key: cord-0868328-np67kl94 authors: Mitaka, Hayato; Kuno, Toshiki; Takagi, Hisato; Patrawalla, Paru title: Incidence and mortality of COVID‐19‐associated pulmonary aspergillosis: A systematic review and meta‐analysis date: 2021-05-06 journal: Mycoses DOI: 10.1111/myc.13292 sha: 097bcced7985761fe25b8abc255fccd9a336674d doc_id: 868328 cord_uid: np67kl94 COVID‐19‐associated pulmonary aspergillosis (CAPA) has been reported worldwide. However, basic epidemiological characteristics have not been well established. In this systematic review and meta‐analysis, we aimed to determine the incidence and mortality of CAPA in critically ill patients with COVID‐19 to improve guidance on surveillance and prognostication. Observational studies reporting COVID‐19‐associated pulmonary aspergillosis were searched with PubMed and Embase databases, followed by an additional manual search in April 2021. We performed a one‐group meta‐analysis on the incidence and mortality of CAPA using a random‐effect model. We identified 28 observational studies with a total of 3148 patients to be included in the meta‐analysis. Among the 28 studies, 23 were conducted in Europe, two in Mexico and one each in China, Pakistan and the United States. Routine screening for secondary fungal infection was employed in 13 studies. The modified AspICU algorithm was utilised in 15 studies and was the most commonly used case definition and diagnostic algorithm for pulmonary aspergillosis. The incidence and mortality of CAPA in the ICU were estimated to be 10.2% (95% CI, 8.0–12.5; I (2) = 82.0%) and 54.9% (95% CI, 45.6–64.2; I (2) = 62.7%), respectively. In conclusion, our estimates may be utilised as a basis for surveillance of CAPA and prognostication in the ICU. Large, prospective cohort studies based on the new case definitions of CAPA are warranted to validate our estimates. bronchoscopies are rarely performed in patients with due to the risk of disease transmission. 14 As the majority of studies on CAPA have been case series 15, 16 and small observational studies, 1, 2, [17] [18] [19] the true incidence and clinical significance of CAPA in ICU patients is uncertain. In this study, we conducted a systematic review and meta-analysis to determine the incidence and mortality of CAPA in patients with COVID-19 for better guidance on surveillance and prognostication. All prospective and retrospective observational studies reporting CAPA were searched using a two-level search strategy. First, we conducted a comprehensive literature search of PubMed and Embase databases through 4 April 2021. The search terms included ("COVID-19" OR "SARS-CoV-2" OR "coronavirus") AND ("aspergillosis" OR "aspergillus"). Second, we performed an additional manual search of secondary sources, including references of initially identified articles, to maximise the completeness of the collection of relevant studies. The search was performed without language restriction. A study was included in the meta-analysis if the following criteria were met: (1) the study was published in a peer-reviewed journal, for Human and Animal Mycology (ECMM/ISHAM) consensus criteria. 5 We excluded observational studies with diagnostic criteria for CAPA not clearly documented, as well as case reports and case series. Two investigators (HM and TK) reviewed the search results separately to select the studies based on the inclusion and exclusion criteria and assessed the eligibility of each study. The full text of articles was retrieved for eligibility assessment and further analyses after the initial screening with title and abstract. Any discrepancies were resolved by discussion and consensus. The following data were extracted from each eligible study: author name, study location, design, setting and case definition or diagnostic algorithm used to classify CAPA. We also collected the following patient characteristics and outcomes: the number of patients in the ICU during the study period, the number of patients with CAPA, the numbers of patients who received systemic steroids, tocilizumab and antifungal treatment, and the number of deaths among the patients with CAPA. If the patient population in a primary study was not limited to the ICU, we used only patients in the ICU for the analysis. The endpoints of this study were the incidence and mortality of CAPA in patients with COVID-19 in the ICU. We conducted a one-group meta-analysis with a random-effects model using the DerSimonian-Laird method. OpenMetaAnalyst version 12.11.14 was used to perform the statistical analysis (available at http:// www.cebm.brown.edu/openm eta/). 23 The I 2 statistic was used to quantify heterogeneity among studies, with I 2 > 50% indicating substantial heterogeneity. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 24 A total of 302 articles were identified through the initial database search and subsequent manual search. After the removal of duplicated items and screening based on title and abstract, 105 articles were assessed for eligibility. We excluded 77 articles including five case series and 38 case reports. Notably, two retrospective observational studies were excluded because the case definitions or diagnostic algorithms used to classify pulmonary aspergillosis were not documented. Finally, 28 observational studies were included in our meta-analysis ( Figure 1 ). The study characteristics included in the meta-analysis are summarised in Table 1 In this meta-analysis, we estimated the incidence and mortality of CAPA in critically ill patients with COVID-19 in the ICU. CAPA occurred in 10.2% of cases in these studies and was associated with high mortality. Since the start of the COVID-19 pandemic, CAPA has been reported as a complication of mechanically ventilated patients with COVID-19 from across the world. However, epidemiological data on incidence and mortality were variable as the reports were mainly based on case series and small observational studies, especially in the early stages of the pandemic. Early studies and case series from Europe reported that pulmonary aspergillosis occurred in 20%-35% of cases in the ICU. [1] [2] [3] 18, 33 However, several more recent prospective cohort studies reported a lower incidence of 3%. 11, 12 Interestingly, studies with larger sample sizes had lower estimates of incidence, potentially suggesting reporting bias in smaller studies. Given that as many as about 10% of mechanically ventilated patients with COVID-19 in the ICU were affected by CAPA as shown in our analysis, routine surveillance with tracheal aspirate and non-bronchoscopic lavage, serum galactomannan and chest CT might be justified. 5 This high incidence, combined with considerable mortality, might also increase the need for clinical trials to determine whether antifungal prophylaxis is beneficial. The high heterogeneity in incidence among each study may be explained by the differences in (1) Mortality from previous reports also varied between 22% 35 and 100%. 11 Based on our pooled estimate at 55%, the mortality of patients who develop CAPA may be higher than that of average ICU patients with COVID-19 who received mechanical ventilation observed in a large, international, multicentre, prospective cohort study in Europe (28-day mortality: 31%, 90-day mortality: 37%). 42 Two observational studies also reported excess mortality rates com- Our study has several limitations. First, our meta-analysis included many retrospective observational studies (the ratio of retrospective to prospective studies was approximately 2:1), which could predispose it to reporting bias. Second, the incidence and mortality of CAPA will likely continue to change due to several reasons. Our analysis integrated patients classified as pulmonary aspergillosis by different criteria, as there were no absolute definitions for CAPA. Our pooled estimates were also based on the results mainly from the first wave of the pandemic before the RECOVERY trial 13 was published. 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