Clinical Manifestations and Outcomes of Activated Phosphoinositide 3-Kinase δ Syndrome from the USIDNET Cohort

Abstract

Background:

Activated phosphoinosidtide 3-kinase δ syndrome (APDS) is a combined primary immunodeficiency characterized by gain-of-function mutations in PIK3CD and PIK3R1. APDS demonstrates a large range of phenotypes including respiratory and herpesvirus infections, lymphadenopathy, autoimmunity, and developmental delay.

Objective:

This study describes clinical phenotypes and disease outcomes of a large APDS cohort from the USIDNET Registry.

Methods:

38 patients were enrolled in USIDNET and 2 additional patients were obtained from the Clinical Immunology division at Mount Sinai Hospital. Each patient’s demographics, disease complications, genetic studies, laboratory data, therapeutic interventions, and clinical outcomes were reviewed.

Results:

There was a high frequency of respiratory infections (70.0% pneumonia) and herpesvirus infections (37.5%). Bronchiectasis was observed in 45.0% of patients. Lymphadenopathy was common (52.5%) and 12.5% of patients developed lymphoma. Neurological and developmental findings were common: 20.0% had developmental delay, 15.0% had seizures, and 10.0% had dysmorphic features. Asthma was more common in PIK3CD compared to PIK3R1 patients (63.6% vs 14.3%). More subjects with PIK3CD had CD3 lymphopenia compared to the PIK3R1 cohort. Seven patients underwent hematopietic stem cell transplantation. One patient died from infectious complications.

Conclusion:

This is the first cohort comparing clinical manifestations in PIK3CD and PIK3R1 patients from the USIDNET Registry. Similar frequencies of respiratory and herpesvirus infections, lymphadenopathy, and developmental delay were observed compared to prior cohort studies. However, a higher frequency of asthma and CD3 lymphopenia in the PIK3CD cohort compared to the PIK3R1 cohort was observed.

BACKGROUND

Activated phosphoinosidtide 3-kinase δ syndrome (APDS) is an autosomal dominant combined primary immunodeficiency characterized by gain-of-function (GOF) mutations in PIK3CD (also referred to as APDS1, OMIM #615513) or PIK3R1 (also referred to as APDS2, OMIM #616005)(1, 2). APDS has also been known as PASLI disease (p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency)(3). The mutations in PIK3CD and PIK3R1 lead to pathologic changes in the receptor components of p110δ and p85α respectively, the catalytic and regulatory subunits of phosphoinositide 3-kinase δ (PI3Kδ). Mutations in PI3Kδ expressed in leukocytes cause overactivation of PI3K/AKT/mTOR/S6K pathways, leading to increased proliferation and activation(1–4).

APDS has been shown to produce a wide spectrum of disease phenotypes with varying degrees of immunodeficiency, lymphoproliferation, autoimmunity, and developmental delay(3). From an infectious standpoint, APDS patients frequently develop classic antibody-deficient respiratory infections often leading to long-term clinical implications such as bronchiectasis and lung scarring. Interestingly, APDS patients are also prone to herpesvirus infections in setting of overactivation of the mTOR pathway, with clinical improvement seen in patients managed on a daily mTOR inhibitor(5). Lymphoproliferation is a classic finding in APDS, and presents as both nonmalignant lymphoproliferation (i.e. splenomegaly, hepatomegaly, lymphadenopathy) and lymphoma(4).

The following study outlines the immune phenotype, disease manifestations, clinical outcomes, and therapeutic interventions in a large cohort of APDS patients (n=40; PIK3CD=33 and PIK3R1=7) from the United States Immunodeficiency Network (USIDNET) Registry. This study describes the differing phenotypes identified in APDS patients with gene mutations in PIK3CD compared to PIK3R1. Although not previously described in the literature, the following study also identifies an allergic phenotype in a subset of patients in the APDS cohort. Given the diverse spectrum of phenotypes in APDS patients, this cohort study adds an important tool in advancing the understanding of disease manifestations and clinical outcomes in this unique subset of immunodeficiency patients.

METHODS

Informed consent for enrollment in the registry was obtained from all patients and/or legal guardians. 38 patients were enrolled in USIDNET; additional data on 2 cases were obtained from the Clinical Immunology Division at the Mount Sinai Medical Center in New York City. None of the patients have been included in previously published cohort studies.

USIDNET entries were based on chart review to identify each patient’s demographics, disease complications, genetic studies, laboratory data, therapeutic interventions, and clinical outcomes. Mutations in PIK3CD and PIK3R1 were identified by Sanger sequencing, whole exome sequencing, or in some cases, polymerase chain reaction-based sequence analysis.

Statistics were obtained via GraphPad Prism software. Statistical significance was determined by a P value of less than 0.050 as calculated by the Fisher’s exact test.

RESULTS

Demographics and Immunologic Features

40 patients (52.5% female) are included in this study, 33 of whom were diagnosed with a PIK3CD GOF mutation and 7 diagnosed with a PIK3R1 GOF mutation. The patient’s year of birth ranged from 1949 to 2007. The race distribution of the cohort includes 77.5% Caucasian, 7.5% African American, one patient who identified as Asian/Pacific Islander, one as Native American, and four subjects who did not identify with any of these categories. Three patients were Hispanic/Latino. The average age of symptom onset was 3.7 years and the average age of an immunodeficiency diagnosis was 15.8 years (though unknown in two patients). 40% of patients reported a family history of primary immunodeficiency ranging from one to five relatives. At the time of data collection, 39 of the 40 patients were living; one patient died of infections in the setting of malignancy. Demographics are listed in Table 1.

Table 1.

Demographics

	APDS (n=40)
Gene Mutation
PIK3CD GOF	33
PIK3R1 GOF	7
Sex (% female)	52.5%
Average Age of Symptom Onset	3.7 years
Family History of PID*	40%
Race
Caucasian	77.5%
African American	7.5%
Asian/Pacific Islander	4.0%
Native American	4.0%
Other (did not identify with above categories)	10%
Ethnicity – Latino or Hispanic	7.5%

^*PID = Primary Immunodeficiency

Of the 33 PIK3CD patients, specific DNA mutations were reported in 19 patients. Of the patients with known DNA mutations, 18 patients had a mutation in p.E1021K (c.3061G>A) and one patient had a mutation in p.E522K (c.1546G>A). The E1021K variant in the C-lobe of the p110δ kinase domain is the most frequently reported mutation in APDS potentially due to its role heightening PI3K activity via facilitating phosphorylation of PIP₂(1, 6, 7). Of the 7 PIK3R1 patients, three patients had a recorded specific DNA mutation, two of which were c.1425+1G>A and one which was c.1425+1G>T.

Laboratory Evaluations

There was a wide range of immunoglobulin values for 39 of the 40 subjects; one patient did not have immunoglobulin values available (Figure 1 and Figure 2). The first available Immunoglobulin G (IgG) level at data entry, not necessarily baseline levels, ranged from 30 to 2153 mg/dL, with a median value of 881 mg/dL. 32.5% of patients had an IgG of less than 700 mg/dL. 53.8% of patients had a low immunoglobulin A (IgA) and 23.1% of patients had a low immunoglobulin M (IgM) levels, based on normal age ranges. We noted that 53.8% of patients had high IgM values (greater than 230 mg/dL). There were no significant differences in quantitative immunoglobulins between the two cohorts. Both B-cell and T-cell lymphopenia were seen in many, with CD4 lymphopenia more pronounced than CD8 lymphopenia. The PIK3CD cohort demonstrated a greater frequency of CD3 lymphopenia when compared to the PIK3R1 cohort. The degree of CD4 and CD8 lymphopenia was also greater in the PIK3CD cohort compared to the PIK3R1 cohort.

Figure 1. Quantitative Immunoglobulins*.

*Laboratory values are first available entry into the USIDNET registry and may not represent baseline values.

The first available Immunoglobulin G (IgG) level at data entry ranged from 30 to 2153 mg/dL, with a median value of 881 mg/dL. 32.5% of patients presented with an IgG of less than 700 mg/dL. 53.8% of patients had a low immunoglobulin A (IgA) and 23.1% of patients had a low immunoglobulin M (IgM) based on normal age ranges. 53.8% of patients had high IgM values (greater than 230 mg/dL). There were no statistically significant differences between the PIK3CD cohort compared to the PIK3R1 cohort.

Figure 2. Lymphocyte Values*.

*Laboratory values are first available entry into the USIDNET registry and may not represent baseline values.

CD4 lymphopenia (77.8%) was more pronounced than cytotoxic CD8 lymphopenia (44.4%). The PIK3CD cohort demonstrated a greater degree of CD3 lymphopenia when compared to the PIK3R1 cohort. The degree of CD4 and CD8 lymphopenia was also greater in the PIK3CD cohort compared to the PIK3R1 cohort.

Infectious Complications

Recurrent upper respiratory tract infections (60.0%), sinusitis (67.5%), pneumonia (70.0%), and otitis (62.5%) were described in the majority of patients (Table 2). The most commonly implicated bacterial pathogens were Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and methicillin-resistant Staphylococcus aureus. One PIK3CD patient developed Pneumocystis jirovecci pneumonia.

Table 2.

Infections

	PI3KCD n=33	PI3KR1 n=7	Combined n=40
RESPIRATORY
Recurrent Sinusitis	25 (75.8%)	2 (28.6%)	27 (67.5%)
Pneumonia	24 (72.7%)	4 (57.1%)	28 (70.0%)
Recurrent URI	20 (60.6%)	4 (57.1%)	24 (60.0%)
Otitis	20 (60.6%)	5 (71.4%)	25 (62.5%)
Dental/oral soft tissue abscesses	7 (21.2%)	0	7 (17.5%)
Thrush	3 (9.1%)	1 (14.3%)	4 (10.0%)
Tonsillitis	1 (3.0%)	0	1 (2.5%)
Ocular infections	1 (3.0%)	1 (14.3%)	2 (5.0%)
VIRAL
Herpesvirus Infection (All)	11 (33.3%)	4 (57.1%)	15 (37.5%)
EBV	7 (21.2%)	1 (14.3%)	8 (20.0%)
HSV	5 (15.2%)	2 (28.6%)	7 (17.5%)
CMV	4 (12.1%)	1 (14.3%)	5 (12.5%)
VZV	3 (9.1%)	2 (28.6%)	5 (12.5%)
Warts	3 (9.1%)	2 (28.6%)	5 (12.5%)
Molluscum	3 (9.1%)	1 (14.3%)	4 (10.0%)
HPV	None	1 (14.3%)	1 (2.5%)
GASTROINTESTINAL
Chronic Diarrhea	4 (12.1%)	4 (57.1%)	8 (20.0%)
Splenic Abscess	1 (3.0%)	1 (14.3%)	2 (5.0%)
Liver Abscess	1 (3.0%)	1 (14.3%)	2 (5.0%)
OTHER
Meningitis	4 (12.1%)	0	4 (10.0%)
Skin Abscess	3 (9.1%)	1 (14.3%)	4 (10.0%)
Endocarditis	1 (3.0%)	0	1 (2.5%)

A large range of infections was exhibited, most commonly bacterial respiratory infections and herpesvirus infections. Opportunistic infections were rare, with only one PI3KCD patient who developed Pneumocystis jirovecci pneumonia. 15.0% of patients reported various abscesses

15.0% of patients reported various abscesses: dental/oral tissue abscesses occurred in 17.5% patients, skin abscesses occurred in 10.0% patients, and 2 patients developed both splenic and hepatic abscesses. Furthermore, 12.5% of patients developed cellulitis, 10.0% of patients developed meningitis and one patient developed endocarditis.

37.5% of patients had a history of herpesvirus infection: 20.0% with Epstein-Barr virus (EBV), 17.5% with herpes simplex virus (HSV), 12.5% with cytomegalovirus (CMV), 12.5% with varicella zoster virus (VZV), and one patient with human papillomavirus (HPV). One patient developed EBV hepatitis as a complication of EBV viremia.

Hematologic, Lymphoproliferative Diseases and Malignancy

30.0% of patients had experienced hematologic disease; this was more common in the PIK3CD cohort (33.3%) as compared to only one patient in the PIK3R1 cohort (14.3%) (Table 3). For the PIK3CD cohort, this included 21.2% with history of hemolytic anemia (including one patient with Evans syndrome), 12.1% with pancytopenia, and three patients (9.1%) with history of immune thrombocytopenia (ITP). Two patients had factor XI deficiency. Single patients had factor IX deficiency, spherocytosis, or thrombotic thrombocytopenic purpura (TTP). The majority of the APDS patients also had chronic lymphadenopathy, splenomegaly, and/or hepatomegaly. Five patients developed lymphoma, including two patients with diffuse large B-cell lymphoma, two patients with mucosa-associated lymphoid tissue (MALT) lymphoma, and one patient with Hodgkin’s lymphoma. The history of lymphoma was significantly associated with EBV (P=0.004) but was not with other herpesviruses (P=0.056). Two patients carried a diagnosis of ovarian dysgerminoma (one patient had a PIK3CD gene mutation and one had a PIK3R1 gene mutation). One other patient had history of Hurthle cell carcinoma of thyroid. Clinical features of all patients described are presented in Figure 3.

Table 3.

Hematologic and Lymphatic Features

	PI3KCD n=33	PI3KR1 n=7	Combined n=40
NON-MALIGNANT
Splenomegaly	18 (54.5%)	4 (57.1%)	22 (55.0%)
Lymphadenopathy	16 (48.5%)	5 (71.4%)	21 (52.5%)
Hepatomegaly	9 (27.2%)	2 (28.6%)	11 (27.5%)
Hemolytic Anemia	7 (21.2%)	0	7 (17.5%)
Nodular Lymphoid Hyperplasia	4 (12.1%)	0	4 (10.0%)
Pancytopenia	4 (12.1%)	0	4 (10.0%)
Immune Thrombocytopenia	3 (9.1%)	1 (14.3%)	4 (10.0%)
Factor XI deficiency	2 (6.1%)	0	2 (5.0%)
Factor IX deficiency	1 (3.0%)	0	1 (2.5%)
Spherocytosis	1 (3.0%)	0	1 (2.5%)
TTP	1 (3.0%)	0	1 (2.5%)
MALIGNANT
Lymphoma – All	4 (12.1%)	1 (14.3%)	5 (12.5%)
Non-Hodgkin’s Lymphoma	1 (3.0%)	1 (14.3%)	2 (5.0%)
Hodgkin’s Lymphoma	1 (3.0%)	0	1 (2.5%)
Diffuse large B cell lymphoma	2 (6.1%)	0	2 (5.0%)
MALT lymphoma	2 (6.1%)	0	2 (5.0%)
Other	- Hurthle cell carcinoma of thyroid (1) - Dysgerminoma (1)	- Dysgerminoma (1)	3 (7.5%)

Benign lymphoid hyperplasia was commonly reported. Five patients (12.5%) developed lymphoma. The history of lymphoma was significantly associated with EBV (P=0.004) but was not with other herpesviruses (P=0.056).

Figure 3. Clinical Features.

Clinical features are identified separately for PIK3CD and PIK3R1 patients. The most common clinical features were benign lymphoid hyperplasia, asthma, gastrointestinal disease, and bronchiectasis.

Neurological, Psychiatric and Developmental Disorders

Ten patients carried a neurological diagnosis, including six patients with a history of seizures (Table 4). Single patients were diagnosed with schizoencephaly (abnormal slits or clefts in the cerebral hemispheres of the brain), cerebral palsy, acute inflammatory demyelinating polyradiculopathy, vertebral vasculitis, and subarachnoid hemorrhage. Six patients with PIK3CD and three with PIK3R1 had hearing loss. 20.0% of patients were diagnosed with developmental delay, including one patient with autism. Four patients had dysmorphic features and four patients had a history of failure to thrive. Other conditions noted were depression, anxiety and attention-deficit hyperactivity disorder.

Table 4.

Other Clinical Features

	PIK3CD n=33	PIK3R1 n=7
Neurological
Developmental Delay	7 (21.2%)	1 (14.3%)
Hearing Loss	6 (18.2%)	3 (42.9%)
Seizures	6 (18.2%)	None
Dysmorphic features	3 (9.1%)	1 (14.3%)
Failure to thrive	2 (6.1%)	2 (28.5%)
Atopic
Atopic Disease	24 (72.7%)	3 (42.9%)
Asthma	21 (63.6%)	1 (14.3%)
Food Allergies	6 (18.2%)	None
Eczema	6 (18.2%)	None
EoE/EGID	4 (12.1%)	None
Pulmonary
Bronchiectasis	17 (51.5%)	1 (14.3%)
Interstitial lung disease/restrictive lung disease	3 (9.1%)	1 (14.3%)
Pneumothorax	1 (3.0%)	1 (14.3%)
Gastrointestinal
Enteropathy/Chronic diarrhea	5 (15.2%)	1 (14.3%)
Nodular Regenerative hyperplasia of the liver	4 (12.1%)	None
Inflammatory Bowel Disease	3 (9.1%)	None
Pancreatic Insufficiency	2 (6.1%)	None
Endocrine
Adrenal insufficiency	4 (12.1%)	None
Hypothyroidism	3 (9.1%)	None
Cardiac
Cardiomyopathy	1 (3.0%)	1 (14.3%)
Renal/Genitourinary
Dysgerminoma	1 (3.0%)	1 (14.3%)
Other
Ehlers-Danlos	1 (3.0%)	1 (14.3%)

Neurological disease was commonly reported. 25.0% of patients carried a neurological diagnosis, including 15% with a history of seizures. 20.0% of patients were diagnosed with developmental delay, including one patient with autism. Atopic manifestations have not previously been described in the APDS cohort. 67.5% of patients had evidence of IgE-mediated allergic disease (asthma, eczema, allergic rhinitis, food allergy), which was higher in the PIK3CD cohort compared to the PIK3R1 cohort (72.7% vs 42.9%). 63.6% of patients in the PIK3CD cohort carried a diagnosis of asthma, while only one PIK3R1 patient was diagnosed with asthma.

Other organ systems

A number of conditions in other systems were noted (Table 4), with bronchiectasis diagnosed in 45.0% of patients, interstitial or restrictive lung disease in 10.0% of patients, and obstructive sleep apnea in three patients. 15.0% of patients had enteropathy/chronic diarrhea and three patients were diagnosed with inflammatory bowel disease (IBD). Three patients had a history of intussusception and two patients had a history of pancreatic insufficiency. Single patients were diagnosed with pneumatosis intestinalis of the large intestine, laryngomalacia, and small intestinal bacterial overgrowth (SIBO).

More endocrinopathies was observed in the PIK3CD cohort: 12.1% of patients were diagnosed with adrenal insufficiency and 9.1% were diagnosed with hypothyroidism, as compared to none of the PIK3R1 patients reporting a history of an endocrinopathy.

Allergic Manifestations

Although allergic disorders have not been previously described in APDS patients, the cohort described had a strong allergic phenotype with 67.5% of patients with evidence of IgE-mediated allergic disease (asthma, eczema, allergic rhinitis, food allergy), which was higher in the PIK3CD cohort compared to the PIK3R1 cohort (72.7% vs 42.9%). 63.6% of patients in the PIK3CD cohort carried a diagnosis of asthma, while only one PIK3R1 patient was diagnosed with asthma. 18.2% of patients in the PIK3CD cohort carried a diagnosis of eczema, compared to none in the PIK3R1 cohort. Similarly, 18.2% of patients in the PIK3CD cohort carried a diagnosis of food allergy, compared to none in the PIK3R1 cohort. Interestingly, eosinophilic esophagitis (EoE) was also present in four PIK3CD patients (12.1%) but this was not reported in the PIK3R1 cohort.

Treatments and Procedures

In terms of medical therapies applied, 60% of patients were treated with an mTOR inhibitor, most frequently sirolimus (55.0%), with four patients treated with everolimus. 22.5% of patients had been treated with rituximab, two patients were treated with mycophenylate and one patient was treated with interferon-γ. 32.5% of patients required steroids at some point in their disease course.

All patients, with one exception, were treated with supplemental immunoglobulin (Ig) replacement therapy. The transfusion history is known in 21 patients. Of these, 57.1% required packed red blood cell transfusions and 52.4% required platelet transfusions. One patient required intravenous Rho(D) Immune Globulin.

In regards to the complexity of medical presentations and complications, 75.0% of patients required at least one surgery or major procedure; on average, 3.8 procedures per patient was required (Figure 4). Specifically, 55.0% of patients required tympanostomy tube placement, 45.0% of patients required tonsillectomy and/or adenoidectomy, 42.5% of patients required bronchoscopy, and 35.0% had at least one lymph node biopsy. Of note, four patients had a splenectomy, three patients required chest/thorax surgery, and one patient required a brain biopsy. Seven patients required stem cell transplant: two patients from unrelated donor (full match), two from haploidentical parental donor, and one from a sibling (full match). For two patients, the indication and details of the stem cell transplant were not recorded. One patient with history of ulcerative colitis and sclerosing cholangitis required a liver transplant.

Figure 4. Procedures and Surgeries.

APDS patients are medically complex, with 75.0% of patients requiring at least one surgery or major procedure. On average, 3.8 procedures were performed per patient. The most common procedures were tympanostomy tubes, tonsillectomy/adenoidectomy, and bronchoscopy.

Some patients also required physical and developmental support, mostly in the setting of respiratory compromise. 17.5% of patients required respiratory support, including three patients who require chronic supplemental oxygen and three patients who required a chest physiotherapy vest. 12.5% of patients required enteral nutritional support. Two patients required speech therapy, physical therapy, and occupational therapy.

DISCUSSION

APDS is characterized by activation of p110δ leading to increased numbers of senescent T cells, lymphadenopathy, and combined immune deficiency. We present the data from the APDS cohort in the USIDNET Registry, describing immunologic and clinical phenotypes seen in those with genetically confirmed PIK3CD GOF mutations (APDS1; n=33) and PIK3R1 GOF mutations (APDS2; n=7). There was a high degree of variability in clinical features, burden of disease based on necessary procedures, and overall outcomes in the cohort described. The clinical spectrum ranged from an asymptomatic patient who did not required supplemental immunoglobulin replacement therapy to another patient with the same gene mutation which necessitated stem cell transplant who subsequently died from overwhelming infections as a complication of diffuse large B-cell lymphoma.

A prior publication by Coulter and colleagues examined two large separate cohorts in order to further evaluate differences between APDS1 (n=53) and APDS2 (n=36); this showed that these groups demonstrated similar phenotypes with the exception that APDS1 patients with higher reported rates of bronchiectasis, lower rates of lymphoma, and lower incidence of growth retardation(3, 4, 8). Our cohort demonstrates similar differences: 51.5% of APDS1 patients versus only one APDS2 patient (14.3%) had history of bronchiectasis. Contrary to the prior publication, the rates of lymphoma in our cohort were similar between APDS1 (12.1%) and APDS2 (14.3%) patients.

As previously reported, APDS patients often suffer from frequent and severe respiratory infections that start early in life (9). Reported rates of upper respiratory infections in this cohort were similar to prior cohorts(4, 8, 10). The majority of patients in our cohort experienced recurrent respiratory infections, including sinusitis (67.5%) and pneumonia (70.0%); bronchiectasis was described in 45.0% of patients. Severity of disease was demonstrated by the quantity of invasive procedures performed, specifically bronchoscopy in 42.5% of patients, video-assisted thoracoscopic surgery (VATS) in three patients, and lung resection in two patients. Recurrent respiratory infections leading to permanent pulmonary disease led to 17.5% requiring chest physiotherapy, of which 4 patients (10.0%) required supplemental oxygen therapy. Recurrent otitis also contributed to a large burden of disease, leading to 55.0% of patients requiring tympanostomy tubes and 22.5% patients suffered from long term hearing loss. The most commonly implicated bacterial pathogens were similar to those previously described(3, 9), notably Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and methicillin-resistant Staphylococcus aureus. One PIK3CD patient developed Pneumocystis jirovecci pneumonia but otherwise no opportunistic infections were observed, which is consistent with previously described cohorts.

The PI3K pathway plays a crucial role in suppressing herpesvirus infections, as herpesviruses are known to manipulate the PI3K pathway for virus entry, replication and reactivation (11–14). EBV and CMV viremia are the most frequent viral infections associated with both PIK3CD and PIK3R1 gain-of-function mutations(11). Persistent herpesvirus infections were again demonstrated in this cohort. 37.5% of patients developed a herpesvirus infection, which was most frequently EBV (20.0%), HSV (17.5%) and CMV (12.5%). A history of EBV infection was significantly associated with development of lymphoma (P=0.0035), but this was not the case with history of other herpesviruses. Another complication of longstanding EBV infection includes the development of EBV hepatitis in one patient, which has not been previously noted in the literature.

Patients with APDS demonstrated a high incidence of neurological and developmental disorders. 20.6% of APDS1 patients had history of developmental delay, similar to the 19% published by Coulter and colleagues (4). Furthermore, there was a large burden of neurological disease; 17.6% of APDS1 patients had history of seizures, compared to none in the APDS2 cohort. High frequency of neurological and developmental involvement is likely due to the high frequency of PI3Kδ present in the central nervous system (15).

An increase in atopic conditions in APDS subjects has not been previously reported, however, we noted a significant degree of atopic disease which was more prevalent in the APDS1 cohort. 63.6% of APDS1 patients carried a diagnosis of asthma compared to only one APDS2 patient. 18.2% of APDS1 patients had eczema, compared to none of the APDS2 patients. Similarly, 18.2% of APDS1 patients had food allergy, compared to none of the APDS2 patients. Furthermore, four patients (11.8%) in the APDS1 cohort had EoE, as compared to none in the APDS2 cohort. This may be due to the nature of the referral patterns of the medical practices at the enrolling centers.

Laboratory evaluation was consistent with combined immunodeficiency. 53.8% of patients had elevated IgM, which is lower than the previously described at 82% in the European cohort reported by Coulter et al(4), but continues to suggest a significant defect in class switch recombination that has previously been noted in the literature (16, 17). T-cell lymphopenia was again demonstrated, which is thought to be due to PI3Kδ mutations inducing overactivation of the mTOR pathway and shortening the lifespan of effector T cells (2, 18). The majority of patients in the cohort had reduced CD4 T-cells while fewer patients had a reduced CD8 T-cells. T-cell lymphopenia was more pronounced in the APDS1 cohort when compared to the APDS2 cohort, which is likely due to the more pronounced CD4 lymphopenia, though this did not reach statistical significance. 60% of all patients were treated with an mTOR inhibitor, most frequently sirolimus. 17.5% of patients received stem cell transplantation.

The large number of surgeries, procedures, and rehabilitation therapies required in the treatment of this cohort emphasizes a heavy disease burden in APDS patients. 75% of patients required at least one surgery or major procedure (average=3.78 per person). Procedures were most frequently sequelae to frequent respiratory infections and as evaluation of lymphadenopathy. The overall burden of disease in the APDS population highlights the importance of early recognition and diagnosis in order to modulate chronic complications of illness, and most importantly, to seek additional therapeutic measures.

There are limitations to this study. Specifically, laboratory data supplied varied in terms of whether they were baseline values versus first-available, which specifically impacted the ability to analyze quantitative IgG in patients on supplemental immunoglobulin replacement therapy. Furthermore, retrospective registry-based studies inherently contain a selection bias and may not accurately represent patients seen elsewhere, who were not included in the registry.

In conclusion, APDS is a combined immunodeficiency resulting from gain-of-function mutations in genes encoding p110δ (PIK3CD leading to APDS1) and p85α (PIK3R1 leading to APDS2) in the PI3Kδ protein. There is a wide range of clinical phenotypes seen with APDS, including severe respiratory infections, diffuse lymphadenopathy, persistent herpesvirus infections, neurodevelopmental disorders, and lymphoma. Patients with APDS carry a large burden of disease and early management, including mTOR inhibitors, stem cell transplant, and selectivePI3Kδ inhibitors may be indicated to modulate the disease process.

Highlights:

1. What is already known about this topic? Activated phosphoinosidtide 3-kinase δ syndrome (APDS) is a combined primary immunodeficiency that exhibits a large range of phenotypes including respiratory and herpesvirus infections, lymphadenopathy, autoimmunity, and developmental delay.

2. What does this article add to our knowledge? This large APDS cohort exhibits similar frequencies of infections, lymphadenopathy, and developmental delay compared to prior cohort studies. A higher frequency of asthma and CD3 lymphopenia was observed in PIK3CD compared to PIK3R1 patients.

3. How does this study impact current management guidelines? Early genetic screening for APDS is recommended for those with symptoms consistent with a combined immunodeficiency including recurrent respiratory infections, herpesvirus infections, bronchiectasis, lymphoma, developmental delay, and atopic manifestations.

Abbreviations

PI3Kδ

Phosphoinositide 3-kinase δ

APDS

Activated phosphoinosidtide 3-kinase δ syndrome

PASLI

p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency

USIDNET

United States Immunodeficiency Network

GOF

Gain-of-function

Ig

Immunoglobulin

T_H

T-helper cell

EBV

Epstein-Barr Virus

HSV

Herpes Simplex Virus

CMV

Cytomegalovirus

VZV

Varicella Zoster Virus

HPV

Human Papillomavirus

MALT Lymphoma

Mucosa-Associated Lymphoid Tissue Lymphoma