Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022.

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020-2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Survival in multiple myeloma and SARS-COV-2 infection through the COVID-19 pandemic: Results from the EPICOVIDEHA registry.

Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and subsequent coronavirus (20)19 disease (COVID-19)-related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID-19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS-CoV-2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow-up was 52 days for the entire cohort and 83 days for survivors. Three-hundred and three patients died (24%) and COVID-19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 × 109 /L was found to be protective. This data suggests that MM patients remain at risk of SARS-CoV-2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic.

The mortality of COVID-19 in CML patients from 2020 until 2022: results from the EPICOVIDEHA survey.

Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.

Guidelines for the management of Toxoplasma gondii infection and disease in patients with haematological malignancies and after haematopoietic stem-cell transplantation: guidelines from the 9th European Conference on Infections in Leukaemia, 2022.

Patients with haematological malignancies might develop life-threatening toxoplasmosis, especially after allogeneic haematopoietic stem-cell transplantation (HSCT). Reactivation of latent cysts is the primary mechanism of toxoplasmosis following HSCT; hence, patients at high risk are those who were seropositive before transplantation. The lack of trimethoprim-sulfamethoxazole prophylaxis and various immune status parameters of the patient are other associated risk factors. The mortality of toxoplasma disease-eg, with organ involvement-can be particularly high in this setting. We have developed guidelines for managing toxoplasmosis in haematology patients, through a literature review and consultation with experts. In allogeneic HSCT recipients seropositive for Toxoplasma gondii before transplant, because T gondii infection mostly precedes toxoplasma disease, we propose weekly blood screening by use of quantitative PCR (qPCR) to identify infection early as a pre-emptive strategy. As trimethoprim-sulfamethoxazole prophylaxis might fail, prophylaxis and qPCR screening should be combined. However, PCR in blood can be negative even in toxoplasma disease. The duration of prophylaxis should be a least 6 months and extended during treatment-induced immunosuppression or severe CD4 lymphopenia. If a positive qPCR test occurs, treatment with trimethoprim-sulfamethoxazole, pyrimethamine-sulfadiazine, or pyrimethamine-clindamycin should be started, and a new sample taken. If the second qPCR test is negative, clinical judgement is recommended to either continue or stop therapy and restart prophylaxis. Therapy must be continued until a minimum of two negative PCRs for infection, or for at least 6 weeks for disease. The pre-emptive approach is not indicated in seronegative HSCT recipients, after autologous transplantation, or in non-transplant haematology patients, but PCR should be performed with a high level of clinical suspicion.

Low utilization of vancomycin in febrile neutropenia: real-world evidence from 4 Brazilian centers.

PURPOSE: The prompt initiation of a betalactam antibiotic in febrile neutropenic patients is considered standard of care, while the empiric use of vancomycin is recommended by guidelines in specific situations, with a low level of evidence. The objective of this study was to assess the utilization of vancomycin in the management of febrile neutropenia within four Brazilian medical centers that implemented more stringent criteria for its administration. METHODS: A comprehensive retrospective analysis was performed encompassing all instances of febrile neutropenia observed during the period from 2013 to 2019. The primary focus was to identify the reasons for initiating vancomycin therapy. RESULTS: A total of 536 consecutive episodes of febrile neutropenia were documented, involving 384 patients with a median age of 52 years (range 18-86). Chemotherapy preceded febrile neutropenia in 59.7% of cases, while 40.3% occurred after hematopoietic stem cell transplantation. The most prevalent underlying diseases were acute myeloid leukemia (26.5%) and non-Hodgkin's lymphoma (22%). According to international guidelines, vancomycin should have been initiated at the onset of fever in 145 episodes (27%); however, it was administered in only 27 cases (5.0%). Three episodes were associated with Staphylococcus aureus bacteremia, two of which were methicillin resistant. The 15-day and 30-day mortality rates were 5.0% and 9.9%, respectively. CONCLUSIONS: The results of this study underscore the notably low utilization rate of vancomycin in cases of febrile neutropenia, despite clear indications outlined in established guidelines. These findings emphasize the importance of carefully implementing guideline recommendations, considering local epidemiological factors, especially when the strength of recommendation is weak.

Invasive fusariosis.

SUMMARYInvasive fusariosis is a serious invasive fungal disease, affecting immunocompetent and, more frequently, immunocompromised patients. Localized disease is the typical clinical form in immunocompetent patients. Immunocompromised hosts at elevated risk of developing invasive fusariosis are patients with acute leukemia receiving chemotherapeutic regimens for remission induction, and those undergoing allogeneic hematopoietic cell transplant. In this setting, the infection is usually disseminated with positive blood cultures, multiple painful metastatic skin lesions, and lung involvement. Currently available antifungal agents have poor in vitro activity against Fusarium species, but a clear-cut correlation between in vitro activity and clinical effectiveness does not exist. The outcome of invasive fusariosis is largely dependent on the resolution of immunosuppression, especially neutrophil recovery in neutropenic patients.

Practical issues related to non-Aspergillus invasive mold infections.

Infection by non-Aspergillus molds has been increasingly reported. The management of such infections is challenging both for diagnosis and treatment, including the need of well-trained mycologists to properly identify rare fungi, difficulties in distinguishing between contamination, colonization and infection, the lack of randomized studies comparing different drugs or regimens, poor activity of available antifungal agents, lack of correlation between in vitro antifungal susceptibility tests and clinical outcome, and poor prognosis. Mucormycosis and fusariosis are the most frequent non-Aspergillus mold infections. Mucormycosis occurs more frequently in four major groups of patients: solid organ transplant recipients, patients with hematologic malignancies receiving chemotherapy or hematopoietic cell transplantation, diabetic patients, and immunocompetent individuals who suffer various types of skin and soft tissue trauma. Invasive fusariosis occurs almost exclusively in patients with hematologic malignancies. In this review we discuss practical issues related to the management of these and other non-Aspergillus mold infections.

Age, successive waves, immunization, and mortality in elderly COVID-19 hematological patients: EPICOVIDEHA findings.

OBJECTIVES: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail. METHODS: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy. RESULTS: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. CONCLUSION: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.

Toxicity and outcome of adults with acute myeloid leukemia receiving consolidation with high-dose cytarabine.

INTRODUCTION: High-dose cytarabine is considered standard of care as consolidation chemotherapy in adults with acute myeloid leukemia (AML) who are not eligible for allogeneic hematopoietic cell transplantation, but may be associated with significant toxicity. We evaluated the toxicity associated with high-dose cytarabine given as consolidation in AML patients treated at a Brazilian public hospital. METHODS: We retrospectively reviewed the charts of all patients with AML treated between 2008 and 2020 who obtained complete remission (CR) after one cycle of induction chemotherapy and received consolidation with at least one cycle of high-dose cytarabine (defined as 3 g/m2 every 12 h days 1, 3 and 5). RESULTS: Among 61 patients who received induction remission, 32 obtained CR and 28 received at least one cycle of high-dose cytarabine, for a total of 67 cycles (median 2 cycles per patient, range 1 - 4). In 45 cycles (67.2%) the patient was discharged after the end of chemotherapy, with a median of 6 days at home (range 3 - 8). Readmission occurred in 31 of the 45 cycles (68.9%). The most frequent toxicities were febrile neutropenia (56.7%), nausea and vomiting (23.9%), oral mucositis (14.9%) and diarrhea (11.9%). Bacteremia was documented in 13 cycles (34.2%). There were three cases of typhlitis and two of invasive fungal disease (aspergillosis and candidemia). Four patients died (14.3%), with two deaths considered treatment-related (candidemia and typhlitis). CONCLUSION: In the setting of a Brazilian public hospital, high-dose cytarabine as consolidation therapy is feasible, with manageable toxicity profile.

Emergence of cryptic species and clades of Meyerozyma guilliermondii species complex exhibiting limited in vitro susceptibility to antifungals in patients with candidemia.

Members of the Meyerozyma guilliermondii species complex are able to cause superficial and life-threatening systemic infections with low susceptibility to azoles and echinocandins. We tested 130 bloodstream M. guilliermondii complex isolates collected from eight Latin American medical centers over 18 years (period 1 = 2000-2008 and period 2 = 2009-2018) to investigate trends in species distribution and antifungal resistance. The isolates were identified by rDNA ITS region sequencing, and antifungal susceptibility tests were performed against fluconazole, voriconazole, anidulafungin, and amphotericin B using the CLSI microbroth method. M. guilliermondii sensu stricto (s.s.; n = 116) was the most prevalent species, followed by Meyerozyma caribbica (n = 12) and Meyerozyma carpophila (n = 2). Based on rDNA ITS identification, three clades within M. guilliermondii sensu stricto were characterized (clade 1 n = 94; clade 2 n = 19; and clade 3 n = 3). In the second period of study, we found a substantial increment in the isolation of M. caribbica (3.4% versus 13.8%; P = 0.06) and clade 2 M. guilliermondii s.s. exhibiting lower susceptibility to one or more triazoles. IMPORTANCE Yeast-invasive infections play a relevant role in human health, and there is a concern with the emergence of non-Candida pathogens causing disease worldwide. There is a lack of studies addressing the prevalence and antifungal susceptibility of different species within the M. guilliermondii complex that cause invasive infections. We evaluated 130 episodes of M. guilliermondii species complex candidemia documented in eight medical centers over 18 years. We detected the emergence of less common species within the Meyerozyma complex causing candidemia and described a new clade of M. guilliermondii with limited susceptibility to triazoles. These results support the relevance of continued global surveillance efforts to early detect, characterize, and report emergent fungal pathogens exhibiting limited susceptibility to antifungals.

Infections in patients with chronic lymphocytic leukemia

ABSTRACT Introduction: Infection is a major complication in patients with chronic lymphocytic leukemia (CLL). Newly diagnosed patients are at high risk of developing infection caused by encapsulated bacteria, such as Streptococcus pneumoniae and Haemophylus influenzae. Method and Results: However, once treatment is initiated, the spectrum of pathogens causing infection broadens, depending on the treatment regimens. With disease progression, cumulative immunosuppression occurs as a consequence of multiple treatment lines and the risk of infection further increases. On the other hand, the use of targeted therapies in the treatment of CLL have brought new risks of infection, with an increased incidence of invasive fungal diseases, particularly aspergillosis, in patients receiving Bruton kinase inhibitors. Conclusion: In this article, we review the epidemiology of infection in patients with CLL, taking into account the treatment regimen, and briefly discuss the management of infection.

Treatment of Fusarium Infection of the Central Nervous System: A Review of Past Cases to Guide Therapy for the Ongoing 2023 Outbreak in the United States and Mexico.

INTRODUCTION: Fusariosis of the central nervous system (CNS) is extremely uncommon. Treatment and outcome data from previously published cases may provide some guidance in light of the ongoing fungal meningitis outbreak in 2023 involving Fusarium spp. in the United States and Mexico. METHODS: We reviewed the published literature describing cases of invasive fusariosis of the (CNS) that included data on patient demographic characteristics, treatment, and outcome. RESULTS: Twenty-six cases met inclusion criteria. The mean age was 36 years, 55% involved females, 60% had underlying hematologic malignancy, and another 16% were on immunosuppressants. The majority of infections were from Fusarium solani species complex. Overall 72% of patients died. The majority received monotherapy with amphotericin B, although some received voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole with or without adjuvant surgery. Among the survivors, 3 received amphotericin B monotherapy, 2 voriconazole monotherapy, 1 combination therapy of both, and one surgery only. CONCLUSION: The overall mortality rate in published cases of fusariosis of the CNS was high, although-unlike during the current outbreak-the preponderance of patients were severely immunocompromised. While historically the majority were treated with amphotericin B monotherapy, some recent patients were treated with voriconazole monotherapy or combination therapy with amphotericin B plus voriconazole. Current guidelines recommend monotherapy with voriconazole or lipid formulations of amphotericin B or combination of both for the treatment of invasive fusariosis, which is in line with the findings from our literature review and should be considered during the ongoing 2023 outbreak.

Infections in patients with chronic lymphocytic leukemia.

INTRODUCTION: Infection is a major complication in patients with chronic lymphocytic leukemia (CLL). Newly diagnosed patients are at high risk of developing infection caused by encapsulated bacteria, such as Streptococcus pneumoniae and Haemophylus influenzae. METHOD AND RESULTS: However, once treatment is initiated, the spectrum of pathogens causing infection broadens, depending on the treatment regimens. With disease progression, cumulative immunosuppression occurs as a consequence of multiple treatment lines and the risk of infection further increases. On the other hand, the use of targeted therapies in the treatment of CLL have brought new risks of infection, with an increased incidence of invasive fungal diseases, particularly aspergillosis, in patients receiving Bruton kinase inhibitors. CONCLUSION: In this article, we review the epidemiology of infection in patients with CLL, taking into account the treatment regimen, and briefly discuss the management of infection.

Complex considerations - Fever and pancytopenia after solid organ transplantation.

This case describes a 42-year-old man who underwent kidney transplantation and developed fevers, pancytopenia, and elevated liver function tests starting on post-operative day 9. An extensive microbiologic and molecular workup was performed, ultimately leading to a diagnosis of donor-derived toxoplasmosis with associated hemophagocytic lymphohistiocytosis in the recipient. This case highlights the potential for post-transplant toxoplasmosis in high-risk mismatch (D+/R-) recipients, as well as the role of Toxoplasma-targeted prophylaxis in such patients.

Invasive Fungal Infections Associated with COVID-19.

The COVID-19 pandemic caused >6 million deaths worldwide, often from respiratory failure. Complications frequently occurred in hospitalized patients, particularly in the intensive care unit. Among these, fungal infections were a cause of high morbidity and mortality. Invasive aspergillosis, candidiasis and mucormycosis were the most serious of these infections. Risk factors included alterations in immune defense mechanisms by COVID-19 itself, as well as immunosuppression due to various therapies utilized in severely ill patients. Diagnosis was often challenging due to lack of sensitivity of current testing. Outcomes were generally poor, due to significant co-morbidities and delayed diagnosis, with mortality rates >50% in some studies. High index of clinical suspicion is needed to facilitate early diagnosis and initiation of appropriate antifungal therapy.

Performance of the beta-glucan test for the diagnosis of invasive fusariosis and scedosporiosis: a meta-analysis.

The (1→3)-ß-D-glucan (BDG) is a component of the fungal cell wall that can be detected in serum and used as an adjunctive tool for the diagnosis of invasive mold infections (IMI) in patients with hematologic cancer or other immunosuppressive conditions. However, its use is limited by modest sensitivity/specificity, inability to differentiate between fungal pathogens, and lack of detection of mucormycosis. Data about BDG performance for other relevant IMI, such as invasive fusariosis (IF) and invasive scedosporiosis/lomentosporiosis (IS) are scarce. The objective of this study was to assess the sensitivity of BDG for the diagnosis of IF and IS through systematic literature review and meta-analysis. Immunosuppressed patients diagnosed with proven or probable IF and IS, with interpretable BDG data were eligible. A total of 73 IF and 27 IS cases were included. The sensitivity of BDG for IF and IS diagnosis was 76.7% and 81.5%, respectively. In comparison, the sensitivity of serum galactomannan for IF was 27%. Importantly, BDG positivity preceded the diagnosis by conventional methods (culture or histopathology) in 73% and 94% of IF and IS cases, respectively. Specificity was not assessed because of lacking data. In conclusion, BDG testing may be useful in patients with suspected IF or IS. Combining BDG and galactomannan testing may also help differentiating between the different types of IMI.

IF and IS are severe fungal infections for which diagnosis is often delayed. This meta-analysis shows that beta-glucan testing in serum had a sensitivity of about 80% for IF/IS and could detect the disease earlier compared to conventional diagnostic tests.

Should patients with acute myeloid leukemia treated with venetoclax-based regimens receive antifungal prophylaxis?

Invasive fungal disease (IFD) is a major complication in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy, and the use of anti-mold prophylaxis is considered standard of care. On the other hand, the use of anti-mold prophylaxis in AML patients receiving less-intensive venetoclax-based regimens is not well established, basically because the incidence of IFD may not be high enough to justify primary antifungal prophylaxis. Furthermore, dose adjustments in venetoclax are needed because of drug interactions with azoles. Finally, the use of azoles is associated with toxicity, including liver, gastrointestinal and cardiac (QT prolongation) toxicity. In a setting of low incidence of invasive fungal disease, the number needed to harm would be higher than the number needed to treat. In this paper we review the risk factors for IFD in AML patients receiving intensive chemotherapeutic regimens, the incidence and risk factors for IFD in patients receiving hypomethylating agents alone, and in patients receiving less-intensive venetoclax-based regimens. We also discuss potential problems with the concomitant use of azoles, and present our perspective on how to manage AML patients receiving venetoclax-based regimens without primary antifungal prophylaxis.

Outcome of COVID-19 in allogeneic stem cell transplant recipients: Results from the EPICOVIDEHA registry.

Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT. Methods: This multicenter retrospective study promoted by the European Hematology Association - Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022. Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53). Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection.

Evaluation of the knowledge of hematologists about the management of infectious complications in hematologic patients.

INTRODUCTION: Infection is a serious complication among patients with hematologic malignancies (HMs) and in hematopoietic cell transplant (HCT) recipients. In most centers, the management of these complications is provided by the hematologist in person, thus demanding a knowledge of basic aspects of infection. METHODS: To evaluate the knowledge of the hematologist on infections, we invited clinicians to answer two questionnaires with 20 multiple-choice questions covering epidemiology, prophylaxis, diagnosis and treatment of infection in patients with HMs and HCT. RESULTS: We obtained 289 answers: 223 in survey 1 (febrile neutropenia) and 66 in survey 2 (infection in HCT). The median score was 5.0 in both surveys (range 0.5 - 9.0). In survey 1, the questions with the lowest number of correct answers were Q3 (8%), concerning the cefepime dose, and Q1 (9%), which asked about the epidemiologic link between the use of high dose cytarabine and viridans streptococcal bacteremia. In survey 2, two questions about cytomegalovirus (CMV) infection had the lowest percentage of correct answers (Q4, 12% and Q11, 18%). Clinicians attending to HCT recipients had higher scores, compared to clinicians attending to patients with HM only (median score of 5.0 and 4.5, p = 0.03, in survey 1 and 6.0 and 4.5, p = 0.001, in survey 2). In both surveys staff clinicians, residents and professors had similar scores. CONCLUSION: This is the first study in Brazil assessing the knowledge of hematologists on infectious complications. The low median score overall indicates an urgent need for continuous education. Such initiatives will eventually result in better patient care.