APDS Features

Whatever their current symptoms, people with APDS have the potential to develop life-threatening complications, including malignancy, at any time, So early diagnosis and management is essential

Typical features of APDS

APDS is associated with a wide range of clinical manifestations.1,2

Recurrent respiratory tract infections are the first clinical manifestations of APDS in the majority (~65%) of patients; other common first presentations are organomegaly (~16%) and other infections (~11%).3 Respiratory infections typically occur in infancy or childhood, followed by bronchiectasis and autoimmunity in later childhood.3,4

Lymphoproliferation is a common clinical manifestation in APDS, being reported in 70.4% of patients at a median age of 3 years (range: 1-6 years).3 Lymphadenopathy has been found to be the most frequent manifestation (reported in ~58% of patients, and more common in APDS2 than in APDS1), followed by splenomegaly (~44%) and hepatomegaly (~24%, and almost three-times more frequent in APDS1 patients).3 Other benign lymphoid proliferations that have been reported in APDS patients include reactive hyperplasia and lymphadenitis in the gastrointestinal and respiratory tract (~25%, and more often in APDS 1), and tonsillar hypertrophy (~9%; more often in APDS2 patients).3

Lymphoma, often presenting by the late teens or early adulthood is one of the major complications of APDS, with diffuse large B cell lymphoma (DLBCL) being the predominant type.1 The cumulative risk of lymphoid malignancy is very high: it has been estimated to be 78% at the age of 40 years.2

As APDS was only recognised recently (2013), the majority of adults diagnosed with APDS suffered from recurrent infections in childhood that were not perceived to be severe enough to require further testing or investigation. The most common initial referrals for adults are to haematologists (due to lymphoproliferative symptoms leading to lymphoma).

 

  1. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606.
  2. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218.
  3. Jamee M, et al. Clin Rev Allergy Immunol. 2020;59:323-333.
  4. Michalovich D and Nejentsev S. Front Immunol. 2018;9:369.

APDS evolves over time and is likely to be underdiagnosed

Symptoms of APDS can vary, even among family members carrying the same genetic condition. While some APDS patients are asymptomatic, others present with severe, recurrent sinopulmonary infections; persistent, severe, or recurrent herpesvirus infections, particularly Epstein-Barr Virus (EBV) and cytomegalovirus (CMV); lymphadenopathy, hepatomegaly, splenomegaly, and/or nodular lymphoid hyperplasia; autoimmune cytopenias and autoinflammatory diseases; enteropathy; or lymphoma.

APDS is a progressive disease that can lead to end-organ damage and early mortality. Most commonly, manifestations begin in infancy with severe, recurrent sinopulmonary infections, while the lymphoproliferative and autoimmune disorders mentioned above often occur later in childhood.

Typical features of APDS

Children
  • Recurrent sinopulmonary infections
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Bronchiectasis
  • Hypogammaglobulinemia
  • High IgM, low IgG
  • Fever of unknown origin
  • Lymphoma-like presentation / Benign chronic lymphoproliferation
  • MAS-like presentation
  • Immune dysregulation (cytopenias, enteropathy, arthritis)
  • Diarrhoea
  • Malignancy
Adults
  • Recurrent sinopulmonary infections
  • Recurrent viral infections
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Bronchiectasis
  • Hypogammaglobulinemia
  • High IgM, low IgG
  • Benign chronic lymphoproliferation
  • Warts
  • Immune dysregulation (cytopenias, enteropathy, arthritis)
  • Autoinflammatory features and autoimmune phenomena combined
  • Diarrhoea
  • Malignancy

MAS: macrophage activation syndrome

People with APDS usually suffer from any two or more of the complications below:

Recurrent sinopulmonary infections are often severe and include upper respiratory tract infections, otitis media (which can progress to a permanent hearing loss), sinusitis, pneumonia, and bronchitis. These infections are typically the first disease manifestation and have been reported to appear as soon as early infancy. However, these are all characteristic of PIDs, so these symptoms alone cannot suggest a more specific diagnosis.

Lymphoproliferation including lymphadenopathy, splenomegaly, and/or hepatomegaly has been reported to affect 71-89% of patients with APDS, with organomegaly being the first clinical manifestation in 16% of patients. Lymphoproliferation may progress to malignancy; persistent or recalcitrant lymphoproliferation may suggest the need to evaluate for lymphoma. In the respiratory and gastrointestinal tracts, lymphoproliferation has been reported to appear in the form of mucosal nodular lymphoid hyperplasia in 24–36% of patients with APDS. Nodular lymphoid hyperplasia in the gastrointestinal tract has been reported to be associated with enteropathy in just over a quarter of patients with APDS. Onset of lymphoproliferation with lymphadenopathy and splenomegaly has been shown to begin at a median age of 3 years.2-5

Lung damage from infections, combined with lymphadenopathy and nodular mucosal hyperplasia, may progress to permanent end organ damage in the form of bronchiectasis. Onset has been reported to have occurred at around 11–13 years of age.2-6

Chronic diarrhoea, malabsorption, and colitis have been frequently observed in patients with APDS at around 5 years of age. Enteropathy may be associated with nodular mucosal hyperplasia in the gastrointestinal tract and failure to thrive.2,4,5

Both acute and chronic viral infections or reactivations have been observed, particularly Epstein-Barr virus (EBV) and Cytomegalovirus (CMV). EBV and CMV infections, including chronic viremia and disseminated infections, are the most severe and have been reported to occur in 24-30% and 15-17% of patients, respectively. Chronic EBV infection can also lead to lymphoma in patients with APDS. Herpes simplex virus (HSV) and varicella zoster virus (VZV) have also been seen in patients with APDS.2-5,7

Other complications of APDS

While cytopenias are the most common autoimmune diseases in APDS, other autoimmune and autoinflammatory conditions such as autoimmune thyroidosis, arthritis, glomerulonephritis, cirrhosis, sclerosing cholangitis, autoimmune hepatitis, diabetes, and eczema have been reported. Onset of autoimmunity has been reported to begin around 10.5 years of age.2-5

In patients with APDS, cytopenias may affect multiple blood lineages and include anaemia, thrombocytopenia, and leukopenia. Patients with APDS1 have been reported to be more frequently affected than patients with APDS2.2-5

In patients with APDS2 in particular, height and weight may be severely impaired. This inadequate growth may be associated with enteropathy.2,3,5

Lymphoma has been reported to have been the most common malignancy seen in patients with APDS and includes classical Hodgkin lymphomas as well as non-Hodgkin lymphomas such as diffuse large B cell lymphoma and marginal zone B cell lymphoma. The risk of lymphoma appears to be greater in patients with a history of viral infections, particularly EBV. Onset has been reported to occur at a median age of 18–23 years of age, and was the initial diagnosis for 21% of patients. Lymphoma may result in early mortality, and it has been calculated that 62% of APDS fatalities are due to lymphoma. Other malignancies such as leukaemias and solid organ malignancy may also affect patients with APDS, though less frequently than lymphoma. The cumulative risk for malignancy at 40 years of age is 78% for patients with APDS2.2-5,7

Neurodevelopmental delay and neuropsychiatric disorders observed in patients with APDS include global developmental delay, isolated speech delay, mild cognitive impairment, learning disabilities, autism, Asperger syndrome, anxiety, depression, and behavioural disorders.2-5,8 Neurodevelopmental delay has been reported in 10-19% of patients with APDS13,4,8 and 27-31% of patients with ASD2.3,5

  1. Lucas CL, et al. Nat Immunol. 2014;15(1):88-97.
  2. Maccari ME, et al. Front Immunol. 2018;9:543.
  3. Jamee M, et al. Clin Rev Allergy Immunol. 2020;59(3):323-333.
  4. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606.e4.
  5. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218.e9.
  6. Condliffe AM, Chandra A. Front Immunol. 2018;9:338.
  7. Carpier JM, Lucas CL. Front Immunol. 2018;8:2005.
  8. Wang Y, et al. J Clin Immunol. 2018;38(8):854-863.

Impact on patients’ quality of life

APDS can have a significant burden on quality of life.1-3 In particular, the frequent sinus and lung infections that lead to the development of bronchiectasis have ensuing implications for the patients’ prognosis and quality of life.4-6

In addition to the physical impacts of disease, hospitalisations and surgical interventions are common, polypharmacy is often necessary to manage symptoms, and patients see multiple doctors throughout both the diagnosis and management stages.1 These factors can cause patients to miss school, work, or social activities, and cause anxiety, depression and stress.7-9 Fatigue is also common among patients with primary immunodeficiencies such as APDS and can negatively impact quality of life.7-10

APDS is also likely to have a negative psychological impact on patients. In a recent study of 293 adult patients with PIDs and age-matched control subjects, the 4-Dimensional Symptom Questionnaire (4-DSQ) was used to assess the psychological impact of their condition. The 4-DSQ is a self-reported questionnaire which measures four symptom dimensions: distress, depression, anxiety, and somatisation, across 50 subitems. The proportions of PID patients reporting moderate or high levels for each dimension (33.9% distress, 18.9% depression, 22.4% anxiety, and 36.2% somatisation) were significantly higher than those of the control subjects (16.3% distress, 5.7% depression, 8.0% anxiety, and 11.2% somatisation).11 This illustrates that PID patients are at increased risk of several mental health difficulties, including fear of infections, social isolation, maladaptation to illness, and concerns over the future impact of their illness.11

  1. Maccari ME, et al. Front Immunol. 2018;9:543.
  2. Tessarin G, et al. J Clin Med. 2020;9(10):3335.
  3. Ewertowska M, et al. Allergy Asthma Clin Immunol. 2020;16:22.
  4. Coulter TI, et al. J Allergy Clin Immunol. 2017;139:597-606.
  5. Elkaim E, et al. J Allergy Clin Immunol. 2016;138:210-218.
  6. Lougaris V, et al. Pediatr Allergy Immunol. 2022 Jan;33 Suppl 27:69-72.
  7. Rider NL, et al. J ClinImmunol. 2017;37(5):461-475.
  8. Jiang F, et al. Allergy Asthma Clin Immunol. 2015;11:27.
  9. Kuburovic NB, et al. Patient Prefer Adherence. 2014;8:323-330.
  10. Hajjar J, et al. J Clin Immunol. 2017;37(2):153-165.
  11. Manusama OR et al. [Published online ahead of print, 2022 Jan 19]. J Clin Immunol. 2022;10.1007/s10875-022-01207-7.

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

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