Functional patterns of cytomegalovirus (CMV) pp65 and immediate early-1-specific CD8(+) T cells that are associated with protection from and control of CMV DNAemia after allogeneic stem cell transplantation.

BACKGROUND: The functional profile of cytomegalovirus (CMV)-specific CD8(+) T cells that associate with protection from and control of CMV DNAemia in allogeneic stem cell transplant (allo-SCT) recipients remains incompletely characterized. METHODS: We enumerated pp65 and immediate early (IE)-1-specific CD8(+) T cells expressing interferon-gamma, tumor necrosis factor-alpha, and CD107a, by flow cytometry in 94 patients at days +30 and +60 after allo-SCT. RESULTS: Fifty of 94 patients had CMV DNAemia within the first 100 days after transplant. CMV-specific CD8(+) T-cell responses (of any functional type) were more likely to be detected in patients who did not display CMV DNAemia than in those who did (P = 0.04). Qualitatively, no major differences in the functional signature of CMV-specific CD8(+) T cells were noted between patients who had or did not have CMV DNAemia. Patients displaying levels of polyfunctional CD8(+) T cells at day +30 >0.30 cell/µL had a lower risk of CMV DNAemia (positive predictive value 76%, and negative predictive value 43%). CONCLUSION: The presence of polyfunctional CD8(+) T cells (either expressing CD107a or not) was associated with lower levels of CMV replication, and higher frequency of self-resolved episodes. The data reported further clarify the role of polyfunctional CD8(+) T cells in control of CMV DNAemia in allo-SCT recipients.

European guidelines for prevention and management of influenza in hematopoietic stem cell transplantation and leukemia patients: summary of ECIL-4 (2011), on behalf of ECIL, a joint venture of EBMT, EORTC, ICHS, and ELN.

Influenza may cause severe disease and mortality in leukemia patients and in hematopoietic stem cell transplantation recipients. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for prevention and management of influenza infections in these patients. Real-time reverse-transcription polymerase chain reaction is the diagnostic test of choice, as it is the most sensitive and specific test for influenza. The risks for severe influenza and fatal outcome include lymphopenia, older age, influenza soon after transplantation or chemotherapy, steroid treatment, and lack of early antiviral therapy. Neuraminidase inhibitors (oral oseltamivir or inhalation of zanamivir) are currently the most effective therapeutic agents for influenza. Main preventive measures include annual vaccination of patients, household contacts, and hospital staff. This review summarizes ECIL-4's main recommendations.

Fresh or frozen grafts for allogeneic stem cell transplantation: conceptual considerations and a survey on the practice during the COVID-19 pandemic from the EBMT Infectious Diseases Working Party (IDWP) and Cellular Therapy & Immunobiology Working Party (CTIWP).

The COVID-19 pandemic has had a significant impact on medical practices, including the delivery of allogeneic hematopoietic cell transplantation (HCT). In response, transplant centers have made changes to their procedures, including an increased use of cryopreservation for allogeneic haematopoietic progenitor cell (HPC) grafts. The use of cryopreserved grafts for allogeneic HCT has been reviewed and analysed in terms of potential benefits and drawbacks based on existing data on impact on cell subsets, hematological recovery, and clinical outcomes of approximately 2000 patients from different studies. A survey of European Society for Blood and Marrow Transplantation centers was also conducted to assess changes in practice during the pandemic and any unnecessary burdens on HPC donors. Before the pandemic, only 7.4% of transplant centers were routinely cryopreserving HPC products, but this percentage increased to 90% during the pandemic. The results of this review and survey suggest that cryopreservation of HPC grafts is a viable option for allogeneic HCT in certain situations, but further research is needed to determine long-term effects and ethical discussions are required to balance the needs of donors and patients when using frozen allografts.

Impact of the COVID-19 pandemic on the diagnosis and treatment of onco-hematologic patients: a discussion paper.

We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.

Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT.

These recommendations were prepared by the European Conference on Infections in Leukaemia following a predefined methodology. Literature searches were made to identify studies pertinent to management of CMV, HHV-6, -7 and -8 infections. For CMV, 76 studies were reviewed: 72 published and 4 presented as abstracts. Twenty-nine of these studies were prospective randomized trials. For the other herpesviruses, HHV-6, -7 and -8, no randomized controlled trial has been performed, although data from some studies with other primary endpoints have been used to assess the management of HHV-6 infection. Works presented only as abstracts were used to a very limited extent. The quality of evidence and level of recommendation were graded according to the Center for Disease Control (CDC) criteria.

Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication.

The proportion of multiple myeloma patients in long-term complete response (LTCR-MM) for more than 6 years after autologous stem cell transplantation (ASCT) is small. To evaluate whether this LTCR is associated with a particular immune signature, peripheral blood samples from 13 LTCR-MM after ASCT and healthy blood donors (HBD) were analysed. Subpopulations of T-cells (naïve, effector, central memory and regulatory), B-cells (naïve, marginal zone-like, class-switched memory, transitional and plasmablasts) and NK-cells expressing inhibitory and activating receptors were quantified by multiparametric flow cytometry (MFC). Heavy/light chains (HLC) were quantified by nephelometry. The percentage of CD4+ T-cells was lower in patients, whereas an increment in the percentage of CD4+ and CD8+ effector memory T-cells was associated with the LTCR. Regulatory T-cells and NK-cells were similar in both groups but a particular redistribution of inhibitory and activating receptors in NK-cells were found in patients. Regarding B-cells, an increase in naïve cells and a corresponding reduction in marginal zone-like and class-switched memory B-cells was observed. The HLC values were normal. Our results suggest that LTCR-MM patients express a particular immune signature, which probably reflects a 'high quality' immune reconstitution that could exert a competent anti-tumor immunological surveillance along with a recovery of the humoral immunity.

[Consensus opinion on antifungal prophylaxis in haematologic patients: Results of the PROMIC project]. / Posicionamiento y actitudes de manejo sobre la profilaxis antifúngica en el paciente hematológico (proyecto PROMIC).

OBJECTIVE: Invasive fungal disease (IFD) is an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis (AFP) is indicated for a number of clinical scenarios in this group of patients. The aim of this study was to reach a consensus on IFD prophylaxis in haematological patients in order to optimize their management. METHODS: A committee of experts in haematology and infectious diseases compiled a survey of 79 items with controversial aspects about antifungal prophylaxis in haematological patients. The survey was evaluated in two rounds by a panel of experts following a modified Delphi methodology. RESULTS: Forty-four experts in haematology and infectious diseases answered the survey. After two evaluation rounds, consensus was reached in 67 of the 79 items (84.8%), specifically 48 items were consensually agreed on (60.7%) and 19 were disagreed on (24.0%). Consensus was reached on prophylaxis candidates profiles and questions related to indications, mechanisms of action, spectrum of activity, toxicity and interactions of antifungal were elucidated. The usefulness of micafungin in IFD prophylaxis was particularly analysed. The consensus reached was that micafungin is an antifungal to be considered in this context as its safety profile and lower interaction potential may be advantageous. CONCLUSIONS: A broad consensus was found in the management of IFD prophylaxis in the haematological patient. This consensus provides practical indications about its optimal management and can help determine the profile of patients eligible for this type of intervention.

[Consensus document on pneumococcal vaccination in adults at risk by age and underlying clinical conditions. 2017 Update]. / Consenso sobre la vacunación anti-neumocócica en el adulto por riesgo de edad y patología de base. Actualización 2017.

Invasive pneumococcal disease (IPD) and pneumococcal pneumonia (PP) represent an important health problem among aging adults and those with certain underlying pathologies and some diseases, especially immunosuppressed and some immunocompetent subjects, who are more susceptible to infections and present greater severity and worse evolution. Among the strategies to prevent IPD and PP, vaccination has its place, although vaccination coverage in this group is lower than desirable. Nowadays, there are 2 vaccines available for adults. Polysacharide vaccine (PPV23), used in patients aged 2 and older since decades ago, includes a greater number of serotypes (23), but it does not generate immune memory, antibody levels decrease with time, causes an immune tolerance phenomenon, and have no effect on nasopharyngeal colonization. PCV13 can be used from children 6 weeks of age to elderly and generates an immune response more powerful than PPV23 against most of the 13 serotypes included in it. In the year 2013 the 16 most directly related to groups of risk of presenting IPD publised a series of vaccine recommendations based on scientific evidence regarding anti-pneumococcal vaccination in adults with underlying pathologies and special conditions. A commitment was made about updating it if new scientific evidence became available. We present an exhaustive revised document focusing mainly in recommendation by age in which some more Scientific Societies have been involved.

Donor age and degree of HLA matching have a major impact on the outcome of unrelated donor haematopoietic cell transplantation for chronic myeloid leukaemia.

We analysed the outcome of 92 consecutive unrelated donor haematopoietic cell transplantations (UD-HCTs) performed in Spain to treat adult patients with CML in the first chronic phase (1CP). Patients' and donors' median age was 32 (15-49) and 36 (22-56) years, respectively. In all, 73 pairs (79%) matched for A, B+/-C and DRB1+/-DQB1 loci and 19 had > or =1 mismatch. Their probability of survival and disease-free survival at 4 years were 50 and 46%, respectively. Pretransplant factors associated with a better survival were patient age <25 years (P=0.035), donor age < or =36 years (P=0.012), use of cyclosporine since day -7 (P=0.001), and matching 8/8, 9/10 or 10/10 loci at allele level (P=0.003). In multivariate analysis only donor age (P=0.003; RR=3.1 (95% CI: 1.3-7.1)) and degree of HLA-matching (P=0.009; RR: 7.7 (95% CI: 1.8-33)) maintained their significance. The addition of these two variables to the EBMT prognostic score allowed an adequate risk assessment for patients receiving a UD-HCT during 1CP. Our analysis shows that in patients with a young and fully allele-matched donor, UD-HCT should be considered in the initial therapeutic algorithm due to its excellent outcome (92% survival at 2 years).

UGT2B17 minor histocompatibility mismatch and clinical outcome after HLA-identical sibling donor stem cell transplantation.

Minor histocompatibility Ags (mHags) have been implicated in the pathogenesis of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Uridine diphospho-glucuronosyltransferase 2B17 (UGT2B17) gene deletion may act as a mHag and its association with acute GVHD (aGVHD) has been described. We retrospectively studied the clinical impact of a UGT2B17 mismatch in a cohort of 1127 patients receiving a HSCT from an HLA-identical sibling donor. UGT2B17 mismatch was present in 69 cases (6.1%). Incidence of severe aGVHD was higher in the UGT2B17 mismatched pairs (22.7% vs 14.6%), but this difference was not statistically significant (P: 0.098). We did not detect differences in chronic GVHD, overall survival, relapse-free survival, transplant-related mortality or relapse. Nevertheless, when we analyzed only those patients receiving grafts from a male donor (616 cases), aGVHD was significantly higher in the UGT2B17 mismatched group (25.1% vs 12.8%; P: 0.005) and this association was confirmed by the multivariate analysis (P: 0.043; hazard ratio: 2.16, 95% confidence interval: 1.03-4.57). Overall survival was worse for patients mismatched for UGT2B17 (P: 0.005). We conclude that UGT2B17 mismatch has a negative clinical impact in allogeneic HSCT from HLA-identical sibling donors only when a male donor is used. These results should be confirmed by other studies.

Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT.

Over the last 25 years, the numbers of hematopoietic stem cell transplant (SCT) patients have increased rapidly. Infections have been major obstacles for successful transplantation. Thus, infection prevention is very important in transplant recipients. As the results of transplantation have improved, the number of long-term survivors has increased. Vaccination is a potentially important strategy for reducing the risk for vaccine-preventable infections after SCT. The EBMT produced recommendations for vaccination of SCT recipients published in Bone Marrow Transplantation in 1995. This paper updates the previous recommendations based on current knowledge.

Fungal and viral infections after allogeneic hematopoietic transplantation from unrelated donors in adults: improving outcomes over time.

Umbilical cord blood (CB) is increasingly used as an alternative source of stem cells in adult unrelated transplantation. Although registry studies report similar overall outcomes in comparison with BM/PB, comparative studies focusing on severe infections and infection-RM (IRM) with a long follow-up are scarce. A total of 434 consecutive unrelated transplants (1997-2009) were retrospectively analyzed to compare overall outcomes, incidence and risk factors of severe viral and invasive fungal infections in CB (n=65) vs BM/PB recipients (n=369). The 5-year OS was 38 vs 43%, respectively (P=0.2). CB transplantation (CBT) was associated with a higher risk of invasive aspergillosis (100-days-cumulative incidence 16 vs 6%, P=0.04) and CMV infection without differences in RM. No statistically significant differences were found regarding NRM (NRM of 38% in CB vs 37% in BM/PB at 1 year) nor IRM (30% in CB vs 27% in BM/PB at 1 year). In the overall population, NRM and IRM improved in more recent years. In adults who receive a single CBT, the risk of severe infections is increased when compared with unrelated BM/PB recipients, but mortality from infections is similar, leading to similar NRM and survival.

High dose busulfan and seizures.

Three cases of busulfan-associated convulsions in 28 bone marrow transplant recipients are reported. Convulsions occurred in spite of anticonvulsant prophylaxis in two of the three cases. Fits were generalized; no neurological deficit was found after the episodes and there were no recurrences. Although conditioning regimens including busulfan are used increasingly only rare cases have been reported and little mention of this side effect is made. We emphasize that convulsions are not infrequent side effect of conditioning regimens including high dose busulfan, and efficient anticonvulsant prophylactic regimens should be used.

Erythropoietin treatment in allogeneic BMT accelerates erythroid reconstitution: results of a prospective controlled randomized trial.

Twenty-eight allogeneic BMT patients (16 with acute leukemia, 12 with chronic myeloid leukemia) were included in a single center, prospective, randomized, controlled trial to assess the value of recombinant human erythropoietin (rh-Epo) in this setting. rh-Epo was administered through a central venous catheter as a single bolus injection (days 0-7: 100 U/kg/d; days 7-30: 150 U/kg/d). No secondary effects to rh-Epo treatment were detected. An earlier appearance of reticulocytes and a diminished need of red blood cells (RBCs) transfusions were observed in patients who were treated with rh-Epo (4 units vs 12 units; p < 0.05). The time to unsupported platelets above 25 x 10(9)/l was less in patients treated with rh-Epo than in control patients (19 days vs 31; p < 0.05), and they received significantly fewer platelet transfusions (36 units vs 138.5; p < 0.05). Our results show that rh-Epo treatment is capable of accelerating the erythroid reconstitution and decreasing the need for RBC transfusions. A beneficial effect on platelet reconstitution is also suggested, but further studies are necessary to confirm this point.

Allogeneic bone marrow transplantation for high risk acute lymphoblastic leukemia. Results from a single institution.

We present our experience with bone marrow transplantation (BMT) in 30 consecutive patients with high risk acute lymphoblastic leukemia. With a median follow-up of 4 years the disease-free survival (DFS) was 44% for the whole group, with a significant difference between patients in first or second complete remission (CR 1 and 2, as one group), compared with patients with more advanced disease (greater than CR2), 69.5% versus 15.4% (p less than 0.01). The main cause of BMT failure was leukemic relapse, with a relapse rate of 15% for patients in CR 1 and 2 and of 77% for patients with greater than CR2 (p less than 0.01). Among patients with active disease at BMT those who had 15% blast cells or less in the marrow fared better than those with more advanced disease or extramedullary relapse. Transplant-related death was 17%. Graft-versus-host disease (GVHD) was associated with an antileukemic effect; the DFS for patients with acute and/or chronic GVHD was better than for patients with no GVHD at all.

Penicillium brevicompactum as the cause of a necrotic lung ball in an allogeneic bone marrow transplant recipient.

The non-Candida, non-Aspergillus fungal infections are being reported with increasing frequency in BMT patients. One of these agents is Penicillium which has rarely been implicated as a pathogen in these patients. Only a few cases of isolated fungemias have been reported to date. We present the first documented case of invasive lung infection due to Penicillium brevicompactum in an allogeneic BMT recipient. As this case shows, the diagnosis of non-Candida, non-Aspergillus fungal infections may be incorrect if only histologic findings are available, mainly because misdiagnosis with other more common fungus can occur. A positive culture is required in order to make an accurate diagnosis.

Bronchoalveolar lavage cell composition in allogeneic bone marrow transplant patients without symptomatic lung complications.

The purpose of this study was to assess the cytological composition of bronchoalveolar lavage (BAL) fluid in allogeneic BMT patients without lung complications and compare it with that obtained from healthy volunteers. During the first 6 months post-BMT we studied the differential cell counts of 98 BALs from 56 patients as well as the total cell count of 44 BALs from 27 patients. The BAL cellular composition in BMT patients was clearly different from that of healthy subjects: there was a marked increase in alveolar neutrophils (in 82% of the patients when sequential BALs were performed) and an increase in lymphocytes, with a lower percentage of macrophages and similar numbers of eosinophils. A greater variation in cellular populations was found without an evident cause. The total number of cells per ml of fluid recovered appeared similar to that of healthy volunteers. A high frequency of neutrophilic alveolitis was found in patients with asymptomatic CMV on BAL. Owing to the variability of BAL cellular composition in asymptomatic BMT patients and its difference from that in healthy volunteers, great caution should be taken when interpreting the BAL composition data from patients with lung complications. In order to avoid drawing wrong conclusions these data should be compared with those obtained from a control group of BMT patients without lung complications and not from healthy volunteers.

Progressive multifocal leukoencephalopathy after stem cell transplantation, unsuccessfully treated with cidofovir.

We report a patient with progressive multifocal leukoencephalopathy (PML) after autologous stem cell transplantation (SCT) for non-Hodgkin's lymphoma (NHL). This is an unusual association, and to date only seven cases have been reported. This is the first case of PML after SCT treated with cidofovir, and the fifth case treated with this drug in a patient without human immunodeficiency virus (HIV) infection. In the previous four patients treated with cidofovir the outcome was discouraging, as was the case in this patient.

Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Spanish Group on Infectious Complications in Hematopoietic Transplantation.

A national survey of tuberculosis after hematopoietic stem cell transplant (SCT) was undertaken to study incidence, clinical presentation and outcome. Twenty confirmed cases were found among 8,013 patients (eight in 5,147 autologous and 12 in 2,866 allogeneic SCT). The estimated incidence in cases/10(5) patients/year (95% CI) was 101 (56.5-145) for the whole group, 71.1 (21.8-120) in autologous and 135.6 (58.9-212) in allogeneic transplants. Compared with the general population, tuberculosis was more frequent after allogeneic (RR 2.95) but not after autologous SCT. Tuberculosis after SCT is a late infection (median 324 days post transplant), predominately affects the lungs (80% of the cases), appears to respond well to treatment but has a high mortality (25%) in allogeneic recipients. It can also complicate the post-transplant management as antituberculosis drugs frequently decrease the serum levels of cyclosporine causing an aggravation of GVHD. Graft-versus-host disease, corticosteroid treatment and total body irradiation appear to be associated with tuberculosis in allogeneic recipients. No obvious factors were associated with tuberculosis in autologous transplants. Finally, we found that the published literature on tuberculosis after solid and SCT has overestimated its incidence due to the direct translation of tuberculosis frequency into incidence.