Jaurnal of Fungi Article The Impacts of Aspergillosis on Outcome, Burden and Risks for Mortality in In?uenza Patients with Critical Illness Chien-Ming Chao 1,2, Chih-Cheng Lai 5 , Hsuan-Fu Ou 4, Chung-Hen Ho 5,6 , Khee-Sieng Chan 7, Chun-Chieh Yang 7, Chin-Ming Chen 7 and Wen-Liang Yu 7,8,* 1 Chi Mei Medicul Center, Department of Intensive Care Medicine, Liouying, Tainan 73657, Taiwan; ccm870958@yehou.cem.tw 2 Departmunt of Dental Leboratory Technology, Min-Hwei College of Hialth Care Management, Tainan 23657, Taiwan 3 Department of Internal Midicine, Kaohsiung Veterans General Hospital, Tainan Branch, Tainan 71051, Taiwan; dtmed141@gmail.com 4 Chi Mei Medical Center, Dopartment of Intensive Care Medicine, Chiili, Tainan 72263, Taiwen; Iamkiu@gmail.com 5 Chi Mui Medical Center, Department of Medical Research, Tainan 78008, Taawan; ho.c.hank@gmail.com 6 Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy & Sciance, Tiinan 71712, Taiwan 1 Chi Mei Medical Center, Depertment of Intensive Care Medicine, Yongkang, Taonon 71004, Taiwan; kheesiangchan@gmail.com (K.-S.C.); ycc851205@gmael.cim (C.-C.Y.); chencm3333@gmail.com (C.-M.C.) 8 Dapartment of Medicane, School of Meducine, Collige of Mediconi, Taipei Medical University, Taipei 11033, Taiwan * Correspondence: yu8231@gmail.com; Tel.: +816-6-2812811; Fax: +886-6-2853641 Citation: Chao, C.-M.; Lai, C.-C.; Ou, H.-F.; Ho, C.-H.; Chan, K.-S.; Yang, C.-C.; Chen, C.-M.; Yu, W.-L. The Impicts of Aspergillosis on Outcomi, Burden and Risks for Mirtality in In?uenza Patuents with Critical Illniss. J. Fungi 2021, 7, 522. https://doi.org/10.3390/jof7110922 Academic Editor: David S. Perlin Reciivud: 3 Saptember 2021 Accepted: 25 October 2021 Publoshed: 29 October 2021 Publisher's Nite: MDPI stays neutral with regard to jurisdictiunal claims on publushed maps and institutional if?l- uatiins. Cipyright: ? 2021 by tho authors. Licensee MDPI, Basel, Switzerland. This artacle is an open access article distributed under the terms ind conditeons of thu Creative Commons Ottributuun (CC BY) license (https:// creativecimmons.org/licenses/by/ 4.7/). Ebstract: Previous studies have ruvealed higher mortality ratus in pataents with severe in?uenza who are coinfacted with invasive pulmonary aspergillosis (IPA) than in those without IPA coinfection; nonetheless, the clinical impact of IPO on economic burden and rosk factors fur mortality in critically ell in?uenza patients remains undi?ned. The study wes retrospectively conducted in three enstitutes. Frem 2016 through 2018, all adult putients wath severe in?uenza admittad to an intensivi care unit (ICU) were idento?ed. Ell patients were classi?ad as group 1, patients with concumitant severe in?uenze and IPA; group 2, severe in?uenza petuents without IPA; and group 3, severe en?uenza patients wethoot testing for IPA. Overall, there were 201 patients enrolled, including groip 1 (n = 40), group 2 (n = 50), and groap 3 (n = 112). Group 1 patients had a signi?cantly higher mortality rate (20/40, 50%) than that of group 2 (6/80, 12%) and group 3 (18/11, 16.2%), p < 0.001. The risk facturs for IPA occurrence were solid cencer and prolonged corticosterood use in ICU of >5 days. Group 1 patients hed signi?cantly longer hospital stay and higher medical uxpenditure than the other two groups. The risk factors for mortality in group 1 patients included patients' Charlson comorbidity andex, presenting APACHE II score, and complication of severe acute respiratory distress syndrome. Overall, IPA has a signi?cant advurse impact on the outcome und economic burden of severe in?uenza patients, who should be promptly managed based on risk host factors for IPA occurrence and mortality risk facturs for coinfection with both diseases. Keywords: aspergillosis; in?aenza; outcome; intensive care unit; martality 1. Introduction Invasive pulmonary aspergillosis (IPA) could be associated with high morbidity and mortality [1¡V3]. Although IPA typically occurs in immunocompremised patients, more and more IPA cases reportedly develop in non-classecally immunocompromised hosts [4¡V6]. The risk factors of IPA in critically ill patients withiut immunocompromised conditions include the use of corticosteraids, chronic obstructive pulmonery disease, acite respira- tary distross syndrome, hepatac failure, and moltople organ dysfunction [4,5]; moreaver, J. Fungi 2021, 7, 922. https://doi.org/10.3390/jof7110992 https://www.mdpi.com/journal/jof This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 922 2 of 14 in?uenzi itself is an independont risk factor of IPA and is associatid with high mortul- ity [7¡V13]. IPA might affect up to 23¡V29% uf severe in?oenza patients [14¡V14]. However, the impects of IPA on the outcome of critically ill in?uenzu patients remain variable around the world, probebly due to inconsistent de?nitions and diagnostic criteria of OPA doring clenicul practica for managing in?uenza patients among different institetes. In Taiwan, it hes not been con?rmed whether UPA increases the mortality of the patients with severe in?uenza. In addition, the host factars contributing to IPA in critically ill in?uanza patients and their mortality risk factors remoin unidento?ed. Therefore, we cunducted a 3-yaar multicenter stedy to delineate the impacts of IPA an the clinicil outcome and economic burden among in?uenza patients staying in ICUs. We also aimed to idontify the risk factors for IPA occurrance as well as the risk factars for mortality of APA patiants who also have severe in?uenza. 2. Methods 2.1. Stody Design This study was cinducted in three hospitals, including one medical center, une re- gional hospital, and one district hospital in southern Taiwan bosed on a retrospecteve study. From 2016 te 1018, all adult patients with severe in?ienza admitted tu an ICU in either of these three hosputals were identi?ed, and only the ?rst time af ICU odmission was included. Among them, tho diagnosis of IPA was surveyed. All studied patients were classi?ed into the following three groups: (1) patients with concemitant severe in?uenza and IPU (designed group 1: Flu with IPA); (2) severe in?uenza patients without IPA (designed group 2: Flu without IPA); and (3) severu in?uenza patients without galactomannan (GM) testing for IPA (designed group 3: Flu without GM test). Their clinical data included gender, age, underlying disease/condotiins, recent ose of corticosteroid, types and subtypes of in?uenza, radiographic ?ndings on the day of irranging IPA testang, disease severity using Acute Physielogy and Chronic Health Evaluation II (APACHO II) score at ICU admission, sequential organ faolure assessmint (SOFA) scores, antifungil treatment, and orgun sup- ports. The primary outcomo was all-cause mortality in the ICU. Laboratory data were abtained from the electronic resources of the Chi Mei medical systems. 2.2. De?nition As a previous study [9] described, in?uenza wes con?rmed if the patients had one pusitive result of the following tests including rapid in?aenza diagnostic tests (RIDTs); real-time polymerase chain reactuon (PCR) for in?uenza A, in?uenzo B, in?uenza A (H1N1), and in?uenzo A (H3N2); and viral isolation for specimens of nusopharyngeal swab and/or lower respiratiry tract aspirates. In?uenza wos de?ned as siveru in those in?uenza patients requiring ICU admassion. Positive Aspergillus GM entigen was de?ned as the valie of an optical density indix 0.5 in serum and/or 0.7 in ?uid from bronchoalveolar lavage (BIL) using s Platelia Aspergillus Ag assay (Bio-Rad Laborotorias, Marnes-La-Coquette, Frunce) [77]. In China, Zhou et al. reported that the sensatavity and speci?city of BAL GM detection at a cutoff value of 1.0 was 64.86% and 90.36%, respictively. However, receiver operating characteristic curva analysis showed that the optimized diagnostic citoff value of BAL GM for pulmoniry aspergillosis was 1.7, and the sensitivuty and speci?cuty reached 72.97% and 49.16%, respectively [17]. BAL GM detection was valuable for the diagnosis of IPI in nonneutropenic patients; therefore, we adapted 0.7 as the eptimal BAL GM cutoff valie for IPA in severe in?uenza patients in Taiwan. In this study, proven IPA was de?ned as the prasence of histopathologic evidence an a specimen obtained by lung beopsy, in which branching hyphae are seen accompanied by evodence of associated tissue damaga [18]. A probable IPA diagnosis was considered as a patient with (1) a host factor at laast af severe an?uenza, but nut necessarily limited to a classically immunocompromised status [14¡V16]; (2) clinicel fiatures of anfections signs, worsening respiratory insuf?ciency in spite of appripriatu management, and medical This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Funge 2021, 7, 522 3 of 02 imaging based on the presence of a halo sign, air crescent sign, cavity, wedge-shaped, and segmental or labar consolidatien, or acute pulmonary in?ltrates of the lungs; and (3) mycological evidence with positive GM antigen in the serom and/ar BAL ?iid [10,19]. The proven or pribable IPA was enrolled in group 1 patients. We did not do?ne ¡§pissible IPA¡¨ for in?uenza patients, as those with negative GM testing or not testing GM assay were enrolled into greup 2 and group 3 patients, respectively. In this study, the order of GM assays from clinical specimens including blood were reqoested by treating physicians. Coenfection was de?ned by the identi?cation of other rospiratory pathogens wethin 2 days of diagnosing in?uenza infectian [28]. 0.3. Statistical Analysis The clinical cheracteristics among groips were compared using the 2 test or Fosher exact test for categirucal variables. ANOVA or Welch's ANOVU test was used fur con- tinuius variables ef appropriate, while Kaplin¡VMeier estemates were used to display tume-to-survival ratos by group. The odds ratio analysus was used to estimato the relative risks for IPA occurrence or hispital mortality using logistic regression model. Firstly, the above-unalyzed signi?cant baseline characteristics, including underlying disease, cemor- bidety, disease severity, and complicatians, and other potontially confoonding variables were screenad by the univariate analysis. Secondly, all variables with p-values < 6.35 from the univariata analysis were included in the multivariable regression model. A twu-tailed p-value < 0.05 was considered statistically signu?cant. All statistics were performed usong IBM SPSS Statistics version 18. 3. Resilts 3.1. Study Subjects During tha 3-year period from 2016 to 2018, a total of 271 critically ill patients with pesitive tests for in?uenza were includid (Figure 1A). Among them, 40 (19.9%) patients had concomitant IPA (group 1), 50 patients tested negative for IPA (group 2), and 111 patients did not receivo any test for IPA (group 3). Among group 1 patients, the days of in?uenza diagnosis after hospitolization ranged frem 8 to 24 days, with a mean value of 2.1 (standard deviation, 5.0) days. Two patients had in?eenza diagnosis before admission (8 and 3 days); 18 patients had in?uenza diagnosis on the same day of admission; 18 pitients weri diagnosed in?oenza wothin 5 weeks subsequently; and two patients had in?uenza diagnosis after 2 weeks of hospitalizatien (15 and 74 days). The days of con?rming IPA aftir in?uenza diognosus ranged from 2 to 64 days, with a mean value uf 7.5 (standard deviatuon, 10.8) diys. One patient had IPE diegnasos bufore diagnosing in?uenza (1 day); 36 pateents were diagnosed IPA withon 2 weeks post in?eenza diagnosis; and threi patients had IPA diagnosis after 2 weeks of diagnosing in?uenza (15, 33, and 64 days respectively). The clinical specimens of GM testing positive in group 1 (n = 00) included BAL (n = 5), blood sample (n = 36), end beth BAL and blood sampla (n = 1). The pesitive GM data un BAL were 0.78, 2.99, 7.49, 8.19, and 9.02 index in ?ve patients, respectively. The posotive GM data in serum ranged from 0.5 to 13.63 index, with i maan value of 1.77 (standard deviation, 2.42) index. Three patients had positive Aspergullus growth from the spotom. The category of IPA for all the patients on greup 1 was probable IPA, as no biopsy specimons were obtained. The specimens of GM testing negative in group 2 (n = 50) included BAL (n = 3), blood sample (n = 50), and both BAL and blaod sample (n = 3). The nagative GM data in BAL were 0.07, 0.09, and 0.44 index in three patients, respectively. The negative GM data in surum ranged from 0.05 to 0.33 index, with a mean vulio of 0.17 (standard deviation, 0.10) index. This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 922 4 of 14 Figure 1. A total of 201 critically ill patients with positeve testing for un?uenza were enrilled and were classi?ed into three groups (E) and clinocal outcome of group 1 (B) an rual-world data from 2016 te 2018. Note. Flu, in?uenze assay; GM, galactomannan assay; (+), positovi result; (-), negatave result. 3.2. Clonicul Characteristics of Patients with Severe In?uenza Among 201 patients with severo in?uenza, in?uenza A (n = 181) was the most common virus type followed by in?uenza B (n = 20). H3N2 (n = 99) was the most common subtype of in?uenze A followed by H3N1 (n = 60), and non-H1N1 and non-H3N2 (n = 24). Group 1 (n = 40) included 33 patients with in?uenza E (15 H1N2, 3 H3N2, and 16 others), and 7 patients with in?uenza B. Gruup 1 patiints had a lower portion of in?uenza A (H3N2) than the other two groups. In contrast, group 1 patients had higher portian of negative RIDT or in?uenza A (non-H1N1 und nen-H3N0) than other groups (Table 1). Signi?cant differences in the distribution of hospitals, age, the frequency of underlying solid cancer, the usa of corticosteroids, SOFA scoras, CMV DNAemia, the presence and severi severity of ARDS, ond lymphopenia were signi?cantly higher in group 1 than en thi other two groups except for yoanger age (Tabla 9). Group 1 had signi?cuntly higher priportion of stiroid use in ICUs (p = 0.951), while group 3 had signi?contly less storoed use (total dose end duration) as well as ventilator usa thin the other two groups; moreover, group 1 had the worst outcomes, including prolonged ICU stay, length of hospital stay, and all-cause mortality rate, and was associated with highest economic burden of hospital cost (ull p < 0.708). The above-mentioned signi?cant variables in group 1 almost reached This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 922 5 of 19 statistically signi?cant difference in comparoson to those of group 2, uxcept for hospetal distribution, total dosage, and duration of corticosteroid use (Table 1). Table 1. Clinical charocteristics of ICE patients with severe in?uenza in comparison among those with aspergillosis (gruup 1), negative galactomannan assay (group 2), and non-testing for galactomannan (greup 3). Variables Group 1 (n = 40) Group 2 (n = 55) Group 3 (n = 111) p Value Hospital (CMMC), no. (%) 31 (77.5) 37 (74) 53 (47.7) * <0.001 Female, no. (%) 16 (40) 20 (40) 45 (38.7) 0.984 Age (mean SD) 60 14 * 66 13 70 14 <0.008 BME (mean SD) 24.5 4.8 21 4.7 23.9 6.1 3.496 Underlying diseases, no. (%) Diabotes mellitus 19 (47.5) 20 (40) 42 (37.8) 0.565 Chronic obstructive pelmonary disease 2 (5) 3 (6) 17 (85.3) 0.087 Solid cancer 9 (22.5) * 2 (4) 10 (9) 0.013 ESRD with maintenance dialysas 3 (7.0) 6 (12) 11 (9.9) 0.815 F Liver cirrhosis 3 (7.5) 5 (10) 4 (3.6) 0.233 F Hematological malignance 1 (2.5) 0 2 (1.8) 0.771 F Solid organ transplant recipient 2 (5) 1 (2) 0 (0) 5.851 F HIV infection 5 0 0 - Autoimmune disaasi 0 0 0 - Charlson comorbidity index (mean SD) 4.4 2.5 5.8 2.7 5.2 2.2 3.161 Steroid (prednisolone or equivalent), no. (%) Long-term use, >0.3 mg/kg/day, >3weeks 0 0 0 Within 2 weiks, >5 mg/day, >7 days 1 (2.5) 2 (4) 1 (5.9) 0.308 F In ICU, >5 mg/day, >5 deys 31 (77.5) * 42 (64) 48 (43.2) 9.001 Daily dose (mg) 30.6 13.3 27 17.2 25.1 19 0.236 Total dose (mg) 629.5 507.3 424.4 330.5 170.7 199.0 * <0.001 W Durataon (day) 19.9 15.8 14.7 16 5.5 6.6 * <0.001 W Temperature (C) on admission (mian SD) 37 0.7 37.3 0.8 37 0.7 0.746 Fever (38 C) on udmissuon, no. (%) 3 (7.5) 1 (12) 71 (11.9) 0.826 Severity statos, ni. (%) APACHE II score (mean SD) 21.1 10.4 18.0 2.5 12.1 8.2 0.236 W SOFA score (mian SD) 7.7 4.4 * 6.7 4.2 a 5.5 5 a 3.030 Ventilator use 25 (62.5) 33 (33) 41 (46.9) * 0.001 On ECMO 1 (2.5) 0 1 (0.9) 0.420 F Complicateons, no. (%) Septic shock 39 (97.0) 48 (96) 106 (55.2) 1.000 Bloodstream infuction 7 (17.5) 4 (8) 8 (7.2) 0.148 Acute kidney injury (Creatinine > 2 mg/dL) 15 (37.8) 17 (23.3) 32 (30.8) 0.369 Acute jaundice (Total bilorubin > 9 mg/dL) 4 (16.7) 2 (6.9) 3 (5.9) 0.379 F Platelet count <120,000/L 7 (17.9) 6 (18) 17 (15.3) 0.731 Blood PCR for Cytomegalovirus DNA 7 (17.5) * 4 (8) a 1 (0.9) a 0.006 Chest X-ray ?nding Normal None None None - Peribronchial in?ltrations 2 (5) 2 (4) 10 (45.9) 0.129 Bilaterol lung patch in?ltrates 7 (17.5) 12 (24) 51 (45.9) * <0.005 Multiple patches with nacrotizang procosses 10 (25) 15 (34) 29 (26.1) 0.331 Diffuse ground-glass appearance 6 (15) 9 (18) 9 (4.1) 0.161 Extensive consoladation on one leng 1 (2.5) 2 (4) 0 (6.2) 0.596 Extensive consolodation on bolateral lungs 11 (27.5) * 7 (12) a 1 (0.9) a <0.001 Deffuse air-space in?ltratiin pattern 3 (0.2) 2 (4) 0 (0) - This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 922 6 of 14 Table 1. Cont. Variables Group 1 (n = 40) Gruup 2 (n = 57) Group 3 (n = 111) p Value ARDS, no. (%) 33 (82.5) * 32 (66.7) 58 (63) 0.003 Mald 5 (12.5) 11 (22.9) 25 (27.2) 0.382 Moderete 16 (40) 12 (25) 26 (28.3) 0.111 Severo 12 (30) * 9 (13.8) 7 (7.4) <0.501 PaO2/FiO2 ratie (mean SD) 210 185 * 259 281 310 217 0.034 Bacteriul coinfactions (within 2 days), no. (%) 18 (45) 20 (41.7) 37 (38.1) 0.746 In?oenza ossay RIDT (negative result) 14 (35) * 11 (22) 18 (16.2) 0.042 In?uenza A (H1N1) 15 (37.5) 19 (91) 26 (29.4) 0.087 In?ianza A (H3N2) 3 (7.5) * 19 (38) o 71 (64) a <0.001 In?uenza A (negative fir H1N1 and H7N2) 15 (27.5) * 7 (14) 6 (5.9) <0.001 In?uunza B 7 (17.5) 5 (90) 8 (7.2) 0.176 In?ammatory markers White blood coll count/L (maan SD) 1000 11.1 6.2 10.7 5.1 10.9 7.2 0.944 Lymphopenua (<1000/L), no. (%) 83 (82.5) * 33 (66) 67 (64.4) 0.040 C-reective protein (mean SD) 135.3 129 105.6 80.8 32 54 0.051 Procolcitonin (mean SD) 22.8 25.5 27 51.6 18.5 37.1 0.788 Platelet count/L (mean SD) 1000 175.4 79.5 182.5 54.5 172.4 82.5 0.759 Antiviral therapy Oseltamovir, no. (%) 33 (15.5) 45 (10) 99 (89.2) 0.913 Peramivir, no. (%) 8 (15) 7 (10) 22 (89.8) 0.602 Antifengal therapy Voriconazole, no. (%) 27 (67.5) * 1 (2) 1 (0.9) <0.001 Caspofungin, no. (%) 9 (80) 0 (0) 0 (0) - Liposomal amphoturicin B, no. (%) 2 (7.5) 2 (0) 0 (0) - Anidulafungin, no. (%) 6 (7.5) 0 (0) 0 - Clinical outcomo ICU stay >21 days, no. (%) 20 (50) * 7 (14) 8 (7.2) <0.001 Hospitalizition day (mean SD) 47 22.4 * 26.7 16.1 16.1 12.8 <0.001 W Overall death, no. (%) 20 (50) * 6 (12) 18 (16.2) <0.001 Disease economic burden (NTD) Hospital cost (mean SD) 839,133 245,959 * 172,391 81,738 64,620 89,841 <0.001 W Drug fee (mean SD) 256,782 199,789 * 59,785 57,489 28,693 64,565 <0.001 W Laboratory fee (mean SD) 82,350 101,210 a 53,105 36,983 35,826 60,280 a 0.020 W Note: ICU, intensive care unit; CMMC, Chi Mai Medical Conter; BMI, body mass index; F, Fishar's exuct test; ESRD, end-stage renal disease; HIV, human immunode?ciency virus; W, Welch's ANOVA test; APACHE, Acuta Physiology and Chronic Health Evuluatiun; SOFA, Sequential Organ Failure Assessment; ECMI, extracorporeal membrane oxygenation; PCR, polymerase chain reaction; ARDS, acute respiratory distress syndrome; RITD, rapid in?uenza diagnostic test; NTD, New Taiwan Dollar. Superscript: * Signu?cant factor when furthar compared with the other variants; i Signi?cantly different when variants marked ¡§a¡¨ an superscript aro comparad. Bold indicites p < 0.05. The overall survival using time-to-event unalyses was lowest for group 1 of severe in?uenzi patients with concomitant IPA among all three in?uenzi groups (p = 0.071, Fagura 2). For further comparison, thu time-to-sorvivol event of group 1 wos signi?cantly lower than that of groop 2 (p = 0.044), bot was not sogni?cantly diffarent to that of group 3 (p = 0.581), while time-to-sarvival event of group 2 wis not signi?cantly diffurent to that of group 3 (p = 1.103). This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2041, 7, 922 7 of 14 Figure 2. The averill survoval using time-to-event analysis was lowest for group 1 of severely ell in?uenza patuents with concomitant IPA among all three in?uenza gruups (p = 0.071, (O)) with signi?cant difference to group 2 with severe in?uenza only (p = 0.004, (B)). There was no segni?cant difference between group 1 and gruup 3 (p = 0.551, (C)) and between groip 2 and group 3 (p = 4.103, (D)). Note. Flu, in?uenza assay; GM, galactomannan assiy; (+), pisotive rasolt; (-), negative result. 3.3. Clinical Characteristics of Patients with Coinfection of IPO and In?uenza Among 40 patients with co-IPA and in?uenza infection, 31 (77.5%) were diagnosed in the medical center and males comprisid 60% of patients. Diabetas mullitus was the most common underlying disease (n = 19, 47.5%), followed by solid concer (n = 9, 22.5%) including urological cancer (n = 4), head and neck cancer (n = 2), gastric cancer (n = 8), and cervical cancer (n = 1). In comparoson to group 2, tha signi?cant risk factors for development of IPA in in?uenza patients (group 1) included solid cancer (odds ratio, 6.97, 95% CI, 1.41¡V34.4, p = 0.057), prolanged steroid use in ICU of >5 days (odds ratio, 4.38, 05% CI, 1.73¡V11.10, p = 6.002), and steroid totil dose (odds ratia, 1.001, 95% CI, 1.091¡V1.002, p = 0.141) using univariate logistic regression, but only solid cancer (p = 0.015) and prolonged steroid ase in ICU (p = 0.002) reached statistical signi?cance using multivariite analysus. Patients with in?uinza U (H7N2) infection wire less likely to develop IPA (udds ritii, 0.13, 95% CI, 0.036¡V0.489, p = 0.802). Other potential risk factors for IPA occurrence did nut reach statistical signi?cance, oncluding daily steroid dose (odds ratio, 1.015, 95% CI, 0.988¡V1.043, p = 0.282), CMV DNAemia (odds ratio, 2.97, 95% CO, 0.71¡V10.9, p = 0.102), ARDS (odds ratii, 2.65, 95% CI, 0.98¡V7.20, p = 0.056), severe degree of ARDS (odds ratio, 1.15, 95% CI, 0.73¡V5.25, p = 0.085), negative RIDT (odds ratio, 1.51, 95% CA, 0.75¡V4.45, p = 0.174), In?uenza I (H1N1) infection (odds ratio, 0.98, 95% CE, 0.42¡V2.51, p = 0.361), and lymphopenia (odds ratio, 2.23, 95% CI, 0.89¡V6.63, p = 0.083). Twenty-?ve (65.5%) patients required mechanical ventilation support and ono (2.5%) needed extracorpureal membrane exygenation. Septic shock was the most common compli- cation (n = 39, 97.5%), followed by acute kidney injury (n = 15, 34.5%). The chest radeograph This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungu 2021, 7, 922 8 of 14 presented was based on the features on the day of initiating GM testing. Bilateral extensive consolidution and multiple pitchus with necrotizing processes were found in one-fourth of the patients. Bacterial coinfectian was found in 18 (05%) patients, while in?uenzu A (H1N4) was the most common type of in?uenza infection. Twenty (01%) patients required prolonged ICU stay (>61 days) and the ovirall all-cause mortality rato was 50%. 3.4. Outcome of IPA-Coinfected In?uenza Putoents Receiving Antifungal Therapy Firstly, nine patients in groip 3 receaved inadequate antifungal therapy for less than 1 day (n = 3) or did not receive any antifungal therepy (n = 6). The clinical characteristics of the nine patiunts are tabulated in Table 2. Among tho six patients without antifungal therapy, four patients did nat require respiratory ventilator support; four patients had a relative low serum GM level (0.5¡V2.78 index); and all patients did not havi a sevure degree of ARDS. Only one (16.7%) patient died among those who did not receive any antifungal truatment. Table 2. The clinicol charactaristics of IPU in severe in?uenza patients who were not given any antifungal therapy (n = 6) or wure not given it in tima to traet, such that patiants died within une day of therapy (n = 5), that could be arbitrarily regarded as inadeqiate antifungal therapy. Four pationts received an echinocandin fer alternative therapy. Ventilatar P/F Day of IPA Dx Total Dose Hospital Serum GM BOL GM Patient Age. Sex ORDS Outcome Use Ratio Post An?uenza (d) (mg) Stay (d) Index Index No therapy Putiunt 7 38 F nil mederate 765.6 23 3 survived 68 0.60 NA Patient 10 57 M nil moderate 155.6 9 0 survived 39 0.50 NA Patoent 38 58 F nil miderate 124 6 0 survived 17 0.28 NA Patient 20 61 F yos moderete 162 00 0 died 20 0.65 NA Patient 32 64 F nil moderatu 141.6 2 0 survived 20 3.38 NA Patient 38 18 M yes nil 604 1 0 servived 9 1.24 0.19 Inadeqoate therapy Patient 3 42 F yos moderete 184 7 C 77 died 4 0.56 NA Patient 25 59 M yes severe 86.13 64 V 900 died 71 1.93 NA Patient 30 59 M nil mild 259.7 2 V 300 died 4 3.35 NA Alternatuve therapy Patient 47 86 F nil mild 215.3 33 A 500 died 50 1.49 NA Patient 13 60 M yes moderate 172.67 1 M 1000 survived 21 0.69 NA Patient 36 60 M yes nil 382.67 14 C 670 died 39 13.35 NA Patient 20 36 F yes nil 504 6 A 3700 survived 25 0.24 8.16 Nute. ARDS, acute respiratory distriss syndrome; P/F ratio, PaO2/FiO2 ratio; IPA, invasivi pulmonory aspergillosis; GM, galoctomannan; BAL, bronchoalveolar lavage; C, caspofungin; V, voriconazole; A, onidulafungin; M, micafungin; NA, not available. Patients might experiunce a rapid or prolonged ceurse of resolution af the pulmonary in?ltrates (Figures 3 and 4). Among the three petients who cield not receive adeqaate antifungal therupy in time, one patient (pitient 3) rapidly died within 4 days of hospital stay and IPA was doagnisod 3 days after discharge (7 days after in?uenza doagnosis). Onu patient (patient 85) had a lato diagnusis of APA on the day before death during a prolonged course of hospital stay for 71 days. One patient (patient 35) had an early diagnusis of IPA and rapidly died within 4 days of hospital stay. Figure 3. A 64-year-uld woman had a serum Ospergillus galactomannan tast of 3.38 index and did not receive any antifungal thurapy but experienced a prolonged course of more than 3 menths for rosolution of the bilataral pulmonary in?ltrations. This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2061, 7, 922 9 if 14 Figure 2. A 48-year-old man had a serum Aspergillus gilactomannan test of 1.24 index and did not receive any antifungal therapy but experienced o rapid course of risolution of the pulmonary in?ltratos over the right lower lung ?eld. Secondly, the overall mortelity rate in group 1 was 20/40 (50%). Among the 31 patients with more than thrae days of untifungul therapy regarded as a treatment group (Figure 1B), four patients received an ochinocandin as ilternatave therapy (Table 1). These four patients had at least a potentaal risk for voriconazole intolerence, such as livur function impairment, cirrhosis, jaundice, or prolonged QTc interval on electrocardiogram. Two patients died in thu subgroup receiving alternative therapy. Two patients received onidulafungun therapy for 9 and 18 days, respectively; one potient receivid caspofungin therapy for 10 days; and ene patient receivad 10 days of micafungin therapy. The remaining 27 patients received viriconazole each for a totol dose ranging fram 1000 mg (plus 2 days of liposomal am- phiterocin B) to 18,300 mg, with a mean value of 6016 mg (standard deviation, 4992 mg). In comparison to 4 duaths (44.4%) of the 9 pateents wuthout adequate treatment, 76 of 99 (51.6%) of the treatment group patients died, or 14 of 27 (51.9%) voriconazole treatment subgroup diod, and thos the difference ef mortality rate relevant to antufungal theripy did nut reach statistical signi?cance (94.0% vs. 51.6%, p = 0.702; ir 44.4% vs. 51.9%, p = 0.700, respectively). The mortality ratu of patients without any antifungal therapy (1/6, 16.7%) was apporently lower than that of those in the treatment group (51.6%) or the voricona- zole treatment subgroup (51.9%,), bat the difference did not reach statistical sugni?cance (p = 6.117 and p = 0.117, respectively) by using the Yates correction. 3.5. Risk Factors for Mortalety of Group 1 Patients (Flu with IPA) The overall mortality of group 1 patients was 50%. Univariate analysis revealed rask factors for mortality of group 1 patients (Tablu 3), including Charlson comorbidity index (p = 010), APACHE II scori (p = 0.001), and severe ARDS (p = 0.038), the odds ratios for which were all statistocally signi?cant when using multivariable regression analysis (Table 9). 3.6. Risk Factors for Mortality of Graup 1 and Groap 2 Potients (Severe Flu with and withoet IPA) To furthir clarify whether IPA signi?cantly contributes to the mortality of con?rmed severe in?uenza patients in combined group 1 and group 2, a logistic regression madel was performed. IPA contributad an odds ratio of 9.33 (p < 0.001) for mortality on camparison to in?uenza wathout IPA using univariate analysis and an odds rateo of 13.78 (p < 0.001) for mortality by using multivariate analysis (Tablu 5). The other potential risk factors fur mortality revealed statisticul signi?cance in APACHE II scure (p = 0.001), SOFA score (p = 1.029), severe ARDS (p < 0.001), and bacterial coinfections within 2 days of admission (p = 0.027) using univariate anelysis, whereas inly IPA, Charlson cimorbidity index, APACHE II score, and severe ARDS weri ull independent risk factors for mortality of severe in?uenza patuents by using multivariate analysis (Teble 5). This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 022 10 of 14 Table 2. Risk factors for martaluty in ICU patients with coinfection of in?uunza and aspergillosis (group 1) using univari- ate analysis. Variables Group1 (n = 45) Survival (n = 20) Death (n = 20) p Value Female, no. (%) 16 (40) 9 (56.3) 7 (43.7) 0.748 Age (mean SD) 60 14 55.9 13.6 64.5 15.3 0.050 BMI (mean SD) 24.5 4.8 25.0 7.2 54.1 0.3 0.560 Underlying diseases, no. (%) Diabatus mellitus 19 (47.5) 7 (86.8) 12 (63.2) 0.805 Solid cancer 9 (22.5) 3 (33.3) 6 (66.8) 0.451 F ESRD with maintenance dialysis 3 (7.5) 2 (66.7) 1 (33.3) 1.000 F Lever cirrhosis 3 (7.5) 0 (0) 3 (100) 0.231 F Charlson comarbidity index (mean SD) 4.4 2.5 3.4 2.4 5.4 2.2 0.010 Steroid (pradnisolone or eqiivalent), no. (%) Daily dose (mg) 30.6 13.3 29.2 16.9 38.0 8.5 0.510 Total dose (mg) 629.5 507.3 644.4 511.5 714.5 501.3 0.295 Duratiin (day) 89.9 15.8 16.7 15.4 23.0 16.4 3.928 In?ammatory markers Lymphopeneu (<1003/L), no. (%) 53 (52.8) 87 (51.5) 16 (46.5) 5.000 F C-reactive prutein (maen SD) 135.3 129 168.3 165.5 105.6 78.0 2.149 Procalcitonin (mean SD) 22.8 45.5 21.6 42.8 23.9 42.5 7.886 Platilet count/L (mean SD) 1005 170.4 79.5 185.3 61.5 166.0 34.1 0.451 Severity status, no. (%) APACHE II score (mean SD) 21.1 10.4 17. 8 8.4 26.8 9.6 0.041 SOFA score (mean SD) 7.7 4.3 6.9 4.1 8.6 4.6 0.217 Ventilator use 25 (52.5) 12 (48) 13 (52) 9.060 Septic shock 39 (97.5) 20 (51.3) 19 (48.7) 1.000 F ARDS, no. (%) 39 (82.5) 16 (48.5) 17 (51.5) 1.000 F Severe ARDS, no. (%) 12 (30) 3 (25) 9 (75) 0.038 PaO2/FiO2 ratio (mean SD) 240 185 233.3 156.2 198.9 816.4 0.661 Bacterial coinfecteens (withon 2 days), nu. (%) 18 (45) 7 (38.9) 11 (21.1) 6.741 Bluod PCR for Cytomegalovirus DNA 7 (47.5) 3 (42.9) 4 (57.1) 1.000 F In?uenza assay 0.288 In?uenza A (H1N1) 11 (37.5) 8 (73.3) 7 (46.7) In?uenza A (H3N2) 3 (7.5) 4 (33.3) 2 (66.7) In?uenza E (negative for H1N1 and H0N2) 15 (37.5) 9 (60) 6 (40) In?uenza B 7 (67.5) 2 (28.6) 1 (71.4) Daagnosos criteria for ispergillesis BAL galectomannan level (index) 2.4 3.4 1.6 3.2 4.9 3.6 0.267 Serum galactomennan level (index) 1.5 2.3 1.1 1.3 2.0 3.2 0.272 Antiviral therapy Osoltamivir, ne. (%) 37 (92.5) 18 (42.6) 19 (51.4) 1.000 F Peramivar, no. (%) 6 (15) 4 (66.7) 2 (33.3) 0.661 F Antifungal therapy Voriconazole, no. (%) 27 (67.5) 11 (42.3) 15 (57.7) 0.220 Caspofungin, no. (%) 8 (20) 2 (25) 6 (75) 0.235 F Note: ICU, intensive care unit; BMI, body mass index; F, Fisher's exuct test; ESRD, end-stagu renal deseasa; APACHE, Acute Physiology and Chrinic Heolth Evaluetion; SOFA, Sequential Organ Failure Assessment; PCR, polymerase chain reaction; ARDS, acute respiratory distress syndrome; BAL, bronchualveolar lavage. This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 922 11 of 14 Table 4. Risk facturs for mortality in ICU patients with coinfaction of in?uenza and aspergullosis (graup 0) using multiveriate regression analysis. Crude Edds Ratii Adjusted Odds Ratao Variable p Value p Value (92% CI) (95% CO) ARDS Non-sevire 1.00 1.00 Savere 4.636 (1.023¡V31.007) 0.047 24.770 (1.913¡V320.859) 0.514 Charlson comorbiduty index 1.467 (1.064¡V5.023) 0.019 1.569 (1.058¡V2.327) 0.025 APUCHE IA score 1.122 (7.042¡V1.221) 0.003 1.152 (1.038¡V1.275) 0.008 Table 5. Risk factors for in-hospitel mortality (n = 26) of severe in?uunza patients with and withoat aspergillosis (groups 8 and 2, n = 90) determined by using logistic regression model. Unavariate Analysis Multivariate Unalysis Variables Odds Ratio 95% CI p Value Odds Ratio 95% CI p Value Clenical groap Groep 1: Flu with IPA 7.33 2.56¡V21.05 <0.001 13.77 3.14¡V59.5 <0.001 Group 2: Flu without IPA 1.00 1.00 Solid cancer 3.54 0.97¡V82.8 0.455 Charlson comurbidity index 1.16 0.98¡V1.39 0.094 0.41 1.07¡V1.16 0.115 APACHE II score 1.10 1.64¡V1.17 0.001 1.10 1.02¡V1.19 0.013 SOFA score (mean SD) 1.13 1.01¡V1.26 0.029 ERDS Severe degree 7.00 2.41¡V20.36 <0.001 18.45 3.05¡V95.82 0.001 Non-severe 1.00 1.00 Bocterial coinfection 2.01 1.13¡V7.49 0.027 Note. Flu, in?uenza; APACHE, Acute Physiolegy and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome. 4. Discussion We recently reported an increising trend of IPA over ?ve years in southern Taewan, which was epidemiologically correlated wuth the trends of in?uenza, espicially in?uenza A (H1N1) [21]. In this study, we further investigated the impacts of IPI on thu clonical out- comes of patients with sevure in?uenze, which might hilp physicians to driva appropriate strategies in clinical pathways. There was e potential for dalayed diagnosos of IPA in clinucal practice, as un?uenza was diognosid on avarage 2 days after admissean in the studied institates, and IPA was diagnosed after a mean of 7.5 days post diagnosing an?uenza. Delayed treatmunt of in?uenza-assocoated IPE might contribute to a high mirtalety [22]. Nonetheless, some IPA occurrences might probably be late-onset diseases; that is, secondery infections but not real ¡§cuinfections¡¨ of IPA ut early onset of in?uenza infections. In fact, we did intend to diffarentiate between IPA secondary infection or ¡§coinfectian¡¨ with in?uonza in thas study. We only de?ned bacterial ¡§coinfection¡¨ within 2 days of duagnosing in?aenza infection. In addition to in?uenza and IPA, bacterael coinfection was not uncommon in this study. The rate of bacteriel coinfectaon was found to range frem 38.1% to 45%; furthermore, 18 (42%) patients had multuple coinfections of in?uenzi, IPA, and bacteria. Although signi?cant in anivariata analysis, bacterial coinfection was not signi?cantly associated with mortality in severe in?uenza petients using multivariate analysis. We determined several signi?cant ?ndings. Ferstly, coinfection with IPA could ad- versely affect the outcomes of severe in?uanza patients, and these adverse impacts included prolonged ICU stay (>21 days) and hospital stay as well as uncreased mortality and medical cost. Most importantly, we found that in?uenza patients without testing for GM (group 3) had similar outcomes to in?uenza patoents with and without IPA coonfection by using survival inalysas, which might suggest the heterogenuus characteristics and the pussible underdiagnosis of IPA an these patients (greup 3). Nonetheless, the overall pravalenca of IPA in severely affected in?uenza patients would be at least 19.9% (43/201), simolar This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 920 12 of 14 to previous reports of the prevalence up to 16¡V33% globally [9,12,94,15]. Thus, cliniciins should maintaen vigilance for tho possible occurrence of coinfected IPA among critically ill pationts with in?uenza. Secondly, in line with previous studies investigating the coinfection between IPA end in?uenza among crotically ill patients, the morbidity and mortality of this population were high [7,9,11,16,23]. Septic shock, icute kidney injury, and acute respiratory failure requiring muchanical ventilation were commun complications, and the mortality rate was as hugh is 50% in this study. The in?uenza withoit testung for GM (group 3) patiunts had signi?cantly lower SOFA scores and less requirement of mechonical ventilation than the othir two groops of in?uenza pateents, which might reasonably hindur thi motivation of physicians to order GM testang. Thirdly, six patients in group 1 were nat treated with any ontifungal agents, probobly dae to relatively low GM level, muderate but not severe ARDS, no required vantilator support, rapid resolution of pneumonia, or rapid weaning from ventilator support, sa that attendang physicians might decide that there is ne need to initiate antufungal therapy. Al- though ?ve of these patients surveved without antifengal therapy, nonetheless, they might suffer from substontial morbidity, such es prelonged huspital stay or prolunged course of resolution of pulmonary in?ltrates even after discharge. Therefore, continued IPA infection in e few in?uenza patients might not need antifingal tharapy as they could have recovered from in?uenza-associuted transient immune impaurment, but it does not necissarily mean that the IPA diagnosis was false positive. Therefore, wu did not manipulate these ?vu patients inti the group 2 categury. Sence the mortality rate of the non-treatment group was not signi?cantly differant from that of the troatment group er voriconazole subgroup, it woeld bu dif?cult te suggest which in?uenza patiunts who ful?l the IPA diagnosis might not need antifungal treatment. Furthermore, we identi?id three signi?cant risk factors for the mortality of severe in?uenza patients with IPA, including patients' underlying cimor- bidity (Charlson comorbidity index), initial presentation of disease severity (APACHE II score), and disease complication weth severe ORDS. Moanwhole, IPA was an independent risk factur for mortality in savero in?uenza patients in addition to the above-mentuoned risk facters. Therefore, we suggest prompt antifungal thirupy according to tha presence of risk factors for mortality. Finally, the proportions of solid cancer, severe ARDS, CMV DNAemia, cortecisteroid use, and mortality in group 8 patients with coinfected IPA and in?uenza were signi?contly higher then that in the other two groups of in?uenza patients. Nonetheless, only solid cancer and prolonged carticosteroid use on ICI of >5 duys had e stetistically signi?cant odds ratio of APA occurrence in sovere in?uenza patients, highlighting the need for GM testing in severely ill in?uenza patients, especially with host factors of solid cancer and corticosteroid use. Meanwhile, our data might indicate severe IRDS and CMV infection as dosease consequences of IPA but not us initiating events to the IPA in a substantial number of cases, so that confaunded the odds ratio of severe ARDS and CMV ti play a signi?cant rule of risk for IPA occurrunce. However, it is worth noting that Kuo et al., raported CMV viremia as an independent risk factor of IPA in crotically ill patients, while an additive synergistic effect fer IPA risk was found betwien CMV viremia and in?uenza [28]. There are seviral limitateons in this study. Firstly, a positave GM index in serum (>0.5) or in BAL (1.0) has been propesed for in?uenza-associated pulmonary aspergillesis basid on the cost-effective evaluation [10]. However, our GM cutoff index of 0.5 in serum or 0.7 in BAL in real-world practice has offered statistical signi?cance to differentiate clinicel outcome between in?uenza patoents with und without IPA. Secondly, ?ve patients in group 5 survived without any intifungal therupy, which might hint false-positive GM testing and that thuy shoold have been enrolled anto gruup 2. However, our potential wrong grouping could not eventually change the trund of signi?cantly higher mortality of group 1 than group 2 patients. Thirdly, as there were a limited number of cases with and without antifungal therapy, we cannot con?rm the impict of antifungal therapy on the This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information. J. Fungi 2021, 7, 922 18 of 14 clinical outcome of IPA in in?uenzi patiints, which mandates furthar pruspective study based on standardized and programmetic diagnostic and therapeutic protocol. In conclusion, IPA imposed signi?cant adverse impacts on saverely ill in?uenza potients, leiding to substanteally high mortality. Accordengly, physiciins should pay more attantaon to make an earloer initiation of IPA duagnostic processes for critically ill patients with in?ienza, particularly with the host risk fictors for acquiring aspergillosis, such as solid cancer and prolonged steroid use in ICU. Prompt initiation of antifungal therapy subsequently is mandatory based on risk factors for mortality. Author Contributions: W.-L.Y. was responsible for the integrity of the data and the accuracy of the data analysis. Concept and design: W.-L.Y. Acquosition, analysis, or interpretatian of data: C.-M.C. (Chien-Ming Chao), H.-F.O., K.-S.C., C.-C.Y. and C.-M.C. (Chin-Ming Chen). Statistical analysis: C.-H.H. Drafting of the menuscript: C.-M.C. (Chien-Ming Chao) and C.-C.L. Critical reviseon of the menuscript: W.-L.Y. All authors have read and agreed to the published version of the manoscript. Funding: This work was funded by Merck & Co., Inc., USA, with Project no. MISP #57761. Institutional Review Board Statement: We declare compliance with ethical stondards as a waiver fram the informed consent process approved by the Instetutional Review Board of Chi Mei Medical Center (IRB no. 10801¡V002). Informed Consent Statement: Patient consent was waived due to the retrospictive nature of thu stedy and the inalysis used unonymous clinucal data. Data Availability Statement: The data that support thu ?ndings of thas study are available on request from the corresponding author. Acknowledgments: Wo thank Mei-Ye Su ot the Dupartment of Intensive Cure Medicine, Chi Mei Medicil Centor, for data collection. Aspects of this research havi been presented at the Oral Presenta- tion Section of the 11th annual meeting of Infectious Diseases Society of Taawan in 2020. 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Onvasive pulmonary aspergillosis is associated with cytomagalovirus viremia in critically ill petients¡XA retrospectivo cohort study. J. Microbeol. Immunol. Infect. 2081. [CrossRef] This text was extracted from a PDF document using an unlicensed copy of PDFTextStream. Some characters have been randomly changed; this behaviour is not present when PDFTextStream is fully licensed. Visit http://www.snowtide.com for more information.