Primary immune regulatory disorders (PIRD): expanding the mutation spectrum in Turkey and identification of sixteen novel variants.

Human Inborn Errors of Immunity (IEIs) encompass a clinically and genetically heterogeneous group of disorders, ranging from mild cases to severe, life-threatening types. Among these, Primary Immune Regulatory Disorders (PIRDs) constitute a subset of IEIs characterized by diverse clinical phenotypes, prominently featuring severe atopy, autoimmunity, lymphoproliferation, hyperinflammation, autoinflammation, and susceptibility to malignancies. According to the latest report from the International Union of Immunological Societies (IUIS), PIRDs arise from mutations in various genes including LYST, RAB27A, AP3B1, AP3D1, PRF1, UNC13D, STX11, STXBP2, FAAP24, SLC7A7, RASGRP1, CD70, CTPS1, RLTPR, ITK, MAGT1, PRKCD, TNFRSF9, SH2DIA, XIAP, CD27 (TNFRSF7), FAS (TNFRSF6), FASLG (TNFSF6), CASP10, CASP8, FADD, LRBA, STAT3, AIRE, ITCH, ZAP70, TPP2, JAK1, PEPD, FOXP3, IL2RA, CTLA4, BACH2, IL2RB, DEF6, FERMT1, IL10, IL10RA, IL10RB, NFAT5, TGFB1, and RIPK1 genes. We designed a targeted next-generation sequencing (TNGS) workflow using the Ion AmpliSeq™ Primary Immune Deficiency Research Panel to sequence 264 genes associated with IEIs on the Ion S5™ Sequencer. In this study, we report the identification of 38 disease-causing variants, including 16 novel ones, detected in 40 patients across 15 distinct PIRD genes. The application of next-generation sequencing enabled rapid and precise diagnosis of patients with PIRDs.

Psychosocial Evaluation of Adults with Primary Immunodeficiency.

PURPOSE: Primary immunodeficiency disorder (PID) is a heterogeneous group of diseases characterized by immune dysregulation and increased susceptibility to infections, with various cognitive, emotional, behavioral, and social effects on patients. This study aimed to evaluate loneliness, social adaptation, anxiety, and depression and to identify associated factors in adults with immunodeficiency. METHODS: A cross-sectional study in Turkey (Feb-Aug 2022) obtained sociodemographic data from patient records. The Social Adaptation Self-Evaluation Scale (SASS), UCLA-Loneliness Scale (UCLA-LS), and Hospital Anxiety and Depression Scale (HADS) were administered in individual patient interviews. HADS-Anxiety (HADS-A) and HADS-Depression (HADS-D) scores were assessed using cut-offs of 10 and 7, respectively; SASS cut-offs for social imbalance and normalcy were < 25 and > 35, respectively. RESULTS: A total of 104 patients (60 women, 44 men) with a median age of 34 years (range: 18-89) were included in the study. Mean scores were SASS: 34.46 ± 8.11, UCLA-LS: 44.89 ± 12.66, HADS-A: 9.87 ± 4.77, and HADS-D: 9.12 ± 4.80. SASS score was negatively correlated with HADS-A, HADS-D, and UCLA-LS scores. There were positive correlations between UCLA-LS and HADS-A (r = -0.355, p < 0.01) and HADS-D (r = -0.614, p < 0.01) and between HADS-A and HADS-D (r = -0.454, p < 0.01). Low-income level was associated with higher HADS-A, HADS-D, and UCLA-LS scores and lower SASS score (p = 0.012, p = 0.041, p = 0.008, and p = 0.001, respectively). CONCLUSION: Adults with PID are at risk for depression and experience high levels of loneliness. Social maladjustment and loneliness contribute to anxiety and depression, and loneliness is correlated with impaired social functioning. These findings emphasize the importance of biopsychosocial evaluation of individuals diagnosed with PID.

Comparison of chest computed tomography and 3-T magnetic resonance imaging results in patients with common variable immunodeficiency.

BACKGROUND: Patients with common variable immunodeficiency (CVID) have an increased incidence of pulmonary infections and require frequent follow-up computed tomography (CT) scans. PURPOSE: To evaluate the diagnostic performance of 3-T magnetic resonance imaging (MRI) in patients with CVID. MATERIAL AND METHODS: In this prospective study, 3-T MRI was performed in 20 patients with CVID. The patients were imaged with CT and MRI scans on the same day. The MRI protocol included a T2-weighted HASTE sequence (TR=1400 ms, TE=95 ms, slice thickness (ST)=3 mm), T2-weighted BLADE sequence (TR=5379 ms, TE=100 ms, ST=3 mm), and 3D VIBE sequence (TR=3.9 ms, TE=1.32 ms, ST=3 mm). Mediastinal and parenchymal changes were compared. A modified Bhalla scoring system was used in the evaluation of CT and MRI scans. RESULTS: A total of 17 (85%) patients had parenchymal abnormalities identified by CT or MRI. Similar findings were detected with CT and MRI in the assessment of the severity of bronchiectasis (P=0.083), bronchial wall thickening (P=0.157), and mucus plugging (P=0.250). Consolidations were detected with both modalities in all patients. There was excellent concordance between the two modalities in the evaluation of nodules >5 mm (nodule size 5-10 mm, P=0.317; nodule size >10 mm, P=1). However, MRI failed to detect most of the small nodules (<5 mm). CONCLUSION: 3-T MRI detected mediastinal and parenchymal alterations in patients with CVID and provided findings that correlated well with CT. Despite a few limitations, MRI is a well-suited radiation-free technique for patients requiring longitudinal imaging.

Spectrum of Hepatic Manifestations of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.

Gastrointestinal findings in 26 adults with common variable immunodeficiency: The fickle nature of the disease manifests in gastrointestinal biopsies.

BACKGROUND/AIMS: The aim of the present study was to demonstrate the histopathological findings in gastrointestinal (GI) biopsies in adults with common variable immunodeficiency (CVID). MATERIALS AND METHODS: A total of 172 GI biopsies of 26 patients with CVID obtained over a 16-year period were reevaluated. Findings were analyzed using descriptive analyzes and χ2 test. RESULTS: Female-to-male ratio was 1.36. The median age at diagnosis was 36±13.94 (16-72) years. Chronic esophagitis was noted in 3 patients. The absence of plasma cells in the stomach, duodenum, and colon was observed in 16, 14, and 9 patients, respectively. Divergent results for the presence of plasma cells in concurrent stomach and duodenum samples were found in 11 (44%) patients. Nodular lymphoid hyperplasia (NLH) was notable in the duodenum (56%). The mean number of eosinophils in one high-power field was significantly higher in duodenal biopsies with NLH (27.21 vs. 14.37, p=0.002). Active inflammation was more prominent in the colon (91%) than in the stomach (65%) and duodenum (60%). Helicobacter pylori infection was found in 57.6%, including a case with persistent infection by the coccoid form. Celiac-like villous blunting and increased intraepithelial lymphocytes were seen in 40% and 24%, respectively. In addition, 23% had giardiasis associated with acute duodenitis and duodenal NLH (p<0.05). CONCLUSION: CVID gastroenteropathy is a challenging entity, and due to the heterogeneity in the presence and distribution of plasma cells throughout the GI tract and diverse disease course, multiple concurrent biopsies may be needed for tissue diagnosis. Duodenal CVID may present with villous alterations and giardiasis, and NLH appears to be an important clue in the duodenum. The association between duodenal NLH and eosinophil infiltration deserves further investigation.

Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity.

BACKGROUND: The actin-interacting protein WD repeat-containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. OBJECTIVE: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects. METHODS: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes. RESULTS: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation. CONCLUSION: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses.

Misleading Allergens in the Diagnosis of Latex Allergy: Profilin and Cross-Reactive Carbohydrate Determinants.

BACKGROUND: It has been suggested that latex-specific IgE analysis may lead to false-positive results, especially in patients with pollen allergy. In the present study, the reasons underlying clinically irrelevant latex-specific IgE positivity were investigated. METHODS: Thirty patients with latex allergy (group 1), 89 patients sensitised to aeroallergens (group 2a), and 98 healthy individuals without allergy (group 2b) were enrolled. Participants from all 3 groups were subjected to skin prick tests with aeroallergens including latex, latex-specific IgE analysis (ImmunoCAP), and nasal provocation test with latex. All cases demonstrating positive latex-specific IgE also underwent specific IgE tests (ImmunoCAP) with latex profilin, birch pollen profilin, peach lipid transfer protein, and pineapple bromelain as cross-reactive carbohydrate determinants. RESULTS: Comparison of the atopic and healthy control groups showed that the rate of positive latex-specific IgE was significantly higher in group 2a. Latex profilin-, birch pollen profilin-, and bromelain-specific IgE were remarkably higher in group 2a. CONCLUSION: False positivity to latex-specific IgE in ImmunoCAP analysis may be observed in approximately 19% of patients with pollen allergy. Profilins and bromelain are the main contributors to clinically irrelevant positive latex-specific IgE.

Incidence of Parasitic Diarrhea in Patients with Common Variable Immune Deficiency.

OBJECTIVE: Parasites might cause atypical and severe infections in immunocompromised hosts. The prevalence of diarrhea among common variable immune deficiency (CVID) syndrome patients varies between 20% and 94%, which indicates that diarrhea and gastrointestinal system (GIS) complaints could be the second leading cause of morbidity in CVID patients after respiratory tract infections. This study aimed to assess the prevalence of intestinal parasites in CVID patients with GIS complaints and diarrhea. METHODS: In this study, all cases followed up in the Immunology and Allergy Clinic of Ege University School of Medicine from July 2008 to August 2015 with the diagnosis of CVID were reviewed retrospectively. The stool samples of patients with diarrhea were identified using direct microscopy of native (0.09% NaCl) and Lugol's iodine preparations followed by formol-ethyl acetate concentration to apply modified Kinyoun, trichrome, acid-fast trichrome, and modified trichrome stains for the presence of intestinal parasites. RESULTS: Overall, 26 of 37 CVID patients had diarrhea; white and red blood cells (WBCs and RBCs, respectively) were identified in 11 and 10 of these 26 samples, respectively. Intestinal parasites were found to be present in 7 of the 11 patients with WBCs and 3 of the 10 patients with RBCs. With the addition of patients who neither had WBCs nor RBCs in their stool, a parasitic agent was detected in 13 (50%) of the 26 patients with diarrhea. There was no significant difference between the diarrheic patients with or without intestinal parasites with respect to cramps, fever, nausea and vomiting, tenesmus, bloody feces, and presence of mucus in the stool. Only one patient had malabsorption, which was not associated with intestinal parasites. The most common parasites detected in this study were Cryptosporidium spp. (n=9; 69.2%), Giardia spp. (n=7; 53.8%), and Blastocystis spp. (n=3; 23.1%). We also identified that parasitic diarrhea in CVID patients tended to last longer (M (mean): 16.2 days) than other causes of infectious diarrhea; this is in accordance with previous studies. CONCLUSION: Cryptosporidium spp. was found be the major cause of parasitic intestinal infection in this patient population. It was concluded that parasitic infections may cause chronic diarrhea, which are major causes of morbidity in CVID patients. Therefore, special attention is necessary for the identification of intestinal parasites in CVID patients with diarrhea.

ß2-Microglobulin deficiency causes a complex immunodeficiency of the innate and adaptive immune system.

BACKGROUND: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described ß2-microglobulin (ß2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. OBJECTIVE: We sought to describe the molecular and immunologic features of ß2m deficiency in 2 Turkish siblings with new diagnoses. METHODS: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry. RESULTS: Here we provide the first extensive clinical and immunologic description of ß2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of ß2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except ß2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." CONCLUSION: The clinical presentation of patients with ß2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of ß2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency.

Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. OBJECTIVE: We sought to define the outcomes of HSCT for patients with CVID. METHODS: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. RESULTS: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. CONCLUSION: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.

Phagocytic and oxidative burst activity of neutrophils in patients with spinal cord injury.

OBJECTIVE: To evaluate phagocytic activity and neutrophil oxidative burst functions in patients with spinal cord injury (SCI) because alterations in neutrophil metabolic activity can be one of the causes of immune mechanism damage contributing to repeated bacterial infections. DESIGN: A controlled and cross-sectional study. SETTING: Departments of physical medicine and rehabilitation and immunology. PARTICIPANTS: Patients with SCI (N=34) and 28 healthy controls. INTERVENTIONS: Phagocytosis and oxidative burst in whole-blood neutrophils were assessed by flow cytometry. The percentage of phagocytizing cells after in vitro incubation with Escherichia coli, phagocytic activity (mean intensity of fluorescence [MIF]) and the percentage of neutrophiloxidative burst, and the MIF value of the production of reactive oxygen intermediates (ROIs) were analyzed. In addition, clinical assessment including the level of injury, American Spinal Injury Association scores, and functional status were carried out. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Although the percentage of E. coli phagocytizing neutrophils was not different between groups, the MIF value of absorbed E. coli was significantly lower in patients with SCI than in controls (P<.05). The MIF value of ROI production by neutrophils with both stimulator of phorbol 12-myristate 13-acetate and E. coli was significantly higher in patients with SCI (P<.05). CONCLUSIONS: In patients with SCI, decreased phagocytic activity of neutrophils may be a result of a regulatory mechanism to minimize the deleterious effects of increased neutrophil burst activity.

Desensitization effect of preseasonal seven-injection allergoid immunotherapy with olive pollen on basophil activation: the efficacy of olive pollen-specific preseasonal allergoid immunotherapy on basophils.

BACKGROUND: It has previously been demonstrated that subcutaneous immunotherapy with allergoids positively affects clinical and immunological parameters even after 7 preseasonal injections. However, its effect on basophil activation remains unclear. We investigated the effect of preseasonal allergoid immunotherapy on basophils and concomitantly assessed its clinical and immunological efficacy in olive pollen-monosensitized patients. METHODS: This study enrolled 437 consecutive patients with respiratory allergy and positive skin prick tests (SPTs); 212 (48.5%) patients were sensitized to olive pollen, and 33 (7.5%) patients were sensitized to olive pollen only. Of these patients, 23 received preseasonal immunotherapy with an olive pollen allergoid. The olive pollen-specific basophil activation, the titrated nasal provocation test, the nasal symptom score, and olive pollen-specific IgE, IgG1 and IgG4 levels were evaluated before immunotherapy and 8 months after the end of immunotherapy in the follow-up visit. RESULTS: In comparison to baseline evaluation, 7 preseasonal injections of an allergoid resulted in a significant decrease in the percentage of basophils expressing CD63 (29 vs. 7%, respectively, p < 0.0001) and a significant increase in the titrated nasal provocative dose (1/10 vs. 1/1, respectively, p < 0.01). SPT induration diameters caused by an olive pollen extract decreased (12 mm at baseline vs. 5.5 mm at follow-up, p < 0.005), as did nasal symptom score (7 at baseline vs. 3 at follow-up, p < 0.01). Olive pollen-specific IgE (17.5 vs. 50 kU/l, p < 0.012), IgG1 (0.16 vs. 2.9 µg/ml, p < 0.0001) and IgG4 (0.07 vs. 1.92 µg/ml, p < 0.0001) levels significantly increased. CONCLUSIONS: Immunotherapy with 7 preseasonal injections of an olive pollen allergoid decreases olive pollen-specific basophil activation over 8 months, an effect observed in vitro and in vivo.

Diagnostic value of specific IgE analysis in latex allergy.

BACKGROUND: The precision of the methods used to diagnose latex allergy is of great importance due to false-positive results. Neither the skin prick test (SPT) nor the latex-specific IgE assay has 100% diagnostic accuracy. We analysed the diagnostic value of latex-specific IgE by the first-ever concomitant use of the SPT and nasal provocation test (NPT). METHODS: Twenty-seven latex-sensitive patients (group 1), 46 aeroallergen-sensitive patients (group 2a) and 33 healthy subjects (group 2b) participated in the study. All groups underwent an SPT with latex and aeroallergens and an NPT with latex. Latex-specific IgE and total IgE levels were measured by the ImmunoCAP assay. RESULTS: Latex-specific IgE was positive in 92.6, 30.4 and 9.1% of groups 1, 2a and 2b, respectively. The 11 aeroallergen-sensitive patients in group 1 and all of the patients in group 2a were predominantly sensitised to pollens (grass, weed and tree) and reacted to a lesser degree to house dust mite, moulds and animal dander. Combined pollinosis was remarkably more prevalent in patients with positive latex-specific IgE in group 2a than in those with negative latex-specific IgE (p = 0.001). The NPT was positive in 84.6% of group 1 and negative in all control subjects. The sensitivity, specificity, negative predictive value and positive predictive value of the latex-specific IgE assay were 90.9, 72.2, 96.3 and 50%, respectively. CONCLUSION: The high rate of false-positive results for latex-specific IgE by ImmunoCAP should be taken into account when making a diagnosis of latex allergy in patients with pollinosis, especially in those sensitised to more than one pollen species.

The Turkish Hereditary Angioedema Pilot Study (TURHAPS): the first Turkish series of hereditary angioedema.

BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients. METHODS: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE. RESULTS: The majority of patients were female (60%), the mean age was 37.7 ± 14.1 years. The mean age at the time of first angioedema symptom was 12.5 ± 9.2 years. Mean time lag between first symptom and diagnosis was 26 ± 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described. CONCLUSION: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease.

Granulomatous disease in common variable immunodeficiency.

Granulomatous disease occurs in 8-22% of patients with common variable immunodeficiency (CVID). We examined the clinical and immunologic information of all 37 of 455 (8.1%) CVID subjects with this complication. The median age at diagnosis of CVID was 26 (2-59). 14 had granulomas 1-18 years before diagnosis of CVID. In 6 detection of granulomas coincided with this diagnosis; for 17, granulomas were documented later. 54% had lung granulomas, 43% in lymph nodes and 32% in liver. 54% of the group had had autoimmune diseases, mostly immune thrombocytopenia and hemolytic anemia. 24% had had a splenectomy. Nineteen (51.3%) required steroid treatment for granulomas; other immune suppressants were used in some. Over 25 years 28.5% died (median age 37.5), but not significantly more when compared to our CVID patients without granulomas (19.8%). Those with lung granulomas had similar mortality to those with granulomas in other tissues.

Vitamin D deficiency in the absence of enteropathy in three cases with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and a defect in antibody production. Herein we describe 3 patients diagnosed with CVID in whom vitamin D deficiency was detected in the absence of enteropathy. METHODS: Biochemical and immunological analysis, serum osteocalcin, parathyroid hormone, 25-OH vitamin D, 1,25(OH)(2) vitamin D, vitamin A, vitamin E, urinary calcium, and deoxypyridinoline measurements were carried out. Vitamin D receptor (VDR) expression was examined in the peripheral blood mononuclear cells and hair follicles by reverse transcriptase polymerase chain reaction. VDR gene polymorphism was evaluated by high-performance liquid chromatography. RESULTS: None of the patients presented nutrient deficiencies other than vitamin D. Two of them were free of osteomalacia-related symptoms. VDR expression was found to be lower in the peripheral blood mononuclear cells and hair follicles when compared to the control group. CONCLUSIONS: Patients with CVID may present asymptomatic vitamin D deficiency. Vitamin D and VDRs play an important role in the innate immune system and modulate Toll-like receptor-related responses. Delay in diagnosis may predispose these patients not only to irreparable bone loss but also to infections, and autoimmune and malignant disorders, thus emphasizing the importance of prompt intervention.

[T-lymphocyte subgroups and tuberculin skin test reactivity in patients with chronic renal failure]. / Kronik böbrek yetmezlikli olgularda tüberkülin cilt testi yaniti ve T-lenfosit alt gruplari.

As anergy is common in patients with chronic renal failure (CRF), the use of tuberculin skin test (TST) is controversial. Therefore, determination of the factors that affect the TST reactivity would increase the diagnostic value of the test. The aim of the present study was to investigate the factors affecting TST reactivity and evaluate the relationship between T-lymphocyte subsets and TST reactivity. We thus examined 44 patients (mean age 46.6 +/- 15.6 years, 25 males, duration of CRF 5.6 +/- 5.2 years), performed TST (an induration with a diameter of 5 mm or more was considered as positive) and measured Tlymphocyte subsets and biochemical parameters. Twenty-three patients were on hemodialysis, six were on peritoneal dialysis, seven were transplant recipients, and eight were on medical treatment. Eleven patients (25%) had immunosuppressive treatment. Eleven patients (25%) had two, 29 patients (66%) had one, and four patients (9%) had no BCG scars. Five patients (11%) had low body mass index (BMI). T-lymphocyte subsets were as follows: CD4= 40.7 +/- 7.6%, CD8= 32 +/- 8.9%, CD4/CD8= 1.7 +/- 2.5%, CD3= 71.4 +/- 9.4%, CD19= 6.3 +/- 5.1%, NK= 9.7 +/- 5.9. Twenty-two patients had positive TST reactivity. No relation was found between TST reactivity and age, gender, co-morbidity, BCG vaccination, BMI, immunosuppressive therapy, duration and treatment of CRF. Similarly, TST reactivity was not related to the biochemical parameters and Tlymphocyte subsets. These data provide that tuberculin reactivity does not seem to be associated with T-lymphocyte dysfunction and clinical features in patients with chronic renal failure.

Common variable immunodeficiency (CVID) presenting with malabsorption due to giardiasis.

Common variable immunodeficiency is characterized with B-cell and T-cell dysfunction and hypogammaglobulinemia. Recurrent bacterial infections, such as otitis media, chronic sinusitis and recurrent pneumonia due to diminished immunoglobulin (Ig) levels and impaired antibody production are frequently observed in common variable immunodeficiency. Almost half of the patients with common variable immunodeficiency have problems related to the gastrointestinal system. A 39-year-old woman was referred to our department with the complaint of chronic diarrhea. She had experienced diarrhea without mucus or blood in the last year and had lost 30 kg. In her medical history, she had suffered from recurrent upper and lower respiratory infections like sinusitis, otitis media and pneumonia since childhood. Serum immunoglobulin levels were low. There were no parasites or ova in her stool examinations. Esophagogastroduodenoscopy detected widespread macroscopic nodular appearance on duodenum, and biopsies from the duodenum revealed giardiasis invading the tissue. She was diagnosed as common variable immunodeficiency. After metronidazole therapy and intravenous immunoglobulin infusion was started, her diarrhea attacks ceased and she regained her normal weight. Common gastrointestinal system problems in patients with common variable immunodeficiency are lactose intolerance, lymphoid hyperplasia/diffuse lymphoid infiltration, loss of villi and infection, especially with Giardia lamblia. Giardiasis may lead to severe mucosal flattening and sometimes to lymphoid hyperplasia at the lamina propria of the duodenum. Medical history should be evaluated carefully regarding recurrent respiratory infections. In such cases with chronic diarrhea, common variable immunodeficiency should be kept in mind as a possible cause.

Chlamydia pneumoniae arthritis in a patient with common variable immunodeficiency.

BACKGROUND: Arthritis is an important and sometimes life-threatening complication in patients with common variable immunodeficiency (CVID). OBJECTIVE: To describe a patient with CVID and arthritis due to Chlamydia pneumoniae, which is usually regarded as a respiratory tract pathogen and has not previously been detected in the synovial fluid by cell culture technique. METHODS: Routine bacteriologic, virologic, mycologic, and tuberculosis cultures were performed. The patient's synovial fluid was examined for fastidious organisms that might be causative pathogens of arthritis, such as chlamydiae, and special cell culture methods were used. Serologic tests were performed to determine viral and bacteriologic etiology. RESULTS: The patient had a history of recurrent respiratory tract infections, and the latest exacerbation was followed by arthritis. Cytologic examination of the fluid yielded abundant lymphocytes. Chlamydia pneumoniae was detected in synovial fluid specimens by cell culture technique. Her nasopharyngeal swab and sputum culture specimens were also positive for this pathogen. She was diagnosed as having arthritis caused by C pneumoniae and was given antibiotherapy. CONCLUSION: Chlamydia pneumoniae should be kept in mind as a causative pathogen in patients with CVID and arthritis, especially when effusion fluid is full of lymphocytes rather than polymorphonuclear cells and no organism is grown on routine cultures.