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.

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