Association of Oxygen Therapy with the Natural Disease Progression of Cystic Fibrosis: A Multi-State Model of the European Cystic Fibrosis Society Patient Registry

Figures & data

Figure 1 Multi-state model for pwCF: arrows denote direction of transition probabilities (T): from alive without LTx to alive with LTx (T1) or to death (T2); and from alive with LTx to death (T3).

Table 1 Main Demographic and Clinical Characteristics of the 48,343 Considered pwCF

	Total N=48343		Room Air N=45408		Oxygen Therapy N=2935		OR (95% CI)	P-value
	Missing	n (%)	Missing	n (%)	Missing	n (%)
Sex (male)		25,516 (52.78%)		24,103 (53.08%)		1413 (48.14%)	0.82 (0.76–0.88)	<0.001
Age
6–11		18,036 (37.31%)		17,702 (38.98%)		334 (11.38%)	(reference)
12–24		17,708 (36.63%)		16,482 (36.30%)		1226 (41.77%)	3.94 (3.49–4.46)	<0.001
25–34		7775 (16.08%)		6941 (15.29%)		834 (28.42%)	6.37 (5.60–7.26)	<0.001
35–50		4824 (9.98%)		4283 (9.43%)		541 (18.43%)	6.69 (5.82–7.71)	<0.001
CFTR genotype
Mild		6158 (12.74%)		6004 (13.22%)		154 (5.25%)	(reference)
Severe		33,813 (69.94%)		31,613 (69.62%)		2200 (74.96%)	2.71 (2.31–3.21)	<0.001
Unknown		8372 (17.32%)		7791 (17.16%)		581 (19.80%)	2.91 (2.43–3.49)	<0.001
FEV1 z-score < LLN	6581	20,923 (50.10%)	6154	18,572 (47.31%)	427	2351 (93.74%)	16.68 (14.22–19.70)	<0.001
BMI < nutritional goal	3605	28,751 (64.27%)	3330	26,493 (62.96%)	275	2258 (84.89%)	3.30 (2.97–3.69)	<0.001
Chronic Pseudomonas aeruginosa	11,912	11,388 (31.26%)	10,840	10,135 (29.32%)	1072	1253 (67.26%)	4.95 (4.49–5.47)	<0.001
Use of pancreatic enzymes	2552	37,638 (82.20%)	2326	35,061 (81.38%)	226	2577 (95.13%)	4.47 (3.76–5.35)	<0.001
CFRD	4095	5920 (13.38%)	3636	4899 (11.73%)	459	1021 (41.24%)	5.28 (4.85–5.75)	<0.001
Chronic Burkholderia cepacia complex	12,095	1032 (2.85%)	11,035	907 (2.64%)	1060	125 (6.67%)	2.64 (2.16–3.18)	<0.001
Pneumothorax	5718	341 (0.80%)	4968	234 (0.58%)	750	107 (4.90%)	8.85 (6.99–11.14)	<0.001
Hemoptysis (>250mL)	5337	912 (2.12%)	4592	720 (1.76%)	745	192 (8.77%)	5.35 (4.53–6.30)	<0.001

Notes: The number of patients and the percentage (in brackets) were reported unless otherwise stated. Functional grouping as mild/severe was based on published data from the CFTR2 project (www.cftr2.org).

Abbreviations: CFTR, Cystic Fibrosis Transmembrane Regulator; CFRD, Cystic Fibrosis-related Diabetes; FEV₁, Forced Expiratory Volume in the first second; LLN, lower limit of normal; BMI, Body Mass Index.

Figure 2 Percentage of pwCF on OT, stratified by year of follow-up, age class and economic status. Low income: Albania, Armenia, Bulgaria, Czech Republic, Greece, Croatia, Hungary, Latvia, Lithuania, North Macedonia, Republic of Moldova, Poland, Portugal, Romania, Russian Federation, Serbia, Slovak Republic, Slovenia, Turkey, Ukraine; high income: Austria, Belgium, Denmark, France, Germany, Ireland, Israel, Italy, Luxembourg, The Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom.

Figure 3 Probabilities of moving from state 1 (alive without LTx) to state 2 (alive with LTx) or state 3 (death) (upper panels) and probabilities for pwCF moving from state 2 to state 3 (lower panels), according to treatment with supplemental oxygen in pwCF at 20 years of age. Adjusting covariates are held constant at the most frequent occurrence.

Table 2 Adjusted Hazard Ratio (HR) for the Transition Probabilities from the Multi-State Model

	Alive without LTx-->Alive with LTx		Alive without LTx-->Death		Alive with LTx -->Death
	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value
Exposure to oxygen therapy	5.78 (5.32–6.29)	<0.001	4.32 (3.93–4.76)	<0.001	1.75 (1.41–2.16)	<0.001
FEV1 z-score (<LLN vs ≥ LLN)	6.41 (5.28–7.79)	<0.001	5.00 (4.11–6.08)	<0.001	1.63 (1.18–2.25)	0.003
Age at diagnosis
1–18 years vs <1 year	0.96 (0.88–1.05)	0.342	0.79 (0.72–0.88)	<0.001	0.82 (0.67–0.99)	0.043
>18 years vs <1 year	0.85 (0.67–1.08)	0.185	0.60 (0.46–0.78)	<0.001	0.53 (0.28–1.00)	0.051
Sex (male vs female)	0.81 (0.74–0.87)	<0.001	0.83 (0.75–0.91)	<0.001	0.95 (0.79–1.13)	0.547
CFTR Genotype
Severe vs mild	1.76 (1.35–2.28)	<0.001	1.07 (0.83–1.37)	0.611	0.62 (0.36–1.07)	0.086
Unknown vs mild	1.67 (1.27–2.19)	<0.001	2.55 (1.98–3.28)	<0.001	1.03 (0.58–1.84)	0.909
BMI nutritional goal (< nutritional goal vs ≥ nutritional goal)	2.20 (1.94–2.49)	<0.001	1.33 (1.18–1.50)	<0.001	1.00 (0.77–1.31)	0.975
CFRD (yes vs no)	1.11 (1.01–1.23)	0.029	1.63 (1.47–1.81)	<0.001	1.39 (1.15–1.67)	0.001
Chronic Pseudomonas aeruginosa (yes vs no)	1.25 (1.14–1.37)	<0.001	1.78 (1.60–1.98)	<0.001	0.93 (0.77–1.12)	0.438
Chronic Burkholderia cepacia complex (yes vs no)	1.00 (0.82–1.21)	0.967	3.19 (2.78–3.67)	<0.001	0.90 (0.54–1.50)	0.689
Use of pancreatic enzymes (yes vs no)	1.71 (1.35–2.15)	<0.001	1.72 (1.37–2.18)	<0.001	2.44 (1.26–4.70)	0.008
History of pneumothorax (yes vs no)	1.92 (1.55–2.39)	<0.001	1.62 (1.24–2.12)	<0.001	0.87 (0.53–1.44)	0.595
History of hemoptysis >250mL (yes vs no)	1.77 (1.53–2.05)	<0.001	1.08 (0.88–1.32)	0.470	1.44 (1.06–1.96)	0.021
Country (low vs high income)	0.63 (0.52–0.76)	<0.001	1.94 (1.69–2.23)	<0.001	0.99 (0.58–1.67)	0.965

Notes: Data are presented as hazard ratios with 95% Confidence Intervals (CI). Functional grouping as mild/severe was based on published data from the CFTR2 project (www.cftr2.org).

Abbreviations: FEV₁, Forced Expiratory Volume in the first second; LLN, lower limit of normal; CFTR, Cystic Fibrosis Transmembrane Regulator; CFRD, Cystic Fibrosis-related Diabetes; BMI, Body Mass Index.

Figure 4 Probabilities to move from state 1 (alive without LTx) to state 2 (alive with LTx) or state 3 (death) (upper panels) and probabilities for pwCF to move from state 2 to state 3 (lower panels), according to GNI in pwCF at 20 years of age. Adjusting covariates are held constant at the most frequent occurrence.