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BACKGROUND: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection. METHODS: We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants. RESULTS: Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects. CONCLUSION: Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.

Background: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection. Methods: We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants. Results: Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects. Conclusion: Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.

Aspergillus fumigatus has been found to coinfect patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA, including the prevalence of resistance-associated alleles. We present a population genomic analysis of 21 CAPA isolates from four European countries with these isolates compared against 240 non-CAPA A. fumigatus isolates from a wider population. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically encoded azole-resistant mechanisms. The phylogenetic analysis of the 21 CAPA isolates showed that they were representative of the wider A. fumigatus population with no obvious clustering. The prevalence of phenotypic azole resistance in CAPA was 14.3% (n = 3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. The relatively high prevalence of azole resistance alleles that we document poses a probable threat to treatment success rates, warranting the enhanced surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes when CAPA is suspected. [ABSTRACT FROM AUTHOR]

INTRODUCTION: COVID-19-associated pulmonary aspergillosis (CAPA) is a serious complication affecting patients with severe SARS-CoV-2 infection, and is associated with increased mortality. OBJECTIVE: The objective of this study was to investigate potential risk factors, and to estimate the incidence and mortality in patients diagnosed with CAPA. METHODS: A single-center retrospective observational study was conducted on patients admitted to the intensive care unit (ICU) with severe COVID-19 from October 2020 to May 2022. Patients with deterioration of their clinical status were evaluated with serum galactomannan (GM) for probable CAPA. Baseline demographic patient characteristics, vaccination status, and time period during which each patient was infected with SARS-CoV-2 were obtained, and risk stratification according to underlying comorbidities was performed in an effort to assess various risk factors for CAPA. The incidence of CAPA in the entire cohort was measured, and mortality rates in the CAPA and non-CAPA groups were calculated and compared. RESULTS: Of 488 patients admitted to the ICU, 95 (19.4%) had deterioration of their clinical status, which prompted testing with serum GM. Positive serum testing was observed in 39/95 patients, with an overall CAPA incidence in the entire study cohort reaching 7.9% (39/488). The mortality rate was 75% (42/56) in the non-CAPA group that was tested for serum GM, and 87.2% (34/39) in the CAPA group (P = 0.041). Multivariable Cox regression hazard models were tested for 28- and 90-day survival from ICU admission. An invasive pulmonary aspergillosis (IPA) risk-stratified cox regression model corrected for the SARS-CoV-2 variant of the patient identified the diagnosis of probable CAPA and elevated procalcitonin (PCT) levels measured at least 10 days after ICU admission, as significantly associated with death in the IPA-risk subgroup only, with hazard ratio (HR): 3.687 (95% confidence interval [CI], 1.030-13.199, P = 0.045) for the diagnosis of probable CAPA, and HR: 1.022 (95% CI, 1.003-1.042, P = 0.026) for every 1 ng/mL rise in PCT. CONCLUSIONS: Patients in the IPA-risk subgroup that were diagnosed with CAPA had a lower 90-day survival when compared to patients in the same group without a CAPA diagnosis. [ABSTRACT FROM AUTHOR]

Background: Nearly 10% of COVID-19 cases will require admission to the intensive care unit (ICU). Our aim was to assess the clinical and microbiological outcomes of secondary infections among critically ill COVID-19 adult patients treated with/without immunomodulation. Methods: A prospective observational cohort study was performed between 2020 and 2022 at a single ICU. The diagnosis and severity classification were established by the ECDC and WHO criteria, respectively. Eligible patients were included consecutively at admission, and followed for +30 days post-inclusion. Bloodstream-infections (BSIs), ventilator-associated bacterial pneumonia (VAP), and COVID-19-associated invasive pulmonary aspergillosis (CAPA) were defined according to international guidelines. Patient stratification was performed by immunomodulatory therapy administration (dexamethasone, tocilizumab, baricitinib/ruxolitinib). The primary outcome was any microbiologically confirmed major infectious complication, secondary outcomes were invasive mechanical ventilation (IMV) requirement and all-cause mortality. Results: Altogether, 379 adults were included. At baseline, 249/379 (65.7%) required IMV and 196/379 (51.7%) had a cytokine storm. At +30 days post-inclusion, the rate of any microbiologically confirmed major infectious complication was 151/379 (39.8%), IMV requirement and all-cause mortality were 303/379 (79.9%) and 203/379 (53.6%), respectively. There were no statistically significant outcome differences after stratification. BSI, VAP, and CAPA episodes were mostly caused by Enterococcus faecalis (27/124, 22.1%), Pseudomonas aeruginosa (26/91, 28.6%), and Aspergillus fumigatus (20/20, 100%), respectively. Concerning the primary outcome, Kaplan–Meier analysis showed similar probability distributions between the treatment subgroups (118/299, 39.5% vs. 33/80, 41.3%, log-rank p = 0.22), and immunomodulation was not retained as its independent predictor in multivariate logistic regression. Conclusions: Secondary infections among critically ill COVID-19 adult patients represent a relevant burden, probably irrespective of immunomodulatory treatment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: COVID-19-associated pulmonary aspergillosis (CAPA) is a serious complication affecting patients with severe SARS-CoV-2 infection, and is associated with increased mortality. OBJECTIVE: The objective of this study was to investigate potential risk factors, and to estimate the incidence and mortality in patients diagnosed with CAPA. METHODS: A single-center retrospective observational study was conducted on patients admitted to the intensive care unit (ICU) with severe COVID-19 from October 2020 to May 2022. Patients with deterioration of their clinical status were evaluated with serum galactomannan (GM) for probable CAPA. Baseline demographic patient characteristics, vaccination status, and time period during which each patient was infected with SARS-CoV-2 were obtained, and risk stratification according to underlying comorbidities was performed in an effort to assess various risk factors for CAPA. The incidence of CAPA in the entire cohort was measured, and mortality rates in the CAPA and non-CAPA groups were calculated and compared. RESULTS: Of 488 patients admitted to the ICU, 95 (19.4%) had deterioration of their clinical status, which prompted testing with serum GM. Positive serum testing was observed in 39/95 patients, with an overall CAPA incidence in the entire study cohort reaching 7.9% (39/488). The mortality rate was 75% (42/56) in the non-CAPA group that was tested for serum GM, and 87.2% (34/39) in the CAPA group (P = 0.041). Multivariable Cox regression hazard models were tested for 28- and 90-day survival from ICU admission. An invasive pulmonary aspergillosis (IPA) risk-stratified cox regression model corrected for the SARS-CoV-2 variant of the patient identified the diagnosis of probable CAPA and elevated procalcitonin (PCT) levels measured at least 10 days after ICU admission, as significantly associated with death in the IPA-risk subgroup only, with hazard ratio (HR): 3.687 (95% confidence interval [CI], 1.030–13.199, P = 0.045) for the diagnosis of probable CAPA, and HR: 1.022 (95% CI, 1.003–1.042, P = 0.026) for every 1 ng/mL rise in PCT. CONCLUSIONS: Patients in the IPA-risk subgroup that were diagnosed with CAPA had a lower 90-day survival when compared to patients in the same group without a CAPA diagnosis.

Aspergillus fumigatus has been found to coinfect patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA, including the prevalence of resistance-associated alleles. We present a population genomic analysis of 21 CAPA isolates from four European countries with these isolates compared against 240 non-CAPA A. fumigatus isolates from a wider population. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically encoded azole-resistant mechanisms. The phylogenetic analysis of the 21 CAPA isolates showed that they were representative of the wider A. fumigatus population with no obvious clustering. The prevalence of phenotypic azole resistance in CAPA was 14.3% (n = 3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. The relatively high prevalence of azole resistance alleles that we document poses a probable threat to treatment success rates, warranting the enhanced surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes when CAPA is suspected.

In the current pandemic, the incidence of fungal infections-associated COVID-19 is surging. Diabetes mellitus, overzealous steroid, and antibiotic use for COVID-19 management may cause or exacerbate the fungal disease. In paranasal sinus (PNS), ethmoids followed by the maxillary sinus are commonly involved with the risk of intra-orbital or/and intracranial involvement is quite common. In lungs, COVID-19 infection has higher mortality rate, if there is an associated fungal infection. Aspergillus fumigates is the most common fungus that cause lung infection and present as discrete lesion different from COVID-19 manifestation. Two cases of COVID-associated fungal infections, i.e., rhino-mucormycosis and pulmonary aspergillosis are described here. In the first case, computed tomography (CT) of PNS was done for the complaints of mild right-sided facial swelling and mild restriction of the eye globe on day 27 of illness. CT showed hyperdense content involving the right-sided nasal sinus with the remodeling of bones with erosion and thinning of the inferior and medial orbital wall with the extension of soft tissue into the extraorbital space. The patient was treated with Amphotericin B and posaconazole oral suspension as the first-line antifungal monotherapy. In the second case, on complaints of cough with expectoration on the 20th day of illness, X-ray chest and CT chest were done which confirmed a thick-walled cavity in the right lung and other post COVID features. The tracheal aspirate culture was suggestive of Aspergillus fumigatus and Aspergillus antigen galactomannan was found positive in the fluid. The patient was treated for the same with antifungal therapy. Hence it is important to pay attention to the high probability of fungal infections in COVID-19 patients. The association of coronavirus with mucormycosis of the PNSs and aspergillosis of the lung must be given outmost consideration. Noncontrast CT of the PNSs is usually the first investigation of choice for PNS involvement, and CT chest help in the diagnosis of pulmonary fungal infection. Uncontrolled diabetes and use of steroids are two of the main factors for aggravating factors. Both early surgical intervention and anti-fungal treatment should be sought for the management.

The reported incidence of COVID-19-associated pulmonary aspergillosis (CAPA) ranges between 2.4% and 35% in intensive care unit (ICU) patients, and awareness in the medical community is rising. We performed a regional retrospective observational study including patients diagnosed with CAPA defined according to the Modified AspICU Dutch/Belgian Mycosis Study Group and CAPA–EECMM, from five different ICUs, admitted between March, 2020 and September, 2021. Forty-five patients were included. The median age was 64 (IQR 60–72), mostly (73%) males. At ICU admission, the median Charlson comorbidity index was 3 (2–5), and the simplified acute physiology score (SAPS)-II score was 42 (31–56). The main underlying diseases were hypertension (46%), diabetes (36%) and pulmonary diseases (15%). CAPA was diagnosed within a median of 17 days (IQR 10–21.75) after symptoms onset and 9 days (IQR 3–11) after ICU admission. The overall 28-day mortality rate was 58%, and at univariate analysis, it was significantly associated with older age (p = 0.009) and SAPS-II score at admission (p = 0.032). The use of immunomodulatory agents, p = 0.061; broad-spectrum antibiotics, p = 0.091; positive culture for Aspergillus on BAL, p = 0.065; and hypertension, p = 0.083, were near reaching statistical significance. None of them were confirmed in multivariate analysis. In critically ill COVID-19 patients, CAPA acquired clinical relevance in terms of incidence and reported mortality. However, the risk between underdiagnosis—in the absence of specific invasive investigations, and with a consequent possible increase in mortality—and over-diagnosis (case identification with galactomannan on broncho-alveolar fluid alone) might be considered. Realistic incidence rates, based on local, real-life epidemiological data, might be helpful in guiding clinicians. [ABSTRACT FROM AUTHOR]

Bacterial coinfections, which increase the severity of respiratory viral infections, are frequent causes of mortality in influenza pandemics but have not been well characterized in patients with Coronavirus disease 2019 (COVID-19). Moreover, the association of COVID-19 infection with pulmonary Mycobacterium tuberculosis disease (TB) and concurrent pulmonary fungal infection is not well known. The classification of patients with COVID-19-associated pulmonary aspergillosis (CAPA) using the current definitions for invasive fungal diseases has proven difficult. In this study, we aimed to provide information about three patients with underlying diseases ongoing with COVID-19 and co-infection with pulmonary TB, and with COVID-19-associated pulmonary aspergillosis (CAPA). At the time of hospital admission, each patient presented complications such as decompensated T2DM with diabetic ketoacidosis and/or hypertension. Findings of chest computed tomography and serum galactomannan by radioimmunoassay were useful for classifying them as possible CAPA. One of the three possible CAPA cases was fatal. These three cases are rare and are the first of their kind reported worldwide. The generation of reliable algorithms, early diagnosis, standardization of classification criteria, and the selection of specific and personalized treatments for COVID-19-associated opportunistic infections, including CAPA, are necessary to improve outcomes in these kinds of patients. [ABSTRACT FROM AUTHOR]

Abstract Invasive pulmonary aspergillosis (IPA) has always been a challenging diagnosis and risk factors an important guide to investigate specific population, especially in Intensive Care Unit. Traditionally recognized risk factors for IPA have been haematological diseases or condition associated with severe immunosuppression, lately completed by chronic conditions (such as obstructive pulmonary disease, liver cirrhosis, chronic kidney disease and diabetes), influenza infection and Intensive Care Unit (ICU) admission. Recently, a new association with SARS-CoV2 infection, named COVID-19-associated pulmonary aspergillosis (CAPA), has been reported worldwide, even if its basic epidemiological characteristics have not been completely established yet. In this narrative review, we aimed to explore the potential risk factors for the development of CAPA and to evaluate whether previous host factors or therapeutic approaches used in the treatment of COVID-19 critically ill patients (such as mechanical ventilation, intensive care management, corticosteroids, broad-spectrum antibiotics, immunomodulatory agents) may impact this new diagnostic category. Reviewing all English-language articles published from December 2019 to December 2020, we identified 21 papers describing risk factors, concerning host comorbidities, ICU management, and COVID-19 therapies. Although limited by the quality of the available literature, data seem to confirm the role of previous host risk factors, especially respiratory diseases. However, the attention is shifting from patients’ related risk factors to factors characterizing the hospital and intensive care course, deeply influenced by specific features of COVID treatment itself. Prolonged invasive or non-invasive respiratory support, as well as the impact of corticosteroids and/or immunobiological therapies seem to play a pivotal role. ICU setting related factors, such as environmental factors, isolation conditions, ventilation systems, building renovation works, and temporal spread with respect to pandemic waves, need to be considered. Large, prospective studies based on new risk factors specific for CAPA are warranted to guide surveillance and decision of when and how to treat this particular population.

Background: COVID-19 superinfection by Aspergillus (COVID-19-associated aspergillosis, CAPA) is increasingly observed due to increased awareness and use of corticosteroids. The aim of this study is to compare clinical and imaging features between COVID-19 patients with and without associated pulmonary aspergillosis. Material and Methods: In this case–control study, hospitalized patients between March 2020 and March 2021 were evaluated. Two observers independently compared 105 chest CTs of 52 COVID-19 patients without pulmonary aspergillosis to 40 chest CTs of 13 CAPA patients. The following features were evaluated: lung involvement, predominant main pattern (ground glass opacity, crazy paving, consolidation) and additional lung and chest findings. Chronological changes in the abnormal extent upon CT and chronological changes in the main patterns were compared with mixed models. Patient-wise comparisons of additional features and demographic and clinical data were performed using Student's t-test, Chi-squared test, Fisher's exact tests and Wilcoxon rank-sum tests. Results: Compared to COVID-19 patients without pulmonary aspergillosis, CAPA patients were older (mean age (±SD): 70.3 (±7.8) versus 63.5 (±9.5) years (p = 0.01). The time-dependent evolution rates for consolidation (p = 0.02) and ground glass (p = 0.006) differed. In early COVID-19 disease, consolidation was associated with CAPA, whereas ground glass was less common. Chronological changes in the abnormal extent upon CT did not differ (p = 0.29). Regardless of the time point, bronchial wall thickening was observed more frequently in CAPA patients (p = 0.03). Conclusions: CAPA patients showed a tendency for consolidation in early COVID-19 disease. Bronchial wall thickening and higher patient age were associated with CAPA. The overall lung involvement was similar between both groups. [ABSTRACT FROM AUTHOR]

Coronavirus disease-2019 (COVID-19) causes severe pneumonia and acute respiratory distress syndrome. According to the current consensus, immunosuppressants, such as dexamethasone and anti-interleukin-6 receptor monoclonal antibodies, are therapeutic medications in the early stages of infection. However, in critically ill patients, viral, fungal, and bacterial coinfection results in higher mortality. We conducted a single-center, retrospective analysis of 29 mechanically ventilated patients with artificial airways. Patients were adults with confirmed COVID-19 infection and severe pneumonia. Acute respiratory distress syndrome was diagnosed according to the Kigali modification of the Berlin definition. Six patients had invasive pulmonary aspergillosis coinfection based on elevated serum galactomannan levels and/or bronchoalveolar lavage fluid. We present two cases with brief histories and available clinical data. We also conducted a literature review to determine whether immunosuppressants, such as tocilizumab, increase infection risk or invasive aspergillosis in patients with COVID-19. There is no conclusive evidence to suggest that tocilizumab increases coinfection risk. However, further studies are needed to determine the optimal dose, between-dose interval, and timing of tocilizumab administration in patients with COVID-19. [ABSTRACT FROM AUTHOR]

COVID-19 is a new disease and the acute clinical presentation is mostly clear now. It is also known now that the disease may have sequelae affecting various systems. The respiratory sequelae include pulmonary fibrosis due to the immune-mediated mechanisms that follow a cytokine storm, diffuse alveolar damage, and microvascular thrombosis. A decline in lung function may be seen in patients who still have residual symptoms and hypoxia. COVID-19-associated pulmonary aspergillosis, a well-recognized complication, especially in patients with acute respiratory distress syndrome, has emerged as a significant risk factor for increased mortality. Fatigue is a common symptom that patients come back with, in the post-COVID period. Dyspnea without hypoxia has been attributed to respiratory muscle dysfunction and deconditioning resulting in decreased exercise tolerance. Palpitation is another common persisting symptom. Thromboembolic disease, a common association during the acute phase of illness, is not an uncommon entity that is seen even after “recovery” from COVID-19. Thromboembolic events causing stroke have been identified as an immediate complication of COVID-19, but can occur during the recovery phase as well, in high-risk patients. The return of smell and taste sensations could take a few weeks to months even after complete recovery from the illness. Mood swings, anxiety, and sleep deprivation have all been reported by patients recovering from this viral illness. The last 14 months have been feverishly spent in trying to understand this particular disease, but the long-term complications of COVID-19 are still elusive.

Background: Systemic corticosteroids have become the standard of care for severe to critically ill patients with coronavirus disease 2019 (COVID-19). However, the real-world efficacy and safety outcomes associated with a higher dose of corticosteroids remain uncertain., Methods: We conducted a nationwide, population-based, matched cohort study of severe to critically ill adult patients with COVID-19 between January 2020 and June 2021 in Korea using the National Health Information Database. Patients using systemic corticosteroids were included and high-dose corticosteroid use was defined as a daily mean prescribed dose of more than 6 mg of dexamethasone. We then employed a proportional hazard regression model to identify prognostic factors for 28-day all-cause mortality and conducted a Fine and Gray regression model to assess risk factors for developing COVID-19-associated pulmonary aspergillosis (CAPA)., Results: During the study period, 102,304 patients with COVID-19 were screened, 5,754 met the eligibility criteria, and 2,138 were successfully matched. The mean prescribed daily dose was 4.2 mg and 13.4 mg in the standard- and high-dose groups, respectively, and the mean duration of use was not different between the groups. High-dose corticosteroid use independently increased all-cause mortality at 28 days (adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.25-1.76) and 90 days (aHR, 1.63; CI, 1.44-1.85) after admission. Subgroup analysis revealed a statistically significant elevation in the risk of mortality among patients using low-flow or high-flow nasal cannulas, with aHRs of 1.41 and 1.46, respectively. No significant impact of high-dose steroids was observed, even in patients who underwent mechanical ventilation at 28 days (aHR, 1.17; CI, 0.79-1.72). As a safety outcome, high-dose corticosteroid use showed an association with the development of CAPA (aHR, 2.97; 95% CI, 0.94-9.43)., Conclusion: Among severe to critically ill patients with COVID-19, high-dose corticosteroid use was associated with increased 28-day all-cause mortality and showed a trend toward the development of CAPA., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

배경: Systemic corticosteroids have become the standard of care for patients with severe to critical coronavirus disease 2019 (COVID-19). However, the real-world efficacy and safety outcomes of a higher dose of corticosteroids remain uncertain. This study aimed to determine the impact of higher dose corticosteroids on the survival and development of COVID-19-associated pulmonary aspergillosis (CAPA). 방법: We conducted a nationwide, population-based study using the National Health Information Database between January 2020 and June 2021. Adult patients with severe to critical COVID-19 were enrolled. The high-dose corticosteroid group included patients who received more than 60 mg of dexamethasone or an equivalent dose over 10 days. Analyses were performed using both a propensity-score matched cohort and an entire cohort. 결과: During the study period, 102,304 patients were screened, 10,417 met the eligibility criteria, and 2,457 were successfully matched. High-dose corticosteroid use significantly reduced all-cause mortality at 28 days (hazard ratios [HRs], 0.543; confidence intervals [CIs], 0.475–0.619), but increased the risk of CAPA (HRs, 5.824; CIs, 2.260–15.008). As a prespecified exploratory outcome, all-cause mortality at 90 days was lower and mechanical ventilation (MV) free days at 28 days were longer in the high-dose corticosteroid group (all p < 0.05). However, there was no difference in the rate of MV applying at 28 days, and all-cause mortality according to the development of CAPA. 결론: Among patients with severe to critical COVID-19, higher dose corticosteroids resulted in a decrease in all-cause mortality at 28 and 90 days but the risk of CAPA development increased. Clinical awareness and active surveillance for CAPA should be needed to avoid associated unfavorable outcomes. [ABSTRACT FROM AUTHOR]

The reported incidence of COVID-19-associated pulmonary aspergillosis (CAPA) ranges between 2.4% and 35% in intensive care unit (ICU) patients, and awareness in the medical community is rising. We performed a regional retrospective observational study including patients diagnosed with CAPA defined according to the Modified AspICU Dutch/Belgian Mycosis Study Group and CAPA–EECMM, from five different ICUs, admitted between March, 2020 and September, 2021. Forty-five patients were included. The median age was 64 (IQR 60–72), mostly (73%) males. At ICU admission, the median Charlson comorbidity index was 3 (2–5), and the simplified acute physiology score (SAPS)-II score was 42 (31–56). The main underlying diseases were hypertension (46%), diabetes (36%) and pulmonary diseases (15%). CAPA was diagnosed within a median of 17 days (IQR 10–21.75) after symptoms onset and 9 days (IQR 3–11) after ICU admission. The overall 28-day mortality rate was 58%, and at univariate analysis, it was significantly associated with older age (p = 0.009) and SAPS-II score at admission (p = 0.032). The use of immunomodulatory agents, p = 0.061; broad-spectrum antibiotics, p = 0.091; positive culture for Aspergillus on BAL, p = 0.065; and hypertension, p = 0.083, were near reaching statistical significance. None of them were confirmed in multivariate analysis. In critically ill COVID-19 patients, CAPA acquired clinical relevance in terms of incidence and reported mortality. However, the risk between underdiagnosis—in the absence of specific invasive investigations, and with a consequent possible increase in mortality—and over-diagnosis (case identification with galactomannan on broncho-alveolar fluid alone) might be considered. Realistic incidence rates, based on local, real-life epidemiological data, might be helpful in guiding clinicians.

Invasive pulmonary aspergillosis (IPA) has always been a challenging diagnosis and risk factors an important guide to investigate specific population, especially in Intensive Care Unit. Traditionally recognized risk factors for IPA have been haematological diseases or condition associated with severe immunosuppression, lately completed by chronic conditions (such as obstructive pulmonary disease, liver cirrhosis, chronic kidney disease and diabetes), influenza infection and Intensive Care Unit (ICU) admission. Recently, a new association with SARS-CoV2 infection, named COVID-19-associated pulmonary aspergillosis (CAPA), has been reported worldwide, even if its basic epidemiological characteristics have not been completely established yet. In this narrative review, we aimed to explore the potential risk factors for the development of CAPA and to evaluate whether previous host factors or therapeutic approaches used in the treatment of COVID-19 critically ill patients (such as mechanical ventilation, intensive care management, corticosteroids, broad-spectrum antibiotics, immunomodulatory agents) may impact this new diagnostic category. Reviewing all English-language articles published from December 2019 to December 2020, we identified 21 papers describing risk factors, concerning host comorbidities, ICU management, and COVID-19 therapies. Although limited by the quality of the available literature, data seem to confirm the role of previous host risk factors, especially respiratory diseases. However, the attention is shifting from patients' related risk factors to factors characterizing the hospital and intensive care course, deeply influenced by specific features of COVID treatment itself. Prolonged invasive or non-invasive respiratory support, as well as the impact of corticosteroids and/or immunobiological therapies seem to play a pivotal role. ICU setting related factors, such as environmental factors, isolation conditions, ventilation systems, building renovation works, and temporal spread with respect to pandemic waves, need to be considered. Large, prospective studies based on new risk factors specific for CAPA are warranted to guide surveillance and decision of when and how to treat this particular population. [ABSTRACT FROM AUTHOR]

Severe cases of coronavirus disease 2019 (COVID-19) managed in the intensive care unit are prone to complications, including secondary infections with opportunistic fungal pathogens. Systemic fungal co-infections in hospitalized COVID-19 patients may exacerbate COVID-19 disease severity, hamper treatment effectiveness and increase mortality. Here, we reiterate the role of fungal co-infections in exacerbating COVID-19 disease severity as well as highlight emerging trends related to fungal disease burden in COVID-19 patients. Furthermore, we provide perspectives on the risk factors for fungal co-infections in hospitalized COVID-19 patients and highlight the potential role of prolonged immunomodulatory treatments in driving fungal co-infections, including COVID-19-associated pulmonary aspergillosis (CAPA), COVID-19-associated candidiasis (CAC) and mucormycosis. We reiterate the need for early diagnosis of suspected COVID-19-associated systemic mycoses in the hospital setting. [ABSTRACT FROM AUTHOR]

Bacterial coinfections, which increase the severity of respiratory viral infections, are frequent causes of mortality in influenza pandemics but have not been well characterized in patients with Coronavirus disease 2019 (COVID-19). Moreover, the association of COVID-19 infection with pulmonary Mycobacterium tuberculosis disease (TB) and concurrent pulmonary fungal infection is not well known. The classification of patients with COVID-19-associated pulmonary aspergillosis (CAPA) using the current definitions for invasive fungal diseases has proven difficult. In this study, we aimed to provide information about three patients with underlying diseases ongoing with COVID-19 and co-infection with pulmonary TB, and with COVID-19-associated pulmonary aspergillosis (CAPA). At the time of hospital admission, each patient presented complications such as decompensated T2DM with diabetic ketoacidosis and/or hypertension. Findings of chest computed tomography and serum galactomannan by radioimmunoassay were useful for classifying them as possible CAPA. One of the three possible CAPA cases was fatal. These three cases are rare and are the first of their kind reported worldwide. The generation of reliable algorithms, early diagnosis, standardization of classification criteria, and the selection of specific and personalized treatments for COVID-19-associated opportunistic infections, including CAPA, are necessary to improve outcomes in these kinds of patients.

Background: COVID-19 superinfection by Aspergillus (COVID-19-associated aspergillosis, CAPA) is increasingly observed due to increased awareness and use of corticosteroids. The aim of this study is to compare clinical and imaging features between COVID-19 patients with and without associated pulmonary aspergillosis. Material and Methods: In this case–control study, hospitalized patients between March 2020 and March 2021 were evaluated. Two observers independently compared 105 chest CTs of 52 COVID-19 patients without pulmonary aspergillosis to 40 chest CTs of 13 CAPA patients. The following features were evaluated: lung involvement, predominant main pattern (ground glass opacity, crazy paving, consolidation) and additional lung and chest findings. Chronological changes in the abnormal extent upon CT and chronological changes in the main patterns were compared with mixed models. Patient-wise comparisons of additional features and demographic and clinical data were performed using Student’s t-test, Chi-squared test, Fisher’s exact tests and Wilcoxon rank-sum tests. Results: Compared to COVID-19 patients without pulmonary aspergillosis, CAPA patients were older (mean age (±SD): 70.3 (±7.8) versus 63.5 (±9.5) years (p = 0.01). The time-dependent evolution rates for consolidation (p = 0.02) and ground glass (p = 0.006) differed. In early COVID-19 disease, consolidation was associated with CAPA, whereas ground glass was less common. Chronological changes in the abnormal extent upon CT did not differ (p = 0.29). Regardless of the time point, bronchial wall thickening was observed more frequently in CAPA patients (p = 0.03). Conclusions: CAPA patients showed a tendency for consolidation in early COVID-19 disease. Bronchial wall thickening and higher patient age were associated with CAPA. The overall lung involvement was similar between both groups.

Background: During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection., Methods: We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants., Results: Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects., Conclusion: Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was funded by 10.13039/100007705Astellas Pharma Global Development, Inc. All authors have received funding from Astellas but they did not influence the work reported in this paper., (© 2024 The Authors.)

Coronavirus disease-2019 (COVID-19) causes severe pneumonia and acute respiratory distress syndrome. According to the current consensus, immunosuppressants, such as dexamethasone and anti-interleukin-6 receptor monoclonal antibodies, are therapeutic medications in the early stages of infection. However, in critically ill patients, viral, fungal, and bacterial coinfection results in higher mortality. We conducted a single-center, retrospective analysis of 29 mechanically ventilated patients with artificial airways. Patients were adults with confirmed COVID-19 infection and severe pneumonia. Acute respiratory distress syndrome was diagnosed according to the Kigali modification of the Berlin definition. Six patients had invasive pulmonary aspergillosis coinfection based on elevated serum galactomannan levels and/or bronchoalveolar lavage fluid. We present two cases with brief histories and available clinical data. We also conducted a literature review to determine whether immunosuppressants, such as tocilizumab, increase infection risk or invasive aspergillosis in patients with COVID-19. There is no conclusive evidence to suggest that tocilizumab increases coinfection risk. However, further studies are needed to determine the optimal dose, between-dose interval, and timing of tocilizumab administration in patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes direct damage to the pulmonary epithelium, enabling Aspergillus invasion. Rapid progression and high mortality of invasive aspergillosis have been reported. In the present study, we report a rare case of possible COVID-19-associated pulmonary aspergillosis (CAPA) caused by A. niger in a Greek patient. Diagnosis was based on ECMM/ISHAM specific criteria and the new algorithm “BM-AspICU” for the invasive pulmonary aspergillosis diagnostic strategy. The fungal isolate was recovered in a non-bronchoalveolar lavage (non-BAL) sample and its identification was performed by standard macroscopic and microscopic morphological studies. MALDI-TOF analysis confirmed the identification of A. niger. In addition, galactomannan antigen and Aspergillus real-time PCR testing were positive in the non-BAL sample, while in serum they proved negative. The A. niger isolate showed an MIC for fluconazole ≥128 μg/mL, for itraconazole and posaconazole 0.25 μg/mL, for voriconazole 0.5 μg/mL, for flucytosine 4 μg/mL, for amphotericin B 1 μg/mL, and for all echinocandins (caspofungin, anidulafungin, micafungin) >8 μg/mL. The patient was initially treated with voriconazole; amphotericin B was subsequently added, when a significant progression of cavitation was demonstrated on chest computed tomography. A. niger was not isolated in subsequent samples and the patient’s unfavorable outcome was attributed to septic shock caused by a pandrug-resistant Acinetobacter baumannii strain.

We studied the risk factors, etiology, clinical features and the effectiveness of therapy of COVID-19-associated pulmonary aspergillosis (CAPA) in adult patients. In this retrospective study, we included 45 patients with proven (7%) and probable (93%) CAPA. The ECMM/ISHAM, 2020 criteria were used to diagnose CAPA. A case-control study was conducted to study the risk factors of CAPA; the control group included 90 adult COVID-19 patients without IA. In CAPA patients, the main underlying diseases were diabetes mellitus (33%), and hematological and oncological diseases (31%). The probability of CAPA developing significantly increased with lymphocytopenia >10 days (OR = 8.156 (3.056–21.771), p = 0.001), decompensated diabetes mellitus (29% vs. 7%, (OR = 5.688 (1.991–16.246), p = 0.001)), use of glucocorticosteroids (GCS) in prednisolone-equivalent dose > 60 mg/day (OR = 4.493 (1.896–10.647), p = 0.001) and monoclonal antibodies to IL-1ß and IL-6 (OR = 2.880 (1.272–6.518), p = 0.01). The main area of localization of CAPA was the lungs (100%). The clinical features of CAPA were fever (98% vs. 85%, p = 0.007), cough (89% vs. 72%, p = 0.002) and hemoptysis (36% vs. 3%, p = 0.0001). Overall, 71% of patients were in intensive care units (ICU) (median—15.5 (5–60) days), mechanical ventilation was used in 52% of cases, and acute respiratory distress syndrome (ARDS) occurred at a rate of 31%. The lung CT scan features of CAPA were bilateral (93%) lung tissue consolidation (89% vs. 59%, p = 0.004) and destruction (47% vs. 1%, p = 0.00001), and hydrothorax (26% vs. 11%, p = 0.03). The main pathogens were A. fumigatus (44%) and A. niger (31%). The overall survival rate after 12 weeks was 47.2%.

Severe cases of coronavirus disease 2019 (COVID-19) managed in the intensive care unit are prone to complications, including secondary infections with opportunistic fungal pathogens. Systemic fungal co-infections in hospitalized COVID-19 patients may exacerbate COVID-19 disease severity, hamper treatment effectiveness and increase mortality. Here, we reiterate the role of fungal co-infections in exacerbating COVID-19 disease severity as well as highlight emerging trends related to fungal disease burden in COVID-19 patients. Furthermore, we provide perspectives on the risk factors for fungal co-infections in hospitalized COVID-19 patients and highlight the potential role of prolonged immunomodulatory treatments in driving fungal co-infections, including COVID-19-associated pulmonary aspergillosis (CAPA), COVID-19-associated candidiasis (CAC) and mucormycosis. We reiterate the need for early diagnosis of suspected COVID-19-associated systemic mycoses in the hospital setting.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes direct damage to the pulmonary epithelium, enabling Aspergillus invasion. Rapid progression and high mortality of invasive aspergillosis have been reported. In the present study, we report a rare case of possible COVID-19-associated pulmonary aspergillosis (CAPA) caused by A. niger in a Greek patient. Diagnosis was based on ECMM/ISHAM specific criteria and the new algorithm "BM-AspICU" for the invasive pulmonary aspergillosis diagnostic strategy. The fungal isolate was recovered in a non-bronchoalveolar lavage (non-BAL) sample and its identification was performed by standard macroscopic and microscopic morphological studies. MALDI-TOF analysis confirmed the identification of A. niger. In addition, galactomannan antigen and Aspergillus real-time PCR testing were positive in the non-BAL sample, while in serum they proved negative. The A. niger isolate showed an MIC for fluconazole ≥128 μg/mL, for itraconazole and posaconazole 0.25 μg/mL, for voriconazole 0.5 μg/mL, for flucytosine 4 μg/mL, for amphotericin B 1 μg/mL, and for all echinocandins (caspofungin, anidulafungin, micafungin) >8 μg/mL. The patient was initially treated with voriconazole; amphotericin B was subsequently added, when a significant progression of cavitation was demonstrated on chest computed tomography. A. niger was not isolated in subsequent samples and the patient's unfavorable outcome was attributed to septic shock caused by a pandrug-resistant Acinetobacter baumannii strain. [ABSTRACT FROM AUTHOR]

We studied the risk factors, etiology, clinical features and the effectiveness of therapy of COVID-19-associated pulmonary aspergillosis (CAPA) in adult patients. In this retrospective study, we included 45 patients with proven (7%) and probable (93%) CAPA. The ECMM/ISHAM, 2020 criteria were used to diagnose CAPA. A case-control study was conducted to study the risk factors of CAPA; the control group included 90 adult COVID-19 patients without IA. In CAPA patients, the main underlying diseases were diabetes mellitus (33%), and hematological and oncological diseases (31%). The probability of CAPA developing significantly increased with lymphocytopenia >10 days (OR = 8.156 (3.056–21.771), p = 0.001), decompensated diabetes mellitus (29% vs. 7%, (OR = 5.688 (1.991–16.246), p = 0.001)), use of glucocorticosteroids (GCS) in prednisolone-equivalent dose > 60 mg/day (OR = 4.493 (1.896–10.647), p = 0.001) and monoclonal antibodies to IL-1ß and IL-6 (OR = 2.880 (1.272–6.518), p = 0.01). The main area of localization of CAPA was the lungs (100%). The clinical features of CAPA were fever (98% vs. 85%, p = 0.007), cough (89% vs. 72%, p = 0.002) and hemoptysis (36% vs. 3%, p = 0.0001). Overall, 71% of patients were in intensive care units (ICU) (median—15.5 (5–60) days), mechanical ventilation was used in 52% of cases, and acute respiratory distress syndrome (ARDS) occurred at a rate of 31%. The lung CT scan features of CAPA were bilateral (93%) lung tissue consolidation (89% vs. 59%, p = 0.004) and destruction (47% vs. 1%, p = 0.00001), and hydrothorax (26% vs. 11%, p = 0.03). The main pathogens were A. fumigatus (44%) and A. niger (31%). The overall survival rate after 12 weeks was 47.2%. [ABSTRACT FROM AUTHOR]

Diagnosis of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) remains unclear especially in nonimmunocompromised patients. The aim of this study was to evaluate seven mycological criteria and their combination in a large homogenous cohort of patients. All successive patients ( n  = 176) hospitalized for COVID-19 requiring mechanical ventilation and who clinically worsened despite appropriate standard of care were included over a 1-year period. Direct examination, culture, Aspergillus quantitative PCR ( Af -qPCR), and galactomannan testing were performed on all respiratory samples ( n  = 350). Serum galactomannan, β-d-glucan, and plasma Af -qPCR were also assessed. The criteria were analyzed alone or in combination in relation to mortality rate. Mortality was significantly different in patients with 0, ≤2, and ≥3 positive criteria (log rank test, P  = 0.04) with death rate of 43.1, 58.1, and 76.4%, respectively. Direct examination, plasma qPCR, and serum galactomannan were associated with a 100% mortality rate. Bronchoalveolar lavage (BAL) galactomannan and positive respiratory sample culture were often found as isolated markers (28.1 and 34.1%) and poorly repeatable when a second sample was obtained. Aspergillus DNA was detected in 13.1% of samples (46 of 350) with significantly lower quantitative cycle (Cq) when associated with at least one other criterion (30.2 versus 35.8) ( P  < 0.001). A combination of markers and/or blood biomarkers and/or direct respiratory sample examination seems more likely to identify patients with CAPA. Af -qPCR may help identifying false-positive results of BAL galactomannan testing and culture on respiratory samples while quantifying fungal burden accurately.

During the COVID-19 pandemic, there have been increasing reports of invasive fungal disease (IFD) in critical care, where rapid access to (1-3)-β-d-glucan (BDG) testing may have enhanced diagnosis. The potential benefit of rapidly accessible BDG results is limited by local availability of BDG testing, with low demand resulting in testing being performed in specialist centers. The recent release of the Associates of Cape Cod STAT assay provides a simple, low-throughput BDG platform, potentially increasing accessibility. During the pandemic, BDG testing using the Fungitell assay (FA) was a critical component of screening for IFD in our critical care. The performance of the STAT was retrospectively determined through a case-control study of 107 serum samples from critical-care COVID-19 patients with IFD defined according to international guidelines. The STAT demonstrated excellent qualitative (observed agreement, 97.2%; kappa, 0.94) and quantitative (Spearman's coefficient, 0.8962) agreement with the FA. Sample positivity was greater ( P  < 0.0001) in samples from cases (67.7%) versus controls (6.1%). Using the manufacturer's threshold (≥1.2), sensitivity and specificity for the detection of proven/probable IFD were 67.9% and 93.9%, respectively. Using a lower positivity threshold of ≥0.87 increased sensitivity to 71.4% without compromising specificity. When the STAT BDG index was >2.86, specificity was 100%. The STAT provides a simple, comparable alternative to the FA for detecting BDG. Sensitivity is moderate, and specificity is excellent for the diagnosis of IFD in the critical-care COVID-19 patient. The potential for enhancing access to BDG testing through the uptake of STAT at centers where FA is not available is beneficial, especially during the COVID-19 pandemic.