COVID‐19 associated pulmonary aspergillosis

Summary Objectives Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID‐19) associated invasive aspergillosis at a single centre in Cologne, Germany. Methods A retrospective chart review of all patients with COVID‐19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. Results COVID‐19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. Conclusion Clinicians caring for patients with ARDS due to COVID‐19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co‐infection.


| INTRODUC TI ON
Since December 2019 coronavirus disease 2019  emerged from Wuhan City, Hubei province, China and rapidly spread around the globe becoming a pandemic threat. 1 Risk factors for invasive pulmonary aspergillosis (IPA) are well defined in immunocompromised populations. However, patients with acute respiratory distress syndrome (ARDS) due to viral infection are prone to secondary complications like invasive aspergillosis despite lack of underlying well-defined immunocompromising disease. [2][3][4] Possible explanations for this could be an immune-paralysis caused by viral infection-induced ARDS and hypoxia compromising the innate host defence. 5 In light of influenza-pulmonary associated aspergillosis, we retrospectively analysed our patients with COVID-19 associated ARDS in the intensive care unit (ICU) at a single centre.

| PATIENTS AND ME THODS
We performed a retrospective chart review of patients with COVID-19 and ARDS admitted to the medical and surgical ICU at the University Hospital of Cologne, a 1540-bed teaching hospital between 7 March 2020 and 22 April 2020 (Table 1).
Respective C t values are given in Table 1

| RE SULTS
A 62-year-old woman was admitted to our ICU. She was intubated and developed severe ARDS with a Horowitz-Index of 53 mm Hg.
At the contrast-enhanced CT a combination of emphysema, bilateral ground-glass opacities with crazy paving and some peripheral nodular consolidations were seen (Video S1, patient #1, Figure 1A).
The patient developed severe intrapulmonary bleeding from the right main bronchus, which was stanched by cold lavages and instillation of tranexamic acid. BALF culture grew Aspergillus fumigatus, was positive for galactomannan, and intravenous voriconazole treatment was commenced.
A 70-year-old man was admitted to the ICU because of ARDS with a Horowitz-Index of 93 mm Hg. PCR on BALF was tested positive for hMPV, SARS-CoV-2 and Aspergillus fumigatus. Two days before, serum galactomannan had turned positive. BALF was tested positive for galactomannan. Chest CT showed ground-glass opacities with some small nodular infiltrations of up to 1 cm (Video S2, patient #2 Figure 1B). Due to acute renal failure requiring slow low-efficient daily dialysis (SLEDD) and elevated liver enzymes, intravenous isavuconazole treatment was started.
A 54-year-old man presented with ARDS with a Horowitz-Index of 128 mm Hg. TA revealed SARS-CoV-2 PCR positive and Aspergillus fumigatus in culture. BALF was positive for galactomannan. Chest CT showed bilateral ground-glass opacities, diffuse nodular infiltrates and cystic cavities and partly air crescent sign (Video S3, patient #3 Figure 1C). Intravenous voriconazole treatment was initiated.
A 73-year-old man was transferred to the ICU due to ARDS with PCR on TA tested positive for SARS-CoV-2, and Aspergillus fumigatus that also grew in culture. Chest CT showed known bullous emphysema with ground-glass opacities and consolidations with nodular infiltrates (Video S4, patient #4, Figure 1D). Intravenous voriconazole was begun.
A 54-year-old woman was transferred to the ICU due to ARDS with PCR on TA tested positive for SARS-CoV-2. Serum galactomannan returned positive in two consecutive serum samples. Chest CT showed bilateral ground-glass opacities, smaller areas with crazy paving pattern, central and peripheral consolidations, and smaller nodular infiltrates (Video S5, patient #5, Figure 1E). Intravenous caspofungin was started. No autopsies were performed. Detailed patient characteristics are given in Table 1.

| D ISCUSS I ON
Patients with ARDS triggered by viral infection, in particular influenza, are prone to invasive aspergillosis even in absence of prior immunodeficiency. 2 PCR TA: positive for hMPV and SARS-CoV-2 (E-gene: C t 13.29; S-gene: CT imaging studies Combined bilateral ground-glass opacities with crazy paving and peripheral nodular consolidations (Video S1, Figure 1A) Ground-glass opacities with occasional nodules (Video S2, Figure 1B) Bilateral ground-glass opacities, nodular infiltrates with cavities and air crescent sign (Video S3, Figure 1C) Ground-glass opacities with occasional nodules, known bullous emphysema (Video S4, Figure 1D) Ground-glass opacities, smaller areas with crazy paving pattern, central and peripheral consolidations, and smaller nodular infiltrates (Video S5, Figure 1E) Therapy Antifungal treatment Voriconazole iv ( Our findings need to be confirmed in clinical trials to elucidate the role of potential IPA after COVID-19. With this report, we aim to call attention to the critical phenomenon of COVID-19 associated IA in ARDS patients.

ACK N OWLED G M ENT
The authors thank Susann Blossfeld for technical assistance.

CO N FLI C T O F I NTE R E S T
PK has received non-financial scientific grants from Miltenyi Biotec