Clinical Implications of Cytopenias in the U.S. Immunodeficiency Network Registry

Rationale The correlation between cytopenias and infection, malignancy, and mortality has not been systematically characterized in patients with inborn errors of immunity (IEIs). Methods We evaluated the association between anemia, thrombocytopenia, lymphopenia, and neutropenia and infection, malignancy, and mortality rates in IEI patients enrolled in the United States Immunodeficiency Network (USIDNET) registry. Results Of the 4,005 IEI patients enrolled in the USIDNET cohort through April 2019, we excluded 438 patients due to prior solid organ or hematopoietic stem cell transplantation. In the final cohort (n = 3,657), the median age of participants was 27 (IQR 16-50) years. Approximately 47.9% of participants were female. The majority of patients (57.2%) were classified as predominantly antibody deficiencies per the International Union of Immunological Societies (IUIS) categorization with common variable immunodeficiency being the most common diagnosis (38.9%). A total of 1,093 (29.9%) patients had one or more cytopenias, including 656 (17.9%) with anemia, 481 (13.2%) with thrombocytopenia, 323 (8.8%) with lymphopenia, and 336 (9.2%) with neutropenia. Approximately 274 (7.5%) of patients had immune-mediated cytopenias. Patients with cytopenias exhibited higher odds of infection (OR = 4.00, 95% CI 3.07-5.28), malignancy (OR = 2.51, 95% CI 1.93-3.25), and mortality (OR = 2.81, 95% CI 2.01-3.92) as compared with patients without cytopenias. Neutropenic patients frequently developed bacterial infections (58.6%), followed by viral (51.5%), fungal (35.4%), and parasitic (5.1%). Our cohort also demonstrated a high rate of sinopulmonary infections (75.8%) and skin and soft tissue infections (31.9%). Conclusions Cytopenias are a common manifestation across various IEIs. Patients with cytopenias exhibited a heightened risk of infection, malignancy, and mortality, highlighting underlying immune dysregulation and calling for the need to address cytopenias in the management of IEIs. Table 1.Cytopenias in primary immunodeficiencies and IUIS categoriesImmunodeficiency# Thrombocytopenia# Anemia# Neutropenia# Lymphopenia# Any cytopeniaTotal count (N = 3511)Agammaglobulinemia10 (4%)25 (10%)23 (9%)3 (1%)45 (18%)257Ataxia telangiectasia6 (23%)6 (23%)2 (8%)7 (27%)11 (42%)26Autoimmune lymphoproliferative syndrome (ALPS)14 (22%)29 (45%)9 (14%)7 (11%)34 (53%)64Autoinflammatory disease1 (8%)0 (0%)1 (8%)0 (0%)2 (17%)12CHARGE syndrome0 (0%)0 (0%)0 (0%)1 (33%)1 (33%)3Chronic granulomatous disease9 (6%)45 (31%)3 (2%)0 (0%)51 (35%)145Combined immune deficiency9 (17%)11 (21%)10 (19%)16 (31%)22 (42%)52Common variable immune deficiency (CVID)210 (15%)259 (18%)86 (6%)79 (6%)416 (29%)1416Complement deficiency1 (4%)2 (8%)0 (0%)0 (0%)2 (8%)26DiGeorge syndrome20 (4%)16 (3%)7 (1%)41 (8%)63 (13%)496Dyskeratosis congenita0 (0%)0 (0%)0 (0%)1 (100%)1 (100%)1Ectodermal dysplasia with immunodeficiency (nemo and others)0 (0%)5 (21%)2 (8%)3 (12%)8 (33%)24HLH, including XLP and pigmentary disorders5 (31%)5 (31%)4 (25%)4 (25%)8 (50%)16Hyper IgE syndrome3 (3%)14 (15%)3 (3%)0 (0%)18 (19%)96Hyper IgM syndrome1 (2%)4 (9%)18 (38%)1 (2%)19 (40%)47Hypogammaglobulinemia11 (5%)21 (10%)10 (5%)10 (5%)35 (17%)209IgA deficiency1 (1%)2 (3%)2 (3%)7 (10%)11 (16%)68IgG subclass deficiency1 (4%)3 (12%)1 (4%)0 (0%)6 (23%)26Immune deficiency with syndromic features (not otherwise listed)0 (0%)1 (12%)0 (0%)0 (0%)1 (12%)8Immune dysregulation22 (29%)25 (33%)17 (23%)18 (24%)40 (53%)75Immunodeficiency unknown cause3 (16%)4 (21%)2 (11%)2 (11%)5 (26%)19Immunodeficiency with myelodysplasia (GATA2 and others)9 (33%)11 (41%)8 (30%)9 (33%)14 (52%)27Interferonopathy (Aicardi-Goutières and others)0 (0%)2 (29%)0 (0%)0 (0%)4 (57%)7Leukocyte adhesion deficiency0 (0%)3 (33%)0 (0%)0 (0%)3 (33%)9Mucocutaneous candidiasis0 (0%)5 (12%)1 (2%)1 (2%)7 (16%)43Neutropenia0 (0%)0 (0%)2 (100%)0 (0%)2 (100%)2NK cell defect1 (25%)0 (0%)1 (25%)0 (0%)2 (50%)4Omenn syndrome0 (0%)1 (100%)1 (100%)1 (100%)1 (100%)1Other immune deficiency - known cause3 (6%)7 (13%)2 (4%)0 (0%)9 (17%)54Other T-cell problems1 (14%)1 (14%)0 (0%)1 (14%)2 (29%)7Predisposition to severe viral infections6 (20%)12 (40%)23 (77%)1 (3%)24 (80%)30Severe combined immune deficiency (SCID)3 (5%)11 (17%)8 (12%)16 (24%)22 (33%)66Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells4 (4%)12 (12%)2 (2%)4 (4%)18 (19%)97Susceptibility to mycobacteria (MSMD)0 (0%)1 (12%)0 (0%)0 (0%)1 (12%)8TLR pathway abnormality0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)2Transient hypogammaglobulinemia of infancy with normal numbers of b cells0 (0%)0 (0%)1 (7%)0 (0%)1 (7%)14Wiskott-Aldrich syndrome35 (65%)13 (24%)3 (6%)3 (6%)38 (70%)54Table 2.Sites of infection in IEIImmunodeficiencyUrogenitalSSTISino-pulmonaryCardiacOdontogenicOphthalmicMSKCNSGIBloodstreamAny siteTotal count (N = 3511)Agammaglobulinemia18 (7%)92 (36%)221 (86%)0 (0%)1 (0%)67 (26%)25 (10%)34 (13%)66 (26%)29 (11%)235 (91%)257Ataxia telangiectasia1 (4%)3 (12%)21 (81%)0 (0%)0 (0%)2 (8%)1 (4%)1 (4%)8 (31%)3 (12%)24 (92%)26Autoimmune lymphoproliferative syndrome (ALPS)9 (14%)32 (50%)33 (52%)0 (0%)0 (0%)1 (2%)0 (0%)2 (3%)16 (25%)9 (14%)54 (84%)64Autoinflammatory disease1 (8%)3 (25%)5 (42%)0 (0%)0 (0%)2 (17%)0 (0%)1 (8%)1 (8%)0 (0%)9 (75%)12CHARGE syndrome1 (33%)1 (33%)2 (67%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)2 (67%)3 (100%)3Chronic granulomatous disease13 (9%)115 (79%)123 (85%)0 (0%)5 (3%)8 (6%)17 (12%)14 (10%)75 (52%)15 (10%)143 (99%)145Combined immune deficiency5 (10%)25 (48%)40 (77%)1 (2%)0 (0%)11 (21%)3 (6%)5 (10%)12 (23%)12 (23%)43 (83%)52Common variable immune deficiency (CVID)242 (17%)381 (27%)1211 (86%)4 (0%)18 (1%)126 (9%)32 (2%)62 (4%)248 (18%)91 (6%)1265 (89%)1416Complement deficiency1 (4%)9 (35%)21 (81%)0 (0%)0 (0%)1 (4%)2 (8%)7 (27%)3 (12%)6 (23%)23 (88%)26DiGeorge syndrome22 (4%)34 (7%)157 (32%)7 (1%)0 (0%)11 (2%)2 (0%)1 (0%)11 (2%)19 (4%)171 (34%)496Dyskeratosis congenita0 (0%)0 (0%)1 (100%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)1 (100%)1Ectodermal dysplasia with immunodeficiency (nemo and others)2 (8%)16 (67%)18 (75%)0 (0%)0 (0%)1 (4%)1 (4%)8 (33%)8 (33%)5 (21%)24 (100%)24HLH, including XLP and pigmentary disorders2 (12%)5 (31%)12 (75%)0 (0%)0 (0%)1 (6%)0 (0%)1 (6%)3 (19%)2 (12%)13 (81%)16Hyper IgE syndrome18 (19%)84 (88%)88 (92%)1 (1%)3 (3%)4 (4%)7 (7%)5 (5%)19 (20%)7 (7%)91 (95%)96Hyper IgM syndrome3 (6%)12 (26%)43 (91%)0 (0%)1 (2%)4 (9%)0 (0%)3 (6%)11 (23%)5 (11%)44 (94%)47Hypogammaglobulinemia34 (16%)56 (27%)162 (78%)0 (0%)2 (1%)10 (5%)3 (1%)1 (0%)23 (11%)6 (3%)173 (83%)209IgA deficiency8 (12%)15 (22%)63 (93%)0 (0%)0 (0%)4 (6%)1 (1%)3 (4%)16 (24%)1 (1%)66 (97%)68IgG subclass deficiency7 (27%)6 (23%)25 (96%)0 (0%)2 (8%)1 (4%)1 (4%)1 (4%)2 (8%)0 (0%)25 (96%)26Immune deficiency with syndromic features (not otherwise listed)4 (50%)3 (38%)6 (75%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)1 (12%)1 (12%)8 (100%)8Immune dysregulation15 (20%)40 (53%)66 (88%)1 (1%)5 (7%)9 (12%)1 (1%)5 (7%)20 (27%)9 (12%)69 (92%)75Immunodeficiency unknown cause2 (11%)5 (26%)12 (63%)2 (11%)0 (0%)0 (0%)1 (5%)2 (11%)3 (16%)1 (5%)16 (84%)19Immunodeficiency with myelodysplasia (GATA2 and others)7 (26%)14 (52%)16 (59%)1 (4%)0 (0%)0 (0%)0 (0%)0 (0%)3 (11%)1 (4%)22 (81%)27Interferonopathy (Aicardi-Goutières and others)0 (0%)2 (29%)3 (43%)0 (0%)0 (0%)0 (0%)0 (0%)1 (14%)0 (0%)1 (14%)4 (57%)7Leukocyte adhesion deficiency3 (33%)9 (100%)8 (89%)1 (11%)2 (22%)2 (22%)1 (11%)0 (0%)4 (44%)1 (11%)9 (100%)9Mucocutaneous candidiasis10 (23%)37 (86%)32 (74%)1 (2%)0 (0%)3 (7%)3 (7%)3 (7%)11 (26%)4 (9%)42 (98%)43Neutropenia0 (0%)0 (0%)2 (100%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)2 (100%)2NK cell defect1 (25%)3 (75%)4 (100%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)1 (25%)4 (100%)4Omenn syndrome0 (0%)1 (100%)1 (100%)0 (0%)0 (0%)1 (100%)0 (0%)0 (0%)1 (100%)1 (100%)1 (100%)1Other immune deficiency - known cause6 (11%)13 (24%)44 (81%)0 (0%)0 (0%)4 (7%)1 (2%)1 (2%)11 (20%)3 (6%)46 (85%)54Other T-cell problems0 (0%)3 (43%)4 (57%)0 (0%)0 (0%)0 (0%)1 (14%)0 (0%)1 (14%)0 (0%)6 (86%)7Predisposition to severe viral infections11 (37%)21 (70%)26 (87%)0 (0%)2 (7%)4 (13%)3 (10%)3 (10%)7 (23%)3 (10%)26 (87%)30Severe combined immune deficiency (SCID)9 (14%)23 (35%)45 (68%)0 (0%)2 (3%)4 (6%)3 (5%)2 (3%)17 (26%)8 (12%)51 (77%)66Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells19 (20%)29 (30%)96 (99%)0 (0%)1 (1%)6 (6%)0 (0%)2 (2%)16 (16%)3 (3%)96 (99%)97Susceptibility to mycobacteria (MSMD)3 (38%)5 (62%)4 (50%)0 (0%)0 (0%)0 (0%)1 (12%)2 (25%)2 (25%)1 (12%)7 (88%)8TLR pathway abnormality0 (0%)1 (50%)1 (50%)0 (0%)0 (0%)0 (0%)0 (0%)2 (100%)2 (100%)0 (0%)2 (100%)2Transient hypogammaglobulinemia of infancy with normal numbers of b cells3 (21%)2 (14%)13 (93%)0 (0%)0 (0%)2 (14%)0 (0%)0 (0%)0 (0%)2 (14%)14 (100%)14Wiskott-Aldrich syndrome0 (0%)20 (37%)33 (61%)0 (0%)1 (2%)6 (11%)3 (6%)2 (4%)9 (17%)5 (9%)39 (72%)54Table 3.Infection types in IEIImmunodeficiencyBacterialViralFungalParasiticAny InfectionTotal count (N = 3511)Agammaglobulinemia129 (50%)81 (32%)23 (9%)12 (5%)235 (91%)257Ataxia telangiectasia8 (31%)7 (27%)3 (12%)0 (0%)24 (92%)26Autoimmune lymphoproliferative syndrome (ALPS)17 (27%)22 (34%)39 (61%)3 (5%)54 (84%)64Autoinflammatory disease1 (8%)2 (17%)0 (0%)0 (0%)9 (75%)12CHARGE syndrome1 (33%)1 (33%)0 (0%)0 (0%)3 (100%)3Chronic granulomatous disease98 (68%)33 (23%)75 (52%)2 (1%)143 (99%)145Combined immune deficiency25 (48%)28 (54%)12 (23%)2 (4%)43 (83%)52Common variable immune deficiency (CVID)503 (36%)332 (23%)218 (15%)35 (2%)1265 (89%)1416Complement deficiency14 (54%)5 (19%)3 (12%)0 (0%)23 (88%)26DiGeorge syndrome51 (10%)53 (11%)29 (6%)0 (0%)171 (34%)496Dyskeratosis congenita0 (0%)0 (0%)0 (0%)0 (0%)1 (100%)1Ectodermal dysplasia with immunodeficiency (nemo and others)19 (79%)10 (42%)3 (12%)0 (0%)24 (100%)24HLH, including XLP and pigmentary disorders5 (31%)5 (31%)2 (12%)0 (0%)13 (81%)16Hyper IgE syndrome72 (75%)29 (30%)63 (66%)4 (4%)91 (95%)96Hyper IgM syndrome14 (30%)16 (34%)19 (40%)4 (9%)44 (94%)47Hypogammaglobulinemia70 (33%)51 (24%)26 (12%)0 (0%)173 (83%)209IgA deficiency24 (35%)13 (19%)5 (7%)0 (0%)66 (97%)68IgG subclass deficiency6 (23%)5 (19%)7 (27%)0 (0%)25 (96%)26Immune deficiency with syndromic features (not otherwise listed)7 (88%)4 (50%)0 (0%)0 (0%)8 (100%)8Immune dysregulation44 (59%)39 (52%)23 (31%)3 (4%)69 (92%)75Immunodeficiency unknown cause11 (58%)8 (42%)4 (21%)0 (0%)16 (84%)19Immunodeficiency with myelodysplasia (GATA2 and others)16 (59%)10 (37%)8 (30%)0 (0%)22 (81%)27Interferonopathy (Aicardi-Goutières and others)2 (29%)3 (43%)1 (14%)0 (0%)4 (57%)7Leukocyte adhesion deficiency9 (100%)6 (67%)4 (44%)0 (0%)9 (100%)9Mucocutaneous candidiasis23 (53%)20 (47%)38 (88%)1 (2%)42 (98%)43Neutropenia1 (50%)0 (0%)0 (0%)1 (50%)2 (100%)2NK cell defect2 (50%)3 (75%)2 (50%)0 (0%)4 (100%)4Omenn syndrome1 (100%)1 (100%)0 (0%)0 (0%)1 (100%)1Other immune deficiency - known cause26 (48%)23 (43%)6 (11%)1 (2%)46 (85%)54Other T-cell problems2 (29%)3 (43%)2 (29%)0 (0%)6 (86%)7Predisposition to severe viral infections17 (57%)21 (70%)13 (43%)3 (10%)26 (87%)30Severe combined immune deficiency (SCID)26 (39%)29 (44%)23 (35%)1 (2%)51 (77%)66Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells49 (51%)27 (28%)18 (19%)1 (1%)96 (99%)97Susceptibility to mycobacteria (MSMD)7 (88%)2 (25%)3 (38%)1 (12%)7 (88%)8TLR pathway abnormality1 (50%)1 (50%)1 (50%)0 (0%)2 (100%)2Transient hypogammaglobulinemia of infancy with normal numbers of b cells6 (43%)3 (21%)1 (7%)0 (0%)14 (100%)14Wiskott-Aldrich syndrome18 (33%)15 (28%)6 (11%)0 (0%)39 (72%)54Table 4.Malignancy in IEIImmunodeficiencyHematologicSolid / LymphomaAny MalignancyTotal count (N = 3511)Agammaglobulinemia2 (1%)0 (0%)2 (1%)257Ataxia telangiectasia4 (15%)2 (8%)5 (19%)26Autoimmune lymphoproliferative syndrome (ALPS)3 (5%)1 (2%)4 (6%)64Autoinflammatory disease1 (8%)0 (0%)1 (8%)12CHARGE syndrome0 (0%)0 (0%)0 (0%)3Chronic granulomatous disease3 (2%)0 (0%)3 (2%)145Combined immune deficiency4 (8%)0 (0%)4 (8%)52Common variable immune deficiency (CVID)126 (9%)14 (1%)135 (10%)1416Complement deficiency0 (0%)0 (0%)0 (0%)26DiGeorge syndrome1 (0%)0 (0%)1 (0%)496Dyskeratosis congenita0 (0%)0 (0%)0 (0%)1Ectodermal dysplasia with immunodeficiency (nemo and others)0 (0%)0 (0%)0 (0%)24HLH, including XLP and pigmentary disorders0 (0%)0 (0%)0 (0%)16Hyper IgE syndrome7 (7%)1 (1%)8 (8%)96Hyper IgM syndrome3 (6%)0 (0%)3 (6%)47Hypogammaglobulinemia14 (7%)2 (1%)16 (8%)209IgA deficiency2 (3%)1 (1%)2 (3%)68IgG subclass deficiency2 (8%)0 (0%)2 (8%)26Immune deficiency with syndromic features (not otherwise listed)0 (0%)0 (0%)0 (0%)8Immune dysregulation6 (8%)1 (1%)6 (8%)75Immunodeficiency unknown cause3 (16%)1 (5%)3 (16%)19Immunodeficiency with myelodysplasia (GATA2 and others)9 (33%)9 (33%)15 (56%)27Interferonopathy (Aicardi-Goutières and others)1 (14%)0 (0%)1 (14%)7Leukocyte adhesion deficiency0 (0%)0 (0%)0 (0%)9Mucocutaneous candidiasis3 (7%)0 (0%)3 (7%)43Neutropenia0 (0%)1 (50%)1 (50%)2NK cell defect1 (25%)0 (0%)1 (25%)4Omenn syndrome0 (0%)0 (0%)0 (0%)1Other immune deficiency - known cause3 (6%)0 (0%)3 (6%)54Other T-cell problems0 (0%)0 (0%)0 (0%)7Predisposition to severe viral infections4 (13%)0 (0%)4 (13%)30Severe combined immune deficiency (SCID)11 (17%)0 (0%)11 (17%)66Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells9 (9%)0 (0%)9 (9%)97Susceptibility to mycobacteria (MSMD)0 (0%)0 (0%)0 (0%)8TLR pathway abnormality0 (0%)0 (0%)0 (0%)2Transient hypogammaglobulinemia of infancy with normal numbers of b cells0 (0%)0 (0%)0 (0%)14Wiskott-Aldrich syndrome4 (7%)2 (4%)6 (11%)54