2. Case Report and Results
A 74-year-old patient was admitted because of respiratory insufficiency amid the COVID-19 crisis. Eleven days prior to admission, she had been suffering from fever (38.5 °C) and a dry cough. Three days after symptom onset, she developed diarrhea. Her medical history included complaints of reflux and pain due to arthrosis of the hip and knees, for which she uses a proton-pump inhibitor and a nonsteroidal anti-inflammatory drug pantoprazol and etoricoxib, respectively. She stopped smoking 20 years ago and was healthy and fit otherwise. Patient characteristics can be found in Table 1. This study, “Clinical course and prognostic factors for COVID-19” with project identification code CWZ-nr 027-2020, was approved in March 20202 by the Canisius Wilhelmina Hospital medical ethics committee and patient informed consent was acquired antemortem with opt out possibility.
At presentation to the emergency department, she had been feeling progressively dyspneic for two days. On physical examination, her oxygenation was 82%, with 28 breaths per minute in room air, pulmonary wheezing and an extended expiration. Oxygenation improved to 94% with 5 L O2 via a nasal cannula, but she desaturated during speech. Her BMI was 27.7 (80 kg) and her temperature 37.8 °C. No other aberrant observations on physical examination were made. Her Glasgow Coma Scale was 15 and her ECG was normal. Her C-reactive protein (CRP) was 214 mg/L, and other laboratory findings included slightly elevated leucocytes (12.6 × 109 /L) and neutrophils (8.4 × 109 /L), elevated liver enzymes (alkaline phosphatase 528 U/L; GGT 376 U/L; AST 76 U/L; LD 745 U/L), slightly elevated pro-calcitonin (0.25 µg/L; <0.5 µg/L not suggestive of bacterial infection), increased ferritin (1442 µg/L), and normal electrolyte, glucose and renal function. SARS-CoV-2 nasopharyngeal and throat swabs were taken. A low-dose chest CT demonstrated extensive centralized and peripheral bilateral ground glass opacities with left-sided consolidations and bilateral fibrotic bands without pleural effusions and vascular enlargement (Figure 1). The CO-RADS score was 5 and CT-severity score was 24 out of 25 [11].
Because of the high probability of SARS-CoV-2 infection, chloroquine treatment was started (600 mg and 300 mg on day 1, 300 mg q12h days 2–5), which was national policy at the time. The SARS-CoV-2 PCR of a nasopharyngeal swab was positive (Ct 30.59; E gene [12]). Blood cultures remained negative, as were nasopharynx bacterial cultures taken at admission. The patient was subsequently admitted to our general inpatient respiratory ward. An overview of her hospital course is depicted in Figure 2.
The CRP remained highly stable over the following days at around 200 mg/L with a range of 192–214. However, the patient needed increasing oxygenation with a non-rebreathing mask. Empirical treatment of a suspected bacterial superinfection was started with ceftriaxone i.v. 2000 mg q24h. Five days after admission, the maximum (15 L O2) oxygenation with the non-rebreathing mask became insufficient and the patient was admitted to the ICU for respiratory support and intensive monitoring.
In the ICU, HFNO (high-flow nasal oxygen therapy) and selective digestive decontamination (SDD) were initiated, which includes ceftriaxone i.v. 2000 mg q24h for 4 days and a combined oral non-absorbable suspension of amphotericin B, colistin and tobramycin q6h. In this patient, ceftriaxone was continued de facto for another 4 days. Routine bacterial and fungal (peri-anal, throat and tracheal aspirate) surveillance cultures were done twice weekly in adherence with our local SDD policy [13]. Within a few hours after admission to the ICU, her blood oxygenation became insufficient with HFNO at FiO2 100% and 60 L/min flow. Therefore, she was sedated, intubated and put on a mechanical ventilator. A CT angiography of the chest was performed which demonstrated significant bilateral pulmonary emboli. Anticoagulants (enoxaparine anti-factor Xa) were initiated in therapeutic dosages. Pressure control ventilation was required with the patient in prone position. Because of the need for increasing noradrenaline dosages during circulatory shock, hydrocortisone 100 mg q8h was initiated and continued for five days. Cardiac ultrasound showed a minor tricuspid insufficiency but no major pathology.
Aspergillus fumigatus was recovered from high-volume tracheal aspirate cultures [14] obtained at ICU admission. Aspergillus galactomannan (Platelia Aspergillus; Bio-Rad, Marnes-La-Coquette, France) ratio at this time was >3.0 (positive) in a tracheal aspirate and β-d-glucan (Fungitell assay; Associates of Cape Cod Inc., East Falmouth, MA, USA) in serum was 1590 pg/mL (positive), after which a putative diagnosis of CAPA was made. Serum galactomannan remained negative (<0.5) in three subsequent samples. Voriconazole i.v. 6 mg/kg q12h was started in addition to caspofungin i.v. 70 mg q24h until the VIPcheck (Mediaproducts BV, Groningen, The Netherlands), used to detect azole resistance, was negative. MICs determined with broth microdilution using CLSI methodology of the A. fumigatus isolate were as follows: amphotericin B 0.5 mg/L, micafungin and anidulafungin <0.016 mg/L, itraconazole 1 mg/L, voriconazole 0.25 mg/L, and posaconazole 0.063 mg/L. Voriconazole was switched to oral administration of 200 mg q12h with discontinuation of caspofungin. During SDD, bacterial cultures remained negative throughout her stay in the ICU.
On day 6 after admission (day 2 at the ICU), continuous venovenous hemofiltration was initiated because of rapidly progressive acute renal failure. A. fumigatus was persistently cultured from tracheal aspirate samples during voriconazole treatment and β-d-glucan levels remained positive with 1149 and 1458 pg/µl, at 1 and 6 days (day 8 and 13 after hospital admission) of voriconazole therapy, respectively. Voriconazole serum therapeutic drug monitoring was performed as recommended [15], with therapeutic concentrations of 4.72 mg/L, 2.78 mg/L and 1.43 mg/L at day 13, 15 and 17, respectively.
The respiratory situation improved marginally in the subsequent 7 days but declined steadily thereafter. Pressure support and pressure control ventilation were alternated between days 12 and 19 and attempts to return the patient to a supine position failed several times. After 7 days, A. fumigatus grew on the itraconazole and voriconazole wells of the second VIPcheck on day 19 (tracheal aspirate culture). MICs of this A. fumigatus isolate were as follows: amphotericin B 0.5 mg/L, anidulafungin and micafungin <0.016 mg/L, itraconazole 16 mg/L, voriconazole 2 mg/L and posaconazole 0.5 mg/L. Voriconazole treatment was changed to liposomal amphotericin B 200 mg q24h. Subsequent cyp51A gene sequencing identified a TR34/L98H mutation, probably responsible for the observed azole resistance. On day 22, ventilation and oxygenation of the patient deteriorated further without further treatment options and therapy was discontinued on day 23. An autopsy was not performed.