Primary vaccination in adult patients after allogeneic hematopoietic stem cell transplantation – A single center retrospective efficacy analysis

Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6–70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients’ characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p < 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.     

HLA-B evolutionary divergence is associated with outcomes after SARS-CoV-2 infection

We examined the correlation between class I HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of 234 adult inpatients with confirmed SARS-CoV-2 infection. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HED scores for HLA class I (HLA-A, -B, and -C) genotypes were calculated using Grantham’s distance. Higher HED scores for HLA-B, but not HLA-A or -C, are significantly associated with a decreased probability of poor outcomes including ICU admission, mechanical ventilation, and death (OR = 0.93; P = 0.04) in the univariate analysis. In the multivariate analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). This finding is consistent with the notion that broader peptide repertoires presented by class I HLA may be beneficial in infection control.     

A prime-boost concept using a T-cell epitope-driven DNA vaccine followed by a whole virus vaccine effectively protected pigs in the pandemic H1N1 pig challenge model

Influenza A virus (IAV) vaccines in pigs generally provide homosubtypic protection but fail to prevent heterologous infections. In this pilot study, the efficacy of an intradermal pDNA vaccine composed of conserved SLA class I and class II T cell epitopes (EPITOPE) against a homosubtypic challenge was compared to an intramuscular commercial inactivated whole virus vaccine (INACT) and a heterologous prime boost approach using both vaccines. Thirty-nine IAV-free, 3-week-old pigs were randomly assigned to one of five groups including NEG-CONTROL (unvaccinated, sham-challenged), INACT-INACT-IAV (vaccinated with FluSure XP® at 4 and 7 weeks, pH1N1 challenged), EPITOPE-INACT-IAV (vaccinated with PigMatrix EDV at 4 and FluSure XP® at 7 weeks, pH1N1 challenged), EPITOPE-EPITOPE-IAV (vaccinated with PigMatrix EDV at 4 and 7 weeks, pH1N1 challenged), and a POS-CONTROL group (unvaccinated, pH1N1 challenged). The challenge was done at 9 weeks of age and pigs were necropsied at day post challenge (dpc) 5. At the time of challenge, all INACT-INACT-IAV pigs, and by dpc 5 all EPITOPE-INACT-IAV pigs were IAV seropositive. IFNγ secreting cells, recognizing vaccine epitope-specific peptides and pH1N1 challenge virus were highest in the EPITOPE-INACT-IAV pigs at challenge. Macroscopic lung lesion scores were reduced in all EPITOPE-INACT-IAV pigs while INACT-INACT-IAV pigs exhibited a bimodal distribution of low and high scores akin to naïve challenged animals. No IAV antigen in lung tissues was detected at necropsy in the EPITOPE-INACT-IAV group, which was similar to naïve unchallenged pigs and different from all other challenged groups. Results suggest that the heterologous prime boost approach using an epitope-driven DNA vaccine followed by an inactivated vaccine was effective against a homosubtypic challenge, and further exploration of this vaccine approach as a practical control measure against heterosubtypic IAV infections is warranted.     

Innovative immunosuppression in kidney transplantation: A challenge for unmet needs

Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.     

麻黄附子细辛汤联合常规疗法治疗感染后咳嗽的临床研究

目的探讨麻黄附子细辛汤治疗感染后咳嗽的临床效果。方法选取漯河市郾城区惠生堂门诊部和河南省漯河市第三人民医院呼吸内科于2017年5月—2018年10月诊治的感染后咳嗽患者240例,采用随机数字表法分为两组,对照组患者120例实施常规治疗(退热、吸氧、补液等),观察组患者120例联用麻黄附子细辛汤(紫苏子9 g,射干9 g,地龙9 g,炙麻黄6 g,细辛6 g)治疗,于治疗前后行生化指标(C反应蛋白、白细胞计数、白细胞介素-4)检测和症状(咳嗽、喘息、咳痰、哮鸣音)评分,比较两组患者的症状(咳嗽、喘息、咳痰、哮鸣音)改善时间、临床效果(显效、有效、无效、总有效)、不良反应情况(恶心呕吐、头晕头痛、胃肠道反应)。结果两组治疗后C反应蛋白、白细胞计数、白细胞介素-4、症状评分(咳嗽、喘息、咳痰、哮鸣音)较治疗前显著降低(P<0.05)。观察组治疗后C反应蛋白、白细胞计数、白细胞介素-4、症状评分(咳嗽、喘息、咳痰、哮鸣音)低于对照组(P<0.05)。观察组症状改善时间(咳嗽、喘息、咳痰、哮鸣音)早于对照组(P<0.05)。观察组总有效率(99.2%,119/120)高于对照组(90.0%,108/120)(P<0.05)。结论麻黄附子细辛汤治疗感染后咳嗽的效果显著,可缩短治疗时间并改善病症,值得临床推广使用。     

New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

Prognostic Impact of Programmed Death-ligand 1 and Surrounding Immune Status on Stage I Lung Cancer

BackgroundThe programmed death 1/programmed death-ligand 1 (PD-L1) pathway reportedly is as an important factor determining effects of immunotherapy; however, its prognostic impact is controversial, and its association with the surrounding immune microenvironment has not yet been elucidated.Patients and MethodsWe retrospectively analyzed 126 patients with pathologic stage I non–small-cell lung cancer. Patients with lepidic-dominant adenocarcinoma were excluded. PD-L1 expression was evaluated with immunohistochemistry correlated with clinicopathologic features and surrounding immune microenvironment status, including CD4, CD8, regulatory T cells, and human leukocyte antigen class I. Factors affecting prognosis were assessed by Kaplan-Meier and Cox regression analyses.ResultsTwenty-three (18.3%) patients were positive for PD-L1 expression. No significant correlation was observed between PD-L1 expression and the surrounding immune microenvironment status. The PD-L1–positive group had a worse prognosis than the PD-L1–negative group (5-year recurrence-free survival rates, 63.4% vs. 81.0%; P = .061). Among surrounding immune cells, intratumoral CD8 status had the strongest impact on prognosis (P = .12). In the intratumoral CD8–high group, PD-L1 expression demonstrated no significant prognostic impact, whereas in the intratumoral CD8–low group, patients positive for PD-L1 demonstrated a significantly worse prognosis than those negative for PD-L1 (5-year recurrence-free survival rates, 41.7% vs. 78.6%; P = .034). Multivariable Cox regression analysis revealed that ‘PD-L1–positive and intratumoral CD8–low’ status was an independent prognostic factor (hazard ratio, 3.80; 95% confidence interval, 1.22-10.5; P = .023).ConclusionsThe prognostic impact of the PD-1/PD-L1 pathway may be distinct according to concurrent intratumoral CD8 status.     

Immunotherapy for recurrent pregnancy loss

When immunomodulation is used on an unselected population with recurrent miscarriage (RM), there is no improvement in the live birth rate. However, when the population is selected for a poor prognosis, or immune phenomena, immunotherapy has been shown to be effective. This review discusses four immunomodulatory agents, namely, paternal leukocyte immunization, intravenous immunoglobulin (IVIg), intralipid, and filgrastim. The presence of embryonic aneuploidy may confound the results of treatment, therefore creating an impression of futility when treatment may be highly effective in saving pregnancies that can be saved. Additionally, in an unselected population with RM, there is a relatively good prognosis of 60–80% for a subsequent live birth depending on whether the definition of ≥2 or ≥3 miscarriages is used. Hence, spontaneous prognosis must be taken into account, which has not been the case in previous trials.This review discusses the possible immune-mediated mechanisms of pregnancy loss and the means whereby immunotherapy may modulate these mechanisms.     

Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function

Background

Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.