3  RESULTS
A total of seven patients with COVID‐19 who had one or more positive respiratory cultures for Aspergillus fumigatus were identified. According to the AspICU algorithm, 7  four patients were classified as putative IPA. None of the patients had European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) host factors, including neutropenia and prolonged use of corticosteroids. Only one patient had a pre‐existing lung disease (chronic obstructive pulmonary disease in Patient 1). All four patients had compatible signs (fever refractory to at least 3 days of appropriate therapy or worsening respiratory insufficiency despite appropriate antibiotic therapy and ventilatory support), host factor (glucocorticoid treatment with prednisone equivalent > 20 mg/d) and abnormal radiographic findings. Radiographic abnormalities included worsening infiltrates (Patient 1), opacities with dense consolidations (Patient 2), cavitary pneumonia (Patient 3) and diffuse interstitial and patchy hazy opacities (Patient 4). The remaining three patients were classified as having colonisation as they lacked compatible clinical signs. For those three patients, subsequent clinical deterioration was explained by other causes. Clinical characteristics of the patients with putative IPA are shown in Table 1. The median age was 79 years. All experienced worsening respiratory status leading to invasive mechanical ventilation before the isolation of Aspergillus fumigatus. The patients had been mechanically ventilated for a mean of 6.8 days (range: 1‐14 days) before Aspergillus isolation. At Aspergillus isolation, fever and leukocytosis were present in one and all four patients, respectively. Serum galactomannan level was positive for only one patient (Patient 2). All patients received concomitant broad‐spectrum antibiotic therapy.
Table 1  Clinical characteristics of critically ill COVID‐19‐infected patients with putative invasive pulmonary aspergillosis
Patient 1  Patient 2  Patient 3  Patient 4
Age (y)  82  79  77  77
Gender  Male  Male  Male  Male
Comorbid conditions
Hypertension  No  Yes  No  No
Diabetes  No  No  No  Yes
Coronary artery disease  No  Yes  No  No
Chronic obstructive pulmonary disease  Yes  No  No  No
History of cerebrovascular accident  No  Yes  No  No
History of cancer  Yes  Yes  No  No
Dementia  No  No  No  No
Timing of positive culture for Aspergillus fumigatus (hospital day)  Day 15 and 20  Day 7, 10, and 16  Day 10 and 14  Day 10
Clinical features at Aspergillus isolation
Fever  No  No  Yes  No
Respiratory status at Aspergillus isolation  IMV  IMV  IMV  IMV
New radiographic abnormalities on chest CT or X‐ray  Worsening infiltrates  Opacities with dense consolidations  Cavitary pneumonia  Diffuse interstitial and patchy hazy opacities
White blood cell count (103/μL)  32.9  21.1  20.1  20.2
Platelet count (103/μL)  376  146  420  123
Procalcitonin (ng/mL)  0.16  0.30  3.30  9.34
Lactic acid (mmol/L)  1.0  3.6  1.6  3.7
Total bilirubin (mg/dL)  2.4  1.1  1.4  2.9
Serum creatinine (mg/dL)  2.6  3.1  1.5  4.1
Serum galactomannan  NA  0.71  Negative  Negative
Vasopressor support  Yes  Yes  Yes  Yes
Inpatient medications
Glucocorticoids
Cumulative dose in prednisone equivalent (mg)  932  1000  870  87
Starting date (hospital day)  Day 8  Day 2  Day 2  Day 10
Duration (d)  10  10  12  3
Tocilizumab  No  Yes  No  No
Antibiotics  Cefepime + Vancomycin  Cefepime + Vancomycin  Meropenem + Vancomycin  Cefepime + Vancomycin
Antifungal therapy  Voriconazole  Voriconazole  Voriconazole  Caspofungin
Abbreviations: IMV, invasive mechanical ventilation; NA, not available.
John Wiley & Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. All four patients concomitantly received glucocorticoids, with three of which were already given steroids for a mean of 6.6 days (range: 5‐8 days) before the isolation of Aspergillus. In the remaining one patient (patients 4), glucocorticoid therapy was administered at Aspergillus isolation. The overall mean duration of glucocorticoid exposure was 8.5 days (range: 3‐11 days) with a mean cumulative prednisone equivalent dose of 722 mg (range: 87‐1000 mg). One patient received tocilizumab after Aspergillus isolation (Patient 3).
Patient 1 was an 82‐year‐old man with a history of COPD and pharyngeal cancer who was transferred to the ICU on hospital day 3 for acute respiratory distress syndrome (ARDS) and septic shock. He was afebrile at Aspergillus isolation on hospital day 15, but respiratory status deteriorated with increased FiO2 from 50% to 80%. A chest radiograph showed worsening bilateral infiltrates. He was initially treated with cefepime and vancomycin. Voriconazole was added 3 days after the first positive culture for Aspergillus. Leukocytosis persisted on broad‐spectrum antibiotics and voriconazole. He developed intermittent fever with worsening respiratory status and required continued vasopressor support. The family subsequently requested no further aggressive treatment, and he passed away 17 days after the initiation of antifungal therapy.
Patient 2 was a 79‐year‐old man with a history of hypertension, coronary artery disease, transient ischaemic attack, and renal cell carcinoma who was transferred to the ICU on hospital day 6 for worsening acute hypoxemic respiratory failure requiring intubation and mechanical ventilation. He was afebrile and had been on non‐invasive ventilation (NIV) for 6 days before Aspergillus isolation on hospital day 7. Respiratory culture grew Aspergillus fumigatus and Staphylococcus aureus. A chest CT showed dense bilateral lower lobe consolidations, multifocal ground‐glass opacities, pneumomediastinum and pneumopericardium. He was initially treated with cefepime and vancomycin. Voriconazole was started at the second positive culture for Aspergillus. A repeat chest CT showed similar findings together with worsening ground‐glass opacities. Despite subsequent treatment with meropenem, vancomycin, and voriconazole, he continued to deteriorate with persistent leukocytosis, worsening respiratory status, and multiorgan dysfunction. He expired 13 days after the initiation of antifungal therapy.
Patient 3 was a 77‐year‐old man with no past medical history who was admitted to the ICU for acute hypoxemic respiratory failure requiring intubation. He developed a fever at Aspergillus isolation on hospital day 10. Respiratory status had remained stable. He was initially treated with meropenem and vancomycin. Fever persisted for 4 days, and voriconazole was added. A chest CT showed bilateral patchy ground‐glass opacities, bilateral mid to lower lung zone predominant consolidative opacities, bilateral lower lobe cavitary lesions, the largest of which is seen within the right lung base and one of which contains an air‐fluid level. He was then treated with voriconazole only. Fever and leukocytosis subsided within 6 days. A repeat chest CT after 2 weeks of voriconazole showed improved bilateral ground‐glass opacities, stable to mildly improved cavitary pneumonia within the bilateral lower lobes, and a new cavitary lesion within the subpleural left lower lobe. The subsequent course was complicated by intravenous catheter‐related thrombophlebitis with Staphylococcus epidermidis bacteremia, which was treated with vancomycin. He had a protracted hospital course with persistent metabolic encephalopathy, chronic respiratory failure required tracheostomy, multiorgan dysfunction and subsequent Staphylococcus pneumonia. Due to a lack of improvement, the family requested comfort care, and he expired after 1 month of antifungal therapy.
Patient 4 was a 77‐year‐old man with a history of type 2 diabetes mellitus who was transferred to the ICU on hospital day 8 for worsening acute hypoxemic respiratory failure. He had been on NIV for 8 days and on cefepime and vancomycin until respiratory status further deteriorated, which required intubation and transfer to the ICU 2 days before Aspergillus isolation. He was afebrile at Aspergillus isolation on hospital day 10. Chest radiographs showed diffuse ground‐glass opacities. Caspofungin was started together with meropenem and vancomycin. He continued to deteriorate with multiorgan dysfunction and expired after 3 days of antifungal therapy.