Common Variable Immunodeficiency Disease Research Articles

Common Variable Immunodeficiency Presenting with Hodgkin's Disease.

We report a case of a 32 year old man with classic Common Variable Immunodeficiency Disease (CVID) and Hodgkin's disease. Repeated immunoglobulin studies as a child showed hypogammaglobulinemia and decreased mitogen responses, with the suggestion of CVID. He presented to the oncology clinic with nearly three decades of recurrent reactive lymphadenopathy and multiple lymph node biopsies throughout his lifetime, recurrent pulmonary infections, and multiple autoimmune manifestations including diabetes mellitus onset at age 4, autoimmune hemolytic anemia and autoimmune thrombocytopenia. He developed Hodgkin's disease at the age of 30, which has not previously been described in CVID. We also report two other cases of CVID with the diagnosis of non-Hodgkin's lymphoma in the same oncology practice. CVID is a relatively common and yet rarely identified syndrome. Specific treatment is recommended. We suggest that oncologists should be aware of this unusual and yet relatively common disorder that carries up to 400 times the risk for the development of lymphoma (Cunningham-Rundles, C, et al. J Clin Immunol 1987; 7:294–299).

Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature

Granulomatous disease resembling sarcoidosis is a well-described condition associated with common variable immunodeficiency (CVID). Its treatment remains problematic, and new therapeutic options are needed. To report the efficacy of treatment with infliximab, a chimeric anti-tumor necrosis factor alpha monoclonal antibody, in a patient with granulomatous CVID and to review the literature on the treatment of patients with granulomatous CVID. A 22-year-old white man with CVID developed acute multiorgan failure, with granulomatous inflammation on lung and liver biopsy specimens. He was initially treated with antibiotics, intravenous immunoglobulin, and corticosteroids for 5 weeks without improvement. High-dose infliximab was then infused weekly for 6 weeks and then monthly for 9 months. The response to infliximab was determined by changes on clinical examination, imaging studies, and histologic studies. The patient's condition dramatically improved after 1 dose of infliximab infusion, with decreasing hepatosplenomegaly, ventilatory support requirements, and pulmonary infiltrates. Ventilatory support was successfully discontinued within 3 weeks. The corticosteroid dose was tapered without reactivation of the disease. After 9 months of therapy, follow-up imaging studies showed resolution of pulmonary infiltrates, no hepatosplenomegaly, and no portal hypertension, and a percutaneous liver biopsy revealed no granulomas; then, infliximab use was discontinued. The patient remains free of granulomatous disease after 18 months of follow-up. To our knowledge, this is the first report of severe visceral granulomatous CVID successfully treated with infliximab. Infliximab may be an effective therapy for granulomas in CVID. Further studies of infliximab and other tumor necrosis factor a antagonist therapies in granulomatous CVID are warranted.

Granulomatous disease in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency of unknown etiology characterized by low levels of immunoglobulin (Ig)G, failure to make specific antibodies in response to infection or immunization, and variable T-cell abnormalities. Multisystemic granulomatous disease is a well-documented complication of CVID, and its presence is associated with significant morbidity and early mortality. Although the lung is the most common organ system affected, granulomas are also found frequently in other organs, including skin, liver, spleen, and the gastrointestinal tract. Autoimmune disorders are common in these patients, and there appears to be an increased propensity to develop lymphoproliferative disorders. Common physical, radiographic, and laboratory abnormalities in patients with CVID and granulomatous disease include splenomegaly, hilar and mediastinal lymphadenopathy with ground glass or nodular opacities in the lung parenchyma, and reduced T-cell numbers and function. The etiology of granulomatous disease in patients with CVID is unknown, and optimal treatment of granulomatous disease in CVID remains to be established. Further studies are needed to elucidate the underlying etiology of granulomatous lymphoproliferative interstitial lung disease and to delineate appropriate treatments for this disease.

Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID)

Common variable immunodeficiency (CVID) is associated with autoimmunity, most commonly immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA). In a retrospective chart review of 326 CVID patients, 35 (11%) patients had a history of autoimmune hematologic disease. Fifteen patients had ITP, 9 had AIHA, and 11 had Evans syndrome (both ITP and AIHA). The age at diagnosis for CVID ranged from 5 to 66 years and for autoimmunity, from 2 to 66 years. There were 16 males and 19 females. Nineteen patients (54%) had the first episode of thrombocytopenia or hemolytic anemia prior to the diagnosis of immunodeficiency, 11 (32%) were diagnosed concurrently, and 5 (14%) developed one or both of these autoimmune diseases following the diagnosis of CVID. Eight patients were known to have granulomatous changes in one or more organs. Treatments for autoimmunity included corticosteroids, anti-Rh immunoglobulin, and intravenous immunoglobulin; 11 patients underwent splenectomy. While 5 patients had recurrences of autoimmune hemolytic disease while receiving maintenance intravenous immunoglobulin, most episodes occurred for subjects not yet on this therapy ( P < 0.0001). Most patients with frequent infections and hematologic autoimmunity should be evaluated for CVID.

Caseating granulomatous disease in common variable immunodeficiency treated with infliximab

RATIONALE: Non-caseating granulomas have been reported to occur in 5.4%-10% of common variable immunodeficiency (CVID) patients. Caseating granulomas, on the other hand, have been only rarely described. We report a patient with caseating granulomas successfully treated with infliximab. CASE REPORT: A 31-year-old white male, with CVID since age 4 (complicated by splenomegaly and thrombocytopenia, and maintained on IVIG infusions), presented with fever and massive lymphadenopathy in axillae, groins, chest, abdomen and pelvis. Several biopsies showed caseating granulomas. No infectious organisms, including atypical mycobacteria, were identified despite culture of several tissues including bone marrow. Steroids and increasing IVIG infusions resulted in a significant but incomplete response. Six months later, he developed multiple splenic abscesses measuring up to 4 cm in diameter. He also developed an enlarging, thick, oval skin plaque over his back, which, by biopsy, showed a focal granulomatous response. A trial of Rituximab resulted in a transient response and a 4 cm decrease in the size of the spleen. Fever, lymphadenopathy and the skin plaque continued to worsen. He was started on infliximab infusions. Following the third infusion, the plaque was almost completely healed. The lymphadenopathy and splenic abscesses, by CT, were decreased by at least 50%. CONCLUSIONS: TNF-α is believed to be essential for the maintenance of granulomas. Blockade of TNF, especially by infliximab, has resulted in reactivation of granulomatous infections. We have utilized the ability of infliximab to reverse granuloma formation to treat granulomatous disease associated with CVID.

The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency

Recurrent lower respiratory tract infections caused by encapsulated bacteria might cause permanent organ damage in patients with common variable immunodeficiency (CVID). Despite the profound hypogammaglobulinemia, some patients do not experience bacterial pneumonia. We have shown that IgM memory B cells and natural antibodies play an important role in the defense against encapsulated bacteria. In this study we addressed the question of whether the apparent paradox of patients with severe hypogammaglobulinemia but no increased frequency of respiratory infections can be explained by the presence of IgM memory B cells and anti-pneumococcal polysaccharide (anti-PnPS) IgM. We measured the frequency of memory B cells and the levels of anti-PnPS IgM antibodies in 26 patients with CVID with recurrent bacterial pneumonia and bronchiectasis (group 1) and 22 who never had pneumonia and showed no lung lesions (group 2). An additional 6 patients had a clinical history of recurrent pneumonia without lung abnormalities at computed tomographic scanning. Patients of group 1 lacked IgM memory B cells and failed to produce anti-PnPS IgM antibodies, and those of group 2 had a normal frequency of IgM memory B cells and produced anti-PnPS IgM antibodies. IgM memory B cells and anti-PnPS IgM antibodies protect patients with CVID from bacterial pneumonia. Evaluation of these 2 parameters discriminates patients with low or high risk of recurrent infections caused by encapsulated bacteria and low or high risk of bronchiectasis. Identification of high-risk individuals at diagnosis might help in the planning of a more effective therapeutic strategy and prevent permanent organ damage.

Vitamin E deficiency induced neurological disease in common variable immunodeficiency: two cases and a review of the literature of vitamin E deficiency

Vitamin E deficiency causes a neurological disorder characterised by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage. Symptomatic vitamin E deficiency has been reported in genetic defects of the vitamin E transport protein and in malabsorption complicating cholestasis, abetalipoproteinaemia, celiac disease, cystic fibrosis and small bowel resection. There are no reports to date of vitamin E deficiency in patients with primary immunodeficiencies. We describe two CVID patients with the associated enteropathy who developed neurological disease because of vitamin E deficiency, suggesting a possible predisposition to developing this complication. We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae.

SAP is required for generating long-term humoral immunity.

Long-lived plasma cells and memory B cells are the primary cellular components of long-term humoral immunity and as such are vitally important for the protection afforded by most vaccines. The SAP gene has been identified as the genetic locus responsible for X-linked lymphoproliferative disease, a fatal immunodeficiency. Mutations in SAP have also been identified in some cases of severe common variable immunodeficiency disease. The underlying cellular basis of this genetic disorder remains unclear. We have used a SAP knockout mouse model system to explore the role of SAP in immune responses. Here we report that mice lacking expression of SAP generate strong acute IgG antibody responses after viral infection, but show a near complete absence of virus-specific long-lived plasma cells and memory B cells, despite the presence of virus-specific memory CD4+ T cells. Adoptive transfer experiments show that SAP-deficient B cells are normal and the defect is in CD4+ T cells. Thus, SAP has a crucial role in CD4+ T-cell function: it is essential for late B-cell help and the development of long-term humoral immunity but is not required for early B-cell help and class switching.

Granulomatous renal disease in a patient with common variable immunodeficiency

Common variable immunodeficiency (CVID), the most common cause of primary hypogammaglobulinemia, is characterized by a decreased serum immunoglobulin level, recurrent infections, and the occurrence of various autoimmune diseases. Granulomatous disease has been reported previously in several patients with CVID, with granuloma occurring in the lymph nodes, spleen, liver, central nervous system, and bone marrow. We report the first published case of renal granulomatous disease in a CVID patient presenting with subacute renal failure. Renal function partially recovered after corticosteroid treatment and intravenous immunoglobulin infusions. The pathogenesis of granulomatous disease in CVID is unclear but may involve monocyte and T-cell abnormalities. [copy ] 2001 by the National Kidney Foundation, Inc.

Diagnóstico molecular de inmunodeficiencias primarias

Knowledge of the molecular defects responsible for some primary immunodeficiency diseases (PIDs) offers undoubted advantages in establishing a reliable diagnosis. Such knowledge would allow us not only to establish a prognosis but also to instigate the most appropriate therapy. After molecular diagnosis, some patients could benefit from gene therapy. However, apart from the diagnosis of the disease, molecular biological techniques also enable more reliable identification of carriers and, when suggested by the family history and when the familial defect is already known, prenatal diagnosis will also be possible, thus establishing the earliest possible treatment. Using the single-stranded conformational polymorphism technique followed by direct sequencing, we found 22 different mutations in 22 patients from unrelated families and with a phenotype compatible with x-linked agammaglobulinemia. Fourteen of these are new, previously undescribed mutations and the remaining eight are already included in the data base (http://www.uta.fi/imt/bioinfo/Btkbase). Analysis of the female carrier was performed in all the mothers and the mutation was de novo in only one patient. Study of the BtK gene enabled differential diagnosis with common variable immunodeficiency disease in some patients who showed absent or very low lymphocyte B counts as well as forms of autosomal recessive agammaglobulinemia. Using the same techniques, we were able to identify mutations in the CD40 ligand gene in three families in which one of the members had clinical and biological phenotype compatible with X-linked hyper-IgM. Molecular diagnosis was very useful in identifying carriers in these families as well as in making the differential diagnosis among patients with common variable immunodeficiency disease. Purely on this were we able to provide appropriate genetic counseling.

Impact of IgG Replacement Therapy and Antibiotic Treatment on the Colonization of Non-encapsulated Haemophilus Influenzae in the Nasopharynx in Patients with Hypogammaglobulinaemia

Non-typable Haemophilus influenzae (NTHI) and Streptococcus pneumoniae are regarded as the main pathogens in patients with humoral immunodeficiency. These patients have been given IgG replacement therapy since the 1950s. However, a number of individuals still suffer from recurrent episodes of respiratory tract infections. Nasopharyngeal cultures were obtained on a regular basis over a 3-6-month period from 11 patients with common variable immunodeficiency disease in 1989 and 1998. The proportion of cultures positive for NTHI decreased from 56% in 1989-90 to 16% in 1998-99 (p < 0.003). After 9 y of IgG therapy, 7 of the 11 patients were free from NTHI in the nasopharynx. Specific NTHI strains were analysed by pulsed-field gel electrophoresis and compared, with regard to genetic relatedness, on an intra-individual basis. In 1 patient the same NTHI strain was found in both 1989 and 1999. The apparent absence of NTHI from the nasopharynx in most of the patients was assumed to be due to subcutaneous IgG treatment, as well as adequate antibiotic treatment.

H. pylori infection in common variable immunodeficiency disease (CVID)

H. pylori infection in common variable immunodeficiency disease (CVID)

Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency.

Mannose binding lectin (MBL) is an important component of the innate immune response. Low producing MBL alleles are associated with an increased risk of infection, especially when adaptive immunity is already compromized. We investigated the role of MBL polymorphism in common variable immunodeficiency (CVID), a disease of unknown aetiology characterized by defective humoral immunity, recurrent infections and highly variable clinical phenotype. Six biallelic single nucleotide polymorphisms in the MBL promoter and coding region (- 550, - 221, + 4, codons 52, 54 and 57) were haplotyped using a novel PCR-SSP method in 163 CVID patients and 100 controls. Low producing coding alleles and promoter haplotypes were associated with early age of disease onset. The mean age of disease onset was 14.5 years in patients with low producing MBL coding alleles, compared with 25 years in patients with wild type coding regions (t-test P = 0.002). Mean age of onset in patients with the low producing LXPA haplotype was 6.8 years, compared with 29.3 years for the HYPA haplotype (P = 0.003). The MBL + 4 Q allele was associated with autoimmune disease (P = 0.003, OR 4.4). These results suggest that MBL deficiency compounds the antibody deficiency in CVID, and reinforces the ostensible role of MBL in innate immunity. MBL deficiency may also facilitate the development of autoimmune disease in CVID.

Tumor Necrosis Factor (TNF) and Lymphotoxin-α PolymorphismsAssociated With Common Variable Immunodeficiency: Role in thePathogenesis of Granulomatous Disease

Mullighan CG, Fanning GC, Chapel HM, Welsh KIJ Immunol.159199762366241Common variable immunodeficiency is a polygenic disorder of uncertain cause, which is often associated with autoimmune disease. There appear to be several distinct subtypes of common variable immunodeficiency and one subtype includes patients with granulomatous splenomegaly, decreased numbers of circulating CD4 T cells, and lymphadenopathy. This study investigated whether inherited polymorphisms in the MHC class III region (which includes tumor necrosis factor [TNF]-α and lymphotoxin-α) contributed to the development of this subtype of common variable immunodeficiency.Ninety patients with common variable immunodeficiency were studied. Twenty of those 90 patients had granulomas and were felt to belong to a distinct subgroup.Eight HLA class I and class II loci were typed using standard polymerase chain reaction (PCR) methods. Three biallelic TNF-α polymorphisms were genotyped and three lymphotoxin-α polymorphisms were genotyped using allele-specific PCR. Peripheral blood phenotyping was performed using standard flow cytometry techniques.The presence of granulomas correlated strongly with decreased numbers of total T cells, decreased numbers of total B cells, and depletion of naive T cells. This subpopulation of patients with granulomas also had an overrepresentation of the haplotype: A*01−Cw*0701−B*0801−DRB1*0301−DQB1*0201 which contains the TNF-308A polymorphism. In addition, as association between granulomas and the TNF+488A allele was demonstrated.This important study confirms that there is a clinically distinct subset of patients with common variable immunodeficiency and granulomatous disease. This subset appears to have a distinct genetic cause and characteristic derangements of peripheral blood lymphocyte subsets.TNF is essential for the formation of granulomas and this study hypothesized that inherited differences in TNF production might predispose patients to the granulomatous complications of common variable immunodeficiency. In whites, the TNF-308A polymorphism is in linkage disequilibrium with the haplotype cited above, which makes it difficult to prove whether the TNF polymorphism itself is responsible for the granulomatous complications. Despite this limitation, this study makes a compelling case that overproduction of TNF is implicated in the granulomatous complications of common variable immunodeficiency.

Peripheral T Cell Lymphoma in a Patient with Common Variable Immunodeficiency Disease: Case Report and Literature Review

This report documents the occurrence of a peripheral T cell lymphoma arising in the bone marrow and liver of a patient with common variable immunodeficiency disease. The T cell origin of this lymphoma was demonstrated by immunohistochemical phenotyping and gene rearrangement studies and was not associated with EBV infection of the lymphoma cells. The frequency and characteristics of lymphomas complicating CVID are reviewed.

Granulomatous disease in common variable immunodeficiency.

Granulomatous lesions are occasionally found in the lymphoid or solid organs of patients with common variable immunodeficiency. To examine the clinical and immunologic conditions in patients with common variable immunodeficiency who have granulomas. Case series. Large tertiary care medical center. 17 hypogammaglobulinemic patients with common variable immunodeficiency whose organ or tissue biopsy samples contained noncaseating granulomas. Results of lymphocyte function tests. Eight of 17 patients had granulomas at some point before hypogammaglobulinemia was diagnosed. Sixteen of the 17 had deficient T-cell proliferation to mitogens. Although 14 patients received standard treatment with intravenous immunoglobulin, they have had substantial illness, including frequent autoimmune disease. Dysregulated T-cell function or macrophage activation may have been involved in formation of granulomas and increased illness in hypogammaglobulinemic patients with common variable immunodeficiency. Delay in recognition of antibody deficiency may have contributed to the severity of illness in these patients.

Clonal Hematopoiesis and Acquired Thalassemia in Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is defined by hypogammaglobulinemia and increased susceptibility to infections. The gene defect responsible for CVID remains unknown. During the course of their CVID disease, a female and three male patients developed microcytic anemia. The investigation of this anemia forms the basis for this report. Reticulocyte globin chain synthesis studies revealed the abnormal alpha/beta ratios that are pathognomonic of thalassemia. Through transcriptional analysis of the glucose-6-phosphate-dehydrogenase (G6PD) locus of the active X-chromosome in blood cells, we determined that the female patient has clonal reticulocytes, platelets, granulocytes, and B and T lymphocytes. The simultaneous presence of globin synthesis abnormalities and panhypogammaglobulinemia suggests that a common insult at the stem cell level could contribute to the development of CVID and acquired thalassemia.

Multifocal Adenocarcinoma of the Stomach in a Child With Common Variable Immunodeficiency

SummaryThe clinical course of a child who developed an adenocarcinoma of the stomach at 11 years of age is described. At 6 years of age, the child was evaluated for abdominal pain, weight loss, and vomiting. She was found to have hemorrhagic, atrophic gastritis, achlorhydria, and panhypogammaglobulinemia. The gastritis improved with corticosteroid therapy, but relapsed each time that the steroid dosage was tapered. The clinical course was marked by severe growth failure, recurrent infections, and intermittent abdominal pain. Radiographic studies done when the patient was 11 years of age demonstrated a large fungating mass on the lesser curvature of the stomach. Endoscopy and biopsies done 1 year previously had not revealed any sign of malignancy. A radical gastrcctomy was performed. Microscopic studies revealed multifocal adenocarcinoma of the stomach with no evidence of invasion of the submucosa or local lymph nodes. The patient died of Candida septicemia and pneumonia 6 months after the gastrectomy. There was no evidence of recurrence of the tumor on autopsy. The relationship between common variable immunodeficiency and gastrointestinal disease is described.

Childhood common variable immunodeficiency with autoimmune disease

Clinical and laboratory findings in eight patients with childhood common variable immunodeficiency and autoimmune disease are described. Six of the eight patients had initial signs of the disease, persistent secretory diarrhea, recurrent upper respiratory tract infections, or both, in the first year of life. Autoimmune manifestations included idiopathic thrombocytopenia (4/8), hemolytic anemia (3/8), secretory diarrhea (4/8), arthritis (2/8), chronic active hepatitis (2/8), parotitis (2/8), and Guillain-Barré syndrome (2/8). In addition to the expected sinusitis, otitis, and pneumonia caused by encapsulated bacteria, these patients also had severe infections with viruses of the herpes group. Most of these patients had lymphadenopathy, splenomegaly, growth failure, and failure to develop secondary sexual characteristics. Laboratory studies demonstrated a significant increase in the ratio of T cells expressing the T helper phenotype (OKT4) to T cells expressing the T suppressor-cytotoxic phenotype (OKT8) (T4/T8). This increase could be attributed to a decrease in the absolute number of T8 cells. Additional findings included fluctuating levels of serum immunoglobulins and markedly diminished in vitro antibody production by B cells. The clinical course was relapsing and remitting, and dominated by the autoimmune manifestations of the disease. This group of patients constitutes a distinct subset of children with hypogammaglobulinemia, a subset with a complex, multisystemic disorder associated with significant morbidity and mortality.