Rafael de la Cámara

Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients

Summary. We have analysed the incidence and risk factors for the occurrence of invasive fungal infections (IFI) among 395 recipients of an allogeneic peripheral blood stem cell transplantation (PBSCT) from a human leucocyte antigen (HLA)‐identical sibling. IFI (n = 50) occurred in 46 patients, giving an overall probability of 14%. There were 12 cases of invasive candidiasis (3%), with only one death. Non‐Candida IFI occurred in 37 patients (12% probability), mostly invasive aspergillosis (n = 32). In multivariate analysis the only two significant variables associated with a higher risk of developing a non‐Candida IFI were the development of moderate‐to‐severe graft‐versus‐host disease (GvHD, P < 0·0001; OR 4·6) and having received steroid prophylaxis for GvHD (P = 0·04; OR 2·1). In multivariate analysis the variables associated with a lower overall survival after PBSCT were development of a non‐Candida IFI (P < 0·0001; OR 5·6), non‐early disease phase (P = 0·0001; OR 1·9), steroid prophylaxis (P = 0·02; OR 1·4), moderate‐to‐severe GvHD (P = 0·01; OR 1·6) and cytomegalovirus infection post transplant (P = 0·001; OR 1·8). Our results show that non‐Candida IFI (in particular aspergillosis) was an important cause of infectious morbidity and mortality after an HLA‐identical sibling PBSCT, while invasive candidiasis was rare. Use of steroid prophylaxis and, in particular, the development of moderate‐to‐severe GvHD post transplant were risk factors for non‐Candida IFI. Prophylactic strategies for these infections should thus take into account these risk factors.

Blastoschizomyces capitatus Infection in Patients with Leukemia: Report of 26 Cases

Twenty-six cases of Blastoschizomyces capitatus infection were diagnosed in 25 patients at 7 tertiary care hematology units in Spain over a 10-year period. Most patients (92%) had acute leukemia and developed infection during a period of severe and prolonged neutropenia. Two patients had esophagitis, and the rest had invasive infection. Fungemia (20 cases) was a common finding, with frequent visceral dissemination. The 30-day mortality associated with this infection was 52%, compared with 57% among patients with systemic infection. In a univariate analysis, the following 3 variables had a positive impact on 30-day survival: removal of the central venous catheter within 5 days after the onset of infection (P=.02), a good performance status (P=.003), and receipt of systemic prophylactic or empirical antifungal therapy before infection onset (P=.006). Outcome for neutropenic patients with B. capitatus infection is still poor. Rapid removal of the central venous catheter and novel antifungal therapies are recommended for treatment of this rare infection.

Voriconazole for secondary prophylaxis of invasive fungal infections in allogeneic stem cell transplant recipients: results of the VOSIFI study

Background Recurrence of prior invasive fungal infection (relapse rate of 30–50%) limits the success of stem cell transplantation. Secondary prophylaxis could reduce disease burden and improve survival. Design and Methods A prospective, open-label, multicenter trial was conducted evaluating voriconazole (4 mg/kg/12 h intravenously or 200 mg/12 h orally) as secondary antifungal prophylaxis in allogeneic stem cell transplant recipients with previous proven or probable invasive fungal infection. Voriconazole was started 48 h or more after completion of conditioning chemotherapy and was planned to be continued for 100–150 days. Patients were followed for 12 months. The primary end-point of the study was the incidence of proven or probable invasive fungal infection. Results Forty-five patients were enrolled, 41 of whom had acute leukemia. Previous invasive fungal infections were proven or probable aspergillosis (n=31), proven candidiasis (n=5) and other proven or probable infections (n=6); prior infection could not be confirmed in three patients. The median duration of voriconazole prophylaxis was 94 days. Eleven patients (24%) died within 12 months of transplantation, but only one due to systemic fungal disease. Three invasive fungal infections occurred post-transplant: two relapses (one candidemia and one fatal scedosporiosis) and one new zygomycosis in a patient with previous aspergillosis. The 1-year cumulative incidence of invasive fungal disease was 6.7±3.6%. Two patients were withdrawn from the study due to treatment-related adverse events (i.e. liver toxicity). Conclusions Voriconazole appears to be safe and effective for secondary prophylaxis of systemic fungal infection after allogeneic stem cell transplantation. The observed incidence of 6.7% (with one attributable death) is considerably lower than the relapse rate reported in historical controls, thus suggesting that voriconazole is a promising prophylactic agent in this population.

Donor Cytomegalovirus Status Influences the Outcome of Allogeneic Stem Cell Transplant: A Study by the European Group for Blood and Marrow Transplantation

BACKGROUND The use of a cytomegalovirus (CMV)-seronegative donor for a CMV-seronegative allogeneic hematopoietic stem cell transplant (HSCT) recipient is generally accepted. However, the importance of donor serostatus in CMV-seropositive patients is controversial. METHODS A total of 49 542 HSCT patients, 29 349 seropositive and 20 193 seronegative, were identified from the European Group for Blood and Marrow Transplantation database. Cox multivariate models were fitted to estimate the effect of donor CMV serological status on outcome. RESULTS Seronegative patients receiving seropositive unrelated-donor grafts had decreased overall survival (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.06-1.21; P < .0001) compared with seronegative donors, whereas no difference was seen in patients receiving HLA-matched sibling grafts. Seropositive patients receiving grafts from seropositive unrelated donors had improved overall survival (HR, 0.92; 95% CI, .86-.98; P < .01) compared with seronegative donors, if they had received myeloablative conditioning. This effect was absent when they received reduced-intensity conditioning. No effect was seen in patients grafted from HLA-identical sibling donors. The same association was found if the study was limited to patients receiving transplants from the year 2000 onward. CONCLUSIONS We confirm the negative impact on overall survival if a CMV-seropositive unrelated donor is selected for a CMV-seronegative patient. For a CMV-seropositive patient, our data support selecting a CMV-seropositive donor if the patient receives a myeloablative conditioning regimen.

Randomized Study of Early versus Late Immunization with Pneumococcal Conjugate Vaccine after Allogeneic Stem Cell Transplantation

BACKGROUND Invasive pneumococcal disease is a life-threatening complication after allogeneic stem cell transplantation, and at least 20% of cases occur within 1 year after transplantation. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has limited efficacy, especially during the first year after transplantation. The immune response to the conjugated vaccines is expected to be better than that to the polysaccharide vaccine, but the optimal timing of vaccination is not defined. Our objective was to show that a 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) was not inferior when first given 3 months after transplantation, compared with when first given 9 months after transplantation. METHODS We performed a multicenter, randomized, noninferiority study involving 158 patients from 13 European Group for Blood and Marrow Transplantation centers who were randomly allocated at approximately 100 days after myeloablative stem cell transplantation to receive a series of vaccinations (3 doses of PCV7 given 1 month apart) that was started immediately (i.e., 3 months after transplantation) or 6 months later (i.e., 9 months after transplantation). The primary evaluation criterion was the rate of response (antibody level, > or = 0.15 microg/mL for each of the 7 serotypes) at 1 month after the third dose of PCV7. The noninferiority margin was 20%. All patients were followed up for 24 months after transplantation or until death, whichever occurred first. RESULTS We found that the response rate was not lower after early vaccination (79% [45 of 57 patients]) than after late vaccination (82% [47 of 57 patients]) (difference, -3.5%; 90% confidence interval, -15.6 to 8.6; not significant). CONCLUSIONS We conclude that PCV7 vaccination at 3 months after stem cell transplantation is not inferior to PCV7 vaccination at 9 months after transplantation. Because invasive pneumococcal disease can occur early, we recommend starting the PCV7 vaccination series at 3 months after transplantation to ensure earlier protection against Streptococcus pneumoniae. However, the early vaccination may result in only short-lasting response and may not prime for a 23-valent pneumococcal polysaccharide vaccine boost as efficiently as the late vaccination.

Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients.

During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01–1.04; P=0.002) and lymphopenia (OR 2.49; 1.33–4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients.

Response to Rituximab-Based Therapy and Risk Factor Analysis in Epstein Barr Virus–Related Lymphoproliferative Disorder After Hematopoietic Stem Cell Transplant in Children and Adults: A Study From the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

BACKGROUND  The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. METHODS  A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. RESULTS  One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0-1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. CONCLUSIONS  More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.

Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation

Disparity for the minor histocompatibility antigen HA‐1 between patient and donor has been associated with an increased risk of acute graft‐versus‐host disease (GvHD) after allogeneic human leucocyte antigen (HLA)‐identical sibling donor stem cell transplantation (SCT). However, no data concerning the impact of such disparity on chronic GvHD, relapse or overall survival are available. A retrospective multicentre study was performed on 215 HLA‐A2‐positive patients who received an HLA‐identical sibling SCT, in order to determine the differences in acute and chronic GvHD incidence on the basis of the presence or absence of the HA‐1 antigen mismatch. Disease‐free survival and overall survival were also analysed. We detected 34 patient–donor pairs mismatched for HA‐1 antigen (15·8%). Grades II–IV acute GvHD occurred in 51·6% of the HA‐1‐mismatched pairs compared with 37·1% of the non‐mismatched. The multivariate logistic regression model showed statistical significance (P: 0·035, OR: 2·96, 95% CI: 1·07–8·14). No differences were observed between the two groups for grades III–IV acute GvHD, chronic GvHD, disease‐free survival or overall survival. These results confirmed the association between HA‐1 mismatch and risk of mild acute GvHD, but HA‐1 mismatch was not associated with an increased incidence of chronic GvHD and did not affect relapse or overall survival.

Recomendaciones GESITRA-SEIMC y RESITRA sobre prevención y tratamiento de la infección por citomegalovirus en pacientes trasplantados

La infeccion por citomegalovirus (CMV) es una complicacion importante del trasplante. La ultima decada se ha caracterizado por los avances en su tratamiento, reduciendo su morbilidad y la mortalidad. Estos avances han sido decisivos en el diagnostico y prevencion. Se han desarrollado tecnicas de diagnostico rapidas y sensibles. Entre las estrategias de prevencion destaca el uso correcto de los productos sanguineos, las inmunoglobulinas y los farmacos antivirales, empleados en profilaxis o en terapia anticipada. El reciente desarrollo de farmacos eficaces por via oral como el valganciclovir permitira el tratamiento ambulatorio de los pacientes infectados. Es necesario trasladar este conocimiento a la practica clinica diaria. Con este objetivo el Grupo de Estudio de la Infeccion en el Trasplante (GESITRA) de la Sociedad Espanola de Microbiologia Clinica y Enfermedades Infecciosas (SEIMC) ha desarrollado este documento de consenso que incluye las ultimas recomendaciones en el tratamiento de la infeccion por CMV postrasplante.

Immune response to the 23-valent polysaccharide pneumococcal vaccine after the 7-valent conjugate vaccine in allogeneic stem cell transplant recipients : Results from the EBMT IDWP01 trial

The current recommendations for active immunization after stem cell transplant (SCT) include 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7) from 3 months after transplant, followed by a 23-valent polysaccharide pneumococcal vaccine (PPV23). However, until now, the immune response to PPV23 after PCV7 has not been assessed after SCT. In the EBMT IDWP01 trial, 101 patients received 1 dose of PPV23 at 12 or 18 months, both after 3 doses of PCV7. The efficacy of PPV23 was assessed 1 month later and at 24 months after transplant by the pneumococcal serotype 1 and 5 antibody levels. Serotype 1 and 5 are not included in PCV7. Although the geometric mean concentrations were significantly higher 1 month after PPV23, for both antigens, the response rates (> or =0.15 microg/mL), in the range of 68-94%, were not different between groups independent of the assessment date. One PPV23 dose after 3 PCV7 doses, already known to increase the response to PCV7, also extends the serotype coverage given 12 or 18 months after transplant.