A multicentre study of amphotericin B treatment for histoplasmosis: assessing mortality rates and adverse events.

BACKGROUND: Progressive disseminated histoplasmosis is a significant issue in Latin America, particularly in Brazil, contributing to high mortality rates. OBJECTIVES: Our objectives were to comprehensively describe histoplasmosis treatment with various amphotericin B (AmB) formulations, including mortality rates, adverse effects and risk factors for mortality. METHODS: This multicentre retrospective cohort study (January 2014-December 2019) evaluated medical records of patients with proven or probable histoplasmosis treated with at least two doses of AmB in seven tertiary medical centres in Brazil. We assessed risk factors associated with death during hospitalization using univariate and multivariate analyses. RESULTS: The study included 215 patients, mostly male (n = 158, 73%) with HIV infection (n = 187, 87%), and a median age of 40 years. Only 11 (5%) patients initiated treatment with liposomal amphotericin B (L-AmB). Amphotericin B deoxycholate (D-AmB) was administered to 159 (74%) patients without changes in the treatment. The overall mortality during hospitalization was 23% (50/215). Variables independently associated with mortality were use of D-AmB (OR 4.93) and hospitalization in ICU (OR 9.46). There was a high incidence of anaemia (n = 19, 90%), acute kidney injury (n = 96, 59%), hypokalaemia (n = 73, 55%) and infusion reactions (n = 44, 20%) during treatment. CONCLUSIONS: We found that D-AmB was the main formulation, which was also associated with a higher mortality rate. Lipid formulations of AmB have become more readily available in the public health system in Brazil. Further studies to evaluate the effectiveness of L-AmB will likely show improvements in the treatment outcomes for patients with disseminated histoplasmosis.

Assessing the Clinical Impact of the SARS-CoV-2 Gamma Variant on Intensive Care Unit Admissions: Insights from a Reference Hospital in Northeastern Brazil.

The global challenge posed by the prolonged COVID-19 pandemic underscores the critical need for ongoing genomic surveillance to identify emerging variants and formulate effective public health strategies. This retrospective observational study, conducted in a reference hospital in Northeast Brazil and comprising 2116 cases, employed PCR genotyping together with epidemiological data to elucidate the impact of the Gamma variant during its emergence, revealing distinct patterns in hospitalization rates, severity of illness, and outcomes. The study emphasizes the challenges posed by the variant, particularly an increased tendency for ICU admissions and respiratory support, especially among adults aged 18 to 59 without comorbidities. Laboratory analyses further demonstrate elevated inflammatory, coagulation, and hepatic markers in the Gamma variant cohort, suggesting a more severe systemic response. Despite limitations, including a retrospective approach and single-institution data, the study underscores the importance of ongoing genomic surveillance. Overall, this research contributes valuable insights into the impact of the Gamma variant on COVID-19 dynamics, advocating for continued research and surveillance to inform effective public health strategies regarding evolving viral variants.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study.

PURPOSE: Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. METHODS: This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. FINDINGS: Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. IMPLICATIONS: ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

Standardized Brazilian green propolis extract (EPP-AF®) in COVID-19 outcomes: a randomized double-blind placebo-controlled trial.

SARS-CoV-2 and its different variants caused a "wave and wave" pandemic pattern. During the first wave we demonstrated that standardized Brazilian green propolis extract (EPP-AF®) reduces length of hospital stay in adult patients with COVID-19. Afterwards, we decided to evaluate the impact of EPP-AF in hospitalized patients during the third wave of the pandemic. BeeCovid2 was a randomized, double-blind, placebo-controlled clinical trial in hospitalized COVID-19 adult patients. Patients were allocated to receive an oral dose of 900 mg/day of EPP-AF® or placebo for 10 days. The primary outcome was length of hospital stay. Secondary outcomes included safety, secondary infection rate, duration of oxygen therapy dependency, acute kidney injury and need for intensive care. Patients were followed up for 28 days after admission. We enrolled 188 patients; 98 were assigned to the propolis group and 90 to the placebo group. The post-intervention length of hospital stay was of 6.5 ± 6.0 days in the propolis group versus 7.7 ± 7.1 days in the control group (95% CI - 0.74 [- 1.94 to 0.42]; p = 0.22). Propolis did not have significant impact on the need for oxygen supplementation or frequency of AKI. There was a significant difference in the incidence of secondary infection between groups, with 6.1% in the propolis group versus 18.9% in the control group (95% CI - 0.28 [0.1-0.76], p = 0.01). The use of EPP-AF was considered safe and associated with a decrease in secondary infections. The drug was not associated with a significant reduction in length of hospital stay. ClinicalTrials.gov (NCT04800224).

SARS-CoV-2 Detection via RT-PCR in Matched Saliva and Nasopharyngeal Samples Reveals High Concordance in Different Commercial Assays.

BACKGROUND: Self-collected saliva samples can increase the diagnostic efficiency and benefit healthcare workers, patient care, and infection control. This study evaluated the performance of self-collected saliva samples compared to nasopharyngeal swabs using three commercial kits for the qualitative detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Matched nasopharyngeal and saliva samples were collected from 103 patients with either asymptomatic or symptomatic COVID-19. Both samples were evaluated using three commercial kits (TaqCheck, Allplex, and TaqPath). To evaluate sample stability, viral RNA extraction was performed in the presence or absence of an RNA-stabilizing solution. Storage conditions, including the duration, temperature, and stability after freezing and thawing of the samples, were also evaluated. RESULTS: All the saliva samples showed 100% concordance with the nasopharyngeal swab results using TaqCheck and Allplex kits, and 93% using TaqPath kit. No difference was observed in the samples that used the RNA-stabilizing solution compared to the group without the solution. The Ct values of the freeze-thawed samples after 30 days were higher than those on day 0; however, the results were consistent the fresh samples. CONCLUSION: The high concordance of SARS-CoV-2 detection via reverse transcription-polymerase chain reaction (RT-PCR) in matched saliva and nasopharyngeal samples using different commercial assays reinforces the concept that self-collected saliva samples are non-invasive, rapid, and reliable for diagnosing SARS-CoV-2 infection.

The use of standardized Brazilian green propolis extract (EPP-AF) as an adjunct treatment for hospitalized COVID-19 patients (BeeCovid2): a structured summary of a study protocol for a randomized controlled trial.

BACKGROUND: The 2019 coronavirus disease (COVID-19) pandemic continues to spread and affects large numbers of people with unprecedented impacts. Experimental evidence has already been obtained for use of the standardized extract of Brazilian green propolis (EPP-AF) against viral targets, and clinical rationality has been demonstrated for testing this extract as an adjunct to treatment in patients affected by COVID-19. The BeeCovid2 study aims to assess whether EPP-AF has an impact on the improvement of patients hospitalized with COVID-19 by reducing the length of hospital stay. METHODS: BeeCovid2 is a randomized, double-blinded, placebo-controlled clinical study being conducted in Brazil to provide further evidence on the effectiveness of standardized green propolis extract as an adjunctive treatment for adults hospitalized with COVID-19. Hospitalized patients over 18 years of age with a confirmed diagnosis of COVID-19 and up to 14 days of symptoms were included. Patients under mechanical ventilation at randomization, pregnant women, cancer patients, transplanted or using immunosuppression, HIV patients, patients who used propolis in the last 30 days, bacterial or fungal infection at randomization, impossibility of using medication orally or enterally, and advanced chronic diseases (e.g., advanced heart failure, severe liver disease, and end-stage chronic kidney disease). Enrolled patients are randomized at a 1:1 ratio to receive placebo or standardized propolis extract (900 mg/day) for 10 days. The study treatments are administered in a double-blinded manner, and patients are followed for 28 days. The primary outcome is the difference in length of hospital stay in days between groups. Secondary outcomes include the need for mechanical ventilation, the rate of secondary infection, rate of acute kidney injury, the need for renal replacement therapy, the requirement for vasoactive drugs, the use of an intra-aortic balloon pump (IABP), and the use of extracorporeal membrane oxygenation (ECMO). DISCUSSION: This trial is very useful and will provide more data on the effectiveness of using the standardized Brazilian green propolis extract as an adjunctive treatment in association with standard care in adults hospitalized with moderate to severe acute COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04800224 . Registered on March 16, 2021.

SARS-CoV-2 variant of concern P.1 (Gamma) infection in young and middle-aged patients admitted to the intensive care units of a single hospital in Salvador, Northeast Brazil, February 2021.

OBJECTIVES: To evaluate changes in the characteristics of patients with coronavirus disease 2019 (COVID-19) after the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) P.1 (Gamma), by comparing the clinical, demographic, and laboratory profiles of patients hospitalized during the first (May to July 2020) and second (December 2020 to February 2021) pandemic waves. METHODS: Data were collected from the records of COVID-19 patients (n = 4164) admitted to a single hospital in Salvador, Northeast Brazil. SARS-CoV-2 genome sequencing was performed on nasopharyngeal swab samples from 12 patients aged <60 years admitted to the intensive care unit (ICU) in February 2021. RESULTS: Between June 2020 and February 2021, the median age of patients admitted to the ICU decreased from 66 to 58 years (P < 0.05). This was accompanied by an increased proportion of patients without comorbidities (15.32% vs 32.20%, P < 0.0001). A significant reduction in the cycle threshold values of SARS-CoV-2 RT-PCR tests was observed in the second wave (P < 0.0001). Sequencing analysis detected lineage Gamma in all 12 ICU patients sampled in February 2021. CONCLUSIONS: The results of this study demonstrated an increased proportion of younger adults without comorbidities with severe disease during the second COVID-19 wave, shortly after the confirmation of local Gamma circulation.

Efficacy of Brazilian green propolis (EPP-AF®) as an adjunct treatment for hospitalized COVID-19 patients: A randomized, controlled clinical trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes challenging immune and inflammatory phenomena. Though various therapeutic possibilities have been tested against coronavirus disease 2019 (COVID-19), the most adequate treatment has not yet been established. Propolis is a natural product with considerable evidence of immunoregulatory and anti-inflammatory activities, and experimental data point to potential against viral targets. We hypothesized that propolis can reduce the negative effects of COVID-19. METHODS: In a randomized, controlled, open-label, single-center trial, hospitalized adult COVID-19 patients were treated with a standardized green propolis extract (EPP-AF®ï¸) as an adjunct therapy. Patients were allocated to receive standard care plus an oral dose of 400 mg or 800 mg/day of green propolis for seven days, or standard care alone. Standard care included all necessary interventions, as determined by the attending physician. The primary end point was the time to clinical improvement, defined as the length of hospital stay or oxygen therapy dependency duration. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs. Patients were followed for 28 days after admission. RESULTS: We enrolled 124 patients; 40 were assigned to EPP-AF®ï¸ 400 mg/day, 42 to EPP-AF®ï¸ 800 mg/day, and 42 to the control group. The length of hospital stay post-intervention was shorter in both propolis groups than in the control group; lower dose, median 7 days versus 12 days (95% confidence interval [CI] -6.23 to -0.07; p = 0.049) and higher dose, median 6 days versus 12 days (95% CI -7.00 to -1.09; p = 0.009). Propolis did not significantly affect the need for oxygen supplementation. In the high dose propolis group, there was a lower rate of acute kidney injury than in the controls (4.8 vs 23.8%), (odds ratio [OR] 0.18; 95% CI 0.03-0.84; p = 0.048). No patient had propolis treatment discontinued due to adverse events. CONCLUSIONS: Addition of propolis to the standard care procedures resulted in clinical benefits for the hospitalized COVID-19 patients, especially evidenced by a reduction in the length of hospital stay. Consequently, we conclude that propolis can reduce the impact of COVID-19.

Differential impact of on-site or telepharmacy in the intensive care unit: a controlled before-after study.

BACKGROUND: Clinical pharmacists have an important role in the intensive care unit (ICU) team but are scarce resources. Our aim was to evaluate the impact of on-site pharmacists on medical prescriptions in the ICU. METHODS: This is a retrospective, quasi-experimental, controlled before-after study in two ICUs. Interventions by pharmacists were evaluated in phase 1 (February to November 2016) and phase 2 (February to May 2017) in ICU A (intervention) and ICU B (control). In phase 1, both ICUs had a telepharmacy service in which medical prescriptions were evaluated and interventions were made remotely. In phase 2, an on-site pharmacist was implemented in ICU A, but not in ICU B. We compared the number of interventions that were accepted in phase 1 versus phase 2. RESULTS: During the study period, 8797/9603 (91.6%) prescriptions were evaluated, and 935 (10.6%) needed intervention. In phase 2, there was an increase in the proportion of interventions that were accepted by the physician in comparison to phase 1 (93.9% versus 76.8%, P < 0.001) in ICU A, but there was no change in ICU B (75.2% versus 73.9%, P = 0.845). CONCLUSION: An on-site pharmacist in the ICU was associated with an increase in the proportion of interventions that were accepted by physicians.

Impact of cytomegalovirus and grafts versus host disease on the dynamics of CD57+CD28-CD8+ T cells after bone marrow transplant.

OBJECTIVES: The present study aimed to evaluate the dynamics of CD28 and CD57 expression in CD8+ T lymphocytes during cytomegalovirus viremia in bone marrow transplant recipients. METHODS: In a prospective study, blood samples were obtained once weekly once from 33 healthy volunteers and weekly from 33 patients. To evaluate the expression of CD57 and CD28 on CD8+ T lymphocytes, flow cytometry analysis was performed on blood samples for four months after bone marrow transplant, together with cytomegalovirus antigenemia assays. RESULTS: Compared to cytomegalovirus-seronegative healthy subjects, seropositive healthy subjects demonstrated a higher percentage of CD57+ and a lower percentage of CD28+ cells (p<0.05). A linear regression model demonstrated a continuous decrease in CD28+ expression and a continuous increase in CD57+ expression after bone marrow transplant. The occurrence of cytomegalovirus antigenemia was associated with a steep drop in the percentage of CD28+ cells (5.94%, p<0.01) and an increase in CD57+ lymphocytes (5.60%, p<0.01). This cytomegalovirus-dependent effect was for the most part concentrated in the allogeneic bone marrow transplant patients. The development of acute graft versus host disease, which occurred at an earlier time than antigenemia (day 26 vs. day 56 post- bone marrow transplant), also had an impact on the CD57+ subset, triggering an increase of 4.9% in CD57+ lymphocytes (p<0.05). CONCLUSION: We found continuous relative changes in the CD28+ and CD57+ subsets during the first 120 days post- bone marrow transplant, as part of immune system reconstitution and maturation. A clear correlation was observed between the expansion of the CD57+CD28-CD8+ T lymphocyte subpopulation and the occurrence of graft versus host disease and cytomegalovirus viremia.

Impact of cytomegalovirus and grafts versus host disease on the dynamics of CD57+CD28-CD8+ T cells after bone marrow transplant

OBJECTIVES: The present study aimed to evaluate the dynamics of CD28 and CD57 expression in CD8+ T lymphocytes during cytomegalovirus viremia in bone marrow transplant recipients. METHODS: In a prospective study, blood samples were obtained once weekly once from 33 healthy volunteers and weekly from 33 patients. To evaluate the expression of CD57 and CD28 on CD8+ T lymphocytes, flow cytometry analysis was performed on blood samples for four months after bone marrow transplant, together with cytomegalovirus antigenemia assays. RESULTS: Compared to cytomegalovirus-seronegative healthy subjects, seropositive healthy subjects demonstrated a higher percentage of CD57+ and a lower percentage of CD28+ cells (p<0.05). A linear regression model demonstrated a continuous decrease in CD28+ expression and a continuous increase in CD57+ expression after bone marrow transplant. The occurrence of cytomegalovirus antigenemia was associated with a steep drop in the percentage of CD28+ cells (5.94 percent, p<0.01) and an increase in CD57+ lymphocytes (5.60 percent, p<0.01). This cytomegalovirus-dependent effect was for the most part concentrated in the allogeneic bone marrow transplant patients. The development of acute graft versus host disease, which occurred at an earlier time than antigenemia (day 26 vs. day 56 post- bone marrow transplant), also had an impact on the CD57+ subset, triggering an increase of 4.9 percent in CD57+ lymphocytes (p<0.05). CONCLUSION: We found continuous relative changes in the CD28+ and CD57+ subsets during the first 120 days post- bone marrow transplant, as part of immune system reconstitution and maturation. A clear correlation was observed between the expansion of the CD57+CD28-CD8+ T lymphocyte subpopulation and the occurrence of graft versus host disease and cytomegalovirus viremia.

New guidelines for the clinical management of febrile neutropenia and sepsis in pediatric oncology patients.

OBJECTIVES: To provide a foundation for the diagnostic, prophylactic and therapeutic management of febrile neutropenia and sepsis in children with oncological diseases, with special attention to new protocols and guidelines. SOURCES: A review of the scientific literature utilizing an electronic bibliographic search on MEDLINE, Medscape, SciELO, Google, Cochrane and PubMED using the keywords febrile, neutropenic, cancer, children, sepsis, intensive, care. Articles published between 1987 and 2007 were selected, with preference given to review articles, protocols, systematic reviews, epidemiological studies, task force recommendations and phase III clinical trials. Consensus documents published by the Infectious Diseases Society of America, the Center for Diseases Control and the Infectious Diseases Working Party of the German Society of Hematology and Oncology, in addition to the recommendations of the World Federation of Pediatric Intensive and Critical Care Societies and Society of Critical Care Medicine, were also reviewed. SUMMARY OF THE FINDINGS: The use of aggressive chemotherapy regimens, bone marrow transplantation and intensive care resources have increased the survival rates of children with cancer and also their infectious morbidity, with septic complications as the principal cause of mortality. Several risk factors have been identified, such as neutropenia, oncology type, clinical signs and inflammatory response markers (polymerase chain reaction, procalcitonin) and also increased resistance to antimicrobials and antifungal agents. Protocols for risk classification, diagnosis and treatment should be established at each service, taking into account the microbiological flora of each population. Pediatric intensive care has increased the short and long-term survival of these patients. CONCLUSIONS: Oncology patients are particularly vulnerable to infectious complications. Early identification and treatment are fundamental to improving survival rates.

Novas diretrizes na abordagem clínica da neutropenia febril e da sepse em oncologia pediátrica / New guidelines for the clinical management of febrile neutropenia and sepsis in pediatric oncology patients

OBJETIVOS: Fornecer subsídios à abordagem diagnóstica, profilática e terapêutica da neutropenia febril e da sepse em criança com doença oncológica, dando especial atenção aos novos protocolos e diretrizes. FONTES DE DADOS: Revisão de literatura científica utilizando uma busca bibliográfica eletrônica nas páginas do MEDLINE, Medscape, SciELO, Google, Cochrane e PubMED com as palavras-chave febrile, neutropenic, cancer, children, sepse, intensive, care. Foram selecionados artigos publicados entre 1987 e 2007, preferencialmente artigos de revisão, protocolos, revisões sistemáticas, estudos epidemiológicos, recomendações de força-tarefa e ensaios clínicos fase III. Foram revistos os consensos publicados pela Infectious Diseases Society of America, Center for Diseases Control e Infectious Diseases Working Party da German Society of Hematology and Oncology, além de recomendações da World Federation of Pediatric Intensive and Critical Care Societies e da Society of Critical Care Medicine. SíNTESE DOS DADOS: A utilização de esquemas quimioterápicos agressivos, transplante de medula óssea e recursos de terapia intensiva aumentaram a sobrevida nas crianças com câncer e também a morbidade infecciosa, sendo as complicações sépticas a principal causa de mortalidade. Diversos fatores de risco têm sido identificados, como neutropenia, tipo oncológico, sinais clínicos e marcadores de resposta inflamatória (reação em cadeia da polimerase, procalcitonina), assim como a maior resistência aos antimicrobianos e antifúngicos. Protocolos de classificação de risco, de diagnóstico e tratamento devem ser estabelecidos em cada serviço, respeitando a flora microbiológica da população estudada. A terapia intensiva pediátrica tem aumentado a sobrevida a curto e longo prazo nestes pacientes. CONCLUSÕES: Pacientes oncológicos são particularmente vulneráveis a complicações infecciosas. A identificação e o tratamento precoce são fundamentais para a melhora da sobrevida.

OBJECTIVES: To provide a foundation for the diagnostic, prophylactic and therapeutic management of febrile neutropenia and sepsis in children with oncological diseases, with special attention to new protocols and guidelines. SOURCES: A review of the scientific literature utilizing an electronic bibliographic search on MEDLINE, Medscape, SciELO, Google, Cochrane and PubMED using the keywords febrile, neutropenic, cancer, children, sepsis, intensive, care. Articles published between 1987 and 2007 were selected, with preference given to review articles, protocols, systematic reviews, epidemiological studies, task force recommendations and phase III clinical trials. Consensus documents published by the Infectious Diseases Society of America, the Center for Diseases Control and the Infectious Diseases Working Party of the German Society of Hematology and Oncology, in addition to the recommendations of the World Federation of Pediatric Intensive and Critical Care Societies and Society of Critical Care Medicine, were also reviewed. SUMMARY OF THE FINDINGS: The use of aggressive chemotherapy regimens, bone marrow transplantation and intensive care resources have increased the survival rates of children with cancer and also their infectious morbidity, with septic complications as the principal cause of mortality. Several risk factors have been identified, such as neutropenia, oncology type, clinical signs and inflammatory response markers (polymerase chain reaction, procalcitonin) and also increased resistance to antimicrobials and antifungal agents. Protocols for risk classification, diagnosis and treatment should be established at each service, taking into account the microbiological flora of each population. Pediatric intensive care has increased the short and long-term survival of these patients. CONCLUSIONS: Oncology patients are particularly vulnerable to infectious complications. Early identification and treatment are fundamental to improving...