Clinical Relevance of Diagnosing COPD by Fixed Ratio or Lower Limit of Normal: A Systematic Review

Figures & data

Figure 1.  Flowchart of articles progressing through the selection criteria.

Table 1.  Characteristics of studies that analyzed the associations between diagnostic criteria and clinical relevance

Study reference	Year	Population	Design	Number	Male (%)	Age (mean)	FEV1%	Criteria ratio	Post-BD	LLN reference
Progression
Akkermans ^35	2012	Referred from family doctor to diagnostic centre, Netherlands	prospective 3.4 yr	3,324	45%	>40 (58)	80%	Fixed, LLN	Yes	a, b, c, d, e, f
Acute events
Guder^5	2012	COPD diagnosed by family doctor, Netherlands	prospective 4.2 yr	405	55%	>65 (72)	82%	Fixed, LLN, expert diagnosis	Yes	b, c, g
Lizak^36	2011	^$CHF, Poland	prospective	178	83%	n/a (52)	n/a	Fixed, LLN	n/a	n/a
Mannino (1)^31	2007	General, USA (CHS)	prospective <11yr	4,965	43%	>65 (n/a)	n/a	Fixed, LLN	No	f
Mannino (2)^28	2012	General, USA (NHANES III)	prospective 12–18 yr	13,847	48%	>25 (n/a)	n/a	Fixed, LLN*	No	f, from study
Patient-reported outcomes
Ko^37	2008	Social centres, China	cross-sectional/retrospective 1yr	1,008	27%	>60 (74)	87%	Fixed, LLN	Yes	h
Lamprecht^32	2011	General, Austria (BOLD)	cross-sectional	1,258	54%	>40 (n/a)	95%	Fixed, LLN	Yes	f
Wang^33	2011	General, China	cross-sectional	2,055	n/a	n/a	n/a	Fixed, LLN	n/a	i
Acute events and patient-reported outcomes
Cerveri^29	2008	General, Europe (ECRHS)	prospective 9 yr	6,249	47%	20-44 (n/a)	106%	Fixed, LLN	No	from study
Garcia-Rio^30	2011	General, Spain (EPI-SCAN)	cross-sectional/retrospective 1yr	885	58%	40-80 (58)	101%	Fixed, LLN	Yes	j
Izquierdo^34	2012	Matched COPD(GOLD), prim. care, Spain (CONSISTE)	retrospective 1 yr	1,248	72%	>40 (63)	58%	Fixed, LLN	Yes	B

ECRHS: European Community Respiratory Health Survey; EPI-SCAN: Epidemiologic Study of COPD in Spain; CONSISTE: Consecuencias Sistémicas de la EPOC; NHANES: National Health and Nutrition Examination Survey; CHS: cardiovascular health study; BOLD: Burden of Obstructive Lung Disease. ^$CHF: cardiac heart failure, on list for transplantation; n/a not available; *LLN = FEV₁/FVC <LLN and FEV₁ <LLN.

^a Swanney MP, et al. Thorax 2008; 63(12):1046–1051; ^b Quanjer PH, et al. Eur Respir J Suppl 1993; 16:5–40; ^c Falaschetti E, et al. Eur Respir J 2004; 23(3):456–463; ^d Kuster SP, et al. Eur Respir J 2008; 31(4):860–868; ^e Brandli O, et al. Thorax 2000; 55(2):173–174; ^f Hankinson JL, et al. Chest 2010; 137(1):138–145; ^g Enright PL, et al. Chest 2006; 129(2):384–392; ^h Ip, et al. Chest 2006; 129(2):384–392; ⁱ Cerveri I, et al. Thorax 2008; 63(12):1040–1045; ^j Roca J, et al. Bull Eur Physiopathol Respir 1986; 22(3):217–224.

Table 2.  COPD prevalence and clinical relevance according to the different diagnostic criteria

	Fixed%	LLN%	Discordant	Outcomes studied	Method & statistics	Results	Bias	CEBM
Progression
Akkermans	27.6%	15.9%	11.7% fixed	FEV1-decline	(B) Random coefficient regression	Discordant similar to non-obstructed	2	1b
Acute events
Guder	60.2%	35–43%	17–25%	All-cause death, exacerbation, resp. hospital	(A) Univariate survival	Death: expert diagnosis better; Exacerbation: similar;Hospital: fixed ratio similar to little worse	2	1b
Lizak	n/a	n/a	n/a	All-cause death, all-cause/cardiac hospital	(A) X^2, Anova, K. Meier	Hospital: LLN stronger association	5	4
Mannino (1)	42.1%	19.3%	22.8% fixed	All-cause death, “COPD” hospitalization	(C) Survival*	Death: FEV1>80%; discordant similar to non-obstructed.Death: FEV1<80%; discordant similar to obstructed.Hospital: discordant in between.	2	1b
Mannino (2)	8.7%	6.5%	3.2% both	All-cause death, (respiratory death)	(C) Survival^#*	Discordant in between (LLN+ discordant unstable results)	2	1b
Patient-reported outcomes
Ko	25.9%	12.4%	13.5% fixed	Cough, sputum, wheeze, dyspnoea	(A) Logistic regression	Fixed ratio associated with dyspnoea only. LLN associated with both wheeze and dyspnoea (larger odds ratio).	2	2b
Lamprecht	24.2%	15.8%	9.5% both	Cough, phlegm, dyspnoea.Comorbidity (prevalence)	(B) X^2, Wilcoxon^#	Cough and phlegm: discordant similar to non-obstructed.Dyspnoea: similar to obstructed.Heart disease: discordant similar to obstructed.	2	2c
Wang	7.6%	6.9	0.7% fixed	Respiratory symptoms	(B) n/a	Discordant are all asymptomatic elderly	4	4
Acute events and patient-reported outcomes
Cerveri	4.3%	9.4%	5.1% LLN	Respiratory ED visit and/or hospitalization,dyspnoea medication, chronic cough/phlegm	(B) Two level Poisson regression	Hospital use/symptoms: LLN+discordant similar to obstructed. Medication: LLN+discordant in between	3	1b^
Garcia-Rio	10.2%	5.5%	4.6% fixed	Exacerbations, any hospitalization , SGRQ, EQ-5D, LCADL, mMRC,.Comorbidity (prevalence)	(C) Anova*	SGRQ: discordant in betweenEQ-5D: discordant in between/similar to mild obstructed.Rest: discordant in between/similar to non- & (mild) obstructed.	2	2b
Izquierdo	78%	59%	19% fixed	ED visits, (exacerbation-) hospitalization.Comorbidity (prevalence)	(B) Anova	Discordant similar to obstructed	2	2b

Discordant subjects are defined as presence of airflow obstruction according to one criterion but absent according to the other. If applicable, they are compared to the obstructed and non-obstructed subjects in the results section.

n/a: not available; (A): GOLD+ group compared to <LLN group, (B): discordant group compared to concordant goup(s), (C): discordant group compared to concordant goup(s) and according to disease severity (FEV₁%); * adjustments for both sex and age; ^# many patients with pulmonary restriction, which are analysed in a separate group; SGRQ: St. George respiratory questionnaire; EQ-5D: EuroQoL 5 Dimensions; LCADL: London Chest Activity of Daily Living; mMRC: modified medical research council dyspnoea scale; ED: emergency department; Anova: analysis of variance; CEBM: level of evidence; ^Due to the design, less than 80% of participants at baseline could be assessed for their outcomes.

Figure 2.  Airflow limitation according to the fixed ratio (FR) — and lower limit of normal (LLN) —.

Table 3.  Preference of diagnostic criteria according to different outcomes studied

	GOLD better(or discordant (fixed+) similar to obstructed)	In between(discordant (fixed+) between non- /obstructed)	LLN better (or discordant (fixed+)similar to non-obstructed)	No preference(no discordant analysisor statistics)
Progression
FEV1-decline	–	–	Akkermans	–
Mortality
All-cause death	Mannino(1)^(for FEV1 <80%)	Mannino(2)^(for FEV1 <80%)	Mannino(1)^(for FEV1 >80%)	Guder, [Lizak]
Health service use
(Any) hospitalization	Izquierdo	Mannino(1)	Garcia-Rio, [Lizak]	Guder
Exacerbation	–	Garcia-Rio	–	Guder
Any hospital use	Izquierdo	–	Cerveri	–
Patient-reported outcome
Respiratory symptoms	Lamprecht	Garcia-Rio	Cerveri, Lamprecht, Ko, [Wang]	–
Activity of daily living	–	–	Garcia-Rio	–
Dyspnoea medication	–	Cerveri	–	–
Health status	–	Garcia-Rio	–	–
Comorbidity	Lamprecht ^(CVD), Izquierdo	Garcia-Rio ^(CVD)	–	–

Each study represents a preference for that given outcome. Studies with CEBM #4 are between [ ]. Between ( ) are specific outcome restrictions. Discordant is based on fixed+ and LLN-, except for Cerveri (29): discordant based on fixed- and LLN+; Guder (5), Lizak (36) and Ko (37) did not separately analyze a discordant group; Mannino2 (28) and Lamprecht (32) separated out subjects with restrictive pulmonary function; Mannino2 (28), Garcio Rao (30) and Mannino1 (31) adjusted for both sex and age.