The fifth edition of the WHO-Classification - what is new for cutaneous lymphomas?

The recently published 5th edition of the "World Health Organization classification of hematolymphoid tumors: lymphoid neoplasms" provides a hierarchical reorganization. In general, new (definitive) entities as well as tumor-like lesions were included. Primary cutaneous B-cell lymphomas (CBCL) received a thorough review. A new class/family of cutaneous follicle center lymphomas was defined. Primary cutaneous marginal zone lymphoma is now presented as a separate entity independent from extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. In primary cutaneous T-cell lymphoma, former provisional entities were upgraded to definite entities. Sézary Syndrome was sorted into the class/family of mature T-cell and NK-cell leukemias. Additionally, a newly formed entity of primary cutaneous peripheral T-cell lymphoma, NOS was created for CTCL entities that do not fit into the already described CTCL entities. The increasing importance of genomic and molecular data has already been recognized in classifying leukemias and systemic lymphomas. However, in PCL the genomic landscape has not yet been fully described and validated. Therefore, future research is necessary to describe the genomic and molecular mechanisms underlying the disease entities more clearly. This would both meet a diagnostic need and valuably contribute to future classification schemes.

Epstein-Barr virus-driven lymphoproliferation in inborn errors of immunity: a diagnostic and therapeutic challenge.

INTRODUCTION: Inborn errors of immunity (IEI) are a group of genetically heterogeneous disorders with a wide-ranging clinical phenotype, varying from increased predisposition to infections to dysregulation of the immune system, including autoimmune phenomena, autoinflammatory disorders, lymphoproliferation, and malignancy. Lymphoproliferative disorder (LPD) in IEI refers to the nodal or extra-nodal and persistent or recurrent clonal or non-clonal proliferation of lymphoid cells in the clinical context of an inherited immunodeficiency or immune dysregulation. The Epstein-Barr virus (EBV) plays a significant role in the etiopathogenesis of LPD in IEIs. In patients with specific IEIs, lack of immune surveillance can lead to an uninhibited proliferation of EBV-infected cells that may result in chronic active EBV infection, hemophagocytic lymphohistiocytosis, and LPD, particularly lymphomas. AREAS COVERED: We intend to discuss the pathogenesis, diagnosis, and treatment modalities directed toward EBV-associated LPD in patients with distinct IEIs. EXPERT OPINION: EBV-driven lymphoproliferation in IEIs presents a diagnostic and therapeutic problem that necessitates a comprehensive understanding of host-pathogen interactions, immune dysregulation, and personalized treatment approaches. A multidisciplinary approach involving immunologists, hematologists, infectious disease specialists, and geneticists is paramount to addressing the diagnostic and therapeutic challenges posed by this intriguing yet formidable clinical entity.

Looking for ALPS: The value of a combined assessment of biochemical markers.

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder caused by defect of the extrinsic apoptotic pathway. The current diagnostic criteria combine clinical features and typical biomarkers but have not been the object of clear international consensus. METHODS: We conducted a retrospective study on pediatric patients who were investigated for autoimmune cytopenia and/or lymphoproliferation at the CHU Sainte-Justine Hospital over 10 years. Patients were screened using the combination of TCRαß+ CD4- CD8- "double negative" (DN) T cells and soluble plasmatic FAS ligand (sFASL). RESULTS: Among the 398 tested patients, the median sFASL and DN T cells were 200 ng/mL and 1.8% of TCRαß+ T cells, respectively. sFASL was highly correlated with vitamin B12 levels. We identified five patients diagnosed with ALPS for whose sFASL and vitamin B12 levels were the more discriminating biomarkers. While ALPS diagnostic criteria had high sensibility, their predictive value remained low. CONCLUSION: sFASL level can efficiently discriminate patients with ALPS when using the appropriate thresholds. Our study highlights the need for an international consensus to redefine the place and threshold of biological biomarkers for ALPS diagnosis.

The Dark Side of Activated Phosphoinositide 3-Kinase-δ Syndrome 2: A Story Rewritten through FDG-PET.

Background: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is characterized by lymphoproliferation and increased risk of malignancy. FDG-PET/CT may represent a helpful diagnostic tool for differentiating these clinical features and correctly diagnosing inborn errors of immunity (IEI). Case report: We present the case of a female patient diagnosed with Hodgkin's lymphoma at 19 years of age, although atypical imaging aspects emerged: baseline FDG-PET/CT revealed several hot lymph nodes with a symmetrical distribution, and increased tracer uptake in spleen, axial, and appendicular bone marrow. Imaging repeated after chemotherapy and autologous stem cell transplantation showed persistent increased FDG uptake at multiple supradiaphragmatic nodes and in bone marrow. After the diagnosis of APDS2 and rapamycin treatment, FDG-PET/CT confirmed complete metabolic normalization of all sites. Conclusions: In the IEI scenario, FDG-PET/CT plays an effective role in differentiating malignant proliferation and immune dysregulation phenotypes. Atypical patterns at FDG-PET/CT should be interpreted as a red flag for the need of an early immunological evaluation.

What is new in the 5th edition of the World Health Organization classification of mature B and T/NK cell tumors and stromal neoplasms?

The classification of tumors is essential in the diagnosis and clinical management of patients with malignant neoplasms. The World Health Organization (WHO) provides a globally applicable classification scheme of neoplasms and it was updated several times. In this review, we briefly outline the cornerstones of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours on lymphoid neoplasms. As is adopted throughout the 5th edition of the WHO classification of tumors of all organ systems, entities are listed by a hierarchical system. For the first time, tumor-like lesions have been included in the classification, and modifications of nomenclature for some entities, revisions of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities are presented along with mesenchymal lesions specific to the stroma of lymph nodes and the spleen. In addition to specific outlines on constitutional and somatic genetic changes associated with given entities, a separate chapter on germline predisposition syndromes related to hematologic neoplasms has been added.

Infections in Disorders of Immune Regulation.

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein-Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject.

Indolent T Cell Lymphoproliferation of the Gastrointestinal Tract: An Evolving Disease Entity.

Background: Indolent T cell lymphoproliferation of the gastrointestinal tract is a novel entity recently added to the 2016 WHO classification of lymphoid neoplasms. Classically, these patients demonstrate an immunophenotype consistent with T cell proliferation and can be either CD4-positive or CD8-positive but with a low Ki67 index, highlighting the indolent nature of this disease compared to its more aggressive T cell lymphoma counterparts such as enteropathy-associated T cell lymphoma and monomorphic epitheliotropic intestinal T cell lymphoma. Methods: Here, we describe one rare case of such a neoplasm under our care, initially presenting with non-specific signs and symptoms and requiring extensive investigations to diagnose. Available cases in the literature reflect a wide variety of ages and ethnicities affected, and any part of the gastrointestinal sites can be affected, which makes diagnosis difficult and prolonged; however, progression beyond lymph nodes is rare, and prognosis is otherwise favourable, particularly if CD8-positive. The optimal management of these patients remains yet to be defined, given the paucity of available cases currently. The current evidence suggests the utility of steroids, cyclosporine, radiotherapy, and a potential role for JAK inhibitors. Conclusions: Our case showed an excellent response to the initial course of steroids, with a subsequent successful transition to cyclosporine, keeping symptoms at bay with ongoing stable disease.

Enrichment of Immune Dysregulation Disorders in Adult Patients with Human Inborn Errors of Immunity.

Human inborn errors of immunity (IEI) comprise a group of diseases resulting from molecular variants that compromise innate and adaptive immunity. Clinical features of IEI patients are dominated by susceptibility to a spectrum of infectious diseases, as well as autoimmune, autoinflammatory, allergic, and malignant phenotypes that usually appear in childhood, which is when the diagnosis is typically made. However, some IEI patients are identified in adulthood due to symptomatic delay of the disease or other reasons that prevent the request for a molecular study. The application of next-generation sequencing (NGS) as a diagnostic technique has given rise to an ever-increasing identification of IEI-monogenic causes, thus improving the diagnostic yield and facilitating the possibility of personalized treatment. This work was a retrospective study of 173 adults with IEI suspicion that were sequenced between 2005 and 2023. Sanger, targeted gene-panel, and whole exome sequencing were used for molecular diagnosis. Disease-causing variants were identified in 44 of 173 (25.43%) patients. The clinical phenotype of these 44 patients was mostly related to infection susceptibility (63.64%). An enrichment of immune dysregulation diseases was found when cohorts with molecular diagnosis were compared to those without. Immune dysregulation disorders, group 4 from the International Union of Immunological Societies Expert Committee (IUIS), were the most prevalent among these adult patients. Immune dysregulation as a new item in the Jeffrey Model Foundation warning signs for adults significantly increases the sensitivity for the identification of patients with an IEI-producing molecular defect.

Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model.

Introduction: Leaky gut has been linked to autoimmune disorders including lupus. We previously reported upregulation of anti-flagellin antibodies in the blood of lupus patients and lupus-prone mice, which led to our hypothesis that a leaky gut drives lupus through bacterial flagellin-mediated activation of toll-like receptor 5 (TLR5). Methods: We created MRL/lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice. Result: Contrary to our hypothesis that the deletion of Tlr5 would attenuate lupus, our results showed exacerbation of lupus with Tlr5 deficiency in female MRL/lpr mice. Remarkably higher levels of proteinuria were observed in Tlr5 -/- MRL/lpr mice suggesting aggravated glomerulonephritis. Histopathological analysis confirmed this result, and Tlr5 deletion significantly increased the deposition of IgG and complement C3 in the glomeruli. In addition, Tlr5 deficiency significantly increased renal infiltration of Th17 and activated cDC1 cells. Splenomegaly and lymphadenopathy were also aggravated in Tlr5-/- MRL/lpr mice suggesting impact on lymphoproliferation. In the spleen, significant decreased frequencies of regulatory lymphocytes and increased germinal centers were observed with Tlr5 deletion. Notably, Tlr5 deficiency did not change host metabolism or the existing leaky gut; however, it significantly reshaped the fecal microbiota. Conclusion: Global deletion of Tlr5 exacerbates lupus-like disease in MRL/lpr mice. Future studies will elucidate the underlying mechanisms by which Tlr5 deficiency modulates host-microbiota interactions to exacerbate lupus.

Interim analysis: Open-label extension study of leniolisib for patients with APDS.

BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. RESULTS: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P = .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727.

[Unusual gluteal localization of unicentric Castleman's disease: A case report and review of the literature]. / Localisation intramusculaire d'une maladie de Castleman unicentrique : cas clinique et revue de la littérature.

BACKGROUND: Castleman's disease is a rare and benign lymphoproliferative disorder which can be unicentric (UCD) or multicentric (MCD). UCD usually involves a single lymph node or less frequently a group of lymph nodes. The most common sites of nodal UCD presentation are the mediastinum, neck, abdomen and retroperitoneum. Rarely extranodal involvement has been reported. The intramuscular location is very unusual with only about 10 cases described in medical literature so far. CASE REPORT: We present a case of atypical localization of Castleman's disease occurring in the right gluteal area in a 40-years-old female patient. The patient was asymptomatic and clinical examination was unremarkable except for a right gluteal palpable mass. The CT scanner-guided needle core biopsy was inconclusive. A surgical excision was then performed that revealed a hyaline-vascular type of Castleman's disease. The patient has an uneventful post-operative course. CONCLUSION: The present case is instructive in the work-up of primary soft tissue tumors, for which Castleman's disease is extremely rare and not considered in the differential diagnosis of clinicians. Pathologists must be aware of its existence so that it can be evoked in the presence of a lymphoid population on histological examination.

Clinical features and outcomes in patients with human immunodeficiency virus-negative, Castleman's disease: a single medical center study in Tunisia.

INTRODUCTION: Castleman's disease (CD), known as angiofollicular lymph node hyperplasia, is an uncommon condition. The two most common histological subtypes are hyaline vascular and plasma cell. We performed a retrospective analysis to define the clinic-pathological features and survival of CD, which is quite rare focusing on the particularities of our series with a review of the recent literature. METHODS: This is a retrospective study conducted in the department of internal medicine of Hedi Chaker hospital in Sfax, Tunisia over 25 years. The disease was histologically confirmed in all patients. For each file, we collected a set of data by filling in a pre-designed form. RESULTS: 18 patients were included. There were 8 men and 10 women with a mean age of 42.8 years. CD was monocentric in 5 cases (28%) and multicentric in 13 cases (72%). Clinically, peripheral adenopathy was present in 77.7% of patients and deep adenopathy in 72.2%. Systemic signs were found in 13 patients, including general condition (4.4%), fever (16.6%), serositis (27.7%), and skin involvement (33.3%). A biological inflammatory syndrome accompanied the clinical picture in 66% of patients. Abnormalities in the blood count were found in 12 cases (66%), with anemia in 11 cases, thrombocytosis in 3 cases, and hypereosinophilia in 3 cases. Cutaneous Kaposi's sarcoma was associated with Castleman's disease in 2 cases, Hodgkin's lymphoma, angioimmunoblastic T-cell lymphoma, and lymph node T-cell lymphoma were found in 1 case respectively. 3 of the patients had associated connective tissue diseases such as Sjögren's syndrome in 2 cases and rheumatoid arthritis in 1 case. HHV8 serology was positive in 1 case with a multicentric plasma cell form. Histologically, the plasma cell form represented 50% of cases, hyaline-vascular (39% of cases), and mixed (11% of cases). Therapeutically, high-dose corticosteroid therapy was initiated in 13 cases. As a second-line treatment, MOPP chemotherapy was used in 1 case due to transformation into Hodgkin's lymphoma, and biotherapy (rituximab) was used in 2 cases in the multicentric form. Surgical removal of superficial adenopathy was performed in 2 patients with monocentric CD. CONCLUSION: : Castleman's disease (CD) is a non-malignant lymphoproliferation of localized or multicentric form with a wide and heterogeneous clinical spectrum. Diagnosis can be difficult due to the lack of clinical and radiological specificity. Management depends on the clinical form involving surgical and/or medical management.

High occurrence of autoimmune and lymphoproliferative manifestations in adults with common variable immunodeficiency in southernTaiwan.

There are no reported case series of common variable immunodeficiency (CVID) from southern Taiwan. A 20-year review was performed in adult CVID from a southern Taiwan medical center. Patients with ages of 18 years or older were enrolled from May, 2003 to April, 2023. Twelve patients were identified, 8 females/4 males aged 23 to 68 (38.9 ± 13.4) with one to 11 years (5.0 ± 3.3) delay of diagnosis after disease onset. There were concomitant autoimmune disorders in 7 (58 %), splenomegaly in 10 (83 %), lymphadenopathy in 4 (25 %) and B-cell lymphoma in 2 (17 %). All received intravenous immunoglobulin (IVIg) infusion with improved autoimmune-mediated arthritis in 2. Patients with higher IgG trough levels (above 500 mg/dL) had a better survival than those with lower IgG trough levels. Adult CVID in southern Taiwan has a high occurrence of autoimmune and lymphoproliferative manifestations. Early diagnosis with IVIg infusion might improve the presentations.

Understanding the Spectrum of Immune Dysregulation Manifestations in Autoimmune Lymphoproliferative Syndrome and Autoimmune Lymphoproliferative Syndrome-like Disorders.

As a disorder of immune dysregulation, autoimmune lymphoproliferative syndrome (ALPS) stems from pathogenic variants in the first apoptosis signal-mediated apoptosis (Fas) and Fas-ligand pathway that result in elevations of CD3+ TCRαß+ CD4- CD8- T cells along with chronic lymphoproliferation, a heightened risk for malignancy, and importantly for the rheumatologist, increased risk of autoimmunity. While immune cytopenias are the most encountered autoimmune phenomena, there is increasing appreciation for ocular, musculoskeletal, pulmonary and renal inflammatory manifestations similar to more common rheumatology diseases. Additionally, ALPS-like conditions that share similar clinical features and opportunities for targeted therapy are increasingly recognized via genetic testing, highlighting the need for rheumatologists to be facile in the recognition and diagnosis of this spectrum of disorders. This review will focus on clinical and laboratory features of both ALPS and ALPS-like disorders with the intent to provide a framework for rheumatologists to understand the pathophysiologic drivers and discriminate between diagnoses.

An Unusual Case of Recurrent Gingival Epstein-Barr Virus-Positive B-Cell Lymphoproliferation.

Epstein-Barr virus (EBV)-positive mucocutaneous ulceration commonly presents as a B-cell lymphoproliferative process with manifold aspects. There is scarce data on its oral manifestation in the scientific literature. We report the case of a 57-year-old male immunocompromised renal transplant patient who developed recurrent chronic and symptomatic mucosal ulceration facing the mandibular incisor teeth. Pathological examination with microscopic and immunohistochemistry studies revealed a B plasma cell infiltration as well as positive staining for EBV, leading to a diagnosis of EBV-positive mucocutaneous ulceration with B-cell lymphoproliferation after extensive workup. Treatment with rituximab was implemented and led to the healing of the lesion. This lesion develops in geriatric and immunodeficient patients and may require oncological therapies. While it is generally associated with an excellent prognosis, it may be indicative of underlying immunosuppression, and hence oral cavity specialists must be aware of this particular entity.

EBV Reactivation and Lymphomagenesis: More Questions than Answers.

PURPOSE OF REVIEW: Epstein-Barr Virus (EBV) is a ubiquitous herpesvirus that affects almost all humans and establishes lifelong infections by infecting B-lymphocytes leading to their immortalization. EBV has a discrete life cycle with latency and lytic reactivation phases. EBV can reactivate and cause lymphoproliferation in both immunocompetent and immunocompromised individuals. There is sparse literature on monitoring protocols for EBV reactivation and no standardized treatment protocols to treat EBV-driven lymphoproliferation. RECENT FINDINGS: While there are no FDA-approved therapies to treat EBV, there are several strategies to inhibit EBV replication. These include immunosuppression reduction, nucleoside analogs, HDAC inhibitors, EBV-specific cytotoxic T-lymphocytes (CTLs), and monoclonal antibodies, such as rituximab. There is currently an open clinic trial combining the use of a HDAC inhibitor, nanatinostat, and ganciclovir to treat refractory/relapsed EBV lymphomas. Another novel therapy includes tabelecleucel, which is an allogenic EBV-directed T-cell immunotherapy that was approved by the European Medicines Agency, but is currently only available in the US for limited use in relapsed or refractory EBV-positive PTLD. Further research is needed to establish EBV monitoring protocols in high-risk populations, such as those with autoimmune disease, cancer, HIV, or receiving immunosuppressive therapy. Additionally, standardized treatments for both the prevention of EBV reactivation in high-risk populations and treatment of EBV reactivation and lymphoproliferation need to be established.

Phenotyping of lymphoproliferative tumours generated in xenografts of non-small cell lung cancer.

Background: Patient-derived xenograft (PDX) models involve the engraftment of tumour tissue in immunocompromised mice and represent an important pre-clinical oncology research method. A limitation of non-small cell lung cancer (NSCLC) PDX model derivation in NOD-scid IL2Rgammanull (NSG) mice is that a subset of initial engraftments are of lymphocytic, rather than tumour origin. Methods: The immunophenotype of lymphoproliferations arising in the lung TRACERx PDX pipeline were characterised. To present the histology data herein, we developed a Python-based tool for generating patient-level pathology overview figures from whole-slide image files; PATHOverview is available on GitHub (https://github.com/EpiCENTR-Lab/PATHOverview). Results: Lymphoproliferations occurred in 17.8% of lung adenocarcinoma and 10% of lung squamous cell carcinoma transplantations, despite none of these patients having a prior or subsequent clinical history of lymphoproliferative disease. Lymphoproliferations were predominantly human CD20+ B cells and had the immunophenotype expected for post-transplantation diffuse large B cell lymphoma with plasma cell features. All lymphoproliferations expressed Epstein-Barr-encoded RNAs (EBER). Analysis of immunoglobulin light chain gene rearrangements in three tumours where multiple tumour regions had resulted in lymphoproliferations suggested that each had independent clonal origins. Discussion: Overall, these data suggest that B cell clones with lymphoproliferative potential are present within primary NSCLC tumours, and that these are under continuous immune surveillance. Since these cells can be expanded following transplantation into NSG mice, our data highlight the value of quality control measures to identify lymphoproliferations within xenograft pipelines and support the incorporation of strategies to minimise lymphoproliferations during the early stages of xenograft establishment pipelines.

Clinical manifestations and approach to the management of patients with common variable immunodeficiency and liver disease.

Purpose: The clinical spectrum of common variable immunodeficiency (CVID) includes predisposition to infections, autoimmune/inflammatory complications and malignancy. Liver disease is developed by a proportion of patients with CVID, but limited evidence is available about its prevalence, pathogenesis and prognostic outcome. This lack of evidence leads to the absence of guidelines in clinical practice. In this study, we aimed at defining the characteristics, course and management of this CVID complication in Spain. Methods: Spanish reference centers were invited to complete a cross-sectional survey. Thirty-eight patients with CVID-related liver disease from different hospitals were evaluated by a retrospective clinical course review. Results: In this cohort, abnormal liver function and thrombocytopenia were found in most of the patients (95% and 79% respectively), in keeping with the higher incidence of abnormal liver imaging and splenomegaly. The most common histological findings included nodular regenerative hyperplasia (NRH) and lymphocytic infiltration, which have been associated with portal hypertension (PHTN) leading to a poorer prognosis. Autoimmune/inflammatory complications occurred in 82% of the CVID patients that developed liver disease and 52% of the patients treated with immunomodulators showed a reduction in the liver function tests' abnormalities during treatment. Among the experts that conducted the survey, there was 80% or more consensus that the workup of CVID-related liver disease requires liver profile, abdominal ultrasound and transient elastography. The majority agreed that liver biopsy should be essential for diagnosis. There was 94% consensus that endoscopic studies should be performed in the presence of PHTN. However, there was 89% consensus that there is insufficient evidence on the management of these patients. Conclusion: Liver disease varies in severity and may contribute substantially to morbidity and mortality in patients with CVID. Hence the importance of close follow-up and screening of this CVID complication to prompt early targeted intervention. Further research is needed to evaluate the pathophysiology of liver disease in patients with CVID to identify personalized treatment options. This study emphasizes the urgent need to develop international guidelines for the diagnosis and management of this CVID complication.