Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and ...durability of this effect are uncertain.
We conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period.
At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, -55.2 percentage points). Significant between-group differences were also observed in total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection-site reaction (12.7 per 100 person-years).
In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954 , NCT01968967 , NCT01968980 , NCT02100514 , NCT02135029 , and NCT02458287 .).
Fotoférese Extracorpórea (FEC) se baseia na manipulação dos linfócitos T com substâncias fotossensibilizantes que quando expostos à luz ultravioleta (UV) sofrem apoptose e ao serem devolvidos ao ...paciente desencadeiam uma série de efeitos imunomodulatórios. Poucos serviços dispõem do equipamento e relatamos a primeira experiência do setor de Aférese do Hospital Santa Marcelina no uso da FEC.
Paciente 55 anos, masculino, com Linfoma Cutâneo de Células T desde 2017, tratado antes com corticoide e CHOEP, sem resposta; de dez/2017 a jan/2018 fez metotrexato, resposta parcial; mudou para GVD de fev/2018 a mai/2018 e novamente resposta parcial. Novo tratamento com Cladribina em jun/2018 com resposta completa. Out/2018 apresenta novamente eritema e biópsia evidenciou recaída. Prescrito interferon e encaminhado em ago/2019 para no nosso Serviço de Transplante de Medula Óssea (TMO), foi constatado atividade da doença e indicado FEC antes do TMO. Proposto o protocolo da ASFA (American Society for Apheresis) que recomenda para Linfoma Cutâneo de Células T/Micose Fungoide/Síndrome de Sezary duas sessões de fotoférese em dias consecutivos (considerado um ciclo) e repetido o ciclo depois de 2–4 semanas, por 5–6 meses. O procedimento de fotoférese é contraindicado quando a leucometria está acima de 25.000/mm3, no dia 05/02/2020 o paciente apresentava leucócitos totais de 26.540/mm3, sendo necessário aumentar a dose do interferon e associar corticoide, novo hemograma de 07/02/2020 com contagem em 22.800/mm3, o primeiro ciclo foi programado e realizado nos dias 10 e 11/02/2020. Houve um treinamento prévio para equipe de enfermagem pela empresa do Sistema THERAKOS CELLEX Photopheresis e os dois primeiros procedimentos, do primeiro ciclo, foram com acompanhamento in loco . Os ciclos seguintes foram realizados com suporte remoto, no total foram realizados 5 ciclos (10 sessões de FEC), sempre o paciente recebendo orientações sobre os cuidados, em especial sobre uso de proteção UVA: óculos escuros, protetor solar, evitar exposição solar direta. Desde o primeiro procedimento apresentou febre horas após o procedimento, reação adversa mais comum. Porém apresentou piora da eritrodermia, no segundo ciclo ficou mais pronunciada, e no terceiro ciclo os sintomas foram intensificados com lesões bolhosas, e paciente foi internado em 25/03/2020. Após avaliação dermatológica, suspeitou-se de penfigóide bolhoso ou farmacodermia secundária à medicação ou radiação ultravioleta. A FEC ficou suspensa um ciclo e retomamos em 22 e 23/4/2020, fizemos um intervalo maior, realizando o 5°ciclo em 26 e 27/05/2020. Mas o paciente continuou apresentando as lesões bolhosas, e após o 5°ciclo permaneceu internado para tratamento, e as sessões foram suspensas. Paciente recebe alta em 25/06/2020 com orientação de acompanhamento ambulatorial.
Com o Sistema THERAKOS CELLEX Photopheresis o procedimento de FEC é de fácil execução, cabendo ao responsável pelo procedimento ações pontuais, como montagem do kit com cuidado para o conjunto de lâmpadas de luz ultravioleta e a colocação da solução fotossensibilizante (UVADEX Methoxsalen) no produto coletado. É rápido, menos de 60 minutos, devendo o paciente ter um acesso venoso adequado ao fluxo periférico ou por cateter. Uma boa história clínica, verificar se o paciente não é esplenectomizado (o que contraindica o procedimento) e conferência dos exames pré-procedimento como leucograma, coagulograma, perfil lipídico e bilirrubina devem ser realizados. A primeira experiência em Fotoférese Extracorpórea do Serviço de Aférese foi fundamental para elaborarmos os protocolos internos com capacitação da equipe e interações entre todos os setores envolvidos.
Os transplantes hepáticos possuem um risco de sangramento intra-operatório bastante variável. Em alguns cenários devido à coagulopatia associada à hepatopatia crônica e ao porte cirúrgico complexo ...(antecedente de trombose de veia porta, hipertensão portal com colaterais, cirurgia abdominal prévia entre outros), sangramentos de grande volume são frequentes e podem requerer o uso de transfusões sanguíneas. O uso de recuperação intra-operatória tem o potencial de reduzir a necessidade de transfusão alogênica.
Analisar o impacto nas solicitações de transfusões alogênicas nos pacientes submetidos à transplante hepático de doador cadáver com o uso de recuperação intra-operatória.
Estudo retrospectivo, com levantamento de dados baseados nos registros internos do Departamento de Hemoterapia. Foram analisados os transplantes hepáticos de doador cadáver realizados no período de janeiro de 2017 à julho de 2021 no Hospital Municipal Vila Santa Catarina (HMVSC), quanto aos dados demográficos dos pacientes, dados do procedimento de recuperação intra-operatória (RIO) e de consumo transfusional de concentrado de hemácias heterólogo e autólogo em dois grupos de pacientes de pacientes: com ou sem uso de RIO.
Foram analisados 285 transplantes hepáticos realizados no período de janeiro de 2017 à julho de 2021 no Hospital Municipal Vila Santa Catarina (HMVSC). A mediana de idade dos pacientes foi 55 anos, sendo 68% dos pacientes do sexo masculino (193) e 32% do sexo feminino (92). 218 receberam transfusão de CH alogênica (76,5%), sendo a mediana de consumo transfusional de 2,0 unidades. Entre os 285 transplantes, 216 destes utilizaram a RIO (75,8%) e 69 não utilizaram (24,2%) sendo as principais contra-indicações para uso de RIO: hepatocarcinoma celular e transplante com baixo risco de sangramento. Dos 216 pacientes que utilizaram RIO, a mediana de volume recuperado da RIO foi de 743,5 mL por procedimento (o que equivale a cerca de 2,7 unidades de CH autólogo) e mediana de transfusão alogênica de 1 unidade de CH. Dos 69 pacientes que não utilizaram RIO, a mediana de transfusão alogênica foi de 2 unidades de CH.
No HMVSC, a maioria dos pacientes submetidos a transplante hepático usou RIO (75,8% casos) e 76,5% dos pacientes recebeu pelo menos 1 unidade de CH alogênica. Alguns estudos demonstraram que a transfusão alogênica causa imunossupressão e impacta negativamente no desfecho clínico nos pacientes submetidos a transplante hepático. Além disso, há o risco de exposição à reações transfusionais (tais como infecciosas e imunológicas). A utilização de transfusão autóloga é uma estratégia para diminuir a incidência dos efeitos negativos da transfusão alogênica, assim evitando a utilização excessiva do sangue proveniente de doações, um recurso limitado, sendo o sangue recuperado na RIO uma boa estratégia transfusional. Na população estudada, o uso de recuperação intra-operatória minimizou o uso de CH alogênico, o que poupou o consumo de 2,7 unidades de CH.
O uso de recuperação intra-operatória minimiza o uso perioperatório de CH alôgenico, prevenindo a exposição de transfusão alogênica e seus possíveis efeitos negativos.
Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic–pituitary–adrenal ...(HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.
Post-COVID syndrome, inflammation, and diabetes Rizvi, Ali A.; Kathuria, Amita; Al Mahmeed, Wael ...
Journal of diabetes and its complications,
11/2022, Letnik:
36, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The raging COVID-19 pandemic is in its third year of global impact. The SARS CoV 2 virus has a high rate of spread, protean manifestations, and a high morbidity and mortality in individuals with ...predisposing risk factors. The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and varying degrees of glucose intolerance. The latter can be evident as significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease. Unfortunately, the clinical course beyond the acute phase of the illness may persist in the form of a variety of symptoms that together form the so-called “Long COVID” or “Post-COVID Syndrome”. It is thought that a chronic, low-grade inflammatory and immunologic state persists during this phase, which may last for weeks or months. Although numerous insights have been gained into COVID-related hyperglycemia and diabetes, its prediction, course, and management remain to be fully elucidated.
•SARS CoV 2 infection beyond the acute phase may continue to cause symptoms that together form the so-called “Long COVID” or “Post-COVID Syndrome”•The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and glucose intolerance•Significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease may occur•The prediction, course, and management of COVID-related hyperglycemia remain to be fully elucidated
Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as “Cardiometabolic Disease” (CMD). Just under 50% of patients with CMD increased the risk ...of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus.
One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD.
The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19.
•There is a bidirectional impact of COVID-19 and CMD•The pathogenesis of COVID-19 dysregulates the immune response and triggeres a “cytokine storm”•Proinflammatory response is already present in CMD patients significantly affecting their health during SARS-CoV2 infection.•Targeting of inflammatory biomarkers could be promising for early identification of patients at risk of adverse outcomes
The growing amount of evidence suggests the existence of a bidirectional relation between coronavirus disease 2019 (COVID-19) and type 2 diabetes mellitus (T2DM), as these two conditions exacerbate ...each other, causing a significant healthcare and socioeconomic burden. The alterations in innate and adaptive cellular immunity, adipose tissue, alveolar and endothelial dysfunction, hypercoagulation, the propensity to an increased viral load, and chronic diabetic complications are all associated with glucometabolic perturbations of T2DM patients that predispose them to severe forms of COVID-19 and mortality. Severe acute respiratory syndrome coronavirus 2 infection negatively impacts glucose homeostasis due to its effects on insulin sensitivity and β-cell function, further aggravating the preexisting glucometabolic perturbations in individuals with T2DM. Thus, the most effective ways are urgently needed for countering these glucometabolic disturbances occurring during acute COVID-19 illness in T2DM patients. The novel classes of antidiabetic medications (dipeptidyl peptidase 4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are considered candidate drugs for this purpose. This review article summarizes current knowledge regarding glucometabolic disturbances during acute COVID-19 illness in T2DM patients and the potential ways to tackle them using novel antidiabetic medications. Recent observational data suggest that preadmission use of GLP-1 RAs and SGLT-2is are associated with decreased patient mortality, while DPP-4is is associated with increased in-hospital mortality of T2DM patients with COVID-19. Although these results provide further evidence for the widespread use of these two classes of medications in this COVID-19 era, dedicated randomized controlled trials analyzing the effects of in-hospital use of novel antidiabetic agents in T2DM patients with COVID-19 are needed.
Efforts in the fight against COVID-19 are achieving success in many parts of the world, although progress remains slow in other regions. We believe that a syndemic approach needs to be adopted to ...address this pandemic given the strong apparent interplay between COVID-19, its related complications, and the socio-structural environment. We have assembled an international, multidisciplinary group of researchers and clinical practitioners to promote a novel syndemic approach to COVID-19: the CArdiometabolic Panel of International experts on Syndemic COvid-19 (CAPISCO). This geographically diverse group aims to facilitate collaborative-networking and scientific exchanges between researchers and clinicians facing a multitude of challenges on different continents during the pandemic. In the present article we present our "manifesto", with the intent to provide evidence-based guidance to the global medical and scientific community for better management of patients both during and after the current pandemic.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been shown to disrupt many organ systems in the human body. Though several medical ...disorders have been affected by this infection, a few illnesses in addition may also play a role in determining the outcome of COVID-19. Obesity is one such disease which is not only affected by the occurrence of COVID-19 but can also result in a worse clinical outcome of COVID-19 infection. This manuscript summarizes the most recent evidence supporting the bidirectional impact of COVID-19 and obesity. It highlights how the presence of obesity can be detrimental to the outcome of COVID-19 in a given patient because of the mechanical limitations in lung compliance and also by the activation of several thrombo-inflammatory pathways. The sociodemographic changes brought about by the pandemic in turn have facilitated the already increasing prevalence of obesity. This manuscript highlights the importance of recognizing these pathways which may further help in policy changes that facilitate appropriate measures to prevent the further worsening of these two pandemics.
PDF
