Pulmonary Hypertension in Patients with Common Variable Immunodeficiency

Journal of Clinical Immunology - Common variable immunodeficiency (CVID) is known to cause infectious, inflammatory, and autoimmune manifestations. Pulmonary hypertension (PH) is an unusual...     

Altered Serum Cytokine Signature in Common Variable Immunodeficiency

Purpose

Common variable immunodeficiency (CVID) is the most frequent form of primary symptomatic hypogammaglobulinemia. CVID patients display a number of abnormalities in lymphocyte subpopulations including chronic T-cell activation and decreased numbers of circulating CD4⁺ T cells and NK cells. We and others have recently shown that CVID is associated with increased concentration of soluble CD14 (sCD14) and other factors indicating limited microbial translocation.

Methods

To address the mechanisms of chronic immune activation in CVID, we performed a detailed analysis of cytokine serum levels in 36 patients with CVID, 52 patients with selective IgA deficiency (IgAD), and 56 healthy volunteers.

Results

We show that CVID is associated with elevated serum levels of CXCL-10/IP-10, IL-1R antagonist, TNF-α, IL-10, IL-12 (p40), CCL-2/MCP-1, G-CSF, and CCL-11/eotaxin. The detected cytokine signature is consistent with an ongoing activation of cells of myeloid lineage. In contrast, the levels of cytokines typically produced by CD4⁺ T helper cells of Th1 (IFN-γ, IL-2), Th2 (IL-9, IL-13), and Th17 (IL-17) subtypes were suppressed in CVID patients compared to healthy donors.

Conclusions

Presented data suggest that the altered cytokine profile observed in patients with CVID may be attributed to the activation of monocyte-macrophage and granulocyte lineages, possibly driven by the translocation of bacterial components across the gastrointestinal or respiratory tracts mucosal barrier.     

Vitamin A Deficiency in Patients with Common Variable Immunodeficiency

Vitamin A, a naturally occuring antioxidant micronutrient, has immunomodulating effect in patients with immunodeficiency, including an influence on cytokine production and lymphocyte growth and functions. Vitamin A deficiency is associated with a shift from type 2 cytokines to predominantly type 1 cytokines. The aims of this study were to determine Vitamin A status in Common variable immunodeficiency (CVID) patients and the relationship between Vitamin A status and cytokines production. Serum Vitamin A, neopterin, TNF-alpha, IL-2, IL-4, and IL-10 levels were determined in 19 CVID patients and 15 healthy children. Effects of 9-cis retinal, Vitamin A derivative, on cytokines (TNF-alpha, IL-2, IL-4 and IL-10) production in lymphocytes were tested in vitro condition using lymphocyte cultures obtained from CVID patients and healthy children.Serum Vitamin A level in CVDI patients was, 21.1± 1.5 μg/dL, significantly (p < 0.001) lower than the value, 35.7± 1.8 μg/dL, observed in healthy children. Serum neopterin level in the patients was, 9.8± 2.9 nmol/L, higher (p < 0.05) than the value, 3.9± 0.7 nmol/L, observed in control group. Common variable immunodeficiency patients, serum IL-4 level was significantly (p < 0.05) lower than the value observed for healthy children. Serum TNF-alpha, IL-2 and IL-10 levels were similar in the patients and healthy children. Vitamin A derivative, 9-cis retinal, increased TNF-alpha and IL-4 production in cultured mononuclear cells obtained from control and CVID patients. Vitamin A derivative, also, increased IL-2 and Il-4 production in cultured mononuclear cells obtained from CVID patients.These results show that CVID patients have low serum Vitamin A levels and high serum neopterin levels. A supplementation with Vitamin A may have role in downregulation of inflammatory responses in CVID patients.The contributions by Sara Sebnem Kilic and Esra Yapici Kezer are equal and the order of authorship is arbitrary.     

Diagnostic Findings in 95 Finnish Patients with Common Variable Immunodeficiency

Common variable immunodeficiency is the most frequent of the primary hypogammaglobulinemias. It is manifested by a wide variety of clinical signs and symptoms. In this retrospective, nationwide survey data were collected on all patients with common variable immunodeficiency who were receiving immunoglobulin replacement therapy in Finland to study the prediagnostic clinical picture, diagnostic delay, and diagnostic findings. Ninety-five patients were identified. The median age of the patients was 33 years. Sixteen of the patients were children. Sinopulmonary infections were the most common prediagnostic signs and symptoms; 66% had suffered from recurrent pneumonia, 60% from recurrent maxillary sinusitis, and 45% from recurrent bronchitis. There was a considerable delay in diagnosis. The mean delay was 8 years. At the time of diagnosis chronic pulmonary complications had already developed in 17% of the patients. The diagnosis was based on low serum immunoglobulin concentrations. This study showed that the awareness of common variable immunodeficiency is low. To improve the recognition of hypogammaglobulinemia, it should be suspected in every patient with recurrent bacterial infections. In addition to a low serum IgG concentration, measurement of specific antibody production is recommended to establish the diagnosis before initiation of a life-long and costly replacement therapy.     

Specificity of Bactericidal Antibody Response to Serogroup B Meningococcal Strains in Brazilian Children after Immunization with an Outer Membrane Vaccine

Pre- and postvaccination serum samples from 77 children aged 2 to 6 years, who received the Cuban BC vaccine (B:4:P1.15), were analyzed for bactericidal antibodies against a local B:4:P1.15 strain (N44/89). Sera from 16 individuals with bactericidal antibodies against the B:4:P1.15 strain were tested against 23 Brazilian isolates. These include B:4 strains of distinct serosubtypes: P1.15, P1.7,1, P1.3, P1.9, P1.nt, and a B:8,19,23:P1.16 strain. A Cuban B:4:P1.15 strain (Cu385/83) was also included in the study. The specificities of bactericidal antibodies were analyzed by using mutant strains lacking a class 1 protein (PorA protein) or a class 5 protein or both. The results indicated that PorA and class 5 proteins are the main targets recognized by the bactericidal antibodies of vaccinees. Nonetheless, a complex pattern of recognition by bactericidal antibodies was found, and vaccinees were grouped according to antibody specificity. Antibodies from some individuals recognized PorA of serosubtype P1.15. However, antibodies from these individuals could not kill all P1.15 strains tested. Antibodies from a second group recognized both PorA and class 5 proteins, and antibodies from a third group recognized an as yet unidentified target antigen. The results demonstrate the importance of determining the fine epitope specificity of bactericidal antibodies to improve the existing vaccines against B meningococci.Group B meningococcal disease remains a significant public health problem in Brazil and in many other countries (17, 22). In contrast to polysaccharides A and C, B polysaccharide is poorly immunogenic in humans (18). Development of vaccines against group B meningococcal disease has focused on the use of lipo-oligosaccharide (LOS)-depleted outer membrane proteins (OMPs) (2, 3). Between 1989 and 1990 an OMP vaccine produced in Cuba was used to immunize 2.4 million children ranging from 3 months to 6 years of age in the city of São Paulo, Brazil. Results of a case control study performed from June 1990 to June 1991 (12 months) showed that vaccine efficacy was age dependent. In children aged 24 to 48 months and aged over 48 months, estimated efficacies were 47 and 74%, respectively. There was no vaccine efficacy in children aged up to 23 months (14). In spite of being statistically significant, levels of protection observed in children 24 months or older were far from ideal and did not have a significant impact on public health as the incidence of the disease was not significantly reduced in São Paulo (14). Also, the duration of the protection induced by the vaccine remains unknown.Several factors may account for the performance of this OMP vaccine in Brazil. The fact that only a portion (∼44%) of the bacterial isolates from infected individuals matched the vaccine type strain (B:4:P1.15) could be a factor that reduced its efficacy (14). An analysis of the presence of bactericidal antibodies in the sera of the vaccinated children found that only 40% had bactericidal antibodies to a B:4:P1:1.15 strain (13). As bactericidal antibodies are believed to be important for the immunity of vaccinated individuals (5), the fact that this vaccine failed to elicit bactericidal antibodies in the majority of children may account for its poor performance. In agreement with this possibility is the fact that a correlation between vaccine efficacy and the increasing prevalence of induced bactericidal antibodies with age was found (13).Among the five main classes of proteins found in the outer membrane vesicles (OMVs) (classes 1 through 5), PorA protein and class 5 proteins have been suggested to be of great importance for the induction of bactericidal antibodies after immunization and disease (11, 19, 26). In a recent study (25), the specificity of bactericidal antibodies of individuals vaccinated with hexavalent meningococcal PorA protein vesicle vaccine was evaluated by using isogenic strains differing only in their PorA protein compositions. This study demonstrated that the epitopes that contributed predominantly to the bactericidal activity were present in loops 1 and 4 of PorA protein, which contain variant region 1 (VR1) and VR2, respectively. In a parallel study, Rosenqvist et al. (19) demonstrated that PorA protein and class 5 proteins are the major targets of bactericidal antibodies of individuals vaccinated twice with an OMV vaccine.The present study was designed to evaluate the specificity of bactericidal antibodies from Brazilian children vaccinated with the Cuban OMP vaccine. For that purpose we determined the bactericidal activities of serum samples from selected individuals against local strains as well as against mutant strains lacking either class 1 or class 5 proteins or both.     

Effect of Increased CRM197 Carrier Protein Dose on Meningococcal C Bactericidal Antibody Response

New multivalent CRM₁₉₇-based conjugate vaccines are available for childhood immunization. Clinical studies were reviewed to assess meningococcal group C (MenC) antibody responses following MenC-CRM₁₉₇ coadministration with CRM₁₉₇-based pneumococcal or Haemophilus influenzae type b conjugate vaccines. Infants receiving a total CRM₁₉₇ carrier protein dose of ∼50 μg and concomitant diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccine tended to have lower MenC geometric mean antibody titers and continued to have low titers after the toddler dose. Nevertheless, at least 95% of children in the reported studies achieved a MenC serum bactericidal antibody (SBA) titer of ≥1:8 after the last infant or toddler dose. SBA was measured using an assay with a baby rabbit or human complement source. Additional studies are needed to assess long-term antibody persistence and MenC CRM₁₉₇ conjugate vaccine immunogenicity using alternative dosing schedules.     

Mutational Analysis of Human BLyS in Patients with Common Variable Immunodeficiency

BLyS, a TNF family member, is crucial for B cell proliferation and differentiation by acting through its three receptors, TACI, BCMA and BAFF-R. The knock out model for BLyS is characterized by an immunological phenotype reminiscent of the human phenotype of common variable immunodeficiency (CVID). CVID is characterized by a defective B cell compartment, evidencing the putative importance of BLyS in its pathogenesis. On the contrary, the transgenic model for BLys is characterized by autoimmune manifestations, underlying its role in B cell regulation. In fact, mutations in TACI, one of the three BLyS receptors, are associated with CVID. Based on these facts, we hypothesized that BLyS could be a candidate gene for CVID. We screened 78 patients with CVID using DHPLC and direct sequencing: No disease causing mutations were identified. A novel heterozygous single nucleotide polymorphism (SNP) was found in exon 1 of one individual, however this SNP (G189A) does not lead to an amino acid substitution.     

Increased Serum Levels of Soluble CD30 in Patients with Common Variable Immunodeficiency and Its Clinical Implications

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by hypogammaglobulinemia and increased susceptibility to recurrent pyogenic infections, autoimmunity, and malignancies. Twenty-five cases with CVID (18 male and 7 female) and 25 healthy volunteers were investigate in this study. Soluble CD30 (sCD30) serum levels of the subjects were measured and compared. Serum levels of sCD30 in the patients with CVID were significantly increased in comparison with controls (36.93 ± 32.38 vs 5.27 ± 1.32 U/ml, P < 0.001). The group of patients with splenomegaly and reversed ratio of CD3+CD4+ T cells/CD3+CD8+ T cells had the highest serum levels of sCD30 (66.01 ± 43.34 U/ml) in comparison with other patients (P = 0.010). High levels of sCD30 in the CVID patients with splenomegaly and the presence of lymphoma in a patient with the highest level of sCD30 may suggest a soluble form of this marker as a prognostic tool in such diseases.     

Thymic and Bone Marrow Output in Patients with Common Variable Immunodeficiency

Objective  

The study aims to obtain more information about the immune deficit of common variable immunodeficiency (CVID) patients.     

A Modified Enzyme-Linked Immunosorbent Assay for Measurement of Antibody Responses to Meningococcal C Polysaccharide That Correlate with Bactericidal Responses

The standardized enzyme-linked immunosorbent assay (ELISA) for measurement of serum immunoglobulin G (IgG) antibody responses to meningococcal C polysaccharide has been modified to employ assay conditions that ensure specificity and favor detection primarily of high-avidity antibodies. The modified and standard assays were used to measure IgG antibody concentrations in sera of toddlers vaccinated with meningococcal polysaccharide vaccine or a meningococcal C conjugate vaccine. The results were compared to the respective complement-mediated bactericidal antibody titers. In sera obtained after one or two doses of vaccine, the correlation coefficients, r, for the results of the standard assay and bactericidal antibody titers were 0.45 and 0.29, compared to 0.85 and 0.87, respectively, for the modified assay. With the standard assay, there were no significant differences between the geometric mean antibody responses of the two vaccine groups. In contrast, with the modified assay, 5- to 20-fold higher postvaccination antibody concentrations were measured in the conjugate than in the polysaccharide group. Importantly, the results of the modified assay, but not the standard ELISA, paralleled the respective geometric mean bactericidal antibody titers. Thus, by employing conditions that favor detection of higher-avidity IgG antibody, the modified ELISA provides results that correlate closely with measurements of antibody functional activity that are thought to be important in protection against meningococcal disease.     

Salivary and Serum Antibody Response Against Neisseria meningitidis After Vaccination With Conjugate Polysaccharide Vaccines in Ethiopian Volunteers

Meningococcal conjugate vaccines induce serum antibodies crucial for protection against invasive disease. Salivary antibodies are believed to be important for hindering meningococcal acquisition and/or clearance of established carriage. In this study, we measured salivary IgA and IgG antibodies induced by vaccination with a monovalent serogroup A conjugate vaccine or a tetravalent A, C, W and Y conjugate vaccine, in comparison with antibody levels in serum. Saliva and serum samples from Ethiopian volunteers (1–29 years) collected before and eight times on a weekly basis after receiving the serogroup A conjugate vaccine, the tetravalent serogroup A, C, W and Y conjugate vaccine, or no vaccine (control group), were analysed using a multiplex microsphere immunoassay for antibody detection. Serogroup‐specific IgG antibody levels in saliva increased significantly after vaccination with both vaccines. The monovalent serogroup A vaccine also induced an increase in salivary IgA antibodies. A strong correlation between serogroup‐specific IgG antibodies in saliva and serum, and a somewhat lower correlation for IgA, was observed for all serogroups. There was also a strong correlation between specific secretory IgA and IgA antibodies in saliva for all serogroups. Meningococcal conjugate vaccines are able to elicit salivary antibodies against serogroup A, C, W and Y correlating with antibody levels in serum. The strong correlation between saliva and serum antibody levels indicates that saliva may be used as a surrogate of systemic antibody responses.     

Impaired Proliferative Response to B-Lymphocyte Activators in Common Variable Immunodeficiency

The cell-mediated immune responses of 39 patients with common variable immunodeficiency (CV1) were studied in vitro, using Staphylococcus aureus and Escherichia coli prepared as whole cells and Candida albicans extract. These microbial activators were found to require intact B-lymphocyte function for normal proliferative response. The patient group was observed to have significantly depressed lymphocyte responses compared with those of controls studied in parallel (P<0.01). Negative lymphocyte response to one activator and strongly positive response to another were found in individual patients. Examination of patients' lymphocyte response to S. aureus and E. coli in association with serum IgG levels demonstrated that a rough correlation could be drawn, showing that patients with serum IgG < 125 mg/dl had markedly lower (P<0.01) lymphocyte responses than those with serum IgG > 300mg/dl. No similar correlation with phytohaemagglutinin activation was observed. Since depressed lymphocyte responses did not correlate with reduced B-cell number in these patients, intrinsic B-lymphocyte deficiency was indicated. These preparations of microbial activators are potentially useful tools in exploring lymphocyte subpopulation functions in primary immunodeficiency diseases.     

Infliximab for Treatment of Granulomatous Disease in Patients with Common Variable Immunodeficiency

Purpose

Eight to 22 % of common variable immunodeficiency (CVID) patients exhibit granulomas of the lungs, spleen, liver, and/or skin. Granulomas can be the most medically significant day-to-day problem for CVID patients. Currently, there are limited options for treatment of granulomas associated with CVID.

Methods

We treated five patients with CVID who exhibited significant clinical symptoms secondary to granulomas with infliximab. The patients were selected and treated based solely on clinical need and were not otherwise controlled or blinded to the therapy. After obtaining baseline studies (labs, spirometry, radiology) and excluding infection, they were treated with infliximab 5 mg/kg at week 0, 2, 6 and every 4 weeks thereafter.

Results

Post treatment improvements were seen in all 5 patients with significant clinical responses observed for both visceral and cutaneous granulomata. Four of the five patients were maintained on infliximab for 5 to 18 months (mean 9.4 months) without adverse reaction or increased susceptibility to infection. One patient completed 6 months of therapy with improvement of respiratory parameters but discontinued infliximab due to joint stiffness and rash that she attributed to the medication.

Conclusion

In our series, infliximab (5 mg/kg monthly) was an effective treatment for cutaneous and visceral granulomas in patients with CVID.     

Clinical and Immunological Features of 65 Iranian Patients with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and recurrent bacterial infections. The records of 65 patients with CVID (37 males and 28 females) in the age range of 24 to 537 months were reviewed. By the year 2003, 11 patients had died and seven patients could not be located. The total follow-up period was 221 patient-years. The median diagnostic delay (time between onset and diagnosis) in our patient group was 60 months. At the time of diagnosis, the baseline serum immunoglobulin G (IgG), IgM, and IgA levels were below the level normal for the patients' age; the medians for this group were 120, 10, and 0 mg/dl, respectively. All of the patients presented with infectious diseases at the time of onset, the most common of which were otitis media, diarrhea, pneumonia, and sinusitis. Acute and recurrent infections were also found in almost all of the patients, particularly involving respiratory and gastrointestinal systems. The most common infections, before diagnosis and during follow-up, were pneumonia, acute diarrhea, acute sinusitis, and otitis media. CVID should be considered in any patient with a history of recurrent infections and decreased levels of all serum immunoglobulin isotypes.     

The Spectrum of Disease Manifestations in Patients with Common Variable Immunodeficiency Disorders and Partial Antibody Deficiency in a University Hospital

Background

Common variable immunodeficiency disorders (CVIDs) represents a heterogeneous disease spectrum that includes recurrent infections and complications such as autoimmunity, inflammatory organ disease and an increased risk of cancer. A diagnostic delay is common in CVIDs patients.

Purpose

To determine the spectrum of clinical manifestations, immunological characteristics, and the time to diagnosis of 61 adult CVIDs and 18 patients with a partial antibody deficiency (SADNI and IgG subclass deficiency).

Methods

A retrospective cohort study was performed in patients who met the ESID/PAGID for CVIDs, IgG subclass deficiency and SADNI. Medical records were reviewed to obtain patient demographics, clinical and laboratory data.

Results

Infections were the main presentation of all antibody deficient patients and the number of patients with infections declined during IgG therapy. The development of bronchiectasis continued despite IgG therapy, as well as the development of autoinflammatory conditions. Non-infectious disease complications were present in 30% of CVIDs patients at the time of diagnosis and this increased to 51% during follow up despite IgG therapy. The most common complications were autoimmunity or lymphoproliferative disease. The median time to diagnosis was 10?years and in the patients with non-infectious complications the time to diagnosis was considerably longer when compared to the group of patients without complications (17.6 vs. 10.2?years, p?=?0.026).

Conclusion

In contrast to the partial antibody deficiencies we found a considerable delay in the diagnosis of CVIDs, especially in those patients who were dominated by non-infectious complications, and thus increased awareness would be beneficial. Pulmonary and other complications may continue despite adequate IgG replacement therapy suggesting other causes responsible for these complications.     

Antibody Response to Meningococcal Polysaccharides A and C in Patients with Complement Defects

Patients with defects of terminal complement components are particularly exposed to the risk of developing neisserial infections and seem to respond poorly to meningococcal capsular polysaccharide (PS) C via natural immunization. The sole meningococcal PSC is. on the other hand, an excellent immunogen in normal people. Considering the great importance of vaccine prophylaxis for the prevention of meningococcal infections in patients with complement defects, it is crucial to study the antibody response to the sole meningococcal PS in these patients. We therefore analysed the levels of anti-PSA and PSC antibodies in the members of four families including patients with homozygous and heterozygous defects of C7, C8 or factor H, before and after vaccination with the sole PSA+C.
Surprisingly, we found the highest levels of antibodies before vaccination In homozygous subjects, followed by heterozygous and normal controls, whereas, after vaccination, homozygous subjects showed the lowest increase of specific antibodies, indicating their relative incapability to respond to sole meningococcal PS.
In conclusion, this study demonstrates (1) the capacity to respond to meningococcal PS via natural immunization by patients with total complement defects, and (2) the low responsiveness to meningococcal PS via vaccine immunization by the same patients. We propose that vaccination should be given to patients lacking specific antibodies and their serological response should be assessed. In addition this study confirms previous observations on a likely lower immunogenic power of meningococcal serogroup C via natural immunization compared with the better immunogenicity of the sole PSC.     

Neurologic Complications of Common Variable Immunodeficiency

Common variable immunodeficiency is a rare disorder of immunity associated with a myriad of clinical manifestations including recurrent infections, autoimmunity, and malignancy. Though rare, neurologic complications have been described in a small number of case reports and case series of CVID patients. In this article, we present a patient with CVID who suffered significant neurologic morbidity and categorize the reported range of neurologic complications associated with CVID. Our case highlights the complex nature of neurologic manifestations in CVID patients, and our review of the current database suggests that infection and inflammatory neurologic disorders are the cause of most neurologic presentations.     

Long-Term Follow-Up and Outcome of a Large Cohort of Patients with Common Variable Immunodeficiency

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies. WITHIN THE IPINET (Italian Primary Immunodeficiency Network) IPINET: De Mattia D, Martire B, Bari, Cossu F, Cagliari, Schirilló G, Catania, Castagnola E, Genova, Pietrogrande MC, Delle Piane RM, Milano, Putti C, Padova, Trizzino A, Amato GM, Palermo, Bertolini P, Parma, Zecca M, Pavia, Consolini R, Pisa, Moschese V, Rossi P, Cancrini C, Roma, Cazzola GA, Verona