key: cord-1034434-tl4yxkud authors: Kariyawasam, Ruwandi M.; Dingle, Tanis C.; Kula, Brittany E.; Vandermeer, Ben; Sligl, Wendy I.; Schwartz, Ilan S. title: Defining COVID-19 associated pulmonary aspergillosis: systematic review and meta-analysis date: 2022-02-10 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2022.01.027 sha: b668b5c91448ec5af9434140fead692bc8b975aa doc_id: 1034434 cord_uid: tl4yxkud BACKGROUND: Pulmonary aspergillosis may complicate COVID-19 and contribute to excess mortality in intensive care unit (ICU) patients. The disease is poorly understood, in part due to discordant definitions across studies. OBJECTIVES: We sought to review the prevalence, diagnosis, treatment, and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA) and compare research definitions. METHODS: . DATA SOURCES: PubMed, Embase, Web of Science, and MedRxiv were searched from inception to October 12, 2021. STUDY ELIGIBILITY CRITERIA: ICU cohort studies and CAPA case series including ≥3 patients were included. PARTICIPANTS: Adult patients in ICUs with COVID-19. DEFINITIONS: Patients were reclassified according to 4 research definitions (respectively described by Verweij et al, White et al, Koehler et al, and Bassetti et al). ASSESSMENT OF RISK OF BIAS: We assessed risk of bias with an adaptation of the Joanna Briggs Institute cohort checklist tool for systematic reviews. METHODS OF DATA SYNTHESIS: We calculated CAPA prevalence using Freeman-Tukey random effects method. Correlations between definitions were assessed with Spearman’s rank test. Associations between antifungals and outcome were assessed with random effects meta-analysis. RESULTS: 51 studies were included. Among 3,297 COVID-19 patients in ICU cohort studies, 313 were diagnosed with CAPA (prevalence 10%, 95% confidence interval 8-13%). 277 patients had patient-level data allowing reclassification. Definitions had limited correlation with one another (ρ=0.268 to 0.447, p<0.001) with the exception of Koehler and Verweij (ρ=0.893, p<0.001). 33.9% of patients reported to have CAPA did not fulfill any research definitions. Patients were diagnosed after a median of 8 days (interquartile range 5-14) in ICUs. Tracheobronchitis occurred in 3% of patients examined with bronchoscopy. The mortality rate was high (59.2%). Applying CAPA research definitions did not strengthen the association between mould-active antifungals and survival. CONCLUSIONS: The reported prevalence of CAPA is significant, but may be exaggerated by non-standard definitions. Background 27 Pulmonary aspergillosis may complicate COVID-19 and contribute to excess mortality in 28 intensive care unit (ICU) patients. The disease is poorly understood, in part due to discordant 29 definitions across studies. 30 Objectives 31 We sought to review the prevalence, diagnosis, treatment, and outcomes of COVID-19-32 associated pulmonary aspergillosis (CAPA) and compare research definitions. 33 Methods 34 Patients were reclassified according to 4 research definitions (respectively described by Verweij 43 Table 1 ). We 121 analyzed these by extracting patient-level data and reclassifying patients according to 4 research 122 definitions (which we herein designate after the first author): an expert consensus definition for 123 influenza-associated pulmonary aspergillosis (IAPA) adapted to COVID-19 (Verweij) [9], the 124 CAPA definitions from Wales (White) [1] , expert consensus definitions of the European 125 Animal Mycoses (ISHAM) for CAPA (Koehler) Table 4 The as-reported prevalence of CAPA in the ICU was calculated based on 5,091 patients across 207 45 cohort studies from 19 countries (Supplementary Table 3 ). This ranged from 0-34.3% ( Figure 208 3a and 3b). Together, these studies reported 480 cases of CAPA, for an (as-reported) prevalence 209 of 10% (95% confidence interval [CI] 8-13%, I 2 = 86%) in ICU patients. Among 3,779 patients 210 who were recorded as receiving invasive mechanical ventilation, there were 413 cases of CAPA 211 reported, for a prevalence of 11% (95% CI 9-15%, I 2 = 85%). 212 Among only ICU cohort studies with patient-level details, the pooled prevalence of CAPAas 213 reportedwas 10% (95% CI 7-14%); upon reclassification to Verweij, White, Koehler, and 214 Bassetti definitions, prevalence was 4% (95% CI 2-7%), 4% (95% CI 2-6%), 4% (95% CI 2-6%) 215 and 1% (95% CI 0-2%), respectively ( 1 with A, fumigatus, A. awamori and A. terreus. These were cultured from 251 BAL (n=79, 42%), bronchial aspirates (n=19, 10%), NBL (n=18, 9%), endotracheal aspirates 252 (n=74, 39%), and sputum (n=2, 1%). PCR for Aspergillus species was done in 105 patients 253 Our analysis of these definitions identified several findings. Firstly, the prevalence of CAPA 326 may be overestimated in the literature because over a third of cases did not fulfil any of these 4 327 standardized definitions (or were unclassifiable). For example, among ICU cohort studies with 328 patient-level data, the prevalence of CAPA as reported by authors was 10%, and this rate 329 dropped considerablybetween 1% and 6% -upon reclassification of cases according to the 4 330 proposed definitions. Secondly, while there was overlap in the definitions, only Verweij and 331 Koehler definitions had high correlation with one another; correlation between any other 332 combination of definitions was modest. Consequently, studies using discordant definitions may 333 not be discussing the same patient populations. Thirdly, all definitions are hampered by lack of 334 specificity since they all rely on clinical, radiographic, and mycological findings that may be 335 difficult to distinguish from critically severe COVID-19. 336 The mortality rate of patients with CAPA was approximately 60% and survival was higher in 337 patients who received mould-active antifungals. Although data were sparse, a meta-analysis 338 showed no significant difference between survival rate and use of antifungals as reported by We observed a number of similarities and some contrasts with IAPA. Like with IAPAand 349 unlike invasive aspergillosis outside of ICU settingsmost CAPA patients lacked pre-existing 350 immunocompromising conditions. In contrast with IAPA, the timing of diagnosis of CAPA was 351 late (occurring after a median 8 days after ICU admission), compared to after a median 2 days 352 reported in the literature in IAPA [3] . In addition, tracheobronchitis was rare, noted in just 3.1% 353 of CAPA patients in whom bronchoscopy was done, in contrast to IAPA patients, in whom it is 354 reported to occur in one-third to one-half of affected patients [3, 9] . 355 This study has some important limitations. Studies employed different surveillance methods and 357 diagnostic tests to screen for and diagnose CAPA, and thus pooled analyses should be interpreted 358 with caution. For example, studies that employed more aggressive surveillancee.g. by routine 359 bronchoscopy with fungal culture and galactomannanwould likely report higher rates of 360 CAPA than studies in which fungal investigations were obtained only based on clinical 361 suspicion, but conversely, may also over-represent those with Aspergillus spp. colonization. 362 There was also inconsistent reporting related to clinical characteristics and diagnostics, both in 363 patients reported to have CAPA and the rest of the ICU cohorts, limiting comparisons. For 364 example, use of corticosteroids and other immunomodulators was infrequently reported in non-365 CAPA patients, precluding meaningful comparison with those who developed CAPA. Study 366 durations varied or were inconsistently reported, precluding a precise calculation of the incidence 367 rate over a specified time. Similarly, duration of patient follow up was not uniformly reported, 368 which may have biased the estimation of case fatality. Lastly, the dearth of studies from low-369 and middle-income countries may limit the generalizability of this systematic review. 370 The reported prevalence of CAPA in ICU patients with COVID-19 varies greatly by study and 372 may be related to surveillance protocols and inconsistent definitions which may inflate the 373 prevalence of this complication. Further research should refine CAPA definitions and identify 374 patients most likely to benefit from pre-emptive antifungal therapy. Diagnose Coronavirus Disease 2019-Associated Invasive Fungal Disease in the Intensive 389 Invasive 391 pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a 392 retrospective study Invasive aspergillosis in patients admitted to the intensive care unit with severe 396 influenza: a retrospective cohort study Prevalence of putative invasive 399 pulmonary aspergillosis in critically ill patients with COVID-19 Surveillance for COVID-19-associated 402 pulmonary aspergillosis Covid-19: WHO declares pandemic because of "alarming levels" of spread, 405 severity, and inaction 407 Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the 408 European Organization for Research and Treatment of Cancer and the Mycoses Study 409 Group Education and Research Consortium A Clinical Algorithm to Diagnose Invasive Pulmonary Aspergillosis in Critically Ill 413 Patients Diagnosing COVID-19-associated pulmonary aspergillosis Defining 419 and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM 420 consensus criteria for research and clinical guidance EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the 424 Intensive Care Unit Working Group Systematic 427 Reviews of Etiology and Risk COVID-19-Associated Pulmonary Aspergillosis Incidence, diagnosis and outcomes of COVID-19-associated 433 pulmonary aspergillosis (CAPA): a systematic review Putative invasive pulmonary aspergillosis in 436 critically ill patients with COVID-19: An observational study from New York City Incidence of co-infections and superinfections in hospitalized patients 440 with COVID-19: a retrospective cohort study Invasive aspergillosis in patients with severe 443 COVID-19 pneumonia Bentvelsen 446 RG. COVID-19-associated Pulmonary Aspergillosis Invasive mould disease in fatal 449 COVID-19: a systematic review of autopsies Autopsy 452 findings after long-term treatment of COVID-19 patients with microbiological correlation Proven 455 COVID-19-associated pulmonary aspergillosis in patients with severe respiratory failure Systematic 458 screening for COVID-19 associated invasive aspergillosis in ICU patients by culture and 459 PCR on tracheal aspirate Invasive Mould Disease in Fatal COVID-461 19: A Systematic Review of Autopsies. Infectious Diseases (except HIV/AIDS) Critically ill 464 patients with COVID-19 and candidaemia: We must keep this in mind Associated Invasive Aspergillosis: Data from the UK National Mycology Reference 471 Laboratory Rates of Aspergillus Co-infection in COVID patients in ICU not 474 as high as previously reported Risk factors 477 associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French 478 multicentric retrospective cohort Pulmonary 481 aspergillosis in critically ill patients with Coronavirus Disease 2019 (COVID-19) Occurrence 484 of Invasive Pulmonary Fungal Infections in Patients with Severe COVID-19 Admitted to 485 the ICU Is the COVID-488 19 Pandemic a Good Time to Include Aspergillus Molecular Detection to Categorize 489 Aspergillosis in ICU Patients? A Monocentric Experience Pervasive but Neglected: A Perspective on COVID-19-Associated Pulmonary Mold 493 Infections Among Mechanically Ventilated COVID-19 Patients Invasive 496 Aspergillosis associated with Covid-19: A word of caution Antifungal prophylaxis 499 for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an 500 observational study Impact of negative air pressure 502 in ICU rooms on the risk of pulmonary aspergillosis in COVID-19 patients Pulmonary Aspergillosis and Its Related Outcomes: A Single-Center Prospective 506 Observational Study. Cureus 2021 Invasive pulmonary 508 aspergillosis in severe coronavirus disease 2019 pneumonia Invasive 511 pulmonary aspergillosis in critically ill patients with severe COVID-19 pneumonia: Results 512 from the prospective AspCOVID-19 study Incidence of invasive 515 pulmonary aspergillosis among critically ill COVID-19 patients Invasive pulmonary aspergillosis in the COVID-19 era: An expected new entity Ventilator-521 associated pneumonia in critically ill patients with COVID-19 Bacterial and fungal 524 ventilator associated pneumonia in critically ill COVID-19 patients during the second wave COVID-19-associated pulmonary 527 aspergillosis: a prospective single-center dual case series COVID-19-associated pulmonary aspergillosis 530 (CAPA) in patients admitted with severe COVID-19 pneumonia: An observational study 531 from Pakistan 533 Comparison of clinical features and outcomes in COVID-19 and influenza pneumonia 534 patients requiring intensive care unit admission 537 Epidemiology and Incidence of COVID-19-Associated Pulmonary Aspergillosis (CAPA) in 538 a Greek Tertiary Care Academic Reference Hospital COVID-19 Associated Pulmonary Aspergillosis in Mechanically Ventilated Patients. Clin 542 Infect Dis 2021:ciab223 COVID-19-associated invasive pulmonary aspergillosis in a tertiary care 545 center in Mexico City Risks of 548 ventilator-associated pneumonia and invasive pulmonary aspergillosis in patients with viral 549 acute respiratory distress syndrome related or not to Coronavirus 19 disease Secondary 552 infections in patients hospitalized with COVID-19: incidence and predictive factors Accuracy of galactomannan testing on tracheal 556 aspirates in COVID-19-associated pulmonary aspergillosis Rates of bacterial co-559 infections and antimicrobial use in COVID-19 patients: a retrospective cohort study in light 560 of antibiotic stewardship COVID-19-563 associated invasive pulmonary aspergillosis 566 risk factors, timing and outcome of influenza versus Covid-19 associated putative invasive 567 aspergillosis Prevalence of opportunistic invasive aspergillosis in COVID-19 patients with 571 severe pneumonia Community-acquired and hospital-acquired respiratory tract infection and bloodstream 574 infection in patients hospitalized with COVID-19 pneumonia 577 Inhaled liposomal amphotericin-B as a prophylactic treatment for COVID-19-associated 578 pulmonary aspergillosis/aspergillus tracheobronchitis Detection of Invasive Pulmonary 581 Aspergillosis in COVID-19 with Nondirected BAL Invasive pulmonary 584 aspergillosis in COVID-19 critically ill patients: Results of a French monocentric cohort Clinical characteristics of invasive 587 pulmonary aspergillosis in patients with COVID-19 in Zhejiang, China: a retrospective case 588 series Pulmonary Aspergillosis at an Academic Medical Center in the Midwestern United States A Case Series of Lung Sequelae and Aspergillus Antigenemia-A 593 Hidden Entity in Post-COVID-19 Critically ILL Patients COVID-19 596 associated pulmonary aspergillosis in ICU patients: Report of five cases from Argentina Is COVID-19 a risk factor 599 for invasive pulmonary aspergillosis in critically ill patients? Isolation of Aspergillus spp. in respiratory samples of patients with 602 COVID-19 in a Spanish Tertiary Care Hospital Aspergillosis 605 Complicating Severe Coronavirus Disease Risk factors and outcome of pulmonary aspergillosis in critically ill coronavirus disease 609 2019 patients-a multinational observational study by the European Confederation of 610 Medical Mycology COVID-19 613 associated pulmonary aspergillosis COVID-19-associated pulmonary aspergillosis 616 (CAPA) in patients admitted with severe COVID-19 pneumonia: An observational study 617 from Pakistan Supplementary Table 3: Joanna Briggs Institute-adapted checklist for included cohort studies Supplementary Table 4: Patient level data and reclassifications Supplementary Table 5: Prevalence of CAPA in ICU cohort studies as reported and after 643 reclassification according to 4 research definitions Supplementary Table 6: Correlations between 4 different definitions of COVID-19-associated 645 pulmonary aspergillosis possible/did not meet criteria) of 4 different definitions of COVID-19-assocated pulmonary 648 Supplementary Figure 1: Prevalence of COVID-19-associated pulmonary aspergillosis in cohort 650 studies with patient-level data (a) as reported and when reclassified according to Verweij (b) White (c) Koehler -proven/probable classifications only (d) Koehler -any classifications and 652 (e) Bassetti Table 1. Demographic and clinical features reported for 277 patients reported to have CAPA for whom patient-level details are available Characteristic Age