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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 One was withdrawn due to possible isavuconazole-related adverse side effects.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.

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. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID‐19)‐associated pulmonary aspergillosis (CAPA) is one of the noticeable complications of COVID‐19 and its incidence varies widely. In Japan, research on the incidence, risk factors and mortality associated with CAPA is limited. Objectives: This study aimed to explore the incidence and potential risk factors for CAPA in patients with severe or critical COVID‐19 and evaluate the relationship between CAPA and mortality of patients with severe or critical COVID‐19. Methods: We investigated the incidence of CAPA in patients with severe and critical COVID‐19 using administrative claims data from acute care hospitals in Japan. We employed multivariable regression models to explore potential risk factors for CAPA and their contribution to mortality in patients with severe and critical COVID‐19. Results: The incidence of CAPA was 0.4%–2.7% in 33,136 patients with severe to critical COVID‐19. Age, male sex, chronic lung disease, steroids, immunosuppressants, intensive care unit admission, blood transfusion and dialysis were potential risk factors for CAPA in patients with severe to critical COVID‐19. CAPA was an independent factor associated with mortality. Conclusions: CAPA is a serious complication in patients with severe and critical COVID‐19 and may increase mortality. [ABSTRACT FROM AUTHOR]

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

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.

COVID‐19‐associated pulmonary aspergillosis (CAPA) remains a high mortality mycotic infection throughout the pandemic, and glucocorticoids (GC) may be its root cause. Our aim was to evaluate the effect of systemic GC treatment on the development of CAPA. We systematically searched the PubMed, Google Scholar, Scopus and Embase databases to collect eligible studies published until 31 December 2022. The pooled outcome of CAPA development was calculated as the log odds ratio (LOR) with 95% confidence intervals (CI) using a random effect model. A total of 21 studies with 5174 patients were included. Of these, 20 studies with 4675 patients consisting of 2565 treated with GC but without other immunomodulators (GC group) and 2110 treated without GC or other immunomodulators (controls) were analysed. The pooled LOR of CAPA development was higher for the GC group than for the controls (0.54; 95% CI: 0.22, 0.86; p <.01). In the subgroups, the pooled LOR was higher for high‐dose GC (0.90; 95% CI: 0.17, 1.62: p =.01) and dexamethasone (0.71; 95% CI: 0.35, 1.07; p <.01) but had no significant difference for low‐dose GC (0.41; 95% CI: −0.07, 0.89; p =.09), and non‐dexamethasone GC (0.21; 95% CI: −0.36, 0.79; p =.47), treated patients versus controls. GC treatment increases the risk of CAPA development, and this risk is particularly associated with the use of high‐dose GC or dexamethasone treatment. [ABSTRACT FROM AUTHOR]

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.

Invasive pulmonary aspergillosis (IPA) is an important complication of coronavirus disease 2019 (COVID-19), and while there are case reports and epidemiological studies, few studies have isolated Aspergillus strains from patients. Therefore, we analyzed the strains, sensitivities, and genetic homology of Aspergillus spp. Isolated from patients with COVID-19. We investigated the Aspergillus strains detected from patients with COVID-19 hospitalized in Osaka Metropolitan University Hospital from December 2020 to June 2021. A molecular epidemiological analysis of Aspergillus spp. was performed using drug susceptibility tests and TRESPERG typing, and data on patient characteristics were collected from electronic medical records. Twelve strains of Aspergillus were detected in 11 of the 122 patients (9%) with COVID-19. A. fumigatus was the most common species detected, followed by one strain each of Aspergillus aureolus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus. A. aureolus was resistant to voriconazole, and no resistance was found in other strains. All A. fumigatus strains were genetically distinct strains. Six of the 11 patients that harbored Aspergillus received antifungal drug treatment and tested positive for β-D-glucan and/or Aspergillus galactomannan antigen. The results indicated that Aspergillus infections were acquired from outside the hospital and not from nosocomial infections. Strict surveillance of Aspergillus spp. is beneficial in patients at high-risk for IPA. When Aspergillus is detected, it is important to monitor the onset of IPA carefully and identify the strain, perform drug sensitivity tests, and facilitate early administration of therapeutic agents to patients with IPA. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT. [ABSTRACT FROM AUTHOR]

Background: Early identification of COVID‐19‐associated pulmonary aspergillosis (CAPA) is particularly challenging in low‐ middle‐income countries where diagnostic capabilities are limited, and risk factors for CAPA have not been identified. It is also essential to recognise CAPA patients who are likely to have a poorer outcome to decide on aggressive management approaches. Therefore, this study aimed to identify risk factors and outcomes for CAPA among admitted moderate to critical COVID‐19 patients at our centre in Pakistan. Methods: An unmatched case–control study with ratio of 1:2 was conducted on hospitalised adult patients with COVID‐19 from March 2020–July 2021. Cases were defined according to European Confederation of Medical Mycology and the International Society for Human and Animal Mycology consensus criteria. Controls were defined as patients hospitalised with moderate, severe or critical COVID‐19 without CAPA. Results: A total of 100 CAPA cases (27 probable CAPA; 73 possible CAPA) were compared with 237 controls. Critical disease at presentation (aOR 5.04; 95% CI 2.18–11.63), age ≥ 60 years (aOR 2.00; 95% CI 1.20–3.35) and underlying co‐morbid of chronic kidney disease (CKD) (aOR 3.78; 95% CI 1.57–9.08) were identified as risk factors for CAPA. Patients with CAPA had a significantly greater proportion of complications and longer length of hospital stay (p‐value <.001). Mortality was higher in patients with CAPA (48%) as compared to those without CAPA (13.5%) [OR = 6.36(95% CI 3.6–11)]. Conclusions: CAPA was significantly associated with advanced age, CKD and critical illness at presentation, along with a greater frequency of complications and higher mortality. [ABSTRACT FROM AUTHOR]

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]

Background: COVID‐19‐associated pulmonary aspergillosis (CAPA) has been widely reported but homogenous large cohort studies are needed to gain real‐world insights about the disease. Methods: We collected clinical and laboratory data of 1161 patients hospitalised at our Institute from March 2020 to August 2021, defined their CAPA pathology, and analysed the data of CAPA/non‐CAPA and deceased/survived CAPA patients using univariable and multivariable models. Results: The overall prevalence and mortality of CAPA in our homogenous cohort of 1161 patients were 6.4% and 47.3%, respectively. The mortality of CAPA was higher than that of non‐CAPA patients (hazard ratio: 1.8 [95% confidence interval: 1.1–2.8]). Diabetes (odds ratio [OR] 1.92 [1.15–3.21]); persistent fever (2.54 [1.17–5.53]); hemoptysis (7.91 [4.45–14.06]); and lung lesions of cavitation (8.78 [2.27–34.03]), consolidation (9.06 [2.03–40.39]), and nodules (8.26 [2.39–28.58]) were associated with development of CAPA by multivariable analysis. Acute respiratory distress syndrome (ARDS) (2.68 [1.09–6.55]), a high computed tomography score index (OR 1.18 [1.08–1.29]; p <.001), and pulse glucocorticoid treatment (HR 4.0 [1.3–9.2]) were associated with mortality of the disease. Whereas neutrophilic leukocytosis (development: 1.09 [1.03–1.15] and mortality: 1.17 [1.08–1.28]) and lymphopenia (development: 0.68 [0.51–0.91] and mortality: 0.40 [0.20–0.83]) were associated with the development as well as mortality of CAPA. Conclusion: We observed a low but likely underestimated prevalence of CAPA in our study. CAPA is a disease with high mortality and diabetes is a significant factor for its development while ARDS and pulse glucocorticoid treatment are significant factors for its mortality. Cellular immune dysregulation may have a central role in CAPA from its development to mortality. [ABSTRACT FROM AUTHOR]

Background: Galactomannan Enzyme Immunoassay (GM‐EIA) is proved to be a cornerstone in the diagnosis of COVID‐19‐associated pulmonary aspergillosis (CAPA), its use is limited in middle and low‐income countries, where the application of simple and rapid test, including Galactomannan Lateral Flow Assay (GM‐LFA), is highly appreciated. Despite such merits, limited studies directly compared GM‐LFA with GM‐EIA. Herein we compared the diagnostic features of GM‐LFA, GM‐EIA and bronchoalveolar lavage (BAL) culture for CAPA diagnosis in Iran, a developing country. Materials/Methods: Diagnostic performances of GM‐LFA and GM‐EIA in BAL (GM indexes ≥1) and serum (GM indexes >0.5), i.e. sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and areas under the curve (AUC), were evaluated using BAL (n = 105) and serum (n = 101) samples from mechanically ventilated COVID‐19 patients in intensive care units. Patients were classified based on the presence of host factors, radiological findings and mycological evidences according to 2020 ECMM/ISHAM consensus criteria for CAPA diagnosis. Results: The Aspergillus GM‐LFA for serum and BAL samples showed a sensitivity of 56.3% and 60.6%, specificity of 94.2% and 88.9%, PPV of 81.8% and 71.4%, NPV of 82.3% and 83.1%, when compared with BAL culture, respectively. GM‐EIA showed sensitivities of 46.9% and 54.5%, specificities of 100% and 91.7%, PPVs of 100% and 75%, NPVs of 80.2% and 81.5% for serum and BAL samples, respectively. Conclusion: Our study found GM‐LFA as a reliable simple and rapid diagnostic tool, which could circumvent the shortcomings of culture and GM‐EIA and be pivotal in timely initiation of antifungal treatment. [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]

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. [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.

Purpose of Review: Severe-acute respiratory coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) has been the single most important pathogen driving health care delivery system for the last one and half years. Now, as the time is passing, many issues related to co-infections/secondary infections/superinfections in COVID-19 patients are emerging. The literature is getting enriched everyday by addition of reports from all over the world for the same. The purpose of this review is to decipher the plethora of fungal infections in COVID-19. Recent Findings: COVID-19 infection along with it brought many risk factors namely lung injury, immunosuppression, need for oxygen therapy, monoclonal antibodies, steroid therapy, etc. which are known predisposing factors for fungal infections. Rather the extent and severity of fungal pathogens has been so much that it has led to new terminologies like CAC (COVID-19-associated Candida), CAPA (COVID-19-associated pulmonary aspergillosis) and CAM (COVID-19-associated mucormycosis). There is increase in invasiveness of Candida, prevalence of aspergillosis in COVID-19 damaged lung and outbreak of mucormycosis in COVID-19 patients resulting in "double trouble," keeping laboratory personnel, clinicians, and intensivists on their toes in managing these patients. Summary: Awareness and understanding regarding these possible complications is necessary to decrease the morbidity and mortality among patients. The COVID-19 and fungal coinfections may bring more insight into ways of pathogenesis of fungal infections, need for better antifungal agents, quick diagnostic modalities, and better management policies in the near future. [ABSTRACT FROM AUTHOR]

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.

Purpose: Invasive pulmonary aspergillosis has been increasingly recognized in COVID-19 patients, termed COVID-19-associate pulmonary aspergillosis (CAPA). Our meta-analysis aims to assess the clinical characteristics and outcomes of patients diagnosed with CAPA compared to those without CAPA. Methods: We searched the Pubmed, Cochrane Library, SCOPUS, and Web of Science databases for studies published between January 1, 2020 and August 1, 2021, containing comparative data of patients diagnosed with CAPA and those without CAPA. Results: Eight cohort studies involving 729 critically ill COVID-19 patients with comparative data were included. CAPA patients were older (mean age 66.58 vs. 59.25 years; P = 0.007) and had underlying chronic obstructive pulmonary disease (COPD) (13.7 vs. 6.1%; OR 2.75; P = 0.05). No differences in gender, body mass index (BMI), and comorbidities of diabetes and cancer were observed. CAPA patients were more likely to receive long-term corticosteroid treatment (15.0 vs. 5.3%; OR 3.53; P = 0.03). CAPA patients had greater severity of illness based on sequential organ failure assessment (SOFA) score with a higher all-cause in-hospital mortality rate (42.6 vs. 26.5%; OR 3.39; P < 0.001) and earlier ICU admission from illness onset (mean 11.00 vs. 12.00 days; P = 0.003). ICU length of stay (LOS), invasive mechanical ventilation (IMV) duration, the requirement of inotropic support and renal replacement therapy were comparable between the two groups. Conclusions: CAPA patients are typically older with underlying COPD and received long-term corticosteroid treatment. Furthermore, CAPA is associated with higher SOFA scores, mortality, and earlier onset of ICU admission from illness onset. [ABSTRACT FROM AUTHOR]

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]

We report four cases of invasive pulmonary aspergillus co‐infection in patients with coronavirus disease 2019 (COVID‐19) infection and acute respiratory distress syndrome requiring intensive care unit (ICU) admission. Aspergillus fumigatus and Aspergillus terreus were isolated, with early infection onset following ICU admission. Clinicians should be aware of invasive pulmonary aspergillosis in ICU patients with COVID‐19 infection, particularly those receiving dexamethasone. We propose screening of these high‐risk patients with twice‐weekly fungal culture from tracheal aspirate and, if feasible, Aspergillus polymerase chain reaction. Diagnosis is challenging and antifungal treatment should be considered in critically ill patients who have new or worsening pulmonary changes on chest imaging and mycological evidence of infection. [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]

COVID-19-associated pulmonary aspergillosis (CAPA) is defined as invasive pulmonary aspergillosis occurring in COVID-19 patients. The purpose of this review was to discuss the incidence, characteristics, diagnostic criteria, biomarkers, and outcomes of hospitalized patients diagnosed with CAPA. A literature search was performed through Pubmed and Web of Science databases for articles published up to 20th March 2021. In 1421 COVID-19 patients, the overall CAPA incidence was 13.5% (range 2.5-35.0%). The majority required invasive mechanical ventilation (IMV). The time to CAPA diagnosis from illness onset varied between 8.0 and 16.0 days. However, the time to CAPA diagnosis from intensive care unit (ICU) admission and IMV initiation ranged between 4.0-15.0 days and 3.0-8.0 days. The most common diagnostic criteria were the modified AspICU-Dutch/Belgian Mycosis Study Group and IAPA-Verweij et al. A total of 77.6% of patients had positive lower respiratory tract cultures, other fungal biomarkers of bronchoalveolar lavage and serum galactomannan were positive in 45.3% and 18.2% of patients. The CAPA mortality rate was high at 48.4%, despite the widespread use of antifungals. Lengthy hospital and ICU stays ranging between 16.0-37.5 days and 10.5-37.0 days were observed. CAPA patients had prolonged IMV duration of 13.0-20.0 days. The true incidence of CAPA likely remains unknown as the diagnosis is limited by the lack of standardized diagnostic criteria that rely solely on microbiological data with direct or indirect detection of Aspergillus in respiratory specimens, particularly in clinical conditions with a low pretest probability. A well-designed, multi-centre study to determine the optimal diagnostic approach for CAPA is required. [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.

CAPA (COVID-19 associated pulmonary aspergillosis) is an important complication of COVID-19. It has been reported that the incidence of CAPA is as high as 19%–33% worldwide. However, its onset has not been reported in Japan. A 72-year-old Japanese man was diagnosed with COVID-19 and was transferred to our hospital due to deterioration of respiratory condition. Treatment with remdesivir, dexamethasone (DEXA), and antibiotics was performed under mechanical ventilation. Although the condition improved temporarily, a new shadow appeared in the lung, and Aspergillus fumigatus was cultured from sputum. The patient was clinically diagnosed with CAPA and treated with voriconazole. However, his progress deteriorated and he died. High-risk COVID-19 patients should be tested for Aspergillus to ensure early diagnosis of CAPA. [ABSTRACT FROM AUTHOR]

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.

The recent global outbreak of coronavirus disease-19, also known as COVID-19, has infected more than 142 million people worldwide, causing more than 3 million deaths. It has been shown that up to 40% of hospitalized COVID-19 patients may develop ARDS. Although not proven, anti-inflammatory and anti-cytokine treatments are recommended to suppress the cytokine storm that develops in the early stages of the disease. In this case report, a case of pulmonary aspergillus developed as a complication of treatment for ARDS caused by covid 19 in a 50-year-old male patient will be presented in the light of current literature. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the interest of systematic screening of serum fungal markers in patients hospitalized in a medical ward., Methods: We retrospectively analyzed all patients hospitalized in our infectious disease department from October 1st to October 31st, 2020 for COVID-19 without prior ICU admission, and for whom systematic screening of serum fungal markers was performed., Results: Thirty patients were included. The majority of patients received corticosteroids (96.7%). The galactomannan antigen assay was positive for 1/30 patients at D0, and 0/24, 0/16, 0/13 and 0/2 at D4, D7, D10 and D14 respectively. 1,3-ß-D-glucan was positive for 0/30, 1/24, 1/12, 0/12, 0/2 at D0, D4, D7, D10 and D14 respectively. No Aspergillus fumigatus PCR was positive. No cases of aspergillosis were retained., Conclusion: Our study does not support the interest of systematic screening of fungal markers in immunocompetent patients with COVID-19 in a conventional unit., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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.

Introduction: Since the onset of the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described. Possible risk factors for the development of this condition have been proposed, although evidence in Latin American populations is limited. The objectives were to identify risk factors for the development of CAPA and describe the characteristics of this infection., Materials and Methods: A retrospective case-control study was conducted. The population consisted of adult patients with severe COVID-19, hospitalized in ICU and who had undergone diagnostic tests for invasive pulmonary aspergillosis., Results: Seventy-five patients were evaluated, 21 in the case group and 54 in the control group. 64% were male, with an average age of 62.7 years. It was found that a history of diabetes (OR 3.3, CI 1.09-9.95, p=0.03), smoking (OR 3.47, CI 1.20-10, p=0.02), coronary artery disease (OR 5, CI 1.24-20.08, p=0.02), and a Charlson score equal to or greater than 5 (OR 1.27, CI 1-1.60, p=0.013) could be associated with the development of CAPA. Most cases were considered as possible CAPA (87.5%). The time between orotracheal intubation to the diagnosis of CAPA was 11.5 days. Fever was the most common symptom (90%), and only 24% of patients had compatible radiographic findings. Mortality in the case group was 61.9%., Discussion: A history of diabetes, smoking, coronary artery disease, and a Charlson score equal to or greater than 5 may increase the risk of developing CAPA.