Influenza vaccination is associated with a reduced risk of invasive aspergillosis in high-risk individuals in Taiwan: a population-based cohort study

Figures & data

Figure 1. Flow chart of the study population from 2016–2017 to 2018–2019 influenza season.

Note: Figure 1 shows how the study population was selected according to the inclusion and exclusion criteria.

Table 1. Baseline characteristics of people at high-risk for invasive aspergillosis based on vaccination status.

	Total	Non-vaccinated	Vaccinated	p-Value
	N = 8,544,451	N = 5,407,974	N = 3,136,477	36.7%
Age, year, mean (SD)	63.0 (14.1)	60 (14.2)	68.1 (12.4)	<.001
Male sex, n (%)	4,247,235 (49.7)	2,709,313 (50.1)	1,537,922 (49)	<.001
Insurance amount, TWD, n (%)				<.001
0–20,000	1,963,350 (23)	1,192,316 (22.1)	771,034 (24.6)
20,000–30,000	3,742,825 (43.8)	2,310,061 (42.7)	1,432,764 (45.7)
30,000–40,000	931,638 (10.9)	630,480 (11.7)	301,158 (9.6)
40,000–50,000	899,379 (10.5)	610,331 (11.3)	289,048 (9.2)
>50,000	1,007,259 (11.8)	664,786 (12.3)	342,473 (10.9)
Region, n (%)				<.001
Northern	3,992,788 (46.7)	2,675,198 (49.5)	1,317,590 (42)
Central	2,011,773 (23.5)	1,204,337 (22.3)	807,436 (25.7)
Southern	2,261,372 (26.5)	1,360,602 (25.2)	900,770 (28.7)
Eastern and offshore islands	278,518 (3.3)	167,837 (3.1)	110,681 (3.5)
Medications
Systemic corticosteroids, cDDD, mean (SD)	4.4 (24.2)	4.7 (23.3)	3.8 (25.5)	<.001
Inhaled corticosteroids, n (%)	347,818 (4.1)	193,620 (3.6)	154,198 (4.9)	<.001
Immunosuppressive agents, n (%)	434,302 (5.1)	317,662 (5.9)	116,640 (3.7)	<.001
Comorbidities, n (%)
Hematopoietic stem cell transplantation	3621 (<0.1)	2467 (0.1)	1154 (<0.1)	<.001
Solid-organ transplantation	34,415 (0.4)	26,564 (0.5)	7851 (0.3)	<.001
Hematological malignancy	73,326 (0.9)	48,778 (0.9)	24,548 (0.8)	<.001
Metastatic malignancy	153,207 (1.8)	118,014 (2.2)	35,193 (1.1)	<.001
Solid-organ malignancy	1,365,984 (16.0)	872,238 (16.1)	493,746 (15.7)	<.001
Autoimmune diseases	536,314 (6.3)	353,565 (6.5)	182,749 (5.8)	<.001
Immunodeficiency disorders and HIV	67,681 (0.8)	37,879 (0.7)	29,802 (1)	<.001
Asthma	793,445 (9.3)	507,048 (9.4)	286,397 (9.1)	<.001
COPD	807,629 (9.5)	416,553 (7.7)	391,076 (12.5)	<.001
Other chronic respiratory diseases	250,708 (2.9)	140,143 (2.6)	110,565 (3.5)	<.001
CKD stage 5 and ESRD	365,049 (4.3)	197,010 (3.6)	168,039 (5.4)	<.001
CKD stage 1–4	123,279 (1.4)	71,225 (1.3)	52,054 (1.7)	<.001
Aplastic anaemia	12,077 (0.1)	8286 (0.2)	3791 (0.1)	<.001
Myelodysplastic syndrome	6084 (0.1)	3791 (0.1)	2293 (0.1)	.112
Diabetes with chronic complications	1,339,825 (15.7)	784,058 (14.5)	555,767 (17.7)	<.001
Diabetes without chronic complications	3,619,027 (42.4)	2,293,585 (42.4)	1,325,442 (42.3)	<.001
Liver cirrhosis/failure	266,968 (3.1)	182,772 (3.4)	84,196 (2.7)	<.001
Heart failure	666,305 (7.8)	392,398 (7.3)	273,907 (8.7)	<.001
Health care use, mean (SD)
No. of admissions	0.4 (1)	0.4 (1.1)	0.3 (0.9)	<.001
No. of OPD visits	17.2 (12.3)	15.3 (11.3)	20.6 (13.1)	<.001
No. of admissions for ILI	0.1 (0.4)	0.1 (0.4)	0.1 (0.4)	<.001
No. of OPD visits for ILI	3 (4.7)	2.7 (4.3)	3.5 (5.1)	<.001

Abbreviations: SD, standard deviation; cDDD, cumulative defined daily dose; HIV, human immunodeficiency virus; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; ESRD, end-stage renal disease; No., number; OPD, outpatient department; ILI, influenza-like illness.

Table 2. Association between influenza vaccination and invasive aspergillosis.

Outcome	IA/vaccinated	IA/non-vaccinated	cOR (95% CI)	aOR^a (95% CI)
Overall	412/3,136,477	767/5,407,974	0.93 (0.82–1.04)	0.79 (0.70–0.90)
Age
≥65	312/1,975,560	362/1,997,288	0.87 (0.75–1.01)	0.85 (0.73–0.99)
<65	100/1,160,917	405/3,410,686	0.73 (0.58–0.90)	0.63 (0.50–0.79)
Sex
Male	264/1,537,922	494/2,709,313	0.94 (0.81–1.09)	0.78 (0.67–0.92)
Female	148/1,598,555	273/2,698,661	0.92 (0.75–1.12)	0.82 (0.67–1.02)
EORTC/MSGERC host factors^b
With host factors	126/198,100	334/460,964	0.88 (0.72–1.08)	0.78 (0.63–0.97)
Without host factors	286/2,938,377	433/4,947,010	1.11 (0.96–1.29)	0.79 (0.67–0.92)
Comorbidities
Immunocompromised status	113/208,690	313/463,639	0.80 (0.65–1.00)	0.76 (0.61–0.95)
Malignancy	129/549,610	306/1,031,442	0.79 (0.64–0.97)	0.80 (0.64–0.99)
Chronic respiratory diseases	196/669,448	239/943,528	1.16 (0.96–1.40)	0.98 (0.81–1.20)
Diabetes	174/1,881,209	286/3,077,643	1.00 (0.82–1.20)	0.76 (0.63–0.93)
Season
2016–2017	124/1,012,935	226/1,714,009	0.93 (0.75–1.16)	0.85 (0.67–1.07)
2017–2018	118/1,082,845	186/1,762,722	1.03 (0.82–1.30)	0.90 (0.71–1.15)
2018–2019	170/1,040,697	355/1,931,243	0.89 (0.74–1.07)	0.72 (0.59–0.87)

Abbreviations: IA, invasive aspergillosis; cOR, crude odds ratio; aOR, adjusted odds ratio; EORTC/MSGERC, European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.

^a Adjusting for age, sex, insurance amount, region, systemic corticosteroids, inhaled corticosteroids, immunosuppressive agents, hematopoietic stem cell transplant, solid-organ transplantation, hematological malignancy, metastatic malignancy, solid-organ malignancy, autoimmune diseases, immunodeficiency disorders, HIV, asthma, COPD, other chronic respiratory diseases, CKD stage 5 and ESRD, CKD stage 1–4, aplastic anaemia, myelodysplastic syndrome, diabetes with chronic complications, diabetes without chronic complications, liver cirrhosis/failure, heart failure, no. of admissions, no. of OPD visits, no. of admissions for ILI, and no. of OPD visits for ILI.

^b Hematopoietic stem cell transplant, solid-organ transplantation, immunodeficiency, hematological malignancy, systemic corticosteroids ≥44.1 cDDD, immunosuppressive agents.

^c Hematopoietic stem cell transplant, solid-organ transplantation, immunodeficiency and HIV, systemic corticosteroids ≥44.1 cDDD, immunosuppressive agents.

Table 3. The association between influenza vaccination and mortality of invasive aspergillosis.

Outcome	Deaths/vaccinated	Deaths/non-vaccinated	cOR (95% CI)	aOR^a (95% CI)
60-day mortality after admission	128/3,136,477	208/5,407,974	1.06 (0.85–1.32)	0.82 (0.65–1.04)
90-day mortality after admission	148/3,136,477	250/5,407,974	1.02 (0.83–1.25)	0.83 (0.67–1.03)

Abbreviations: cOR, crude odds ratio; aOR, adjusted odds ratio.

^a Adjusting for age, sex, insurance amount, region, systemic corticosteroids, inhaled corticosteroids, immunosuppressive agents, hematopoietic stem cell transplant, solid-organ transplantation, hematological malignancy, metastatic malignancy, solid-organ malignancy, autoimmune diseases, immunodeficiency disorders, HIV, asthma, COPD, other chronic respiratory diseases, CKD stage 5 and ESRD, CKD stage 1–4, aplastic anaemia, myelodysplastic syndrome, diabetes with chronic complications, diabetes without chronic complications, liver cirrhosis or failure, heart failure, no. of admissions, no. of OPD visits, no. for admissions for ILI and no. of OPD visits for ILI.

Table 4. Sensitivity analyses for the risks of invasive aspergillosis.

	Events/vaccinated	Events/non-vaccinated	cOR (95% CI)	aOR^a (95% CI)
Changing IA definition
IA with using antimycotic agents	324/3,136,469	611/5,407,950	0.91 (0.80–1.05)	0.81 (0.70–0.94)
Any pulmonary aspergillosis	227/3,136,347	469/5,407,756	0.84 (0.71–0.98)	0.72 (0.61–0.85)
Invasive pulmonary aspergillosis	84/3,136,226	169/5,407,502	0.86 (0.66–1.11)	0.81 (0.61–1.07)
Influenza-associated aspergillosis	20/3,136,160	48/5,407,386	0.72 (0.43–1.21)	0.52 (0.30–0.90)
Changing the end of follow-up
30-day after influenza season	388/3,137,728	739/5,409,913	0.91 (0.80–1.02)	0.77 (0.68–0.88)
Positive control outcome
Hospitalization with influenza	12,176/3,136,161	17,028/5,407,974	1.23 (1.21–1.26)	0.86 (0.84–0.88)
Hospitalization with ILI	191,269/3,128,774	240,164/5,407,974	1.40 (1.39–1.41)	0.87 (0.87–0.88)
Negative control outcome
Fracture	87,633/2,603,906	125,803/4,698,975	1.27 (1.26–1.28)	0.94 (0.93–0.94)^b

Abbreviations: cOR, crude odds ratio; aOR, adjusted odds ratio; IA, invasive aspergillosis; ILI, influenza-like illness.

^a Adjusting for age, sex, insurance amount, region, systemic corticosteroids, inhaled corticosteroids, immunosuppressive agents, hematopoietic stem cell transplant, solid-organ transplantation, hematological malignancy, metastatic malignancy, solid-organ malignancy, autoimmune diseases, immunodeficiency disorders, HIV, asthma, COPD, other chronic respiratory diseases, CKD stage 5 and ESRD, CKD stage 1–4, aplastic anaemia, myelodysplastic syndrome, diabetes with chronic complications, diabetes without chronic complications, liver cirrhosis/failure, heart failure, no. of admissions, no. of OPD visits, no. of admissions for ILI, and no. of OPD visits for ILI.

^b aOR (95% CI) was 1.00 (0.99–1.01) when the model was only adjusted for age, sex, insurance amount, and region.

Table 5. The association between influenza hospitalization and invasive aspergillosis.

	IA/influenza	IA/no influenza	cOR (95% CI)	aOR^a (95% CI)
Overall	68/30,181	1111/8,514,270	17.30 (13.54–22.11)	8.54 (6.64–10.99)

Abbreviations: cOR, crude odds ratio; aOR, adjusted odds ratio.

^a Adjusting for age, sex, insurance amount, region, systemic corticosteroids, inhaled corticosteroids, immunosuppressive agents, hematopoietic stem cell transplant, solid-organ transplantation, hematological malignancy, metastatic malignancy, solid-organ malignancy, autoimmune diseases, immunodeficiency disorders, HIV, asthma, COPD, other chronic respiratory diseases, CKD stage 5 and ESRD, CKD stage 1–4, aplastic anaemia, myelodysplastic syndrome, diabetes with chronic complications, diabetes without chronic complications, liver cirrhosis or failure, heart failure, no. of admissions, no. of OPD visits, no. for admissions for ILI and no. of OPD visits for ILI.

Data availability statement

The data that support the findings of this study are available from the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan; however, restrictions apply to the availability of these data, which were under approval for the current study, and therefore are not publicly available. The dataset used in this study was analysed in person at the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan.