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1.
Front Immunol ; 10: 1914, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456808

RESUMO

Common Variable Immunodeficiency (CVID) is the most frequent symptomatic immune disorder characterized by reduced serum immunoglobulins. Patients often suffer from infectious and serious non-infectious complications which impact their life tremendously. The monogenic cause has been revealed in a minority of patients so far, indicating the role of multiple genes and environmental factors in CVID etiology. Using 16S and ITS rRNA amplicon sequencing, we analyzed the bacterial and fungal gut microbiota, respectively, in a group of 55 participants constituting of CVID patients and matched healthy controls including 16 case-control pairs living in the same household, to explore possible associations between gut microbiota composition and disease phenotype. We revealed less diverse and significantly altered bacterial but not fungal gut microbiota in CVID patients, which additionally appeared to be associated with a more severe disease phenotype. The factor of sharing the same household impacted both bacterial and fungal microbiome data significantly, although not as strongly as CVID diagnosis in bacterial assessment. Overall, our results suggest that gut bacterial microbiota is altered in CVID patients and may be one of the missing environmental drivers contributing to some of the symptoms and disease severity. Paired samples serving as controls will provide a better resolution between disease-related dysbiosis and other environmental confounders in future studies.

2.
J Clin Immunol ; 38(7): 810-815, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30280305

RESUMO

PURPOSE: Hereditary angioedema (HAE) is a rare disease caused by a C1 inhibitor (C1-INH) deficit. Clinically, HAE is manifested by repeated episodes of localized subcutaneous or submucosal oedema attacks. Managing HAE patients in pregnancy is challenging, since there are only limited data on the safety and efficacy of various therapeutic approaches. METHODS: We present our clinical experience treating acute HAE attacks during pregnancy in six consecutive patients. RESULTS: During the pregnancies, 79 HAE attacks occurred. The most frequent were abdominal 53 (67.1%) followed by peripheral 21 (26.6%), facial 10 (12.7%), and laryngeal 10 (12.7%) oedemas; 13 (16.5%) attacks were combined. Fifty (63.3%) attacks were treated with recombinant human C1-INH (rhC1-INH); 17 (21.5%) with plasma-derived, pasteurized, nanofiltered C1-INH (pnfC1-INH); 13 (16.5%) with icatibant; and 1 (1.3%) with plasma-derived, nanofiltered C1-INH (nfC1-INH). Treatment had to be repeated in 5 attacks (6.3%). All six deliveries (one caesarean section and five spontaneous vaginal deliveries) were complication free. All pregnancies went to the full term and the patients delivered healthy babies with a birth weight ranging from 2850 to 3690 g. No congenital abnormalities were detected in the neonates. No abortions occurred. CONCLUSIONS: Our results show good C1-INH or icatibant treatment efficacy for HAE attacks in pregnancy. The treatment by the first drug used was effective in 93.7% of all attacks. In 6.3% of attacks, a second treatment had to be used. No adverse effects were observed.

3.
Front Immunol ; 9: 3135, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30723478

RESUMO

Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors Methods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.

4.
J Clin Immunol ; 37(6): 559-574, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28730517

RESUMO

PURPOSE: Primary selective IgM deficiency (sIgMD) is a primary immunodeficiency with unclear pathogenesis and a low number of published cases. METHODS: We reviewed clinical and laboratory manifestations of 17 sIgMD patients. Serum IgM, IgG, and its subclasses, IgA, IgE, antibodies against tetanus toxoid, pneumococcal polysaccharides and Haemophilus influenzae type b, isohemagglutinins, and T and B lymphocyte subsets, expressions of IgM on B cells and B lymphocyte production of IgM were compared with previously reported case reports and a small series of patients, which included 81 subjects in total. RESULTS: We found that some patients in our cohort (OC) and published cases (PC) had increased IgE levels (OC 7/15; PC 21/37), decreased IgG4 levels (OC 5/14), very low titers of isohemagglutinins (OC 8/8; PC 18/21), increased transitional B cell counts (OC 8/9), decreased marginal zone B cell counts (OC 8/9), and increased 21low B cell counts (OC 7/9). Compared with the PC (20/20), only two of five OC patients showed very low or undetectable production of IgM after stimulation. A majority of the patients had normal antibody production to protein and polysaccharide antigens, basic lymphocyte subset counts, and expression of surface IgM molecules on B cells. CONCLUSIONS: Low IgM levels are associated with various immunopathological disorders; however, pathogenic mechanisms leading to decreased IgM serum level in selective IgM deficiency remain unclear. Moreover, it is difficult to elucidate how strong these associations are and if these immunopathological conditions are primary or secondary.


Assuntos
Linfócitos B/imunologia , Imunoglobulina M/metabolismo , Síndromes de Imunodeficiência/imunologia , Infecção/imunologia , Adulto , Idoso , Autoimunidade , Estudos de Coortes , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imunoglobulina M/deficiência , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
N Engl J Med ; 376(12): 1131-1140, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28328347

RESUMO

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).


Assuntos
Proteína Inibidora do Complemento C1/administração & dosagem , Angioedema Hereditário Tipos I e II/prevenção & controle , Adulto , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Angioedema Hereditário Tipos I e II/classificação , Humanos , Injeções Subcutâneas , Masculino , Risco , Autoadministração , Índice de Gravidade de Doença
7.
Vnitr Lek ; 61(9): 778-84, 2015 Sep.
Artigo em Tcheco | MEDLINE | ID: mdl-26465276

RESUMO

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune multisystem disease. The aim of our study was to clarify the frequency of decreased serum immunoglobulin levels in SLE patients. There were evaluated 799 results of serum immunoglobulin levels gained from 157 patients fulfilling revised ACR criteria in the retrospective study. RESULTS: The immunoglobulin levels under the normal range were found in 29/157 (18.5 %) patients. The most frequent was isolated reduction of IgG 12/157 (7.6 %), two persons fulfilled criteria for selective IgA deficiency, and one case possible diagnosis of common variable immunodeficiency (CVID). Additionally we report two cases of SLE patients complicated by severe hypogammaglobulinaemia and infectious complications with necessity of long-term immunoglobulin substitution therapy. The diagnosis of CVID is highly probable in the first case. The second case presents sever drug-induced hypogammaglobulinaemia. This female with lymphoma history and multiorgan impairment due to acute SLE was treated with rituximab after convention therapy failure. CONCLUSION: Humoral immunodeficiency may occur in SLE patients. The monitoring of serum immunoglobulin levels could be a routine in these patients. The CVID diagnosis is possible in patients suffering from recurrent sinopulmonary infections, especially in combination with absence of lupus activity. Rituximab therapy could cause long-term suppression of B lymphocytes with secondary humoral deficiency requiring immunoglobulin substitution therapy.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Imunodeficiência Adquirida/diagnóstico , Adulto , Imunodeficiência de Variável Comum/induzido quimicamente , Imunodeficiência de Variável Comum/complicações , Feminino , Humanos , Imunoglobulinas/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Estudos Retrospectivos , Rituximab/efeitos adversos , Rituximab/uso terapêutico
8.
J Clin Immunol ; 35(6): 531-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26280892

RESUMO

PURPOSE: The aim of our retrospective study was to clarify fertility, pregnancy complications and outcomes in common variable immunodeficiency (CVID) females. METHODS: Retrospective data were obtained from three Czech referral centres. The data were compared with data obtained from the Czech National Registry of Reproduction Health. RESULTS: Our cohort of patients comprised 54 women with 115 pregnancies; 88 pregnancies in 50 females were finished with live births (77 %). In only 8 women (15%) was the diagnosis of CVID established before the first pregnancy. Replacement immunoglobulin therapy was performed in 10 patients without any moderate or severe adverse effects. Compared with the Czech population, the CVID patients suffered significantly more frequently from the threat of preterm labour (p < 0.0001), vaginal bleeding (p = 0.0001), eclampsia/preeclampsia (p = 0.009) and a higher number of stillbirths (p < 0.0001). Furthermore, the frequency of babies with low birth weight (less than 2500 g) born to the CVID patients was increased compared with the normal population (p < 0.0001). Serum IgG, IgA and IgM determination was done in 57 children of 50 mothers showing 13 cases of IgA deficiency (23%). There was no significant difference among the non-symptomatic, symptomatic untreated and symptomatic treated females in any of the determined gynaecological complications. The number of unsuccessful pregnancies was higher in the symptomatic untreated women. CONCLUSIONS: Fertility in CVID patients is not decreased, and their pregnancies could be considered more risky compared with those of the general population.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Complicações na Gravidez/imunologia , Gravidez/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Imunodeficiência de Variável Comum/complicações , Feminino , Humanos , Imunoglobulina A/genética , Pessoa de Meia-Idade , Trabalho de Parto Prematuro/etiologia , Resultado da Gravidez , Hemorragia Uterina/etiologia , Adulto Jovem
9.
Int Arch Allergy Immunol ; 168(3): 197-204, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26796963

RESUMO

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by disturbed antibody production and a dysregulated immune system. Aside from recurrent infections, the most common complications of CVID are autoimmune complications, particularly autoimmune cytopenias. To date, type 1 diabetes mellitus (T1D) in combination with CVID has only been described as an unusual complication in several reports, but the true incidence of T1D with CVID remains unknown. We describe 2 patients with a combination of T1D and CVID with serious impairment of antibody production. We also provide a review of the available literature. T1D-specific insulin autoantibodies and autoantibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 were not detected in either of our patients at the time of diagnosis or during the course of the disease. In both cases, T1D manifestation and diagnosis preceded the discovery of CVID by several years. Following the diagnosis of immunodeficiency and the start of immunoglobulin substitution therapy, their clinical status improved, manifesting as a lower frequency of infections and improved T1D control, with decreased glycosylated hemoglobin A1c values. Based on these reported cases, we assume that T1D might be more frequent than previously reported in patients with CVID. To verify the actual incidence of T1D among CVID patients, we searched the European Society for Immunodeficiencies Registry database, and found 25 cases of T1D in 1,671 listed CVID patients, suggesting a higher occurrence of T1D among CVID patients than previously thought. Early diagnosis and treatment of immunodeficiency improve both the prognosis and the course of CVID, reduce the frequency and severity of infections and may contribute to better management of T1D.


Assuntos
Autoanticorpos/sangue , Imunodeficiência de Variável Comum/complicações , Diabetes Mellitus Tipo 1/imunologia , Adolescente , Adulto , Humanos , Masculino
10.
In Vivo ; 28(5): 953-9, 2014 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25189913

RESUMO

BACKGROUND/AIM: Increased concentrations of neopterin, a biomarker of systemic immune response, have been reported after administration of cytokines, cytotoxic chemotherapy or external-beam radiation, but little is known about the effects of targeted-agents on neopterin. PATIENTS AND METHODS: Urinary neopterin was studied in pre-treated patients with metastatic colorectal carcinoma during therapy with cetuximab, administered mostly in combination with irinotecan, 5-fluorouracil and leucovorin. Urinary neopterin was determined by high-performance liquid chromatography. RESULTS: High initial urinary neopterin concentrations predicted poor prognosis. A significant correlation was observed between urinary neopterin and peripheral blood leukocyte count, hemoglobin and carcinoembryonic antigen concentrations. Urinary neopterin concentrations significantly increased during therapy only in patients with initially low neopterin concentrations. CONCLUSION: Urinary neopterin concentrations predict prognosis in patients with metastatic colorectal carcinoma treated with cetuximab. Rising neopterin concentrations indicate an activation of systemic immune response that could be responsible for the antitumor activity of cetuximab.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/terapia , Neoplasias Colorretais/urina , Neopterina/urina , Adulto , Idoso , Antígeno Carcinoembrionário/sangue , Cetuximab , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Terapia Combinada , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Retratamento , Fatores de Tempo , Resultado do Tratamento
11.
Int Arch Allergy Immunol ; 163(1): 69-74, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24247002

RESUMO

Common variable immunodeficiency (CVID) is the most frequent clinically relevant primary immunodeficiency and shows enormous heterogeneity in clinical presentation. Despite clinical immunodeficiency, opportunistic infections are not a typical manifestation of CVID. A retrospective study of 32 patients followed up for 335 patient-years was performed to determine the frequency of cytomegalovirus (CMV) disease. Symptomatic CMV infection was documented in 3 CVID patients. Patients No. 1 and 2 suffered from CMV pneumonia, with complications due to atypical mycobacteriosis in patient No. 1. Patient No. 3 suffered from CMV enteritis. A history of cancer and chronic hepatitis C infection (patient No. 1), immunosuppressive therapy for interstitial lung disease (patient No. 2) and serious enteropathy complicated with malnutrition (patient No. 3) may have contributed to the complications despite only mild abnormalities in T-cell subpopulations. The direct detection of CMV in bronchoalveolar lavage, stool or tissue samples was the most beneficial diagnostic laboratory method, whereas the detection of CMV DNA in blood did not produce positive results. Adequate treatment of CMV disease led to significant clinical improvement in all 3 patients. The frequency of CMV disease appears to be higher than previously described. In our experience, the probability of opportunistic infections in CVID patients increases with secondary comorbidities and their management.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Infecções por Citomegalovirus/diagnóstico , DNA Viral/isolamento & purificação , Enterite/diagnóstico , Infecções por Micobactéria não Tuberculosa/diagnóstico , Pneumonia Viral/diagnóstico , Líquido da Lavagem Broncoalveolar/virologia , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/patologia , Imunodeficiência de Variável Comum/virologia , Citomegalovirus , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Enterite/complicações , Enterite/patologia , Enterite/virologia , Fezes/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Infecções por Micobactéria não Tuberculosa/complicações , Infecções por Micobactéria não Tuberculosa/patologia , Infecções por Micobactéria não Tuberculosa/virologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia
12.
Hepatogastroenterology ; 59(114): 366-71, 2012 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22353500

RESUMO

BACKGROUND/AIMS: Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma. Among the side-effects of cetuximab hypomagnesaemia has been described, but the information is still limited. METHODOLOGY: We have evaluated retrospectively serum magnesium, potassium, calcium, creatinine and albumin in 51 consecutive patients with metastatic colorectal carcinoma treated with cetuximab, mostly combined with irinotecan-based combination chemotherapy. RESULTS: A significant decrease of serum magnesium, potassium, calcium and corrected serum calcium, creatinine and albumin concentrations was already evident one week after the start of treatment. Hypomagnesaemia of any grade was detected in 56% of evaluable patients, but grade 3 or grade 4 hypomagnesaemia was observed in 6% and 4% of patients, respectively. Grade 1 hypokalemia was detected in 47%, grade 3 in 17% and grade 4 hypokalemia was detected in 6% of the patients. Among evaluable patients grade 1 hypocalcaemia was detected in (36%), grade 2 hypocalcaemia in 42%, grade 3 in 4% and grade 4 in 13% of patients. Baseline hypocalcaemia of grade 1 or higher was associated with significantly inferior survival. CONCLUSIONS: Asymptomatic hypomagnesaemia, hypokalemia and hypocalcaemia are common in metastatic colorectal carcinoma patients treated with cetuximab. Hypocalcaemia is a predictor of poor prognosis.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Magnésio/sangue , Doenças Metabólicas/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Doenças Assintomáticas , Biomarcadores/sangue , Cálcio/sangue , Carcinoma/enzimologia , Carcinoma/mortalidade , Carcinoma/secundário , Cetuximab , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Creatinina/sangue , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Hipocalcemia/sangue , Hipocalcemia/induzido quimicamente , Hipopotassemia/sangue , Hipopotassemia/induzido quimicamente , Estimativa de Kaplan-Meier , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/mortalidade , Pessoa de Meia-Idade , Potássio/sangue , Estudos Retrospectivos , Albumina Sérica/metabolismo , Albumina Sérica Humana , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
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