Informe diário de evidências COVID-19: busca realizada em 28 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 28, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 18 artigos e 3 protocolos.

Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation

Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2–4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2–4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

Alemtuzumab in refractory Sézary syndrome

Abstract: Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by the triad of erythroderma, lymphadenopathy and circulating atypical cells. The emergence of new molecular targets has enabled the development of drugs such as alemtuzumab, an anti-CD52 monoclonal antibody, which has shown promising results in the treatment of this entity. We report the case of a 70-year-old male with refractory Sézary syndrome in whom treatment with alemtuzumab achieved an 80% skin lesion clearance with complete haematologic and radiologic response. The treatment was discontinued after 4 months due to adverse effects, with the patient showing a sustained response without disease progression after 13 months of follow-up.

Effect of alemtuzumab on intestinal intraepithelial lymphocytes and intestinal barrier function in cynomolgus model / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia). However, serious infectious complications frequently occur after treatment. The reason for increased infections postalemtuzumab treatment is unknown at this stage. We explore the effect of alemtuzumab on intestinal intraepithelial lymphocytes (IELs) and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment.</p><p><b>METHODS</b>Twelve male cynomolguses were randomly assigned to either a treatment or control group. The treatment group received alemtuzumab (3 mg/kg, intravenous injection) while the control group received the same volume of physiological saline. Intestinal IELs were isolated from the control group and the treatment group (on day 9, 35, and 70 after treatment) for counting and flow cytometric analysis. Moreover, intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay.</p><p><b>RESULTS</b>The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 10 8 and 1.35 ± 0.09 × 10 8 , respectively; P < 0.05) and were not fully restored until day 70 after treatment. There were significant differences among four groups considering IELs subtypes. In addition, the proportion of apoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 ± 3.67 and 6.01 ± 1.42, respectively; P < 0.05). Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.</p><p><b>CONCLUSIONS</b>Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model. The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment. Notably, intestinal barrier function may be disrupted after alemtuzumab treatment.</p>

Effect of Campath-1H induction on immunosuppression in small intestine transplantation / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the effect of Campath-1H induction on immunosuppression in small intestine transplantation.</p><p><b>METHODS</b>Clinical data of a patient who underwent small intestine transplantation were retrospectively summarized.</p><p><b>RESULTS</b>Intraoperative Campath-1H induction by intravenous injection was administered. Triple immunosuppression(FK506, MMF and methylprednisolone) was used postoperatively. The lymphocyte and leukocyte decreased significantly following Campath-1H induction, and returned to normal after adjusting the dose of immunosuppressant and use of colony stimulating factor. There were no acute rejection, graft versus host disease, or severe infection during the immediate postoperative period. The patient recovered and discharged.</p><p><b>CONCLUSION</b>Intraoperative Campath-1H induction and postoperative triple immunosuppression using FK506, MMF, and methylprednisolone may prevent rejection and graft versus host disease in the early stage after small intestine transplantation.</p>

Alemtuzumab induction therapy in highly sensitized kidney transplant recipients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Immunosuppression for immunologically high-risk kidney transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, was expected to be a promising induction therapy agent for kidney transplantation. However, currently no consensus is available about its efficacy and safety. This study aimed to evaluate the efficacy and safety of alemtuzumab as immune induction therapy in highly sensitized kidney transplant recipients.</p><p><b>METHODS</b>In this prospective, open-label, randomized, controlled trial, we enrolled 23 highly immunological risk patients (panel reactive antibody > 20%). They were divided into two groups: alemtuzumab group (trial group) and anti-thymocyte globulin (ATG) group (control group). Patients in the alemtuzumab group received intravenous alemtuzumab (15 mg) as a single dose before reperfusion. At the 24th hour post-operation, another dosage of alemtuzumab (15 mg) was given. The control group received a bolus of rabbit ATG (9 mg/kg), which was given 2 hours before kidney transplantation and lasted until the removal of vascular clamps when the anastomoses were completed. Maintenance immunosuppression in both groups comprised standard triple therapy consisting of tacrolimus, prednisone, and mycophenolate mofetil (MMF). Acute rejection (AR) and infection episodes were recorded, and kidney function was monitored during a 2-year follow-up. χ(2) test, t test and Kaplan-Meier analysis were performed with SPSS17.0 software.</p><p><b>RESULTS</b>Median follow-up was 338 days. In both the alemtuzumab group and ATG group, creatinine and blood urea nitrogen values in surviving recipients were similar (P > 0.05). White blood cell counts were significantly reduced in the alemtuzumab group for the most time points up to 6 months (P < 0.05). One patient receiving alemtuzumab died for acute myocardial infarction at the 65th day post-operation. Two ATG patients died for severe pulmonary infection or cardiac and pulmonary failure. Cumulative 2-year graft survival rate was 90.9% in the alemtuzumab group and 81.8% in ATG group (P > 0.05) respectively. There was one graft failure in the alemtuzumab group and two graft failures in ATG group, with all graft failures at tributed to rejection episodes. The alemtuzumab group had a 2-year cumulative freedom from rejection rate of 81.8%, compared with 72.7% for the ATG group (P > 0.05).</p><p><b>CONCLUSION</b>Alemtuzumab induction therapy for highly sensitized kidney transplant recipients is an effective and safe protocol yielding an acceptable acute rejection rate.</p>

Efficacy and safety of induction therapy with alemtuzumab in kidney transplantation: a meta-analysis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Alemtuzumab, a humanized CD52 monoclonal antibody, with its profound lymphocyte depletion property, was expected to be a promising induction therapy agent for kidney transplantation (KTx). However, currently no consensus is available about its efficacy and safety. The aim of this meta-analysis was to make a profound review and an objective appraisal of this issue.</p><p><b>METHODS</b>Relevant papers were searched, essentially in the PubMed database and the Cochrane library. After a thorough review, randomized controlled trials (RCTs) comparing the outcome of KTx using alemtuzumab induction therapy (test group) with a control group were collected according to the inclusion criteria. Data of general characteristic of studies and major outcomes of Ktx were extracted and meta-analyses were performed with RevMan 4.2 software. The odds ratio (OR) with a 95% confidence intervals (CI) was the principle measurement of effect.</p><p><b>RESULTS</b>Five RCTs were included. The chi square test showed no significant between-study heterogeneity, thus fixed effect model was employed. Sub-group analysis with studies including alemtuzumab induction followed by a tacrolimus-based immunosuppressive regimen showed that the acute rejection rate (ARR) was lower relative to the control (OR = 0.59, 95% CI 0.34 - 1.01, P = 0.05). However, meta-analysis with all included studies revealed that neither ARR nor patient/graft survival rates differ significantly between the test and the control group, but the cytomegalovirus (CMV) infection rate was higher in the test group (OR 2.50, 95% CI 1.22 - 5.12, P = 0.01). A great number of the test group recipients safely remained on a regimen that was steroid-free and with a reduced dose of conventional immunosuppressive drugs.</p><p><b>CONCLUSIONS</b>Alemtuzumab induction therapy for KTx was an effective and safe protocol in the tested follow-up period. Steroid avoidance and a dose reduction of conventional immunosuppressive drugs after alemtuzumab induction therapy may have clinical importance. However, high quality RCTs with larger population and longer follow-up are needed for a more accurate and objective appraisal of this novel protocol.</p>

Preliminary experience with Campath 1H induction combined with low-dose monotherapy of tacrolimus in small bowel transplantation / 中华外科杂志

<p><b>OBJECTIVE</b>To report preliminary experience of the protocol of combining Campath 1H induction with low-dose monotherapy of tacrolimus and no steroid in two cases of small bowel transplantation.</p><p><b>METHODS</b>Campath 1H 30 mg was infused during the small bowel transplantation, and the patients were given 1 gram of methylprednisolone followed by the Campath 1H and another gram of methylprednisolone before reperfusion. Tacrolimus was infused just after the reperfusion. The tacrolimus was administered from vein first and then from gut tract, the blood tacrolimus level was controlled at 10 to 15 microg/L within the first 3 months after the operation, and reduced to 5 microg/L thereafter.</p><p><b>RESULTS</b>The two recipients have survived more than 1 year, one received surgical closure of intestinal graft terminal stoma 13 months after the transplantation. One episode of indeterminate to mild acute rejection was verified by pathology through routine ileoscopical biopsy in each cases, and one episode of mild to moderate acute rejection occurred 8 months after the transplantation, and the patients recovered after low dose or bolus steroid therapy. The peripheral lymphocyte counts and monocyte counts decreased greatly after Campath 1H was given, and recovered very slowly thereafter. No sign of infection and graft versus host disease (GVHD) was found, and the grafted intestine achieved excellent function. The total parenteral nutrition was ceased on the day 21 and 14 after the operation, respectively, and the patients lived on oral intake to maintain nutrition status.</p><p><b>CONCLUSIONS</b>It's showed that the protocol combining Campath 1H induction with low-dose monotherapy of tacrolimus without steroid in small bowel transplantation can control graft rejection effectively without increasing the opportunity of infection, no sign of GVHD is found, and the grafted intestine could achieve excellent function.</p>