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Vaccines targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been pivotal in curtailing the spread of infection. Health care workers, as frontline responders, were among the first to receive vaccination to mitigate coronavirus disease in 2019 (COVID-19) transmission. This study aimed to assess the humoral response elicited by mRNA vaccines, specifically measuring antibodies against the spike S1 protein, a marker of immune response. A cohort of 649 health care workers received three doses of mRNA vaccine, with antibody levels evaluated before and after each dose within a 2- to 3-week interval. Participants were stratified into groups based on prior exposure to the virus: those without prior contact (440 individuals) and those with a history of infection (209 individuals). Among the latter, cases of SARS-CoV-2 infection ranged from asymptomatic (92 individuals) to mild symptomatic (117 individuals). Participants with a history of infection exhibited elevated levels of IgG antibodies against the S1 protein prior to vaccination. Notably, both immunoglobulin IgA class (IgA) and immunoglobulin IgG class (IgG) antibody responses increased significantly post-vaccination, peaking after the second dose for IgG and after the third dose for IgA. Interestingly, the immune response to the vaccine did not vary significantly based on the symptomatic or asymptomatic nature of prior infection. Furthermore, the study findings indicate that completion of the vaccination regimen led to sustained antibody production lasting between 6 months and 9 months. This study underscores the robust and enduring humoral response elicited by mRNA vaccines, particularly among health care workers, irrespective of prior SARS-CoV-2 exposure.
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Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Pessoal de Saúde , Imunidade Humoral , Imunoglobulina G , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinação , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Masculino , Glicoproteína da Espícula de Coronavírus/imunologia , Feminino , Pessoa de Meia-Idade , Adulto , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Vacinas de mRNA , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/administração & dosagem , Formação de Anticorpos/imunologiaRESUMO
Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .
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Agamaglobulinemia , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Humanos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Adenosina Desaminase/genética , Adenosina Desaminase/uso terapêutico , Bussulfano/efeitos adversos , Terapia Genética , Retroviridae/genéticaRESUMO
Aim: This retrospective study investigated real-world hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) treatment patterns in pediatric patients with primary immunodeficiency diseases (PIDs) in Poland. Methods: Clinical and demographic information, fSCIG treatment parameters and clinical outcomes were extracted from medical records of 28 participants (aged ≤18 years) with PIDs who received fSCIG. Results: 18 participants (64.3%) started fSCIG with a ramp-up (median duration: 35.5 days). 27 patients (96.4%) were administered fSCIG every 4 weeks and one patient every 3 weeks. 25 patients (89.3%) used one infusion site. No serious bacterial infections occurred. Conclusion: Data support the feasibility of administering fSCIG to children and adolescents with PIDs every 3-4 weeks using a single infusion site and indicate flexibility in modifying fSCIG infusion parameters. Clinical Trial Registration: NCT04636502 (ClinicalTrials.gov).
Antibodies, also known as immunoglobulins, are proteins that are made by the immune system to help fight infections. In primary immunodeficiency diseases (PIDs), part of the immune system may be missing or not working properly. This study looked at the use of an antibody treatment called hyaluronidase-facilitated subcutaneous immunoglobulin (or fSCIG) in Polish children aged 18 years or younger with PIDs. Information on patients, their disease, how fSCIG was being used and how patients responded to treatment was taken from medical records. Out of 28 patients, 18/28 (64.3%) had their fSCIG dose slowly increased, which took an average of 35.5 days. Overall, 27/28 patients were treated with fSCIG every 4 weeks (96.4%), and 25/28 patients used one place to inject fSCIG (89.3%). No serious infections caused by bacteria happened during the study. The study results suggest that children with PIDs could be treated every 3 to 4 weeks with fSCIG, and that flexibility in how fSCIG is injected may offer options suited to individual patients.
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Hialuronoglucosaminidase , Doenças da Imunodeficiência Primária , Adolescente , Criança , Humanos , Imunoglobulinas/uso terapêutico , Infusões Subcutâneas , Doenças da Imunodeficiência Primária/terapia , Estudos RetrospectivosRESUMO
SARS-CoV-2 virus responsible for acute respiratory disease affected other organs leading to co-existence symptoms or complications. Thyroid gland was one of them due to expression of angiotensin-converting enzyme 2 (ACE2), the protein facilitating viral binding to the host cells. Moreover, thyroid gland, important for regulation of hormonal network, is extremely sensitive to any changes in homeostasis and metabolism. It was shown, that COVID-19 was associated with induction of thyroid disease or increasing existing functional disturbances or autoimmune process. Thyroid diseases are mainly based on immunological pathomechanism although the relation between immune system and thyroid function is bidirectional e.g. thyroid hormones modulate specific immune responses, including cell-mediated immunity, NK cell activity, the production of antiviral interferon (IFN) and proliferation of T- and B-lymphocytes. The effects of COVID-19 and mRNA vaccine on thyroid function and diseases are discussed.
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Transient hypogammaglobulinemia of infancy (THI) is one of the most common forms of hypogammaglobulinemia in the early childhood. THI is usually associated with chronic, recurrent bacterial and viral infections, life-threatening in some cases, yet its pathogenesis is still largely unknown. As our previous findings indicated the possible role of Treg cells in the pathomechanism of THI, the aim of the current study was to investigate gene expression profile of Treg cells isolated from THI patients. The transcriptome-wide gene profiling was performed using microarray technology on THI patients in two time-points: during (THI-1), and in resolution phase (THI-2) of hypogammaglobulinemia. As a result, a total of 1086 genes were differentially expressed in THI-1 patients, when compared to THI-2 as well as control group. Among them, 931 were up- and 155 downregulated, and part of them encodes genes important for Treg lymphocyte biology and function, i.e. transcription factors/cofactors that regulate FOXP3 expression. Thus, we postulate that Treg cells isolated from THI patients during hypogammaglobulinemia display enhanced suppressor transcriptome signature. Treg expression profile of THI children after normalization of Ig levels largely resembles the results obtained in healthy control group, suggesting THI Treg transcriptome seems to return to that observed in healthy children. Taken together, we suggest that THI pathomechanism is associated not only with transiently elevated Treg cell numbers, but also with their enhanced regulatory/inhibitory functions. These findings expand our knowledge of human Treg cells and may be useful for the future diagnosis or management of THI.
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Agamaglobulinemia , Doenças da Imunodeficiência Primária , Criança , Humanos , Pré-Escolar , Linfócitos T Reguladores/patologia , Agamaglobulinemia/genética , Agamaglobulinemia/diagnóstico , Perfilação da Expressão Gênica , TranscriptomaRESUMO
Vaccination with Bacillus Calmette-Guérin (BCG) can be harmful to patients with combined primary immunodeficiencies. We report the outcome of BCG vaccination in a series of twelve patients affected by adenosine deaminase deficiency (ADA-SCID). BCG vaccination resulted in a very high incidence of complications due to uncontrolled replication of the mycobacterium. All patients who developed BCG-related disease were treated successfully and remained free from recurrence of disease. We recommend the prompt initiation of enzyme replacement therapy and secondary prophylaxis to reduce the risk of BCG-related complications in ADA-SCID patients.
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BACKGROUND: Subcutaneous administration of immunoglobulins is associated with fewer systemic adverse events and easier infusion compared to intravenous administration. Ig20Gly is a 20% immunoglobulin formulation effective and safe in patients with primary immune deficiency diseases (PIDDs). Real-world data are scarce, therefore our study aimed to examine the real-life treatment regimen and clinical outcomes of Ig20Gly in Polish children with PIDDs. RESEARCHDESIGN: We retrospectively analyzed the medical documentation of 75 pediatric patients aged 0-17 years (mean 9.9) who received Ig20Gly (Cuvitru®; Baxalta US, Inc.; part of Takeda, MA, U.S.A.). RESULTS: The median exposure to treatment of the study population was 22.3 months. At the end of the study, 59 (78.7%) were still on Ig20Gly. The median monthly dose was 0.40 g/kg. The median treatment interval was 7.7 days. Most patients (96%) used one infusion site. The median infusion rate increased with patient age. The median IgG level in the study population, 8.0 g/L, was stable. There was one case of serious bacterial infection. CONCLUSION: This is the largest, long-term real-world study to date on the treatment patterns of Ig20Gly in pediatric patients with PIDDs. The results of this study support the feasibility and tolerability of Ig20Gly usage in PIDD patients across the pediatric age spectrum. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT04636502).
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Síndromes de Imunodeficiência , Criança , Humanos , Estudos Retrospectivos , Síndromes de Imunodeficiência/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Injeções Subcutâneas , Protocolos Clínicos , Imunoglobulinas Intravenosas/uso terapêutico , Infusões SubcutâneasRESUMO
Immunofluorescence is a basic method for detection of autoantibodies in serum. It is used as screening for people with symptoms suggesting autoimmune process and disease. Antinuclear antibodies (ANA) assay detecting antibodies against nuclear proteins used commonly for diagnosis of systemic autoimmune disease, although antibodies against cytoplasmic components and mitotic structures are usable in clinic. The majority of ANA nuclear patterns have been comprehensively studied with increasing data. However, the cytoplasmic and mitotic patterns are underestimated and still require further assessment. In this review the clinical associations and significance of uncommon types of autoantibodies are presented and discussed.
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Autoanticorpos , Doenças Autoimunes , Humanos , Anticorpos Antinucleares , Imunofluorescência , Técnica Indireta de Fluorescência para Anticorpo/métodosRESUMO
At the beginning of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, patients with inborn errors of immunity (IEI) appeared to be particularly vulnerable to a severe course of the disease. It quickly turned out that only some IEI groups are associated with a high risk of severe infection. However, data on the course of Coronavirus Disease 2019 (COVID-19) in patients with IEI are still insufficient, especially in children; hence, further analyses are required. The retrospective study included 155 unvaccinated people with IEI: 105 children and 50 adults (67.7% and 32.3%, respectively). Male patients dominated in the study group (94 people, 60.6%). At least two comorbidities were found in 50 patients (32.3%), significantly more often in adults (56% vs. 21%). Adult patients presented significantly more COVID-19 symptoms. Asymptomatic and mildly symptomatic course of COVID-19 was demonstrated in 74.8% of the entire group, significantly more often in children (88.6% vs. 46%). Moderate and severe courses dominated in adults (54% vs. 11.4%). Systemic antibiotic therapy was used the most frequently, especially in adults (60% vs. 14.3%). COVID-19-specific therapy was used almost exclusively in adults. In the whole group, complications occurred in 14.2% of patients, significantly more often in adults (30% vs. 6.7%). In the pediatric group, there were two cases (1.9%) of multisystem inflammatory syndrome in children. Deaths were reported only in the adult population and accounted for 3.9% of the entire study group. The death rate for all adults was 12%, 15.4% for adults diagnosed with common variable immunodeficiency, 12.5% for those with X-linked agammaglobulinemia, and 21.4% for patients with comorbidity. The results of our study imply that vaccinations against COVID-19 should be recommended both for children and adults with IEI. Postexposure prophylaxis and early antiviral and anti-SARS-CoV-2 antibody-based therapies should be considered in adults with IEI, especially in those with severe humoral immune deficiencies and comorbidity.
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COVID-19 , Adulto , Antibacterianos , Antivirais , COVID-19/complicações , Criança , Progressão da Doença , Humanos , Masculino , Polônia , Estudos Retrospectivos , SARS-CoV-2 , Síndrome de Resposta Inflamatória SistêmicaRESUMO
In the SARS-CoV-2 virus pandemic, the questions about specific activity of this virus in induction and/or inhibition of the innate and adaptive immune response are still open. Clinical observations of the severe and critical course of infection showed the hyperinflammation and cytokine storm. In organs and tissues that are a target for viral entry the lymphocytes and monocytes are dominant cells in tissue infiltration. There are different ways and different mechanisms leading to immune response disorders. In peripheral blood in the severe and fatal course of disease lymphopenia is frequent as a poor prognosis factor. Reduced numbers of lymphocytes, mainly T cells and NK cells, are noted in the majority of these patients. The NK cells belonging to the innate immunity system are dedicated to the antiviral response due to production of interferon (IFN) and direct lysis of virus infected cells. In SARS-CoV-2 infection NK cells' activity against this pathogen is impaired based on inhibition of IFN production and functional exhaustion. The restoration of NK cell number and function might support elimination of the SARS-CoV-2 virus, increasing chances of recovery. The use of activated NK cells in SARS-CoV-2 therapy is under clinical trials.
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Severe, recurrent or atypical Herpes simplex virus (HSV) infections are still posing clinical and diagnostic problem in clinical immunology facilities. However, the molecular background of this disorder is still unclear. The aim of this study was to investigate the expression of activating receptors on NK cells (CD16, NKp46, NKG2D, NKp80, 2B4, CD48 and NTB-A) and checkpoint molecule PD-1 on T lymphocytes and NK cells, in patients with severe and/or recurrent infections with HSV and age-matched healthy control subjects. As a result, we noticed that patients with severe and/or recurrent infection with HSV had significantly lower percentage of CD16brightCD56dim and higher percentage of CD16dimCD56bright NK cell subsets, when compared to control subjects, which may be associated with abnormal NK cell maturation during chronic HSV infection. Patients had also significantly downregulated expression of CD16 receptor on CD16bright NK cells. The expression of activating receptors was significantly reduced on patients' NK cells - either both the percentage of NK cells expressing the receptor and MFI of its expression (NKp46, NKp80 and 2B4 on CD16brightCD56dim cells and NKp46 on CD16dimCD56bright cells) or only MFI (NKG2D on both NK cell subsets). It should be noted that the reduction of receptor expression was limited to NK cells, since there was no differences in the percentage of receptor-positive cells or MFI on T cells. However, NTB-A receptor was the only one which expression was not only simultaneously changed in patients' NK and T cells, but also significantly upregulated on CD16dimCD56bright NK cell and CD8+ cell subsets. Patients had also upregulated proportion of CD4+ T cells expressing PD-1. Thus, we suggest that an increased percentage of PD-1+ cells may represent an independent indirect mechanism of downregulation of antiviral response, separate from the reduction of NK cell activating receptors expression. Altogether, our studies indicate two possible mechanisms which may promote perpetuation of HSV infection: 1) selective inhibition of activating receptors on NK cells, but not on T cells, and 2) upregulation of checkpoint molecule PD-1 on CD4+ T cells.
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Regulação da Expressão Gênica , Herpes Simples/etiologia , Herpes Simples/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptores Desencadeadores da Citotoxicidade Natural/genética , Criança , Pré-Escolar , Feminino , Herpes Simples/diagnóstico , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunofenotipagem , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Receptores Desencadeadores da Citotoxicidade Natural/metabolismo , Recidiva , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary.
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Doenças Pulmonares Intersticiais/etiologia , Doenças da Imunodeficiência Primária/complicações , Adolescente , Corticosteroides/uso terapêutico , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Masculino , Polônia , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Severe and/or recurrent infection with Herpes simplex virus (HSV) is observed in a large group of patients treated in clinical immunology facilities. Atypical and prolonged HSV infection is the most common clinical manifestation of disturbed NK cell development and functions, yet the molecular basis of these disorders is still largely unknown. Since recent findings indicated the importance of miRNA in regulating NK cell development, maturation and functions, the aim of our study was to investigate miRNA expression pattern in NK cells in patients with severe and/or recurrent infections with HSV and analyze the role of these miRNAs in NK cell antiviral response. As a result, miRNA expression pattern analysis of human best known 754 miRNAs revealed that patients with severe and/or recurrent HSV infection had substantially upregulated expression of four miRNAs: miR-27b, miR-199b, miR-369-3p and miR-491-3p, when compared to healthy controls. Selective inhibition of miR-27b, miR-199b, miR-369-3p and miR-491-3p expression in NK-92 cells resulted in profound upregulation of 4 genes (APOBEC3G, MAP2K3, MAVS and TLR7) and downregulation of 36 genes taking part in antiviral response or associated with signaling pathways of Toll-like receptors (TLR), NOD-like receptors, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and type I IFN-related response. Additionally, flow cytometry analysis revealed that miR-369-3p and miR-491-3p inhibitors downregulated NK cell intracellular perforin expression, while the expression of granzyme B and IFNγ remained unchanged. Taken together, our study suggests a novel mechanism which may promote recurrence and severity of HSV infection, based on miRNAs-dependent posttranscriptional regulation of genes taking part in antiviral response of human NK cells.
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Regulação da Expressão Gênica , Herpes Simples/genética , Herpes Simples/imunologia , Células Matadoras Naturais/imunologia , MicroRNAs , Adolescente , Linhagem Celular , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
BACKGROUND: The phenotypic heterogeneity of circulating tumor cells (CTC) in peripheral blood and disseminated tumor cells (DTC) in bone marrow is an important constraint for clinical decision making. Here, we investigated the implications of two different subpopulations of these cells in gastric cancer (GC). METHODS: GC patients (n = 228) who underwent elective gastric resections were prospectively examined for CTC/DTC. The cells obtained from peripheral blood and bone marrow aspirates were sorted by flow cytometry and CD45- cells expressing cytokeratins (8, 18, and 19) and CD44 were identified by immunofluorescent double staining. RESULTS: Ninety-three (41%) patients had cytokeratin-positive tumor cells in either blood or bone marrow, while cells expressing CD44 were found in 22 (10%) cases. CK+CD44+ cells were significantly more common among patients with distant metastases (50 vs 19%, P = 0.001), while no such correlations were demonstrated for CK+CD44- cells. Detection of CK+CD44+ cells, but not CK+CD44-, was associated with significantly shortened survival. Moreover, the Cox proportional hazards model identified CK+CD44+ cells as a negative prognostic factor with an odds ratio of 2.38 (95% CI 1.28-4.41, P = 0.006). CONCLUSION: CD44+ phenotype of cytokeratin-positive cells in blood and bone marrow is an independent prognostic factor in patients with gastric cancer.
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Medula Óssea/patologia , Receptores de Hialuronatos/biossíntese , Queratinas/biossíntese , Células Neoplásicas Circulantes/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
INTRODUCTION: In this study we describe a patient with gross deletion containing the BTK and TIMM8A genes. Mutations in these genes are responsible for X-linked agammaglobulinemia and Mohr-Tranebjaerg syndrome, respectively. X linked agammaglobulinemia is a rare primary immunodeficiency characterized by low levels of B lymphocytes and recurrent microbial infections, whereas, Mohr-Tranebjaerg syndrome is a progressive neurodegenerative disorder with early onset of sensorineural deafness. MATERIAL AND METHODS: For neuroimaging, the magnetic resonance imaging and magnetic resonance spectroscopy of the brain were performed. Microarray analysis was performed to establish the extent of deletion. RESULTS: The first clinical symptoms observed in our patient at the age of 6 months were connected with primary humoral immunodeficiency, whereas clinical signs of MTS emerged in the third year of live. Interestingly, the loss of speech ability was not accompanied by hearing failure. Neuroimaging of the brain suggested leukodystrophy. Molecular tests revealed contiguous X-chromosome deletion syndrome encompassing BTK (from exons 6 through 19) and TIMM8A genes. The loss of the patient's DNA fragment was accurately localized from 100 601 727 to 100 617 576 bp on chromosome's loci Xq22.1. CONCLUSIONS: We diagnosed XLA-MTS in the first Polish patient on the basis of particular molecular methods. We detected neurodegenerative changes in MRI and MR spectroscopy in this patient. Our results provide further insight into this rare syndrome.
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AIM: To assess the safety and efficacy of an intravenous immunoglobulin (IVIG) 10% preparation (Panzyga®; Octapharma AG, Lachen, Switzerland) in predominantly antibody-deficient children with primary immunodeficiency disease. METHODS: Data from two prospective, open-label and noncontrolled multicenter Phase III studies of IVIG 10% that included 25 patients <16 years of age were analyzed for efficacy, pharmacokinetics and safety. RESULTS: The rate of serious bacterial infections was 0.04/patient-year. A maximal infusion rate of 0.14 ml/kg/min was achieved in 82% of pediatric patients (n = 9). Infusions of immunoglobulin G trough levels between infusions remained ≥5-6 g/l; median half-life was 32.79-36.62 days. Abdominal pain, headache and chills were the most common treatment-related adverse events. CONCLUSION: IVIG 10% is safe and effective for the treatment of predominantly antibody-deficient children.
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Agamaglobulinemia/terapia , Infecções Bacterianas/epidemiologia , Imunodeficiência de Variável Comum/terapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Adolescente , Adulto , Agamaglobulinemia/epidemiologia , Idoso , Infecções Bacterianas/etiologia , Criança , Imunodeficiência de Variável Comum/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
The extracellular matrix (ECM) is a dynamic environment involved in the regulation of haematopoiesis. A crucial role of this structure is the promotion of proliferation, maturation, and differentiation of haematopoietic stem cells (HSC), and adhesion and migration of HSC in bone marrow. In the present study the effect of ECM proteins (fibronectin, collagens, laminin, thrombospondin, and vitronectin) on proliferation and apoptosis of acute lymphoblastic leukaemia cells isolated from acute lymphoblastic leukaemia (ALL) patients (in vitro) was assessed. The leukaemia cells were obtained as interphase on Ficoll/Isopaque (Pancoll human, PAN-Biotech) density gradient and, after washing, counted in a chamber. Subsequently, cells were used for culture and apoptosis assay. Presence of fibronectin, collagen type IV, and laminin was associated with inhibition of lymphoblastic leukaemia cell proliferation. Analysis of the culture of lymphoblastic leukaemia cells in the presence of ECM showed fibronectin as the most active protein.
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Apoptose , Proliferação de Células , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Antígenos CD34/metabolismo , Criança , Pré-Escolar , Colágeno Tipo IV/metabolismo , Matriz Extracelular/patologia , Feminino , Humanos , Laminina/metabolismo , Masculino , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2-75â¯years with common variable immunodeficiency (nâ¯=â¯43) or X-linked agammaglobulinaemia (nâ¯=â¯8). Patients were treated with IVIG 10% every 3 (nâ¯=â¯21) or 4â¯weeks (nâ¯=â¯30) at a dose of 200-800â¯mg/kg for 12â¯months. Total immunoglobulin G (IgG) and subclass concentrations approximately doubled from pre- to 15â¯min post-infusion. The maximum concentration of total IgG (mean⯱â¯SD) was 21.82⯱â¯5.83â¯g/L in patients treated 3-weekly and 17.42⯱â¯3.34â¯g/L in patients treated 4-weekly. Median trough IgG concentrations were nearly constant over the course of the study, remaining between 11.0 and 12.2â¯g/L for patients on the 3-week schedule and between 8.10 and 8.65â¯g/L for patients on the 4-week schedule. The median terminal half-life of total IgG was 36.1 (range 18.5-65.9) days, with generally similar values for the IgG subclasses (26.7-38.0â¯days). Median half-lives for specific antibodies ranged between 21.3 and 51.2â¯days for anti-cytomegalovirus, anti-Haemophilus influenzae, anti-measles, anti-tetanus toxoid, anti-varicella zoster virus antibodies, and anti-Streptococcus pneumoniae subtype antibodies. Overall, IVIG 10% demonstrated pharmacokinetic properties similar to those of other commercial IVIG 10% preparations and 3- or 4-weekly administration achieved sufficient concentrations of IgG, IgG subclasses, and specific antibodies, exceeding the recommended level needed to effectively prevent serious bacterial infections.
Assuntos
Agamaglobulinemia/metabolismo , Imunodeficiência de Variável Comum/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Imunoglobulinas Intravenosas/farmacocinética , Adolescente , Adulto , Agamaglobulinemia/sangue , Idoso , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/sangue , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE: To assess the efficacy and safety of panzyga® (intravenous immunoglobulin 10%) in preventing serious bacterial infections (SBIs) in patients with primary immunodeficiency diseases (PIDs), a prospective, open-label, multicenter, phase 3 study and an open-label extension study were undertaken. METHODS: Initially, the study drug (infusion rate ≤0.08 mL/kg/min) was administered at intervals of 3 or 4 weeks for 12 months, followed by 3 months of panzyga® at infusion rates increasing from 0.08 to 0.14 mL/kg/min. The primary endpoint in the main study was the rate of SBIs per patient-year on treatment. Secondary outcomes included non-serious infections, work/school absence, episodes of fever, quality of life, and adverse events (AEs). RESULTS: The main study enrolled 51 patients (35% female, mean age 26.8 years), with 21 participating in the extension study. The rate of SBIs per patient-year was 0.08 in the total population; there were four SBIs in the 4-weekly treatment group (2/30 patients) and none in the 3-weekly group (n = 21). Compared with 4-weekly treatment, 3-weekly treatment was associated with a higher rate of upper respiratory tract infections (RTIs), ear infections, and work/school absences, but a lower rate of lower RTIs and fever. Treatment was generally well tolerated; no AE led to treatment withdrawal or death. CONCLUSIONS: Overall, the use of panzyga® in patients with antibody-deficient PID was associated with a low rate of AEs and was effective in preventing SBIs, exceeding US FDA and European Medicines Agency recommendations for efficacy.
Assuntos
Infecções Bacterianas/terapia , Imunoglobulina G/uso terapêutico , Imunoglobulinas/deficiência , Síndromes de Imunodeficiência/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Adolescente , Adulto , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento , Adulto JovemRESUMO
Common variable immunodeficiency (CVID) comprise different kinds of primary hypogammaglobulinemias of mostly unknown etiology. The onset of the disease and its clinical symptoms may appear as well in children as in adults. Apart from susceptibility to bacterial, viral and fungal infections, other clinical signs (autoimmunization, non-infectious lung and gastrointestinal diseases, neoplasm) are frequently observed. About 58% of patients with CVID develops granulomatous and lymphocytic interstitial lung disease (GLILD) associated with early mortality.