Diagnosis of APDS

This post describes how to diagnose APDS, and immunological lab results that should raise concern.

The clinical laboratory phenotype of patients identified to date with the E1021K mutation and APDS phenotype is distinctive in both children and adults and may be easily identified using standard diagnostics available in Primary Immunodeficiency Centres. Overall there is picture of altered humoral and cellular immunity although the serological profile may be more subtle than is seen in known humoral immune defects such as X-Linked Agammaglobulinaemia or Common Variable Immunodeficiency and is more similar to that reported in Hyper IgM Syndromes.

Immunoglobulin isotypes may show an increase in IgM and reduction in IgG2 with a normal or low total IgG. Vaccine responses may be suboptimal, however the profile is variable with some patients demonstrating normal vaccination responses particularly to protein antigens. As with other humoral immune deficiencies, suboptimal response pneumococcal vaccines (both plain polysaccharide and conjugate vaccine) is more consistently impaired. Lymphopaenia affecting both T and B cell subsets is seen in some patients. Extended lymphocyte profiling has however provided the most distinctive signature. Using the Euroclass B cell profiling panel (Wehr et al. 2008), there is trend for reduced number of class switched (IgM-CD27+) and IgM memory (IgM+CD27+) B cells and a dramatic expansion of cells of Transitional phenotype (CD38high, IgMhigh) with numbers reaching up to 90% of the circulating B cell population. T cell profiling is also distinctive. Whilst absolute T cell counts may be normal, a marked expansion of cells of CD25-CD45RA-/CD127- phenotype (consistent with effector memory T cells) in both CD4 and CD8 compartments is seen. This is a population that has best been described in the context of chronic HIV infection and is thought to represent chronic immune activation. A summary of routine investigations that may help in the diagnosis of APDS is given in the table below:

Immunology findings

Serum IgGNormal or reduced
Serum IgANormal
Serum IgMIncreased
Serum IgG2Reduced
Vaccine responses to Streptococcus pneumoniaNormal or reduced
Vaccine responses to Haemophilus influenzaeNormal or reduced
Vaccine responses to TetanusNormal or reduced
CD19+IgM+CD27+ B cellsNormal or reduced
CD19+IgM-CD27- B cellsNormal or reduced
CD19+IgM+CD38+ B cellsSignificantly increased
CD3+CD4+CD25-CD127- Helper T cellsIncreased
CD3+CD4+CD25-CD45RA- Helper T cellsIncreased
CD3+CD8+CD25-CD127- cytotoxic T cellsSignificantly increased
CD3+CD8+CD25-CD45RA- cytotoxic T cellsSignificantly increased

Clinical features

A detailed account of the clinical features of APDS

The majority of patients with APDS present with recurrent respiratory infections from early infancy or childhood. Lower respiratory tract infections, otitis media and sinusitis are the commonest manifestations, usually secondary to encapsulated bacterial pathogens, particularly Haemophilus influenzae and Streptococcus pneumoniae. These infections are often severe and lead to progressive end-organ damage, particularly bronchiectasis and hearing loss. For this reason, prompt and vigorous treatment of these infections is recommended to prevent or limit such damage. Other bacterial infections have included cellulitis and abscess formation (usually secondary to Staphylococcus aureus), but these are less common. Many patients also suffer recurrent viral infections, with several incidences of severe systemic disease caused by Herpes group viruses (including HSV and VZV pneumonitis, EBV colitis and disseminated CMV). Several patients have also had less severe but frequent problems with recurrent adenovirus or Coxsackie virus infections (particularly respiratory infections and conjunctivitis).

Splenomegaly, lymphadenopathy (particularly cervical and mediastinal) and hepatomegaly are also often (but not always) noted on clinical or radiological examination of these patients; in several cases splenomegaly has been noted before the onset of recurrent infections. Histopathology of lymph nodes, when available, has suggested a picture of reactive hyperplasia consistent with immune deficiency. Importantly, and in keeping with the known signalling role of PI3K in malignant disease, there seems to be an increased incidence of lymphoproliferative disease in this patient cohort. There may also be a risk of autoimmune disease, with 2 cases to date of haemolytic anaemia and one of immune complex glomerulonephritis noted to date. Several patients have been noted to have developmental delay, although this may be secondary to recurrent infections; intriguingly, some patients have exhibited developmental abnormalities including short stature due to growth hormone deficiency (2 patients), micro-ophthalmia (1 patient) and abnormal dentition (1 patient) – the significance of these findings is currently unclear.

It is important to note that the family history may be of major importance – several (but not all) of these patients have affected relatives or a family history of early death from infection-related causes. Likewise, there is a spectrum of severity, and some individuals with relatively mild disease have been identified because of their relationship to more severely affected patients, and it may be that at present we are seeing just the tip of the APDS iceberg.

Genetic testing for APDS

How to arrange genetic testing for patients with APDS

APDS is caused by a rare point mutation in the PIK3CD gene. If you think that your patient has clinical presentation that resembles APDS, sequence analysis would be advisable. We can help you to arrange it.

If you have a collection of samples from a cohort of patients with relevant phenotypes, we could help you to screen these samples for the mutation that causes APDS.

Contact details:

Sergey Nejentsev MD, PhD
Department of Medicine, University of Cambridge
Level 5, Addenbrooke’s Hospital
Hills Road
Cambridge
CB2 0QQ
UK
E-mail: sn262@cam.ac.uk

Learn about APDS

An overview of APDS for clinicians who would like to learn more about the disease

Learn about APDS

Overview

Activated PI3 Kinase Delta Syndrome (APDS) is a newly discovered cause of Primary Immunodeficiency (PID) and Hyper-IgM Syndrome. Clinicians and scientists working on exome sequencing patients with primary immunodeficiency in Cambridge, United Kingdom, observed the same missense mutation in a critical signalling kinase that is particularly highly expressed in immune cells termed PI3 kinase delta. On further testing, this mutation has been shown to be absent from over 4,000 healthy control subjects’ genomes as well as unaffected first degree relatives of affected patients, indicating that this mutation is causative of these subjects’ immunodeficiency. One subject has been identified with an apparent spontaneous mutation causing APDS, indicating that a history of inherited immunodeficiency is not absolutely required for a patient to have APDS.

To date, 17 subjects have been identified as carrying the APDS mutation out of a total of ~240 screened genomes from PID patients. Thus, although rare in the general population APDS is reasonably common among patients with PID.

Clinical features

APDS is a clinically heterogenous condition with variable penetrance among affected individuals. The most common manifestation is susceptibility to recurrent infections with Streptococcus pneumoniae and Haemophilus influenzae, particularly of the ear, sinuses and lungs. Other common features include a rise in circulating IgM, a reduction in IgG2, and lymphopaenia. Many patients also have splenomegaly. A more detailed description of the symptoms and signs seen in APDS is described here.

Diagnosing APDS

At present, and for the foreseeable future, the only way to definitively diagnose APDS is with genetic testing. APDS is never a clinical diagnosis; genotyping the PIK3CD gene is mandatory to prove or exclude the diagnosis. Patients who should be considered for screening include:

  1. Any patient with Primary Immunodeficiency;
  2. Any patient with Hyper-IgM syndrome;
  3. First degree relatives of patients with proven APDS.

Contact details to arrange genetic testing of patients who fulfil one of these criteria can be found here.

Management of APDS

Until now, patients with APDS have been treated with standard regimes used in PID. Many patients (but not all) have received treatment with regular IVIG. Prompt and aggressive management of intercurrent infection with anti-microbials is mandatory. One subject with particularly penetrant and severe disease received a bone marrow transplant at the age of eight, following which his condition markedly improved – however, APDS comprises a spectrum of clinical severity, and not all patients have disease severe enough to justify bone marrow transplantation. More details about the treatment of APDS can be found here.

Future developments

Now that the underlying mutation in APDS has been described and cheap and rapid genotyping is available for other subjects, it may be possible to conduct clinical trials of treatments that interfere in a targetted fashion with the overactive kinase in these patients. Although certain small molecule inhibitors of PI3K-delta would not be an appropriate treatment for patients with PID in general, patients with APDS may represent a subset in whom these treatments may have particular efficacy.