Assessing the safety profile of voriconazole use in suspected COVID-19-associated pulmonary aspergillosis-a two-centre observational study.

The decision to use voriconazole for suspected COVID-19-associated pulmonary aspergillosis (CAPA) is based on clinical judgement weighed against concerns about its potential toxicity. We assessed the safety profile of voriconazole for patients with suspected CAPA by conducting a retrospective study of patients across two intensive care units. We compared changes in any liver enzymes or bilirubin and any new or increasing corrected QT interval (QTc) prolongation following voriconazole use to patient baseline to indicate possible drug effect. In total, 48 patients with presumed CAPA treated with voriconazole were identified. Voriconazole therapy was administered for a median of 8 days (interquartile range [IQR] 5-22) and the median level was 1.86 mg/L (IQR 1.22-2.94). At baseline, 2% of patients had a hepatocellular injury profile, 54% had a cholestatic injury profile, and 21% had a mixed injury profile. There were no statistically significant changes in liver function tests over the first 7 days after voriconazole initiation. At day 28, there was a significant increase in alkaline phospahte only (81-122 U/L, P = 0.006), driven by changes in patients with baseline cholestatic injury. In contrast, patients with baseline hepatocellular or mixed injury had a significant decrease in alanine transaminase and aspartate transaminase. Baseline QTc was 437 ms and remained unchanged after 7 days of voriconazole therapy even after sensitivity analysis for concomitantly administered QT prolonging agents. Therefore, at the doses used in this study, we did not detect evidence of significant liver or cardiac toxicity related to voriconazole use. Such information can be used to assist clinicians in the decision to initiate such treatment.

Our study did not show significant voriconazole-related liver or cardiac side effects in a critically ill cohort of patients with suspected COVID-19-associated pulmonary aspergillosis. These findings may allay specific clinician concerns when commencing therapy for such patients.

Liposomal amphotericin B-the future.

Advances in medicine have led to a growing number of people with compromised or suppressed immune systems who are susceptible to invasive fungal infections. In particular, severe fungal infections are becoming increasingly common in ICUs, affecting people within and outside of traditional risk groups alike. This is exemplified by the emergence of severe viral pneumonia as a significant risk factor for invasive pulmonary aspergillosis, and the recognition of influenza-associated pulmonary aspergillosis and, more recently, COVID-19-associated pulmonary aspergillosis. The treatment landscape for haematological malignancies has changed considerably in recent years, and some recently introduced targeted agents, such as ibrutinib, are increasing the risk of invasive fungal infections. Consideration must also be given to the risk of drug-drug interactions between mould-active azoles and small-molecule kinase inhibitors. At the same time, infections caused by rare moulds and yeasts are increasing, and diagnosis continues to be challenging. There is growing concern about azole resistance among both moulds and yeasts, mandating continuous surveillance and personalized treatment strategies. It is anticipated that the epidemiology of fungal infections will continue to change and that new populations will be at risk. Early diagnosis and appropriate treatment remain the most important predictors of survival, and broad-spectrum antifungal agents will become increasingly important. Liposomal amphotericin B will remain an essential therapeutic agent in the armamentarium needed to manage future challenges, given its broad antifungal spectrum, low level of acquired resistance and limited potential for drug-drug interactions.

Targeting Sterylglucosidase A to Treat Aspergillus fumigatus Infections.

Invasive fungal infections are a leading cause of death in immunocompromised patients. Current therapies have several limitations, and innovative antifungal agents are critically needed. Previously, we identified the fungus-specific enzyme sterylglucosidase as essential for pathogenesis and virulence of Cryptococcus neoformans and Aspergillus fumigatus (Af) in murine models of mycoses. Here, we developed Af sterylglucosidase A (SglA) as a therapeutic target. We identified two selective inhibitors of SglA with distinct chemical scaffolds that bind in the active site of SglA. Both inhibitors induce sterylglucoside accumulation and delay filamentation in Af and increase survival in a murine model of pulmonary aspergillosis. Structure-activity relationship (SAR) studies identified a more potent derivative that enhances both in vitro phenotypes and in vivo survival. These findings support sterylglucosidase inhibition as a promising antifungal approach with broad-spectrum potential. IMPORTANCE Invasive fungal infections are a leading cause of death in immunocompromised patients. Aspergillus fumigatus is a fungus ubiquitously found in the environment that, upon inhalation, causes both acute and chronic illnesses in at-risk individuals. A. fumigatus is recognized as one of the critical fungal pathogens for which a substantive treatment breakthrough is urgently needed. Here, we studied a fungus-specific enzyme, sterylglucosidase A (SglA), as a therapeutic target. We identified selective inhibitors of SglA that induce accumulation of sterylglucosides and delay filamentation in A. fumigatus and increase survival in a murine model of pulmonary aspergillosis. We determined the structure of SglA, predicted the binding poses of these inhibitors through docking analysis, and identified a more efficacious derivative with a limited SAR study. These results open several exciting avenues for the research and development of a new class of antifungal agents targeting sterylglucosidases.

Pulmonary aspergillosis: diagnosis and treatment.

Aspergillus species are the most frequent cause of fungal infections of the lungs with a broad spectrum of clinical presentations including invasive pulmonary aspergillosis (IPA) and chronic pulmonary aspergillosis (CPA). IPA affects immunocompromised populations, which are increasing in number and diversity with the advent of novel anti-cancer therapies. Moreover, IPA has emerged as a complication of severe influenza and coronavirus disease 2019 in apparently immunocompetent hosts. CPA mainly affects patients with pre-existing lung lesions and is recognised increasingly frequently among patients with long-term survival following cure of tuberculosis or lung cancer. The diagnosis of pulmonary aspergillosis is complex as it relies on the presence of clinical, radiological and microbiological criteria, which differ according to the type of pulmonary aspergillosis (IPA or CPA) and the type of patient population. The management of pulmonary aspergillosis is complicated by the limited number of treatment options, drug interactions, adverse events and the emergence of antifungal resistance.

A 64-Year-Old Man Hospitalized for COVID-19 Pneumonia and Treated with Tocilizumab Who Developed Chronic Cavitary Pulmonary Aspergillosis.

BACKGROUND The management of (Coronavirus disease 2019) COVID-19 pneumonia is ever-evolving. Tocilizumab, a monoclonal antibody against interleukin-6 (IL-6) receptor, have known mortality benefit in severe COVID-19 pneumonia, but data are limited regarding safety. Attributable to the immunomodulatory nature of this medication, patients may be at risk for opportunistic infections, including chronic cavitary pulmonary aspergillosis (CPPA), a slowly progressive disease characterized pulmonary infiltrates and often a newly-formed cavity. However, current guidelines do not emphasize post-treatment surveillance of patients for opportunistic infections, including CPPA. CASE REPORT We present a particular case of a 64-year-old man treated for COVID-19 pneumonia with Tocilizumab and dexamethasone who developed cavitary pulmonary aspergillosis. He presented to the emergency department with hemoptysis, associated with worsening productive cough, shortness of breath, and weight loss. Computed tomography (CT) of the chest showed areas of focal consolidation and a cavitary lung lesion within the left upper lobe. Sputum culture was positive for Aspergillus niger. The patient received a long course of oral triazole therapy for CPPA, with clinical improvement. CT scan of the chest at 9 months showed that the Itraconazole therapy was effective in resolving the extensive airspace disease and decreasing the size of the upper-lobe cavity and fungal ball. CONCLUSIONS This article illustrates the possibility of a serious infection such as CCPA as an adverse effect of Tocilizumab treatment, especially with concurrent immunosuppressive therapy. Furthermore, this case highlights the importance of regular monitoring of patients who have received Tocilizumab therapy to ensure that early signs of opportunistic infections such as CPPA are detected and treated promptly to prevent permanent lung damage.

Risk factors and clinical impact of COVID-19-associated pulmonary aspergillosis: Multicenter retrospective cohort study.

BACKGROUND/AIMS: The risk factors and clinical impacts of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) remain controversial, and no data have been reported in Korea. This study aimed to investigate the epidemiology and importance of CAPA diagnostic efforts and to identify the predictors of CAPA and the impacts on clinical outcomes. METHODS: Between January 2020 and May 2021, data of severely to critically ill COVID-19 patients were extracted from seven hospitals of the Catholic Medical Center through a clinical data warehouse. Corticosteroid use was subcategorized into total cumulative dose, early 7-day dose, mean daily dose, and duration of use. RESULTS: A total of 2,427 patients were screened, and 218 patients were included. CAPA was diagnosed in 4.6% (10/218) of all hospitalized and 11.2% (10/89) of intensive care unit patients. Total cumulative dose (over 1,000 mg as methylprednisolone) and daily high-dose corticosteroid use (over 60 mg/day) were independent predictors but not early 7-day high-dose corticosteroid use (over 420 mg/week) (odds ratio [OR], 1.731; 95% confidence interval [CI], 0.350 to 8.571) nor prolonged use (OR, 2.794; 95% CI, 0.635 to 13.928). In-hospital overall mortality was 11.9% (26 of 218). CAPA itself did not affect the outcome; rather, daily high-dose steroid use significantly increased the 30-day mortality (hazard ratio, 5.645; 95% CI, 1.225 to 26.091). CONCLUSION: CAPA was not uncommon, especially in critically ill patients. Daily high-dose corticosteroid use was the predictor of CAPA and associated with high mortality rates. High-dose corticosteroids use after early inflammatory phase should be avoided, and active surveillance methods for CAPA are essential for those high-risk patients.

[COVID-19-associated pulmonary aspergillosis in critically ill patients: experience of a Chilean public hospital]. / Aspergilosis pulmonar asociada a COVID-19 en pacientes críticos: experiencia de un hospital público chileno.

BACKGROUND: Aspergillus spp. fungal coinfections have been described in critically ill COVID-19 patients. AIM: To describe the clinical characteristics, diagnosis, treatment and evolution of patients with acute respiratory distress syndrome with COVID-19, who present with COVID-19 associated pulmonary aspergillosis (CAPA) in a single public hospital. METHODS: Retrospective review of clinical records during 12 months in patients diagnosed with CAPA by cultures of respiratory samples or determination of galactomannan (GM). RESULTS: Probable CAPA was diagnosed in 11 patients (average APACHE II score of 11.7). Respiratory samples were obtained in 73% of cases by bronchoalveolar lavage and in 27% by tracheal aspirate. A. fumigatus was isolated in 4 cultures, A. niger, A. terreus and Aspergillus spp on one occasion each and the cultures were negative in 4 samples. Respiratory sample GM was performed in 7 patients, median: 3.6 (IQR: 1.71 - 4.4). In 10 patients, serum GM was performed, median: 0.5 (IQR: 0.265 - 0.9 75) with 50% of them > 0.5. Two patients showed classic findings suggestive of CAPA on computed tomography. All received antifungal therapy with voriconazole, mean time 14 days. Four patients died. CONCLUSIONS: The presence of CAPA should be a diagnosis to be considered in critically ill COVID-19 patients.

Navigating the Uncertainties of COVID-19-Associated Aspergillosis: A Comparison With Influenza-Associated Aspergillosis.

Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a life-threatening superinfection of severe respiratory viral infections, such as influenza. The pandemic of Coronavirus Disease 2019 (COVID-19) due to emerging SARS-CoV-2 rose concern about the eventuality of IPA complicating COVID-19 in intensive care unit patients. A variable incidence of such complication has been reported, which can be partly attributed to differences in diagnostic strategy and IPA definitions, and possibly local environmental/epidemiological factors. In this article, we discuss the similarities and differences between influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA). Compared to IAPA, the majority of CAPA cases have been classified as putative rather than proven/probable IPA. Distinct physiopathology of influenza and COVID-19 may explain these discrepancies. Whether CAPA represents a distinct entity is still debatable and many questions remain unanswered, such as its actual incidence, the predisposing role of corticosteroids or immunomodulatory drugs, and the indications for antifungal therapy.

COVID-19-associated pulmonary aspergillosis in a tertiary care center in Shenzhen City.

OBJECTIVES: The severe coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome (ARDS) and risk of fungal co-infection, pulmonary aspergillosis in particular. However, COVID-19 associated pulmonary aspergillosis (CAPA) cases remain limited due to the difficulty in diagnosis. METHODS: We describe presumptive invasive aspergillosis in eight patients diagnosed with COVID-19 in a single center in Shenzhen, China. Data collected include underlying conditions, mycological findings, immunodetection results, therapies and outcomes. RESULTS: Four of the eight patients had tested positive for Aspergillus by either culture or Next-generation sequencing analysis of sputum or bronchoalveolar lavage fluid (BALF), while the rest of patients had only positive results in antigen or antibody detection. Although all patients received antifungal therapies, six of these eight patients (66.7%) died. CONCLUSION: Due to the high mortality rate of CAPA, clinical care in patients with CAPA deserves more attention.

Invasive aspergillosis in coronavirus disease 2019: a practical approach for clinicians.

PURPOSE OF REVIEW: Invasive pulmonary aspergillosis (IPA) can affect patients with severe coronavirus disease 2019 (COVID-19), but many questions remain open about its very variable incidence across the world, the actual link between the viral infection and the fungal superinfection, the significance of Aspergillus recovery in a respiratory sample, and the management of such cases. This review addresses these questions and aims at providing some clues for the practical diagnostic and therapeutic approaches of COVID-19-associated pulmonary aspergillosis (CAPA) in a clinical perspective. RECENT FINDINGS: Definitions have been proposed for possible/probable/proven CAPA, but distinction between colonization and invasive fungal infection is difficult and not possible in most cases in the absence of histopathological proof or positive galactomannan in serum. Most importantly, the recovery of an Aspergillus by a direct (culture, PCR) or indirect (galactomannan) test in a respiratory sample is an indicator of worse outcome, which justifies a screening for early detection and initiation of preemptive antifungal therapy in such cases. SUMMARY: The COVID-19 pandemic has increased our awareness of IPA among ICU patients. Although current recommendations are mainly based on experts' opinions, prospective studies are needed to get more evidence-based support for the diagnostic approach and management of CAPA.

COVID-19 Infection and Late Manifestation of Pulmonary Aspergillosis.

We present the case of a 56-year-old woman who was diagnosed with severe coronavirus disease 2019 (COVID-19) pneumonia complicated by severe acute respiratory distress syndrome who was intubated for 19 days. She recovered from COVID-19 after a month. A computed tomography (CT) scan of the chest, after a month, showed improved infiltrates with a small residual cavity within the lingula. A CT angiogram showed a more confluent density in the lingular portion on follow-up 2 months later. She developed intermittent hemoptysis after 3 months in December 2020, which persisted for almost 6 months, and CT of the chest showed the lingular nodular with resolution of the cavitation. She underwent bronchoscopy with bronchoalveolar lavage, confirming Aspergillus fumigatus by galactomannan assay and histology showing branching hyphae. Once she started treatment with itraconazole, her hemoptysis resolved. The follow-up CT of the chest after 2 months of treatment did not show a cavity or a nodule in the lingula. Our patient developed invasive pulmonary aspergillosis (IPA) as a sequela of severe COVID-19 infection. COVID-19-associated invasive pulmonary aspergillosis (CAPA) is an underrecognized complication that needs to be investigated on whether prophylactic treatment is required. Our case also demonstrates that the diagnosis of IPA needs to be considered months after COVID-19 infection when a superimposed fungal infection can occur after a viral infection if the patient continues to have persistent symptoms.

A 67-Year-Old Male Patient With COVID-19 With Worsening Respiratory Function and Acute Kidney Failure.

CASE PRESENTATION: A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.

COVID-19-Associated Pulmonary Aspergillosis, Fungemia, and Pneumocystosis in the Intensive Care Unit: a Retrospective Multicenter Observational Cohort during the First French Pandemic Wave.

The aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) (P < 10-4). For CAPA, the presence of several mycological criteria was associated with death (P < 10-4). Serum galactomannan was rarely positive (<20%). The mortality rates were 76.7% (23/30) in patients with host factors for invasive fungal disease, 45.2% (14/31) in those with a preexisting pulmonary condition, and 36.6% (34/93) in the remaining patients (P = 0.001). Antimold treatment did not alter prognosis (P = 0.370). Candida albicans was responsible for 59.3% of CA-fungemias, with a global mortality of 45.7%. For CA-PCP, 58.8% of the episodes occurred in patients with known host factors of PCP, and the mortality rate was 29.5%. CAPA may be in part hospital acquired and could benefit from antifungal prescription at the first positive biomarker result. CA-fungemia appeared linked to ICU stay without COVID-19 specificity, while CA-PCP may not really be a concern in the ICU. Improved diagnostic strategy for fungal markers in ICU patients with COVID-19 should support these hypotheses. IMPORTANCE To diagnose fungal coinfections in patients with COVID-19 in the intensive care unit, it is necessary to implement the correct treatment and to prevent them if possible. For COVID-19-associated pulmonary aspergillosis (CAPA), respiratory specimens remain the best approach since serum biomarkers are rarely positive. Timing of occurrence suggests that CAPA could be hospital acquired. The associated mortality varies from 36.6% to 76.7% when no host factors or host factors of invasive fungal diseases are present, respectively. Fungemias occurred after 2 weeks in ICUs and are associated with a mortality rate of 45.7%. Candida albicans is the first yeast species recovered, with no specificity linked to COVID-19. Pneumocystosis was mainly found in patients with known immunodepression. The diagnosis occurred at the entry in ICUs and not afterwards, suggesting that if Pneumocystis jirovecii plays a role, it is upstream of the hospitalization in the ICU.

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.

Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis.

PURPOSE: Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance. METHODS: A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology. RESULTS: The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients' clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients. CONCLUSION: CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.