Superinfections in COVID-19 patients receiving extracorporeal membrane oxygenation support.

BACKGROUND: The risk of superinfections and associations with mortality among patients with corona virus disease 2019 (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) is poorly elucidated. METHOD: We identified all patients with COVID-19 treated with VV-ECMO >24 h at Rigshospitalet, Denmark from March 2020 to December 2021. Data were obtained by review of medical files. Associations between superinfections and mortality were assessed by logistic regression analyses adjusted for sex and age. RESULTS: Fifty patients, median age 53 years (interquartile range [IQR] 45-59), 66% male, were included. Median time on VV-ECMO was 14.5 days (IQR 6.3-23.5), 42% were discharged from hospital alive. Bacteremia, ventilator associated pneumonia (VAP), invasive candidiasis, pulmonary aspergillosis, herpes simplex virus, and cytomegalovirus (CMV) were detected in 38%, 42%, 12%, 12%, 14%, and 20% of patients, respectively. No patients with pulmonary aspergillosis survived. CMV was associated with increased risk of death, odds ratio 12.6 (95% confidence interval 1.9-257, p = .05), whereas we found no associations between other superinfections and risk of death. CONCLUSION: Bacteremia and VAP are common but does not seem to affect mortality, whereas pulmonary aspergillosis and CMV are associated with poor prognosis among COVID-19 patients treated with VV-ECMO.

SARS-CoV-2 Associated Immune Dysregulation and COVID-Associated Pulmonary Aspergilliosis (CAPA): A Cautionary Tale.

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

Case Report: Chronic Cavitatory Pulmonary Aspergillosis after COVID-19.

Chronic pulmonary aspergillosis can present in four distinct clinical syndromes, one of which is chronic cavitary pulmonary aspergillosis (CCPA). CCPA is generally associated with a mildly immunosuppressed state or, in immunocompetent patients, with structural lung damage. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with reactivation of previous quiescent infections such as tuberculosis and invasive fungal infections, but CCPA in a patient with COVID-19 is rarely reported. Here we present the case of a 57-year-old man with CCPA associated with COVID-19 infection in whom latent aspergilloma was most likely activated after SARS-CoV-2 infection. The patient presented with severe COVID and, after initial response to treatment, started to deteriorate due to reactivation of latent aspergilloma to a more aggressive CCPA form. After confirmation of the diagnosis, the patient was initiated on treatment with voriconazole. He showed a good response to treatment with clinicoradiological response. This case also depicts one of the common causes of clinical deterioration in otherwise recovering COVID-19 patients.

COVID-19-Associated Pulmonary Aspergillosis in a Series of Complete Autopsies from the Brazilian Amazon.

Between April and July 2020, and, therefore, prior to the broad recommendation of corticosteroids for severe COVID-19, a total of 50 full autopsies were performed in Manaus. We confirmed two invasive cases of aspergillosis through histopathology and gene sequencing (4%) in our autopsy series. The confirmed invasive aspergillosis incidence seems much lower than expected based on the "probable and possible" definitions, and an individualized approach should be considered for each country scenario. Interestingly, a prolonged length of stay in the intensive care unit was not observed in any of the cases. Timely diagnosis and treatment of fungal infection can reduce mortality rates.

Thoracic Air Leak Syndrome, Pulmonary Aspergillosis, and COVID-19 Pneumonia After Allogeneic Stem Cell Transplantation in a Child With Myelodysplastic Syndrome.

Thoracic air leak syndromes (TALS) are very rare among the noninfectious pulmonary complications (PCs). They can either be idiopathic or have several risk factors such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), graft versus host disease and rarely pulmonary aspergillosis. We present a 14-year-old girl with hypoplastic myelodysplastic syndrome who developed graft versus host disease on day 60, TALS on day 150, bronchiolitis obliterans syndrome on day 300, pulmonary aspergillosis on day 400 and COVID-19 pneumonia on day 575 after allo-HSCT. This is the first report of a child who developed these subsequent PCs after allo-HSCT. Therefore, the manifestations of these unfamiliar PCs like TALS and COVID-19 pneumonia, and concomitant pulmonary aspergillosis with management options are discussed.

Proven Aspergillus flavus pulmonary aspergillosis in a COVID-19 patient: A case report and review of the literature.

Severe COVID-19 patients complicated with aspergillosis are increasingly reported. We present a histopathological proven case of fatal COVID-19-associated pulmonary aspergillosis (CAPA), due to Aspergillus flavus. This report and existing published literature indicate diagnostic challenges and poor outcomes of CAPA in ICU patients.

COVID-19-associated pulmonary aspergillosis: a prospective single-center dual case series.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as an invasive fungal disease, often affecting previously immunocompetent, mechanically ventilated, intensive care unit (ICU) patients. Incidence rates of 3.8%-33.3% have been reported depending on the geographic area, with high (47%) mortality. OBJECTIVES: Here, we describe a single-centre prospective case series with CAPA cases from both the first (March-May, n = 5/33) and second (mid-September through mid-December, n = 8/33) COVID-19 wave at a 500-bed teaching hospital in the Netherlands. PATIENTS/METHODS: In the first COVID-19 wave, a total of 265 SARS-CoV-2 PCR-positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, 508 SARS-CoV-2 PCR-positive patients were admitted of whom 33 needed mechanical ventilation. Data were prospectively collected. RESULTS: We found a significant decrease in COVID-19 patients needing mechanical ventilation in the ICU in the second wave (p < .01). From these patients, however, a higher percentage were diagnosed with CAPA (24.2% vs 15.2%), although not significant (p = .36). All CAPA patients encountered in the second wave received dexamethasone. Mortality between both groups was similarly high (40%-50%). Moreover, we found environmental TR34 /L98H azole-resistant Aspergillus fumigatus isolates in two separate patients. CONCLUSIONS: In this series, 19.7% (n = 13/66) of mechanically ventilated SARS-CoV-2 patients were diagnosed with CAPA. In addition, we found a significant reduction in COVID-19 patients needing mechanical ventilation on the ICU in the second wave. Numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS-CoV-2 therapy.

Accuracy of galactomannan testing on tracheal aspirates in COVID-19-associated pulmonary aspergillosis.

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

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

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

A complex COVID-19 case with rheumatoid arthritis treated with tocilizumab.

Recurrences of COVID-19 were observed in a patient with long-term usage of hydroxychloroquine, leflunomide, and glucocorticoids due to her 30-year history of rheumatoid arthritis (RA). Tocilizumab was applied and intended to target both COVID-19 and RA. However, disease of this patient aggravated after usage of tocilizumab. After the discussion of a multiple disciplinary team (MDT) including rheumatologists, antimicrobial treatments were applied to target the potential opportunistic infections (Pneumocystis jirovecii and Aspergillus fumigatus), which were authenticated several days later via high throughput sequencing. As an important cytokine in immune responses, IL-6 can be a double-edged sword: interference in the IL-6-IL-6 receptor signaling may save patients from cytokine release storm (CRS), but can also weaken the anti-infectious immunity, particularly in rheumatic patients, who may have received a long-term treatment with immunosuppressive/modulatory agents. Thus, we suggest careful considerations before and close monitoring in the administration of tocilizumab in rheumatic patients with COVID-19. Besides tocilizumab, several disease-modifying antirheumatic drugs (DMARDs) can also be applied in the treatment of COVID-19. Therefore, we also reviewed and discussed the application of these DMARDs in COVID-19 condition.

Fatal Invasive Aspergillosis and Coronavirus Disease in an Immunocompetent Patient.

Invasive pulmonary aspergillosis is a complication in critically ill patients with acute respiratory distress syndrome, especially those with severe influenza pneumonia. We report a fatal case of invasive pulmonary aspergillosis in an immunocompetent patient in France who had severe coronavirus disease-associated pneumonia.