RESUMO
Immunoglobulin replacement therapy is a life-saving treatment in patients with immunodeficiency and effective in the management of autoimmune disorders. Immunoglobulins are administered intravenously or subcutaneously, with the latter route reducing systemic reactions and providing an option for self-infusion, increasing patient convenience, while decreasing patient burden, healthcare utilization, and costs. A major limitation with subcutaneous administrations is the frequency of infusion due to limited volumes administrable into subcutaneous space, necessitating increased drug concentration, absorption, and dispersion. Increasing the concentration of immunoglobulins from 10 to 20% halves the required volume, but leads to higher dynamic viscosity, limiting infusion rate. Recombinant human hyaluronidase increases dispersion and absorption of immunoglobulins allowing administration of ≤ 600 mL per site, but does not change viscosity. Since the viscosity of fluids depends on temperature, we tested the feasibility of in-line warming of immunoglobulin formulations to physiological temperatures. In vitro analysis showed no negative impact of in-line warming to 38 °C on product quality. Subcutaneous infusion studies in pigs confirmed the feasibility of infusion rates of up to 7.5 mL/min with in-line warmed TAK-881, an immunoglobulin 20% facilitated with recombinant human hyaluronidase. In-line pressures were reduced compared with conventional immunoglobulin 20%, and local tolerance was not altered. Reduction of in-line pressures was more pronounced with thinner needle sets, indicating a potential benefit for patients. In summary, an in in-line warming device can circumvent the limitation of high viscosity, while product quality and local tolerance are maintained. The results of the presented studies warrant further testing in a phase 1 clinical study.
Assuntos
Hialuronoglucosaminidase , Síndromes de Imunodeficiência , Humanos , Animais , Suínos , Hialuronoglucosaminidase/efeitos adversos , Imunoglobulinas/efeitos adversos , Síndromes de Imunodeficiência/tratamento farmacológico , Infusões Subcutâneas , Injeções SubcutâneasRESUMO
Secondary antibody deficiencies (SAD) may require immunoglobulin replacement therapy (IgRT). While the intravenous route (IVIG) is broadly considered effective in SAD, the use of subcutaneous immunoglobulins (SCIG) is mainly adopted from the experience in primary antibody deficiencies (PAD), where SCIG have been shown to perform as effective as IVIG. However, evidence-based data on SCIG administration in SAD patients are still insufficient. Herein we retrospectively evaluated the efficacy and safety profile of SCIG treatment in 131 SAD patients as compared to a group of 102 PAD patients. We found SCIG being equally effective in reducing annual infectious rate both in SAD and PAD patients. However, SAD patients required lower SCIG dosage and lower IgG through level to achieve similar biological effect in terms of infection burden, at the steady state. SAD patients also showed better correlation between SCIG dose and serum IgG achieved value. Furthermore, within SAD, SCIG were found to work irrespective of the underlying disease. Especially in Non-Hodgkin Lymphoma patients, whose indication to IgRT is still not included in all guidelines and for whom evidence-based data are still lacking, SCIG were as effective as in Chronic Lymphocytic Leukemia or Multiple Myeloma patients, and SCIG discontinuation, without evidence of B cell recovery, led to IgG decline and relapsed infections. Finally, treatment tolerance in SAD patients was comparable to the PAD cohort. Globally, our data suggest that SCIG, as already appreciated in PAD, represent a valuable option in SAD patients, independent on the disease leading to antibody deficiency.
Assuntos
Imunização Passiva/métodos , Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Doenças da Imunodeficiência Primária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Calafrios/induzido quimicamente , Feminino , Cefaleia/induzido quimicamente , Humanos , Imunização Passiva/efeitos adversos , Imunoglobulinas/administração & dosagem , Imunoglobulinas/efeitos adversos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Subcutaneous immunoglobulin (SCIg) is an emerging therapeutic alternative in the management of myasthenia gravis (MG) due to its potential efficacy, safety, cost effectiveness and ease of administration. At present, there are no systematic reviews that summarized the effects of SCIg in patients with MG. The objective of this study is to determine the efficacy and safety of SCIg in the treatment of adult patients with myasthenia gravis. Relevant records were identified from August 2018 to January 2019 systematic search. Five relevant articles with a total of 34 patients with MG were included in this review. Data on functional disability score and adverse events were obtained. Based on the included uncontrolled studies, the functional disability scores of adult MG patients after SCIg administration showed consistent improvement. Headache and local site injection reactions were the most common adverse events reported. The evidence from limited uncontrolled studies gathered in this review showed that SCIg may improve functional disability in patients with MG. Local and mild adverse events were reported with its administration, but no systemic and serious adverse events were noted.
Assuntos
Imunoglobulinas/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Adulto , Idoso , Tolerância a Medicamentos , Feminino , Humanos , Imunoglobulinas/administração & dosagem , Imunoglobulinas/efeitos adversos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Since successful cloning of thrombopoietin (TPO) in 1994, significant advances have been made in the development of recombinant TPO receptor agonists. The US Food and Drug Administration (FDA) has approved 2 agents for use in patients with immune thrombocytopenia (ITP): eltrombopag and romiplostim. Romiplostim is a once-weekly subcutaneous injection that has been shown to increase the platelet count, lessen bleeding, and reduce concurrent medication use in adults with ITP. In December 2018, the US FDA approved romiplostim for use in pediatric patients ≥1 year of age with ITP of >6 months' duration and insufficient response to corticosteroids, immunoglobulins, or splenectomy, based on similarly favorable clinical trial data. In addition, romiplostim is well tolerated, making it an attractive option for the treatment of children. Expansion of off-label romiplostim use is being reported in children for ITP <6 months, neonatal thrombocytopenia, hereditary thrombocytopenias, and chemotherapy- and bone marrow transplant-associated thrombocytopenia. We review here the development of romiplostim with a focus on pediatric use.
Assuntos
Benzoatos/farmacocinética , Desenvolvimento de Medicamentos/estatística & dados numéricos , Hidrazinas/farmacocinética , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/farmacocinética , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/farmacocinética , Trombopoetina/genética , Corticosteroides/efeitos adversos , Corticosteroides/farmacologia , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Pré-Escolar , Ensaios Clínicos como Assunto , Clonagem de Organismos/história , Desenvolvimento de Medicamentos/tendências , Hemorragia/prevenção & controle , História do Século XX , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Imunoglobulinas/efeitos adversos , Imunoglobulinas/farmacologia , Lactente , Injeções Subcutâneas , Contagem de Plaquetas/métodos , Contagem de Plaquetas/tendências , Guias de Prática Clínica como Assunto , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/etiologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Receptores Fc/administração & dosagem , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Segurança , Esplenectomia/efeitos adversos , Esplenectomia/métodos , Trombocitopenia Neonatal Aloimune/tratamento farmacológico , Trombopoetina/administração & dosagem , Trombopoetina/farmacocinética , Trombopoetina/farmacologia , Trombopoetina/uso terapêutico , Estados Unidos/epidemiologia , United States Food and Drug AdministrationRESUMO
Sudden cardiac death (SCD) is an unexpected death due to cardiac causes that occurs in a short time period (generally within 1â¯h of symptom onset) in a person with known or unknown cardiac disease. Patients with cardiomyopathies, myocarditis, ischemic heart disease and cardiac channelopathies are at risk of SCD. However, a certain percentage of autopsy-negative cases of SCD in the young (<35â¯years) remain unexplained even after a post-mortem genetic testing. Autoantibodies against cardiac proteins may be potentially involved in the pathogenesis of different heart diseases and in the occurrence of unexplained SCD. In this review we analyze clinical and animal studies that elucidate the prevalence of these autoantibodies in patients with different cardiac diseases and their pathophysiological relevance. We propose a classification of the autoantibodies associated with heart diseases and focus on their molecular and cellular effects. Anti-beta adrenergic receptor antibodies and anti-muscarinic acetylcholine receptor antibodies affect myocardial electrophysiological properties and were reported to be the independent predictors of SCD in patients with different heart diseases. Autoimmune mechanism is proposed for cardiac-related adverse reactions following human papillomavirus (HPV) vaccination. The pentapeptid sharing between HPV's antigens, adrenergic receptors and muscarinic acetylcholine receptors supports this assumption. The dysregulating effects of the autoantibodies against calcium and potassium ion channels can be the basis for autoimmune phenocopies of genetic cardiac channelopathies, which are also associated with SCD.
Assuntos
Autoanticorpos/efeitos adversos , Morte Súbita Cardíaca/etiologia , Imunoglobulinas/efeitos adversos , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/mortalidade , Autoanticorpos/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/mortalidade , Cardiomiopatias/imunologia , Cardiomiopatias/mortalidade , Testes Genéticos , Humanos , Miocardite/complicações , Miocardite/imunologia , Miocardite/mortalidade , Miocárdio/imunologia , Miocárdio/patologia , FenótipoRESUMO
BACKGROUND & AIMS: The combination of hepatitis B immunoglobulin and a nucleos(t)ide analogues has markedly reduced the rate of hepatitis B virus recurrence after liver transplantation; however, the optimal duration of hepatitis B immunoglobulin has not been clarified. This lack of consensus perpetuates the use of different strategies. The aim of this study was to evaluate the risk factors associated to hepatitis B virus recurrence after liver transplantation in a large cohort of patients under different hepatitis B immunoglobulin regimens. METHODS: Retrospective multicentre analysis of hepatitis B virus-related liver transplantation recipients receiving combined prophylaxis (hepatitis B immunoglobulin + nucleos(t)ide analogues). The strategy of short-term hepatitis B immunoglobulin was compared to lifelong administration. Hepatitis B virus recurrence was defined as positive HBsAg after liver transplantation. RESULTS: Three hundred and thirty-eight patients were analysed. After a median follow-up period of 72 months, 37 patients (11%) developed hepatitis B virus recurrence. Hepatocellular carcinoma recurrence and lamivudine resistance after liver transplantation were the only factors independently associated to hepatitis B virus recurrence (HR 5.4 [2.3-12] and 9.3 [4.2-20] respectively P < .001). HBsAg reappearance after hepatitis B virus recurrence was transient (16 patients), persistent (15) or alternant (6). The hepatitis B immunoglobulin regimen did not have an impact on the rate or evolution of hepatitis B virus recurrence. Overall, patient survival was good and not influenced by hepatitis B virus recurrence (82% at 5 years). Fulminant liver failure, hepatitis C coinfection or hepatocellular carcinoma at liver transplantation were independent risk factors for lower survival. CONCLUSIONS: Liver transplantation is an effective treatment for hepatitis B virus-related liver disease. Since the introduction of combined prophylaxis the rate of hepatitis B virus recurrence is very low. However, lifelong hepatitis B immunoglobulin administration does not seem necessary to reduce hepatitis B virus recurrence.
Assuntos
Antivirais/administração & dosagem , Hepatite B/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Transplante de Fígado/efeitos adversos , Adulto , Antivirais/efeitos adversos , Quimioterapia Combinada , Feminino , Hepatite B/mortalidade , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B , Humanos , Imunoglobulinas/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Análise de Sobrevida , Resultado do TratamentoAssuntos
Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Imunoglobulinas/efeitos adversos , Transplante de Fígado/efeitos adversos , Trombofilia/induzido quimicamente , Aloenxertos/irrigação sanguínea , Aloenxertos/patologia , Aloenxertos/cirurgia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Oxigenação por Membrana Extracorpórea , Hepatectomia , Veias Hepáticas/patologia , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Transplante de Rim , Fígado/irrigação sanguínea , Fígado/patologia , Fígado/cirurgia , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Cirrose Hepática/virologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/cirurgia , Reoperação , Trombofilia/terapiaRESUMO
Multiple myeloma is commonly associated with a reduction of non-paraprotein immunoglobulins, resulting in a higher risk of infections that represent the leading cause of the patients' death. Therefore, immunoglobulin replacement therapy appears a logical approach. A total number of 46 myeloma patients were randomly enrolled: 24 of them were assigned to receive subcutaneous immunoglobulins, and 22 were controls. The primary endpoint was the evaluation of the annual rate of severe infections in immunoglobulins-receiving patients as compared with those untreated. Subcutaneous immunoglobulins-treated patients showed a significantly lower number of severe infections per year. Adverse events were limited to the site of infusion and were easily manageable. Health-related quality of life was significantly better in subcutaneous immunoglobulins-receiving patients. By decreasing the rate of infections, the prophylactic administration of SCIg improves both adherence to chemotherapy and health-related quality of life, and is cost-effective by reducing the need of hospitalization and the use of antibiotics.
Assuntos
Agamaglobulinemia/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Agamaglobulinemia/imunologia , Agamaglobulinemia/psicologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulinas/efeitos adversos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/psicologia , Qualidade de VidaRESUMO
BACKGROUND: Hepatitis B immune globulin (HBIG) has been an integral component of prophylaxis against hepatitis B virus (HBV) recurrence in liver transplantation (LT) recipients, but HBIG is costly and inconvenient to administer, prompting consideration of alternative regimens. METHODS: In this retrospective cohort, we report on the success of antiviral therapy combined with a short course (in hospital only) HBIG in liver transplant recipients with HBV DNA less than 100 IU/mL pre-LT. RESULTS: A total of 42 hepatitis B surface antigen (HBsAg) positive, human immunodeficiency virus and hepatitis D virus-negative patients with pretransplant HBV DNA undetectable to 100 IU/mL who received HBIG 5000 IU in anhepatic phase and daily for 5 days together with nucleos(t)ide analogues indefinitely yielded 1- and 3-year cumulative incidences of recurrence, defined by positive serum HBsAg, of 2.9% (upper 95% confidence interval, 19%). One patient had HBV viremia 16 months post-LT without detectable HBsAg. Both patients with either HBsAg positivity or viremia had recurrent hepatocellular carcinoma diagnosed within a month of detection. Post-LT survival was 98% and 94% at 1 and 5 years, respectively. CONCLUSIONS: We conclude that a very short course of HBIG combined with long-term antiviral therapy is highly effective in preventing HBV recurrence and should be the preferred strategy for LT recipients with undetectable or low-level viremia at time of LT.
Assuntos
Antivirais/administração & dosagem , Doença Hepática Terminal/cirurgia , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Transplante de Fígado , Ativação Viral/efeitos dos fármacos , Adulto , Idoso , Antivirais/efeitos adversos , Biomarcadores/sangue , DNA Viral/sangue , DNA Viral/genética , Esquema de Medicação , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/virologia , Feminino , Hepatite B/complicações , Hepatite B/diagnóstico , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/efeitos adversos , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Imunoglobulinas/efeitos adversos , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVE: To investigate the efficacy, tolerability, and safety of subcutaneous immunoglobulin (SCIg) in patients with mild to moderate myasthenia gravis (MG) exacerbation. METHODS: We performed a prospective, open-label, phase 3 trial in patients with MG aged 18 years or older and mild to moderate worsening (transition from Myasthenia Gravis Foundation of America class I to II/III or class II to III), treated with SCIg (2 g/kg), self-administered over 4 weeks. The primary endpoint was change in quantitative MG (QMG) score from baseline to study end at 6 weeks. Secondary endpoints included change in manual muscle testing (MMT), MG activities of daily living (MG-ADL), and MG composite (MGC) scores, as well as occurrence of adverse events, and tolerability as assessed via Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Twenty-two of 23 patients completed the study. QMG score decreased from 14.9 ± 4.1 to 9.8 ± 5.6 (p < 0.0001), MMT score decreased from 16.8 ± 9.5 to 5.2 ± 4.5 (p < 0.0001), MG-ADL score decreased from 9.5 ± 3.0 to 4.6 ± 3.0 (p < 0.0001), and MGC score decreased from 17.4 ± 5.0 to 5.6 ± 4.5 (p < 0.0001). Satisfaction by TSQM was high (79.6 ± 15.6%). Common adverse events included headache and injection site reactions. No serious adverse events occurred. CONCLUSIONS: SCIg is well-tolerated, safe, and effective in mild to moderate MG exacerbation. Comparative safety and efficacy must be established with randomized controlled trials. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with mild to moderate MG exacerbation, SCIg is safe and effective in reducing MG disability measures.
Assuntos
Imunoglobulinas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Humanos , Imunoglobulinas/efeitos adversos , Imunoglobulinas/sangue , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Projetos Piloto , Autoadministração , Índice de Gravidade de Doença , Absorção Subcutânea , Adulto JovemRESUMO
OBJECTIVE: We aimed to describe the current management and outcomes of patients with secondary immunodeficiencies (SID) on intravenous (IV) or subcutaneous (SC) immunoglobulins (IG) as maintenance therapy to prevent infections. METHODS: Non-interventional, prospective study (average follow-up 20.5 months). RESULTS: Of the 307 SID patients (mean age 63.7±14.4 years, 52% males, in 31% IG newly initiated), 95.4% received IV IG (mean dosing interval 4.6 weeks, average dose 199 mg/kg per 4 weeks) and 4.6% were treated with SC IG (2.6 weeks, 343 mg/kg per 4 weeks). Median IG through level at first documentation was 5.8 g/L and did not differ between IV and SC treatment or between underlying malignancies. In 24.1% of patients, treatment was interrupted temporarily, over a mean of 11.6±6.3 months. In patients with newly initiated IG treatment the 82% overall infection rate prior to treatment dropped to 21% at 1 year. CONCLUSIONS: Under clinical practice conditions, IG replacement therapy in SID patients was feasible, diminished infection rates and improved quality of life. Average IG doses were relatively low. Tolerability of IV IG treatment was excellent.
Assuntos
Imunoglobulinas/administração & dosagem , Síndromes de Imunodeficiência/complicações , Controle de Infecções , Infecções/tratamento farmacológico , Infecções/etiologia , Neoplasias/complicações , Adulto , Idoso , Feminino , Humanos , Imunoglobulinas/efeitos adversos , Imunoglobulinas Intravenosas , Síndromes de Imunodeficiência/terapia , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasias/diagnóstico , Neoplasias/terapia , Avaliação de Resultados da Assistência ao Paciente , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
Immunoglobulin therapy is a key element in the management of most patients with primary immunodeficiency disease. Allergist/immunologists should be familiar with the appropriate evaluation of candidates for immunoglobulin, the characteristics of immunoglobulin products, and how to use them to provide the best care to their patients. Available immunoglobulin products appear to be equally efficacious, but they are not interchangeable. Minimizing the risk of serious adverse events and controlling minor side effects is important to ideal patient care. Immunoglobulin may be administered intravenously or subcutaneously. Individualizing the choice of immunoglobulin product, mode of administration, and site of care can optimize the clinical outcome and minimize the burden of care.
Assuntos
Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Animais , Antígenos de Neoplasias/imunologia , Monitoramento de Medicamentos , Histona Acetiltransferases/imunologia , Humanos , Hialuronoglucosaminidase/imunologia , Imunoglobulinas/administração & dosagem , Imunoglobulinas/efeitos adversos , Benefícios do Seguro , Seguro SaúdeRESUMO
Despite improvements in the management of community-acquired pneumonia (CAP), morbidity and mortality are still high, especially in patients with more severe disease. Early and appropriate antibiotics remain the cornerstone in the treatment of CAP. However, two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. Adjuvant treatments, such as corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects. The use of corticosteroids in patients with severe CAP and a strong inflammatory reaction can reduce the time to clinical stability, the risk of treatment failure, and the risk of progression to acute respiratory distress syndrome. The administration of intravenous immunoglobulins seems to reinforce the immune response to the infection in particular in patients with inadequate levels of antibodies and when an enriched IgM preparation has been used; however, more studies are needed to determinate their impact on outcome and to define the population that will receive more benefit.
Assuntos
Corticosteroides/farmacologia , Imunoglobulinas/farmacologia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Infecção Hospitalar/mortalidade , Mortalidade Hospitalar , Humanos , Imunidade Inata/fisiologia , Imunoglobulinas/efeitos adversos , Imunoglobulinas/uso terapêutico , Interleucina-10/análise , Interleucina-10/metabolismo , Interleucina-6/análise , Interleucina-6/metabolismo , Interleucina-8/análise , Interleucina-8/metabolismo , Literatura de Revisão como Assunto , Síndrome de Resposta Inflamatória Sistêmica/complicações , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/etiologiaRESUMO
Intravenous ganciclovir and, increasingly, oral valganciclovir are now considered the mainstay of treatment for cytomegalovirus (CMV) infection or CMV disease. Under certain circumstances, CMV immunoglobulin (CMVIG) may be an appropriate addition or, indeed, alternative. Data on monotherapy with CMVIG are limited, but encouraging, for example in cases of ganciclovir intolerance. In cases of recurrent CMV in thoracic transplant patients after a disease- and drug-free period, adjunctive CMVIG can be considered in patients with hypogammaglobulinemia. Antiviral-resistant CMV, which is more common among thoracic organ recipients than in other types of transplant, can be an indication for introduction of CMVIG, particularly in view of the toxicity associated with other options, such as foscarnet. Due to a lack of controlled trials, decision-making is based on clinical experience. In the absence of a robust evidence base, it seems reasonable to consider the use of CMVIG to treat CMV in adult or pediatric thoracic transplant patients with ganciclovir-resistant infection, or in serious or complicated cases. The latter can potentially include (i) treatment of severe clinical manifestations, such as pneumonitis or eye complications; (ii) patients with a positive biopsy in end organs, such as the lung or stomach; (iii) symptomatic cases with rising polymerase chain reaction values (for example, higher than 5.0 log10) despite antiviral treatment; (iv) CMV disease or CMV infection or risk factors, such as CMV-IgG-negative serostatus; (vi) ganciclovir intolerance; (vii) patients with hypogammaglobulinemia.
Assuntos
Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/imunologia , Transplante de Coração/efeitos adversos , Imunoglobulinas/administração & dosagem , Transplante de Pulmão/efeitos adversos , Infecções Oportunistas/prevenção & controle , Adulto , Agamaglobulinemia/imunologia , Antivirais/administração & dosagem , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Farmacorresistência Viral , Feminino , Interações Hospedeiro-Patógeno , Humanos , Imunização Passiva , Hospedeiro Imunocomprometido , Imunoglobulinas/efeitos adversos , Imunoglobulinas Intravenosas , Imunossupressores/efeitos adversos , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/imunologia , Recidiva , Fatores de Risco , Resultado do Tratamento , Ativação ViralRESUMO
The immune response to cytomegalovirus (CMV) infection is highly complex, including humoral, cellular, innate, and adaptive immune responses. Detection of CMV by the innate immune system triggers production of type I IFNs and inflammatory cytokines which initiate cellular and humoral responses that are critical during the early viremic phase of CMV infection. Sustained control of CMV infection is largely accounted for by cellular immunity, involving various T-cell and B-cell subsets. In solid organ transplant patients, global suppression of innate and adaptive immunities by immunosuppressive agents limits immunological defense, including inhibition of natural killer cell activity with ongoing lowering of Ig levels and CMV-specific antibody titers. This is coupled with a short-term suppression of CMV-specific T cells, the extent and duration of which can predict risk of progression to CMV viremia. CMV immunoglobulin (CMVIG) preparations have the potential to exert immunomodulatory effects as well as providing passive immunization. Specific CMVIG antibodies and virus neutralization might be enhanced by modulation of dendritic cell activity and by a decrease in T-cell activation, effects which are of importance during the initial phase of infection. In summary, the role of CMVIG in reconstituting specific anti-CMV antibodies may be enhanced by some degree of modulation of the innate and adaptive immune responses, which could help to control some of the direct and indirect effects of CMV infection.
Assuntos
Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/imunologia , Transplante de Coração/efeitos adversos , Imunoglobulinas/administração & dosagem , Transplante de Pulmão/efeitos adversos , Infecções Oportunistas/prevenção & controle , Imunidade Adaptativa , Anticorpos Antivirais/imunologia , Antivirais/administração & dosagem , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Imunização Passiva , Hospedeiro Imunocomprometido , Imunoglobulinas/efeitos adversos , Imunoglobulinas Intravenosas , Imunossupressores/efeitos adversos , Linfócitos/imunologia , Linfócitos/virologia , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/imunologia , Fatores de Tempo , Resultado do Tratamento , Ativação ViralRESUMO
A 33-year-old woman with multiple sclerosis, medicated with high doses of methylprednisolone, cyclophosphamide and glatiramer acetate, was referred to our department due to acute liver injury. The laboratory investigation was normal except for weakly positive antinuclear antibodies. Cyclophosphamide and glatiramer acetate were suspended, and intravenous immunoglobulin with maintenance of high doses of methylprednisolone was initiated. The patient developed another episode of acute hepatitis so the immunoglobulin was stopped. After that, she had three more episodes of elevation of liver enzymes with no hepatic insufficiency while medicated only with high doses of methylprednisolone. At this time, liver biopsy showed focal centrilobubar hepatocyte necrosis with minimal interface hepatitis. After the high doses of methylprednisolone were suspended, the patient remained asymptomatic, with normal hepatic enzymes. This case emphasises that, although rare, induced liver injury after high doses of methylprednisolone can occur.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Hepatite/sangue , Fígado/patologia , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Doença Aguda , Adulto , Biópsia , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Acetato de Glatiramer/administração & dosagem , Acetato de Glatiramer/efeitos adversos , Acetato de Glatiramer/uso terapêutico , Hepatite/patologia , Humanos , Imunoglobulinas/administração & dosagem , Imunoglobulinas/efeitos adversos , Testes de Função Hepática , Metilprednisolona/uso terapêuticoRESUMO
Antiviral therapy using newer nucleos(t)ide analogues with lower resistance rates, such as entecavir or tenofovir, suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, and delay or obviate the need for liver transplantation in some patients. After liver transplantation, the combination of long-term antiviral and low-dose hepatitis B Immune globulin (HBIG) can effectively prevent HBV recurrence in greater than 90% of transplant recipients. Some forms of HBV prophylaxis need to be continued indefinitely after transplantation but, in patients with a low-risk of HBV recurrence (i.e., HBV DNA levels undetectable before transplantation), it is possible to discontinue HBIG and maintain only long-term nucleos(t)ide analogue(s) therapy. A more cautious approach is necessary for those patients with high pretransplant HBV DNA levels, those with limited antiviral options if HBV recurrence occurs (i.e., HIV or hepatitis D virus coinfection, preexisting drug resistance), those with a high risk of hepatocellular carcinoma recurrence, and those at risk of noncompliance with antiviral therapy. In this group, HBIG-free prophylaxis cannot be recommended.
Assuntos
Antivirais/administração & dosagem , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Cirrose Hepática/cirurgia , Transplante de Fígado , Prevenção Secundária/métodos , Antivirais/efeitos adversos , Hepatite B/complicações , Hepatite B/diagnóstico , Hepatite B/virologia , Vacinas contra Hepatite B/efeitos adversos , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Imunoglobulinas/efeitos adversos , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Transplante de Fígado/efeitos adversos , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ativação Viral/efeitos dos fármacosRESUMO
OBJECTIVE: Liver transplantation significantly increases recurrence of hepatitis B virus (HBV) among high-risk patients. Hepatitis B immunoglobulin (HBIG) and antiviral nucleotide analogues are effective prophylaxis reagents in preventing HBV recurrence. However, HBV recurrence still occurs with these treatments. METHODS: To explore a more cost-effective prophylaxis protocol in patients after liver transplantation, we treated patients with an initial high dose of 10 000 IU HBIG during the anhepatic phase and a second high dose of HBIG at an optimal time point during surgery. The patients were treated with the traditional European protocol as a control, in which one dose of 10 000 IU HBIG was infused during the anhepatic phase and multiple doses of 10 000 IU HBIG were administered daily for 1 week after liver transplantation. RESULTS: There were two mortalities among 50 patients treated with the new protocol and nine mortalities among 52 patients treated with the European protocol within 3 years after liver transplantation. The new prophylaxis method markedly improved the 3-year survival without HBV recurrence in 50 treated patients. However, there were five recurrences in 52 patients treated with the European protocol. High-risk factors such as HBV DNA+, positive hepatitis B e antigen, and hepatocellular carcinoma were all detected among five patients with HBV recurrence. The suppressed HBV recurrence was associated with significantly lower serum alanine aminotransferase and aspartate aminotransferase in the new protocol-treated patients tested at 1 month and 1 week after liver surgery compared with those treated with the European protocol. CONCLUSION: Infusion of two high doses of HBIG during surgery in combination with entecavir significantly prevented HBV recurrence and improved the 3-year survival after liver transplantation.
Assuntos
Antivirais/administração & dosagem , Doença Hepática Terminal/cirurgia , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Transplante de Fígado , Adulto , Idoso , Alanina Transaminase/sangue , Antivirais/efeitos adversos , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , DNA Viral/sangue , Esquema de Medicação , Quimioterapia Combinada , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/virologia , Feminino , Guanina/administração & dosagem , Guanina/efeitos adversos , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/mortalidade , Humanos , Imunoglobulinas/efeitos adversos , Infusões Parenterais , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Ativação Viral/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVES: Hepatitis B immunoglobulin prophylaxis in combination with antiviral drugs is recommended for prevention of hepatitis B virus reinfection after liver transplant. However, there is no consensus on a standard prophylactic method, and controversy exists over the duration, dose, and route of administration. We conducted a prospective study to evaluate the safety and effectiveness of intramuscular hepatitis B immunoglobulin in combination with lamivudine and/or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year for prevention of hepatitis B virus reinfection. MATERIALS AND METHODS: Patients with hepatitis Brelated liver cirrhosis who had undergone primary liver transplants were enrolled. The prophylactic protocol involved intraoperative intramuscular hepatitis B immunoglobulin at 10 000 IU, tapering to 5000 IU daily for the first 6 days, weekly for a month, every 2 weeks for the next month, and monthly for a year after liver transplant, in combination with antiviral drugs. RESULTS: From January 2002 until March 2014, two hundred sixty-eight liver transplants were performed. Forty-four patients (16.4%) who underwent liver transplants due to hepatitis B-related liver failure were enrolled. Five patients had hepatocellular carcinoma; 20 had both hepatitis D and hepatitis B virus infection. The median age was 47 years (range, 26-59 y) with a median model for end stage liver disease score of 20. Thirty-three patients were men (76%). Sixty-one percent of patients were negative for hepatitis B virus DNA at the time of transplant. The median follow-up was 13.6 months (range, 0-142 mo). Only 1 patient (2.3%) experienced hepatitis B virus reinfection (at 44.7 months posttransplant), which was successfully treated with tenofovir. Five patients died (11.4%) during the follow-up from nonhepatitis B causes. CONCLUSIONS: Intramuscular hepatitis B immunoglobulin in combination with lamivudine or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year posttransplant may provide safe and cost-effective protection against posttransplant hepatitis B reinfection.
Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Imunoglobulinas/administração & dosagem , Lamivudina/administração & dosagem , Falência Hepática/cirurgia , Transplante de Fígado , Tenofovir/administração & dosagem , Ativação Viral/efeitos dos fármacos , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Criança , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hepatite B/complicações , Hepatite B/diagnóstico , Vírus da Hepatite B/crescimento & desenvolvimento , Humanos , Imunoglobulinas/efeitos adversos , Injeções Intramusculares , Lamivudina/efeitos adversos , Falência Hepática/diagnóstico , Falência Hepática/virologia , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Tenofovir/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
AIM: To evaluate the prophylactic efficacy of hepatitis B immunoglobulin (HBIG) in combination with different nucleos(t)ide analogues. METHODS: A total of 5333 hepatitis B surface antigen-positive patients from the China Liver Transplant Registry database were enrolled between January 2000 and December 2009. Low-dose intramuscular (im) HBIG combined with one nucleos(t)ide analogue has been shown to be very cost-effective in recent reports. Hepatitis B virus (HBV) prophylactic outcomes were compared based on their posttransplant prophylactic protocols [group A (n = 4684): im HBIG plus lamivudine; group B (n = 491): im HBIG plus entecavir; group C (n = 158): im HBIG plus adefovir dipivoxil]. We compared the related baseline characteristics among the three groups, including the age, male sex, Meld score at the time of transplantation, Child-Pugh score at the time of transplantation, HCC, pre-transplantation hepatitis B e antigen positivity, pre-transplantation HBV deoxyribonucleic acid (HBV DNA) positivity, HBV DNA at the time of transplantation, pre-transplantation antiviral therapy, and the duration of antiviral therapy before transplantation of the patients. We also calculated the 1-, 3- and 5-year survival rates and HBV recurrence rates according to the different groups. All potential risk factors were analyzed using univariate and multivariate analyses. RESULTS: The mean follow-up duration was 42.1 ± 30.3 mo. The 1-, 3- and 5-year survival rates were lower in group A than in groups B (86.2% vs 94.4%, 76.9% vs 86.6%, 73.7% vs 82.4%, respectively, P < 0.001) and C (86.2% vs 92.5%, 76.9% vs 73.7%, 87.0% vs 81.6%, respectively, P < 0.001). The 1-, 3- and 5-year posttransplant HBV recurrence rates were significantly higher in group A than in group B (1.7% vs 0.5%, 3.5% vs 1.5%, 4.7% vs 1.5%, respectively, P = 0.023). No significant difference existed between groups A and C and between groups B and C with respect to the 1-, 3- and 5-year HBV recurrence rates. Pretransplant hepatocellular carcinoma, high viral load and posttransplant prophylactic protocol (lamivudine and HBIG vs entecavir and HBIG) were associated with HBV recurrence. CONCLUSION: Low-dose intramuscular HBIG in combination with a nucleos(t)ide analogue provides effective prophylaxis against posttransplant HBV recurrence, especially for HBIG plus entecavir.