Last reviewed: 19 Sep 2021
Last updated: 14 Sep 2021



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
  • diarrhoea
  • sinusitis
  • pallor
  • tympanic membrane perforation
  • illness after live vaccines
  • weight loss, night sweats, fevers
  • oedema
  • alopecia, goitre, vitiligo
  • eczema
  • small/absent tonsils
  • lymphadenopathy and hepatosplenomegaly
  • history of coeliac disease or transfusion reactions
  • muscle fatigability, ptosis, diplopia (if thymoma present)
  • dysmorphic features
  • neurological involvement

Risk factors

  • male sex
  • positive family history of primary immunodeficiency
  • severe protein-losing state
  • haematological malignancy
  • anticonvulsant and immunosuppressive drugs

Diagnostic investigations

1st investigations to order

  • FBC
  • serum IgG
  • serum IgA
  • serum IgM
  • serum and urine electrophoresis
  • serum free light chains
  • urine dipstick
  • serum creatinine
  • serum albumin
  • LFTs
  • 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

Treatment algorithm



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.

Peer reviewers

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

Immunology Institute

Mount Sinai School of Medicine

New York



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.

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