Combined Immune Defect in B-Cell Lymphoproliferative Disorders Is Associated with Severe Infection and Cancer Progression.

B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan-Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities.

Trained Immunity-Based Vaccine in B Cell Hematological Malignancies With Recurrent Infections: A New Therapeutic Approach.

Infectious complications are a major cause of morbidity and mortality in B-cell hematological malignancies (HM). Prophylaxis for recurrent infections in HM patients with antibody deficiency consists of first-line antibiotics and when unsuccessful, gammaglobulin replacement therapy (IgRT). Recent knowledge of trained immunity-based vaccines (TIbV), such as the sublingual polybacterial formulation MV130, has shown a promising strategy in the management of patients with recurrent infections. We sought to determine the clinical benefit of MV130 in a cohort of HM patients with recurrent respiratory tract infections (RRTIs) who underwent immunization with MV130 for 3 months. Clinical information included the frequency of infections, antibiotic use, number of visits to the GP and hospitalizations previous and after MV130 immunotherapy. Improvement on infection rate was classified as: clear (>60% reduction of infection), partial (26%-60%) and low (≤25%) improvement. Fifteen HM patients (aged 42 to 80 years; nine females) were included in the study. All patients reduced their infection rate. Analysis of paired data revealed that the median (range, min - max) of respiratory infectious rate significantly decreased from 4.0 (8.0-3.0) to 2.0 (4.0-0.0) (p<0.001) at 12 months of MV130. A clear clinical improvement was observed in 53% (n = 8) of patients, partial improvement in 40% (n = 6) and low improvement in 7% (n = 1). These data correlated with a decrease on antibiotic consumption from 3.0 (8.0-1.0) to 1.0 (2.0-0.0) (p = 0.002) during 12 months after initiation of treatment with MV130. The number of infectious-related GP or emergency room visits declined from 4.0 (8.0-2.0) to 2.0 (3.0-0.0) (p<0.001), in parallel with a reduction in hospital admissions due to infections (p = 0.032). Regarding safety, no adverse events were observed. On the other hand, immunological assessment of serum IgA and IgG levels demonstrated an increase in specific antibodies to MV130-contained bacteria following MV130 immunotherapy. In conclusion, MV130 may add clinical benefit reducing the rate of infections and enhancing humoral immune responses in these vulnerable patients.

Identification of underlying and transfusion-related platelet qualitative alterations in the hemato-oncologic patient.

Hemato-oncologic patients with chemotherapy-induced thrombocytopenia are one of the populations receiving platelet transfusions. The general practice with these patients is to give prophylactic platelet transfusions when platelet counts fall below 10×109PLT/L. However, in more than 40% of these patients, platelet transfusion does not prevent bleeding. The reason of the low efficacy of platelet transfusion in the context of chemotherapy patients is not entirely understood. We therefore aimed at immunophenotyping the expression of platelet surface and activation markers and thrombopoietin levels from hemato-oncologic patients before and after transfusion. A more detailed follow-up was performed in three patients that underwent autologous bone marrow transplantation. As previously reported, basal platelet activation was observed in hemato-oncologic patients. Based on flow cytometry parameters, i.e. the percentage of positivity and mean fluorescence intensity (MFI) distribution, our data provide an additional interpretation of platelet acquired qualitative changes in the hemato-oncologic patient. From our results we propose: first, the underlying activation of platelets in the hemato-oncologic patient is accompanied by loss of expression of the platelet receptors that are susceptible to protease-mediated shedding; second, soon after transfusion, the newly circulating donor platelets show additional activation, which may result in subsequent platelet receptor recycling and potential accelerated clearance of these activated platelets. In conclusion, the immunophenotype of circulating platelets changes after prophylactic platelet transfusion. Next to platelet count increment, exploration of this immunophenotype might help to explain transfusion refractory bleeding in hemato-oncologic patients. Eventually this may lead to personalization and improvement of the present platelet transfusion support regime.

Red blood cell storage time and transfusion: current practice, concerns and future perspectives.

Red blood cells (RBCs) units are the most requested transfusion product worldwide. Indications for transfusion include symptomatic anaemia, acute sickle cell crisis, and acute blood loss of more than 30% of the blood volume, with the aim of restoring tissue oxygen delivery. However, stored RBCs from donors are not a qualitative equal product, and, in many ways, this is a matter of concern in the transfusion practice. Besides donor-to-donor variation, the storage time influences the RBC unit at the qualitative level, as RBCs age in the storage bag and are exposed to the so-called storage lesion. Several studies have shown that the storage lesion leads to post-transfusion enhanced clearance, plasma transferrin saturation, nitric oxide scavenging and/or immunomodulation with potential unwanted transfusion-related clinical outcomes, such as acute lung injury or higher mortality rate. While, to date, several studies have claimed the risk or deleterious effects of "old" vs "young" RBC transfusion regimes, it is still a matter of debate, and consideration should be taken of the clinical context. Transfusion-dependent patients may benefit from transfusion with "young" RBC units, as it assures longer inter-transfusion periods, while transfusion with "old" RBC units is not itself harmful. Unbiased Omics approaches are being applied to the characterisation of RBC through storage, to better understand the (patho)physiological role of microparticles (MPs) that are found naturally, and also on stored RBC units. Perhaps RBC storage time is not an accurate surrogate for RBC quality and there is a need to establish which parameters do indeed reflect optimal efficacy and safety. A better Omics characterisation of components of "young" and "old" RBC units, including MPs, donor and recipient, might lead to the development of new therapies, including the use of engineered RBCs or MPs as cell-based drug delivering tools, or cost-effective personalised transfusion strategies.