COVID-19 associated Pulmonary Aspergillosis in Patients Admitted to the Intensive Care Unit: Impact of Antifungal Prophylaxis.

Early after the beginning of the coronavirus disease 2019 (COVID-19)-pandemic, it was observed that critically ill patients in the intensive care unit (ICU) were susceptible to developing secondary fungal infections, particularly COVID-19 associated pulmonary aspergillosis (CAPA). Here we report our local experience on the impact of mold active antifungal prophylaxis on CAPA occurrence in critically ill COVID-19 patients. This is a monocentric, prospective cohort study including all consecutive patients with COVID-19 associated acute respiratory failure who were admitted to our local medical ICU. Based on the treating physician's discretion, patients may have received antifungal prophylaxis or not. All patients were retrospectively characterized as having CAPA according to the 2020 ECMM/ISHAM consensus definitions. Seventy-seven patients were admitted to our medical ICU during April 2020 and May 2021 and included in the study. The majority of patients received invasive-mechanical ventilation (61%). Fifty-three patients (68.8%) received posaconazole prophylaxis. Six cases of probable CAPA were diagnosed within clinical routine management. All six cases were diagnosed in the non-prophylaxis group. The incidence of CAPA in the overall study cohort was 0.57 events per 100 ICU days and 2.20 events per 100 ICU days in the non-prophylaxis group. No difference of cumulative 84-days survival could be observed between the two groups (p = 0.115). In this monocentric cohort, application of posaconazole prophylaxis in patients with COVID-19 associated respiratory failure did significantly reduce the rate of CAPA.

Suboptimal plasma concentrations with posaconazole suspension as prophylaxis in critically ill COVID-19 patients at risk of Covid-associated pulmonary aspergillosis.

WHAT IS KNOWN AND OBJECTIVE: The safety and efficacy of different antifungal agents in the prophylaxis of invasive fungal infection in patients with haematological disorders are known. We comment on the poor bioavailability of posaconazole suspension to suggest that it is not useful in critically ill COVID patients. COMMENT: The increased mortality and high incidence of COVID-associated pulmonary aspergillosis (CAPA) might justify administration of off-label posaconazole for preventing CAPA, being the only drug officially registered for prophylaxis of fungal infections. We decided to initiate off-label posaconazole prophylaxis in COVID-19 patients, who were mechanically ventilated and exposed to high-dose steroids for progressive pulmonary disease or ARDS. We found that posaconazole suspension was inadequate. Very low trough levels were observed after administration, and the dose adjustments necessary for the therapeutic drug monitoring (TDM) of the drug in our critically ill ICU patients were not useful. WHAT IS NEW AND CONCLUSION: Posaconazole suspension should not be used to prevent CAPA in COVID-19 patients on high-dose steroid therapy.

Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study.

BACKGROUND: Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) emerged as important fungal complications in patients with COVID-19-associated severe acute respiratory failure (ARF). Whether mould active antifungal prophylaxis (MAFP) can prevent CAPA remains elusive so far. METHODS: In this observational study, we included all consecutive patients admitted to intensive care units with COVID-19-associated ARF between September 1, 2020, and May 1, 2021. We compared patients with versus without antifungal prophylaxis with respect to CAPA incidence (primary outcome) and mortality (secondary outcome). Propensity score adjustment was performed to account for any imbalances in baseline characteristics. CAPA cases were classified according to European Confederation of Medical Mycology (ECMM)/International Society of Human and Animal Mycoses (ISHAM) consensus criteria. RESULTS: We included 132 patients, of whom 75 (57%) received antifungal prophylaxis (98% posaconazole). Ten CAPA cases were diagnosed, after a median of 6 days following ICU admission. Of those, 9 CAPA cases were recorded in the non-prophylaxis group and one in the prophylaxis group, respectively. However, no difference in 30-day ICU mortality could be observed. Thirty-day CAPA incidence estimates were 1.4% (95% CI 0.2-9.7) in the MAFP group and 17.5% (95% CI 9.6-31.4) in the group without MAFP (p = 0.002). The respective subdistributional hazard ratio (sHR) for CAPA incidence comparing the MAFP versus no MAFP group was of 0.08 (95% CI 0.01-0.63; p = 0.017). CONCLUSION: In ICU patients with COVID-19 ARF, antifungal prophylaxis was associated with significantly reduced CAPA incidence, but this did not translate into improved survival. Randomized controlled trials are warranted to evaluate the efficacy and safety of MAFP with respect to CAPA incidence and clinical outcomes.

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion.

PURPOSE: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. METHODS: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. RESULTS: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung. CONCLUSION: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.

Voriconazole and the Risk of Keratinocyte Carcinomas Among Lung Transplant Recipients in the United States.

Importance: The antifungal medication voriconazole is used to prevent and treat aspergillosis, a major cause of mortality among recipients of lung transplants (hereinafter referred to as lung recipients). Small studies suggest that voriconazole increases risk of cutaneous squamous cell carcinoma (SCC). Objective: To examine associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas (SCC and cutaneous basal cell carcinoma [BCC]) in lung recipients. Design, Setting, and Participants: This population-based cohort study included non-Hispanic white patients (n = 9599) who underwent lung transplant in the United States from January 1, 2007, to December 31, 2016, identified through the national Scientific Registry of Transplant Recipients with data linkable to pharmacy claims. Data were analyzed from March 1, 2018, to February 13, 2019. Exposures: Antifungal medication use, including voriconazole, itraconazole, posaconazole, and other antifungals, was ascertained from pharmacy claims and treated as a time-varying exposure (assessed every 30 days). Cumulative antifungal exposure was calculated as the total number of exposed months. Main Outcomes and Measures: Primary outcomes were the first SCC or BCC reported to the transplant registry by transplant centers. Follow-up began at transplant and ended at SCC or BCC diagnosis, transplant failure or retransplant, death, loss to follow-up, or December 31, 2016. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (AHRs) for each antifungal medication. Results: Among the 9793 lung transplants in 9599 recipients included in the analysis, median age at transplant was 59 (interquartile range [IQR], 48-65) years, 5824 (59.5%) were male, and 5721 (58.4%) reported ever smoking. During a median follow-up of 3.0 (IQR, 1.4-5.0) years after transplant, 1031 SCCs (incidence, 322 per 10 000 person-years) and 347 BCCs (incidence, 101 per 10 000 person-years) were reported. Compared with lung recipients with no observed voriconazole use, those with 1 to 3 months of voriconazole use experienced increased AHR for SCC of 1.09 (95% CI, 0.90-1.31); 4 to 7 months, 1.42 (95% CI, 1.16-1.73); 8 to 15 months, 2.04 (95% CI, 1.67-2.50); and more than 15 months, 3.05 (95% CI, 2.37-3.91). Ever itraconazole exposure was associated with increased SCC risk (AHR, 1.20; 95% CI, 1.00-1.45). For BCC, risk was not associated with voriconazole use but was increased with itraconazole use (AHR, 1.74; 95% CI, 1.27-2.37) or posaconazole use (AHR, 1.55; 95% CI, 1.00-2.41). Conclusions and Relevance: In this study, voriconazole use was associated with increased SCC risk among lung recipients, especially after prolonged exposure. Further research evaluating the risk-benefit ratio of shorter courses or alternative medications in transplant recipients at high risk for SCC should be considered.

Advances in the diagnosis and management of pulmonary aspergillosis.

Aspergillus is a mould that is ubiquitous in nature and may lead to a variety of infectious and allergic diseases depending on the host's immune status or pulmonary structure. Invasive pulmonaryaspergillosisoccurs primarily in patients with severe immunodeficiency. The significance of this infection has dramatically increased with growing numbers of patients with impaired immune state associated with the management of malignancy, organ transplantation, autoimmune and inflammatory conditions; critically ill patients appear to be at an increased risk as well. The introduction of new noninvasive tests, combined with more effective and better-tolerated antifungal agents, has resulted in lower mortality rates associated with this infection. Chronic pulmonary aspergillosis is a locally invasive disease described in patients with chronic lung disease or mild immunodeficiency. Recently, the European Society for Clinical Microbiology and Infectious Diseases provided a more robust sub-classification of this entity that allows for a straightforward approach to diagnosis and management. Allergic bronchopulmonaryaspergillosis, a hypersensitivity reaction to Aspergillus antigens, is generally seen in patients with atopy, asthma or cystic fibrosis. This review provides an update on the evolving epidemiology and risk factors of the major manifestations of Aspergillus lung disease and the clinical manifestations that should prompt the clinician to consider these conditions. It also details the role of noninvasive tests in the diagnosis of Aspergillus related lung diseases and advances in the management of these disorders.

Aspergilloma in Honeycomb Cysts and Paraseptal Emphysema: An Unusual Association / Aspergiloma en pulmón en panal y enfisema paraseptal: una asociación poco habitual

No disponible

Aspergillus-related pulmonary diseases in lung transplantation.

While lung transplantation is an attractive treatment option for many end stage lung diseases, the relatively high 5-year mortality continues to be a significant limiting factor. Among the foremost reasons for this is the eventual development of obstructive chronic lung allograft dysfunction. Infections, which the lung allograft is especially prone to, are a major risk factor. Specifically, the Aspergillus species cause a higher burden of disease among lung transplant recipients, due to unique risk factors, such as relative hypoxemia. However, these risk factors also provide unique opportunities for treatment and preventative strategies, as outlined in this review.

Recomendaciones para la prevención de infecciones relacionadas con demoliciones, construcciones y remodelaciones / Recommendations for prevention of infection related to demolition, construction and renovation

Las demoliciones, construcciones y/o remodelaciones pueden provocar infecciones intrahospitalarias en pacientes con factores de riesgos, especialmente aspergilosis pulmonar. En la presente guia se describen algunas medidas que pueden ayudar a mitigar estas infecciones en los distintos recintos hospitalarios.

Demolitions, constructions and renovations can produce nosocomial infections in patients with risk factors, specially lung aspergillosis. The following guide describes some actions that could help in the mitigation of these infections in the different hospitals.

Nebulised amphotericin B-polymethacrylic acid nanoparticle prophylaxis prevents invasive aspergillosis.

Aspergillus species are the major life threatening fungal pathogens in transplant patients. Germination of inhaled fungal spores initiates infection, causes severe pneumonia, and has a mortality of >50%. This is leading to the consideration of pre-exposure prophylaxis to prevent infection. We made a very low MWt amphotericin B-polymethacrylic acid nanoparticle. It was not toxic to lung epithelial cells or monocyte-derived-macrophages in-vitro, or in an in-vivo transplant immuno-suppression mouse model of life threatening invasive aspergillosis. Three days of nebuliser based prophylaxis delivered the nanoparticle effectively to lung and prevented both fungal growth and lung inflammation. Protection from disease was associated with >99% killing of the Aspergillus and a 90% reduction in lung TNF-α; the primary driver of tissue destructive immuno-pathology. This study provides in-vivo proof-of-principle that very small and cost-effective nanoparticles can be made simply, and delivered safely and effectively to lung by the aerosol route to prevent fungal infections. FROM THE CLINICAL EDITOR: Aspergillus is an opportunistic pathogen, which affects immunocompromised patients. One novel way to help fight against this infection is pre-exposure prophylaxis. The authors here made PMA based anionic hydrogels carrying amphotericin B, with mucoadhesive behavior. They showed that aerosol route of the drug was very effective in protecting against the disease in an in-vivo model and should provide a stepping-stone towards clinical trials in the future.

Myeloid derived hypoxia inducible factor 1-alpha is required for protection against pulmonary Aspergillus fumigatus infection.

Hypoxia inducible factor 1α (HIF1α) is the mammalian transcriptional factor that controls metabolism, survival, and innate immunity in response to inflammation and low oxygen. Previous work established that generation of hypoxic microenvironments occurs within the lung during infection with the human fungal pathogen Aspergillus fumigatus. Here we demonstrate that A. fumigatus stabilizes HIF1α protein early after pulmonary challenge that is inhibited by treatment of mice with the steroid triamcinolone. Utilizing myeloid deficient HIF1α mice, we observed that HIF1α is required for survival and fungal clearance early following pulmonary challenge with A. fumigatus. Unlike previously reported research with bacterial pathogens, HIF1α deficient neutrophils and macrophages were surprisingly not defective in fungal conidial killing. The increase in susceptibility of the myeloid deficient HIF1α mice to A. fumigatus was in part due to decreased early production of the chemokine CXCL1 (KC) and increased neutrophil apoptosis at the site of infection, resulting in decreased neutrophil numbers in the lung. Addition of recombinant CXCL1 restored neutrophil survival and numbers, murine survival, and fungal clearance. These results suggest that there are unique HIF1α mediated mechanisms employed by the host for protection and defense against fungal pathogen growth and invasion in the lung. Additionally, this work supports the strategy of exploring HIF1α as a therapeutic target in specific immunosuppressed populations with fungal infections.

Itraconazole prophylaxis for invasive Aspergillus infection in lung transplantation.

Invasive Aspergillus infection (IA) is a significant cause of morbidity in lung transplantation (LT). However, its optimal prophylaxis is unclear. We routinely administer itraconazole (ITCZ) prophylaxis to all patients undergoing LT. In this study, we retrospectively evaluated the duration of prophylaxis and risk factors of IA. Among 30 adult patients who underwent LT, 5 patients developed IA. All patients with IA stopped ITCZ treatment within 1 year. At least 1 year of ITCZ prophylaxis is essential for the prevention of IA. Cytomegalovirus infection, renal replacement therapy, and tracheotomy were risk factors for IA.

Genotipificación de aislamientos clínicos de Aspergillus flavus y su relación con aislamientos ambientales de un centro oncohematológico / Genotyping of clinical isolates of Aspergillus flavus and its relationship with environmental isolates of an oncohematological center

Antecedentes. Durante un período de 4 meses, y mientras se llevaba a cabo un muestreo ambiental de aire, se diagnosticaron 2 casos de aspergilosis por Aspergillus flavus en un centro oncohematológico de Buenos Aires, Argentina. Objetivos. Conocer la variabilidad y la relación genética entre los aislamientos clínicos y los ambientales obtenidos en el centro oncohematológico. Métodos. Se utilizaron 2 técnicas de genotipificación con diferente poder discriminatorio (RAPD y AFLP). Una matriz de similitud genética fue calculada usando el método de Jaccard y fue la base para la construcción de un dendrograma por el método de UPGMA. Se estimó el nivel de variabilidad genética por medio del porcentaje de loci polimórficos, número de alelos efectivos y heterocigosidad esperada, y el índice de asociación (IA). Resultados. El dendrograma mostró que los aislamientos de A. flavus recuperados de los pacientes no se relacionaron genéticamente con los del ambiente nosocomial. Los valores más altos de diversidad genética correspondieron a los aislamientos ambientales. El IA estimado para todos los aislamientos sugiere eventos de recombinación. Conclusiones. Los pacientes 1 y 2 no fueron infectados con los aislamientos obtenidos del ambiente hospitalario. Los aislamientos clínicos y ambientales de A. flavus mostraron alta variabilidad genética entre ellos(AU)

Background. During 4 months, and while conducting an environmental sampling of air, 2 cases of aspergillosis by Aspergillus flavus (A. flavus) were diagnosed at an oncohematological center in Buenos Aires, Argentina. Aims. The aim of this study was to know the variability and the genetic relationship between the clinical and environmental isolates, obtained in the oncohematological center. Methods. Two genotyping techniques of different discriminatory power (RAPD and AFLP) were used. A genetic similarity matrix was calculated using Jaccard method and was the basis for the construction of a dendrogram by UPGMA. The level of genetic variability was assessed by measuring the percentage of polymorphic loci, number of effective allele, expected heterocygozity and association index test (IA). Results. The dendrogram reveals that the A. flavus isolates recovered from the patients were not genetically related to those gotten from the rooms occupied by the patients. The environmental isolates had higher values of genetic diversity than the clinical isolates. The IA estimated for all the isolates suggest that recombination events occurred. Conclusions. Patients 1 and 2 were not infected with isolates from the nosocomial environment. Clinical and environmental isolates of A. flavus showed high genetic variability among them(AU)

Antibodies generated against conserved antigens expressed by bacteria and allergen-bearing fungi suppress airway disease.

There has been a sharp rise in allergic asthma and asthma-related deaths in the developed world, in contrast to many childhood illnesses that have been reduced or eliminated. The hygiene hypothesis proposes that excessively sanitary conditions early in life result in autoimmune and allergic phenomena because of a failure of the immune system to receive proper microbial stimulation during development. We demonstrate that Abs generated against conserved bacterial polysaccharides are reactive with and dampen the immune response against chitin and Aspergillus fumigatus. A reduction in Ag uptake, cell influx, cell activation, and cytokine production occurred in the presence of anti-polysaccharide Abs, resulting in a striking decrease in the severity of allergic airway disease in mice. Overall, our results suggest that Ag exposure--derived from environmental sources, self-antigens, or vaccination--during the neonatal period has dramatic effects on the adult Ab response and modifies the development of allergic airway disease.

Breakthrough invasive mould infections in patients treated with caspofungin.

OBJECTIVES: To describe and estimate the rate of breakthrough invasive mould diseases (IMD) in patients receiving caspofungin. METHODS: Retrospective, non-interventional study conducted in three University Hospitals. RESULTS: Nineteen breakthrough infections have been identified including 13 aspergillosis, 2 mucormycosis, a fusariosis, a Hormographiella aspergillata infection and 2 possible IMD. Cases were equally distributed between the centres. Fourteen patients had a haematologic malignancy, four were transplant recipients (allogeneic haematopoietic stem cells in three, liver in one) and one had hepatic cirrhosis. Caspofungin has been prescribed as prophylaxis (n = 3), empirical therapy (n = 9) or directed therapy for candidemia (n = 5) or aspergillosis (n = 2). Aspergillus galactomannan was positive in serum or in bronchoalveolar lavage fluid in 10 of the 13 aspergillosis. Median duration of caspofungin treatment before breakthrough IMD was 15 days. Nine patients died within twelve weeks. Rate of breakthrough IMD in onco-haematology patients has been estimated to 7.3% for all mould infections and to 4.2% when restricted to documented aspergillosis. CONCLUSIONS: Our data call for Aspergillus galactomannan monitoring and close clinical and radiological examination in case of persistence or recurrence of infection signs in high-risk patients receiving caspofungin.

Resultados de profilaxis con itraconazol 800 mg/día vía oral en adultos con leucemia aguda y neutropenia de alto riesgo: Hospital del Salvador 2006-2008 / Itraconazole 800 mg for the prophylaxis of fungal infections in patients with acute leukemia and severe neutropenia

Background: Systemic fungal infections and specifically invasive aspergillosis (IA) are associated with a high morbi-mortality rate in patients with hematologic malignancies. Itraconazole kinetic studies show that plasma levels are not satisfactory, even though there is a reduction of the severity in clinical cases. Aim: To evaluate the results of oral prophylaxis with high dose itraconazole, 400 mg bid, among patients with adult acute leukemia. Material and Methods: Prospective analysis of 93 high risk febrile episodes (with an absolute neutrophil count of less than 500 x mm3 for more 10 days), that occurred in 76 patients. Results: Seventy five percent of episodes occurred in patients with acute myeloid leukemia and 25 percent in patients with acute lymphoblastic leukemia. Fifty two percent occurred during the induction of chemotherapy. Median duration of severe neutropenia was 21 days (range 10-48). Median duration of itraconazole prophylaxis was 17 days (range 6-34). A low frequency of invasive fungal infections was observed (17 percent). According to diagnostic criteria, 5 percent of episodes corresponded to persistent fever , 1 percent and 11 percent of episodes, to probable or possible IA, respectively. No confirmed or proven IA was observed. Mortality of IA was 18 percent. No serious adverse events due to itraconazole were observed. Conclusions: The use of high dose itraconazole prophylaxis in adult patients with acute leukemia and severe neutropenia was associated to low incidence and mortality of invasive mycoses.

A randomized comparison of caspofungin versus antifungal prophylaxis according to investigator policy in acute leukaemia patients undergoing induction chemotherapy (PROFIL-C study).

BACKGROUND: Invasive fungal infections (IFIs) are considered a major problem among patients undergoing acute leukaemia (AL) induction treatment. PROphylaxis of Fungal invasive Infections in Leukaemia-Caspofungin (PROFIL-C) is a multicentre study aiming to assess the comparative yield of using caspofungin versus standard policy (SP) regimens and the overall impact of IFI in routine clinical care conditions. METHODS: All AL patients receiving IFI prophylaxis according to local SP were prospectively included in the study by Northern Italy Leukaemia Group (NILG) centres. To allow the comparison of caspofungin versus SP regimens as prophylaxis strategies, caspofungin treatment was assigned via a centralized randomized procedure. The study was registered at http://www.clinicaltrial.gov (NCT00501098). RESULTS: Over a 2 year period, 175 patients were included. The overall incidence of IFI was 32/175 (18.3%) [10/175 (5.7%) probable/proven and 22/175 (12.6%) possible], with no statistically significant differences between caspofungin-based versus SP-based regimens [overall: 15/93 (16.1%) versus 17/82 (20.7%), relative risk (RR) 0.78, 95% confidence interval (CI) 0.42-1.46; probable/proven: 7/93 (7.5%) versus 3/82 (3.7%), RR 2.06, 95% CI 0.55-7.7; possible: 8/93 (8.6%) versus 14/82 (17.1%), RR 0.5, 95% CI 0.22-1.14]. Only one IFI-related death was recorded (10%). CONCLUSIONS: The incidence and mortality of IFI were lower than expected in this strictly sequential cohort representative of the routine care in the NILG network. The efficacy and safety of caspofungin were similar to other prophylactic regimens.