Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis

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Abstract

Purpose

Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance.

Methods

A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology.

Results

The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients’ clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients.

Conclusion

CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00134-021-06449-4.

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Most cited references 76

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Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Mark Peters (2021)

Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)

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Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Jonathan A. C. Sterne, Srinivas Murthy, Janet V. Diaz … (2021)

Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.

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Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Clark D. Russell, Jonathan Millar, J Baillie (2020)

The 2019 novel coronavirus (2019-nCoV) outbreak is a major challenge for clinicians. The clinical course of patients remains to be fully characterised, little data are available that describe the disease pathogenesis, and no pharmacological therapies of proven efficacy yet exist. Corticosteroids were widely used during the outbreaks of severe acute respiratory syndrome (SARS)-CoV 1 and Middle East respiratory syndrome (MERS)-CoV, 2 and are being used in patients with 2019-nCoV in addition to other therapeutics. 3 However, current interim guidance from WHO on clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected (released Jan 28, 2020) advises against the use of corticosteroids unless indicated for another reason. 4 Understanding the evidence for harm or benefit from corticosteroids in 2019-nCoV is of immediate clinical importance. Here we discuss the clinical outcomes of corticosteroid use in coronavirus and similar outbreaks (table ). Table Summary of clinical evidence to date Outcomes of corticosteroid therapy * Comment MERS-CoV Delayed clearance of viral RNA from respiratory tract 2 Adjusted hazard ratio 0·4 (95% CI 0·2–0·7) SARS-CoV Delayed clearance of viral RNA from blood 5 Significant difference but effect size not quantified SARS-CoV Complication: psychosis 6 Associated with higher cumulative dose, 10 975 mg vs 6780 mg hydrocortisone equivalent SARS-CoV Complication: diabetes 7 33 (35%) of 95 patients treated with corticosteroid developed corticosteroid-induced diabetes SARS-CoV Complication: avascular necrosis in survivors 8 Among 40 patients who survived after corticosteroid treatment, 12 (30%) had avascular necrosis and 30 (75%) had osteoporosis Influenza Increased mortality 9 Risk ratio for mortality 1·75 (95% CI 1·3–2·4) in a meta-analysis of 6548 patients from ten studies RSV No clinical benefit in children10, 11 No effect in largest randomised controlled trial of 600 children, of whom 305 (51%) had been treated with corticosteroids CoV=coronavirus. MERS=Middle East respiratory syndrome. RSV=respiratory syncytial virus. SARS=severe acute respiratory syndrome. * Hydrocortisone, methylprednisolone, dexamethasone, and prednisolone. Acute lung injury and acute respiratory distress syndrome are partly caused by host immune responses. Corticosteroids suppress lung inflammation but also inhibit immune responses and pathogen clearance. In SARS-CoV infection, as with influenza, systemic inflammation is associated with adverse outcomes. 12 In SARS, inflammation persists after viral clearance.13, 14 Pulmonary histology in both SARS and MERS infections reveals inflammation and diffuse alveolar damage, 15 with one report suggesting haemophagocytosis. 16 Theoretically, corticosteroid treatment could have a role to suppress lung inflammation. In a retrospective observational study reporting on 309 adults who were critically ill with MERS, 2 almost half of patients (151 [49%]) were given corticosteroids (median hydrocortisone equivalent dose [ie, methylprednisolone 1:5, dexamethasone 1:25, prednisolone 1:4] of 300 mg/day). Patients who were given corticosteroids were more likely to require mechanical ventilation, vasopressors, and renal replacement therapy. After statistical adjustment for immortal time and indication biases, the authors concluded that administration of corticosteroids was not associated with a difference in 90-day mortality (adjusted odds ratio 0·8, 95% CI 0·5–1·1; p=0·12) but was associated with delayed clearance of viral RNA from respiratory tract secretions (adjusted hazard ratio 0·4, 95% CI 0·2–0·7; p=0·0005). However, these effect estimates have a high risk of error due to the probable presence of unmeasured confounders. In a meta-analysis of corticosteroid use in patients with SARS, only four studies provided conclusive data, all indicating harm. 1 The first was a case-control study of SARS patients with (n=15) and without (n=30) SARS-related psychosis; all were given corticosteroid treatment, but those who developed psychosis were given a higher cumulative dose than those who did not (10 975 mg hydrocortisone equivalent vs 6780 mg; p=0·017). 6 The second was a randomised controlled trial of 16 patients with SARS who were not critically ill; the nine patients who were given hydrocortisone (mean 4·8 days [95% CI 4·1–5·5] since fever onset) had greater viraemia in the second and third weeks after infection than those who were given 0·9% saline control. 5 The remaining two studies reported diabetes and avascular necrosis as complications associated with corticosteroid treatment.7, 8 A 2019 systematic review and meta-analysis 9 identified ten observational studies in influenza, with a total of 6548 patients. The investigators found increased mortality in patients who were given corticosteroids (risk ratio [RR] 1·75, 95% CI 1·3–2·4; p=0·0002). Among other outcomes, length of stay in an intensive care unit was increased (mean difference 2·1, 95% CI 1·2–3·1; p<0·0001), as was the rate of secondary bacterial or fungal infection (RR 2·0, 95% CI 1·0–3·8; p=0·04). Corticosteroids have been investigated for respiratory syncytial virus (RSV) in clinical trials in children, with no conclusive evidence of benefit and are therefore not recommended. 10 An observational study of 50 adults with RSV infection, in which 33 (66%) were given corticosteroids, suggested impaired antibody responses at 28 days in those given corticosteroids. 17 Life-threatening acute respiratory distress syndrome occurs in 2019-nCoV infection. 18 However, generalising evidence from acute respiratory distress syndrome studies to viral lung injury is problematic because these trials typically include a majority of patients with acute respiratory distress syndrome of non-pulmonary or sterile cause. A review of treatments for acute respiratory distress syndrome of any cause, based on six studies with a total of 574 patients, 19 concluded that insufficient evidence exists to recommend corticosteroid treatment. 20 Septic shock has been reported in seven (5%) of 140 patients with 2019-nCoV included in published reports as of Jan 29, 2020.3, 18 Corticosteroids are widely used in septic shock despite uncertainty over their efficacy. Most patients in septic shock trials have bacterial infection, leading to vasoplegic shock and myocardial insufficiency.21, 22 In this group, there is potential that net benefit might be derived from steroid treatment in severe shock.21, 22 However, shock in severe hypoxaemic respiratory failure is often a consequence of increased intrathoracic pressure (during invasive ventilation) impeding cardiac filling, and not vasoplegia. 23 In this context, steroid treatment is unlikely to provide a benefit. No clinical data exist to indicate that net benefit is derived from corticosteroids in the treatment of respiratory infection due to RSV, influenza, SARS-CoV, or MERS-CoV. The available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors. If it is present, the effect of steroids on mortality in those with septic shock is small, and is unlikely to be generalisable to shock in the context of severe respiratory failure due to 2019-nCoV. Overall, no unique reason exists to expect that patients with 2019-nCoV infection will benefit from corticosteroids, and they might be more likely to be harmed with such treatment. We conclude that corticosteroid treatment should not be used for the treatment of 2019-nCoV-induced lung injury or shock outside of a clinical trial.

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Author and article information

Contributors

Paul E. Verweij:

ORCID: http://orcid.org/0000-0002-8600-9860

paul.verweij@radboudumc.nl

Ignacio Martin-Loeches:

ORCID: http://orcid.org/0000-0002-5834-4063

drmartinloeches@gmail.com

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 23 June 2021

Publication date PMC-release: 23 June 2021

Pages: 1-16

Affiliations

[1 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Medical Microbiology, Radboudumc Center for Infectious Diseases (RCI), , Radboud University Medical Center, ; PO box 9101, 6500 HB Nijmegen, The Netherlands

[2 ]GRID grid.413327.0, ISNI 0000 0004 0444 9008, Radboudumc-CWZ Center of Expertise for Mycology, , Radboudumc Center for Infectious Diseases (RCI), ; Nijmegen, The Netherlands

[3 ]GRID grid.31147.30, ISNI 0000 0001 2208 0118, Center for Infectious Disease Research, Diagnostics and Laboratory Surveillance, , National Institute for Public Health and the Environment, ; Bilthoven, The Netherlands

[4 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Pharmacy and Radboud Institute of Health Sciences, , Radboud University Medical Centre, ; Nijmegen, The Netherlands

[5 ]GRID grid.413328.f, ISNI 0000 0001 2300 6614, Medical Intensive Care Unit, , Saint-Louis Hospital, APHP, ; Paris, France

[6 ]Clinica Malattie Infettive, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy

[7 ]GRID grid.5606.5, ISNI 0000 0001 2151 3065, Department of Health Sciences, , DISSAL, University of Genoa, ; Genoa, Italy

[8 ]GRID grid.5342.0, ISNI 0000 0001 2069 7798, Department of Internal Medicine and Paediatrics, Faculty of Medicine and Health Sciences, , Ghent University, ; Ghent, Belgium

[9 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Burns, Trauma, and Critical Care Research Centre, Centre for Clinical Research, Faculty of Medicine, , The University of Queensland, ; Brisbane, QLD Australia

[10 ]GRID grid.8515.9, ISNI 0000 0001 0423 4662, Infectious Diseases Service, Department of Medicine, , Lausanne University Hospital and University of Lausanne, ; 1011 Lausanne, Switzerland

[11 ]GRID grid.416738.f, ISNI 0000 0001 2163 0069, Centers for Disease Control and Prevention, ; Atlanta, GA 30329 USA

[12 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Division of Infectious Diseases, , University of Pittsburgh, ; Pittsburgh, PA USA

[13 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Cologne Excellence Cluster On Cellular Stress Responses in Aging-Associated Diseases (CECAD), , University of Cologne, ; Cologne, Germany

[14 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Department I of Internal Medicine, ECMM Center of Excellence for Medical Mycology, German Centre for Infection Research, Partner Site Bonn-Cologne (DZIF), , University of Cologne, ; Cologne, Germany

[15 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Clinical Trials Centre Cologne (ZKS Köln), , University of Cologne, ; Cologne, Germany

[16 ]GRID grid.410566.0, ISNI 0000 0004 0626 3303, Department of Critical Care Medicine, , Ghent University Hospital, ; Ghent, Belgium

[17 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Department of Microbiology, Immunology and Transplantation, , KU Leuven, ; Leuven, Belgium

[18 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, Department of Laboratory Medicine, National Reference Centre for Mycosis, , University Hospitals Leuven, ; Leuven, Belgium

[19 ]GRID grid.5477.1, ISNI 0000000120346234, Department of Intensive Care Medicine, , University Medical Center, University Utrecht, ; Utrecht, The Netherlands

[20 ]GRID grid.5361.1, ISNI 0000 0000 8853 2677, Division of Hygiene and Medical Microbiology, , Medical University of Innsbruck, ; Innsbruck, Austria

[21 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, Department of Medical and Surgical Sciences, Infectious Diseases Hospital, IRCSS S’Orsola-Malpighi, , University of Bologna, ; Bologna, Italy

[22 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, AP-HP, , Paris University, ; Paris, France

[23 ]GRID grid.4444.0, ISNI 0000 0001 2112 9282, Institut Pasteur, Molecular Mycology Unit, National Reference Center for Invasive Mycoses and Antifungals, , CNRS UMR 2000, ; Paris, France

[24 ]GRID grid.256105.5, ISNI 0000 0004 1937 1063, Department of Emergency and Critical Care Medicine, Fu Jen Catholic University Hospital, , Fu Jen Catholic University, ; New Taipei, Taiwan

[25 ]GRID grid.256105.5, ISNI 0000 0004 1937 1063, School of Medicine, College of Medicine, , Fu Jen Catholic University, ; New Taipei, Taiwan

[26 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, Department of Hematology, , University Hospitals Leuven, ; Leuven, Belgium

[27 ]GRID grid.267309.9, ISNI 0000 0001 0629 5880, Department of Medicine, Division of Infectious Diseases, , University of Texas Health Science Center at San Antonio, ; San Antonio, TX USA

[28 ]GRID grid.280682.6, ISNI 0000 0004 0420 5695, South Texas Veterans Health Care System, ; San Antonio, TX USA

[29 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Internal Medicine and Infectious Diseases, Erasmus MC, , University Medical Center, ; Rotterdam, The Netherlands

[30 ]GRID grid.411435.6, ISNI 0000 0004 1767 4677, Critical Care Department, , Joan XXIII University Hospital, ; Tarragona, Spain

[31 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, Department of Clinical Microbiology, Trinity College Dublin, , St. James’s Hospital, ; Dublin, Ireland

[32 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Intensive Care Medicine, , Radboud University Medical Center, ; Nijmegen, The Netherlands

[33 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Scientific Center for Quality of Healthcare (IQ Healthcare), , Radboud Institute for Health Sciences, Radboud University Medical Center, ; Nijmegen, The Netherlands

[34 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, Department of General Internal Medicine, Medical Intensive Care Unit, , University Hospitals Leuven, ; Leuven, Belgium

[35 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Medicine, , Radboud University Medical Center, ; Nijmegen, The Netherlands

[36 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), , St. James’s Hospital, ; Dublin, Ireland

[37 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Hospital Clinic, IDIBAPS, , Universidad de Barcelona, Ciberes, ; Barcelona, Spain

[38 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, Department of Clinical Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), , St James’s Hospital, ; Dublin, Ireland

Author information

Paul E. Verweij http://orcid.org/0000-0002-8600-9860

Roger J. M. Brüggemann http://orcid.org/0000-0002-7618-725X

Elie Azoulay http://orcid.org/0000-0002-8162-1508

Matteo Bassetti http://orcid.org/0000-0002-0145-9740

Stijn Blot http://orcid.org/0000-0003-2145-0345

Jochem B. Buil http://orcid.org/0000-0003-4031-0778

Thierry Calandra http://orcid.org/0000-0003-3051-1285

Tom Chiller http://orcid.org/0000-0002-2251-8033

Cornelius J. Clancy http://orcid.org/0000-0003-1505-4119

Oliver A. Cornely http://orcid.org/0000-0001-9599-3137

Pieter Depuydt http://orcid.org/0000-0001-5164-5376

Philipp Koehler http://orcid.org/0000-0002-7386-7495

Katrien Lagrou http://orcid.org/0000-0001-8668-1350

Dylan de Lange http://orcid.org/0000-0002-0191-7270

Cornelia Lass-Flörl http://orcid.org/0000-0002-2946-7785

Russell E. Lewis http://orcid.org/0000-0002-2002-4339

Olivier Lortholary http://orcid.org/0000-0002-8325-8060

Peter-Wei Lun Liu http://orcid.org/0000-0001-8593-8492

Johan Maertens http://orcid.org/0000-0003-4257-5980

M. Hong Nguyen http://orcid.org/0000-0002-8564-7529

Thomas F. Patterson http://orcid.org/0000-0002-9513-7127

Bart J. A. Rijnders http://orcid.org/0000-0003-3343-9610

Alejandro Rodriguez http://orcid.org/0000-0001-8828-5984

Thomas R. Rogers http://orcid.org/0000-0003-4336-7729

Jeroen A. Schouten http://orcid.org/0000-0001-9118-4420

Joost Wauters http://orcid.org/0000-0002-5983-3897

Frank L. van de Veerdonk http://orcid.org/0000-0002-1121-4894

Ignacio Martin-Loeches http://orcid.org/0000-0002-5834-4063

Article

Publisher ID: 6449

DOI: 10.1007/s00134-021-06449-4

PMC ID: 8220883

PubMed ID: 34160631

SO-VID: 178ff2b1-a0c3-4e08-87a5-a7871d462b16

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 2 April 2021

Date accepted : 28 May 2021

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Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis

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Abstract

Purpose

Methods

Results

Conclusion

Supplementary Information

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 76

Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

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