Epidemiology and Mortality-Associated Factors of Invasive Fungal Disease in Elderly Patients: A 20-Year Retrospective Study from Southern China

Figures & data

Table 1 Criteria for Diagnosis of IFD in the Elderly Patients

Category	Criteria
Proven	Histopathological examination reveals fungal infection in normally sterile sites, or recovery of a mold/yeast from samples obtained by a sterile procedure, or blood culture yielding a mold/yeast (Aspergillus spp. excluded)
Probable	Elderly patients satisfying the following clinical and mycological criteria were considered to have probable mold infection.
Mold infection	a. Clinical criteria
	Lung infection: pulmonary CT scan showed i) dense, well-circumscribed lesions with or without a halo sign, or ii) air-crescent sign, or iii) cavity; or bronchoscopy found tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar.
	Sinonasal infection: imaging suggesting sinusitis with i) acute localized pain, and/or ii) evidence of bone erosion, and/or iii) nasal ulcer with black eschar revealed by nasal endoscopy
	CNS infection: imaging showing focal lesions or meningeal enhancement
	b. Mycological criteria: satisfying at least one of the following criteria
	i) Mold in sputum, BALF, bronchial brush, or sinus aspirate samples
	ii) Positive GM antigen detection in plasma, serum, BALF or CSF (for aspergillosis only).
Cryptococcosis	Elderly patients showing one of the aforementioned radiographic manifestation along with i) Cryptococcus spp. isolated in sputum, BALF, bronchial brush; or ii) positive CrAg detection in serum or CSF.
Possible
Mold infection/Cryptococcosis	Elderly patients satisfying the aforementioned clinical criteria but without mycological evidence were considered to have possible mold infection/cryptococcosis.
Yeast infection	a. Lung infection: elderly patients satisfying all the following criteria were considered to have possible pulmonary candidiasis: i) clinical symptoms suggesting lung infection and CT scan showing new onset bronchopneumonia or micronodules or diffused infiltrates, ii) positive twice in microscopic examination showing fungal hyphae/pseudohyphae and recovery twice of the same yeast in sputum/BALF culture, iii) positive twice in serum G-test, iv) excluded other possible pathogens
	b. UTI: elderly patients satisfying all the following criteria were considered to have possible urinary candidiasis: i) clinical symptoms indicating urinary infection, ii) increased leukocytes in clean catch midstream urine, iii) positive twice in urine culture for the same yeast, iv) excluded other possible pathogens
	c. Esophageal infection: elderly patients satisfying all the following criteria were considered to have possible esophageal candidiasis: i) white plaques found in endoscopic examination, ii) fungal hyphae, pseudohyphae or spores found in esophageal brushing sample

Abbreviations: BALF, bronchoalveolar lavage fluid; CNS, central nervous system; CrAg, cryptococcal capsule polyglycan antigen; CSF, cerebrospinal fluid; CT, computed tomography; G-test, β-D-glucan detection; GM, galactomannan; IFD, invasive fungal disease; UTI, urinary tract infection.

Table 2 Participants Characteristics According to Age

	Age, Years			P value
	60–69 (n=272)	70–79 (n=198)	≥80 (n=51)
Baseline Characteristics
Male:Female	162:110	126:72	35:16	0.39
BMI, kg/m^2, mean±SD	22.9±3.5	22.4±3.4	22.3±3.0	0.22
Tobacco use, n (%)	58 (21.3)	43 (21.7)	17 (33.3)	0.16
Charlson score, mean±SD	3.7±2.0	5.0±2.0	5.2±2.0	<0.001*
Polypharmacy, n (%)	47 (17.3)	36 (18.2)	11 (21.6)	0.76
Comorbidities
Hypertension, n (%)	94 (34.6)	91 (46.0)	22 (43.1)	0.04*
Hematological or solid organ malignancy, n (%)	62 (22.8)	53 (26.8)	15 (29.4)	0.48
DM, n (%)	55 (20.2)	62 (31.3)	10 (19.6)	0.01*
CKD, n (%)	30 (11.0)	24 (12.1)	8 (15.7)	0.64
CTD, n (%)	25 (9.2)	4 (2.0)	1 (2.0)	0.002*
CAD, n (%)	18 (6.6)	30 (15.2)	10 (19.6)	0.002*
COPD, n (%)	11 (4.0)	30 (15.2)	10 (19.6)	<0.001*
Solid organ transplantation, n (%)	8 (2.9)	2 (1.0)	0 (0)	0.19
Acute stroke, n (%)	6 (2.2)	7 (3.5)	1 (2.0)	0.64
Associated Factors
Prolonged hospitalization, n (%)	29 (10.7)	23 (11.6)	10 (19.6)	0.19
Recent operation, n (%)	72 (26.5)	59 (29.8)	16 (31.4)	0.69
ICU admission, n (%)	81 (29.8)	90 (45.5)	32 (62.7)	<0.001*
Broad-spectrum antibiotics, n (%)	137 (50.4)	123 (62.1)	40 (78.4)	<0.001*
CVC, n (%)	80 (29.4)	73 (36.9)	24 (47.1)	0.03*
Indwelling urinary catheter, n (%)	83 (30.5)	86 (43.4)	32 (62.7)	<0.001*
TPN, n (%)	8 (2.9)	6 (3.0)	5 (9.8)	0.05
Prolonged use of GC, n (%)	23 (8.5)	1 (0.5)	0 (0)	<0.001*
Immunosuppressive therapy, n (%)	26 (9.6)	11 (5.6)	3 (5.9)	0.24
Laboratory Data
Neutropenia, n (%)	12 (4.4)	7 (3.5)	1 (2.0)	0.68
Grade I, n (%)	4 (1.5)	1 (0.5)	0 (0)
Grade II, n (%)	4 (1.5)	1 (0.5)	0 (0)
Grade III, n (%)	2 (0.7)	1 (0.5)	1 (2.0)
Grade IV, n (%)	1 (0.4)	3 (1.5)	0 (0)
Lymphopenia, n (%)	79 (29.0)	71 (35.9)	25 (49.0)	0.02*
Anemia, n (%)	88 (32.4)	80 (40.4)	26 (51.0)	0.02*
Mild, n (%)	50 (18.4)	33 (16.7)	11 (21.6)
Moderate, n (%)	33 (12.1)	42 (21.2)	15 (29.4)
Severe, n (%)	5 (1.8)	4 (2.0)	0 (0)
Very severe, n (%)	0 (0)	1 (0.5)	0 (0)
Hypoalbuminemia, n (%)	114 (41.9)	101 (51.0)	28 (54.9)
All-cause mortality, n (%)	55 (20.2)	60 (30.3)	20 (39.2)	0.004*

Note: *P<0.05.

Abbreviations: BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CTD, connective tissue disease; CVC, central venous catheter; DM, diabetes mellitus; GC, glucocorticoid; ICU, intensive care unit; IFD, invasive fungal disease; SD, standard deviation; TPN, total parenteral nutrition.

Table 3 Distribution of Isolated Fungi

Isolated Fungi	N (%)
Total	521
Candidaspp.	292 (56.0)
C. albicans	176 (33.8)
C. tropicalis	41 (7.9)
C. glabrata	32 (6.1)
C. parapsilosis	32 (6.1)
C. krusei	3 (0.6)
C. lusitaniae	3 (0.6)
C. guilliermondii	2 (0.4)
C. famata	2 (0.4)
C. lipolytica	1 (0.2)
Aspergillusspp.	157 (30.1)
A. fumigatus	46 (8.8)
A. flavus	15 (2.9)
A. niger	4 (0.8)
A. terreus	1 (0.2)
Aspergillus unclassified	92 (17.7)
Zygomycetesspp.	45 (8.6)
Mucor spp.	43 (8.3)
Rhizopus spp.	2 (0.4)
Cryptococcusspp.	20 (3.8)
C. neoformans	18 (3.5)
C. laurentii	2 (0.4)
Penicilliumspp.	7 (1.3)
P. marneffei	7 (1.3)

Figure 1 Prevalence of IFD and the distribution of IFD subtypes in elderly patients since 1998.

Abbreviation: IFD, invasive fungal disease.

Figure 2 Infectious patterns and infective sites of IFD inelderly patients with different underlying diseases. (A) Infectious patterns; (B) Infective sites.

Abbreviations: CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; IFD, invasive fungal disease.

Figure 3 Infectious patterns (A) and infective sites (B) of IFD in elderly patients, by age.

Abbreviation: IFD, invasive fungal disease.

Table 4 Comparison Between Survivors and Non-Survivors with Invasive Mold Infection

	Survivors (n=156)	Non-Survivors (n=37)	P value	Crude OR (95% CI)	Adjusted OR (95% CI)
Baseline Characteristics
Age, years, mean±SD	68.0±6.0	67.5±8.5	<0.001*	1.10 (1.04–1.16)*
Male:Female	85:71	26:11	0.13
BMI, kg/m^2, mean±SD	23.1±3.2	22.8±2.3	0.58
Tobacco use, n (%)	32 (20.5)	14 (37.8)	0.03*	2.36 (1.09–5.09)*
Charlson score, mean±SD	3.3±1.6	5.1±1.9	<0.001*	1.68 (1.36–2.08)*
Polypharmacy, n (%)	7 (4.5)	18 (48.6)	<0.001*	20.17 (7.46–54.55)*	6.11 (2.03–18.36)*
Comorbidities
Hypertension, n (%)	54 (34.6)	16 (43.2)	0.33
Hematological or solid organ malignancy, n (%)	8 (7.1)	9 (24.3)	0.002*	3.64 (1.35–9.83)*
DM, n (%)	28 (17.9)	13 (35.1)	0.02*	2.48 (1.13–5.45)*
CKD, n (%)	6 (3.8)	9 (24.3)	<0.001*	8.04 (2.65–24.36)*	4.45(1.18–16.73)*
CTD, n (%)	6 (3.8)	4 (10.8)	0.09
CAD, n (%)	16 (10.3)	3 (8.1)	0.69
COPD, n (%)	18 (11.5)	11 (29.7)	0.01*	3.24 (1.37–7.66)*
Solid organ transplantation, n (%)	1 (0.6)	1 (2.7)	0.27
Acute stroke, n (%)	3 (1.9)	1 (2.7)	0.76
Associated Factors
Prolonged hospitalization, n (%)	2 (1.3)	3 (8.1)	0.02*	6.79 (1.09–42.24)*
Recent operation, n (%)	5 (3.2)	11 (29.7)	<0.001*	12.78 (4.10–39.80)*
ICU admission, n (%)	14 (9.0)	34 (91.9)	<0.001*	114.95 (31.27–422.59)*
Broad-spectrum antibiotics, n (%)	41 (26.3)	32 (86.5)	<0.001*	17.95 (6.55–49.17)*	6.35 (1.96–20.60)*
CVC, n (%)	11 (7.1)	24 (64.9)	<0.001*	24.34 (9.76–60.56)*
Indwelling urinary catheter, n (%)	15 (9.6)	30 (81.1)	<0.001*	40.29 (15.12–107.33)*
TPN, n (%)	3 (1.9)	4 (10.8)	0.01*	6.18 (1.32–28.94)*
Prolonged use of GC, n (%)	4 (2.6)	5 (13.5)	0.01*	5.94 (1.51–23.34)*
Immunosuppressive therapy, n (%)	6 (3.8)	5 (13.5)	0.02*	3.91 (1.12–13.59)*
Disseminated fungal infection, n (%)	4 (2.6)	1 (2.7)	0.96
Laboratory Data
Neutropenia, n (%)	4 (5.8)	4 (10.8)	0.02*	4.61 (1.10–19.37)*
Grade I, n (%)	1 (0.6)	2 (5.4)
Grade II, n (%)	2 (1.3)	0 (0)
Grade III, n (%)	0 (0)	1 (2.7)
Grade IV, n (%)	1 (0.6)	1 (2.7)
Lymphopenia, n (%)	27 (17.3)	22 (59.5)	<0.001*	7.01 (3.22–15.23)*	3.02 (1.15–7.93)*
Anemia, n (%)	27 (17.3)	18 (48.6)	<0.001*	4.53 (2.10–9.74)*
Mild, n (%)	17 (10.9)	6 (16.2)
Moderate, n (%)	9 (5.8)	12 (32.4)
Severe, n (%)	1 (0.6)	0 (0)
Very severe, n (%)	0 (0)	0 (0)
Hypoalbuminemia, n (%)	43 (27.6)	24 (64.9)	<0.001*	4.85 (2.27–10.38)*
Initial adequate treatment, n (%)	137 (87.8)	24 (64.9)	0.001*	0.26 (0.11–0.59)*

Note: *P<0.05.

Abbreviations: BMI, body mass index; CAD, coronary artery disease; CI, confidential interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CTD, connective tissue disease; CVC, central venous catheter; DM, diabetes mellitus; GC, glucocorticoid; ICU, intensive care unit; OR, odds ratio; SD, standard deviation; TPN, total parenteral nutrition.

Table 5 Comparison Between Survivors and Non-Survivors with IC

	Survivors (n=160)	Non-Survivors (n=76)	P value	Crude OR (95% CI)	Adjusted OR (95% CI)
Baseline Characteristics
Age, years, mean±SD	70.3±7.3	70.9±10.8	0.53	1.01(0.96–1.05)
Male:Female	105:55	49:27	0.86
BMI, kg/m^2, mean±SD	21.5±3.3	21.8±3.9	0.56
Tobacco use, n (%)	44 (27.5)	12 (15.8)	0.05
Charlson score, mean±SD	5.0±2.1	5.4±2.4	0.72
Polypharmacy, n (%)	30 (18.8)	26 (34.2)	0.01*	2.25 (1.21–4.18)*
Comorbidities
Hypertension, n (%)	56 (35.0)	34 (44.7)	0.15
Hematological or solid organ malignancy, n (%)	56 (35.0)	35 (46.1)	0.10	1.50 (0.86–2.62)
DM, n (%)	41 (25.6)	18 (23.7)	0.75
CKD, n (%)	28 (17.5)	12 (15.8)	0.74
CTD, n (%)	13 (8.1)	1 (1.3)	0.04*	0.15 (0.02–1.18)
CAD, n (%)	20 (12.5)	11 (14.5)	0.67
COPD, n (%)	14 (8.8)	5 (6.6)	0.57
Solid organ transplantation, n (%)	1 (0.6)	4 (5.3)	0.02*	8.83 (0.97–80.44)
Acute stroke, n (%)	4 (2.5)	3 (3.9)	0.54
Associated Factors
Prolonged hospitalization, n (%)	27 (16.9)	20 (26.3)	0.09	1.76 (0.91–3.39)
Recent operation, n (%)	68 (42.5)	41 (53.9)	0.10	1.59 (0.92–2.75)
ICU admission, n (%)	59 (36.9)	62 (81.6)	<0.001*	7.58 (3.91–14.71)*	7.58 (3.91–14.71)*
Broad-spectrum antibiotics, n (%)	113 (70.6)	68 (89.5)	0.001*	3.54 (1.58–7.93)*
CVC, n (%)	65 (40.6)	52 (68.4)	<0.001*	3.17 (1.78–5.64)*
Indwelling urinary catheter, n (%)	74 (46.3)	52 (68.4)	0.001*	2.52 (1.42–4.47)*
TPN, n (%)	5 (3.1)	4 (5.3)	0.42
Prolonged use of GC, n (%)	6 (3.8)	3 (3.9)	0.94
Immunosuppressive therapy, n (%)	12 (7.5)	8 (10.5)	0.44
Disseminated fungal infection, n (%)	39 (24.4)	35 (46.1)	0.001*	2.65 (1.49–4.72)*
Laboratory Data
Neutropenia, n (%)	5 (3.1)	3 (3.9)	0.74
Grade I, n (%)	1 (0.6)	0 (0)
Grade II, n (%)	1 (0.6)	1 (1.3)
Grade III, n (%)	2 (1.3)	1 (1.3)
Grade, IV, n (%)	1 (0.6)	1 (1.3)
Lymphopenia, n (%)	61 (38.1)	37 (48.7)	0.12
Anemia, n (%)	82 (51.3)	44 (57.9)	0.34
Mild, n (%)	37 (23.1)	21 (27.6)
Moderate, n (%)	41 (25.6)	19 (25.0)
Severe, n (%)	4 (2.5)	3 (3.9)
Very severe, n (%)	0 (0)	1 (1.3)
Hypoalbuminemia, n (%)	89 (55.6)	51 (67.1)	0.09
Initial adequate treatment, n (%)	79 (49.4)	46 (60.5)	0.11

Note: *P<0.05.

Abbreviations: BMI, body mass index; CAD, coronary artery disease; CI, confidential interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CTD, connective tissue disease; CVC, central venous catheter; DM, diabetes mellitus; GC, glucocorticoid; IC, invasive candidiasis; ICU, intensive care unit; OR, odds ratio; SD, standard deviation; TPN, total parenteral nutrition.