Management of APDS is primarily focused on the treatment of symptoms.

This involves a range of different therapy types including immunosuppresive therapies, prophylactic antimicrobials, and sometimes surgical interventions. These approaches are needed to manage the immune deficiency and immune dysregulation aspects of APDS.1,2

Current treatment options for APDS


Use of antimicrobial prophylaxis is reported in 61-79% of patients, with antibiotics being the most common treatments;2-4 antifungal use has been reported in 6-12% of patients,2,3 and antiviral use in 11%.3

Antimicrobial prophylaxis may only address a small subset of APDS disease manifestations, and IRT may also be required to reduce infections for most patients.3-6 Furthermore, antimicrobial prophylaxis does not address the immune dysregulation aspects of APDS such as lymphoproliferation.7

APDS patients often require antimicrobial prophylaxis in combination with immunoglobulin replacement therapy (IRT) to reduce infection burden.3-6

Physician inspects neck muscles of a female patient during a check-up visit to a clinic.

Immunoglobulin Replacement Therapy (IRT)

IRT can be used to address sinopulmonary infections or autoimmune cytopenias and its use has been reported in 63-89% of patients with APDS,2-4,6,8 starting at a reported median age of 5 years (range: 1-35 years),4 with nearly half of patients receiving treatment by age 10 years.2

IRT administered intravenously (IVIg) or subcutaneously (SCIg),9 often in combination with antibiotics,1 has been shown to reduce respiratory tract infections in many patients.9 However, IRT does not seem to be effective at preventing herpesvirus infections or addressing the immune dysregulation aspects of APDS such as lymphoproliferation, autoimmune/inflammatory complications or lymphoma.9 Furthermore, bronchiectasis has continued to progress in some APDS patients despite IRT.1,9

Almost 50% of APDS patients receive IRT by the age of 10 years.2

A waist-up shot of a male child and his dad washing and drying mugs in the sink together at home.


Corticosteroids target immune dysregulation by inhibiting leukocyte activity and proliferation,2,10 and may reduce lymphoproliferation and cytopenias;4,8,9 46% of patients with APDS are reported to have received corticosteroids, with 87% showing at least partial short-term benefit.2 Prolonged corticosteroid use is associated with long-term toxicity that may cause osteoporosis, diabetes, hyperlipidemia, hypertension and/or ophthalmologic and dermatologic issues.10 Long-term corticosteroid use also increases the susceptibility to infections.10

More than 4 in 5 APDS patients who receive corticosteroid treatment show some short-term benefit.2


Rituximab targets CD20+ B cells for destruction and therefore may reduce B cell overactivation.11 Rituximab has been used to treat lymphoma and autoimmune diseases, both of which are prevalent in patients with APDS.7,9,12 Its use in patients with APDS may be complicated by sustained B cell lymphopenia;9 furthermore, it does not address the inherent immune deficiency13 and can increase the risk of severe infection-a risk that may be mitigated to some extent by initiating or continuing IRT.13

Rituximab can be effective at treating symptoms of immune dysregulation in APDS patients, but may increase the risk of severe infection.7,9,12,13

Mammalian target of rapamycin (mTOR) inhibitors

mTOR, one of the downstream targets of PI3K signalling, has a significant role in the regulation of immune responses.14 mTOR inhibitors such as sirolimus (rapamycin) or everolimus reduce mTOR hyperactivation downstream of PI3Kδ, and ameliorate the severity of non-neoplastic lymphoproliferative disease.14,15 Between 11-38% of patients with APDS have been reported to receive mTOR inhibitors,2,3,12,16 with T cell phenotypes restored to normal ranges in some cases.16 For example, sirolimus treatment decreased CD57+ T cells and increased the proportion of naïve T cells.16

In some cases, mTOR inhibition has been reported to be effective in treating multiple manifestations of APDS, such as lymphoproliferation (lymphadenopathy and hepatosplenomegaly), frequency and severity of infections and bronchiectasis progression (in one case).16 In some patients it has also resulted in steroid-sparing or IRT reduction.16,17

mTOR inhibitors may not be effective for some symptoms of APDS such as enteropathy and cytopenias.14 Assessment of 26 patients in the ESID APDS Registry found that 62% had only a moderate-to-poor response to sirolimus on the physician visual analog score.2 For example, mTOR inhibitor therapy may be difficult to implement and maintain due to dosing, adverse event and compliance challenges.2,3,17-19 In particular, the narrow therapeutic index of mTOR inhibitors may impact dosing, particularly in children,18,19 and adverse events such as headaches, anorexia, mouth ulcers and renal or liver toxicity have led to cessation of therapy.3,17

Haematopoietic stem cell transplant

Haematopoietic stem cell transplant (HSCT) has been used to treat a small proportion (9-17%) of patients with APDS1/2; while HSCT has the potential to resolve the clinical symptoms of APDS, it is associated with a relatively high risk of post-transplant morbidity and mortality.2,3,4,6,8,20-22 Patients with APDS who receive HSCT have a high risk of engraftment failure and unplanned donor cell infusions. Adverse outcomes are frequent and serious and include multiple transplants, graft-versus-host disease, organ toxicity, severe infectious complications, and mortality.6,21,22

Haematopoietic stem cell transplant (HSCT) may be curative but has associated risks.

A young female patient looking down and listening.

91% of patients with APDS experienced adverse events during/after HSCT.21,22

Barriers to improving the success rates of HSCT include high risk of graft instability, significant comorbidities, and poorly controlled infections, autoimmunity, and lymphoproliferation pre-HSCT.23

While phenotype reversal has been shown in 96% of engrafted APDS patients, some patients continued to be vulnerable to renal complications post-HSCT, despite 100% donor chimerism.23 In a small number of patients with mixed chimerism (seen in 17% of engrafted cases), disease manifestations including viral infections persisted for 2 years after engraftment.23

Careful longer-term follow-up of graft stability, late toxicities, immune reconstitution, and phenotype reversal is needed to establish the optimal timing and approach of HSCT for patients with APDS.23

An international retrospective case series study investigated the clinical outcomes of 57 patients with APDS1/2 (median age, 13 years; range, 2–66 years) who underwent HSCT. Regimen-related and infectious post-HSCT complications included: transplant-related mortality, mostly due to infection, 14% (8/57) of patients; acute graft-versus-host disease (GVHD), 39% (22/57); chronic GVHD, 16% (9/57); and various organ toxicities and infectious complications.9

Managing the adult journey

Most adult APDS patients will have suffered from recurrent infections during childhood and common variable immunodeficiency is a common initial diagnosis.1 When diagnosed as adults, family planning becomes an important consideration, with the need for immediate counselling.24 Outcomes with HSCT are generally better in younger APDS patients, so for adult patients, alternative therapies such as sirolimus may be more attractive options.1

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