Hypoglycaemia in a Child Unmasks a Unique Association

Common variable immunodeficiency (CVID) belongs to the diagnostic category of primary immunodeficiency (PID). They are characterized by a heterogeneous group of disorders that include recurrent infections, autoimmunity, granulomatous diseases and malignancies. The incidence of malignancy in CVID patients is around 1.5–20.7% and usually occurs during the 4th–6th decade of life. Non-hodgkin lymphoma is the most frequent malignancy, followed by epithelial tumors of stomach, breast, bladder and cervix. Patients with CVID have a high risk of gastric cancer. It has been suggested that gastric cancer results from an interaction between environmental factors and because of a genetic predisposition. Risk predictors for gastric cancer in the general population and in patients with CVID include Helicobacter pylori infection, Pernicious anemia and p53 gene mutations. Regardless of the presence of pernicious anemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer and are therefore belong to a high-risk population. Here, the authors describe the case of a 47-year-old man who was a known case of CVID and was diagnosed to have carcinoma stomach. He presented with complaints of loss of weight and abdominal fullness. Endoscopy with biopsy revealed a circumferential ulcer proliferative growth which on biopsy was reported as moderately differentiated adenocarcinoma with the presence of Helicobacter pylori. Keywords: Gastric carcinoma, common variable immunodeficiency Cite this Article Devika Sunil, Pavithran K. Uncommon Occurrence of Gastric Adenocarcinoma Occurring in a Patient with Common Variable Immunodeficiency Syndrome. Research & Reviews: Journal of Oncology and Hematology. 2018; 7(1): 16–20p.

Common Variable Immunodeficiency (CVID) in Adults As First Manifestation of (cryptic) Dyskeratosis Congenita

We report on a case of nodular lymphoid hyperplasia (NLH) of the small intestine in a patient with common variable immunodeficiency (CVID) syndrome. The CVID syndrome comprises a group of heterogeneous immunological disorders. It is characterised by hypogammaglobulinemia, recurrent sinopulmonary infections, gastrointestinal disorders (including diarrhea, infestation with Giardia lamblia, chronic-atrophic gastritis and nodular lymphoid hyperplasia (NLH), and an increased risk of malignancy. NLH is frequently associated with gastrointestinal lymphomas. It has also been found in the terminal ileum of children and in adult patients with Gardner's syndrome. NLH is found in about 20% of patients with the CVID syndrome. The diagnosis of NLH requires endoscopic and bioptic-histological examinations and the determination of the immunoglobulins.

Alterations of the X-linked lymphoproliferative disease geneSH2D1A in common variable immunodeficiency syndrome

Diagnosis and Differential Diagnosis of Hypoglycemia

Background and Clinical Significance: Common variable immunodeficiency (CVID) is a primary B-cell immunodeficiency disorder, characterized by severe hypogammaglobulinemia and disturbed antibody production. In addition to increased susceptibility to recurrent respiratory and gastrointestinal infections, CVID can lead to a wide array of complications associated with immune dysregulation, which can also affect the liver. Liver involvement occurs in about 10% of patients with CVID, and can result from a range of causes, including infections, autoimmune disorders, lymphoproliferative conditions, granulomatous inflammation, and infiltrative processes. The most common liver manifestations include nodular regenerative hyperplasia, granulomatous or autoimmune hepatitis, and lymphocytic infiltration. The prevalence, pathophysiology, extent, and prognosis of liver involvement in CVID have not been systematically studied. Case Presentation: The object of this article is to present two patients with CVID-related liver disease and to illuminate the most relevant causes of liver involvement in CVID, describe the clinical features of their liver disease, and summarize the diagnostic and therapeutic approaches for its management. Conclusions: Liver involvement is an expected complication in patients with CVID syndrome. The delayed recognition of this pathology significantly worsens the disease prognosis, making the early detection of this potential complication crucial.

Common variable immunodeficiency can be associated with various hepatic conditions, the most common being nodular regenerative hyperplasia. Multiple cases of liver transplant in adults with common variable immunodeficiency have been reported. Here, we report a 51-year-old man with common variable immunodeficiency and noncirrhotic portal hypertension due to nodular regenerative hyperplasia who underwent liver transplant. The patient received tacrolimus/steroid immunosuppression and remained rejection free; however, he developed cytomegalovirus infection, disseminated nocardiosis, Pseudomonas pneumonia, and Clostridioides difficile- associated colitis. All infections were successfully managed. The graft was well functioning after 18 months; however, alkaline phosphatase remained elevated and a liver biopsy showed evidence of recurrent nodular regenerative hyperplasia. The patient was started on a steroid taper, which led to normalization of the alkaline phosphatase. Two years later, a repeat biopsy confirmed recurrent nodular regenerative hyperplasia. Immunosuppression was kept low, and intravenous immunoglobulin infusions were continued. More than 10 years later, the patient is alive with a functioning graft. This case emphasizes that intensified prophylaxis for infections and less intense immunosuppression may be strategies to enable long-term survival in liver transplant recipients with common variable immunodeficiency and nodular regenerative hyperplasia relapse despite recently reported poor outcomes in this patient population.

Source: Urshel S, Kayikci L, Wintergerst U, et al. Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation. J Pediatr. 2009;154(6):888–894; doi:10.1016/j.jpeds.2008.12.020To characterize the clinical presentation of children with early-onset common variable immunodeficiency (CVID), investigators from Munich, Germany, surveyed patients and reviewed their medical records. To identify study participants, the investigators screened data collected between 1990 and 2004 by the immunology laboratory and the immunodeficiency clinic of a tertiary care center. Study patients had IgG and IgM levels or IgA levels reduced more than two standard deviations (SD) from mean values, evidence of impaired increase of specific antibody titers after vaccination, and recurrent infections. Those with other primary immunodeficiency disorders were excluded.A total of 32 patients with early-onset CVID were analyzed. Among the 32 study patients, 17 were female. The median age at diagnosis was 10.4 years. Most patients had a history of chronic or recurrent infections including bronchitis (88%), pneumonia (78%), sinusitis (78%), otitis media (69%), fungal infections (47%), and various gastrointestinal, skin, oral, and parasitic infections (3%–10%). Eight study children had a history of meningitis and five had culture-proven sepsis. Other clinical manifestations included allergy or allergy-like symptoms (38%); autoimmune diseases were found in 31% of study patients, including hemolytic anemia, thrombocytopenia, arthritis, vasculitis, gluten-sensitive enteropathy, diabetes mellitus, vitiligo, and psoriasis.Overall, 80% of the patients underwent surgical procedures before the diagnosis of CVID was made. Nearly half of the patients had findings suggestive of immunologic disease such as diffuse lymphadenopathy or splenomegaly. Four patients (13%) subsequently developed lymphomas; all survived following chemotherapy. Nine affected children (28%) showed significant growth retardation; of these nine, all had a history of recurrent bronchitis, seven had a history of recurrent pneumonia, and five had a history of allergies and/or diarrhea.At the time of diagnosis, all subjects had serum IgG levels 2 SD or more below the mean; IgM concentrations were reduced in 30 of 32. IgA concentrations were normal in one patient and below detection in 15 of 32. Reduced serum levels of all three immunoglobulin classes were found in 29 of 32 patients. The median duration between symptoms and the definitive diagnosis was 5.8±4.2 years.The authors conclude that CVID’s effects on growth and development are unique to pediatrics but the symptoms and disorders of CVID in children are comparable to the manifestations in adults. Marked delay of diagnosis may be due to the overlap with common pediatric disorders along with lack of familiarity with CVID in children.Dr Nimmagadda has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.CVID is second only to selective IgA deficiency among humoral immunodeficiencies and is thought to have a prevalence of 1:10,000 to 1:50,000. It affects males and females equally.1 CVID is part of a group of genetic disorders that results primarily in hypogammaglobulinemia or failure of antibody production. Patients typically present with recurrent infections, particularly of the respiratory tract, although gastrointestinal disease, autoimmune and inflammatory features, and lymphoma are frequent. Onset of symptoms can occur at any age, although there are peaks in the first and third decades of life. In about 10–20% of patients, other family members are affected.1Over the past few decades, studies on the cells of the immune system in patients with CVID have revealed a spectrum of lymphocyte abnormalities.2 Most patients appear to have normal numbers of B-lymphocytes, but they fail to undergo normal maturation into plasma cells capable of making the different types of immunoglobulins and antibodies. Other patients lack enough function from helper T-lymphocytes necessary for a normal antibody response. A third group of patients have excessive numbers of cytotoxic T-lymphocytes, although the role of these cells in the disease is unclear.The current study highlights the importance of clinical awareness of CVID in younger patients and the frequency of diagnostic delay. CVID usually presents in children as recurrent respiratory infections such as bronchitis, pneumonia, and otitis media, which are managed by primary care physicians until the frequency increases or a sentinel event occurs, prompting further investigation. CVID is under-recognized and underdiagnosed, with an average diagnostic delay of four to seven years from onset of symptoms. These delays in diagnosis often result in long-term sequelae, most commonly bronchiectasis and chronic sinusitis. This permanent damage is responsible for most of the chronic ill health and mortality associated with CVID.3,4The treatment of CVID is similar to that of other disorders characterized by low levels of serum immunoglobulins. In the absence of a significant T-lymphocyte defect or organ damage, immunoglobulin replacement therapy almost always brings improvement of symptoms. Thus, early recognition and diagnosis is critical to optimize the long-term outcome of these patients.

Exogenous leptin restores in vitro T cell proliferation and cytokine synthesis in patients with Common Variable Immunodeficiency Syndrome

Common Variable Immunodeficiency (CVID) and Inclusion Body Myositis (IBM)

A 17-year-old female patient was hospitalized for chronic diarrhea. Since childhood she had experienced recurrent episodes of respiratory tract infections and diarrhea. Endoscopic examination revealed diffuse clustered polypoid nodules in the duodenum. Biopsy specimen showed nodular lymphoid hyperplasia. Common variable immunodeficiency syndrome was suspected and diagnosis was established by demonstrating a significant reduction of plasma gamma-globulin levels. After starting immunoglobulin treatment, daily diarrhea count decreased, and both incidence and severity of respiratory tract infections were significantly reduced. This case report focuses on common variable immunodeficiency syndrome as a potential underlying cause of diarrhea, and the relationship with nodular lymphoid hyperplasia.

Common variable immunodeficiency syndrome (CVID) is a diverse entity characterized by hypogammaglobinemia and a propensity for recurrent infections. Involvement of the gastrointestinal tract has a variable manifestation ranging from asymptomatic involvement to florid signs and symptoms. Due to these incongruous findings, multiple concurrent biopsies are to be done for tissue diagnosis. Here, we present two cases diagnosed with CVID on the basis of clinical findings, lab investigations, and morphological features on biopsy.

Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). The median age on admission and age of diagnosis were 7years (0.3-16.5) and 11years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2years (1-3). In total, one patient died from sepsis during adulthood before HSCT. Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

Common Variable Immuno-Deficiency (CVID) is the most common symptomatic primary antibody-deficiency syndrome, but the basic immunologic defects underlying this syndrome are not well defined. We report here that among eight patients studied (six CVID and two hypogammaglobulinemic patients with recurrent infections), there is in two CVID patients a dramatic reduction in Ig V gene somatic hypermutation with 40-75% of IgG transcripts totally devoid of mutations in the circulating memory B cell compartment. Functional assays of the T cell compartment point to an intrinsic B cell defect in the process of antibody affinity maturation in these two cases.

We reviewed our experience with 30 nodal and extranodal lymphoid lesions from 17 patients with common variable immunodeficiency (CVID). Immunohistochemical studies were performed on biopsies from 15 patients, in situ hybridization for Epstein-Barr virus in nine cases, and gene rearrangement analysis on seven lesions. The biopsies were classified into four groups: malignant lymphoma (two cases); atypical lymphoid hyperplasia (eight cases); reactive lymphoid hyperplasia (14 cases); and chronic granulomatous inflammation (six cases). The two malignant lymphomas were diagnosed using histologic criteria; tissue was not available for the assessment of clonality. In one neoplasm, Epstein-Barr virus was identified in the tumor cells by in situ hybridization. The cases of reactive lymphoid hyperplasia and chronic granulomatous inflammation had no atypical architectural, cytologic, or immunohistochemical features. The cases of atypical lymphoid hyperplasia were of particular interest, as these patients had either widespread involvement or massive disease. The diagnosis of lymphoma was considered likely by the clinicians and, in three cases, the histologic slides were originally interpreted as malignant lymphoma by the referring pathologists. Although the architecture of these lesions appeared to be effaced on hematoxylin and eosin-stained sections, immunohistochemical analysis demonstrated preserved architecture with florid expansion of B-cell and T-cell compartments. In addition, clinical follow-up of these patients was benign, and gene rearrangement analysis in three lesions revealed no evidence of clonality. We conclude that the majority of lymphoid lesions in patients with CVID are benign. Immunohistochemical and gene rearrangement studies are particularly helpful in the assessment of cases of atypical lymphoid hyperplasia.