key: cord-1001668-b3yzf4wx
authors: Sánchez Martín, C.; Madrid Martínez, E.; González Pellicer, R.; Armero Ibáñez, R.; Martínez González, E.; Llau Pitarch, J.V.
title: Invasive pulmonary aspergillosis in patients with acute respiratory syndrome by COVID-19()
date: 2022-01-07
journal: Rev Esp Anestesiol Reanim (Engl Ed)
DOI: 10.1016/j.redare.2021.02.007
sha: c6e3afaa35a8f341f953329b7560cb8f0f018964
doc_id: 1001668
cord_uid: b3yzf4wx

Patients with COVID-19 who are admitted to intensive care unit (ICU) are at high risk of developing secondary infections, including invasive fungal infections such as invasive pulmonary aspergillosis (IPA). The main purpose was to analyse the putative COVID-19 Associated Pulmonary Aspergillosis (CAPA) patients in our setting. In these patients, we performed mycological culture in bronchoalveolar lavage (BAL) for isolation of Aspergillus sp. We followed the AspICU algorithm to diagnose putative IPA. Moreover, we considered relevant the positivity of Galactomannan in BAL. We diagnosed putative IPA in 3 patients. The common features of these 3 patients were: more than 21 days of stay in ICU, severe acute respiratory distress syndrome (ARDS) and treatment with steroids (1 mg/kg per day). Therefore, CAPA has to be systematically considered although a new algorithm to diagnose it is needed to treat patients in early stages in order to avoid catastrophic outcomes.

Case report

Invasive pulmonary aspergillosis in patients with acute respiratory syndrome by COVID 

Between 5%-30% of patients with COVID-19 require admission to the intensive care unit (ICU) 1 , and present a high risk of developing secondary infections, including invasive fungal infections such as invasive pulmonary aspergillosis (IPA) 2 . In 2012, the association of severe infection by the influenza A (H1N1) virus and IPA led to an increase in mortality of up to 40%-60% 3 . COVID-19 has characteristics similar to severe forms of influenza A virus; therefore, it is reasonable to suspect that critical COVID-19 patients may be susceptible to IPA 4 . In addition, corticosteroid therapy is an immunosuppressive factor related to IPA, and has been used in up to 46% of critical COVID-19 patients 5 .

We found several case series in the literature that describe the association between IPA and COVID-19, forming a new entity known as COVID-19 Associated Pulmonary Aspergillosis (CAPA). The earliest studies included 1 in 9 patients in France (33% of the 27 admitted to the ICU with COVID-19), and another with 5 patients in Germany (26% of the 19 admitted) 2,6 -rates similar to those observed in influenza A-associated IPA 3 . This was a red flag for the medical community. Several prospective studies were then published, such as the one performed in Lyon, France where 19 of the 106 patients with COVID-19 analysed presented putative IPA (17.9%) 7 . Another prospective study was performed in Bologna, Italy 8 in 108 patients, of which 30 (27.7%) presented putative CAPA, a rate consistent with the aforementioned studies. This study also analysed the Kaplan-Meier survival curve, which showed an increase in 30-day mortality in patients with putative CAPA compared with no CAPA (44 vs. 19%; p = 0.002). The lack of uniformity in diagnostic criteria for putative CAPA prevents us from determining the exact prevalence of the disease and, therefore, its mortality. However, data from the review article published by Pemán et al. 1 show that the mortality rate for CAPA could be as high as 59.1%, and could justify taking samples from the lower respiratory tract in all critically ill COVID-19 patients to perform systematic aspergillosis screening, and even starting empirical treatment before definitive diagnosis 5 .

We present a series of 4 patients out of a total of 15 admitted for COVID-19 to the Anaesthesiology ICU of the Doctor Peset University Hospital, Valencia between March 22 and May 22 in which IPA was suspected. Our objective was to compare our results with those reported in the medical literature.

All patients were treated according to the COVID-19 protocol in place in our hospital, namely hydroxychloroquine 200 mg/12 h and lopinavir/ritonavir 400/100 mg/12 h (for the first 7 days of admission). Patients with established pneumonia were also given ceftriaxone (2 g/24 J o u r n a l P r e -p r o o f h) and azithromycin (500 mg/24 h), and those with moderate to severe respiratory distress syndrome (ARDS) were also given corticosteroid therapy with intravenous methylprednisolone (0.5 mg/kg/12 h) for 5 days. Patients with elevated IL-6 (> 40 pg/m) received immunosuppressive therapy with tocilizumab 600 mg (single dose) and/or anakinra 100 mg when supplies of tocilizumab became depleted. Interferon 1b (0.25 mg sc/48 h) was used in the pulmonology ward.

Bronchoalveolar lavage (BAL) was performed in patients presenting clinical and radiological deterioration, characterized by increased alveolar infiltrates with appearance of fever and/or progressive respiratory failure despite broad-spectrum antibiotic treatment and ventilatory support. We obtained samples for mycological culture and galactomannan antigen assay (Ag). We followed the AspICU 9 algorithm to establish a diagnosis of putative IPA -the EORT-MSC algorithm 10 was not applicable because the patients had no previous immunodeficiency. We believe the recently published influenza-associated pulmonary aspergillosis (IAPA) diagnostic algorithm 3 , which experts claim can be extrapolated, requires more validation studies.

Only 1 of our study patients had a previous risk factor for IPA (history of solid organ neoplasia). All study patients presented moderate-to-severe ARDS requiring orotracheal intubation at some point in their evolution, 10 received corticosteroid therapy with doses equivalent to more than 20 mg of prednisone and 2 were treated with immunomodulators. None of the patients presented H1N1 superinfection.

Out of a total of 15 patients, BAL was performed in 4 (2 men and 2 women with a mean age of 67 years) due to radiological and clinical deterioration. Three of the 4 patients had 1 or more cardiovascular risk factors (arterial hypertension, dyslipidaemia, obesity and/or diabetes). Only 1 of the patients (patient 3) had no cardiovascular risk factors -his only history of interest being thalassemia minor. All study patients were treated according to the COVID-19 protocol in place in our hospital. The characteristics of these patients are shown in Table 1 .

The mycological diagnostic and therapeutic characterization of study patients with putative IPA is described in Table 2 Putative IPA was diagnosed in 3 study patients (20% of the total of 15 patients). Lung histopathological samples were not obtained by autopsy or post mortem lung biopsy.

The SARS-CoV-2 pandemic challenged healthcare systems around the world in 2020. Around 5%-30% of patients with COVID-19 have required admission to critical care units 1 , and secondary superinfection such as IPA are a possible cause of increased morbidity and mortality in these patients, particularly in those requiring invasive mechanical ventilation 2 .

The literature describes various methods for diagnosing CAPA. Some studies consider COVID-19 to be a prior immunodeficiency and use the EORT-MSC algorithm 10 , while others follow the more complex AspICU algorithm, in which the entry criterion is a BAL fluid sample positive for Aspergillus 9 . We diagnosed CAPA following the AspICU algorithm in 3 patients (20% of the total), which is somewhat lower than the series of 9 patients in France (33% of the total) 2 , the series of 5 patients in Germany (26% of the total) 6 , and the prospective studies performed in Italy and France in which diagnosis was obtained in 30 (27.7% of the total) and 19 (17.9%) patients, respectively 7, 8 .

Aside from differences in the diagnostic method, there is increasing evidence that COVID-19 may be associated with serious nosocomial superinfections, such as IPA 1,2,5-8 . Similarly, some authors claim that the mere isolation of Aspergillus in respiratory samples in critically ill patients with COVID-19 should be considered putative aspergillosis, and should prompt clinicians to start antifungal therapy 1 . Therefore, patients admitted to ICUs for COVID-19 should be systematically screened for fungal superinfections in order to reduce the negative consequences of such colonisation.

The main limitation of this study is the small sample size and our failure to initially perform BAL due to the risk of aerosolization and a shortage of protective material during the pandemic. Likewise, strict adherence to the AspICU diagnostic algorithm and the high rate of early mortality in our patients could have led us to underestimate the presence of CAPA.

IPA superinfection should be systematically considered in COVID-19 patients admitted to the ICU. Given the difficulty involved in diagnosing this type of colonisation using traditional diagnostic algorithms, there is a clear need for a new common CAPA diagnostic algorithm that can give prompt diagnosis leading to early treatment to mitigate the negative outcomes that can be associated with Aspergillus superinfection in critically ill patients with SARS-CoV-2.

This study was approved by the Ethics Committee of the Hospital Universitario Doctor Peset (CEIm code: 144/20).

La presente investigación no ha recibido ayudas específicas provenientes de agencias del sector público, sector comercial o entidades sin ánimo de lucro. CONTRIBUCIÓN AUTORÍA Todos los autores han tenido una contribución significativa en el diseño, elaboración y revisión de este estudio.

Los autores declaran no tener conflictos de intereses para el presente manuscrito.

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Invasive Pulmonary Aspergillosis in Patients with SARS-CoV-2 Infection: A Systematic Review of the Literature

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The authors have not received specific funding from agencies in the private public and non-profit sectors.

All authors made a significant contribution to the design, development and review of this study.

The authors have no conflict of interest to declare.J o u r n a l P r e -p r o o f