Hypogammaglobulinaemia can be primary (congenital) or secondary. It can present in childhood and in adults, and can affect both sexes.
Primary hypogammaglobulinaemia may have a delay of several years between clinical presentation and diagnosis. The most common cause is common variable immunodeficiency (CVID).
Causes of secondary hypogammaglobulinaemia include gastrointestinal losses (e.g., malabsorption/protein-losing enteropathy), nephrotic syndrome, haematological malignancy, and medication (e.g., immunosuppressives, such as corticosteroids and chemotherapy).
Patients can be predisposed to recurrent upper and lower respiratory tract infections.
Treatment is tailored to specific causes and the clinical presentation of each patient, and includes intravenous or subcutaneous immunoglobulin replacement.
Severe combined immunodeficiency (SCID) is a medical emergency and suspected cases require immediate specialist centre referral for diagnosis and treatment.
Hypogammaglobulinaemia is defined as reduced serum immunoglobulin (antibody) levels. This can be due to a variety of underlying primary/congenital intrinsic immune system defects (e.g., common variable immunodeficiency) or secondary immunodeficient states (e.g., medication-related, haematological malignancy, protein-losing diseases). The most commonly recognised clinical feature is recurrent infection.
History and exam
Key diagnostic factors
- presence of risk factors
- recurrent infection
- infection with Streptococcus pneumoniae or Haemophilus species
- infection with atypical pathogens
- repeated antibiotic use
- respiratory crackles, high-pitched inspiratory squeaks, rhonchi
Other diagnostic factors
- absence from school/work
- failure to thrive
- tympanic membrane perforation
- illness after live vaccines
- weight loss, night sweats, fevers
- alopecia, goitre, vitiligo
- small/absent tonsils
- lymphadenopathy and hepatosplenomegaly
- history of coeliac disease or transfusion reactions
- muscle fatigability, ptosis, diplopia (if thymoma present)
- dysmorphic features
- neurological involvement
- male sex
- positive family history of primary immunodeficiency
- severe protein-losing state
- haematological malignancy
- anticonvulsant and immunosuppressive drugs
1st investigations to order
- serum IgG
- serum IgA
- serum IgM
- serum and urine electrophoresis
- serum free light chains
- urine dipstick
- serum creatinine
- serum albumin
- sputum culture
- stool culture
- chest x-ray
Investigations to consider
- flow cytometry: lymphocyte subsets
- specific antimicrobial antibodies
- test immunisation response
- IgG subclasses
- flow cytometry: protein expression
- genetic testing
- enzyme assays
- abdominal ultrasound
- CT chest/sinuses
- CT abdomen
- pulmonary function test
- lymph node biopsy
- small- and large-bowel biopsy
- polymerase chain reaction (PCR) for viral infection
- hepatitis B surface antigen, hepatitis B and C PCR
Sara Barmettler, MD
Allergy and Clinical Immunology Unit
Division of Rheumatology, Allergy & Immunology
Massachusetts General Hospital
SB is an author of one reference cited in this topic. SB declares that she has no competing interests.
Dr Sara Barmettler would like to gratefully acknowledge Dr Mohammed Yousuf Karim, Dr Patrick Yong, and Dr Zoe Adhya, previous contributors to this topic.
MYK serves on the advisory board for Allergy Therapeutics. PY and ZA declare that they have no competing interests.
John B. Ziegler, MD
Associate Professor of Pediatrics
University of New South Wales
Department of Immunology and Infectious Diseases
Sydney Children's Hospital
JBZ declares that he has no competing interests.
Charlotte Cunningham-Rundles, MD, PhD
Professor of Medicine and Pediatrics
Mount Sinai School of Medicine
CCR is an author of several references cited in this topic.
David Webster, MD, FRCP, FRCPath
Honorary Clinical Scientist
UCL Centre for Primary Immunodeficiency
University College London Medical School
Department of Immunology
Royal Free Hospital
DW declares that he has no competing interests.
- Specific antibody deficiency
- Complement deficiency
- Criteria for the clinical use of intravenous immunoglobulin in Australia
- Update on the use of immunoglobulin in human disease: a review of evidence
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