Edited by: Stephen Jolles, University Hospital of Wales, United Kingdom
Reviewed by: Jolan Eszter Walter, University of South Florida, United States; Francisco Javier Espinosa-Rosales, Fundación Mexicana para Niñas y Niños con Inmunodeficiencias (FUMENI), Mexico
This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Non-infectious complications in common variable immunodeficiency (CVID) have emerged as a major clinical challenge. Detailed clinical spectrum, organ-specific pathologies and associated sequelae from 623 CVID patients followed in New York since 1974 were analyzed, and recent insights to pathogenesis were reviewed. Non-infectious manifestations were present in 68.1% of patients, and they do not tend to be present in isolation. They include autoimmunity (33.2%), chronic lung disease (30.3%), lymphoid hyperplasia/splenomegaly (20.9%), liver disease (12.7%), granulomas (9.3%), gastrointestinal disease (7.3%), lymphoma (6.7%), and other malignancies (6.4%). In the lungs, interstitial disease and bronchiectasis were the most common findings, with lymphoma at this site being a rare (
Common variable immunodeficiency (CVID) is considered a primary defect, characterized by reduced serum levels of immune globulin (Ig) G, IgA, and or IgM, with reduced or absent specific antibody production (
The clinical spectrum of CVID is broad but consist of two main phenotypes: one group with predominantly recurrent infections and a second group with additional autoimmune/inflammatory manifestations. These non-infectious complications may be evident at presentation or may appear afterward, and they include progressive lung disease, autoimmunity, gastrointestinal inflammatory disease, granulomatous disease, liver disease, lymphoid hyperplasia and infiltrative disease, and the development of cancer, especially lymphoma (
Recent investigations of this phenotypic syndrome have led to the discovery of a number of monogenic defects, in ~10–30% of CVID patients, providing potential insights into both pathogenesis and more direct therapies (
Large cohort and registry data have provided key insights into non-infectious complications of CVID (
We detail the clinical spectrum, organ-specific pathologies, and associated sequelae from a cohort of 623 patients (277 males, 346 females) confirmed as having CVID based on standard criteria (
Median serum immunoglobulin levels at diagnosis were IgG, 237 mg/dL; IgA, 7 mg/dL; and IgM, 20 mg/dL. Serum IgG was <100 mg/dL in 24.7%; IgA was <7 mg/dL in 49.2%, IgM was <25 mg/dL in 55.9%. For subjects examined in this way, peripheral B cells were <1% of total lymphocytes in 7.6%; isotype switched memory B cells were <0.55% of total B cells in 35% (
Immunologic parameters.
IgG (mg/dL) | 700–1,600 | 237 (UD−687) |
IgA (mg/dL) | 70–400 | 7 (UD−255) |
IgM (mg/dL) | 40–230 | 20 (UD−945) |
CD3+, % ( |
55–89 | 75.5 (16–98) |
CD3+, cells/mm3 | 750–2,500 | 1,080 (160–5,383) |
CD3+CD4+, cells/mm3 ( |
480–1,700 | 633 (76–2,828) |
CD3+CD8+, cells/mm3 ( |
180–1,000 | 381 (26–3,247) |
CD19+, % ( |
5–15 | 9 (0–58) |
CD19+, cells/mm3 | 75–375 | 146 (0–840) |
Isotype-switched memory B cells | ||
(CD19+CD27+IgD–), % ( |
6.5–29.2 | 1 (0–29) |
In our CVID cohort, 68.1% of the patient had one or more non-infectious complications (
Non-infectious complications.
Infection only | 199 | 31.9 | 26% | NR | NR | NR |
Non-infectious complication | 424 | 68.1 | 74% | NR | NR | NR |
Autoimmunity | 207 | 33.2 | NR | 25.9% | 20.3% | NR |
Chronic lung disease | 189 | 30.3 | NR | 46.4% | NR | NR |
Lymphoid hyperplasia/splenomegaly | 130 | 20.9 | 30% | 26.4% |
40.5% |
25.9% |
Gastrointestinal disease | 108 | 17.3 | 9% | 22.4% |
NR | 21.5% |
Liver disease | 79 | 12.7 | 9% |
NR | NR | 9.3% |
Granulomas | 58 | 9.3 | 8% | NR | 11.6% | 20% |
Lymphoma | 42 | 6.7 | 3% | 1.8% | NR | 5% |
Other malignancies | 40 | 6.4 | 3% | 4.5% | NR | 22% |
The prevalence of autoimmunity, chronic lung disease, gastrointestinal disease, and granulomatous disease was comparable to previously published cohort data (
Lung failure has been a leading cause of death amongst CVID patients. The presence of functional or structural lung impairment is associated with increased mortality (hazard ratio 2.06) (
Chronic lung disease was the most common organ-specific complication in our cohort (
Chronic lung disease.
Tissue histology may be useful to guide the selection of therapeutics for the distinct forms of interstitial disease (
Chronic lung disease may lead to significant morbidity, including progressive structural and/or functional decline, as well as chronic oxygen supplementation requirement. Further complications may also develop from either lymphocytic interstitial lung disease, granulomatous lung disease, or bronchiectasis. Pulmonary hypertension was observed in 5.3% (
Six patients underwent lung transplantation. An additional patient underwent combined lung and liver transplant, but follow-up data were unavailable. Clinical information, including primary lung disease, comorbidity, and outcome, is summarized in
Lung transplant outcomes.
Age, sex | 34, F | 69, F | 38, F | 27, M | 25, M | 63, M |
Lung pathology | Pulmonary fibrosis predominates | ILD (granuloma and lymphoid infiltrate), bronchiectasis | ILD | Chronic obstructive disease | Pulmonary fibrosis predominates | ILD |
CVID-associated comorbidities | Liver disease | None | None | Enteropathy | Lymphoid hyperplasia | NRH, AIHA, ITP, lymphoid hyperplasia |
Transplant procedure | Lung | Lung | Lung | Lung and heart | Lung and heart | Lung |
Outcome | Died of hyperacute rejection within days | Died of acute rejection after 8 months | Died of acute rejection after 1 year | Died of chronic rejection after 5 years | Died of chronic rejection after 6 years | Alive 4 months post-transplant |
Autoimmunity was observed in 33.2% (
Autoimmune manifestations.
Hematologic autoimmunity | 135 | 21.7 |
ITP | 101 | 16.2 |
AIHA | 48 | 7.7 |
Evans syndrome | 29 | 4.7 |
Rheumatoid arthritis |
17 | 2.7 |
Anti-IgA antibody | 8 | 1.3 |
Uveitis | 6 | 1.0 |
Alopecia | 5 | 0.8 |
Autoimmune thyroid disease | 5 | 0.8 |
Others |
<5 | <0.8 |
Gastrointestinal disease and malabsorption in CVID are associated with increased mortality (HR = 2.78 and 2.06, respectively) (
Gastrointestinal disease pathologies by location.
34 | 100 | |
27 | 79.4 | |
Intraepithelial lymphocytosis | 22 | 64.7 |
Villous atrophy/blunting | 11 | 32.4 |
Nodular lymphoid hyperplasia | 3 | 8.8 |
Non-specific inflammation | 3 | 8.8 |
Granulomas | 1 | 2.9 |
17 | 50.0 | |
Non-specific inflammation | 10 | 29.4 |
Nodular lymphoid hyperplasia | 4 | 11.8 |
Granulomas | 3 | 8.8 |
20 | 58.8 | |
Gastritis, NOS |
7 | 20.6 |
Gastropathy, NOS | 7 | 20.6 |
Lymphoid aggregates | 3 | 8.8 |
Metaplasia | 2 | 5.9 |
Granulomas | 1 | 2.9 |
3 | 8.8 | |
Eosinophilic esophagitis | 2 | 5.9 |
Esophagitis, NOS | 1 | 2.9 |
Gastric disease was noted in 58.8% (
In our previous report, we found that the presence of liver disease was also associated with increased risk of mortality (HR = 2.48) (
Liver disease and associated sequelae.
Liver disease-associated sequelae were observed in 32.9% (
Five patients underwent liver transplant due to end stage liver failure. Clinical information, including primary liver disease, comorbidity, and outcome, was summarized in
Liver transplant outcomes.
Age, Sex | 54, F | 46, M | 48, M | 46, M | 40, F |
Liver pathology | Primary sclerosing cholangitis, cholangiocarcinoma | Hepatitis (non-A, non-B) |
Primary biliary cholangitis | Nodular regenerative hyperplasia | Granulomatous liver disease |
CVID-associated conditions | ITP, AIHA | Chronic lung disease | Lung granulomas, splenomegaly | Bronchiectasis | AIHA, s/p splenectomy |
Transplant procedure | Liver | Liver | Liver | Liver | Liver |
Outcome | Died of acute rejection within 1 year | Died of acute rejection within 1 year | Died of infections after 2 years | Alive 3 years post-transplant | Alive 6 years post-transplant, recurrence of granulomas in transplanted liver |
Lymphoma in CVID has been shown to be associated with reduced survival (HR = 2.44) (
Lymphoma types.
39 | |
35 | |
B-cell type, not otherwise specified |
10 |
Diffuse large B cell lymphoma | 10 |
T cell rich B cell lymphoma |
3 |
Plasmacytoid lymphoma | 1 |
Marginal zone lymphoma | 5 |
Extranodal marginal zone lymphoma of MALT | 1 |
Diffuse mixed small and large cell lymphoma | 2 |
Diffuse small cleaved cell lymphoma | 1 |
Diffuse poorly differentiated lymphoma | 1 |
Follicular mixed cell lymphoma | 1 |
3 | |
1 |
Other cancers.
40 | |
Breast cancer | 9 |
Colon cancer | 3 |
Lung cancer | 3 |
Ovarian cancer | 3 |
Gastric cancer | 3 |
Melanoma | 3 |
Cholangiocarcinoma | 2 |
Oral cancer | 2 |
Skin cancer | 2 |
Thyroid cancer | 2 |
Colon, prostate cancer | 1 |
Esophageal cancer | 1 |
Hepatic carcinoid tumor | 1 |
Meningioma | 1 |
Pituitary adenoma | 1 |
Prostate, skin cancer | 1 |
Testicular cancer | 1 |
Vaginal cancer | 1 |
The morbidity and mortality impact of granulomatous disease in CVID may be dependent on its location. While the presence of granuloma in general was not previously associated with shorter survival, granulomas found in lungs and liver may lead to tissue destruction and organ-specific sequelae, as observed here and previously (
Granulomatous disease by locations.
58 | |
Lung | 25 |
Liver | 13 |
Skin | 10 |
Lymph node | 9 |
Eye | 3 |
Brain | 2 |
Gastrointestinal tract | 2 |
Oral | 2 |
Parotid gland | 2 |
Soft tissue | 2 |
Spleen | 2 |
Bone marrow | 1 |
Kidney | 1 |
Mesentery mass | 1 |
Lymphoid hyperplasia and/or splenomegaly were common features, seen in 130 subjects (20.9% of overall cohort). Splenomegaly was recorded in 97 subjects, while lymphadenopathy was recorded in 56 subjects. Twenty-three subjects had concurrent splenomegaly and lymphadenopathy. Fifty-four patients (8.7% of overall cohort) underwent a splenectomy due to either uncontrolled cytopenias (ITP or AIHA) or hypersplenism. Amongst this group, 3 patients (5.6%) had documented sepsis due to an infection after splenectomy. Two additional patients had been hospitalized post-splenectomy for meeting clinical criteria for sepsis, though no positive microbiology was recorded. One of these 5 patients were not on immunoglobulin replacement at the time of sepsis. Rare additional complications had been noted in patients who had undergone splenectomy. As reported previously, 2 subjects developed fistulas to other organs or the exterior skin, and 2 subjects developed unexplained portal hypertension and secondary liver failure (
In the past 2 decades, genetic studies of the CVID phenotype have led to the successful identification of a number of monogenic defects (
Amongst immune regulatory genes, pathogenic variants of nuclear factor kappa B subunit 1 (NF-kB1) are the most common defects in the US and European CVID cohorts (
Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) and cytotoxic T lymphocyte antigen 4 (CTLA4) are closely associated proteins primarily known for the regulation of T cell response, but mutations in both genes have been identified in CVID cohorts (
Phosphoinositide 3-kinase (PI3K) defect is another example of immune regulatory proteins that can lead to prominent antibody deficiency in the setting of broader dysregulation. PI3K contains multiple subunits, including the p110δ (PIK3CD) catalytic subunit and p85α (PIK3R1) regulatory subunit. PI3K is expressed predominantly in hematopoietic cells and is involved in signaling downstream of T and B cell receptors, toll-like receptors (TLRs), co-stimulatory receptors and cytokine receptors (
Other notable monogenic defects that can result in concurrent antibody deficiency and non-infectious complications include: signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) germline mutations, inducible T-cell costimulatory (ICOS) deficiency, IKAROS deficiency, and an interferon regulatory factor-2 binding protein 2 (IRF2BP2) mutation. STAT3 is a transcription factor, regulating multiple processes that includes cellular proliferation, differentiation, as well as autoimmunity. Patients with STAT3 GOF mutations have prominent early-onset multiorgan autoimmune and lymphoproliferative features, though more than half of the subjects (18 of 28) also have hypogammaglobulinemia in a recent systematic review (
Deficiencies in B-cell costimulatory molecules are relatively rare, but can lead to a CVID phenotype. These defects are not known for broad inflammatory complications, but select non-infectious complications have been noted in a few cases. CD19 is a transmembrane protein expressed throughout B cell development until the plasma cells stage. It forms a complex with CD21 and CD81 on the surface of mature B cells and together, they are involved in signal transduction through the B cell receptor. Autosomal recessive mutations in these genes, and also in CD20, lead to defective activation of B cells and hypogammaglobulinemia. Amongst these disorders, nephropathy and thrombocytopenia associated with anti-platelet antibodies have been reported in a child with a homozygous CD81 gene defect (
Lastly, in some cases, mutations in B-cell-specific genes have been heavily associated with autoimmunity and inflammation in CVID, though the molecular pathways leading to such a phenotype are not as obvious. Transmembrane activator calcium-modulating cyclophilin ligand interactor (TACI) is a product of the gene TNFRSF13B, and it is a receptor found on B cells. It binds to B-cell activating factor (BAFF) as well as a proliferation-inducing ligand (APRIL), and supports class-switch recombination, plasma cell differentiation, and antibody secretion during later stages of B-cell development. TACI mutations, usually in the heterozygous state, are enriched in the CVID population (8–10%) (
The complexity of genetic defects in those with the CVID phenotype continues to be revealed. There are currently no definitive answers for when genetic studies should be recommended. While many investigations have focused on subjects with non-infectious complications, monogenic defects have also been identified in as many as ~25% of those without in two large Western cohorts (
In addition to the identification of monogenic defects in a subset of patients, broad adaptive and innate immune dysregulation are increasingly recognized in CVID, especially in those with non-infectious complications. In the B cell compartment, a number of phenotypic changes have been observed, and classifying patients based on this framework has found clinical relevance (
In the T cell compartment, CVID is often characterized by broad and substantial T cell impairments, and in some cases, these defects are associated with overt clinical complications. As seen in our previous report (
A wide range of cytokine defects have also been described in CVID; some of these have been more directly linked to specific cellular defects and/or clinical compilations, and will be highlighted here. First, a lack of IL-2 production has long been observed in CVID, and this was thought to contribute to poor T cell proliferation and function in this disorder. In early clinical trials of recombinant IL-2 treatment, some clinical and immunologic benefits of this approach were indeed observed (
Using whole blood mRNA transcriptional profiling, Park et al. have reported a marked up-regulation of interferon responsive genes in CVID subjects with inflammatory complications when compared to those without such complications and from control subjects (
While broad immunologic abnormalities and inflammatory complications in CVID are likely intrinsic to the underlying genetic and immune defects, a potential influence of environmental stimuli, namely commensal bacteria and their products, has been the subject of ongoing investigation in recent years. Perreau et al. detected high levels of endotoxins in plasma of CVID subjects prior to starting Ig replacement therapy (
While CVID is classified among the B-cell defects, additional cellular defects and immune dysregulation have been recognized in this syndrome over time. This is reflected clinically in the broad spectrum of non-infectious manifestations seen in a significant proportion of patients, which can lead to further sequelae with disease progression and increased mortality compared to those without such complications. The introduction of immunoglobulin replacement therapy has reduced the incidence of severe respiratory tract infections and associated mortality seen in the early years. However, with a lack of effective treatment in many cases, chronic non-infectious inflammatory and autoimmune conditions have emerged as challenging clinical problems in CVID. Recent genetic studies of this phenotype have led to the identification of monogenic defects in both B-cell centric genes and broader immune regulatory genes, providing insights to pathogenesis and potentially more targeted treatments in select patients. Moving forward, further genetic and immunologic understanding of this complex and heterogeneous syndrome is needed for the development of new therapeutic approaches.
All datasets generated for this study are included in the article/supplementary material.
The studies involving human participants were reviewed and approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board. Written informed consent to participate in this study was provided by the participants or participants' legal guardian/next of kin.
HH and CC-R conceived the study, collected data, and drafted manuscript. CC-R provided critical revisions of the manuscript and final approval of the version to be published.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors thank the following clinical staff of the Mount Sinai Immunodeficiency Clinic: Cynthia Medina, Sandy Leon, Monica Reiter-Wong, Aurora Barriga, Nadine Bristol, and Elina Petrosyan. They also thank everyone in the Cunningham-Rundles Laboratory.