Diagnosing APDS

The only way to definitively diagnose APDS is through genetic testing1,2

  1. Rotz SJ, et al. [published correction appears in Pediatr Blood Cancer. 2019 Apr;66(4):e27581]. Pediatr Blood Cancer. 2018;65(10):e27260.
  2. Chinn IK, et al. J Allergy Clin Immunol. 2020; 145(1):46-69.

APDS is inherited in an autosomal dominant manner, meaning that a person needs a pathological variant from only one parent to have it themselves,1-4 although studies in one large cohort suggests that around 20% of APDS patients may have de novo variants.5 Even within families, APDS may be difficult to trace due to the wide variety of clinical manifestations.

The heterogeneity of APDS symptomology frequently results in numerous referrals, with some patients seeing up to 6 different specialists over a period of 7-8 years on average, while receiving various symptomatic treatments, before diagnosis.

The presence of a combination of clinical symptoms and laboratory features, as follows, would make a possible diagnosis of APDS more likely6,7:

Reducing the time to diagnosis for APDS increases the chances of preventing further manifestation of the symptoms.

  1. Lucas CL, et al. Nat Immunol. 2014;15(1):88-97. doi:10.1038/ni.2771.
  2. Angulo I, et al. Science.2013;342(6160):866-871.
  3. Lucas CL, et al. J Exp Med. 2014;211(13):2537-2547.
  4. Deau MC, et al. [published correction appears in J Clin Invest. 2015 Apr;125(4):1764-5]. J Clin Invest. 2014;124(9):3923-3928..
  5. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218.e9.
  6. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606.e4.
  7. Asano T, et al. Front Immunol. 2018;9:568.

Typical clinical features of APDS

Children1
  • ≥4 new ear infections within 1 year
  • ≥2 serious sinus infections within 1 year
  • ≥2 months on antibiotics with little effect
  • ≥2 pneumonias within 1 year
  • Failure of an infant to gain weight or grow normally
  • Recurrent, deep skin or organ abscesses
  • Persistent thrush in mouth or fungal infection on skin
  • Need for IV antibiotics to clear infection
  • ≥2 deep-seated infections including septicemia
  • Family history of PI
Adults2
  • ≥2 new ear infections within 1 year
  • ≥2 new sinus infections within 1 year, in the absence of allergy
  • 1 pneumonia per year for ≥1 years
  • Chronic diarrhea and weight loss
  • Recurrent viral infections (colds, herpes, warts, condyloma)
  • Recurrent need for IV antibiotics to clear infections
  • Recurrent, deep abscesses of the skin or internal organs
  • Persistent thrush or fungal infection on skin or elsewhere
  • Infection with normally harmless tuberculosis-like bacteria
  • Family history of PI
  1. Jeffrey Modell Foundation. Ten warning signs of primary immunodeficiency. http://downloads.info4pi.org/pdfs/JMF_10Signs_Generic_082421_v2.pdf. Accessed October 29, 2021.
  2. Jeffrey Modell Foundation. Ten warning signs of primary immunodeficiency for adults. http://downloads.info4pi.org/pdfs/JMF_10Signs_Adult_Poster_082421_v2.pdf. Accessed October 29, 2021

Laboratory tests for suspected PI/APDS

Laboratory test Typical APDS findings

Complete blood count with differential

  • Depending on the individual presentation, several values may or may not be outside the normal range,1,2 for example:
    • RBCs will not be low unless the patient has cytopenias
    • WBC levels may vary based on the presence of infection, though lymphopenia is common
  • While CBC may indicate conditions such as anaemia, it does not indicate the cause

Ig levels

  • High IgM levels: reflective of increased transitional B cells3,4
  • Low to normal IgG and/or IgA levels: reflective of defects in memory B cell class-switching3,4
  • Low to normal concentrations of IgG and IgA4,5
  • Normal or elevated concentration of IgM4,5

Vaccine challenge

  • Many patients have a reduced response3

Flow cytometry

  • T and B cell phenotypes are often altered3,4
  • Distinguishing findings may include:
  • Increased transitional B cells (CD19+, CD38+)3-5
  • Reduced B cells4,5
  • Increased TFH cells (CD4+, CXCR5+, PD1+)3,4
  • Reduced naive T cells (CD4+ CD8+)4,5
  • Reversed CD4/CD8 ratio4,5
  • Reduced CD4+ T cells4,5
  1. Ahmed AA, et al. Allergol Immunopathol (Madr). 2020;48(6):686-693.
  2. Ewertowska M, et al. Allergy Asthma Clin Immunol. 2020;16:22.
  3. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606.
  4. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218.
  5. Angulo I, et al. Science.2013;342(6160):866-871.

APDS diagnosis for haematologists & oncologists

Haematologists/oncologists may encounter patients with primary immunodeficiencies like APDS with the following manifestations:

Lymphoproliferation1,2

Autoimmune cytopenias1,2

Malignancy (primarily lymphoma)1,2

Genetic screening should be considered for these patients. In addition, patients with the following should raise clinical suspicion and be referred for genetic testing for APDS:

Patients with APDS can be misdiagnosed with autoimmune lymphoproliferative syndrome (ALPS) as lymphadenopathy, splenomegaly, cytopenias and lymphoma are common manifestations of both conditions.5,6 Patients with probable but not definitive ALPS should be referred for genetic testing to confirm the diagnosis.

  1. Lucas CL, et al. Nat Immunol. 2014;15(1):88-97.
  2. Angulo I, et al. Science.2013;342(6160):866-871.
  3. Maccari M, et al. Front Immunol. 2018;9:543.
  4. Fischer A, et al. J Allergy Clin Immunol. 2017;140(5):1388-1393.e8.
  5. Kulm E, et al. Oral abstract presented at: 62nd Annual ASH Meeting; December 5-8, 2020.
  6. Rao VK, Oliveira JB. Blood. 2011;118(22):5741-5751.

Genetic testing is the only way to diagnose APDS; existing CVID patients should be screened for APDS

As genetic testing is the only way to definitively diagnose APDS,1,2 people with at least two of the following complications should be considered for genetic testing:3,4

  1. Rotz SJ, et al. [published correction appears in Pediatr Blood Cancer. 2019 Apr;66(4):e27581]. Pediatr Blood Cancer. 2018;65(10):e27260.
  2. Chinn IK, et al. J Allergy Clin Immunol. 2020; 145(1):46-69.
  3. Coulter TI, et al. J AllergyClin Immunol. 2017;139(2):597-606.e4.
  4. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218.e9.

Genetic testing may lead to targeted therapies
Genetic testing of patients with haematological manifestations may reveal underlying primary immunodeficiencies that have treatment options specific to the particular gene identified.1-5 In a study of 80 patients with paediatric Evans syndrome, 40% were discovered to have variants in genes involved with primary immunodeficiency, of which 29 patients were identified with variants that have targeted treatment options.1 Even for patients with PIDs without dedicated therapies, a specific diagnosis provides HCPs with guidance on the potential development of manifestations and allows prospective monitoring for these, such as assessments for enteropathy and malignancy. Genetic diagnosis also allows patients access to specific monogenetic support groups, so they can be part of a community of people who share exactly the same condition. Furthermore, patients can receive appropriate family planning counselling, allowing arrangements to be made as required.1-5

  1. Hadjadj J, et al. Blood. 2019;134(1):9-21.
  2. Jamee M, et al. Clin Rev Allergy Immunol. 2020;59(3):323-333.
  3. Mayor PC, et al. J Allergy Clin Immunol. 2018;141(3):1028-1035.
  4. Shapiro RS. Am J Hematol. 2011;86(1):48-55.
  5. Rotz SJ, et al. [published correction appears in Pediatr Blood Cancer. 2019 Apr;66(4):e27581]. Pediatr Blood Cancer. 2018;65(10):e27260.

The importance of family testing

APDS is inherited in an autosomal dominant manner.1-5 However, de novo variants have also been observed, and while the prevalence has not been fully assessed, a large cohort suggests that around 20% of patients may have de novo variants.

As nearly half (40%) of patients diagnosed with APDS have a family history of PI,6 a careful family history may be especially useful in diagnosis;5,6 however, symptoms frequently do not present in the same manner within a family.7

As there is a 50% of chance of APDS being passed from parent to child, family members of patients with APDS should also be genetically tested.4

  1. Sánchez-Ramón S, et al. Front Immunol. 2019;10:586.
  2. Kulm E et al. Oral poster presented at 62nd ASH Annual Meeting; Dec 5-8, 2020.
  3. Rao VK, Oliveira JB. Blood. 2011;118(22):5741-5751.
  4. Chinn IK, et al. J Allergy Clin Immunol. 2020;145(1):46-69.
  5. Lucas CL, et al. Nat Immunol. 2014;15(1):88-97.
  6. Jamee M, et al. Clin Rev Allergy Immunol. 2020;59(3):323-333.
  7. Genetic Alliance; The New York-Mid-Atlantic Consortium for Genetic and Newborn Screening Services. Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals. Washington, DC: Genetic Alliance; July 8, 2009.

APD-INT-2022-0039    Date of preparation: July 2022

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