An analysis of the degree of concordance among international guidelines regarding alpha-1 antitrypsin deficiency

Figures & data

Table 1 Alpha-1 antitrypsin deficiency (AATD) guidelines analyzed in this study

Year	Guideline title	Reference
1989	Guidelines for the approach to the patient with severe hereditary alpha-1-antitrypsin deficiency - American Thoracic Society	^Citation1
1997	Alpha-1 antitrypsin deficiency: memorandum from a WHO meeting	^Citation5
2001	Alpha-1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society*	^Citation3
2003	American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency	^Citation2
2006	Guidelines for the Diagnosis and Management of Alpha-1 Antitrypsin Deficiency Recommendations of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR)*	^Citation6
2006	α1-Antitrypsin Deficiency: Situation in Spain and Development of a Screening Program*	^Citation7
2009	Belgian Guidelines for Diagnosis and Management of Patients with α1-Antitrypsin Deficiency	^Citation8
2012	Alpha-1 in the European Union Expert Recommendations	^Citation9
2012	Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: A Canadian Thoracic Society clinical practice guideline*	^Citation4
2014	Guidelines on Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency Argentina Association of Respiratory Medicine*	^Citation10
2015	Activity of the Alpha-1 Antitrypsin Deficiency Registry in Belgium	^Citation11
2015	Indications for Active Case Searches and Intravenous Alpha-1 Antitrypsin Treatment for Patients With Alpha-1 Antitrypsin Deficiency Chronic Pulmonary Obstructive Disease: An Update (SEPAR)*	^Citation12
2016	The Diagnosis and Management of Alpha-1 Antitrypsin Deficiency in the Adult. Journal of the COPD Foundation Clinical Practice Guidelines	^Citation15
2016	Standards for diagnosis and care of patients with inherited alpha-1 antitrypsin deficiency. Recommendations of the Polish Respiratory Society, Polish Society of Pediatric Pulmonology and Polish Society of Pediatric Gastroenterology	^Citation13
2017	European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency	^Citation14

Note: *Denotes that the guideline is published in two languages with an English version available.

Table 2 Individual clinical statements and adjudicated guideline ratings

		Number of guidelines receiving each rating
	Clinical statement	Y	YC	Eq/NC	N
When to test
S1	Only patients with suggestive features of AAT deficiency should be tested (eg prominent basilar hyperlucency, <20 pack years smoking with emphysema, emphysema at a young age [eg, <40 years old])	2	0	3	10
S2	Patients with a diagnosis of COPD and/or fixed airflow obstruction (FEV1/FVC ratio <0.70) on PFTs should be tested.	11	0	2	2
S3	Patients with airflow obstruction that is fully reversible with bronchodilators should be tested (ie pure “asthma”).	2	1	3	9
S4	Patients with unexplained bronchiectasis should be tested.	5	3	6	1
S5	Patients with unexplained liver disease should be tested.	7	1	7	0
S6	Patients with panniculitis should be tested.	7	0	8	0
S7	Patients with c-ANCA vasculitis should be tested.	5	2	8	0
S8	All first-degree relatives (children, siblings, parents) of severely deficient homozygotes should be tested.	8	2	5	0
S9	All non-first-degree relatives, including partners, of homozygotes should be tested.	3	3	9	0
S10	Neonatal screening should be undertaken (ie all newborns tested).	0	3	10	2
How to test
S11	Initial testing should include a serum AAT level.	13	0	2	0
S12	Testing should always include both a level and genotype/phenotype. (ie, a genotype/phenotype should be performed irrespective of the AAT level)	2	2	2	9
How to Manage
S13	I should get a CT chest at baseline.	3	1	11	0
S14	I should get serial PFTs on my patients.	7	0	8	0
S15	I should get a liver ultrasound on my patients at baseline.	3	1	11	0
S16	I should administer hepatitis A and B vaccinations.	2	5	6	2
S17	I should get serial LFT testing on my patients.	3	3	9	0
S18	I should refer my patient to a pulmonologist and/or tertiary center.	2	1	12	0
S19	My patient should be encouraged to participate in an AAT registry.	10	0	5	0
S20	I should encourage smoking cessation.	12	0	3	0
When to treat/augment therapy
S21	I should only treat when the serum AAT level is below a protective threshold value (ie, <11 uM) and/or when there is a severe deficient genotype/phenotype.	12	0	3	0
S22	I should treat patients only when some degree of airflow obstruction is present (eg, FEV1 30–60%).	7	4	4	0
S23	I should treat patients with panniculitis as first-line therapy.	2	0	13	0
How to treat/augment therapy
S24	I should treat only with a dose of 60 mg/kg once weekly.	5	1	7	2

Abbreviations: Y, yes; YC, yes, conditional; Eq/NC, equivocal/no comment; N, no; AAT, alpha-1 antitrypsin; PFT = pulmonary function testing. LFT = liver function test.

Table 3 Four rating categories applied to each of the 24 clinical statements for each guideline

Rating	Definition/meaning	Example
Yes (Y)	There is a clear recommendation for the action described in the clinical statement.	For clinical statement Question 22, augmentation therapy should be recommended for individuals with established fixed airflow obstruction, the 2015 Spanish guidelines “Indications for Active Case Searches and IV AAT Treatment for Patients with AAT COPD: An Update (Spain guidelines) 2015” clearly endorses intravenous augmentation therapy.
Yes, conditional (YC)	The recommendation for the action requires an additional decision or that an additional criterion be satisfied.	The 2003 American Thoracic Society/European Respiratory Society guideline states that testing adults with bronchiectasis for AATD should be undertaken only when an alternative cause for bronchiectasis has not been identified. The 2009 Belgian Thoracic Society guideline endorses “considering a baseline chest CT.” The European Union recommends population screening for AATD only when three conditions are met, ie, the prevalence of AATD in the population is high (≥1/1500 or more), smoking is prevalent, and adequate counselling services are available (7).
Equivocal/No Comment (Eq/NC)	The guideline does not mention or address the topic of the clinical statement or if the issue in the statement is addressed in the guideline, there is no definitive position stated.	Many guidelines do not make mention of whether patients with necrotizing panniculitis should be tested, and several guidelines do not make a specific recommendation to encourage smoking cessation. As another example, the 2006 Spanish guideline’s statement regarding treatment of panniculitis with augmentation therapy reads “The possible benefits … in the management of other less common manifestations of AAT deficiency, such as panniculitis, are not documented.” (8)
No (N)	The guideline specifically advises against the clinical practice.	Examples include Grade C or D recommendations in the American Thoracic Society/European Respiratory Society guidelines. Also, the Canadian Thoracic Society recommends against testing for AATD in individuals with unexplained bronchiectasis.

Abbreviations: AAT, alpha-1 antitrypsin; AATD, alpha-1 antitrypsin deficiency.

Table 4 Parameters for quantifying guideline agreement

Terminology	Definition and example
Internal discordance	Definition: Conflicting recommendations within an individual guideline, usually found between the text and a table/graph. In this situation, we favored the recommendations from the text.
	Example: The European Respiratory Society guideline stated in the text that, “The role of CT in the follow-up of patients in routine clinical practice requires further validation.” However, one figure in this guideline listed CT as part of an algorithm to treat patients with AATD. The recommendation from this guideline was ultimately rated as Eq/NC in stating whether a baseline CT chest should be ordered given the fact that the text does not explicitly endorse the practice.
Agreement percentage	Definition: For each clinical statement, 3 reviewers reviewed a guideline independently and then together reaching an adjudicated rating (Y, YC, Eq/NC, N). The proportion of guideline comparisons matching on the rating for the same clinical statement.
	Example: The statement that clinicians should treat only with a dose of 60 mg/kg once weekly (S24: How Treat 1) resulted in the following ratings: Y =5, YC =1, Eq/NC =7, N=2 contributing 10, 0, 21, and 1 matching guideline comparisons, respectively, for a total of 32. Thus, the agreement percentage for this statement is 32/105 (30.5%) (Figure S1).
Affirmative agreement percentage	Definition: For each clinical statement, the proportion of guideline comparisons matching on a rating endorsing an action (with or without an added condition, Y + YC).
	Example: The statement that clinicians should treat only with a dose of 60 mg/kg once weekly (S24: How Treat 1) resulted in the following ratings: Y=5, YC=1, Eq/NC =7, N=2 contributing 10, 0, 21, and 1 matching guideline comparisons, respectively, for a total of 10 Y + YC. Thus, the affirmative agreement percentage for this statement is 10/105 (9.5%) (Figures S1–S3).
Negative agreement percentage	Definition: For each clinical statement, the proportion of guideline comparisons matching on a rating disapproving an action (N).
	Example: The statement that clinicians should treat only with a dose of 60 mg/kg once weekly (S24: How Treat 1) resulted in the following ratings: Y=5, YC =1, Eq/NC =7, N=2 contributing 10, 0, 21, and 1 matching guideline comparisons, respectively, for a total of 1 N. Thus, the negative agreement percentage for this statement is 1/105 (1%) (Figure S3).

Abbreviations: Y, yes; YC, yes, conditional; Eq/NC, equivocal/no comment; N, no; AATD, alpha-1 antitrypsin deficiency.

Table 5 Number of matching guideline comparisons (“overall guideline agreement percentage”)

Number of guidelines receiving rating	Number of matching guideline comparisons
0	0
1	0
2	1
3	3
4	6
5	10
6	15
7	21
8	28
9	36
10	45
11	55
12	66
13	78
14	91
15	105

Notes: To better understand the concept of “overall guideline agreement percentage,” consider a clinical statement where none of the 15 guidelines were rated “Yes.” It would be impossible for a guideline comparison to match on a “Yes” rating for that statement and the number of matches is 0. Now consider a clinical statement where only 1 of the 15 guidelines was rated “Yes.” Again, it would be impossible for a guideline comparison to match on a “Yes” rating for that statement and the number of matches is 0. Finally, consider a clinical statement where 2 of the 15 guidelines were rated “Yes.” It would now be possible for a guideline comparison to match on a “Yes” rating, but there is only one such comparison for which this would occur and the number of matches is 1. This table lists the number of matching guideline comparisons as the number of guidelines receiving a particular rating increases from 0 to 15. Guideline concordance, therefore, is measured with a parameter called the “overall guideline agreement percentage,” which is the proportion of all guideline comparisons matching on the rating for the same clinical statement (example in Table 4).

Figure 1 PRISMA flow diagram. Medline and Embase were searched using search terms “alpha-1 antitrypsin deficiency,” “COPD,” and “guidelines.” Eligible guidelines were published in English and were issued by official respiratory organizations/medical societies and/or by national organizations.

Table 6 Overall guideline agreement percentage and by rating bundle (ie, when to test, etc.)

	Number of statements	Number of comparisons	Number of matching comparisons	Agreement percentage	Agreement breakdown by rating
					Y	YC	Eq/NC	N
Overall	24	2520	1190	47%	470 (39%)	31 (3%)	568 (48%)	121 (10%)
When to test	10	1050	434	41%	150 (34%)	11 (3%)	190 (44%)	83 (19%)
How to test	2	210	118	56%	79 (67%)	1 (1%)	2 (2%)	36 (30%)
How to manage	8	840	425	51%	143 (34%)	13 (3%)	268 (63%)	1 (0%)
When to treat	3	315	181	57%	88 (49%)	6 (3%)	87 (48%)	0 (0%)
How to treat	1	105	32	30%	10 (31%)	0 (0%)	21 (66%)	1 (3%)

Abbreviations: Y, yes; YC, yes, conditional; Eq/NC, equivocal/no comment; N, no.

Figure 2 Affirmative agreement among guidelines on individual clinical statements. For each clinical statement, the affirmative proportions of guideline comparisons endorsing an action (with or without an added condition, Y + YC) are plotted. Negative agreements are also plotted. The highest affirmative agreement percentage was for the statement: “Initial testing should include a serum AAT level” (74%). The highest negative agreement percentage was for the statement: “Only patients with suggestive features of AAT deficiency should be tested” (43%).

Abbreviations: Y, yes; YC, yes, conditional; AAT, alpha-1 antitrypsin.

Table 7 Agreement percentage among guidelines stratified by time periods: 2013–2017, 2008–2012, and 2007 and earlier

	Number of statements	Number of comparisons	Number of matching comparisons	Agreement percentage	Agreement breakdown by rating
					Y	YC	Eq/NC	N
All AATD Guidelines 1996–2017 (N=15)
Overall	24	2520	1190	47%	470 (39%)	31 (3%)	568 (48%)	121 (10%)
When to test	10	1050	434	41%	150 (34%)	11 (3%)	190 (44%)	83 (19%)
How to test	2	210	118	56%	79 (67%)	1 (1%)	2 (2%)	36 (30%)
How to manage	8	840	425	51%	143 (34%)	13 (3%)	268 (63%)	1 (0%)
When to treat	3	315	181	57%	88 (49%)	6 (3%)	87 (48%)	0 (0%)
How to treat	1	105	32	30%	10 (31%)	0 (0%)	21 (66%)	1 (3%)
AATD Guidelines 2013–2017 (N=6)
Overall	24	360	183	51%	96 (52%)	2 (1%)	63 (34%)	22 (12%)
When to test	10	150	80	53%	46 (58%)	1 (1%)	17 (21%)	16 (20%)
How to test	2	30	22	73%	16 (73%)	0 (0%)	0 (0%)	6 (27%)
How to manage	8	120	50	42%	15 (30%)	0 (0%)	35 (70%)	0 (0%)
When to treat	3	45	29	64%	18 (62%)	1 (3%)	10 (34%)	0 (0%)
How to treat	1	15	2	13%	1 (50%)	0 (0%)	1 (50%)	0 (0%)
AATD Guidelines 2008–2012 (N=3)
Overall	24	72	25	35%	10 (40%)	0 (0%)	11 (44%)	4 (16%)
When to test	10	30	10	33%	4 (40%)	0 (0%)	2 (20%)	4 (40%)
How to test	2	6	1	17%	1 (100%)	0 (0%)	0 (0%)	0 (0%)
How to manage	8	24	9	38%	4 (44%)	0 (0%)	5 (56%)	0 (0%)
When to treat	3	9	4	44%	1 (25%)	0 (0%)	3 (75%)	0 (0%)
How to treat	1	3	1	33%	0 (0%)	0 (0%)	1 (100%)	0 (0%)
AATD Guidelines 2007 and earlier (N=6)
Overall	24	360	175	49%	46 (26%)	8 (5%)	111 (63%)	10 (6%)
When to test	10	150	60	40%	3 (5%)	1 (2%)	52 (87%)	4 (7%)
How to test	2	30	16	53%	10 (63%)	0 (0%)	0 (0%)	6 (37%)
How to manage	8	120	74	62%	23 (31%)	7 (9%)	44 (59%)	0 (0%)
When to treat	3	45	21	47%	9 (43%)	0 (0%)	12 (57%)	0 (0%)
How to treat	1	15	4	27%	1 (25%)	0 (0%)	3 (75%)	0 (0%)

Abbreviations: Y, yes; YC, yes, conditional; Eq/NC, equivocal/no comment; N, no; AATD, alpha-1 antitrypsin deficiency.

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