Forced Vital Capacity (FVC) decline, mortality and healthcare resource utilization in idiopathic pulmonary fibrosis

Figures & data

Table 1. Baseline characteristics of IPF patients

Trait		Value	MISSING, (%)
N		266
MALE (%)		64%
Age, years		74.3 ± 8.45
Follow-up time, years		3.03 ± 2.97
FVC % predicted		77 ± 20	7%
DLCO (mmol/min*kPa)		4.02 ± 1.27	49%
BMI kg/m^2*		27.8 ± 4.9	14%
Charlson index		2.1 ± 1.45
Baseline 6 min walking test (m)		335 ± 139	80%
Any 6 min walking test (m)**		349 ± 136	65%
Baseline FVC	FVC>90% pred.; N (%) FVC % predicted	64 (24%) 102 ± 10
	FVC 50-90% pred.; N (%) FVC % predicted	167 (63%) 72 ± 11
	FVC <50% pred.; N (%) FVC % predicted	17 (6%) 39 ± 8
	FVC unknown; N (%) FVC % predicted	18 (7%) NA
Baseline smoking status *	Former, (%)	31%
	Current smoker, (%)	20%
	Never smoked, (%)	41%
	Smoking status unknown, (%)	9%
End of follow up type	Alive 31.12.2017, (%)	41%
	Antifibrotic medication initiated, (%)	16%
	Dead, (%)	42%

*text-mined. Data presented as mean±SD if not otherwise indicated; **complementing baseline data with data from any time during follow-up; value closest to baseline used if multiple values were present

Figure 1. FVC (% predicted) at diagnosis by calendar year

Table 2. Time to change of FVC category according to baseline status, Kaplan-Meier analysis

Baseline value
Event value		FVC>90% ↓ <90%	FVC >90% ↓ <50%	FVC 50-90% ↓ <50%
N total		64	64	166
Time to event, years; median [95% CI]		2.4 [1.1–3.1]	4.9 [3.1 – NA]	4.0 [2.8–5.4]
Event	FVC below event value, N (%)	42 (66%)	1 (1.6%)	30 (18%)
	Dead, N (%)	9 (14%)	21 (33%)	43 (26%)
	Transplant, N (%)	0	0	0
Censoring	End of follow-up [FVC remained above event value], N (%)	11 (17%)	37 (58%)	60 (36%)
	Antifibrotic treatment initiated, N (%)	1 (1.6%)	4 (6.3%)	32 (19%)
	Lost to follow-up, N (%)	1 (1.6%)	1 (1.6%)	1 (0.6)

Figure 2. Overall survival of IPF patients (left) and stratified by baseline FVC (right) to FVC>90%; 50-90%; <50% predicted; and unknown FVC. Time is in years. Censoring events: antifibrotic treatment initiation, lost to follow-up, end of follow-up

Figure 3. Cox regression analysis of overall mortality in IPF patients. FVC group was used as a time-varying covariable. BMI-body mass index, OCS-oral corticosteroid

Figure 4. a) Hospital inpatient days, out-patient visits and emergency room visits (ER) per patient-year, stratified by FVC category. b) Overall healthcare resource utilization related costs (€) per patient-year, at specialty care of IPF patients, stratified by FVC category or lung transplant. The incremental costs per worsening category compared to FVC>90% predicated are presented on top of/in bars with grey

Table A1. Text patterns used to select the IPF patient cohort form the initial cohort of 993 patients with J84.1 or J84.9 diagnoses

Image text statements	Pro IPF: honeycomb, UIP, IPF, idiopathic pulmonary fibrosis, traction bronchiectasis, reticular opacities Against IPF: NSIP-, COP-, LIP, alveolitis, asbestosis, stone dust lung, silicosis, eosinophilic pneumonia, hypersensitivity pneumonia, emphysema
Pathology statement text of lung biopsy	Pro IPF: fibroblast focus, honeycomb, UIP, IPF, idiopathic pulmonary fibrosis Against IPF: unspecific/granulomatous inflammation, eosinophilia, NSIP, COP, LIP, DIP, bronchiolitis, hypersensitivity pneumonia
Clinical diagnosis from lung view of EMR	Pro IPF: honeycomb, UIP, IPF, idiopathic pulmonary fibrosis, progressive restrictive lung disease/fibrosis, auscultation inspiratory rasping sound of small alveoli, no autoimmune antibodies, ANCA antibodies not elevated, ANA antibodies not elevated, ENA antibodies not elevated, rheumatoid factor not elevated, citrulline antibodies not elevated, DNA antibodies not elevated, ssDNA antibodies not elevated, SS-A antibodies not elevated, SS-B antibodies not elevated, anti SM not elevated, nucleus antibodies not elevated, MPO antibodies not elevated Against IPF: Rheumatoid arthritis, SLE, MCTD, Sjögren syndrome, scleroderma, myositis, autoimmune fibrosis, fibroelastosis, bronchiolitis, NSIP, COP, LIP, DIP, asbestosis, significant asbestos exposure, hypersensitivity pneumonia, radiation pneumonitis, condition after radiation, vasculitis, eosinophilic pneumonia, autoimmune antibodies elevated, ANCA antibodies elevated, ANA antibodies elevated, ENA antibodies elevated, rheumatoid factor elevated, citrulline antibodies elevated, DNA antibodies elevated, ssDNA antibodies elevated, SS-A antibodies elevated, SS-B antibodies elevated, anti SM elevated, nucleus antibodies elevated, MPO antibodies elevated

All text patterns were searched in Finnish (as the patient texts are written in Finnish), including plausible different writing forms, most common typing errors and different ways of specifying negative phrases. The performance of text mining cohort formation was assessed by manual validation of randomly selected patients included and excluded from the cohort, and by assessing use of IPF specific antifibrotic medications (pirferidone or nintedanib), see material and methods.

Table A2. Comorbidities in IPF patients at end of follow-up and their frequency in the patients at baseline

ICD10	End of follow-up	Baseline	Description
J84	100%	100%	Other interstitial pulmonary diseases
R91	59%	40%	Abnormal findings on diagnostic imaging of lung
I10	48%	33%	Essential (primary) hypertension
J18	41%	16%	Pneumonia, organism unspecified
R06	35%	27%	Abnormalities of breathing
H25	33%	17%	Senile cataract
Z01	29%	21%	Other special examinations and investigations of persons without complaint or reported diagnosis
I25	27%	19%	Chronic ischaemic heart disease
E11	25%	18%	Non-insulin-dependent diabetes mellitus
Z03	23%	11%	Medical observation and evaluation for suspected diseases and conditions
E78	22%	14%	Disorders of lipoprotein metabolism and other lipidaemias
I48	21%	12%	Atrial fibrillation and flutter
I50	20%	6%	Heart failure
R05	18%	15%	Cough
G47	17%	11%	Sleep disorders
H90	15%	11%	Conductive and sensorineural hearing loss
N40	15%	11%	Hyperplasia of prostate
J44	15%	8%	Other chronic obstructive pulmonary disease
J92	15%	8%	Pleural plaque
M17	14%	13%	Gonarthrosis [arthrosis of knee]
Z71	14%	8%	Persons encountering health services for other counselling and medical advice, not elsewhere classified
R10	14%	8%	Abdominal and pelvic pain
M16	12%	10%	Coxarthrosis [arthrosis of hip]
R07	12%	7%	Pain in throat and chest
I20	12%	8%	Angina pectoris
J96	12%	2 %	Respiratory failure, not elsewhere classified
K21	12%	7%	Gastro-oesophageal reflux disease
Z95	11%	7%	Presence of cardiac and vascular implants and grafts
I21	11%	4 %	Acute myocardial infarction
C44	11%	8%	Other malignant neoplasms of skin
E03	11%	8%	Other hypothyroidism
J45	11%	8%	Asthma
L57	10%	6%	Skin changes due to chronic exposure to nonionizing radiation
M54	10%	5 %	Dorsalgia
Z76	10%	6%	Persons encountering health services in other circumstances

Table A3. Cox regression of overall mortality, with baseline FVC as time-varying class variable (multivariable 1) or continuous variable (multivariable 2)

		Univariable			Multivariable (1)			Multivariable (2)
		HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
FVC (continuous, time-varying)		0.96	0.95–0.98	<0.001				0.96	0.95–0.97	<0.001
FVC class (time-varying)	>90%	1	ref.	–	1	ref.	–
	50-90%	1.77	0.87–3.61	0.114	1.98	0.91–4.28	0.084
	<50%	5.58	2.64–11.81	<0.001	8.75	3.79–20.18	<0.001
	Transplanted	2.03	0.25–16.81	0.511	NA*	NA*	NA*
	Unknown	17.36	7.47–40.32	<0.001	15.02	4.94–45.71	<0.001
Age		1.04	1.02–1.07	<0.001	1.04	1.01–1.07	0.013	1.04	1.01–1.07	0.018
Sex	Male	1	ref.	–	ref.	–	–	ref.	1
	Female	0.59	0.39–0.88	0.010	0.72	0.43–1.20	0.209	0.82	0.48–1.40	0.466
BMI	<20	3.06	1.23–7.60	0.016	4.38	1.64–11.74	0.003	2.92	1.02–8.31	0.045
	20-25	1	ref.	–	1	ref.	–	ref.	1
	25-30	0.95	0.56–1.60	0.833	1.16	0.67–2.01	0.596	1.19	0.66–2.16	0.561
	≥30	0.84	0.48–1.46	0.529	0.86	0.48–1.55	0.617	0.95	0.51–1.77	0.868
Smoking	Non-smoker	1	ref.	–	1	ref.	–	ref.	1
	former	1.41	0.92–2.16	0.114	1.44	0.83–2.52	0.195	1.24	0.70–2.20	0.463
	Current	0.58	0.33–1.03	0.063	0.79	0.39–1.58	0.500	0.75	0.38–1.49	0.412
	Missing	0.69	0.34–1.42	0.319	1.18	0.80–4.15	0.156	1.33	0.57–3.12	0.507
Charlson index		1.11	0.97–1.28	0.127	0.98	0.82–1.16	0.785	1.07	0.9–1.28	0.452
BL OCS	No	1	ref.	–	1	ref.	–	ref.	1
	Yes	2.03	1.38–3.00	<0.001	1.61	1.03–2.49	0.035	1.55	0.98–2.45	0.062

NA* patients with lung transplant dropped due to missing covariate values, BL- baseline, OCS-oral corticosteroids.

Table A4. Overall healthcare resource utilization related costs per FVC or lung transplant categories

HCRU TYPE	CLASS	EVENTS, N	COST, €	EVENTS PER PATIENT YEAR	COST PER PATIENT YEAR, €
OUTPATIENT VISITS	ALL	8,817	885,219	10.91	1,095.53
	FVC >90%	1,380	137,768	9.49	947.43
	FVC 50-90%	5,567	557,783	10.42	1,043.94
	FVC <50%	1,218	124,907	11.52	1,181.68
	Transplant	538	53,257	50.78	5,026.36
	Unknown FVC	114	11,504	9.49	957.57
ER VISITS	ALL	804	156,780	1.00	194.03
	FVC >90%	105	20,475	0.72	140.81
	FVC 50-90%	482	93,990	0.90	175.91
	FVC <50%	156	30,420	1.48	287.79
	Transplant	20	3,900	1.89	368.08
	Unknown FVC	41	7,995	3.41	665.49
HOSPITAL INPATIENT DAYS	ALL	4,451	1,755,334	5.51	2,172.36
	FVC >90%	528	198,155	3.63	1,362.71
	FVC 50-90%	2,363	887,994	4.42	1,661.96
	FVC <50%	1,084	469,430	10.26	4,441.03
	Transplant	124	48,637	11.70	4,590.34
	Unknown FVC	352	151,118	29.30	12,578.79
PROCEDURES	ALL	2,638	844,370	3.26	1,044.97
	FVC >90%	418	124,346	2.87	855.12
	FVC 50-90%	1,605	517,056	3.00	967.72
	FVC <50%	464	162,389	4.39	1,536.28
	Transplant	73	18,311	6.89	1,728.23
	Unknown FVC	78	22,267	6.49	1,853.50
OPERATIONS	ALL	266	369,096	0.33	456.78
	FVC >90%	38	49,381	0.26	339.59
	FVC 50-90%	169	245,081	0.32	458.69
	FVC <50%	50	64,719	0.47	612.27
	Transplant	3	4,150	0.28	391.68
	Unknown FVC	6	5,765	0.50	479.87
IMAGING ETC	ALL	4,787	445,906	5.92	551.84
	FVC >90%	620	58,040	4.26	399.14
	FVC 50-90%	3,036	275,254	5.68	515.16
	FVC <50%	866	80,164	8.19	758.39
	Transplant	145	18,875	13.69	1,781.42
	Unknown FVC	120	13,573	9.99	1,129.80
LABS	ALL	117,216	251,783	145.06	311.60
	FVC >90%	14,440	27,268	99.30	187.52
	FVC 50-90%	63,966	130,236	119.72	243.75
	FVC <50%	26,138	61,400	247.28	580.87
	Transplant	6,852	17,487	646.69	1,650.44
	Unknown FVC	5,820	15,392	484.45	1,281.19
TOTAL COSTS	ALL	–	4,708,488	–	5,827.12
	FVC >90%	–	615,433	–	4,232.32
	FVC 50-90%	–	2,707,395	–	5,067.13
	FVC <50%	–	993,429	–	9,398.31
	Transplant	–	164,617	–	15,536.55*
	Unknown FVC	–	227,614	–	18,946.20

*including post-transplant care only.