Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency

Figures & data

Figure 1. Impact of treatments on disease progression (9). This figure shows the hypothetical effects of symptomatic and disease-modifying treatments on disease progression in early-start and delayed-start trial models. Disease-modifying treatments provide a sustained alteration in disease progression. Reprinted from COPD: Journal of Chronic Obstructive Pulmonary Disease. Halpin and Tashkin. Defining Disease Modification in Chronic Obstructive Pulmonary Disease. COPD 2009: 6: 211–213 with permission of the publisher Taylor & Francis Ltd (www.tandfonline.com).

Table 1. Summary of outcome measures used to monitor COPD and emphysema progression (9, 39, 41, 43, 44, 69).

Outcome measure	Method/measurement	Rationale for use	Advantages	Disadvantages
Physiological parameters
FEV1	Spirometry	The traditional hallmark of COPD was respiratory flow limitation that declines over time	Repeatable measureAccessible/non-invasive	FEV1 changes slowly over time – not easily modified by interventionsIntra-subject variabilityPoor correlation with other endpoints (e.g., mortality, exacerbations)
Bronchoalveolar lavage (BAL)/bronchial biopsy	Measurement of inflammatory changes	Increase in inflammatory cells (e.g., neutrophils, macrophage and CD4/CD8 T lymphocytes) has been demonstrated as disease progresses	Accurate marker of disease progression	InvasiveLack of standardisation (BAL fluid)
Induced sputum	CytokinesChemokines	The presence of cytokines/chemokines is a marker of inflammation	Easy procedureWell-tolerated	Long-term reproducibility unknownPredominantly samples from large but not small airwaysProcedure can induce inflammatory responseSolubilisation procedure can interfere with other cytokine/chemokine radioimmune assays
Exhaled air	NOCOVolatile hydrocarbons (alkanes, pentanes, ethane)	Presence of inhaled gases such as NO, CO and hydrocarbons is a marker of inflammation	Readily accessibleRepeatable	Levels of NO/CO may be only slightly elevated in COPD Long-term reproducibility unknown. Lack of standardisationLittle known regarding correlation with long-term disease progression
Patient-centric outcomes
Dyspnoea	Baseline dyspnoea indexTransition dyspnoea index	Dyspnoea is a clinically important and recognised measure of respiratory and activity limitation	Simple to performRepeatableCorrelates to lung function and mortality	Dyspnoea worsens over time and changes due to intervention can be maskedStandardisation and validity have been questioned
HRQL	SGRQ	HRQL has been shown to worsen over time and show improvements with treatment	Simple to monitor	Reflects effects/symptoms of the disease rather than the disease itselfDepends on accurate patient reporting
Exercise capacity	6-minute walk testCycloergometry testConstant work rate submaximal exercise test	Activity levels have been shown to worsen over time with COPD progression and have shown variable improvements with treatment	Constant work rate submaximal exercise test is repeatable	Measures such as 6-minute walk test show poor repeatability due to learning effect and effort differences
Exacerbations	Patient and/or physician reports of frequency and/or severity	Exacerbations have been shown to worsen over time and show improvements with treatments	Easy to measure	Frequency can vary over time and with different disease stagesDepends on accurate patient reporting
Imaging techniques
CT	Lung densitometry	Accepted by the FDA as a highly sensitive measure for monitoring emphysema progression	ReproducibleHighly sensitiveCorrelates to other surrogate markers (e.g., FEV1, exacerbation, mortality)	ExpenseNot routine in hospital/clinicsEthical discussion regarding exposure to radiation
Mortality
Mortality rate	Physician report	Ultimate measure of disease progression	Useful for studies in disease populations	Not suitable for monitoring disease progression in individual patientsCo-morbidities may affect mortality rate

Outcome measures used in several studies to monitor disease progression in COPD and emphysema together with their advantages and disadvantages for use are shown.

CO, carbon monoxide; COPD, chronic obstructive pulmonary disease; CT, computed tomography; FEV₁, forced expiratory volume in 1 second; HRQL, health-related quality of life; NO, nitric oxide; SGRQ, St George's respiratory questionnaire.

Figure 2. RAPID and RAPID Extension trial design. This figure shows the design of the RAPID trial; subjects in RAPID received A₁-PI or placebo for 2 years. During the RAPID Extension trial all non-US subjects received A₁-PI for a further 2 years.

Figure 3. Disease modification in the RAPID and RAPID Extension trials (10). Graph showing the annualised rate of decline in physiologically adjusted P15 (g/L) at TLC over 48 months (ITT population). Reprinted from The Lancet, Vol 386. Chapman, KR et al., Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial, pp. 360–368. Copyright (2015), with permission from Elsevier.

Halpin DM, Tashkin DP. Defining disease modification in chronic obstructive pulmonary disease. COPD 2009; 6(3):211–225.

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Chapman KR, Burdon JGW, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 386:360–368.

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