All You Need to Know and More about the Diagnosis and Management of Rare Mold Infections

Invasive mold infections caused by molds other than Aspergillus spp. or Mucorales are emerging. The reported prevalences of infection due to these rare fungal pathogens vary among geographic regions, driven by differences in climatic conditions, susceptible hosts, and diagnostic capabilities. These rare molds-Fusarium, Lomentospora, and Scedosporium species and others-are difficult to detect and often show intrinsic antifungal resistance. Now, international societies of medical mycology and microbiology have joined forces and created the Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology (published in Lancet Infect Dis, https://doi.org/10.1016/S1473-3099(20)30784-2), with the goal of improving the diagnosis, treatment, prevention, and survival of persons with rare mold infections. The guideline provides cutting-edge guidance for the correct utilization and application of established and new diagnostic and therapeutic options

Cost-effectiveness analysis of fidaxomicin versus vancomycin in <i>Clostridium difficile</i> infection

Fidaxomicin was non-inferior to vancomycin with respect to clinical cure rates in the treatment of Clostridium difficile infections (CDIs) in two Phase III trials, but was associated with significantly fewer recurrences than vancomycin. This economic analysis investigated the cost-effectiveness of fidaxomicin compared with vancomycin in patients with severe CDI and in patients with their first CDI recurrence. A 1 year time horizon Markov model with seven health states was developed from the perspective of Scottish public healthcare providers. Model inputs for effectiveness, resource use, direct costs and utilities were obtained from published sources and a Scottish expert panel. The main model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY), for fidaxomicin versus vancomycin; ICERs were interpreted using willingness-to-pay thresholds of A 20aEuroS000 pound/QALY and A 30aEuroS000 pound/QALY. One-way and probabilistic sensitivity analyses were performed. Total costs were similar with fidaxomicin and vancomycin in patients with severe CDI (A 14aEuroS515 pound and A 14aEuroS344 pound, respectively) and in patients with a first recurrence (A 16aEuroS535 pound and A 16aEuroS926 pound, respectively). Improvements in clinical outcomes with fidaxomicin resulted in small QALY gains versus vancomycin (severe CDI, +0.010; patients with first recurrence, +0.019). Fidaxomicin was cost-effective in severe CDI (ICER A 16aEuroS529 pound/QALY) and dominant (i.e. more effective and less costly) in patients with a first recurrence. The probability that fidaxomicin was cost-effective at a willingness-to-pay threshold of A 30aEuroS000 pound/QALY was 60% for severe CDI and 68% in a first recurrence. Fidaxomicin is cost-effective in patients with severe CDI and in patients with a first CDI recurrence versus vancomycin

Antifungal prophylaxis and pre-emptive therapy: When and how?

The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii. In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system. In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies. Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology. The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches

Candida-Reactive T Cells for the Diagnosis of Invasive Candida Infection—A Prospective Pilot Study

Background: Blood or tissue culture or histology prove invasive Candida infection, but long time to result, limited feasibility and sensitivity call for new approaches. In this pilot project, we describe the diagnostic potential of quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes in blood of patients with invasive Candida infection.Methods: We used flow cytometry quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes from peripheral blood of patients with invasive Candida infection, from patients at risk and healthy volunteers as controls.Results: Elevated levels of Candida-reactive lymphocytes were measured in 13 patients with proven invasive Candida infection and in one patient with probable hepatosplenic candidiasis. Results of three candidemia patients were uninterpretable due to autofluorescence of samples. Twelve of 13 patients had Candida identified to species level by conventional methods, and T cell reactivity correctly identified Candida species in 10 of 12 patients. Nine hematological high-risk patients and 14 healthy donors had no elevated Candida-reactive T cell counts.Conclusions: This Candida-reactive lymphocyte assay correctly identified the majority of patients with invasive Candida infection and the respective species. Our assay has the potential to support diagnosis of invasive Candida infection to species level and to facilitate tailored treatment even when biopsies are contraindicated or cultures remain negative

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

Background Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases

Identification of Mucormycosis by Fluorescence In Situ Hybridization Targeting Ribosomal RNA in Tissue Samples

Mucormycosis is an invasive fungal infection associated with high mortality, partly due to delayed diagnosis and inadequate empiric therapy. As fungal cultures often fail to grow Mucorales, identification of respective hyphae in tissue is frequently needed for diagnosis but may be challenging. We studied fluorescence in situ hybridization (FISH) targeting specific regions of the fungal ribosomal RNA (rRNA) of Mucorales to improve diagnosis of mucormycosis from tissue samples. We generated a probe combination specifically targeting Mucorales. Probe specificity was verified in silico and using cultivated fungi. Mucorales hyphae in tissue of a mouse model demonstrated a bright cytoplasmatic hybridization signal. In tissue samples of patients with mucormycosis, a positive signal was seen in 7 of 12 (58.3%) samples. However, autofluorescence in 3 of 7 (42.9%) samples impaired the diagnostic yield. Subsequent experiments suggested that availability of nutrients and antifungal therapy may impact on the FISH signal obtained with Mucorales hyphae. Diagnosis of mucormycosis from tissue might be improved by rRNA FISH in a limited number of cases only. FISH signals may reflect different physiological states of fungi in tissue. Further studies are needed to define the value of FISH to diagnose mucormycosis from other clinical samples.Peer Reviewe

Treatment of invasive fungal infections in clinical practice: a multi-centre survey on customary dosing, treatment indications, efficacy and safety of voriconazole

Invasive fungal infections are frequent and often deadly complications in patients with malignant hematological diseases. Voriconazole is a third generation triazole antifungal with broad activity against most clinically relevant fungal pathogens. Clinical practice often deviates from insights gained from controlled randomized trials. We conducted a multi-centre survey to evaluate efficacy, safety, treatment indications and dosing of voriconazole outside clinical trials. Patients receiving voriconazole were documented via electronic data capturing. An analysis was conducted after submission of 100 episodes from September 2004 to November 2005. Voriconazole was administered for suspected or proven invasive fungal infection (IFI) (57%), as empirical treatment in patients with fever of unknown origin (21%) and secondary (19%) as well as primary (3%) prophylaxis of IFI. Investigators’ assessment of fungal infection often diverted from EORTC/MSG 2002 criteria. A favorable response was reported in 61.4% for suspected or proven IFI and 52.4% for empirical treatment. Mortality was 15%, 26.7% of which was attributable to IFI. Breakthrough fungal infections occurred in four (21.1%) patients with voriconazole as secondary prophylaxis. Toxicity and adverse events comprised elevated liver enzymes and visual disturbances. Although indications frequently deviated from clinical evidence and legal approval, voriconazole showed efficacy and safety, comparable to major controlled clinical trials. Data from this survey demonstrate the difficulty of putting drugs to their approved use in IFI

COVID-19 Associated Pulmonary Aspergillosis (CAPA)—From immunology to treatment

Like severe influenza, coronavirus disease-19 (COVID-19) resulting in acute respiratory distress syndrome (ARDS) has emerged as an important disease that predisposes patients to secondary pulmonary aspergillosis, with 35 cases of COVID-19 associated pulmonary aspergillosis (CAPA) published until June 2020. The release of danger-associated molecular patterns during severe COVID-19 results in both pulmonary epithelial damage and inflammatory disease, which are predisposing risk factors for pulmonary aspergillosis. Moreover, collateral effects of host recognition pathways required for the activation of antiviral immunity may, paradoxically, contribute to a highly permissive inflammatory environment that favors fungal pathogenesis. Diagnosis of CAPA remains challenging, mainly because bronchoalveolar lavage fluid galactomannan testing and culture, which represent the most sensitive diagnostic tests for aspergillosis in the ICU, are hindered by the fact that bronchoscopies are rarely performed in COVID-19 patients due to the risk of disease transmission. Similarly, autopsies are rarely performed, which may result in an underestimation of the prevalence of CAPA. Finally, the treatment of CAPA is complicated by drug–drug interactions associated with broad spectrum azoles, renal tropism and damage caused by SARS-CoV-2, which may challenge the use of liposomal amphotericin B, as well as the emergence of azole-resistance. This clinical reality creates an urgency for new antifungal drugs currently in advanced clinical development with more promising pharmacokinetic and pharmacodynamic profiles.AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (CEECIND/03628/2017, UIDB/50026/2020 and UIDP/50026/2020), and the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023). This research received no other external funding