Background
Primary immunodeficiency disorders (PIDs) are a group of immune system diseases, many of them caused by genetic defects [
1,
2].
Phosphoinositide 3-kinases (PI3Ks) are the family of enzymes expressed in various classes of cells and involved in signal transduction via a few main pathways. Class I PI3Ks are expressed in leukocytes and catalyze the synthesis of a second messenger, phosphatidylinositol 3,4,5-triphosphate (PIP3). PI3Ks are heterodimers composed of a catalytic and regulatory unit [
3,
4].
APDS is a consequence of a gain-of-function (activating) mutation. APDS was first described in 2014 in a small group of patients with PID of unknown etiology [
1,
5]. Using next-generation sequencing (NGS), a rare heterozygous mutation of the
PI3KCD gene encoding catalytic subunit of the PI3K (PI3Kδ) has been identified. Then, other mutations of the
PI3KR1 gene encoding the regulatory subunit (p85α PI3Kδ) have been described. Depending on the literature source, between 47 and 100 new cases of APDS have been reported since then [
1,
3]. However, the exact number of patients with this condition is unknown. APDS resulting from mutation of the
PI3KCD has been classified as APDS 1, whereas the disease associated with the mutation of the
PI3KR1 is referred to as APDS 2 [
5].
APDS is a complex deficiency of cellular and humoral immunity, which explains a heterogeneity of its clinical manifestations. Most patients present with recurrent respiratory infections, such as otitis media, sinusitis and pneumonia (typically with
Haemophilus influenzae and
Streptococcus pneumoniae as etiological factors), which suggests the presence of an antibody deficiency [
1,
3,
6]. Also, viral infections, with herpesvirus simplex (HPV), cytomegalovirus (CMV) and Epstein–Barr virus (EBV) are reported, as well as parasitic and fungal infections, suggesting an impairment of T cell function [
1,
3]. According to literature, patients with APDS 1 may also present with gastrointestinal infections [
6,
7]. Another clinical manifestation are local and systemic lymphoproliferative disorders and hepatosplenomegaly observed since early childhood [
3,
7‐
9]. Abnormalities in laboratory results include immune cytopenia and altered distribution of lymphocyte subpopulations [
1,
5,
7,
8]. Because of the tendency to lymphoproliferation, patients with APDS are at increased risk of neoplastic transformation, mainly to hematologic malignancies [
1,
3,
9]. APDS 1 and APDS 2 show some differences in their clinical presentation. Similarities and differences between these two disease entities are summarized in Table
1.
Table 1Clinical characteristics of APDS 1 and APDS 2 reported in the literature and manifestations of these conditions in our patients [
1,
3,
5,
7,
11]
Infectious complications | |
Recurrent respiratory infections |
Pneumonia | + | + | + | + |
Bronchitis | + | + | + | + |
Sinusitis | + | + | + | + |
Otitis | + | − | + | + |
Viral infections |
HPV | + | − | + | − |
CMV | + | + | + | − |
EBV | + | − | + | − |
Adenovirus | + | + | − | − |
Parasitic and fungal infections | + | + | + | − |
Gastrointestinal infections | + | + | − | − |
Non-infectious complications | |
Lymphadenopathy | + | + | + | + |
Splenomegaly | + | + | + | − |
Hepatomegaly | + | + | + | − |
Nodular lymphoid hyperplasia in the gastrointestinal tract | + | + | + | − |
Signs of facial dysmorphia | − | − | + | + |
Short stature | − | − | + | + |
Intellectual disability | − | − | + | − |
Microcephalia | − | − | + | − |
Mutation | |
E1021K | + | + | − | − |
N334K | + | − | − | − |
E525K | + | − | − | − |
C416R | + | − | − | − |
NM_181523 | − | − | + | + |
Laboratory abnormalities | |
Lower concentrations of IgG and IgA | + | + | + | + |
Elevated concentration of IgM | + | + | + | − |
Lymphopenia CD19+ | + | + | + | + |
Elevated count of T lymphocytes CD8+ | + | + | + | − |
Inverted CD4/CD8 ratio | + | + | + | + |
Lower count of naïve T lymphocytes CD4+ (CD4+CD45RA+) | + | + | + | − |
Lower count of naïve T lymphocytes CD8+ (CD8+CD45RA+) | − | − | + | − |
Treatment | |
Immunoglobulin replacement therapy | + | + | + | + |
Immunosuppressive therapy | + | − | + | − |
Allo-HSCT | + | + | + | − |
In this paper, we present two boys who had been diagnosed with APDS 1 and APDS 2, respectively. In the first case, the suspicion of aPID has been raised already in early childhood. However, because of limited access to appropriate diagnostic (in particular, genetic) tests, the diagnosis was established only after a few years. In the second case, clinical manifestations suggestive of an immunodeficiency disorder also emerged during early childhood, but PID was considered as a diagnosis only after the end of the first decade of life. As NGS-based testing has been already available in Poland, it took only a few months to establish the final diagnosis.
Discussion and conclusions
The growing availability of NGS-based testing facilitated detection of rare monogenic disorders. Both our patients presented with recurrent respiratory infections and lymphoproliferation. The boy with APDS 1 also had a history of gastrointestinal infections of both viral and bacterial etiology and hepatosplenomegaly. According to sparse published reports, patients with APDS 2 may present with growth deficits, facial dysmorphia, intellectual disability and microcephalia [
1,
3,
10]. These clinical features can be used to distinguish APDS 2 from APDS 1, as to this date, they have not been reported in patients with the latter condition. Our patient with APDS 2 presented with facial dysmorphia and growth deficit, which is consistent with the previously published reports [
3,
10]. A laboratory finding in APDS patients is impaired antibody production, primarily the deficiency of immunoglobulins G and A, with a concomitant increase in IgM level. While the first of our patients showed this pattern of alterations in immunoglobulin levels, the boy with APDS 2 presented with a severe deficiency of immunoglobulins in all main classes. Other laboratory abnormalities observed in APDS include a decrease in absolute count of B lymphocytes and naïve T lymphocytes, both cytotoxic (CD3+CD4+) and helper (CD3+CD8+) cells [
1,
3,
11].
Most patients with APDS reported in literature received human immunoglobulin replacement therapy since early childhood to reduce the incidence of opportunistic infections [
6,
7]. Some authors used rapamycin in patients with APDS 1 and APDS 2 and reported beneficial effects of the treatment in the form of lesser incidence of opportunistic infections, resolution of lymphoproliferative process and hepatosplenomegaly [
6,
8]. Although long-term treatment with rapamycin may be highly beneficial in patients with APDS 2, it is also associated with the risk of adverse events outside the immune system [
8]. In patients with severe APDS, especially those with enhanced lymphoproliferation and profound lymphocyte dysfunction, allo-HSCT seems to be a therapeutic option, considering the potential risk of neoplastic transformation [
6,
8,
12,
13]. We have implemented immunoglobulin replacement therapy in both our patients. In the boy with APDS 1, the treatment did not contribute to a substantial improvement of clinical status. Conversely, despite the treatment, the patient presented with recurrent bacterial and viral infections and progressive lymphoproliferation and hepatosplenomegaly. Considering the severity of APDS 1, the patient eventually received allo-HSCT from a histocompatible family donor with a good clinical effect. This confirms the appropriateness of such an approach in patients with particularly severe APDS.
In the second patient, the boy with APDS 2, immunoglobulin replacement therapy contributed to a considerable decrease in the incidence of respiratory infections and resolution of lymphoproliferation. As the boy presented with a growth deficit, he also received growth hormone therapy. The treatment has been implemented against the immunologist’s suggestion based on sparse published evidence that APDS 2 may be associated with resistance to growth hormone [
3,
10]. The therapy has been discontinued after a year due to its poor clinical effect and a substantial increase in lymphoproliferative activity, the onset of which co-existed with the implementation of the treatment.
Available evidence suggests that mutation of the
PI3KR1 gene may have an oncogenic potential. Somatic mutations of the
PI3KR1 have been found in patients with Burkitt lymphoma, endometrial cancer, colorectal cancer, ovarian cancer, gastric cancer and malignant melanoma, which points to likely oncogenic potential of this genetic defect [
8]. Therefore, the presence of a severe lymphoproliferative process in our patient with APDS 2 raised an oncological alert. However, after discontinuation of growth hormone therapy, we observed a substantial decrease in lymph node size in all locations, which might confirm a link between lymphoproliferation and the hormonal treatment. Moreover, our experiences are consistent with a sparse published data on resistance to growth hormone in APDS 2 patients. Our observations suggest that treatment with this hormone is not only ineffective but may even pose a threat to the patient (respiratory failure).
To summarize, patients with suspected APDS should undergo genetic testing as it may substantially shorten the time needed to establish the correct diagnosis. Patients with suspected CVID and additional symptoms, such as intellectual disability, facial dysmorphia, allergy, short stature, enhanced lymphoproliferation and lack of adequate response to human immunoglobulin replacement therapy, should be qualified for NGS-based genetic testing. Unfortunately, the availability and financing of NGS in Poland is still limited. Due to these difficulties, future studies should define clinical indices and laboratory biomarkers of APDS 1 and APDS 2, to develop the standards of care in these conditions.
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