Common Variable Immune Deficiency Patients Research Articles

In-depth blood immune profiling of Good syndrome patients.

Good syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity vs. a subtype of Common Variable Immune Deficiency (CVID). Here, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61). All 9 GS patients displayed reduced B-cell counts -down to undetectable levels (<0.1 cells/μL) in 8/9 cases-, together with decreased numbers of total CD4+ T-cells, NK-cells, neutrophils, and basophils vs. age-matched healthy donors. In contrast, they showed expanded TCRγδ+ T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4+ T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4+ cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c+ and CD141+ myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ+ T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected. Our findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect vs. those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.

Reduced numbers of naïve CD4+T cells and an altered CD4/CD8 balance in depressed common variable immune deficiency (CVID) patients. Is thymosin-α1 a possible treatment?

In the 1990's the macrophage-T-cell-theory of depression was posed stating that low grade inflammation and an abnormal T cell system destabilize the development and function of the emotional brain in such a way, that individuals become ultrasensitive to stress. Recently we gathered evidence that indeed higher frequencies of CD4+ memory T cells, lower frequencies of naive CD4+T cells, higher frequencies of CD8+T cells (the latter two in part elicited by Cytomegalovirus, CMV, infection) are a characteristic of Major Depressive Disorder (MDD). In MDD patients with a history of childhood trauma and severe depression monocytes are inflammatory activated. Low grade inflammation and T cell system defects have also been reported in patients with Common Variable Immune Deficiency (CVID) (next to antibody production defects). CVID patients show a higher prevalence of mild depression. The aim of this study was to determine T cell frequencies and monocyte inflammatory activation in CVID patients with and without depression. This study confirms that CVID patients have CMV independent decreases in the frequency of naïve CD4+T cells and it de novo shows a CMV dependent increase in the expression of inflammatory genes in monocytes. CVID patients with depression are additionally characterized by a CMV independent increase in the frequency of naïve CD8+T cells, while lacking monocyte inflammatory activation. In conclusion, depressed CVID patients have T cell abnormalities comparable to that of patients with regular MDD. These abnormalities are presently targeted by thymosin α1 in an open-label proof of concept trial.

Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, Tcell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.

Cardiac Complications in Patients with Common Variable Immune Deficiency: A Longitudinal Study

Background: The common variable immune deficiency (CVID) is known as the most prevalent symptomatic primary immune deficiency (PID) diseases, which is characterized by hypogammaglobulinemia with variable infectious and noninfectious manifestations. In this study, the researchers aimed to evaluate the frequency of cardiac disorders and investigate its association with other manifestations in CVID patients.&#x0D; Method: A total of 337 CVID patients registered in the Iranian Primary Immunodeficiency Registry were evaluated in this study. The questionnaire was completed for all patients to collect the participants’ demographic data, clinical manifestations and laboratory finding. The analysis was performed between the two groups of the study including CVID patients with cardiac manifestation and those without it.&#x0D; Results: The prevalence rate of cardiac manifestation was calculated to be 9.1%. pericardial and myocardial diseases and pulmonary hypertension were the most prevalent complications. CVID patients with a history of cardiac problem had significantly higher prevalence rates of otitis media, lymphoproliferative disorders, splenomegaly, hepatomegaly, failure to thrive and lower numbers of CD8+ T cells and CD19+ B cells compared to the patients without cardiac disorders. Notably, no significant differences were observed in immunoglobulins serum levels, CD3+ and CD4+ T cells between the patients with and without cardiac manifestation.&#x0D; Conclusion: Regular echocardiographic evaluation and of CVID patients for cardiac complications especially for inflammatory cardiac disease, heart failure and pulmonary hypertension, is critical to reduce the risk of heart disease.

Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency.

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4+ T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients’ clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4+ T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19+ B-cells, switched memory B-cells, naïve CD8+ T-cells, and a higher frequency of EM CD8+ T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-022-01296-4.

Mild to moderate clinical course of COVID-19 infection in patients with common variable immune deficiency

The association of immunocompromised patients and severity of COVID-19 infection is not well established. According to the Centers for Disease Control and Prevention (CDC), primary immune deficiencies (PIDs) are among the conditions that can predispose to a more severe course of COVID-19. We report the clinical course and immunological evaluation of five patients with common variable immune deficiency (CVID) who have experienced SARS-CoV-2 virus. Here we assess the severity of the infection, the immunophenotypic profile of the major lymphocyte subgroups, the nonspecific T-cell functional capacity and the SARS-CoV-2 specific effector T-cell immune response. Our results showed that the course of COVID-19 infection in CVID patients was mild to moderate and none of them developed a critical form of the disease. All patients developed a specific SARS-CoV-2 T cell immune response. Lymphopenia as well as impaired T-cell response prior to COVID-19 appeared to be related to a more severe course of the infection. Data on a good specific T cell response against SARS-CoV-2 in CVID patients will help to make the right vaccination decision and establish its efficacy. Clinical outcome even in these individual cases was in agreement with the therapeutic recommendations underlining that regular maintenance with subcutaneous immunoglobulins can be beneficial against immune system overreaction and a severe disease course and convalescent plasma is a treatment option in patients with CVID and COVID-19.

Allergic-like disorders and asthma in patients with common variable immunodeficiency: a multi-center experience

Objective Common variable immune deficiency (CVID) encompasses a variety of diseases characterized by disturbed immunoglobulin (Ig) production and various immune dysregulations. Scarce data are available regarding relationships between CVID and allergic diseases. Here we examined possible associations between allergies and CVID. Methods For this multicenter study, we prospectively enrolled 79 adult CVID patients (≥18 years) who were diagnosed and treated between 2002–2017 at the Hadassah-Hebrew University and Shaare Zedek Medical Centers, Jerusalem, Israel. These patients were examined for allergic manifestations. Patient evaluation comprised medical history, physical examination, skin allergen testing, complete blood count, serum immunoglobulins, IgE levels, and pulmonary function tests. Results After implementing exclusion criteria, 29 patients were included in the final analysis. Allergic-like disorders were diagnosed in 65% of CVID patients with non-elevated serum IgE levels. Moreover, allergic CVID patients exhibited a higher prevalence of bronchiectasis on chest CT. Autoimmunity was diagnosed in 41.3% of CVID subjects. The type I allergy detected in our study was non-IgE mediated. Conclusions Timely diagnosis and stratification of allergy in CVID patients is expected to improve their outcome and quality of life, as well as promote appropriate treatment and better management of pulmonary exacerbations.

Reconstitution of IgG Subclasses Following Immunoglobulin Administration in Adult Patients with Common Variable Immune Deficiency

Background: Immunoglobulin (Ig) therapy reduces the frequency and severity of infection among patients with antibody deficiency disorders. However, a subset of patients lacks adequate clinical response. Objective: The purpose of this study was to determine in adult common variable immune deficiency (CVID) patients (A) if lack of clinical response to Ig therapy correlates with lack of reconstitution of IgG subclass (es), (B) correlation between Ig dosing and/or IgG trough levels and IgG subclass reconstitution, (C) and most common impaired Streptococcus pneumoniae (S. pneumoniae) serotype antibody response. Methods: Single-institution, retrospective chart review for CVID patients at immunology clinics from 2015 to 2019. Patients were monitored every 3–6 months for IgG dosage, IgG trough levels, IgG subclass reconstitution, infectious episodes (chronic sinusitis, bronchitis, upper respiratory, and lower respiratory tract infections), urinary tract infections, and antibiotic use. Follow-up was calculated in patient years. Results: Twenty-five of 41 patients achieved complete reconstitution of all IgG subclasses, and 16/41 demonstrated intermittent or lack of reconstitution. There were significantly less (p < 0.001) infections among fully reconstituted patients (0.66 ± 0.19 infections per patient year) as compared to those with intermittent or lack of reconstitution (1.26 ± 0.13 infections per patient year). There was a significant correlation between IgG trough levels and IgG subclass reconstitution. Most common impaired S. pneumoniae serotype included 3, 4, 9n, 10a, 11a, 12f, and 15b. Conclusions: Incomplete IgG subclass reconstitution was associated with increased frequency of infections. IgG trough levels correlate with IgG subclass reconstitution. A limited number of S. pneumoniae serotype antibodies are commonly impaired in CVID.

Otoimmun Komplikasyonlarla Seyreden Yaygın Değişken İmmün Yetmezlik Hastasında Renal Amiloidoz

Common variable immune deficiency (CVID) is a rare primary immunodeficiency disorder that is characterized by defective antibody production and inadequate B cell differentiation. While frequently recurrent respiratory tract infections are the most prominent clinical feature in CVID patients, CVID is a heterogeneous immune deficiency disorder that involves many systems and organs such as lymphoid hyperplasia, autoimmune cytopenia, chronic lung diseases, granulomatous diseases and susceptibility to malignancy. This may lead to delay in diagnosis and immunoglobulin replacement therapy, not being able to receive antibiotics at the appropriate dose and time, chronic inflammation, and therefore secondary amyloidosis. In this case report it is aimed to present a CVID patient with autoimmune complications and developing renal amyloidosis during follow-up.

The Utility of Liver Elastography in the Evaluation of Nodular Regenerative Hyperplasia (NRH) in Patients with Common Variable Immune Deficiency (CVID)

NRH has been correlated with increased morbidity and mortality in CVID patients. Liver biopsy is the gold standard for NRH diagnosis, however, ideal would be an earlier, noninvasive diagnostic technique. We hypothesized that Fibroscan® (vibration controlled transient liver elastography) may facilitate the diagnosis of NRH in CVID patients. Using a published MGH CVID cohort, we identified CVID patients with biopsy-confirmed NRH (‘NRH’), elevated liver biochemistries without biopsy-confirmed NRH (‘at risk for NRH’), and non-elevated liver biochemistries (‘control’). Patients with chronic viral hepatitis, non-alcoholic steatohepatitis, chronic alcohol use, and/or primary biliary cirrhosis were excluded. We reviewed both clinical Fibroscans, from the electronic medical record, and research-based Fibroscans. Fibroscan-obtained liver stiffness measurements (LSM, kPa) were compared using a two-tailed Student’s t-test. Within the MGH CVID cohort, ‘control’ patients (n=3) had a median LSM of 4.9 kPa (range 4.1 – 5.8 kPa), ‘NRH’ patients (n=4) had a median LSM of 11.2 kPa (range 7.0 – 26.1 kPa), and ‘at risk for NRH’ patients (n=2) had a median LSM of 11.5 kPa (range 9.8-13.1 kPa). Compared to control CVID, LSMs were significantly elevated in CVID patients with known or suspected NRH (P = 0.031). These preliminary data suggest the diagnostic utility of Fibroscan in CVID patients with known or suspected NRH. Elevated liver biochemistries and LSMs may prompt liver biopsy and immediate immunosuppressive intervention. Further studies will extend these findings to the full CVID cohort, correlate Fibroscan reads with NRH disease severity on biopsy, and increase monitoring of liver stiffness following immunosuppressive therapy.

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis

Background: B-1a B cells and gut secretory IgA (SIgA) are absent in asplenic mice. Human immunoglobulin M (IgM) memory B cells, which are functionally equivalent to mouse B-1a B cells, are reduced after splenectomy.Objective: To demonstrate whether IgM memory B cells are necessary for generating IgA-secreting plasma cells in the human gut.Methods: We studied intestinal SIgA in two disorders sharing the IgM memory B cell defect, namely asplenia, and common variable immune deficiency (CVID).Results: Splenectomy was associated with reduced circulating IgM memory B cells and disappearance of intestinal IgA-secreting plasma cells. CVID patients with reduced circulating IgM memory B cells had a reduced frequency of gut IgA+ plasma cells and a disrupted film of SIgA on epithelial cells. Toll-like receptor 9 (TLR9) and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) induced IgM memory B cell differentiation into IgA+ plasma cells in vitro. In the human gut, TACI-expressing IgM memory B cells were localized under the epithelial cell layer where the TACI ligand a proliferation inducing ligand (APRIL) was extremely abundant.Conclusions: Circulating IgM memory B cell depletion was associated with a defect of intestinal IgA-secreting plasma cells in asplenia and CVID. The observation that IgM memory B cells have a distinctive role in mucosal protection suggests the existence of a functional gut-spleen axis.

The evaluation of neutropenia in common variable immune deficiency patients

ABSTRACTObjectives: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication among CVID patients leading to a higher rate of infections and morbidity. Multiple factors (e.g. autoimmunity, infections, drugs and etc.) are found to underlie this complication.Methods: In the present study, demographic, clinical and laboratory data were compared between two groups of CVID patients with and without neutropenia.Results: Frequency of neutropenia was 8.1%. Infectious complications were the most prevalent clinical manifestations regardless of presence of neutropenia. However, candida infection and septicemia were significantly higher in neutropenic patients (p = 0.001 and p = 0.01, respectively). The most prominent clinical phenotypes of CVID patients with neutropenia were polyclonal lymphocytic infiltration and autoimmunity, both being considerably higher compared to the non-neutropenic group (p = 0.04 and p = 0.009, respectively). The mortality rate in neutropenic patients was higher than in patients without neutropenia (61.1 vs. 25.2%, p = 0.004).Conclusion: Although neutropenia is a rare complication among CVID patients, it is associated with frequent and severe clinical complications, including autoimmunity and lymphoproliferative conditions. Also, its accompaniment with higher mortality frequency in CVID patients indicates a need for more precise attention and consideration regarding specific treatment in neutropenic patients.

New approach to investigate Common Variable Immunodeficiency patients using spectrochemical analysis of blood

Common variable immune deficiency (CVID) is a primary immunodeficiency disease, characterized by hypogammaglobulinemia, recurrent infections and various complications. The clinical heterogeneity of CVID has hindered identification of an underlying immune defect; diagnosis relies on clinical judgement, alongside evidence-based criteria. The lack of pathognomonic clinical or laboratory features leads to average diagnostic delays of 5 years or more from the onset. Vibrational spectroscopic techniques such as Fourier-transform infrared (FTIR) spectroscopy have recently gained increasing clinical importance, being rapid-, non-invasive and inexpensive methods to obtain information on the content of biological samples. This has led us to apply FTIR spectroscopy to the investigation of blood samples from a cohort of CVID patients; revealing spectral features capable of stratifying CVID patients from healthy controls with sensitivities and specificities of 97% and 93%, respectively for serum, and 94% and 95%, respectively for plasma. Furthermore we identified several discriminating spectral biomarkers; wavenumbers in regions indicative of nucleic acids (984 cm−1, 1053 cm−1, 1084 cm−1, 1115 cm−1, 1528 cm−1, 1639 cm−1), and a collagen-associated biomarker (1528 cm−1), which may represent future candidate biomarkers and provide new knowledge on the aetiology of CVID. This proof-of-concept study provides a basis for developing a novel diagnostic tool for CVID.

Toll-like receptors pathway in common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA).

Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are two major humoral immunodeficiencies, causing a high rate of early age mortality in children. In order to identifiy the possible factors involved in the pathogenesis of CVID and XLA, recent studies have focused on Toll-like receptors (TLRs) and demonstrate the defects in different TLR pathways in immune cells of CVID and XLA patients. Herein, we measured TLR-4 and TLR-9 RNA levels and consequently TNF-α and IFN-α production in peripheral blood mononuclear cells (PBMCs) of patients with CVID and XLA. Contrary to healthy individuals, TLR-9 expression was not significantly increased after ligand stimulation, whereas ligand-induced TLR-4 expression was not significantly different from that in healthy control PBMCs. Lipopolysaccharide (LPS)-stimulated TNF-α production was significantly reduced in patients compared to controls, whereas IFN-α production was increased in all groups after CpG stimulation without any significant inter-group difference. Our data suggest that defects in TLR-9 activated pathways may be a result of the decreased TLR-9 expression, although TLR-9 is not the only modulator of IFN-α production in these patients. On the other hand, impaired signaling in TLR-4 activated pathways which results in significant reduction in TNF-α production are not related to a defect in TLR-4 expression.

The Clinical and Immunological Features of Patients with Primary Antibody Deficiencies.

Primary antibody deficiency (PAD) comprises a range of diseases from early to late terminal B cells defects and is associated with the various clinical complications. A total of 461 patients (311 males and 150 females) with PADs enrolled in the retrospective cohort study and for all patients' demographic information, clinical records and laboratory data were collected to investigate clinical complications. The most prevalent first presentations of immunodeficiency were respiratory tract infections in 63.5% and chronic diarrhea in 17.2%. Common variable immune deficiency (CVID) patients had a higher diagnostic delay than class switching defect (CSD), and agammaglobulinemia. Among the noninfectious complications, autoimmunity (26.2%), and splenomegaly (23.4%) were the most common. Lymphadenopathy was higher in CSD patients than other PADs, while splenomegaly, hepatomegaly, autoimmunity and bronchiectasis were more common in CVID patients than others. Atopic manifestations were mostly recorded in patients with selective IgA deficiency. Malignancy was only reported in 5.8% of patients with CVID. There was a higher prevalence of autoimmune manifestations in CVID comparing to other PADs. PADs are relatively rare diseases and these patients have a variety of first clinical manifestations, such as diverse infections, autoimmunity, lymphoproliferation, allergy, enteropathy and malignancy. Practitioner's awareness about the heterogeneous presentations of PAD disorders is poor, therefore patients often are lately diagnosed, and they are complicated with several clinical complications before the certain diagnosis.

Defective TLR9-driven STAT3 activation in B cells of patients with CVID

B cell activation by Toll-like receptor 9 (TLR9) ligands is dependent on STAT3 and is important for optimal antibody responses to microbial antigens. B cells from patients with common variable immune deficiency (CVID) have impaired proliferation and differentiation in response to the TLR9 ligand CpG, despite normal levels of TLR9 expression. We demonstrate that CpG-driven STAT3 phosphorylation, but not activation of NFκB and p38, is selectively impaired in B cells from CVID patients. These results suggest that defective STAT3 activation contributes to the defective TLR9 and antibody response of B cells in CVID.

Development of an ambulatory infusion protocol for Abatacept

The identification of the genetic causes of Common Variable Immune Deficiency (CVID) has led to recognition of the need for biological medications to treat the autoimmune manifestations that CVID patients with LRBA and CTLA4 deficiency experience. Immunologists have not traditionally used biological medications as treatment in CVID patients and may not be familiar with the use of them. We present the process and protocol as well as a nursing checklist used by the Division of Rheumatology for the use of Abatacept. Statement of novelty: The methodology used to develop the order set and nursing checklist may be applied to other biologic medications as they become available.

Autoimmune Cytopenias and Associated Conditions in CVID: a Report From the USIDNET Registry.

Autoimmune cytopenia is frequently a presenting manifestation of common variable immune deficiency (CVID). Studies characterizing the CVID phenotype associated with autoimmune cytopenias have mostly been limited to large referral centers. Here, we report prevalence of autoimmune cytopenias in CVID from the USIDNET Registry and compare the demographics and clinical features of patients with and without this complication. Investigators obtained demographic, laboratory, and clinical data on CVID patients within the USIDNET Registry. Patients were considered to have autoimmune cytopenia if they had a diagnosis of hemolytic anemia, immune thrombocytopenia (ITP), or autoimmune neutropenia. Baseline characteristics and associated complications of those with autoimmune cytopenia (+AC) and those without (-AC) were compared. Of 990 CVID patients included in the analysis, 10.2% (N=101) had a diagnosis consistent with autoimmune cytopenia: ITP was diagnosed in 7.4% (N=73), hemolytic anemia in 4.5% (N=45), and autoimmune neutropenia in 1% (N=10). Age at diagnosis, gender, and baseline Ig values did not differ between the +AC and -AC groups. The +AC group was significantly more likely to have one or more other CVID-associated non-infectious complications (OR=2.9; 95%-CI: 1.9-4.6, P<0.001), including lymphoproliferation, granulomatous disease, lymphomas, hepatic disease, interstitial lung diseases, enteropathy, and organ-specific autoimmunity. Autoimmune cytopenias are a common manifestation in CVID and are likely to be associated with other non-infectious CVID-related conditions. In light of prior studies showing increased morbidity and mortality in CVID patients with such complications, a diagnosis of autoimmune cytopenia may have prognostic significance in CVID.

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

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. 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. 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. 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.

Common Variable Immunodeficiency and Circulating TFH.

CD4+ T follicular helper cells (TFH) were assessed in adult patients with common variable immune deficiency (CVID) classified according to the presence of granulomatous disease (GD), autoimmunity (AI), or both GD and AI (Group I) or the absence of AI and GD (Group II). TFH lymphocytes were characterized by expression of CXCR5 and PD-1. TFH were higher (in both absolute number and percentage) in Group I than in Group II CVID patients and normal controls (N). Within CXCR5+CD4+ T cells, the percentage of PD-1 (+) was higher and that of CCR7 (+) was lower in Group I than in Group II and N. The percentages of Treg and TFH reg were similar in both CVID groups and in N. TFH responded to stimulation increasing the expression of the costimulatory molecules CD40L and ICOS as did N. After submitogenic PHA+IL-2 stimulation, intracellular expression of TFH cytokines (IL-10, IL-21) was higher than N in Group I, and IL-4 was higher than N in Group II. These results suggest that TFH are functional in CVID and highlight the association of increased circulating TFH with AI and GD manifestations.