinaemia itself or to haematological illness.
history of coeliac disease or transfusion reactions
IgA deficiency is associated with increased risk of coeliac disease and risk of transfusion reactions from anti-IgA antibodies.
muscle fatigability, ptosis, diplopia (if thymoma present)
Thymoma-associated hypogammaglobulinaemia may present with features of myasthenia gravis.
dysmorphic features
May be seen in some rare syndromes.
neurological involvement
May occur in ataxia-telangiectasia.
Risk factors
strong
male sex
Some primary immunodeficiencies are X-linked (e.g., X-linked agammaglobulinaemia/Bruton's disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome).
positive family history of primary immunodeficiency
Primary hypogammaglobulinaemia 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 agammaglobulinaemia 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 hypogammaglobulinaemia due to loss of protein. Renal protein loss in nephrotic syndrome can be associated with hypogammaglobulinaemia 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).
haematological malignancy
Myeloma causes clonal proliferation of plasma cells and paraprotein formation, which leads to immunoparesis with suppression of normal immunoglobulin production. Leukaemia, especially chronic lymphocytic leukaemia, is associated with impaired immunoglobulin production and function. Lymphoma may be associated with hypo- or hypergammaglobulinaemia; specific antibody responses may be impaired. Hypogammaglobulinaemia secondary to haematological malignancy (e.g., myeloma, chronic lymphocytic leukaemia) 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). Hypogammaglobulinaemia is usually a rare consequence of these drugs, but it is increasingly being recognised as a consequence of rituximab, usually after multiple rather than single doses.[22][23][24][25]
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