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PMC:7344504 JSONTXT 18 Projects

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Id Subject Object Predicate Lexical cue
T1 0-87 Sentence denotes Azole-Resistant COVID-19-Associated Pulmonary Aspergillosis in an Immunocompetent Host:
T2 88-101 Sentence denotes A Case Report
T3 103-111 Sentence denotes Abstract
T4 112-289 Sentence denotes COVID-19-associated pulmonary aspergillosis (CAPA) is a recently described disease entity affecting patients with severe pulmonary abnormalities treated in intensive care units.
T5 290-362 Sentence denotes Delays in diagnosis contribute to a delayed start of antifungal therapy.
T6 363-510 Sentence denotes In addition, the emergence of resistance to triazole antifungal agents puts emphasis on early surveillance for azole-resistant Aspergillus species.
T7 511-647 Sentence denotes We present a patient with putative CAPA due to Aspergillus fumigatus with identification of a triazole-resistant isolate during therapy.
T8 648-819 Sentence denotes We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance.
T9 821-823 Sentence denotes 1.
T10 824-836 Sentence denotes Introduction
T11 837-1028 Sentence denotes There have been suggestions that coronavirus disease 2019 (COVID-19) might increase the risk of superinfections [1] and, particularly, invasive pulmonary aspergillosis (IPA) co-infection [2].
T12 1029-1204 Sentence denotes COVID-19-associated pulmonary aspergillosis (CAPA) is a recently described disease entity affecting patients in intensive care unit (ICUs) with severe pulmonary abnormalities.
T13 1205-1391 Sentence denotes Small cohorts of 31 patients in the Netherlands [3], 27 patients in France [4] and 19 patients in Germany [5] have been published, showing CAPA rates of 19.4%, 33% and 26%, respectively.
T14 1392-1459 Sentence denotes An additional two fatal cases of CAPA were recently reported [6,7].
T15 1460-1715 Sentence denotes The numbers resemble what has been observed in influenza, where influenza in ICU patients has been identified as an independent risk factor for invasive pulmonary aspergillosis and which is associated with an even higher mortality rate than IPA alone [8].
T16 1716-1904 Sentence denotes In addition, in the Netherlands, an estimated 11.3% of cases with invasive aspergillosis are infected with an azole-resistant isolate [9], potentially increasing mortality to 50–100% [10].
T17 1905-2041 Sentence denotes We present the first case of azole-resistant Aspergillus fumigatus in a SARS-CoV-2-positive immunocompetent patient admitted to the ICU.
T18 2043-2045 Sentence denotes 2.
T19 2046-2069 Sentence denotes Case Report and Results
T20 2070-2167 Sentence denotes A 74-year-old patient was admitted because of respiratory insufficiency amid the COVID-19 crisis.
T21 2168-2260 Sentence denotes Eleven days prior to admission, she had been suffering from fever (38.5 °C) and a dry cough.
T22 2261-2316 Sentence denotes Three days after symptom onset, she developed diarrhea.
T23 2317-2541 Sentence denotes 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.
T24 2542-2609 Sentence denotes She stopped smoking 20 years ago and was healthy and fit otherwise.
T25 2610-2658 Sentence denotes Patient characteristics can be found in Table 1.
T26 2659-2942 Sentence denotes 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.
T27 2943-3045 Sentence denotes At presentation to the emergency department, she had been feeling progressively dyspneic for two days.
T28 3046-3182 Sentence denotes On physical examination, her oxygenation was 82%, with 28 breaths per minute in room air, pulmonary wheezing and an extended expiration.
T29 3183-3278 Sentence denotes Oxygenation improved to 94% with 5 L O2 via a nasal cannula, but she desaturated during speech.
T30 3279-3332 Sentence denotes Her BMI was 27.7 (80 kg) and her temperature 37.8 °C.
T31 3333-3398 Sentence denotes No other aberrant observations on physical examination were made.
T32 3399-3452 Sentence denotes Her Glasgow Coma Scale was 15 and her ECG was normal.
T33 3453-3882 Sentence denotes 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.
T34 3883-3937 Sentence denotes SARS-CoV-2 nasopharyngeal and throat swabs were taken.
T35 3938-4163 Sentence denotes 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).
T36 4164-4232 Sentence denotes The CO-RADS score was 5 and CT-severity score was 24 out of 25 [11].
T37 4233-4414 Sentence denotes 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.
T38 4415-4496 Sentence denotes The SARS-CoV-2 PCR of a nasopharyngeal swab was positive (Ct 30.59; E gene [12]).
T39 4497-4589 Sentence denotes Blood cultures remained negative, as were nasopharynx bacterial cultures taken at admission.
T40 4590-4670 Sentence denotes The patient was subsequently admitted to our general inpatient respiratory ward.
T41 4671-4730 Sentence denotes An overview of her hospital course is depicted in Figure 2.
T42 4731-4829 Sentence denotes The CRP remained highly stable over the following days at around 200 mg/L with a range of 192–214.
T43 4830-4909 Sentence denotes However, the patient needed increasing oxygenation with a non-rebreathing mask.
T44 4910-5003 Sentence denotes Empirical treatment of a suspected bacterial superinfection was started with ceftriaxone i.v.
T45 5004-5017 Sentence denotes 2000 mg q24h.
T46 5018-5218 Sentence denotes 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.
T47 5219-5362 Sentence denotes In the ICU, HFNO (high-flow nasal oxygen therapy) and selective digestive decontamination (SDD) were initiated, which includes ceftriaxone i.v.
T48 5363-5480 Sentence denotes 2000 mg q24h for 4 days and a combined oral non-absorbable suspension of amphotericin B, colistin and tobramycin q6h.
T49 5481-5552 Sentence denotes In this patient, ceftriaxone was continued de facto for another 4 days.
T50 5553-5713 Sentence denotes Routine bacterial and fungal (peri-anal, throat and tracheal aspirate) surveillance cultures were done twice weekly in adherence with our local SDD policy [13].
T51 5714-5844 Sentence denotes Within a few hours after admission to the ICU, her blood oxygenation became insufficient with HFNO at FiO2 100% and 60 L/min flow.
T52 5845-5918 Sentence denotes Therefore, she was sedated, intubated and put on a mechanical ventilator.
T53 5919-6021 Sentence denotes A CT angiography of the chest was performed which demonstrated significant bilateral pulmonary emboli.
T54 6022-6104 Sentence denotes Anticoagulants (enoxaparine anti-factor Xa) were initiated in therapeutic dosages.
T55 6105-6182 Sentence denotes Pressure control ventilation was required with the patient in prone position.
T56 6183-6334 Sentence denotes Because of the need for increasing noradrenaline dosages during circulatory shock, hydrocortisone 100 mg q8h was initiated and continued for five days.
T57 6335-6416 Sentence denotes Cardiac ultrasound showed a minor tricuspid insufficiency but no major pathology.
T58 6417-6528 Sentence denotes Aspergillus fumigatus was recovered from high-volume tracheal aspirate cultures [14] obtained at ICU admission.
T59 6529-6849 Sentence denotes 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.
T60 6850-6923 Sentence denotes Serum galactomannan remained negative (<0.5) in three subsequent samples.
T61 6924-6941 Sentence denotes Voriconazole i.v.
T62 6942-6998 Sentence denotes 6 mg/kg q12h was started in addition to caspofungin i.v.
T63 6999-7123 Sentence denotes 70 mg q24h until the VIPcheck (Mediaproducts BV, Groningen, The Netherlands), used to detect azole resistance, was negative.
T64 7124-7373 Sentence denotes 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.
T65 7374-7474 Sentence denotes Voriconazole was switched to oral administration of 200 mg q12h with discontinuation of caspofungin.
T66 7475-7555 Sentence denotes During SDD, bacterial cultures remained negative throughout her stay in the ICU.
T67 7556-7703 Sentence denotes On day 6 after admission (day 2 at the ICU), continuous venovenous hemofiltration was initiated because of rapidly progressive acute renal failure.
T68 7704-7964 Sentence denotes 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.
T69 7965-8152 Sentence denotes 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.
T70 8153-8257 Sentence denotes The respiratory situation improved marginally in the subsequent 7 days but declined steadily thereafter.
T71 8258-8424 Sentence denotes 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.
T72 8425-8561 Sentence denotes After 7 days, A. fumigatus grew on the itraconazole and voriconazole wells of the second VIPcheck on day 19 (tracheal aspirate culture).
T73 8562-8748 Sentence denotes 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.
T74 8749-8824 Sentence denotes Voriconazole treatment was changed to liposomal amphotericin B 200 mg q24h.
T75 8825-8947 Sentence denotes Subsequent cyp51A gene sequencing identified a TR34/L98H mutation, probably responsible for the observed azole resistance.
T76 8948-9096 Sentence denotes On day 22, ventilation and oxygenation of the patient deteriorated further without further treatment options and therapy was discontinued on day 23.
T77 9097-9126 Sentence denotes An autopsy was not performed.
T78 9128-9130 Sentence denotes 3.
T79 9131-9141 Sentence denotes Discussion
T80 9142-9297 Sentence denotes We report the first case of azole-resistant CAPA, which occurred in an immunocompetent host during ICU support without a previous history of azole therapy.
T81 9298-9590 Sentence denotes The A. fumigatus cyp51A gene TR34/L98H mutation found in this patient has been well described as an environmentally acquired mutation [16], which is in line with data from clinical studies where two-thirds of patients with azole-resistant infections had no history of azole pretreatment [10].
T82 9591-9808 Sentence denotes This case underscores the importance of early diagnosis and the need for resistance surveillance, comparable to what has been described in influenza patients [9,17], given the emergence of triazole resistance [18,19].
T83 9809-10077 Sentence denotes The sensitivity for detection of resistance in primary cultures with the VIPcheck plate depends on the number of A. fumigatus colonies that are tested, as clinical cultures may contain both mixed azole-susceptible and azole-resistant isolates during an infection [20].
T84 10078-10275 Sentence denotes We suspect that A. fumigatus isolated in the first tracheal aspirate was already a mixed culture but was missed in initial fungal cultures due to abundance of azole-susceptible A. fumigatus spores.
T85 10276-10424 Sentence denotes Molecular detection could have given a suggestion to the presence of a mixed culture [21] but PCR could not be performed due to absence of material.
T86 10425-10611 Sentence denotes The TR34/L98H had a phenotype with high itraconazole MIC (>16 mg/L) and low voriconazole MIC (2 mg/L), similar to strains which have been described only recently in the Netherlands [22].
T87 10612-10692 Sentence denotes IPA is known to be problematic to diagnose in the non-neutropenic ICU host [23].
T88 10693-10969 Sentence denotes Regardless of the compelling evidence for CAPA in this patient, the EORTC/MSGERC [24] host criteria for invasive fungal disease were not met, nor did the patient meet the AspICU algorithm because we tested tracheal aspirates instead of bronchoalveolar lavage (BAL) fluid [25].
T89 10970-11100 Sentence denotes This is in line with findings from other groups, where CAPA patients did not meet the EORTC/MSGERC host criteria either [3,4,5,6].
T90 11101-11333 Sentence denotes In addition, the American Association for Bronchology and Interventional Pulmonology (AABIP) has issued a statement advising against routine bronchoscopy in COVID-19 patients, as it poses substantial risk to patients and staff [26].
T91 11334-11483 Sentence denotes BAL should only be considered in intubated patients if upper respiratory samples are negative and BAL would significantly change clinical management.
T92 11484-11624 Sentence denotes Tracheal aspirate cultures, as performed twice weekly in our patient, repeatedly identified A. fumigatus as the only micro-organism present.
T93 11625-11772 Sentence denotes In the first positive culture, five colonies were tested for resistance with the VIPcheck plate as is recommended to exclude azole resistance [15].
T94 11773-12043 Sentence denotes When surveillance cultures of tracheal aspirates were persistently cultured positive with A. fumigatus during voriconazole therapy, we suspected the selection of resistant isolates which were probably already present in the first samples, albeit in undetectable numbers.
T95 12044-12083 Sentence denotes An autopsy to confirm IPA was not done.
T96 12084-12251 Sentence denotes Serum galactomannan testing has been shown to be a fairly sensitive diagnostic tool (70%) in neutropenic patients with pathology-proven invasive aspergillosis [27,28].
T97 12252-12507 Sentence denotes However, in patients who are non-neutropenic, serum galactomannan sensitivity of around 25% has been reported [27], which may explain the low number of serum galactomannan positive findings in recently published case reports [6,7] and case series [3,4,5].
T98 12508-12660 Sentence denotes The role of β-d-glucan and the Aspergillus-specific lateral flow device (LFD) as an adjunct to the diagnosis of IPA in COVID-19 is not yet clear [2,23].
T99 12661-12755 Sentence denotes Serum β-d-glucan was persistently strongly positive in this patient over the course of a week.
T100 12756-13003 Sentence denotes The specificity for invasive fungal disease of β-d-glucan testing in a mixed ICU population has been shown to be high (86%), with two consecutive positive results [29] compared to those with only fungal colonization and no invasive fungal disease.
T101 13004-13154 Sentence denotes In addition, multiple other studies report a good sensitivity for the diagnosis of invasive aspergillosis in critically ill patients [30,31,32,33,34].
T102 13155-13299 Sentence denotes BAL β-d-glucan in the ICU setting is, however, not recommended, due to its poor specificity and confounders causing false positive results [35].
T103 13300-13380 Sentence denotes The LFD is particularly interesting in the ICU due to its short turnaround time.
T104 13381-13563 Sentence denotes It has demonstrated a higher sensitivity but lower specificity in BAL fluids compared to galactomannan [36] and β-d-glucan [37] in IPA-probable and proven immunocompromised patients.
T105 13564-13712 Sentence denotes In the ICU setting, however, LFD is suggested to have a lower sensitivity but comparable specificity to galactomannan testing in BAL fluids [35,38].
T106 13713-13805 Sentence denotes Noteworthily, a negative predictive value of >96% has been reported in the ICU setting [39].
T107 13806-13979 Sentence denotes We used the OLM lateral flow device (AspLFD) on sequential patient tracheal aspirates, yielding positive results on all samples confirming the positive galactomannan result.
T108 13980-14158 Sentence denotes Although suitable for its negative predictive value or as an additional diagnostic measure, further evaluation of lateral flow technology in critically ill patients is warranted.
T109 14159-14259 Sentence denotes Altogether, we describe the clinical course of the first reported patient with azole-resistant CAPA.
T110 14260-14430 Sentence denotes The contribution of A. fumigatus to this fatal COVID-19 course is highly likely, although autopsy was not performed, as in all previously reported CAPA cases [3,4,5,6,7].
T111 14432-14447 Sentence denotes Acknowledgments
T112 14448-14501 Sentence denotes We thank Paul E Verweij M.D. for helpful discussions.
T113 14503-14523 Sentence denotes Author Contributions
T114 14524-14800 Sentence denotes Conceptualization, J.F.M. and A.S.M.D.; formal analysis, E.F.J.M.; investigation, O.H. and J.B.B.; resources, J.F.M.; data curation, A.S.M.D. and O.H.; writing—original draft preparation, E.M. and J.F.M.; writing—review and editing, A.S.M.D., O.H., J.B.B.; supervision, J.F.M.
T115 14801-14877 Sentence denotes All authors have read and agreed to the published version of the manuscript.
T116 14879-14886 Sentence denotes Funding
T117 14887-14930 Sentence denotes This research received no external funding.
T118 14932-14953 Sentence denotes Conflicts of Interest
T119 14954-14998 Sentence denotes The authors declare no conflict of interest.
T120 15000-15166 Sentence denotes Figure 1 Low-dose chest CT showing extensive centralized and peripheral bilateral ground glass opacities with left-sided consolidations and bilateral fibrotic bands.
T121 15167-15187 Sentence denotes No pleural effusion.
T122 15188-15257 Sentence denotes No vascular enlargement and no specific suggestions of aspergillosis.
T123 15258-15300 Sentence denotes Figure 2 Case timeline with microbiology.
T124 15301-15333 Sentence denotes Table 1 Patient characteristics
T125 15334-15348 Sentence denotes Gender Female
T126 15349-15364 Sentence denotes Age (years) 74
T127 15365-15433 Sentence denotes Medical history Reflux, polyarthrosis, stopped smoking 20 years ago
T128 15434-15486 Sentence denotes Medication Pantoprazol (PPI) and Etoricoxib (NSAID)
T129 15487-15533 Sentence denotes Underlying immuno-compromising condition None
T130 15534-15588 Sentence denotes Initial symptoms Fever, dry cough, dyspneic, diarrhea
T131 15589-15617 Sentence denotes ARDS Prone positioning Yes
T132 15618-15628 Sentence denotes vvECMO No
T133 15629-15698 Sentence denotes Acute renal failure Yes, continuous venovenous hemofiltration (CVVH)
T134 15699-15738 Sentence denotes IPA definition EORTC/MSG criteria N/A
T135 15739-15771 Sentence denotes (modified) AspICU algorithm N/A