Management of APDS is focused on 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 arms of APDS.1-4
Antimicrobial prophylaxis use is reported in 61-79% of patients, with antibiotics being the most common treatments;1-3 antifungal use has been reported in 6-12% patients,1 and antiviral use in 11%.1,3
Antimicrobial prophylaxis may only address a small subset of APDS disease manifestations, and IRT may also be required to reduce infections for most patients.1,2,4 Furthermore, antimicrobial prophylaxis does not address the immune dysregulation aspects of APDS such as lymphoproliferation.5
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,1-4 starting at a reported median age of 5 years of age (range, 1-35 years),3 with nearly nearly half of patients receiving treatment by age 10.1
Although immunoglobulins administered intravenously (IVIg) or subcutaneously (SCIg) may prevent infections by correcting secondary antibody deficiencies present in patients with APDS,2,3,5,7 they are not always successful individually or in combination.4 IRT does not prevent herpes virus infections;5,6 may not be effective for all sinopulmonary infections;6,7 does not stop the progression of bronchiectasis;5,7 and does not address the immune dysregulation aspects of APDS such as lymphoproliferation, autoimmunity and lymphoma.5,6,8
Corticosteroids target immune dysregulation by inhibiting leukocyte activity and proliferation, particularly T cells,5 and may reduce lymphoproliferation and cytopenias;2-4 46% of patients with APDS are reported to have received corticosteroids, with 87% showing at least partial short-term benefit.1 Prolonged corticosteroid use is associated with long-term toxicity that may cause osteoporosis, diabetes, hyperlipidemia, hypertension and/or ophthalmologic and dermatologic issues.5 Long-term corticosteroid use also increases the susceptibility to infections.
Rituximab targets CD20+ B cells for destruction and therefore may reduce B cell overactivation.1-4 Rituximab has been used to treat lymphoma and autoimmune diseases, both of which are prevalent in patients with APDS.1-4 Its use in patients with APDS may be complicated by sustained B cell lymphopenia in patients with APDS;1 furthermore, it does not address the inherent immune deficiency5 and can increase the risk of severe infection.
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. mTOR inhibitors such as sirolimus (rapamycin) or everolimus reduce mTOR hyperactivation downstream of PI3Kδ1, ameliorate the severity of nonneoplastic lymphoproliferative disease and restore natural killer cell function.9,10 Between 11-40% of patients with APDS have been reported to receive mTOR inhibitors,4-7 with T cell phenotypes restored to normal ranges in some cases.7-9 For example, sirolimus treatment decreased CD8+ and senescent T cells and increased the proportion of naïve T cells.3,4
In some cases, mTOR inhibition has been reported to be effective in treating multiple manifestations of APDS,1-6 such as lymphoproliferation (lymphadenopathy and hepatosplenomegaly), frequency and severity of infections and bronchiectasis progression (in one case). In some patients it has also resulted in steroid-sparing or IRT reduction.4
mTOR inhibitors may not be effective for all patients with APDS: assessment of 26 patients in the ESID APDS Registry identified that 62% had only a moderate-to-poor response to sirolimus on the physician visual analog score.1 For example, mTOR inhibitor therapy may be difficult to implement and maintain due dosing, adverse event and compliance challenges.1-5 In particular, their narrow therapeutic index may impact dosing, particularly in children,1-3 And adverse events such as headaches, anorexia, mouth ulcers and renal or liver toxicity have led to cessation of therapy.4-5
Haematopoietic stem cell transplant (HSCT) may be curative but can involve risk
Haematopoietic stem cell transplant
Haematopoietic stem cell transplant (HSCT) has been used to treat a small number (9-13%) of patients with APDS1/2; while HSCT has the potential to resolve the clinical symptoms of APDS and enable the cessation of immunosuppression or IRT, serious complications and adverse events are frequent, and the risk of mortality at 2 years post-transplant is high.7-13 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.
91% of patients with APDS experienced adverse events during/after HSCT11,12
Barriers to improving the success rates of HCT include high risk of graft instability, significant comorbidities, and poorly controlled infections, autoimmunity, and lymphoproliferation pre-HCT.13-15
As HSCT may not correct the non-immunological manifestations of hyperactive PI3Kδ, patients with APDS may remain at risk of renal complications post-HCT even if the haematopoietic system is fully donor, due to increased vulnerability to renal insults early post-HCT and/or chronic complications.13
Longer-term follow-up of more patients post-HCT is required to establish the kinetics of immune reconstitution and donor chimerism, approaches to reduce graft instability and assess the completeness of phenotype reversal over time.13
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% of 57 patients; acute graft-versus-host disease (GVHD), 39%; chronic GVHD, 16%; and organ toxicities and infections complications.14
Most adult APDS patients will have suffered from recurrent infections during childhood and CVID is the most likely diagnosis. When diagnosed as adults, family planning becomes an important consideration, with the need for immediate counselling. As patients age, the risks associated with stem cell transplantation increase, and patients are more likely to be treated with sirolimus.
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