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 Journal of Intensive Medicine 1 (2021) 71–80

Contents lists available at ScienceDirect

Journal of Intensive Medicine

journal homepage: www.elsevier.com/locate/jointm

Review

COVID-19-Associated Pulmonary Aspergillosis (CAPA)

George Dimopoulos 1,∗, Maria-Panagiota Almyroudi 2, Pavlos Myrianthefs 3, Jordi Rello 4,∗
1
Department of Critical Care, University Hospital ATTIKON, National and Kapodistrian University of Athens, Athens 12462, Greece
2
Department of Emergency Medicine, University Hospital ATTIKON, National and Kapodistrian University of Athens, Athens 12462, Greece
3
Department of Critical Care, Agioi Anargyroi Hospital, National and Kapodistrian University of Athens, Athens 14564, Greece
4
Universitat Internacional de Catalunya, Barcelona 08035, Spain

a r t i c l e i n f o a b s t r a c t

Keywords: Invasive Pulmonary Aspergillosis (IPA) has been recognized as a possible secondary infection complicating Coro-
COVID-19 navirus disease 2019 (COVID-19) and increasing mortality. The aim of this review was to report and summarize
Aspergillosis the available data in the literature concerning the incidence, pathophysiology, diagnosis, and treatment of COVID-
Diagnosis
19-Associated Pulmonary Aspergillosis (CAPA). Currently, the incidence of CAPA is unclear due to different def-
Treatment
initions and diagnostic criteria used among the studies. It was estimated that approximately 8.6% (206/2383) of
Intensive care unit
Severe acute respiratory mechanically ventilated patients were diagnosed with either proven, probable, or putative CAPA. Classical host
syndrome Coronavirus 2 (SARS-CoV-2) factors of invasive aspergillosis are rarely recognized in patients with CAPA, who are mainly immuno-competent
Voriconazole presenting with comorbidities, while the role of steroids warrants further investigation. Direct epithelial injury
and diffuse pulmonary micro thrombi in combination with immune dysregulation, hyper inflammatory response,
and immunosuppressive treatment may be implicated. Discrimination between two forms of CAPA (e.g., tra-
cheobronchial and parenchymal) is required, whereas radiological signs of aspergillosis are not typically evident
in patients with severe COVID-19 pneumonia. In previous studies, the European Organization for Research and
Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria, a clinical algorithm to diagnose Invasive Pul-
monary Aspergillosis in intensive care unit patients (AspICU algorithm), and influenza-associated pulmonary
aspergillosis (IAPA) criteria were used for the diagnosis of proven/probable and putative CAPA, as well as the
differentiation from colonization, which can be challenging. Aspergillus fumigatus is the most commonly isolated
pathogen in respiratory cultures. Bronchoalveolar lavage (BAL) and serum galactomannan (GM), 𝛽-d-glucan (with
limited specificity), polymerase chain reaction (PCR), and Aspergillus-specific lateral-flow device test can be in-
cluded in the diagnostic work-up; however, these approaches are characterized by low sensitivity. Early treatment
of CAPA is necessary, and 71.4% (135/189) of patients received antifungal therapy, mainly with voriconazole,
isavuconazole, and liposomal amphotericin B . Given the high mortality rate among patients with Aspergillus
infection, the administration of prophylactic treatment is debated. In conclusion, different diagnostic strategies
are necessary to differentiate colonization from bronchial or parenchymal infection in intubated COVID-19 pa-
tients with Aspergillus spp. in their respiratory specimens vs. those not infected with severe acute respiratory
syndrome Coronavirus 2 (SARS-CoV-2). Following confirmation, voriconazole or isavuconazole should be used
for the treatment of CAPA.

Introduction
Typically, patients with Coronavirus disease 2019 (COVID-
19) are immunocompetent, of advanced age, and with comor-
bidities (mainly hypertension, diabetes, chronic heart, and
renal disease) [1–3]. Approximately 5% of those will develop
a severe form of the disease with respiratory failure, complex
immune dysregulation, and cytokine storm, requiring hospital-
ization in the intensive care unit (ICU) [4]. Different studies
showed that these patients are at increased risk of secondary
infections [5].
The syndromes of pulmonary aspergillosis complicating se-
vere viral infections are distinct from classic invasive pulmonary
aspergillosis (IPA). IPA, particularly that associated with hema-
tologic malignancies and transplantation, is most frequently
encountered in patients with neutropenia and other immuno

∗
Corresponding authors: Jordi Rello, Universitat Internacional de Catalunya, Barcelona 08035, Spain; George Dimopoulos, Department of Critical Care, University
Hospital ATTIKON, National and Kapodistrian University of Athens, Athens 12462, Greece. Email addresses: jrello@crips.es; gdimop@med.uoa.gr
E-mail addresses: gdimop@med.uoa.gr (G. Dimopoulos), jrello@crips.es (J. Rello).

https://doi.org/10.1016/j.jointm.2021.07.001
Received 22 February 2021; Received in revised form 2 June 2021; Accepted 7 July 2021. Managing Editor: Jingling Bao
Copyright © 2021 Chinese Medical Association. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al.
compromised individuals. Numerous studies have recognized
influenza-associated pulmonary aspergillosis (IAPA) associated
with respiratory epithelium damage. Of note, local anosoparal-
ysis may render patients with influenza more susceptible to
IPA [6,7]. Since the first evidence of secondary aspergillosis re-
ported in China, several studies have shown that steroid and
other immune-modulatory therapies are linked to an increased
risk of a similar syndrome associated with severe COVID-19,
termed COVID-19-associated pulmonary aspergillosis (CAPA).
Actually, the first reports referred to post-mortem results rais-
ing concerns regarding this infection as an additional factor
contributing to patient mortality [7–12]. Three different grades
(e.g., possible, probable, and proven CAPA) have been suggested
by an international panel of experts [13], enabling investigators
to stratify patients in research registries and clinical trials.
This review focused on key controversies in CAPA due to its
contribution to mortality among patients with COVID-19. An
analysis of the available literature (reported until January 2021;
search list presented in Appendix) was performed to identify dif-
ferences in the incidence, pathophysiology, diagnosis, and treat-
ment of CAPA and IPA.
Incidence and Risk Factors
Owing to differences in diagnostic criteria, methods, defini-
tions, and local practices, the incidence of CAPA varies. There-
fore, the estimation of CAPA incidence is challenging due to
the lack of a gold standard and limitations in diagnostic tests.
For this reason, definitions used for IAPA were applied in most
studies; however, this approach generated a wide degree of vari-
ability in the incidence of CAPA among ICU patients (range:
3.8–34%) [7–10,14–32]. In general, the diagnosis of CAPA is
delayed vs. that of IAPA, and the incidence of the angioinvasive
parenchymal form is lower. Table 1 shows all published stud-
ies describing the incidence of CAPA and associated comorbidi-
ties until January 2021. The majority of those studies suggested
that CAPA mostly occurs in severely ill, mechanically ventilated
patients with COVID-19. Among them, three prospective stud-
ies reported an incidence ranging 14–20%, while more recently
published studies indicated a lower incidence ranging 3–15% (a
total of 2407 patients were included) [8,11,26,28,33–41]. Ex-
cluding seven case reports, the diagnosis of CAPA has been con-
firmed in 223 of 2400 ICU patients (incidence of 9.2%). Nev-
ertheless, this percentage may be slightly lower since two stud-
ies did not report the total number of patients admitted in the
ICU during the investigation period. Thus, by deducting 17 pa-
tients from those two studies, the total number of ICU patients
with COVID-19 and a diagnosis of proven/probable/putative
CAPA is 206 (incidence: 8.6%). Interestingly, among eight stud-
ies involving >100 patients each, the incidence of CAPA ranged
from 3.3% to 27.7%, though six of them reported an incidence
<10%. This is in accordance with evidence from Chinese studies
[42,43]. Notably, the majority of CAPA cases were documented
in European countries (26/32 studies); one and two studies were
performed in the USA and China, respectively.
The medical history, underlying conditions, comorbidities,
and risk factors related to the development of CAPA are shown
in Table 1. Two previous studies have identified long-term treat-
ment with corticosteroids as a risk factor for infection with
Aspergillus spp. [8,28]. Moreover, the role of dexamethasone
72
Journal of Intensive Medicine 1 (2021) 71–80
(doses) in the early stage of COVID-19 and that of tocilizumab
in the development of a cytokine storm warrant further investi-
gation [10,44,45].
Possible Pathophysiologic Mechanisms
Currently, the pathogenesis of CAPA is not well defined. In
influenza, disruption of the lung epithelium with dysfunctional
mucociliary clearance, local immuno-paralysis due to influenza-
induced hypoxia, treatment with corticosteroids, acute respi-
ratory distress syndrome, and suppression of the nicotinamide
adenine dinucleotide phosphate oxidase complex favor tissue
invasion by Aspergillus spp. In addition, invasive Aspergillus tra-
cheobronchitis has been described in approximately 55% of pa-
tients with IAPA. Examination through bronchoscopy has re-
vealed the presence of epithelial plaques, pseudo membranes,
and ulceration, as well as sporulating heads of Aspergillus spp.
inside the bronchi [46]. Similar to influenza, in severe COVID-
19 pneumonia, destruction of the bronchial mucosa and alveolar
injury caused by the virus create favorable conditions for fungal
growth [47]. The main histo-pathological findings in 14 patients
with COVID-19 were diffuse alveolar damage in the acute or or-
ganizing phase of the disease, with the virus located in the pneu-
mocytes and tracheal epithelium, and scarce focal pulmonary
micro thrombi. This observation indicated that the increased
pulmonary epithelial and vascular permeability facilitates the
invasion of Aspergillus spp. [2,48].
It is well established that Aspergillus spp. live in the environ-
ment, and the inhalation of its spores (conidia) leads to pul-
monary disease depending on the host immune status. Severe
COVID-19 is frequently associated with immune dysregulation,
characterized by a decrease in the number and functionality of
CD4+ T and CD8+ T-cells and a hyper inflammatory state. Over-
expression of pro- and anti-inflammatory cytokines contributes
to a highly permissive inflammatory environment that enhances
fungal growth [49,50]. Furthermore, damage-associated molec-
ular patterns, which are implicated in the pathogenesis of as-
pergillosis, are released during infection with severe acute respi-
ratory syndrome Coronavirus 2 (SARS-CoV-2), thereby leading
to an excessive inflammatory response and lung injury [49].
COVID-19-associated immune dysregulation and immuno-
suppressive treatment, rather than the pathophysiology of IPA,
are host factors for CAPA. Except for corticosteroids (a known
risk factor for IPA), tocilizumab (monoclonal antibody against
the interleukin-6 [IL-6] receptor), interferon 1𝛽 (IFN1𝛽), and
a combination of tocilizumab with corticosteroids were more
frequently administered in patients with CAPA than in those
without aspergillosis (71.4% vs. 33.3%, P = 0.050; 71.4% vs.
20.9%, P ≤ 0.050; and 57.1% vs. 28.7%, P = 0.180, respectively)
[51]. Blockage of IL-6 inhibits the development of protective
T-helper cells (Th17 cells), leading to a defective immune re-
sponse against infection with Aspergillus fumigatus (A. fumigatus).
In addition, it has been reported that IL-6 enhances epithelial
integrity during injury while the wide use of dexamethasone
in critically ill patients with COVID-19 renders these patients
more susceptible to IPA [52]. The maturation of phagosomes
that degrade A. Fumigatus spores via the process of phagolyso-
somal fusion is impaired by corticosteroids compromising the
host defense against the Aspergillus spp. [53].
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al. Journal of Intensive Medicine 1 (2021) 71–80

Table 1
Incidence and risk factors for CAPA (31 studies identified in the literature).

Study Country Environment, n (%) Comments Comorbitities

Bartoletti et al. [8] Italy ICU, 108 (27.27) Prospective study Obesity, AH, DM, Coronary disease, COPD, CReF,
Hemodialysis, Cerebrovascular disease, Malignancies,
Solid-organ transplant, Chronic steroid treatment
Alanio et al. [9] France ICU, 27 (33.3) Putative IPA mainly AH, Obesity, DM, BA, Cardiac disease
Rutsaert et al. [10] Belgium ICUs, 20 (35) None AH, DM, Hypercholesterinemia, CReF, Obesity, AML,
HIV
Chen et al. [14] China ICU, 48 (27.1) Mixed fungal infections High DM, AH, Heart disease
IL-6 levels
Lescure et al. [15] France 5 patients None Gout, AH, Thyroid cancer
Koehler et al. [16] Germany ICU, 19 (26.3) None AH, COPD, DM, Obesity OSA
van Arkel et al. [17] Netherlands ICU, 31 (19.4) 3 probable/3 possible CAPA Cardiomyopathy, COPD, BA
Blaize et al. [18] France ICU Case report Putative aspergillosis MDS, AH, Hashimoto disease
Prattes et al. [19] Austria ICU Case report 69-year-old patient COPD, OSA, Obesity, DM, AH, Cardiac disease
Antinori et al. [20] Italy ICU Case report None DM, AH, Atrial fibrillation, obesity
Wang et al. [21] China Hospital, 104 (8.5) Mainly elderly patients DM, AH, Cardiac disease, COPD, CReF
Meijer et al. [22] Netherland ICU Case report None Reflux, polyarthrosis
Mohamed et al. [23] Irelend ICU Case report Triazole-resistance DM, AH, Hyperlipidaemia, Obesity
Ghelfenstein-Ferreira France ICU Case report Triazole-resistance DM, AH, Hyperlipidemia, Obesity
et al. [24]
Santana et al. [25] Brazil ICU Case report Autopsy confirmed CAPA AH, DM, CReF
Nasir et al. [26] Pakistan ICU, 23 (21.7) 4 patients with colonization DM, AH, Atrial myxoma, Recent stroke
Lamoth et al. [27] Switzerland ICU, 118 (3.8) None AH, DM, Obesity, Pulmonary fibrosis, BA
Van Biesen et al. [28] Netherlands ICU, 42 (21.4) None COPD, DM, AH, Chronic steroid treatment,
Neutropenia, Stem cell transplant, Immunodeficiency
Flikweert et al. [29] Netherlands ICU, Unknown 7 CAPA cases AH, DM, CReF
number of included
patients
Falces-Romero et al. [30] Spain ICU, Unknown 10 CAPA cases MDS, HIV, DM, COPD, Ankylosing spondylitis,
number of included Acquired hemophilia A, Hypothyroidism, CLL, Cardiac
patients Disease
Helleberg et al. [31] Denmark ICU, 8 (25) Patients under ECMO AH, BA
White et al. [32] UK ICU, 135 (14) None DM, AH, CReF, Obesity, Cancer, CRF malignancy,
Hyperlipidaemia, Cardiac and vascular disease,
Autoimmune disorders
Gangneux et al. [33] France ICU, 45 (15.6) 8 patients with colonization DM, AH, Cancer, Hemopathy, CRF, Cardiovascular
disease
Lahmer et al. [34] Germany ICU, 2 cases None Pulmonary fibrosis
Borman et al. [35] UK ICU, 719 (20) 15 possible/probable CAPA
cases
Machado et al. [36] Spain ICU, 239 (3.3) 5 patients with colonization DM, AH, BA, Obesity, COPD, CReF, CLL, Non-alcoholic
fatty liver disease, CNS disease
Dellière et al. [37] France ICU, 366 (5.7) None Kidney transplant recipient, HIV, Cancer, Steroids
treatment
Brown et al. [38] UK ICU, 62 (20) (+) GM test: 6 patients (+)
PCR 5 patients
Fekkar et al. [39] France ICU, 145 (4.8) 6 CAPA cases, 1 fusariosis DM, AH, Obesity, Tabagism, Kidney and liver
transplantation, Steroids treatment, Dyslipidemia
Razazi et al. [40] France ICU, 90 (11) Probable (8%), Putative (2%) DM, AH, COPD, Dialysis, Stroke, CHF (NYHA
Aspergillus tracheobronchitis classification 3–4), Arrhythmias, CReF
(1%)
Chauvet et al. [41] USA ICU, 46 (13.3) None Atrial fibrilation, COPD, AH, OSA, DM, CRF, Coronary
Disease, CHD, ESRD, Nephrectomy, Vasculitis,
Junctional tachycardia, Bipolar disorder,
Hypercholesterolemia, Obesity, Hypothyroidism,
Gastric ulcer, Atherosclerosis, Sarcopenia
The incidence includes proven/probable and putative cases of CAPA, while patients with colonization are mentioned in comments.
AH: Arterial hypertension; AML: Acute myeloid leukaemia; BA: Bronchial asthma; CAPA: COVID-19-associated aspergillosis; COPD: Chronic ob-
structive pulmonary disease; COVID-19: Coronavirus disease 2019; CHD: Congenital heart disease; CHF: Congestive heart failure; CLL: Chronic
lymphocytic leukemia; CNS: Central nervous system; CRF: Chronic respiratory failure; CReF: Chronic renal failure; DM: Diabetes mellitus; ECMO:
Extracorporeal membrane oxygenation; ESRD: End stage renal disease; GM: Galactomannan; HIV: Human immunodeficiency syndrome; ICU: In-
tensive care unit; IL-6: Interleukin-6; IPA: Invasive pulmonary aspergillosis; OSA: Obstructive sleep apnea; MDS: Mylodysplastic syndrome; NYHA:
New York Heart Association; PCR: Polymerase chain reaction.

Imaging filtrates, complicating the identification of surrounding halos

The use of computed tomography (CT) imaging may be
unsuitable in these patients. It may be difficult to document
changes indicative of CAPA in the parenchyma through CT
imaging. This is because mechanically ventilated COVID-19
patients without invasive aspergillosis often have nodular in-
in the scans. Radiological characteristics of IPA (e.g., solitary
or multiple pulmonary nodules, halo sign, reverse halo sign,
ground-glass opacity, air crescent, and cavitation) may not be
distinct in severe COVID-19 pneumonia, which presents in CT
scans with bilateral, peripheral ground-glass opacities, crazy-
paving pattern, consolidation, and broncho vascular thickening.

73
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al. Journal of Intensive Medicine 1 (2021) 71–80

Table 2
Mycological results.

PCR (BAL, (+) culture (BAL, NBL,

Study (+) serum GM (+) serum BDG Bronchoscopy GM (BAL/TA) TA, serum) TA, sputum) Aspergillus spp. (n)

Machado et al. [36] 4/8 2/8 2/8 2/8 NA 8/8 A. fumigatus (6),
A. citrinoterreus (1), A. lentulus (1)
Koehler et al. [16] 2/5 NA 3/5 3/3 4/5 3/5 A. fumigatus (3)
Nasir et al. [26] 0/5 1/5 NA NA NA 5/5 A. flavus (4), A. fumigatus (1),
A. fumigatus (1),
Alanio et al. [9] 1/9 4/9 9/9 2/9 4/9 7/9 A. fumigatus
Dupont et al. [61] 1/12 NA 9/19 5/8 NA 16/19 A. fumigatus (14),
A. calidoustus (1), A. niger (1)
Prattes et al. [19] 0/1 0/1 0 /1 NA NA 1/1 A. fumigatus (1)
Wang et al. [21] NA NA 4/8 NA NA 8/8 A. fumigatus (8)
Bruno et al. [64] 0/1 NA 1/1 1/1 NA 1/1 A. fumigatus (1)
Meijer et al. [22] 0/1 1/1 0/1 1/1 NA 1/1 A. fumigatus (1)
Santana et al. [25] 1/1 NA 0/1 NA NA NA A. penicillioides (1)
Borman et al. [35] 5/15 13/15 5/15 4/5 3/11 5/8 A. fumigatus
Segrelles-Calvo et al. [51] NA NA 6/7 NA NA 7/7 A. fumigatus (3), A. flavus (2),
A. niger (2)
Patti et al. [54] 0/1 NA 0/1 NA NA 1/1 A. flavus (1)
White et al. [32] 2/4 14/18 0/25 17/19 15/15 11/11 A. fumigatus (11), A. versicolor (1)
Helleberg et al. [31] 1/2 NA 1/2 2/2 NA 2/2 A. fumigatus (2)
Trujillo et al. [65] 0/1 1/1 0/1 0/1 NA 1/1 A. fumigatus (1)
Spadea et al. [66] 1/1 1/1 0/1 0/1 NA NA
Van Biesen et al. [28] NA NA 0/9 9/9 NA 7/9 A. fumigatus (5), A. flavus (1),
A. terreus (1)
Lamoth et al. [27] 1/3 NA 0/3 NA NA 3/3 A. fumigatus (3)
Mitaka et al. [67] 1/3 NA 0/4 NA NA 4/4 A. fumigatus (4)
Nasri et al. [68] 1/1 NA 0/1 NA NA NA NA
Gangneux et al. [33] 2/7 NA 0/7 NA 7/7 6/7 A. fumigatus (6)
Roman-Montes et al. [58] 6/14 NA 0/14 8/14 NA 9/14 A. fumigatus (6), A. flavus (2),
A. niger (1), A. versicolor (1),
Aspergillus spp. (1)
Blaize et al. [18] 0/1 0/1 0/1 0/1 1/2 1/1 A. fumigatus (1)
Schein et al. [55] 1/1 NA 0/1 1/1 1/1 0/1 NA
Fernandez et al. [69] 1/1 NA 0/1 NA NA 1/1 A. flavus (1)
Ghelfenstein-Ferreira et al. [24] 0/1 0/1 0/1 NA 1/2 1/1 A. fumigatus (1)
Falces-Romero et al. [30] 1/2 NA 1/8 1/1 NA 8/8 A. nidulans (1), A. fumigatus (7)
Mohamed et al. [23] 1/1 1/1 0/1 1/1 NA 1/1 A. fumigatus (1)
Antinori et al. [20] 1/1 NA 0/1 NA NA 1/1 A. fumigatus (1)
Lahmer et al. [34] 1/2 NA 2/2 2/2 NA 2/2 A. fumigatus (2)
Chauvet et al. [41] NA NA 3/6 2/3 1/1 4/6 A. fumigatus (4)
Bartoletti et al. [8] 1/30 NA 30/30 30/30 20/30 19/30 A. fumigatus (15), A. niger (3),
A. flavus (1)
van Arkel et al. [17] 0/3 NA 3/6 3/3 NA 5/6 A. fumigatus (5)
Rutsaert et al. [10] 1/6 NA 6/7 6/6 NA 6/7 A. flavus (1), A. fumigatus (5)

BAL: Bronchoalveolar lavage; BDG: 𝛽-d-Glucan; GM: Galactomannan; NA:Not available; NBL: Non directed BAL; PCR: Polymerase chain reaction; TA: Tracheal
aspirate.

Patti et al. [54] reported a mechanically ventilated patient
with COVID-19, whose CT analysis showed bilateral periph-
eral ground glass infiltrates, with newly formed thin-walled
cavitary lesions occupied by fungal ball-like lesions. Aspergillus
flavus was isolated in respiratory cultures. Moreover, a CT
is not always feasible due to the risk associated with the
transportation of critically ill patients. White et al. [32] pro-
posed a diagnostic algorithm for CAPA that, along with clini-
cal and mycological criteria, incorporated typical radiological
signs of IPA, the presence of new infiltrates, and evidence of
sinusitis [36].
Mycological Criteria
Regarding the mycological criteria for the diagnosis of CAPA,
85 of 208 (42%) patients included in all studies underwent
bronchoscopy [Table 2] (one study did not report the num-
ber of patients who underwent bronchoscopy) [26]. At the start
of the epidemic, the use of bronchoscopy was avoided due to
shortages in personal protective equipment. In two studies, non-
directed bronchoalveolar lavage (NBL) was performed; although
this method is less invasive and safer than bronchoscopy, it is
linked to a higher risk of sample contamination by upper respi-
ratory flora [28,55]. Table 2 presents the total number of pos-
itive respiratory cultures for Aspergillus spp. (155 of 189 tested
patients [82%]), including bronchoalveolar lavage (BAL), NBL,
tracheal aspirate (TA), and sputum cultures. In the majority of
these cultures (e.g., 105), A. fumigatus was the most commonly
isolated pathogen.
Other mycological methods, including polymerase chain re-
action (PCR) and the lateral flow test, require validation. The
Aspergillus-specific lateral-flow device test detects an extracellu-
lar glycoprotein antigen secreted by Aspergillus spp. only dur-
ing active growth. This method has been validated in serum
and BAL; it has shown a 79% sensitivity and 85% specificity
for probable or proven IPA in non-COVID-19 ICU patients [56].
The lateral-flow device test was used in two cases in the litera-
ture and is currently being evaluated in patients with influenza
and COVID-19 IPA [19,22] (AspiFlu study ISRCTN51287266;
https://doi.org/10.1186/ISRCTN51287266); however, it re-

74
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al.
quires validation. Serial assessment of serum galactomannan
(GM) (despite its low sensitivity) and serum 𝛽-d-glucan in com-
bination with multiple cultures of TA/bronchial aspirate or NBL
and PCR testing of serum and respiratory specimens have been
included in the diagnostic work-up [50]. Multiple and repetitive
positive mycology tests in combination with typical radiological
and clinical criteria contribute to the diagnosis of CAPA. In tra-
cheobronchial cases suspected of CAPA, bronchial biopsies are
required. Biomarkers are often negative. The use of different di-
agnostic criteria may contribute to the varying mortality rates
reported in the literature. Indeed, the mortality rate is higher
among patients with positive cultures than those with probable
CAPA detected using GM. Moreover, the mortality rate is higher
in patients with multiple positive Aspergillus spp. results than in
those with a single positive biomarker.
Biomarkers
Systemic markers are suboptimal for the diagnosis of CAPA,
with sensitivity <50%. Furthermore, some techniques require
validation. The GM assay has been validated in BAL and serum,
although numerous studies have also used endotracheal aspi-
rates. The specificity of GM in BAL is suboptimal and does not
satisfactorily discriminate infection from contamination. In six
patients with COVID-19 acute respiratory distress syndrome and
a positive value for GM in BAL, the diagnosis of probable CAPA
was not confirmed post mortem [29,46]. Thus, the identifica-
tion of some “probable” cases through this approach remains
uncertain.
Serum GM is a sensitive biomarker for IPA in patients with
neutropenia; however, in non-neutropenic critically ill patients,
serum and BAL GM exhibited a sensitivity of 25% and 88–
90%, respectively [47,57]. Similarly, in a prospective multicen-
ter study, 28% of ICU patients who were screened for CAPA
and 100% of those classified as probable CAPA had a posi-
tive BAL GM-index >1; only 1% and 3% of those had pos-
itive serum GM [8]. Overall, the GM index in serum (>0.5)
and respiratory samples (BAL, NBL, TA) was positive in 37/144
(26%) and 100/129 (78%) patients [Table 2]. Antifungals and
chloroquine/hydroxychloroquine, which exhibit in-vitro activ-
ity against A. fumigatus, may interfere with the GM measurement
and decrease its sensitivity [52]. Furthermore, the reduced re-
lease of serum GM may reflect that CAPA is characterized by
more pronounced pulmonary invasion and less fungal angioin-
vasion. Therefore, a negative serum result cannot exclude the
diagnosis of CAPA.
Although 𝛽-d-glucan is more sensitive than serum GM, it
lacks specificity because it is detected in various invasive fungal
infections [58]. Its levels were elevated in 38/62 (61.3%) pa-
tients with CAPA [Table 2]. Although PCR is mainly performed
for patients with hematologic malignancies and hematopoietic
stem cell transplants, it has shown higher sensitivity for the diag-
nosis of CAPA compared with cultures using respiratory samples
[30,33]. PCR using serum and/or respiratory samples was pos-
itive in 57/81 (70.4%) patients with CAPA [Table 2]. Based on
these findings, the revised European Organization for Research
and Treatment of Cancer/Mycoses Study Group (EORTC/MSG)
mycological criteria include PCR using BAL and serum samples;
this method is recommended for screening and confirmation of
the diagnosis of probable IPA [59].
75
Journal of Intensive Medicine 1 (2021) 71–80
Diagnosis
The presentation of CAPA is variable and involves two dis-
tinct forms, namely tracheobronchial and parenchymal CAPA.
It is important to distinguish between these two forms, as
this may impact the diagnostic and therapeutic approaches.
Discrepancies in the onset of CAPA could be due to differ-
ences between these forms, and examination through bron-
choscopy may be required. The currently available literature
suggests that some patients with CAPA survive without receiv-
ing antifungal therapy. This indicates a potential distinction
between angio-invasion and minimal invasive disease/tissue
invasion.
The diagnosis of CAPA is challenging. The discrimination be-
tween invasive infection and colonization is difficult. This is be-
cause the available diagnostic tests, except for histopatholog-
ical examination, do not yield absolute evidence of infection.
There is considerable clinical uncertainty regarding the accu-
rate identification of “probable” cases of CAPA [7,46,59,60].
Thus far, 213 (including 7 case reports) cases of CAPA have
been reported in the literature [Table 3]: 6 proven and 31
probable according to the EORTC/MSG criteria [59]; 133 pu-
tative according to the AspICU algorithm [7,60]; 38 proba-
ble according to the IAPA criteria proposed by Verweij et al.
[46]; and 5 according to the criteria proposed by White et al.
[32]. Four studies reported 24 cases of Aspergillus spp. colo-
nization that did not meet the clinical, mycological, and radio-
logical criteria for classification as proven/probable or putative
infection.
The EORTC/MSG criteria [Table 4] are targeted toward
immuno-compromised patients. Host factors that are a prereq-
uisite for the diagnosis of probable IPA are not typically present
in ICU patients [59]. Additionally, histopathological confirma-
tion in critically ill patients is difficult either due to coagulation
abnormalities or the risk of complications caused by mechani-
cal ventilation (e.g., pneumothorax). Blot et al. [60] developed
an AspICU algorithm concerning ICU patients. In contrast with
the definition established by the EORTC/MSG, where the pres-
ence of host factors and specific radiological signs (e.g., halo
sign, air-crescent sign, or a cavity) is required, the AspICU al-
gorithm includes general radiological abnormalities observed
on CT or chest X-ray examination; host factors must be present
in case of negative mycological criteria in BAL. Schauwvlieghe
et al. [7] proposed a modified AspICU algorithm for patients
with influenza and IPA, in which the GM indices for BAL and
serum are included in the mycological criteria along with a pos-
itive BAL culture and histo pathologic or direct microscopic ev-
idence of Aspergillus spp. [Table 4]. A positive BAL culture was
found in 60% of patients with IAPA; in the remaining patients,
the diagnosis was based on a positive GM index for BAL [32].
In a prospective cohort study including 135 ICU patients with
COVID-19, 8 patients were classified as putative IPA based on
the AspICU algorithm. Twelve more patients were identified fol-
lowing the application of the modified version of this algorithm
[8]. Limitations of the aforementioned studies include the small
number of patients and the different diagnostic algorithms used.
Larger prospective studies are needed to elucidate whether in-
fection with SARS-CoV-2 predisposes patients to aspergillosis, as
well as the participation of other risk factors in the development
of IPA.
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al. Journal of Intensive Medicine 1 (2021) 71–80

Table 3
Diagnostic criteria used for CAPA diagnosis and all cause mortality.

Study Study design Diagnostic criteria Proven Probable Putative IAPA criteria Colonization Mortality

Machado et al. [36] Prospective EORTC/MSG modified AspICU 0 8 0 0 9 8/8

Koehler et al. [16] Retrospective Modified AspICU algorithm 0 0 5 0 0 3/5
Nasir et al. [26] Retrospective Modified AspICU algorithm 0 0 5 0 4 3/5
Alanio et al. [9] Prospective EORTC/MSG modified AspICU 0 1 8 0 0 4/9
Dupont et al. [61] Prospective Modified AspICU algorithm 0 0 19 0 0 7/19
Prattes et al. [19] Case report AspICU algorithm 0 0 1 0 0 1/1
Wang et al. [21] Retrospective EORTC/MSG 0 8 0 0 0 NA
Bruno et al. [64] Case report Modified AspICU algorithm 0 0 1 0 0 0/1
Meijer et al. [22] Case report Modified AspICU algorithm 0 0 1 0 0 1/1
Santana et al. [25] Case report Post-mortem histopathology 1 0 0 0 0 1/1
Borman et al. [35] Retrospective Modified AspICU algorithm 0 0 15 0 0 NA
Segrelles-Calvo et al. [51] Prospective EORTC/MSG 0 7 0 0 0 5/7
Patti et al. [54] Case report IAPA criteria 0 0 0 1 0 0/1
White et al. [32] Prospective AspICU algorithm, modified 0 0 25 0 0 13/25
AspICU algorithm, CAPA criteria
Helleberg et al. [31] Case series AspICU algorithm 0 0 2 0 0 2/2
Trujillo et al. [65] Case report EORTC/MSG 0 1 0 0 0 0/1
Spadea et al. [66] Case report EORTC/MSG 0 1 0 0 0 0/1
Van Biesen et al. [28] Cohort study AspICU algorithm 0 0 9 0 0 2/9
Lamoth et al. [27] Cohort study Modified AspICU algorithm, IAPA 0 0 2 1 0 1/3
criteria
Mitaka et al. [67] Retrospective AspICU algorithm 0 0 4 0 3 4/4
Nasri et al. [68] Case report EORTC/MSG 0 1 0 0 0 1/1
Gangneux et al. [33] Prospective AspICU algorithm, Modified 0 0 7 0 8 2/7
AspICU algorithm
Roman-Montes et al. [58] Prospective Modified AspICU algorithm 0 0 14 0 0 8/14
Blaize et al. [18] Case report AspICU algorithm 0 0 1 0 0 1/1
Schein et al. [55] Case report EORTC/MSG 0 1 0 0 0 1/1
Fernandez et al. [69] Case report EORTC/MSG 0 1 0 0 0 1/1
Ghelfenstein-Ferreira et al. [24] Case report AspICU algorithm 0 0 1 0 0 1/1
Falces-Romero et al. [30] Retrospective EORTC/MSG, AspICU algorithm 0 1 7 0 0 6/8
Mohamed et al. [23] Case report AspICU algorithm 0 0 1 0 0 1/1
Antinori et al. [20] Case report EORTC/MSG post mortem 1 0 0 0 0 1/1
Lahmer et al. [34] Case report AspICU algorithm 0 0 2 0 0 2/2
Chauvet et al. [41] Retrospective EORTC/MSG, AspICU algorithm, 0 1 5 0 0 4/6
Modified AspICU algorithm
Bartoletti et al. [8] Prospective IAPA criteria 0 0 0 30 0 13/30
van Arkel et al. [17] Cohort study IAPA criteria 0 0 0 6 0 4/6
Rutsaert et al. [10] Case series AspICU algorithm 4 0 3 0 0 4/7
Total 6 31 138 38 24 105/190 (55%)

Cases according to AspICU algorithm is 133, EORTC/MSG criteria is 37, IAPA criteria is 38, CAPA criteria is 5.
AspICU algorithm: A clinical algorithm to diagnose Invasive Pulmonary Aspergillosis in intensive care unit patients; CAPA: COVID-19-associated aspergillosis;
EORTC/MSG: European Organization for Research and Treatment of Cancer/Mycoses Study Group; IAPA: Influenza-associated pulmonary aspergillosis; ICU:
Intensive care unit.

Finally, a group of international experts proposed consensus
criteria for a definition of CAPA [13]. The diagnosis includes
three different grades (e.g., possible, probable, and proven)
based on host factors, clinical factors, and mycological evi-
dence. Proven CAPA is based on direct microscopic detection or
histopathological analysis of fungal elements morphologically
consistent with Aspergillus spp., showing invasive growth into
tissues and associated tissue damage. In non-proven CAPA, clas-
sification relies on respiratory cultures or biomarkers detected
using BAL or NBL in case of probable and possible CAPA, respec-
tively. PCR and lateral flow assay using BAL or NBL are also con-
sidered useful in the diagnosis of CAPA along with GM in BAL,
NBL, and serum. The recognition of probable tracheobronchitis
relies on characteristic lesions observed through bronchoscopy
in conjunction with positive mycological evidence. In this con-
text, distinguishing between invasive infection and colonization
is challenging, and probable/possible definitions may lead to
overdiagnosis.
A more comprehensive diagnostic work-up should be pur-
sued for mechanically ventilated COVID-19 patients with a pos-
itive TA culture, plaques (if bronchoscopies are performed),
worsening hypoxemia, and clinical deterioration. Although
screening could be useful, surveillance is not possible for some
large hospitals or those unable to perform onsite testing. Biopsy
should be performed for tracheobronchial CAPA to confirm it is
caused by Aspergillus spp. Tracheobronchial airways appear as
white plaques; thus, physicians should exercise caution to avoid
misdiagnosis of infection with Candida.
Treatment
Voriconazole (VRC) or isavuconazole (ISV) have been used
as the first-line treatment options for possible, probable, and
proven CAPA; liposomal amphotericin B (L-AMB) has also been
administered as an alternative agent. In all reported studies thus
far, 135 of 189 (71.4%) patients received treatment [Table 5],
whereas data regarding treatment were not reported for 24 pa-
tients. The main reason for not administering antifungal treat-
ment was early death. The most commonly antifungal agent was
VRC, followed by ISV and L-AMB. Dupont et al. [61] reported
a non-statistically significant lower mortality rate among pa-
tients with putative aspergillosis who were treated with VRC

76
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al. Journal of Intensive Medicine 1 (2021) 71–80

Table 4
Diagnostic criteria and algorithms used for the diagnosis of CAPA.
EORTC/MSG criteria, 2020 revision [59]
Proven Aspergillosis: 6/213 (2.8%) CAPA cases
Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy in which hyphae are seen accompanied by evidence of associated
tissue damage.
Culture on sterile material: recovery of Aspergillus spp. by culture of a specimen obtained by lung biopsy. Amplification of fungal DNA by PCR combined with DNA sequencing when molds
are seen in formalin-fixed paraffin-embedded tissue.
Probable Aspergillosis: 31/213 (14.6%) CAPA cases
At least 1 host factor, a clinical feature and mycologic evidence.
Host factors
1. Recent history of neutropenia (<0.5 × 109 neutrophils/L [<500 neutrophils/mm3] for >10 days) temporally related to the onset of invasive fungal disease.
2 .Hematologic malignancy.
3. Receipt of an allogeneic stem cell transplant.
4. Receipt of a solid organ transplant.
5. Prolonged use of corticosteroids (excluding among patients with allergic broncho pulmonary aspergillosis) at a therapeutic dose of ≥0.3 mg/kg corticosteroids for ≥3 weeks in the past
60 days.
6. Treatment with other recognized T-cell immuno suppressants, such as calcineurin inhibitors, tumor necrosis factor-a blockers, lymphocyte-specific monoclonal antibodies,
immunosuppressive nucleoside analogues during the past 90 days.
7. Treatment with recognized B-cell immuno suppressants, such as Bruton’s tyrosine kinase inhibitors, e.g., ibrutinib.
8. Inherited severe immunodeficiency (such as chronic granulomatous disease, STAT 3 deficiency, or severe combined immunodeficiency).
9. Acute graft-vs.-host disease grade III or IV involving the gut, lungs, or liver that is refractory to first-line treatment with steroids.
Clinical features
The presence of 1 of the following 4 patterns on CT:
1. Dense, well-circumscribed lesions(s) with or without a halo sign.
2. Air crescent sign.
3. Cavity.
4. Wedge-shaped and segmental or lobar consolidation.
Mycological evidence
1. Aspergillus recovered by culture from sputum, BAL, bronchial brush, or aspirate.
2. Micro scopical detection of fungal elements in sputum, BAL, bronchial brush, or aspirate indicating a mold.
3. GM antigen detected in plasma, serum, BAL. Any 1 of the following:
- Single serum or plasma: ≥1.0.
- BAL fluid: ≥1.0.
- Single serum or plasma: ≥0.7 and BAL fluid ≥0.8.
4. Aspergillus PCR. Any 1 of the following:
- Plasma, serum, or whole blood 2 or more consecutive PCR tests positive,
- BAL fluid 2 or more duplicate PCR tests positive,
- At least 1 PCR test positive in plasma, serum, or whole blood and 1 PCR test positive in BAL fluid.
Possible Aspergillosis
A host factor and a clinical feature but not mycological evidence
AspICU algorithm, 2012 [60]

Putative (all four criteria must be met): 133/213 (62.4%/) CAPA cases
1. Aspergillus-positive lower respiratory tract specimen culture (entry criterion)
2. Compatible signs and symptoms (one of the following)
- Fever refractory to at least 3 days of appropriate antibiotic therapy.
- Recrudescent fever after a period of defervescence of at least 48 h while still on antibiotics and without other apparent cause.
- Pleuritic chest pain or pleuritic rub.
- Dyspnea.
- Hemoptysis.
- Worsening respiratory insufficiency in spite of appropriate antibiotic therapy and ventilatory support.
3. Abnormal medical imaging by Chest X-ray or CT scan of the lungs
4. Either 4a or 4b
4a. Host risk factors (one of the following conditions)
- Neutropenia (absolute neutrophil count < 500/mm3) preceding or at the time of ICU admission
- Underlying hematological or oncological malignancy treated with cytotoxic agents
- Glucocorticoid treatment (prednisone equivalent, >20 mg/day)
- Congenital or acquired immunodeficiency
4b. Semiquantitative Aspergillus-positive culture of BAL fluid (+ or ++), without bacterial growth together with a positive cytological smear showing branching hyphae
Colonization
When ≥1 criterion necessary for a diagnosis of putative IPA is not met
Modified AspICU algorithm, 2018 [7]

AspICU algorithm 1,2,3

Mycological criteria
One or more of the following:
- Histopathology or direct microscopic evidence of dichotomous septate hyphae with positive culture for Aspergillus from tissue
- A positive Aspergillus culture from a BAL.
A GM optical index on BAL of ≥1
A GM optical index on serum of ≥0.5.
IAPA criteria 2020 [46]

Probable: 38/213 (17.8%) CAPA cases

A: Pulmonary infiltrate and at least one of the following:
Serum GM index > 0.5 or BAL GM index ≥ 1.0 or
Positive BAL culture
B: Cavitating infiltrate (not attributed to another cause) and at least one of the following:
Positive sputum culture or
Positive TA culture

AspICU: A clinical algorithm to diagnose Invasive Pulmonary Aspergillosis in intensive care unit patients; BAL: Bronchoalveolar lavage; CT: Computed tomography;
CAPA: COVID-19-associated aspergillosis; EORTC/MSG: European Organization for Research and Treatment of Cancer/Mycoses Study Group; GM: Galactomannan;
IAPA: Influenza-associated pulmonary aspergillosis; ICU: Intensive care unit; IPA: Invasive pulmonary aspergillosis; PCR: Polymerase chain reaction; TA: Tracheal
aspirate.
77
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al. Journal of Intensive Medicine 1 (2021) 71–80

Table 5
Treatment of CAPA patients.

Study Patients treated (n) Type of antifungal drug (n)

Machado et al. [36] 5/8 ISV (4), L-AMB (2), VRC (2)
Koehler et al. [16] 5/5 VRC (4), ISV (1)
Nasir et al. [26] 5/5 L-AMB (2), VRC (3)
Alanio et al. [9] 2/9 VRC (1), Caspofungin (1)
Dupont et al. [61] 9/19 VRC (9)
Prattes et al. [19] 1/1 VRC (1)
Wang et al. [21] NA NA
Bruno et al. [64] 1/1 VRC (1)
Meijer et al. [22] 1/1 VRC (1)
Santana et al. [25] 0/1 NA
Borman et al. [35] NA NA
Segrelles-Calvo et al. [51] 4/7 L-AMB (1), Itraconazole (3)
Patti et al. [54] 1/1 VRC (1)
White et al. [32] 17/25 VRC (16), L-AMB (6), Caspofungin + VRC (2), L-AMB + Anidulafungin (1)
Helleberg et al. [31] 2/2 VRC (2)
Trujillo et al. [65] 1/1 ISV+ neb L-AMB (1)
Spadea et al. [66] 1/1 L-AMB (1)
Van Biesen et al. [28] 9/9 L-AMB + VRC (9)
Lamoth et al. [27] 3/3 VRC (3)
Mitaka et al. [67] 4/4 VRC (3), Caspofungin (1)
Nasri et al. [68] 1/1 L-AMB (1)
Gangneux et al. [33] 7/7 VRC or ISV
Roman-Montes et al. [58] 12/14 VRC (10), Anidulafungin (2)
Blaize et al. [18] 0/1 NA
Schein et al. [55] 1/1 VRC (1)
Fernandez et al. [69] 1/1 VRC (1)
Ghelfenstein-Ferreira et al. [24] 0/1 NA
Falces-Romero et al. [30] 6/8 VRC (4), VRC + Caspofungin (1), L-AMB (5), ISV (2)
Mohamed et al. [23] 1/1 L-AMB (1)
Antinori et al. [20] 1/1 L-AMB (1)
Lahmer et al. [34] 2/2 L-AMB (2)
Chauvet et al. [41] 4/6 L-AMB (2), VRC (1), VRC + ISV (1), Caspofungin (1)
Bartoletti et al. [8] 16/30 VRC (13)
van Arkel [17] 6/6 VRC + Anidulafungin (5), L-AMB (1)
Rutsaert et al. [10] 6/7 VRC (5), ISV (2)

CAPA: COVID-19 associated aspergillosis, COVID-19: Coronavirus disease 2019; ISV: Isavuconazole; L-AMB: Liposomal am-
photericin B; NA: Not availableVRC: Voriconazole.

(three deaths in nine patients [33.3%]) vs. those not treated
(five deaths in 10 patients [50%])]. VRC is hepatically metab-
olized, and patients should be monitored for possible drug in-
teractions with cytochrome P450 family 2 subfamily C member
19 (CYP2C19) and CYP3A. Therapeutic drug monitoring is re-
quired as toxic levels may lead to hepatotoxicity and neurotox-
icity. ISV exhibits a safer profile with less severe adverse events
and fewer drug–drug interactions, while the role of L-AMB is
limited by acute kidney injury complicating severe COVID-19
[51]. ISV should be preferred in patients for whom liver toxic-
ity is a concern.
Patients should also be monitored for the development of re-
sistance by Aspergillus spp. to azoles. Triazole-resistant A. fumi-
gatus was isolated in a patient who was possibly exposed to or-
ganic matter. The patient expired due to massive pulmonary em-
bolism shortly after the diagnosis of putative aspergillosis [24].
The second case reported in the literature was also a patient
with daily exposure to fungicides [23]. The TR34L98H mutation
in the CYP51A gene, which is associated with resistance, was
identified in Aspergillus strains isolated from both patients. Sus-
ceptibility testing is recommended in regions with a resistance
rate >5%. In case of azole failure or in regions with a resistance
rate >10%, VRC/ISV in combination with an echinocandin or L-
AMB or monotherapy with L-AMB should be administered. New
antifungal agents are currently evaluated in clinical trials. Reza-
fungin, which belongs to echinocandins, and ibrexafungerp (for-
merly termed SCY-078), which inhibits 1,3-𝛽-d-glucan synthase,
have shown in-vitro activity against Aspergillus spp., including
azole-resistant A. fumigatus isolates. The antifungal agents olo-
rofim and fosmanogepix, which have also demonstrated activity
against Aspergillus spp., are currently under development [62].
The diagnosis of CAPA is challenging, and patients with se-
vere COVID-19 pneumonia complicated by IPA may be associ-
ated with a worse prognosis. Therefore, the administration of
prophylactic treatment with posaconazole, VRC, itraconazole,
or inhaled amphotericin B (recommended for prophylaxis in pa-
tients with hematological malignancies and transplants) is cur-
rently under debate. Rutsaert et al. [10] after finding an unex-
pected number of COVID-19 patients with suspected IPA, sub-
sequently used nebulized L-AMB (12.5 mg) for prophylaxis in
every mechanically ventilated patient they treated. Neverthe-
less, this approach was linked to a risk of sudden complications
in ventilated patients due to obstruction of expiratory filters. In
this study, the rate of all-cause mortality was 55%, while a sig-
nificantly higher 30-day mortality rate was observed in patients
with CAPA vs. those without CAPA (44% vs. 19%, P = 0.002 and
74% vs. 26%, P< 0.001 for probable and putative IPA, respec-
tively) [8]. Indeed, there is a general consensus against the use
of prophylactic therapy in patients with COVID-19. This posi-
tion was supported by a recent randomized clinical trial, which
failed to show significant benefit after the administration of pro-
phylactic therapy [63].

78
G. Dimopoulos, M.-P. Almyroudi, P. Myrianthefs et al.
Conclusion
The incidence of CAPA appears lower than that of IAPA, but
varies regionally. In addition, it is influenced by differences in
the standard of care, risk conditions, and poor performance of
diagnostic tests. Different diagnostic strategies are necessary to
differentiate colonization from bronchial or parenchymal infec-
tion in intubated COVID-19 patients with Aspergillus spp. in their
respiratory specimens vs. those not infected with SARS-CoV-2.
The usefulness of imaging techniques (e.g., CT scans) in the di-
agnosis of CAPA in patients with COVID-19 is limited, whereas
bronchoscopy (under safe conditions) is adding value to the di-
agnostic process. Following confirmation, VRC or ISV should be
used for the treatment of CAPA. The appropriate treatment du-
ration for CAPA is currently unknown.
Conflicts of Interest
Jordi Rello served in the speakers bureau and as a consul-
tant for Pfizer. The other authors declare that they have no
known competing financial interests or personal relationships
that could have appeared to influence the work reported in this
paper.
Acknowledgements
None.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Appendix
Search strategy
Data for this work were identified by searches of MED-
LINE, PubMed using the search string “(Aspergill”) AND (“in-
vasive” OR “infection” OR “case” OR “patient” OR “report”)
AND (“COVID∗ ” OR “corona”), AND (“SARS-CoV-2”) AND
(“Aspergill∗ ”), AND (“aspergill∗ ”) AND (guideline OR treatment
OR therapy OR diagnosis). Only articles published in English
until January 31, 2021 were included.
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