Almudena Martín-Peña

Therapeutic effect of the acquisition of cytomegalovirus-specific immune response during preemptive treatment.

Background. It has been suggested that preemptive therapy against cytomegalovirus (CMV) infection after transplantation promotes a CMV-specific immune response. Our objective was to determine whether solid-organ transplant patients at high risk for CMV infection treated preemptively acquire a CMV-specific immune response and whether the acquired immune response confers immunity by controlling subsequent CMV replication episodes and by protecting from late-onset CMV disease. Methods. Patients were followed up for 18 months after transplantation. CMV viral load was determined using real-time polymerase chain reaction assays, and the T-cell immune response was characterized by intracellular cytokine staining. Results. The 21 patients studied developed CMV replication episodes at a median of 4 weeks (range 2–8 weeks) after transplantation and a CMV-specific T-cell response within a median of 12 weeks (range 10–20 weeks). The decline in the incidence of CMV replication episodes is inversely correlated with the acquisition of the CMV-specific T-cell response (linear regression r2=0.781, Pearson correlation=−0.883; P=0.001). There were no CMV replication episodes after week 47 of transplantation. In addition, after acquisition of the immune response, 42 replication episodes were cleared without treatment. The time taken for immune clearance of replication correlated with the peak viral load (P=0.01). No incidence of CMV early or late-onset disease was detected. Conclusions. Our results demonstrate that preemptive therapy is a safe and an effective strategy for the control of CMV infection in solid-organ transplant recipients at high risk for CMV infection. This is the first study that reports a therapeutic effect of the acquisition of CMV-specific immune response during preemptive treatment.

Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach

Background Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients’ risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy. Design and Methods This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed. Results Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively. Conclusions Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients who have received a hematopoietic stem cell transplant, the approach is useful for identifying patients who are not likely to develop invasive fungal infection and do not, therefore, require antifungal therapy. The effectiveness of the strategy is similar to that of universal empirical antifungal therapy reported in controlled trials.

Patterns of Infection in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia Receiving Azacitidine as Salvage Therapy. Implications for Primary Antifungal Prophylaxis

Incidence, etiology, and outcome of infectious episodes in patients with myeloid neoplasms receiving azacitidine are uncertain, with no prospective data available in this group of patients. The aim of the current study was to analyze the incidence and factors related to the probability of infection in a cohort of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with azacitidine who did not receive any type of antimicrobial prophylaxis. Significantly, the group of patients who received prior intensive chemotherapy had more infectious episodes (P = 10(-4)), and particularly, invasive aspergillosis (P = .015), than patients who received frontline azacitidine. Primary antifungal prophylaxis might be recommended in MDS and AML patients receiving azacitidine as salvage therapy after intensive regimens.

Prospective study of infectious complications in allogeneic hematopoietic stem cell transplant recipients.

Martín‐Peña A, Aguilar‐Guisado M, Espigado I, Parody R, Cisneros JM. Prospective study of infectious complications in allogeneic hematopoietic stem cell transplant recipients.
Clin Transplant 2011: 25: 468–474.

Prospective study of infectious complications in a cohort of pediatric renal transplant recipients

Abstract:  Infections are frequent and serious in pediatric RT recipients; however, the information available is scarce. The aim of this study was to determine the incidence, etiology, and risk factors for infection in these patients. This was a prospective, observational study of a consecutive pediatric RT recipient cohort. Risk factors for infection and descriptive analyses during the first two post‐transplantation years were performed. Twenty‐one patients (58.3%) had at least one infection (incidence 1.5 episodes/patient/first year of transplantation). There were 33 bacterial infections (73.3%), 11 viral infections (24.4%), and one protozoal infection. UTI was the most common syndrome (48.3%), followed by CMV infection (15.5%). The main microorganisms isolated were Escherichia coli (28.9%), 46.1% of which were ESBL producers, and CMV (20%). Patient and graft survival at the end of follow‐up were 97.2% and 83.3%, respectively. The only risk factor for infection was cold ischemia time >800 min (OR 5.7, CI 95% 1.7–19.3). Conclusions: In pediatric RT recipients, UTI is the most frequent syndrome. Bacterial infections are the most common, with a high rate of ESBL producer strains. Despite their good prognosis, infections are a cause of morbidity that could potentially be reduced by decreasing cold ischemia times.

Tunneled Hemodialysis Catheter-Related Bloodstream Infections: A Prospective Multicenter Cohort Study from Spain:

Purpose Catheter-related bloodstream infections (CRBSI) are common among patients undergoing long-term hemodialysis (HD) worldwide. The aim of this study was look into the incidence, epidemiology, and risk factors for CRBSI in four medical centers and Spanish dialysis facilities following a common protocol for insertion and management of tunneled hemodialysis catheters (THCs). Methods. Prospective study including all THCs inserted from September-04 to October-05. Follow-up was from THC insertion to its withdrawal, onset of CRBSI or end of study. Data of all THCs, CRBSI episodes, and catheter complications were collected. A descriptive analysis of CRBSI incidence and etiology and multivariate Cox regression to identify risk factors for CRBSI was performed. Results. A total of 130 THCs in 123 patients were inserted. There were 34 879 catheter-days. Twelve CRBSI in 11 patients with a CRBSI rate of 0.34/1000 catheter-days were recorded. CRBSI was caused by gram-positive coccus in 91.7% of the cases. Vascular cause of renal disease (HR 25.5 CI95% 5.5–117.2), and a previous THC (HR 5.1 CI95% 1.3–19.1) were identified as risk factors for CRBSI. CRBSI were satisfactorily resolved in 83.3% of the cases. Overall mortality was 14.6% (18/123), in two cases (2/11) death occurred within 30 days after CRBSI onset. Conclusions. Although some factors, such as vascular cause of renal disease and previous THC medical history, have been related to the onset of tunneled catheter-related bloodstream infections, the incidence of these bacteremia, mainly produced by gram-positive coccus, is low among hemodialysis patients and the mortality rate is not high.

Cost-Effectiveness Analysis Comparing Two Approaches for Empirical Antifungal Therapy in Hematological Patients with Persistent Febrile Neutropenia

ABSTRACT New approaches of empirical antifungal therapy (EAT) in selected hematological patients with persistent febrile neutropenia (PFN) have been proposed in recent years, but their cost-effectiveness has not been studied. The aim of this study was to compare the cost-effectiveness of two different approaches of EAT in hematological patients with PFN: the diagnosis-driven antifungal therapy (DDAT) approach versus the standard approach of EAT. A decision tree to assess the cost-effectiveness of both approaches was developed. Outcome probabilities and treatment pathways were extrapolated from two studies: a prospective cohort study following the DDAT approach and a randomized clinical trial following the standard approach. Uncertainty was undertaken through sensitivity analyses and Monte Carlo simulation. The average effectiveness and economic advantages in the DDAT approach compared to the standard approach were 2.6% and €5,879 (33%) per PFN episode, respectively. The DDAT was the dominant approach in the 99.5% of the simulations performed with average cost-effectiveness per PFN episode of €32,671 versus €52,479 in the EAT approach. The results were robust over a wide range of variables. The DDAT approach is more cost-effective than the EAT approach in the management of PFN in hematological patients.

Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial

BACKGROUND Continuation of empirical antimicrobial therapy (EAT) for febrile neutropenia in patients with haematological malignancies until neutrophil recovery could prolong the therapy unnecessarily. We aimed to establish whether EAT discontinuation driven by a clinical approach regardless of neutrophil recovery would optimise the duration of therapy. METHODS We did an investigator-driven, superiority, open-label, randomised, controlled phase 4 clinical trial in six academic hospitals in Spain. Eligible patients were adults with haematological malignancies or haemopoietic stem-cell transplantation recipients, with high-risk febrile neutropenia without aetiological diagnosis. An independent, computer-generated randomisation sequence was used to randomly enrol patients (1:1) to the experimental or control group. Investigators were masked to assignment only before randomisation. EAT based on an antipseudomonal β-lactam drug as monotherapy (ceftazidime or cefepime, meropenem or imipenem, or piperacillin-tazobactam) or as combination therapy (with an aminoglycoside, fluoroquinolone, or glycopeptide) was started according to local protocols and following international guidelines and recommendations. For the experimental group, EAT was withdrawn after 72 h or more of apyrexia plus clinical recovery; for the control group, treatment was withdrawn when the neutrophil count was also 0·5 × 109 cells per L or higher. The primary efficacy endpoint was the number of EAT-free days. Primary analyses were done in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01581333. FINDINGS Between April 10, 2012, and May 31, 2016, 157 episodes among 709 patients assessed for eligibility were included in analyses. 78 patients were randomly assigned to the experimental group and 79 to the control group. The mean number of EAT-free days was significantly higher in the experimental group than in the control group (16·1 [SD 6·3] vs 13·6 [7·2], absolute difference -2·4 [95% CI -4·6 to -0·3]; p=0·026). 636 adverse events were reported (341 in the experimental group vs 295 in the control group; p=0·057) and most (580 [91%]; 323 in the experimental group vs 257 in the control group) were considered mild or moderate (grade 1-2). The most common adverse events in the experimental versus the control group were mucositis (28 [36%] of 78 patients vs 20 [25%] of 79 patients), diarrhoea (23 [29%] of 78 vs 24 [30%] of 79), and nausea and vomiting (20 [26%] of 78 vs 22 [28%] of 79). 56 severe adverse events were reported, 18 in the experimental group and 38 in the control group. One patient died in the experimental group (from hepatic veno-occlusive disease after an allogeneic haemopoietic stem-cell transplantation) and three died in the control group (one from multiorgan failure, one from invasive pulmonary aspergillosis, and one from a post-chemotherapy intestinal perforation). INTERPRETATION In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe. FUNDING Instituto de Salud Carlos III, Spanish Ministry of Economy (PI11/02674).

Does the current treatment of invasive fungal infection need to be reviewed

Invasive fungal infections (IFIs) are becoming more frequent due to the increasing number of patients at risk. Over the last decade, their prognosis has improved with the diagnostic and therapeutic advances, including new antifungals. In the two years, from 2007 to 2009, antifungal consumption increased by 27%, 67 times more than antibacterial consumption, albeit with great differences between hospitals. The scientific evidence of the indications for antifungal prophylaxis and targeted antifungal therapy is strong; however, it is weak for empirical antifungal therapy, which is the most common indication. Antifungals are not harmless, since they are associated with a wide range of adverse effects and drug interactions, favor the development of resistance, contribute to other fungal superinfections and cause significant healthcare spending. Therefore, the question arises whether this extraordinary increase in consumption is justified, whether the use of antifungals is optimal, or whether it is necessary to reconsider the current treatment of IFIs instead.