Healthcare-associated infections on the intensive care unit in 21 Brazilian hospitals during the early months of the coronavirus disease 2019 (COVID-19) pandemic: An ecological study.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has caused a global health crisis and may have affected healthcare-associated infection (HAI) prevention strategies. We evaluated the impact of the COVID-19 pandemic on HAI incidence in Brazilian intensive care units (ICUs). METHODS: In this ecological study, we compared adult patients admitted to the ICU from April through June 2020 (pandemic period) with the same period in 2019 (prepandemic period) in 21 Brazilian hospitals. We used the Wilcoxon signed rank-sum test in a pairwise analysis to compare the following differences between the pandemic and the prepandemic periods: microbiologically confirmed central-line-associated bloodstream infection (CLABSI) and ventilator-associated pneumonia (VAP) incidence density (cases per 1,000 central line and ventilator days, respectively), the proportion of organisms that caused HAI, and antibiotic consumption (DDD). RESULTS: We detected a significant increase in median CLABSI incidence during the pandemic: 1.60 (IQR, 0.44-4.20) vs 2.81 (IQR, 1.35-6.89) (P = .002). We did not detect a significant difference in VAP incidence between the 2 periods. In addition, we detected a significant increase in the proportion of CLABSI caused by Enterococcus faecalis and Candida spp during the pandemic, although only the latter retained statistical significance after correction for multiple comparisons. We did not detect a significant change in ceftriaxone, piperacillin-tazobactam, meropenem, or vancomycin consumption between the studied periods. CONCLUSIONS: There was an increase in CLABSI incidence in Brazilian ICUs during the first months of COVID-19 pandemic. Additionally, we detected an increase in the proportion of CLABSI caused by E. faecalis and Candida spp during this period. CLABSI prevention strategies must be reinforced in ICUs during the COVID-19 pandemic.

Acute kidney injury in a mouse model of meningococcal disease.

INTRODUCTION: Meningococcal disease is associated with high mortality. When acute kidney injury (AKI) occurs in patients with severe meningococcal disease, it is typically attributable to sepsis, although meningococcal disease and lipopolysaccharide release are rarely investigated. Therefore, we evaluated renal tissue in a mouse model of meningococcal disease. METHODS: Female BALB/c mice were induced to AKI by meningococcal challenge. Markers of renal function were evaluated in infected and control mice. RESULTS: In the infected mice, serum concentrations of tumor necrosis factor alpha, interferon gamma, interleukins (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12), and granulocyte-macrophage colony-stimulating factor were elevated, as was renal interstitial infiltration with lymphocytes and neutrophils (p < 0.01 for the latter). Histological analysis showed meningococcal microcolonies in the renal interstitium, without acute tubular necrosis. Infected mice also showed elevated renal expression of toll-like receptor 2, toll-like receptor 4, and Tamm-Horsfall protein. The expression of factors in the intrinsic pathway of apoptosis was equal to or lower than that observed in the control mice. Urinary sodium and potassium were also lower in infected mice, probably due to a tubular defect. CONCLUSION: Our findings corroborate those of other studies of AKI in sepsis. To our knowledge, this is the first time that meningococci have been identified in renal interstitium and that the resulting apoptosis and inflammation have been evaluated. However, additional studies are needed in order to elucidate the mechanisms involved.

Meningococcal meningitis: clinical and laboratorial characteristics, fatality rate and variables associated with in-hospital mortality.

Meningococcal meningitis is a public health problem. The aim of this study was to describe the clinical characteristics of patients with meningococcal meningitis, and to identify associated factors with mortality. This was a retrospective study, between 2006 and 2011, at a referral center in São Paulo, Brazil. Logistic regression analysis was used to identify factors associated with mortality. We included 316 patients. The median age was 16 years (IQR: 7-27) and 60% were male. The clinical triad: fever, headache and neck stiffness was observed in 89% of the patients. The cerebrospinal triad: pleocytosis, elevated protein levels and low glucose levels was present in 79% of patients. Factors associated with mortality in the multivariate model were age above 50 years, seizures, tachycardia, hypotension and neck stiffness. The classic clinical and laboratory triads of meningococcal meningitis were variable. The fatality rate was low. Age, seizures and shock signs were independently associated with mortality.

Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study.

Salvage therapy followed by high-dose therapy (HDT) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R-DexaBEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT. Patients aged 18-65 years, Eastern Cooperative Oncology Group performance score 0-2, with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) were eligible. R-Dexa-BEAM was given for two cycles followed by stem cell mobilization and HDT. Primary endpoint of the trial was progression-free-survival (PFS). One hundred and three patients were included: aggressive NHL (aNHL): diffuse large B-cell lymphoma 55, mantle cell lymphoma 7, follicular lymphoma (FL) grade 3: 5, indolent Lymphoma (iNHL): FL grade 1-2: 29, marginal zone lymphoma 6, Immunocytoma 1. The overall response rate after salvage therapy was 62% for aNHL and 78% for iNHL patients. 66% of patients with aNHL and 86% with iNHL underwent HDT. Treatment-related mortality for HDT was 1·3%. For aNHL patients, the median PFS was 0·83 years with 44% alive at the median follow-up of 7·3 years. Corresponding figures for iNHL were: median PFS 3·7 years and 72% alive after 8 years. The combination of rituximab with DexaBEAM followed by HDT resulted in high response rates and sustained remissions in responders. R-DexaBEAM followed by HDT can be considered a valid salvage option for NHL.

Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial.

Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE: The role of autologous stem-cell transplantation (ASCT) in Waldenström macroglobulinemia (WM) is not defined. The aim of this study was to analyze the results of ASCT in patients with WM and to determine the prognostic factors that have a significant impact on outcome. PATIENTS AND METHODS: We analyzed 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation (EBMT) between January 1991 and December 2005. Median time from diagnosis to ASCT was 1.7 years (range, 0.3 to 20.3 years), 32% of the patients experienced treatment failure with at least three lines of therapy, and 93% had sensitive disease at the time of ASCT. Conditioning regimen was total-body irradiation-based in 45 patients. Median follow-up for surviving patients was 4.2 years (range, 0.5 to 14.8 years). RESULTS: Nonrelapse mortality was 3.8% at 1 year. Ten patients developed a secondary malignancy, with a cumulative incidence of 8.4% at 5 years. Relapse rate was 52.1% at 5 years. Progression-free survival (PFS) and overall survival were 39.7% and 68.5%, respectively, at 5 years and were significantly influenced by number of lines of therapy and chemorefractoriness at ASCT. The achievement of a negative immunofixation after ASCT had a positive impact on PFS after ASCT. When used as consolidation at first response, ASCT provided a PFS of 44% at 5 years. CONCLUSION: ASCT is a feasible procedure in young patients with advanced WM. ASCT should not be offered to patients with chemoresistant disease and to those who received more than three lines of therapy.

Busulfan systemic exposure after oral administration of extemporeanously prepared high-dose busulfan capsules.

PURPOSE: The aim of the study was to analyze patients' busulfan (BU) exposure after oral administration of extemporeanously prepared BU capsules prior to blood stem cell transplantation. METHODS: Patients were treated with 1 mg/kg body weight BU administered orally every 6h on each of 4 consecutive days prior to blood stem cell transplantation. Each BU dose was administered in 1 gelatine capsule to be swallowed and containing the individually calculated dose of pure BU active substance. Blood samples were obtained from 6 adult patients 0, 30, 60, 90, 120, 180, 240, 300, and 360 min after the 1st, 5th, and 13th BU dose, frozen and analyzed subsequently by using a HPLC assay with UV detection. In addition, in two patients concomitant TDM was executed. BU exposure was monitored concurrently and BU doses were targeted to achieve a steady-state plasma concentration (C(SS)) of 600-900 ng/mL or 900-1100 ng/mL depending on the underlying disease. In these patients blood samples were obtained 0, 60, 120, 180, 240, and 360 min after the 1st, 5th, 9th, and 13th BU dose and analyzed concurrently. RESULTS: For the six patients monitored retrospectively, the time to reach peak plasma BU concentration (C(max)) ranged from 1 to 5 h (mean 2.4 h). BU C(max) - values varied from 728 to 1807 ng/ mL (mean 1174 ng/mL), and BU clearance (CL/F) from 2.32 to 3.75 mL/min/kg (mean 2.97 mL/min/ kg). The mean BU steady state (C(SS)) concentration calculated was 973 ng/mL (range 754-1226 ng/mL) with a mean AUC of 5818 ng.h/mL (range 4521- 7171 ng.h/mL). One of the two patients receiving targeted BU doses required an upward dose adjustment. None of the eight patients suffered from vomiting during BU therapy. CONCLUSIONS: BU active substance encapsulated without further excipients in gelatine capsules is highly suitable for oral BU therapy. However, therapeutic drug monitoring and BU dose adjustment is still advisable to achieve optimal systemic BU exposure in each individual patient.

Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial.

BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). METHODS: Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III-IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. FINDINGS: The number of patients in the ATG-F group who had severe aGVHD grade III-IV or who died within 100 days of transplantation was 12 and 10 (21.4%, 95% CI 13.4-29.3), respectively, compared with 24 and nine (33.7%, 24.3-43.0) patients, respectively, in the control group (adjusted odds ratio 0.59, 95% CI 0.30-1.17; p=0.13). The cumulative incidence of aGVHD grade III-IV was 11.7% (95% CI 6.8-19.8) in the ATG-F group versus 24.5% (17.3-34.7) in the control group (adjusted hazard ratio [HR] 0.50, 95% CI 0.25-1.01; p=0.054), and cumulative incidence of aGVHD grade II-IV was 33.0% (n=34; 95% CI 25.1-43.5) in the ATG-F group versus 51.0% (n=50; 95% CI 42.0-61.9) in the control group (adjusted HR 0.56, 0.36-0.87; p=0.011). The 2-year cumulative incidence of extensive chronic GVHD was 12.2% (n=11; 95% CI 7.0-21.3) versus 42.6% (n=34; 95% CI 33.0-55.0; adjusted HR 0.22, 0.11-0.43; p<0.0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. INTERPRETATION: The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. FUNDING: Fresenius Biotech GmbH.

Recovery of varicella-zoster virus-specific T cell immunity after T cell-depleted allogeneic transplantation requires symptomatic virus reactivation.

Reactivated varicella-zoster virus (VZV) infection causes herpes zoster and commonly occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because VZV-specific T cell immunity is essential to prevent virus reactivation, we developed an interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assay for the sensitive detection of VZV-reactive T cells at the single-cell level ex vivo. We used this assay to monitor the frequency of VZV-reactive T cells in 17 seropositive patients during the first year after T cell-depleted allo-HSCT. The patients did not receive anti-herpesvirus prophylaxis after stem cell engraftment. Independent of the magnitude of transferred donor immunity, VZV-reactive T cell numbers decreased to low levels (median, 2/mL; range, 0 to 35/mL) in peripheral blood early after transplantation. Only patients with subsequent zoster (n = 5) exhibited a dramatic boost in VZV-reactive T cells (median, 366/mL; range, 158 to 756/mL), which was induced by the reactivation event. The postzoster VZV-reactive T cell levels were similar to those seen in healthy virus carriers. In contrast, antiviral T cell levels remained low in patients without VZV disease. Our results demonstrate that VZV-specific T cell immunity recovered efficiently during zoster in T cell-depleted allo-HSCT recipients. It did not reconstitute spontaneously in nonzoster patients, even in the absence of antiviral prophylaxis. Prospective studies should investigate whether VZV vaccination can substitute for natural resensitization by virus disease.

Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell-depleted reduced-intensity transplantation.

Allogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with hematologic malignancies, 11 received a total of 21 CD8-depleted DLIs. Five patients developed transient grade I acute GVHD following transfer. Only 2 patients with HLA-C-mismatched donors showed grade II and III acute GVHD and subsequently progressed to limited chronic GVHD. Following DLIs, 4 patients with declining hematopoietic donor chimerism converted to full chimeras. A 2.1-fold median increase of circulating CD4 T cells was observed within 2 weeks after infusion. Non-DLI patients did not show a comparable rise in CD4 counts. Four patients demonstrated enhanced frequencies of cytomegalovirus-specific CD4 and CD8 T cells following transfer. Our results suggest that prophylactic CD8-depleted DLIs accelerate immune reconstitution after lymphodepleted HLA-matched SCT and carry a low risk of inducing severe GVHD.

Effect of rituximab on the long-term outcome after high-dose therapy for relapsed B-cell non-Hodgkin's lymphoma.

To better define the role of rituximab in salvage and high-dose therapy (HDT) for relapsed or refractory non-Hodgkin's lymphoma (NHL), patients treated before the implementation of rituximab in salvage and HDT (n = 57, control group) were compared with patients with rituximab included in this procedure (n = 36, study group). All patients had been antibody-naive at this point, and analyses were performed separately for 22 and 31 patients with aggressive, and 14 and 26 patients with indolent NHL, respectively. All patients received two courses of salvage therapy, predominantly dexamethasone, BCNU, etoposide, cytosine arabinoside, melphalan. Conditioning regimens included BCNU, etoposide, cytosine arabinoside, melphalan; BCNU, etoposide, cytosine arabinoside, cyclophosphamide or total body irradiation and cyclophosphamide, with rituximab added for patients in the study group. Despite the absence of differences in stem cell collection, haematopoietic recovery was delayed in patients with aggressive NHL treated in the study group: median days to absolute neutrophil count more than 0.5 x 10(9)/l, 11 vs 10 (p = 0.01), and platelets more than 20 x 10(9)/l, 14 vs 11 (p = 0.0005), with an increased requirement for platelet transfusions. No similar observations were made in indolent lymphoma patients. Remission rates were superior for patients with aggressive NHL in the study group. With a median follow-up of 7.25 and 4.5 years, this resulted in an improvement in OS at 4.5 years: 67 vs 45% (95% confidence interval, 47-87% vs 28-64%; p = 0.0468). For patients with indolent lymphoma, no comparable benefit was detectable. Our data support the use of rituximab in HDT for patients with aggressive NHL. For patients with indolent NHL, only longer follow-up and/or randomized trials may help to fully determine the impact of rituximab on the outcome after HDT.

Taxonomic priority in Psoroptes mange mites: P. ovis or P. equi?

The taxonomic priority of Psoroptes mange mites (Acari: Psoroptidae) is reviewed and the original species descriptions re-examined. The question of whether the name Psoroptes equi or Psoroptes ovis has priority has importance with respect to the descriptions used in any legislation required for compulsory treatment of infested animals. It is concluded that in the work by Hering [(1838) Nova Acta Physico-Medica Acadamiae Caesareae Leopoldino-Carolinae Naturae Curiosorum. Tomi 18, Pars 2, Vratislaviae und Bonn], which is generally assumed to present the type description, the first Psoroptes mite described is P. ovis, and that P. ovis (Hering 1838) should therefore, carry taxonomic priority for the synonomised genus.

Reduced-intensity conditioning followed by allografting of CD34-selected stem cells and < or =10(6)/kg T cells may have an adverse effect on transplant-related mortality.

In patients undergoing allogeneic peripheral blood stem cell (PBSC) transplantation after reduced-intensity conditioning (RIC), graft-versus-host disease (GVHD) represents a major cause of morbidity and mortality. T-cell depletion (TCD) prevents GVHD but carries potential risks of graft failure, opportunistic infections, and disease relapse. We explored ex vivo TCD of stem cell allografts that were administered after RIC treatment. Thirteen high-risk patients with hematological malignancies were treated with a fludarabine/melphalan-based RIC regimen followed by transplantation of immunomagnetically selected CD34(+) PBSC from HLA-identical sibling or matched unrelated donors. Patients were sequentially enrolled in two cohorts: group A (n=6) received antithymocyte globulin (ATG) during conditioning and 10(5) donor T cells/kg at transplantation, while group B (n=7) received 10(6) donor T cells/kg without ATG pretreatment. Primary graft failure occurred in two patients of group A and in one patient of group B. Complete donor chimerism persisting more than 1 year was achieved in two cases per cohort. Acute grade II to IV or chronic extensive GVHD were observed in a total of six patients (group A, 2; group B, 4). Procedure-related deaths were mainly due to severe pneumonia occurring in two patients of group A and in five patients of group B. These results suggest that CD34 selection of reduced-intensity PBSC allografts may cause adverse effects upon specific antimicrobial immunity which can lead to fatal infections, particularly in high-risk patients. In our study, simultaneous add-back of < or =10(6)/kg donor T cells was unable to compensate for this deficiency.

Current results on the use of imatinib mesylate in patients with relapsed Philadelphia chromosome positive leukemia after allogeneic or syngeneic hematopoietic stem cell transplantation.

Here, we describe a patient diagnosed with chronic myelogenous leukemia who relapsed after matched unrelated donor SCT. The patient was treated with imatinib mesylate and donor lymphocyte infusions, and achieved a complete molecular remission. Additionally, safety and efficacy of imatinib mesylate in a total of 134 patients from 8 centers who underwent allogeneic or syngeneic stem cell transplantation (SCT) and had a relapse of Philadelphia chromosome positive leukemia was reviewed. Data was compiled from abstracts accepted as oral or poster presentations at the ASH (American Society of Hematology) 2001 and EBMT (European Group for Blood and Marrow Transplantation) 2001 & 2002 meetings and additionally literature published on this patient group. Efficacy of imatinib therapy was assessed by morphology, cytogenetic analysis, and determination of donor chimerism. In the evaluable population, hematologic and cytogenetic responses were observed in 66% and 60% of the patients, respectively. Fifty-one of 114 (45%) patients achieved a complete cytogenetic response. No response or progress of disease was noted in 22 out of evaluable 91 patients. The observation period was limited to a maximum of 28 months. A significant improvement in donor chimerism was frequently observed. Only five cases of significant GVHD were reported. Preliminary results show that imatinib mesylate has the potential to positively influence the ratio of donor and recipient cells without inducing a high incidence of severe GVHD. The data suggest that earlier start of imatinib mesylate prior to hematologic relapse in minimum residual disease (MRD) positive patients is a promising treatment concept.