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Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are increasingly recognised as important complications in patients requiring intensive care for severe viral pneumonia. The diagnosis can typically be made in 10-20% of patients with severe influenza or COVID-19, but only when appropriate diagnostic tools are used. Bronchoalveolar lavage sampling for culture, galactomannan testing, and PCR forms the cornerstone of diagnosis, whereas visual examination of the tracheobronchial tract during bronchoscopy is required to detect invasive Aspergillus tracheobronchitis. Azoles are the first-choice antifungal drugs, with liposomal amphotericin B as an alternative in settings where azole resistance is prevalent. Despite antifungal therapy, IAPA and CAPA are associated with poor outcomes, with fatality rates often exceeding 50%. In this Review, we discuss the mechanistic and clinical aspects of IAPA and CAPA. Moreover, we identify crucial knowledge gaps and formulate directions for future research., Competing Interests: Declaration of interests SF received travel grants for conference attendance from Pfizer and Gilead and a speakers' fee from The Healthbook Company. AC received speakers' fees from Gilead. CJC reports research grants from Merck and Cidara; consulting fees or participation on advisory boards for Shionogi, Scynexis, and Venatorx; and lecture honoraria from Gilead. J-PG received consultancy and speaker fees from Gilead, Mundipharma, and Pfizer. MH received grants and research funding from Astellas, Gilead, MSD, Pfizer, Euroimmun, F2G, Pulmocide, AiCuris, Partners, IMMY, Melinta, Mundipharma, Shionogi, and Scynexis. KL received consultancy fees from MRM Health and Mundipharma; speakers' fees from Pfizer and Gilead; a service fee paid to the institution from Thermo Fisher Scientific and TECOmedical; and fees for advisory board participation from MSD and Pfizer. BJAR received research grants from Gilead; consulting fees from F2G; payment for lectures from Gilead; support for attending meetings from Pfizer, Gilead, and F2G; and reports participation on a data safety monitoring and advisory board for Exevir. LV received support for a public doctoral defence from Pfizer; and travel support from Gilead and Pfizer for conference attendance. PEV received research grants from F2G and Gilead; and speakers' fees from Mundipharma, F2G, Gilead, and Pfizer. JW received an institutional research fund from Pfizer; investigator-initiated grants from Pfizer, Gilead, and MSD; speakers' and travel fees from Pfizer, Gilead, and MSD; declares participation in advisory boards of Pfizer and Gilead; and declares receipt of study drugs from MSD. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

During the COVID-19 pandemic, many patients in intensive care units (ICUs) were affected by invasive fungal infections, including aspergillosis, contributing to a high mortality rate. Diagnosing proven COVID-19-associated pulmonary aspergillosis (CAPA) requires clinical and radiological evaluations, along with laboratory testing of bronchoalveolar lavage samples or lung biopsies. However, these procedures and equipment are often inaccessible in developing countries or regions with limited resources, including Brazil. Consequently, alternative diagnostic methods, such as measuring Aspergillus galactomannan (GM) in tracheal aspirate (TA), have been explored for CAPA diagnosis. Nonetheless, research on the efficacy of TA-based diagnostic tests is limited. This study aimed to assess the performance of the IMMY® Sona Aspergillus lateral flow assay (LFA) for GM detection in TA samples from 60 ICU patients with suspected CAPA at two tertiary hospitals in Campo Grande, Brazil. The ELISA method (Platelia Aspergillus AG, Bio-Rad®) was used to detect Aspergillus GM in TA samples, serving as the microbiological criterion and reference test. Fifteen patients (12.4%) were identified as having possible CAPA. The overall accuracy of LFA was 94%, and the tests demonstrated an agreement of 93.1% (Cohen's kappa of 0.83). Based on our findings, the LFA for Aspergillus GM detection in TA samples exhibited excellent performance, proving to be a valuable diagnostic tool for potential CAPA. In a systematic review, two studies were included, and the meta-analysis revealed pooled estimates provided a sensitivity of 86% (95% CI, 80%-91%) and specificity of 93% (95% CI, 86%-97%). The diagnostic odds ratio (DOR) for identification of Aspergillus using LFA was 103.38 (95% CI, 38.03-281.03). Despite its lower sensitivity compared to our study, the LFA appears to be a promising diagnostic option for CAPA, particularly in suspected cases that have not received antifungal therapy. This enables timely antifungal treatment and could reduce mortality rates in regions where bronchoscopy is unavailable or limited., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus type 2, which is characterized by high infectiousness and diverse clinical manifestations. They are more likely to become critical in people who have underlying diseases or are immunocompromised. In the daunting task of treating patients with COVID-19, those with comorbid fungal infections are susceptible to underdiagnosis or misdiagnosis, which can ultimately lead to increased morbidity and mortality in this group of patients. We report a case of intrapulmonary cavitary lesions after COVID-19, which was eventually diagnosed as pulmonary aspergillosis (PA) by metagenomic Next Generation Sequencing (mNGS) to improve our understanding of the disease., Methods: Appropriate laboratory tests, chest computed tomography (CT), mNGS, and serologic tests were performed for diagnosis., Results: Laboratory tests showed Glactomannan (GM) of 1.41, multiple cavitary lesions in both lungs on chest CT and the presence of aspergillus infection was confirmed by sputum sent for mNGS., Conclusions: In the case of cavitary lesions after COVID-19, we should be alert to the possibility of combined fungi and should promptly perform mNGS to clarify whether there is a combination of specific pathogenic fungal infections.

Introduction: Over the last years, severe respiratory viral infections, particularly those caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the influenza virus, have emerged as risk factor for viral-associated pulmonary aspergillosis (VAPA) among critically ill patients. Delays in diagnosis of VAPA are associated with increased mortality. Point-of-care-tests may play an important role in earlier diagnosis of VAPA and thus improve patient outcomes., Areas Covered: The following review will give an update on point-of-care tests for VAPA, analyzing performances in respiratory and blood specimens., Expert Opinion: Point-of-care tests have emerged, and particularly the IMMY Aspergillus galactomannan lateral flow assay (LFA) shows performances comparable to the galactomannan ELISA for diagnosis of VAPA. Notably, nearly all evaluations of POC tests for VAPA have been performed in COVID-19 patients, with very limited data in influenza patients. For early diagnosis of COVID associated pulmonary aspergillosis (CAPA), the LFA has shown promising performances in respiratory samples, particularly in bronchoalveolar lavage fluid, and may thereby help in improving patient outcomes. In contrast, serum LFA testing may not be useful for early diagnosis of disease, except in cases with invasive tracheobronchial aspergillosis.

Among the co-infectious agents in COVID-19 patients, Aspergillus species cause invasive pulmonary aspergillosis (IPA). IPA is difficult to diagnose and is associated with high morbidity and mortality. This study is aimed at identifying Aspergillus spp. from sputum and tracheal aspirate (TA) samples of COVID-19 patients and at determining their antifungal susceptibility profiles. A total of 50 patients with COVID-19 hospitalized in their intensive care units (ICU) were included in the study. Identification of Aspergillus isolates was performed by phenotypic and molecular methods. ECMM/ISHAM consensus criteria were used for IPA case definitions. The antifungal susceptibility profiles of isolates were determined by the microdilution method. Aspergillus spp. was detected in 35 (70%) of the clinical samples. Among the Aspergillus spp., 20 (57.1%) A. fumigatus, six (17.1%) A. flavus, four (11.4%) A. niger, three (8.6%) A. terreus, and two (5.7%) A. welwitschiae were identified. In general, Aspergillus isolates were susceptible to the tested antifungal agents. In the study, nine patients were diagnosed with possible IPA, 11 patients were diagnosed with probable IPA, and 15 patients were diagnosed with Aspergillus colonization according to the used algorithms. Serum galactomannan antigen positivity was found in 11 of the patients diagnosed with IPA. Our results provide data on the incidence of IPA, identification of Aspergillus spp., and its susceptibility profiles in critically ill COVID-19 patients. Prospective studies are needed for a faster diagnosis or antifungal prophylaxis to manage the poor prognosis of IPA and reduce the risk of mortality., (© 2023. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Introduction: During the Omicron pandemic in China, a significant proportion of patients with Coronavirus Disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) necessitated admission to intensive care unit (ICU) and experienced a high mortality. To explore the clinical risk factors and the application/indication of microbiological examinations of CAPA in ICU for timely diagnosis are very important., Methods: This prospective study included patients with COVID-19 admitted to ICU between December 1, 2022, and February 28, 2023. The clinical data of influenza-associated pulmonary aspergillosis (IAPA) patients from the past five consecutive influenza seasons (November 1, 2017, to March 31, 2022) were collected for comparison. The types of specimens and methods used for microbiological examinations were also recorded to explore the efficacy in early diagnosis., Results: Among 123 COVID-19 patients, 36 (29.3%) were diagnosed with probable CAPA. CAPA patients were more immunosuppressed, in more serious condition, required more advanced respiratory support and had more other organ comorbidities. Solid organ transplantation, APACHEII score ≥20 points, 5 points ≤SOFA score <10 points were independent risk factors for CAPA. Qualified lower respiratory tract specimens were obtained from all patients, and 84/123 (68.3%) patients underwent bronchoscopy to obtain bronchoalveolar lavage fluid (BALF) specimens. All patients' lower respiratory tract specimens underwent fungal smear and culture; 79/123 (64.2%) and 69/123 (56.1%) patients underwent BALF galactomannan (GM) and serum GM detection, respectively; metagenomic next-generation sequencing (mNGS) of the BALF was performed in 62/123 (50.4%) patients. BALF GM had the highest diagnostic sensitivity (84.9%), the area under the curve of the mNGS were the highest (0.812)., Conclusion: The incidence of CAPA was extremely high in patients admitted to the ICU. CAPA diagnosis mainly depends on microbiological evidence owing to non-specific clinical manifestations, routine laboratory examinations, and CT findings. The bronchoscopy should be performed and the BALF should be obtained as soon as possible. BALF GM are the most suitable microbiological examinations for the diagnosis of CAPA. Due to the timely and accuracy result of mNGS, it could assist in early diagnosis and might be an option in critically ill CAPA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Wu, Chen, Cui, Cai, Liu, Weng, Zhan and Huang.)

COVID-19-Associated Pulmonary Aspergillosis (CAPA) is a relatively common complication in patients with severe forms of the disease caused by the SARS-CoV-2 virus. Diagnosing and confirming CAPA is challenging. In this study, Aspergillus spp. isolation in respiratory specimens from patients with COVID-19 was evaluated for identifying cases of CAPA. In 2020‒2021, 17 Aspergillus spp. were isolated from 15 COVID-19 patients admitted to a university hospital in Brazil. Patient records were retrospectively reviewed to obtain clinical-epidemiological data and other markers of Aspergillus spp. infection and then compared with the ECMM/ISHAM criteria for defining CAPA. Probable CAPA was defined in 5/10 patients, who had Aspergillus spp. isolated from Bronchoalveolar Lavage (BAL) or a positive galactomannan blood test. Additionally, anti-Aspergillus antibodies were detected in two of these patients, during active or follow-up phases of CAPA. In another seven patients with Aspergillus spp. isolated from tracheobronchial aspirate or sputum, CAPA was presumed, mainly due to deterioration of clinical conditions and new lung imaging suggestive of fungal infection. Antifungal agents to control CAPA, particularly voriconazole, were used in 9/15 cases. In cases of probable CAPA and remaining patients, clinical conditions and comorbidities were similar, with lethality being high, at 60% and 71%, respectively. The number of CAPA cases defined by scientific criteria was lower than that assumed in the clinical context. This was largely due to the lack of BAL collection for fungal culture and the non-intensive use of other markers of invasive aspergillosis. The isolation of Aspergillus spp. in different respiratory specimens should alert clinicians to the diagnosis of CAPA., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Aspergillus is one of the important pathogens that contribute to high mortality in patients with coronavirus disease 2019 (COVID-19) in intensive care units (ICUs). Although incidence rates of Aspergillus coinfection are high globally, a Japanese national survey reported a low incidence. This study aimed to describe the clinical characteristics of patients with COVID-19-associated pulmonary aspergillosis at our institute., Methods: We identified patients with microbiologically confirmed COVID-19 on mechanical ventilation in the ICU. Of these patients, we identified patients in whom Aspergillus was cultured from the respiratory specimen., Results: Of a total of 169 patients, seven had aspergillosis (4.1%), which included three patients, three patients, and one patient with possible, probable, and proven aspergillosis, respectively, according to the criteria of the European Confederation of Medical Mycology International Society. All patients received systemic steroid therapy. Two patients (one each with proven and probable aspergillosis) had tracheobronchitis diagnosed by bronchoscopy. All patients in whom Aspergillus was repeatedly isolated from samples died. The mortality rates for all cases and probable and proven cases were 57% (4/7) and 75% (3/4), respectively., Conclusions: The incidence rate of aspergillosis in patients with COVID-19 in the ICU was higher in our institute than that reported by a Japanese national survey (4.1% vs. 0.5%). Repeated detection of Aspergillus might suggest a true Aspergillus infection, such as chronic aspergillosis, rather than colonization. In patients with severe COVID-19 patients, it is important to always keep CAPA in mind., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Since February 2021 active screening of COVID-19-associated pulmonary aspergillosis (CAPA) has been implemented in our institution., Objectives: To evaluate CAPA incidence in our centre and evaluate performance of our screening protocol., Methods: We screened once per week, collecting endotracheal aspirates for fungal culture and galactomannan (GM) and serum for 1,3-ß-D-glucan (BG). In case of positivity (GM more than 4.5, platelia assay, and/or BG >7 pg/ml, wako and/or positive fungal culture), second-level investigations were performed to pursue CAPA diagnosis according to ECMM/ISHAM criteria: bronchoalveolar lavage (BAL) fungal culture and GM, chest computed tomography (CT), serum GM., Results: A total of 102 patients were screened (median age 64 years, range 39-79; 28 (27.4%) females). Twenty-two patients were diagnosed with CAPA (21%). 12 patients were positive for serum BG, 17 patients were positive for endotracheal aspirates GM and 27 patients were positive for endotracheal aspirates fungal culture. Thirty-two BALs were performed, and 26 patients underwent CT chest. Following the second level investigations 61% of the patients with positive screening tests were diagnosed with CAPA. Serum BG above 20 pg/ml or positive serum GM were always associated with typical CT chest signs of aspergillosis. Compared with 1 single positive test, having 2 positive screening test was significantly more associated with CAPA diagnosis (p = .0004)., Conclusions: Active CAPA screening with serum 1,3-ß-D-glucan and endotracheal aspirates galactomannan and fungal cultures and consequent second level investigations led to high number of CAPA diagnosis. Combining more positive fungal biomarkers was more predictive of CAPA diagnosis., (© 2022 Wiley-VCH GmbH.)

Aspergillus spp. isolated from non-BAL cultures of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) patients may reflect colonization rather than infection. Sera (n = 181) from 49 adult ICU CAPA patients (24 probable and 25 possible CAPA) with bronchial secretions (BS) culture positive for Aspergillus spp. were collected and tested for Aspergillus DNA detection by species-specific real-time PCR. Overall, 30/49 (61%) patients were PCR positive. BS culture/serum PCR agreement was moderate (21/30; 70%). Based on serum PCR positive patients, all CAPAs were due to A. fumigatus (80%), A. flavus (10%), and A. terreus (10%). No A. niger/A. nidulans or mixed infections were found despite positive BS cultures., (© The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

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., Competing Interests: Conflict of interest: F. Lamoth has research funding from Gilead, MSD, Pfizer and Novartis, and has participated in Advisory boards for Gilead, MSD and Pfizer. All contracts were made with and fees paid to his institution (CHUV). Conflict of interest: T. Calandra has participated in advisory boards or consulted for Menarini, Shinogi, Cytosorbent, ThermoFisher and GE Healthcare for projects unrelated to the submitted work and on data safety monitoring boards for Cidara and Novartis. All contracts were made with and fees paid to his institution (CHUV)., (Copyright ©The authors 2022.)

Background: Invasive pulmonary aspergillosis (IPA) is seen during coronavirus-2019 (COVID-19), has been reported in different incidences, and is defined as COVID-19-associated pulmonary aspergillosis (CAPA). Detection of galactomannan antigen is an important diagnostic step in diagnosing IPA. Enzyme-linked immunoassay (ELISA) is the most frequently used method, and lateral flow assay (LFA) is increasingly used with high sensitivity and specificity for rapid diagnosis. The present study aimed to compare the sensitivity of LFA and ELISA in the diagnosis of CAPA in COVID-19 patients followed in our hospital's ICU for pandemic (ICU-P)., Methods: This study included patients with a diagnosis of COVID-19 cases confirmed by polymerase chain reaction and were followed up in ICU-P between August 2021 and February 2022 with acute respiratory failure. The diagnosis of CAPA was based on the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology 2020 (ECMM/ ISHAM) guideline. Galactomannan levels were determined using LFA and ELISA in serum samples taken simultaneously from the patients., Results: Out of the 174 patients followed in the ICU-P, 56 did not meet any criteria for CAPA and were excluded from the analysis. The rate of patients diagnosed with proven CAPA was 5.7% (10 patients). A statistically significant result was obtained with LFA for the cut-off value of 0.5 ODI in the diagnosis of CAPA (p < 0.001). The same significant statistical relationship was found for the cut-off value of 1.0 ODI for the ELISA (p < 0.01). The sensitivity of LFA was 80% (95% CI: 0.55-1.05, p < 0.05), specificity 94% (95% CI: 0.89-0.98, p < 0.05); PPV 53% (95% CI: 0.28-0.79, p > 0.05) and NPV was 98% (95% CI: 0.95-1.01, p < 0.05). The risk of death was 1.66 (HR: 1.66, 95% CI: 1.02-2.86, p < 0.05) times higher in patients with an LFA result of ≥ 0.5 ODI than those with < 0.5 (p < 0.05)., Conclusions: It is reckoned that LFA can be used in future clinical practice, particularly given its effectiveness in patients with hematological malignancies and accuracy in diagnosing CAPA., (© 2022. The Author(s).)

Purpose of Review: Coronavirus disease (COVID-19)-associated pulmonary aspergillosis (CAPA) may concern up to one third of intensive care unit (ICU) patients. The purpose of this review is to discuss the diagnostic criteria, the pathogenesis, the risk factors, the incidence, the impact on outcome, and the diagnostic and therapeutic management of CAPA in critically ill patients., Recent Findings: The incidence of CAPA ranges 3--28% of critically ill patients, depending on the definition used, study design, and systematic or triggered screening. COVID-19 is associated with direct damage of the respiratory epithelium, immune dysregulation, and common use of immunosuppressive drugs which might promote Aspergillus respiratory tract colonization and invasion. Positive Aspergillus tests among COVID-19 critically patients might reflect colonization rather than invasive disease. CAPA usually appears during the second week after starting invasive mechanical ventilation and is independently associated with ICU mortality., Summary: Further studies are needed to validate CAPA case definitions, to determine the accurate incidence of CAPA in comparison to adequate controls, and its evolution during the pandemic. A pro-active diagnostic strategy, based on risk stratification, clinical assessment, and bronchoalveolar lavage could be recommended to provide early antifungal treatment in patients with high probability of CAPA and clinical deterioration., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Coronavirus disease-2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a new disease characterized by secondary Aspergillus mold infection in patients with COVID-19. It primarily affects patients with COVID-19 in critical state with acute respiratory distress syndrome, requiring intensive care and mechanical ventilation. CAPA has a higher mortality rate than COVID-19, posing a serious threat to affected individuals. COVID-19 is a potential risk factor for CAPA and has already claimed a massive death toll worldwide since its outbreak in December 2019. Its second wave is currently progressing towards a peak, while the third wave of this devastating pandemic is expected to follow. Therefore, an early and accurate diagnosis of CAPA is of utmost importance for effective clinical management of this highly fatal disease. However, there are no uniform criteria for diagnosing CAPA in an intensive care setting. Therefore, based on a review of existing information and our own experience, we have proposed new criteria in the form of practice guidelines for diagnosing CAPA, focusing on the points relevant for intensivists and pulmonary and critical care physicians. The main highlights of these guidelines include the role of CAPA-appropriate test specimens, clinical risk factors, computed tomography of the thorax, and non-culture-based indirect and direct mycological evidence for diagnosing CAPA in the intensive care unit. These guidelines classify the diagnosis of CAPA into suspected, possible, and probable categories to facilitate clinical decision-making. We hope that these practice guidelines will adequately address the diagnostic challenges of CAPA, providing an easy-to-use and practical algorithm to clinicians for rapid diagnosis and clinical management of the disease.

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.

Background: Pulmonary aspergillosis may complicate coronavirus disease 2019 (COVID-19) and contribute to excess mortality in intensive care unit (ICU) patients. The disease is poorly understood, in part due to discordant definitions across studies., Objectives: We sought to review the prevalence, diagnosis, treatment, and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA) and compare research definitions., Data Sources: PubMed, Embase, Web of Science, and MedRxiv were searched from inception to October 12, 2021., Study Eligibility Criteria: ICU cohort studies and CAPA case series including ≥3 patients were included., Participants: Adult patients in ICUs with COVID-19., Interventions: Patients were reclassified according to four research definitions. We assessed risk of bias with an adaptation of the Joanna Briggs Institute cohort checklist tool for systematic reviews., Methods: We calculated CAPA prevalence using the Freeman-Tukey random effects method. Correlations between definitions were assessed with Spearman's rank test. Associations between antifungals and outcome were assessed with random effects meta-analysis., Results: Fifty-one studies were included. Among 3297 COVID-19 patients in ICU cohort studies, 313 were diagnosed with CAPA (prevalence 10%; 95% CI 8%-13%). Two hundred seventy-seven patients had patient-level data allowing reclassification. Definitions had limited correlation with one another (ρ = 0.268-0.447; p < 0.001), with the exception of Koehler and Verweij (ρ = 0.893; p < 0.001); 33.9% of patients reported to have CAPA did not fulfill any research definitions. Patients were diagnosed after a median of 8 days (interquartile range 5-14) in ICUs. Tracheobronchitis occurred in 3% of patients examined with bronchoscopy. The mortality rate was high (59.2%). Applying CAPA research definitions did not strengthen the association between mould-active antifungals and survival., Conclusions: The reported prevalence of CAPA is significant but may be exaggerated by nonstandard definitions., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aspergillosis is a disease caused by Aspergillus , and invasive pulmonary aspergillosis (IPA) is the most common invasive fungal infection leading to death in severely immuno-compromised patients. The literature reports Aspergillus co-infections in patients with COVID-19 (CAPA). Diagnosing CAPA clinically is complex since the symptoms are non-specific, and performing a bronchoscopy is difficult. Generally, the microbiological diagnosis of aspergillosis is based on cultural methods and on searching for the circulating antigens galactomannan and 1,3-β-D-glucan in the bronchoalveolar lavage fluid (bGM) or serum (sGM). In this study, to verify whether the COVID-19 period has stimulated clinicians to pay greater attention to IPA in patients with respiratory tract infections, we evaluated the number of requests for GM-Ag research and the number of positive tests found during the pre-COVID-19 and COVID-19 periods. Our data show a significant upward trend in GM-Ag requests and positivity from the pre-COVID to COVID period, which is attributable in particular to the increase in IPA risk factors as a complication of COVID-19. In the COVID period, parallel to the increase in requests, the number of positive tests for GM-Ag also increased, going from 2.5% in the first period of 2020 to 12.3% in the first period of 2021.

COVID-19-associated pulmonary aspergillosis (CAPA) incidence varies depending on the country. Serum galactomannan quantification is a promising diagnostic tool since samples are easy to obtain with low biosafety issues. A multicenter prospective study was performed to evaluate the CAPA incidence in Argentina and to assess the performance of the lateral flow assay with digital readout (Sōna Aspergillus LFA) as a CAPA diagnostic and screening tool. The correlation between the values obtained with Sōna Aspergillus LFA and Platelia® EIA was evaluated. In total, 578 serum samples were obtained from 185 critically ill COVID patients. CAPA screening was done weekly starting from the first week of ICU stay. Probable CAPA incidence in critically ill patients was 10.27% (19/185 patients when LFA was used as mycological criteria) and 9% (9/100 patients when EIA was used as mycological criteria). We found a very good correlation between the two evaluated galactomannan quantification methods (overall agreement of 92.16% with a Kappa statistic value of 0.721). CAPA diagnosis (>0.5 readouts in LFA) were done during the first week of ICU stay in 94.7% of the probable CAPA patients. The overall mortality was 36.21%. CAPA patients' mortality and length of ICU stay were not statistically different from for COVID (non-CAPA) patients (42.11 vs 33.13% and 29 vs 24 days, respectively). These indicators were lower than in other reports. LFA-IMMY with digital readout is a reliable tool for early diagnosis of CAPA using serum samples in critically ill COVID patients. It has a good agreement with Platelia® EIA., Lay Summary: The incidence of COVID-associated pulmonary aspergillosis (CAPA) in critically-ill Argentinian patients was established (10.27%). Serum galactomannan quantification was useful as a screening tool for this mycosis. A good agreement between Platelia® EIA and Sōna Aspergillus LFA is reported., (© The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

As the global SARS-CoV-2 pandemic continues to plague healthcare systems, it has become clear that opportunistic pathogens cause a considerable proportion of SARS-CoV-2-associated mortality and morbidity cases. Of these, Covid-Associated Pulmonary Aspergilliosis (CAPA) is a major concern with evidence that it occurs in the absence of traditional risk factors such as neutropenia and is diagnostically challenging for the attending physician. In this review, we focus on the immunopathology of SARS-CoV-2 and how this potentiates CAPA through dysregulation of local and systemic immunity as well as the unintended consequences of approved COVID treatments including corticosteroids and IL-6 inhibitors. Finally, we will consider how knowledge of the above may aid in the diagnosis of CAPA using current diagnostics and what treatment should be instituted in probable and confirmed cases.

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., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This multicenter study evaluated the IMMY Aspergillus Galactomannan Lateral Flow Assay (LFA) with automated reader for diagnosis of pulmonary aspergillosis in patients with COVID-19-associated acute respiratory failure (ARF) requiring intensive care unit (ICU) admission between 03/2020 and 04/2021. A total of 196 respiratory samples and 148 serum samples ( n  = 344) from 238 patients were retrospectively included, with a maximum of one of each sample type per patient. Cases were retrospectively classified for COVID-19-associated pulmonary aspergillosis (CAPA) status following the 2020 consensus criteria, with the exclusion of LFA results as a mycological criterion. At the 1.0 cutoff, sensitivity of LFA for CAPA (proven/probable/possible) was 52%, 80% and 81%, and specificity was 98%, 88% and 67%, for bronchoalveolar lavage fluid (BALF), nondirected bronchoalveolar lavage (NBL), and tracheal aspiration (TA), respectively. At the 0.5 manufacturer's cutoff, sensitivity was 72%, 90% and 100%, and specificity was 79%, 83% and 44%, for BALF, NBL and TA, respectively. When combining all respiratory samples, the receiver operating characteristic (ROC) area under the curve (AUC) was 0.823, versus 0.754, 0.890 and 0.814 for BALF, NBL and TA, respectively. Sensitivity and specificity of serum LFA were 20% and 93%, respectively, at the 0.5 ODI cutoff. Overall, the Aspergillus Galactomannan LFA showed good performances for CAPA diagnosis, when used from respiratory samples at the 1.0 cutoff, while sensitivity from serum was limited, linked to weak invasiveness during CAPA. As some false-positive results can occur, isolated results slightly above the recommended cutoff should lead to further mycological investigations.

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.

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., (© 2021. The Author(s).)

Pulmonary aspergillosis has been reported at high rates in patients with coronavirus disease 2019 (COVID-19) and is associated with high morbidity and mortality. We retrospectively assessed all patients admitted to an intensive care unit during the early COVID-19 surge (3/17/20-5/10/20) at our medical center in the midwestern USA for the presence of COVID-19-associated pulmonary aspergillosis (CAPA). Patients were not routinely screened for CAPA; diagnostic work-up for fungal infections was pursued when clinically indicated. Among 256 patients admitted to the ICU with severe COVID-19, 188 (73%) were intubated and 62 (24%) ultimately expired within 30 days of admission to the ICU. Only three patients (1%) were found to have CAPA; diagnosis was made by tracheal aspirate cultures in two cases and by bronchoalveolar lavage fluid Aspergillus galactomannan in one case. None of the patients who developed CAPA had classic risk factors for invasive fungal infection. The occurrence of CAPA was much lower than that reported at other centers, likely reflecting the local epidemiology., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Our aim was to evaluate the performance of two galactomannan (GM) assays (Platelia Aspergillus EIA, Bio-Rad ® , and Aspergillus GM LFA, IMMY ® ) in tracheal aspirate (TA) samples of consecutive critically ill patients with COVID-19., Methods: We included critically ill patients, performed GM-EIA and GM-Lateral Flow Assay (GM-LFA) in TA and followed them until development of COVID-19-associated pulmonary aspergillosis (CAPA) or alternate diagnosis. CAPA was defined according to the modified AspICU criteria in patients with SARS-CoV-2 infection. We estimated sensitivity, specificity, positive and negative predictive values for GM-EIA, GM-LFA, the combination of both or either positive results for GM-EIA and GM-LFA. We explored accuracy using different breakpoints, through ROC analysis and Youden index to identify the optimal cut-offs. We described antifungal treatment and 30-day mortality., Results: We identified 14/144 (9.7%) patients with CAPA, mean age was 50.35 (SD 11.9), the median time from admission to CAPA was 8 days; 28.5% received tocilizumab and 30-day mortality was 57%. ROC analysis and Youden index identified 2.0 OD as the best cut-off, resulting in sensitivity and specificity of 57.1% and 81.5% for GM-EIA and 60% and 72.6% for GM-LFA, respectively., Conclusions: The diagnostic performance of GM in tracheal aspirates improved after using a cut-off of 2 OD. Although bronchoalveolar lavage testing is the ideal test, centres with limited access to bronchoscopy may consider this approach to identify or rule out CAPA., (© 2020 Wiley-VCH GmbH.)

Pneumonia caused by severe acute respiratory syndrome coronavirus 2 emerged in China at the end of 2019. Because of the severe immunomodulation and lymphocyte depletion caused by this virus and the subsequent administration of drugs directed at the immune system, we anticipated that patients might experience fungal superinfection. We collected data from 186 patients who had coronavirus disease-associated pulmonary aspergillosis (CAPA) worldwide during March-August 2020. Overall, 182 patients were admitted to the intensive care unit (ICU), including 180 with acute respiratory distress syndrome and 175 who received mechanical ventilation. CAPA was diagnosed a median of 10 days after coronavirus disease diagnosis. Aspergillus fumigatus was identified in 80.3% of patient cultures, 4 of which were azole-resistant. Most (52.7%) patients received voriconazole. In total, 52.2% of patients died; of the deaths, 33.0% were attributed to CAPA. We found that the cumulative incidence of CAPA in the ICU ranged from 1.0% to 39.1%.

Objectives: With the outbreak of coronavirus disease 2019 (COVID-19), clinicians have used personal protective equipment to avoid transmission of severe acute respiratory syndrome coronavirus 2. However, they still face occupational risk of infection, when treating COVID-19 patients. This may be highest during invasive diagnostic procedures releasing aerosols and droplets. Thereby, the use of diagnostic procedures for Covid-19 associated aspergillosis may be delayed or impeded, as use of bronchoscopy has been discouraged. This leads to avoidance of a crucial procedure for diagnosing invasive aspergillosis. We intent to visualise aerosol and droplet spread and surface contamination during bronchoscopy and address which measures can avoid exposure of health-care workers., Methods: We created a simulation model to visualise aerosol and droplet generation as well as surface contamination by nebulising fluorescent solution detected by using ultraviolet light- and slow-motion capture. We repurposed covers for ultrasound transducers or endoscopic cameras to prevent surface and ambient air contamination., Results: In our bronchoscopy simulation model, we noticed extensive aerosol generation, droplet spread and surface contamination. Exposure of health-care workers and contamination of surfaces can be efficiently reduced by repurposing covers for ultrasound transducers or endoscopic cameras to seal the tube opening during bronchoscopy in mechanically ventilated patients., Conclusion: Adequate personal protective equipment and safety strategies allow to minimise contamination during bronchoscopy in mechanically ventilated COVID-19 patients., (© 2020 The Authors. Mycoses published by Wiley-VCH GmbH.)