CAPA
Influenza-associated pulmonary aspergillosis (IAPA) presents a known risk to critically unwell patients with influenza [12–14] and the clinical course of COVID-19 shows many features that are shared with severe influenza infection. These include ARDS, lymphopenia, bilateral pulmonary infiltrates, systemic pro-inflammatory cytokine responses and sepsis leading to multiple organ failure [14, 15]. It is therefore reasonable to suspect that patients with severe COVID-19 may be similarly susceptible to invasive aspergillosis. Corticosteroid use is an important acquired immunological risk factor for IAPA [16] and, during the SARS-CoV 2003 epidemic, there were case reports of patients developing SARS-associated invasive aspergillosis after corticosteroid use [5]. Corticosteroid use has been reported in hospitalised patients with COVID-19 [1] and may further contribute to the risk of CAPA. Importantly, the recent finding by the UK RECOVERY trial (ISRCTN50189673) [17] of a one-third mortality reduction conferred by dexamethasone in ventilated patients with COVID-19, while leading to a crucial new therapeutic avenue, may increase the risk of patients acquiring CAPA and emphasises the need for enhanced fungal surveillance.
Table 1 summarises individual patient-level data in 33 cases of CAPA that have been reported to date. The median (interquartile range) age of cases is 70 (57–75) years, of whom only two (6%) had a European Organization for Research and Treatment of Cancer (EORTC) host factor. Of these 16 (48%) had exposure to inhaled or systemic corticosteroids, 10 (30%) had diabetes and nine (27%) had underlying chronic lung disease; COPD (n=5), asthma (n=3), bullous emphysema (n=1), pulmonary fibrosis (n=1) and post-radiotherapy for nonsmall-cell lung cancer (n=1). CAPA was diagnosed a median (interquartile range) 5.5 (4.3–9) days after intensive care unit (ICU) admission and 21 (63.6%) patients had died by the time of publication. This mortality is in excess of most cohorts of ventilated patients with COVID-19, as a comparison in the UK ISARIC cohort 618 (37%) out of 1658 ventilated patients had died by the time of publication (17% discharged and 46% still receiving care) [23].
TABLE 1 Summary of reported cases of coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis in the intensive care unit (ICU) setting
Location [ref.] Age years Sex IPA risk factors Radiology BAL culture TA culture BAL GM Serum GM Other diagnostics Onset days post-ICU EORTC status Mod AspICU status Treatment Outcome
Cologne, Germany [11] 62 F Ex-smoker, moderate COPD, inhaled steroids Ground-glass opacities, crazy paving, peripheral nodular consolidation A. fumigatus NR (+) >2.5 (-) BAL PCR A. fumigatus NR No host factor# Putative V Died
Cologne, Germany [11] 70 M Ex-smoker Ground-glass opacities, occasional nodules (-) NR (+) >2.5 (+) 0.7 BAL PCR A. fumigatus NR No host factor Putative I Died
Cologne, Germany [11] 54 M Diabetes, systemic corticosteroids0.4 mg·kg−1·day−1×13 days Ground-glass opacities, nodular infiltrates with cavities, air crescent sign (-) A. fumigatus (+) >2.5 (-) BAL PCR A. fumigatus NR No host factor Putative C, V Alive
Cologne, Germany [11] 73 M Smoker, bullous emphysema, severe COPD, inhaled steroids Ground-glass opacities, occasional nodules, known bullous emphysema ND A. fumigatus ND (-) TA PCR A. fumigatus NR No host factor Putative only if TA considered equivalent to BAL V Died
Cologne, Germany [11] 54 F None Ground-glass opacities, crazy paving, central and peripheral consolidation, smaller nodular infiltrates ND (-) ND (+) 2.7, 1.3 TA PCR (-) NR No host factor Putative C, V Alive
Munich, Germany [18] 80 M Pulmonary fibrosis Typical signs for COVID-19 pneumonia but no specific signs for IPA A. fumigatus NR (+) >6 (+) 1.5 5 No host factor Putative L-AmB Died
Munich, Germany [18] 70 M None Typical signs for COVID-19 pneumonia but no specific signs for IPA A. fumigatus NR (+) >6 (-) 6 No host factor Putative L-AmB Died
Paris, France [19] 74 M Myelodysplastic syndrome NR ND A. fumigatus ND (-) x2 TA PCR A. fumigatus x2, TA GM (-)×1, BDG and serum PCR (-) x2 4 No host factor Putative only if TA considered equivalent to BAL None Died
Paris, France [9] 53 M Dexamethasone 20 mg·day−1 days 1–5, 10 mg·day−1 days 6–10 Typical COVID-19 (-) NR (-) 0.89 (-) BAL PCR (-), Serum PCR (-), BDG (+) >500 NR No host factor Putative only if BAL GM cut-off lowered to >0.8 None Alive
Paris, France [9] 59 F Diabetes Typical COVID-19 A. fumigatus NR (-) (-) BAL PCR (-), serum PCR (-) NR No host factor Putative but note BAL culture (+) but BAL GM (-) None Alive
Paris, France [9] 69 F Dexamethasone 20 mg·day−1 days 1–5, 10 mg·day−1 days 6–10 Typical COVID-19 ND A. fumigatus ND (-) TA PCR A. fumigatus, serum PCR (-), BDG (-) NR No host factor Putative only if TA considered equivalent to BAL None Alive
Paris, France [9] 63 F Diabetes, dexamethasone 20 mg·day−1 days 1–5, 10 mg·day−1 days 6–10 Typical COVID-19 (-) NR (-) (+) 0.51 BAL PCR (-), BDG (+) 105 NR No host factor Putative but relies on serum GM of only 0.51 None Died
Paris, France [9] 43 M Asthma, corticosteroids Typical COVID-19 A. fumigatus NR (-) (-) BAL PCR (-), serum PCR (-), BDG (-) NR No host factor Putative but note BAL culture (+) but BAL GM (-) None Alive
Paris, France [9] 79 M Diabetes, Dexamethasone 20 mg·d−1 days 1–5, 10 mg·d−1 days 6–10 Typical COVID-19, segmental lung atelectasis A. fumigatus NR (-) (-) BAL PCR A. fumigatus, serum PCR (-), BDG (-) NR No host factor Putative but note BAL culture (+) but BAL GM (-) None Alive
Paris, France [9] 77 M Asthma, dexamethasone 20 mg·day−1 days 1–5, 10 mg·day−1 days 6–10 “Typical COVID-19”, emphysema A. fumigatus NR (+) 3.9 (-) BAL PCR A. fumigatus, serum PCR (-), BDG (+) 135 NR No host factor Putative V Died
Paris, France [9] 75 F Diabetes, dexamethasone 20 mg·day−1 days 1–5, 10 mg·day−1 days 6–10 Typical COVID-19 A. fumigatus NR (-) (-) BAL PCR, A. fumigatus, serum PCR (-), BDG (+) 450 NR No host factor Putative but note BAL culture (+) but BAL GM (-) C Died
Paris, France [9] 47 M Myeloma, corticosteroids Typical COVID-19, one peripheral nodule ND A. fumigatus ND (-) TA PCR A. fumigatus, serum PCR (-), BDG (-) NR Probable Putative only if TA considered equivalent to BAL None Died
Graz, Austria [20] 70 M Moderate COPD, steroid inhaler, obstructive sleep apnoea, diabetes Ground-glass opacities, crazy paving, reversed halo sign, progression of the bilateral infiltrates on day 2 chest radiography ND A. fumigatus ND (-) TA LFD (+), BDG (-) 3 No host factor Putative only if TA considered equivalent to BAL V Died
Antwerp, Belgium [8] 86 M None ND ND A. flavus ND (-) 9 No host factor Putative only if TA considered equivalent to BAL None Died
Antwerp, Belgium [8] 38 M None (+) A. fumigatus NR (+) >2.8 (-) Histology from bronchoscopy (+) 6 Proven Proven V, I Alive
Antwerp, Belgium [8] 62 M Diabetes ND A. fumigatus NR (+) >2.0 (-) Histology from bronchoscopy (+) 16 Proven Proven V Died
Antwerp, Belgium [8] 73 M Diabetes ND A. fumigatus NR (+) >2.8 (-) Histology from bronchoscopy (+) 5 Proven Proven V Alive
Antwerp, Belgium [8] 77 M Diabetes, chronic corticosteroids for pemphigus foliaceous ND A. fumigatus NR (+) 2.79 (-) Histology from bronchoscopy (+) 2 Proven Proven V Alive
Antwerp, Belgium [8] 55 M HIV (CD4 count >250, viral load <20) copies) ND (-) NR (-) (+) 0.8 Histology from bronchoscopy (-) 13 No host factor Putative but relies on serum GM of only 0.8 V, I Died
Antwerp, Belgium [8] 75 M AML with IPA 2012 ND A. fumigatus NR (+) 2.63 ND 8 No host factor Putative V Died
Breda, The Netherlands [10] 83 M Prednisolone 0.13 mg·kg−1·day−1×28 days for cardiomyopathy NR ND A. fumigatus ND (-) 3 Probable if steroid requirement reduced to <0.3 mg·kg−1·day−1 Putative only if TA considered equivalent to BAL V+A, or L-AmB Died
Breda, The Netherlands [10] 67 M Severe COPD, Post RT for NSCLC 2014, prednisolone 0.37 mg·kg−1·day−1×2 days NR ND A. fumigatus ND ND 3 No host factor Putative only if TA considered equivalent to BAL V+A, or L-AmB Died
Breda, The Netherlands [10] 75 M Moderate COPD NR A. fumigatus NR (+) 4.0 ND Mucoid white sputum left bronchus at bronchoscopy 5 No host factor Putative V+A, or L-AmB Died
Breda, The Netherlands [10] 43 M None NR (-) NR (+) 3.8 (-) 14 No host factor Putative V+A, or L-AmB Alive
Breda, The Netherlands [10] 57 M Asthma, inhaled steroids NR A. fumigatus NR (+) 1.6 (-) 5 No host factor Putative V+A, or L-AmB Died
Breda, The Netherlands [10] 58 M None NR ND A. fumigatus ND ND 28 No host factor Putative only if TA considered equivalent to BAL V+A, or L-AmB Alive
Paris, France [21] 80 M None Pleural effusions, alveolar condensation, ground-glass opacities, pulmonary cysts ND A. flavus ND ND NR No host factor Putative only if TA considered equivalent to BAL V, I Died
Milan, Italy [22] 73 M Diabetes Interstitial opacities with right upper lobe focal consolidation which progressively worsened A. fumigatus NR ND (+) 8.6 Lung histology from PM (+), PM tissue PCR Aspergillus spp. 9 Proven Proven L-AmB Died
Summary Median (IQR)70 (57–75) M: 26 (79%) out of 33 EORTC host factor: n=2 (6%); inhaled/systemic steroid exposure: n=16 (48%); diabetes: n=10 (30%); chronic lung disease: n=9 (27%) Nodules: n=6 (31.6%), cavity/halo-sign: n=2 (10.5%) 16 (72.7%) out of 22 with BAL 14 (66.7%) out of 21 with BAL GM 6 (21.4%) out of 28 with serum GM Median (IQR)5.5 (4.3–9) Proven: n=5; probable: n=1; no host factor: n=27 Proven: n=5; putative: n=11; putative with caveats: n=17 24 (72.7%) treated 21 (63.6%) died
IPA: invasive pulmonary aspergillosis; BAL: bronchoalveolar lavage; TA: tracheal aspirate; GM: galactomannan; EORTC: European Organization for Research and Treatment of Cancer; AspICU: clinical criteria to diagnose IPA; M: male; F: female; BDG: (1–3)-β-D-glucan; LFD: Aspergillus lateral-flow device; PM: post mortem; AML: acute myeloid leukaemia; RT: radiotherapy; NSCLC: nonsmall-cell lung cancer; NR: not recorded; V: voriconazole; I: isavuconazole; L-AmB: liposomal amphotericin B; C: caspofungin; A: anidulafungin; ND: no data; (+): positive result; (-): negative result. #: without histological evidence of “proven” IPA a patient host factor (e.g. recent neutropenia, haematological malignancy) is required to meet the probable/possible definition, corticosteroids must be given at ≥0.3 mg·kg−1 for ≥3 weeks to classify as a host factor result.Invasive aspergillosis is difficult to diagnose in critically unwell patients without traditional host factors because radiological changes are usually nonspecific (e.g. infiltrates, consolidation or nodules), with features such as halo sign, air-crescent sign or cavitation being rare [24]. For these reasons Schauwvlieghe et al. [13] developed the modified AspICU criteria to help diagnose IAPA which (in the absence of histology) essentially relies on mycological evidence of Aspergillus spp. in the form of a positive bronchoalveolar lavage (BAL) culture or positive galactomannan (GM) in serum/BAL. Applying these modified AspICU criteria, five cases of CAPA in table 1 were “proven”, 11 “putative” and 17 might be considered putative but with caveats which have been described in the table. For example, in many cases a tracheal aspirate, rather than BAL, provided the only mycological evidence of invasive aspergillosis (in the absence of tracheobronchitis/cavitation). There should therefore be caution about over-estimating the incidence of CAPA from such case series, which may include some patients with aspergillus colonisation or contamination only. In the study by Alanio et al. [9] which reported evidence of CAPA in nine (33%) out of 27 ventilated patients who underwent BAL/tracheal aspirate, one case was defined based on a BAL GM of 0.89 (below the usual cut-off of 1.0), two based on tracheal aspirate rather than BAL culture, one based on a serum GM of 0.51 (cut-off being 0.50) and in four cases BAL culture was positive but BAL GM negative, which suggests a lack of tissue invasion. Indeed, out of seven cases that were not treated with antifungals, five survived. Accordingly, larger, prospective, multi-site studies are needed to refine the AspICU criteria for patients with COVID-19, as well as to estimate incidence and the impact of CAPA on survival [25, 26].