Coronavirus Disease 2019–Associated Pulmonary Aspergillosis in Mechanically Ventilated Patients

Abstract

Background

Coronavirus disease 2019 (COVID-19)–associated pulmonary aspergillosis (CAPA) occurs in critically ill patients with COVID-19. Risks and outcomes remain poorly understood.

Methods

A retrospective cohort study of mechanically ventilated adult patients with COVID-19 admitted to 5 Johns Hopkins hospitals was conducted between March and August 2020. CAPA was defined using composite clinical criteria. Fine and Gray competing risks regression was used to analyze clinical outcomes and, multilevel mixed-effects ordinal logistic regression was used to compare longitudinal disease severity scores.

Results

In the cohort of 396 people, 39 met criteria for CAPA. Patients with CAPA were more likely than those without CAPA to have underlying pulmonary vascular disease (41% vs 21.6%, respectively; P = .01), liver disease (35.9% vs 18.2%; P = .02), coagulopathy (51.3% vs 33.1%; P = .03), solid tumors (25.6% vs 10.9%; P = .02), multiple myeloma (5.1% vs 0.3%; P = .03), and corticosteroid exposure during the index admission (66.7% vs 42.6%; P = .005), and had lower body mass indexes (median, 26.6 vs 29.9 [calculated as weight in kilograms divided by height in meters squared]; P = .04). Patients with CAPA had worse outcomes, as measured by ordinal severity of disease scores, requiring longer time to improvement (adjusted odds ratio, _1.081.09_1.1; P < .001), and advancing in severity almost twice as quickly (subhazard ratio, _1.31.8_2.5; P < .001). They were intubated twice as long as those without CAPA (subhazard ratio, _0.40.5_0.6; P < .001) and had longer hospital stays (median [interquartile range], 41.1 [20.5–72.4) vs 18.5 [10.7–31.8] days; P < .001).

Conclusion

CAPA is associated with poor outcomes. Attention to preventive measures (screening and/or prophylaxis) is warranted in people with high risk of CAPA.

Aspergillosis, CAPA, COVID-19, SARS-CoV-2

(See the Editorial Commentary by Baddley on pages 92–4.)

As of November 2020, the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–associated coronavirus disease 2019 (COVID-19) has infected >50 million patients and resulted in >1.25 million deaths worldwide. Approximately 15%–30% of infections are severe, requiring oxygen support, and 5%–15% of those with infection are critically ill, requiring mechanical ventilation in intensive care units (ICUs) [1–3]. With severe pulmonary inflammation, compromised pulmonary defenses, ventilator dependence, and receipt of immunosuppressive drugs, patients with severe COVID-19 are at risk for secondary infections. Recent studies have drawn attention to high rates of COVID-19–associated pulmonary aspergillosis (CAPA), with reports from Europe estimating prevalence of 5%–30% in patients with severe COVID-19 [4–11].

European investigators have proposed case definitions for “probable” CAPA, which includes positive galactomannan (GM) results in serum or bronchoalveolar lavage (BAL) samples, recovery of Aspergillus species in BAL culture, positive polymerase chain reaction (PCR) for Aspergillus species in BAL or blood samples, or chest imaging consistent with a fungal infection [4, 5, 7, 12]. However, these definitions underestimate disease burden in centers that do not routinely perform bronchoscopy. Some centers, especially those in North America, use lower limits to define positivity of biomarkers and use screening with multiple antigen tests, including those that detect (1, 3)-β-D-glucan (BDG). Given diagnostic variability and clinical use of empirical antifungal therapy, a pragmatic approach to understanding the impact of CAPA warrants inclusion of multiple criteria to define disease. In the current study, we aimed to describe risk factors, clinical course, and outcomes in adult patients with CAPA by applying proposed and expanded CAPA definitions in a large cohort of people with severe COVID-19 in the Johns Hopkins Medicine (JHM) Health System [13].

METHODS

Study Design and Data Source

This is a retrospective study that used the COVID-19 Precision Medicine Analytics Platform Registry (JH-CROWN), which includes data from all patients with COVID-19 cared for at 5 hospitals in JHM. The registry includes patients who were admitted and had COVID-19 diagnosed by means of a positive SARS-CoV-2 nucleic acid amplification test. Patient-level information available for analyses included demographics, medical history, laboratory tests, inpatient therapy (including specific time points of each intervention), and discharge disposition. This study was approved by the Institutional Review Board at Johns Hopkins University.

Study Population

This study included mechanically ventilated adult patients with COVID-19 with admission dates between March and August 2020. Patients who were intubated before admission or hospital transfer were analyzed as having been intubated since admission. Patients who were extubated before admission (such as in the emergency department) were excluded. All patients were followed up from the time of admission until death or discharge, with the last patient discharged on 19 October 2020.

Starting in April 2020, institutional recommendations were to screen mechanically ventilated patients in ICUs for fungal infections by means of serum Aspergillus GM enzyme immunoassay (EIA) (Platelia; BIO-RAD), serum BDG (Fungitell; Associates of Cape Cod), and fungal cultures from respiratory samples. Radiography included chest radiography and computed tomography, if deemed feasible. Antimicrobials, including antifungal therapies. were administered by clinical teams when a fungal infection was considered to be associated with clinical deterioration, and when laboratory and radiographic findings compelled consideration of secondary complications of COVID-19. Bronchoscopy was performed when considered feasible.

CAPA Case Definitions

“Probable CAPA” was defined as the presence of ≥1 of the following conditions: presence of new cavitary lung lesion(s) at chest computed tomography without alternative explanation, positive serum GM EIA index ≥0.5, positive BAL GM index ≥1.0, or positive culture for Aspergillus species in BAL sample [4, 5, 7]. Because our institution relies on Food and Drug Administration–cleared cutoffs for positive BAL GM at index ≥0.5, uses additional markers (BDG) to screen for fungal infections, and performs screening cultures with other respiratory fluids, we included a pragmatic definition of “possible CAPA.” This included at least ≥1 of the following conditions: positive BAL GM index 0.5–1.0, positive serum BDG ≥80 pg/mL without alternative explanation, or culture with growth of Aspergillus species in non-BAL respiratory samples, namely, endotracheal aspirates. Individual case ascertainment was confirmed through rigorous record review.

The time of CAPA diagnosis was defined as the earliest date when a diagnostic feature was identified. The main analysis used the expanded CAPA definitions, which included probable and possible CAPA (hereafter simply “CAPA”). Additional subgroup analyses were performed to compare differences between the more conservative definition (probable CAPA) and those without infection. Sensitivity analyses were performed to compare outcomes between people whose CAPA was based only on positive serum BDG results versus other CAPA criteria.

Statistical Analysis

All analyses were performed using Stata 15.1/SE software. Patient comorbid conditions were derived from the defined International Classification of Diseases, Tenth Revision, code components of Elixhauser comorbidity index (Supplementary Table 1), in conjunction with record review [14]. Analyses of patient demographics and baseline characteristics among different groups were conducted using Wilcoxon rank sum and Fisher exact test depending on types of variables. An α value cutoff of .05 was used to determine statistical significance. All confidence intervals were 95% and reported using the method of Louis and Zeger [15].

Using the time stamps of events available in the JH-CROWN and patient records, we evaluated longitudinal COVID-19 severity throughout admission. The World Health Organization COVID-19 ordinal severity score ranges from 1 (ambulatory, no limitations) to 8 (death) and has previously been used as a metric of COVID-19 severity [16, 17]. COVID-19 severity scores at admission and peak severity scores during admission were compared among different CAPA definitions, using Wilcoxon rank sum tests.

The trajectory of severity scores throughout admission among different groups were analyzed using multilevel mixed-effects ordinal logistic regression, adjusting for severity within 24 hours of admission, including a patient-level random intercept and an interaction between CAPA diagnosis and time since admission. The odds ratio (OR) of this interaction represented the difference in the “slope” of severity plotted against time; statistical significance indicates that one group has faster disease progression (OR for increasing severity, >1) or recovery (OR for decreasing severity, <1) over time during admission. Because a patient’s severity score could change several times in a day, the duration of time at a given severity score was calculated in minutes and later converted to days. The maximum score from each “day” represented patient’s severity in each 24-hour time frame and was used to graph and analyze the trajectory of disease severity.

Intravenous vasopressors (IVP), extracorporeal membrane oxygenation, and continuous renal replacement therapy were included in advanced life support therapy. We used Fine and Gray competing risks regression to obtain subhazard ratio (sHRs) for outcomes, similar to hazard ratios used in Cox regression but accounting for competing events [18]. In analyses of deaths and hospital discharge, death was considered a competing event. Similarly, death was considered a competing event in analyses of receipt of advanced life support therapy, and extubation. Times from intubation to an event were converted from minutes to days, allowing for noninteger follow-up durations. Because IVP could be administered before intubation, patients who received IVP before intubation were given a minute’s duration of follow-up time to reflect the progression of severity in the entire cohort.

RESULTS

Patients Demographics and Baseline Characteristics

A total of 396 patients were included in this cohort: 20 with probable CAPA, 19 with possible CAPA, and 357 without CAPA. Demographic and baseline characteristics of the cohort (39 CAPA and 357 non-CAPA) are shown in Table 1. Compared with patients without CAPA (controls), those with CAPA had significantly lower median body mass index (BMI; 26.6 vs 29.9 [calculated as weight in kilograms divided by height in meters squared]; P = .04) but more underlying pulmonary vascular disorders, which included pulmonary hypertension and chronic pulmonary emboli (41% vs 21.6%; P = .01), liver disease (35.9% vs 18.2%; P = .02), coagulopathy (51.3% vs 33.1%; P = .03), solid tumors (25.6% vs 10.9%; P = .02), and multiple myeloma (5.1% vs 0.3%; P = .03) (Table 1). Patients with CAPA, compared with controls, had similar median age (interquartile range [IQR]) (66 [55–70] vs 63 [53–72 years], respectively; P = .8) and sex distribution (43.6% vs 40.1% female; P = .7). The median (IQR) duration from COVID-19 diagnosis to CAPA diagnosis was 15 (9–23) days, and the median duration from intubation to CAPA diagnosis was 12 (3–22) days. Similar baseline characteristics were seen in the more limited group of patients who met criteria only for probable CAPA (Supplementary Table 2).

Table 1.

Demographic and Baseline Characteristics in Patients With or Without Coronavirus Disease 2019–Associated Pulmonary Aspergillosis

	Patients, No. (%)a
Characteristic	Non-CAPA (n = 357)	CAPA (n = 39)	P Value
Age, median (IQR), y	63 (53–72)	66 (55–70)	.8
Female sex	143 (40.1)	17 (43.6)	.7
Race/ethnicity
White	88 (24.6)	8 (20.5)	.9
Black	140 (39.2)	15 (38.5)
Hispanic	89 (24.9)	12 (30.8)
Asian and other	38 (10.6)	4 (10.3)
Unknown	2 (0.6)	0 (0.0)
BMI, median (IQR)b	29.9 (25.6–35.4) (n = 268)	26.6 (24.5–28.7) (n = 25)	.04c
Smoking status
Never smoked	169 (47.3)	19 (48.7)	.9
Ever smoked	125 (35.0)	15 (38.5)
Unknown	63 (17.6)	5 (12.8)
Diabetes mellitus, uncomplicated	182 (51.0)	15 (38.5)	.18
Diabetes mellitus, complicated	178 (49.9)	15 (38.5)	.18
Hypertension	265 (74.2)	29 (74.4)	>.99
Hypertension, complicated	163 (45.7)	22 (56.4)	.24
Chronic pulmonary disease	112 (31.4)	16 (41.0)	.28
Pulmonary vascular diseases	77 (21.6)	16 (41.0)	.01c
Congestive heart failure	125 (35.0)	18 (46.2)	.22
Obesity	188 (52.7)	16 (41.0)	.18
Peripheral vascular disorders	62 (17.4)	6 (15.4)	>.99
Renal failure	115 (32.2)	17 (43.6)	.16
Fluid and electrolyte disorders	337 (94.4)	38 (97.4)	.7
Liver disease	65 (18.2)	14 (35.9)	.02c
Hypothyroidism	54 (15.1)	4 (10.3)	.6
Peptic ulcer disease excluding bleeding	11 (3.1)	3 (7.7)	.15
Anemia, nutritional deficiency	220 (61.6)	28 (71.8)	.23
Anemia, blood loss	16 (4.5)	4 (10.3)	.12
Coagulopathy	118 (33.1)	20 (51.3)	.03c
Psychosis	42 (11.8)	5 (12.8)	.8
Depression	101 (28.3)	12 (30.8)	.7
Alcohol abuse	26 (7.3)	1 (2.6)	.50
Drug abuse	30 (8.4)	3 (7.7)	>.99
Other neurologic disorders	170 (47.6)	21 (53.8)	.50
Paralysis	41 (11.5)	7 (17.9)	.30
Rheumatoid arthritis/collagen vascular diseases	25 (7.0)	1 (2.6)	.50
Weight loss	79 (22.1)	14 (35.9)	.07
HIV/AIDS	7 (2.0)	1 (2.6)	.57
Solid tumor (with or without metastasis)	39 (10.9)	10 (25.6)	.01c
Lymphoma	1 (0.3)	1 (2.6)	.19
Multiple myeloma	1 (0.3)	2 (5.1)	.03c
Monoclonal gammopathy	9 (2.5)	0 (0.0)	.6
Solid organ transplant	4 (1.1)	0 (.0)	>99

Abbreviations: AIDS, adult immunodeficiency syndrome; BMI, body mass index; CAPA, coronavirus disease 2019–associated pulmonary aspergillosis; HIV, human immunodeficiency virus; IQR, interquartile range.

^aData represent no. (%) of patients, unless otherwise specified.

^bBMI calculated as weight in kilograms divided by height in meters squared.

^cSignificant at P < .05.

Diagnostic characteristics incorporated within the 2 different definitions of CAPA were compared (Supplementary Table 3). Among 20 patients with probable CAPA, 9 (45%) had cavitary lung lesions, 8 (40%) had a positive serum GM EIA index ≥0.5, 2 (10%) had positive BAL GM EIA index ≥1, and 2 (10%) had culture positive for Aspergillus species in BAL samples. Among 19 patients with possible CAPA, 1 (5%) had positive BAL GM EIA index ≥0.5 (but <1.0), 9 (47%) had cultures revealing Aspergillus species from non-BAL respiratory samples, and 11 (60%) had positive BDG ≥80 pg/mL without alternative explanation (Supplementary Table 3). Probable CAPA was diagnosed later than possible CAPA relative to COVID-19 diagnosis; the median (IQR) durations from COVID-19 diagnosis to probable and possible CAPA diagnosis were 19 (11–37) and 10 (4–15) days, respectively (P = .006), and the median durations from intubation to probable or possible CAPA diagnosis were 13 (8.5–28) and 8 (1–13) days, respectively (P = .029). Eleven of 20 patients (55%) with probable CAPA and 8 of 19 (42.1%) with possible CAPA received mold-active antifungal agents.

Therapeutic Course and Outcomes

Patients with CAPA were more likely than controls to have received corticosteroids during the index admission, particularly after intubation (53.8% vs 28.6%, respectively; P = .005, Table 2). Among different types of corticosteroids used during admission, there was a significant difference between patients with CAPA and controls only for hydrocortisone (38.5% vs 12%, respectively; P < .001). There was no significant difference in dexamethasone use between patients with CAPA and controls (23.1% vs 21%, respectively; P = .8), and there were no differences in the use of tacrolimus, mycophenolate mofetil, tocilizumab, remdesivir, or hydroxychloroquine (Table 2). The same differences were evident when considering only patients with probable CAPA (Supplementary Table 4).

Table 2.

Immunosuppressive Agents and Coronavirus Disease 2019 (COVID-19)–Specific Therapy in Patients With or Without COVID-2019–Associated Pulmonary Aspergillosis

	Patients, No. (%)a
Therapy During Hospital Admission	Non-CAPA (n = 357)	CAPA (n = 39)	P Value
Corticosteroids
Before intubation	50 (14.0%)	5 (12.8%)	.005b
After intubation	102 (28.6)	21 (53.8)
No corticosteroids use	205 (57.4)	13 (33.3)
Prednisone	34 (9.5)	2 (5.1)	.56
Total dose, median (IQR), mg	120 (60–270)	160 (120–200)	.7
Duration, median (IQR), d	6 (2–23)	2 (2, 2)	.27
Methylprednisolone	62 (17.4)	10 (25.6)	.20
Total dose, median (IQR), mg	160 (60–420)	245 (60–400)	.8
Duration, median (IQR), d	3 (1–5)	3 (1–7)	.8
Hydrocortisone	43 (12.0)	15 (38.5)	<.001
Total dose, median (IQR), mg	500 (150–1000)	425 (300–900)	.9
Duration, median (IQR), d	4 (1–8)	4 (3–9)	.7
Dexamethasone	75 (21.0)	9 (23.1)	.8
Total dose, median (IQR), mg	50 (20–60)	36 (20–60)	.8
Duration, median, (IQR), d	5 (2–10)	6 (1–10)	>.99
Tacrolimus	4 (1.1)	0 (.0)	>.99
Mycophenolate mofetil	1 (.3)	0 (.0)	>.99
COVID-19–specific therapy
Tocilizumab	63 (17.6)	9 (23.1)	.39
Remdesivir	83 (23.2)	9 (23.1)	>.99
Hydroxychloroquine	104 (29.1)	9 (23.1)	.58

Abbreviations: CAPA, COVID-19 associated pulmonary aspergillosis; COVID-19, coronavirus disease 2019; IQR, interquartile range.

^aData represent no. (%) of patients, unless otherwise specified.

^bSignificant at P < .05.

Patients with CAPA and controls had similar disease severity scores at admission. However, the CAPA group had a higher maximum severity scores during admission, with median (IQR) scores of 8 (7–8) versus 7 (7–8) for controls (rank sum P = .02). (Table 3 and Supplementary Figure 1). While both people with CAPA and controls showed increases in the severity scales, those with CAPA required significantly longer durations of any oxygen therapy (median [IQR] duration, 40.7 [20–69.9] vs 16.7 [10–29.4] days for controls; P < .001), ventilator support (36.6 [14.6–63] vs 8.9 [3.8–18.0] days; P < .001), IVP (24.8 [12.3–46] vs 6.2 [1.7–14.2] days; P < .001), extracorporeal membrane oxygenation therapy (55.4 [33.2–68.5] vs 14.9 [11.4–27.0] days; P = .02), and hospital length of stay (41.1 [20.5–72.4] vs 18.5 [10.7–31.8] days; P < .001) (Table 3). Differences in severity of illness can be appreciated in the longitudinal depiction of mean daily ordinal score (Figure 1). Patients with CAPA had significantly slower recovery than controls (adjusted OR, ₁.₀₈1.09_1.1; P < .001).

Table 3.

World Health Organization Coronavirus Disease 2019 (COVID-19) Severity Scores, Advanced Life Support Therapy, and Clinical Outcomes in Patients With or Without COVID-19–Associated Pulmonary Aspergillosis

	Patients, No. (%)a
Severity Scores, Therapy, and Outcomes	Non-CAPA (n = 357)	CAPA (n = 39)	P Value
WHO severity score on day of admission, median (IQR)	5 (4–6)	5 (4–6)	.55
Maximum WHO severity scores during admission
Intubation	33 (9.2)	0 (0.0)	.04b
Intubation with advanced life support therapy	180 (5.4)	17 (43.6)
Death	144 (4.3)	22 (56.4)
Maximum WHO severity score during admission, median (IQR)	7 (7–8)	8 (7–8)	.02b
Highest oxygen requirement on day of admission
Oxygen not needed	34 (9.5)	5 (12.8)	.11
Oxygen needed, but not HFNC or NIPPV	136 (38.1)	9 (23.1)
HFNC or NIPPV	56 (15.7)	11 (28.2)
Ventilator/intubation	131 (36.7)	14 (35.9)
Duration of oxygen therapy, median (IQR), d	16.7 (10.0–29.4)	4.7 (20.0–69.6)	<.001b
Any HFNC therapy during admission	217 (6.8)	27 (69.2)	.39
Duration of HFNC, median (IQR), d	4.1 (0.9–11.3) (n = 217)	3.7 (2.0–15.5) (n = 27)	.32
Duration of ventilator, median (IQR), d	8.9 (3.8–18.0)	36.6 (14.6–63.0)	<.001b
Any CRRT during admission	59 (16.5)	15 (38.5)	.002b
Duration of CRRT, median (IQR), d	6.7 (2.6–14.2) (n = 59)	12.0 (3.1–22.6) (n = 15)	.12
Any ECMO treatment	13 (3.6)	4 (10.3)	.08
Duration of ECMO, median (IQR), d	14.9 (11.4–27.0) (n = 13)	55.4 (33.2–68.5) (n = 4)	.02b
Any inpatient hemodialysis	35 (9.8)	8 (20.5)	.055
Duration of inpatient hemodialysis, median (IQR), d	13.7 (4.9–31.5) (n = 35)	31.4 (12.4–55.1) (n = 8)	.22
Any vasopressor treatment	297 (83.2)	38 (97.4)	.02b
Duration of vasopressor therapy, median (IQR), d	6.2 (1.7–14.2) (n = 297)	24.8 (12.3–46.0) (n = 38)	<.001b
Death at discharge	144 (40.3)	22 (56.4)	.06
DNR/DNI at admission	27 (7.6)	1 (2.6)	.34
DNR/DNI during entire admission	155 (43.4)	24 (61.5)	.04b
Hospital length of stay (admission to discharge), median (IQR), d	18.5 (10.7–31.8)	41.1 (20.5–72.4)	<.001b
Time from intubation to discharge, median (IQR), d	15.9 (8.3–29.2)	39.8 (19.7–66.1)	<.001b

The WHO severity scale is an eight-point scale for patients infected with COVID-19 comprising the following scores: 1 (ambulatory, no limitations); 2 (limitation on activities); 3 (admitted to hospital, not on oxygen); 4 (oxygen mask or nasal prong); 5 (high-flow oxygen or noninvasive positive pressure ventilation [NIPPV]); 6 (intubation); 7 (intubation and advanced life support); and 8 (death).

Abbreviations: CAPA, COVID-19 associated pulmonary aspergillosis; COVID-19, coronavirus disease 2019; CRRT, continuous renal replacement therapy; DNI, do-not-intubate order; DNR, do-not-resuscitate order; ECMO, extracorporeal membrane oxygenation; HFNC, high-flow nasal cannula; IQR, interquartile range; NIPPV, noninvasive positive-pressure ventilation; WHO, World Health Organization.

^aData represent no. (%) of patients, unless otherwise specified.

^bSignificant at P < .05.

Figure 1.

Trajectory of mean daily maximum World Health Organization (WHO) severity scores in patients with or without coronavirus disease 2019–associated pulmonary aspergillosis (CAPA). A, Time since admission. B, Time since intubation.

There were no differences in mortality rates between patients with CAPA and controls (sHR, _0.91.3_1.9; P = .2) (Figure 2). Using subhazard functions for competing risk estimations, patients with CAPA were extubated 2 times more slowly than those without (sHR, _0.40.5_0.6; P < .001) (Figure 2). Similarly, progression from severity score 6 (intubation) to 7 (receipt of other advanced life support) was 1.8 times faster among people with CAPA (sHR, _1.31.8_2.5; P < .001) (Figure 2). There was no difference in overall survival. However, people with CAPA had longer inpatient stays and their discharge rate was slower, compared with controls (sHR, _0.40.5_0.8; P = .006) (Figure 2).

Figure 2.

Cumulative incidence of inpatient death (A), extubation (B), advanced life support therapy (C), and hospital discharge (D) after intubation, in patients with or without coronavirus disease 2019–associated pulmonary aspergillosis (CAPA).

Findings were largely the same when CAPA was analyzed using the probable definition only (Supplementary Table 5 and Supplementary Figure 2). As in the larger group, patients with probable CAPA also had longer durations of mechanical ventilation, hemodynamic support, and dynamics of severity scores after intubation (Supplementary Table 5 and Supplementary Figure 3). Patients with probable CAPA had no difference in mortality rate compared with those without CAPA but took longer to be extubated. Rate to extubation and progression in severity scores showed similar differences (Supplementary Figure 4). In this analysis with a smaller case sample size, there was only a trend toward differences in hospital length of stay between patients with probable CAPA and controls (sHR, _0.40.6_1.0; P = .08, Supplementary Figure 4). Sensitivity analyses did not reveal differences in clinical outcomes among patients with CAPA based on positive serum BDG result alone and those with CAPA by other criteria (Supplementary Table 6).

DISCUSSION

We describe outcomes associated with CAPA among a large cohort of mechanically ventilated patients from 5 hospitals in the JHM Health System. Depending on definitions applied, the incidence of recognized CAPA ranged from 5% to 10%. People with CAPA had different underlying conditions, especially with regard to BMI and pulmonary, liver, and oncologic diseases before COVID-19, compared with those who without CAPA. Regardless of definitions used, people with CAPA had uniformly worse outcomes than those without CAPA, especially with regard to severity of illness, ventilatory and hemodynamic support, and duration of hospitalization.

Aspergillosis as a complication of severe viral infection has been best documented in people with influenza [19–23]. Several large cohort studies have showed that rates of pulmonary aspergillosis in influenza patients requiring ICU admission range from 7% to 30%, depending on the methods applied to diagnostic screening, seasonal viral epidemiology, and definitions applied in the reporting of “influenza-associated aspergillosis” [19–23]. Early in the COVID-19 pandemic, European centers reported similarly high rates of CAPA; rates have similarly varied depending on diagnostic methods and definitions [4–10].

It has been suggested that risks for both airway and invasive aspergillosis in this setting occur because of viral-mediated damage in airway fungal clearance and concurrent suppression of secondary immunologic defenses [21, 24]. Underlying defects in fungal clearance and preexisting immunosuppression likely explain observed risks associated with pulmonary disorders, solid tumors, and multiple myeloma in this cohort. Receipt of corticosteroids during admission, particularly hydrocortisone, appeared to be associated with increased risks for CAPA. Because hydrocortisone is given to people with critical illness, it is difficult to determine whether this reflects actual incremental risk or serves as a marker for illness severity.

European investigators have proposed “probable” CAPA definitions that substantially reflect clinical practices that include aggressive bronchoscopy, use of PCR-based assays, and application of antigen (Platelia galactomannan) assay cutoffs at higher index levels (positive BAL GM index ≥1.0) to define positivity, compared with what is currently recommended by the Food and Drug Administration [12]. Similarly to many hospitals in North America, we do not commonly perform bronchoscopy for CAPA diagnosis or use PCR tests for Aspergillus species [25]. With these diagnostic differences, we observed lower CAPA rates than those found in European prospective studies [4, 7].

Given the different diagnostic approaches to CAPA, we used a priori expanded CAPA definitions to include a more pragmatic “possible” category reflective of diagnostic practices in our institutions. Growth of organisms in endotracheal aspirate cultures, positive BDG assays, and low-positive BAL GM EIA results (positive BAL GM index, 0.5–1.0) informed the majority of diagnoses within the this category. The definition is less conservative and may include more people with false-positive microbiologic evidence (especially with the BDG assay), but possible CAPA represents approximately half of those patients by our current diagnostic approach. Earlier recognition of probable versus possible CAPA may suggest that this group contains more people with invasive aspergillosis; however, the groups did not differ when considering host characteristics and outcomes.

Patients with CAPA (regardless of the definition applied) had similar severity of illness compared with controls, at admission. However, their conditions improved more slowly during hospitalization than those in the counterpart control groups, with longer durations of mechanical and hemodynamic support. Although there was no difference in overall mortality, rates it is likely that this study lacked the power to detect small differences among mechanically ventilated patients with COVID-19. Here, rates of death in patients with CAPA were consistent with those reported by other centers [4].

Whether CAPA caused these differences in outcomes or occurred because of other variables that dictate severe COVID-19 is unclear. It is notable that the underlying risks for CAPA do not mimic those that are typically associated with severe COVID-19. People with CAPA had lower BMIs than to controls, and no differences in age, hypertension, or sex, all risks classically associated with severe COVID-19 [1, 26–29]. Although we did not compare outcomes of CAPA according to receipt of antifungal therapy because of the clinical bias inherent in retrospective design, results of prospective studies have suggested that antifungal therapy can improve outcomes [4, 7]. Approximately 50% of people with probable or possible CAPA received mold-active antifungal agents. We suspect that the low rate of treatment likely reflected lack of recognition of this emerging condition and difficulty in differentiating between invasive mold disease and colonization without standardized definitions, particularly early in the COVID-19 pandemic.

The current study has several strengths: (1) the cohort included people with much heterogeneity in comorbid conditions, facilitating understanding of CAPA risks; (2) the study provided substantial CAPA cases as well as robust controls; (3) data were confirmed by rigorous review of patient-level records; (4) longitudinal analyses were performed to understand the clinical course trajectory of patients CAPA and their controls; and (5) attention was focused on diagnostic definitions, including those that best reflect clinical practice in the institution. Limitations include those inherent to retrospective studies, including the potential of unknown confounders affecting clinical outcomes, the use of International Classification of Diseases, Tenth Revision, data for patient comorbid conditions, and variability in clinical practice for ordering fungal biomarkers.

In conclusion, this large cohort study verified small, but substantial risks of CAPA in mechanically ventilated patients with COVID-10 in a large health system in the United States. While differences in reported rates may reflect diagnostic heterogeneity or differences in patient comorbid conditions and therapeutic approaches, our findings mimic and expand on those reported in smaller studies, in that CAPA is associated with poor outcomes, and risks reflect numerous underlying conditions that may predict poor airway clearance of fungus, combined with deficits in secondary antifungal defenses. Given difficulties in invasive sampling, improved noninvasive diagnostics that enable screening, and/or prophylactic antifungal therapy may be warranted to improve COVID-19 outcomes in high-risk patients.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The data used for this publication were part of the COVID-19 Precision Medicine Analytics Platform Registry (JH-CROWN), which is based on the contributions of many patients and clinicians.

Author contributions. Study design: N. P., T. P. Y. C., A. B. M., S. X. Z., R. K. A., and K. A. M. Data collection: N. P. and T. P. Y. C. Data analysis: N. P., T. P. Y. C., A. B. M., and K. A. M. Manuscript writing and critical review: all authors.

Financial support. This work was supported by Hopkins in Health, the Johns Hopkins Precision Medicine Program (funding to JH-CROWN)

Potential conflicts of interest. N. P. received consulting/advisory board income from Shionogi; study grant support from the Health Systems Research Institute, Ministry of Public Health, Thailand; the National Institutes of Health; the Cystic Fibrosis Foundation; and the Fisher Center Discovery Program at Johns Hopkins School of Medicine. S. X. Z. received research funds from IMMY Diagnostics and Vela Diagnostics. R. K. A. received study grant support from Aicuris, Astellas, Chimerix, Merck, Oxford Immunotec, Qiagen, and Takeda/Shire. S. N. received grant support from the Fisher Center Discovery Program. D. L. S. received consulting/speaking honoraria from Sanofi, Novartis, CSL Behring, and Veloxis. K. A. M. received consulting/advisory board income from Cidara, Merck, and Sfunga; equity and licensing revenue from MycoMed Technologies; and a research grant from Merck. A. B. M. received award K01DK101677 from the National Institute of Diabetes and Digestive and Kidney Diseases. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Author notes

N. P. and T. P. Y. C. contributed equally to this work.