Specific allergen immunotherapy for the treatment of atopic eczema

Herman Tam; Moises A Calderon; Logan Manikam; Helen Nankervis; Ignacio García Núñez; Hywel C Williams; Stephen Durham; Robert J Boyle

doi:10.1002/14651858.CD008774.pub2

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Figure 1

PRISMA flow diagram

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Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

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Analysis 1.1

Comparison 1 Immunotherapy versus control, Outcome 1 Participant‐ or parent‐reported specific symptoms of eczema.

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Analysis 1.2

Comparison 1 Immunotherapy versus control, Outcome 2 Adverse events.

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Analysis 1.3

Comparison 1 Immunotherapy versus control, Outcome 3 Investigator‐ or physician‐rated global disease severity.

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Analysis 1.4

Comparison 1 Immunotherapy versus control, Outcome 4 Participant‐ or parent‐rated eczema severity using a non‐published scale.

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Analysis 1.5

Comparison 1 Immunotherapy versus control, Outcome 5 Investigator‐rated eczema severity assessed using a published scale.

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Analysis 1.6

Comparison 1 Immunotherapy versus control, Outcome 6 Use of other medications for eczema.

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Analysis 2.1

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 1 Participant‐ or parent‐reported specific symptoms of eczema ‐ SCORAD part C by route of immunotherapy.

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Analysis 2.2

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 2 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by route of immunotherapy.

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Analysis 2.3

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 3 Participant‐ or parent‐reported specific symptoms of eczema ‐ SCORAD part C by allergen type.

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Analysis 2.4

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 4 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by allergen type.

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Analysis 2.5

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 5 Participant‐ or parent‐reported specific symptoms of eczema ‐ SCORAD part C by participant age.

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Analysis 2.6

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 6 Participant‐ or parent‐reported specific symptoms of eczema ‐ itch severity by participant age.

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Analysis 2.7

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 7 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by participant age.

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Analysis 2.8

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 8 Participant‐ or parent‐reported specific symptoms of eczema ‐ itch severity by severity at randomisation.

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Analysis 2.9

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 9 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by severity at randomisation.

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Analysis 2.10

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 10 Adverse events: any local reaction by route of immunotherapy.

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Analysis 2.11

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 11 Adverse events: any systemic reaction by route of immunotherapy.

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Analysis 2.12

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 12 Adverse events: any local reaction by allergen type.

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Analysis 2.13

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 13 Adverse events: any systemic reaction by allergen type.

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Analysis 2.14

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 14 Adverse events: any local reaction by participant age.

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Analysis 2.15

Comparison 2 Planned subgroup analyses: immunotherapy versus control, Outcome 15 Adverse events: any systemic reaction by participant age.

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Summary of findings for the main comparison. Specific allergen immunotherapy versus no immunotherapy

Specific immunotherapy compared with no immunotherapy for atopic eczema
Patient or population: adults and children with atopic eczema and inhalant allergen sensitisation Settings: specialist allergy centres in the UK (2 trials), Italy (3 trials), USA, Germany, Belgium, Poland, Columbia, and China Intervention: specific allergen immunotherapy Comparison: no immunotherapy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No immunotherapy	Specific allergen immunotherapy
Participant‐ or parent‐reported global assessment of disease severity Follow‐up: 6 to 12 months	See comments	See comments	Not estimable	44^a (2)	⊕⊕⊝⊝ low^b	Improvement in 7/9 participants (78%) in the immunotherapy group and 3/11 participants (27%) in the placebo group (RR 2.85, 95% CI 1.02 to 7.96; P = 0.04 (Warner 1978)) 8/13 participants (62%) in the immunotherapy group and 9/11 participants (81%) in the placebo group (RR 0.75, 95% CI 0.45 to 1.26; P = 0.38 (Glover 1992)) Due to unexplained statistical heterogeneity, we did not pool the data
Participant‐ or parent‐reported specific symptoms of eczema Follow‐up: 12 to 18 months SCORAD part C measured as a combination of 2 Visual Analogue Scales (1 for itch, 1 for sleep disturbance), each on a scale from 0, no specific symptoms, to 10, maximum specific symptoms	The mean SCORAD part C score ranged across control groups from 3.07 to 5.29 The mean SCORAD part C sleep severity score ranged across control groups from 0.8 to 2.31 (Di Rienzo 2014; Novak 2012)	The mean SCORAD part C score in the immunotherapy group was on average 0.74 lower (95% CI ‐1.98 to 0.50) The mean SCORAD part C sleep severity score in the immunotherapy group was on average 0.49 lower (95% CI ‐1.03 to 0.06) (Di Rienzo 2014; Novak 2012)	‐	339^a (6)	⊕⊝⊝⊝ very low^c	Itch: SCORAD part C itch severity at the end of treatment: MD ‐0.24, 95% CI ‐1.00 to 0.52; I² = 0% for Di Rienzo 2014 and Novak 2012 Itch severity score: MD ‐4.20, 95% CI ‐3.69 to ‐4.71 for Sanchez 2012 Due to unexplained statistical heterogeneity, we did not pool the data
Adverse events ‐ any systemic reaction Follow‐up: 6 to 18 months	Low‐risk population		RR 0.78 (0.41 to 1.49)	492^a (7)	⊕⊕⊕⊝ moderate^d	‐
	0 per 1000	0 per 1000 (0 to 0)
	Medium‐risk population
	71 per 1000	55 per 1000 (29 to 106)
	High‐risk population
	163 per 1000	127 per 1000 (67 to 243)
Investigator‐ or physician‐rated global assessment of disease severity Follow‐up: 1 to 3 years	Low‐risk population		RR 1.48 (1.16 to 1.88)	286^a (7)	⊕⊝⊝⊝ very low^e	‐
	0 per 1000	0 per 1000 (0 to 10)
	Medium‐risk population
	471 per 1000	697 per 1000 (546 to 885)
	High‐risk population
	778 per 1000	1151 per 1000 (903 to 1462)
Investigator‐ or physician‐rated eczema severity using a published scale Follow‐up: 12 to 18 months	The mean SCORAD score ranged across control groups from 26.7 to 32.6 (Di Rienzo 2014; Novak 2012; Sanchez 2012)	The mean SCORAD score in the immunotherapy group was on average 5.79 lower (95% CI ‐7.92 to ‐3.66) (Di Rienzo 2014; Novak 2012; Sanchez 2012)	‐	435^a (6)	⊕⊝⊝⊝ very low^f	‐
Participant or parent‐rated eczema severity using a published scale Follow‐up: 12 to 18 months	See comment	See comment	Not estimable	184^a (2)	⊕⊕⊝⊝ low^g	SCORAD part C used as the specific eczema symptom score (Di Rienzo 2014; Novak 2012)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IQR: interquartile range; MD: mean difference; RR: risk ratio; SCORAD: SCORing Atopic Dermatitis.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risks are based on the total control group risk across all included studies (medium risk population) and the included studies with the lowest (low risk population) and highest (high risk population) control group risks. ^aThe number of total participants did not include those that were lost to follow up. The number of total participants and trials included those that contributed to narrative synthesis. ^bWe downgraded the quality of the evidence by two levels because of unexplained heterogeneity (serious, ‐1) and imprecision (serious, ‐1). There was significant heterogeneity (I² = 83%) between the estimate of dichotomous effects in two studies (Glover 1992 and Warner 1978), and data were not pooled. The information size was small. ^cWe downgraded the quality of the evidence by three levels because of study limitations (serious, ‐1), imprecision (serious, ‐1), and unexplained heterogeneity (serious, ‐1). Two trials were non‐blinded (Di Rienzo 2014; Sanchez 2012). Moderate proportions of participants were not analysed (losses to follow up). The information size was small. Most subgroups of estimate of treatment effects were not significant, with high heterogeneity displayed by itch (I² = 98%). We did not pool data from all studies because of different symptoms and different scoring systems reported. ^dWe downgraded the quality of the evidence by one level because of imprecision (serious, ‐1). The estimate of treatment effect relied largely on two studies (Novak 2012; Qin 2014). It is unclear whether the estimate obtained from a small number of adverse reactions to two different dust mite extracts can be generalised. Indeed, data from other populations suggest that specific allergen immunotherapy is generally associated with a small but significant risk of systemic adverse reactions. ^eWe downgraded the quality of the evidence by three levels because of study limitations (serious, ‐2) and imprecision (serious, ‐1). The estimate of treatment effect relied on two non‐blinded studies. The information size was small. ^fWe downgraded the quality of the evidence by three levels because of study limitations (serious, ‐2) and imprecision (serious, ‐1). Two studies were non‐blinded. Moderate proportions of participants were not analysed (losses to follow up). The information size was small. ^gWe downgraded the quality of the evidence by two levels because of study limitations (serious, ‐1) and imprecision (serious, ‐1). One study was non‐blinded. Moderate proportions of participants were not analysed (losses to follow up). The information size was small. We did not include analyses of non‐published scales in this summary table.

Summary of findings for the main comparison. Specific allergen immunotherapy versus no immunotherapy

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Table 1. Glossary of unfamiliar terms

Term	Definition
Anaphylaxis	A serious, life‐threatening allergic reaction
Fissuration	Formation of tears in the skin
Intradermally	Into the skin (dermis), below the epidermis
Lichenification	Thickening and hardening of the skin
Monovalent	1 kind of antibody
Perennial	Long‐lasting continually
Photopheresis	A form of apheresis and photodynamic therapy
Sublingual	Under the tongue
Vesicles	Fluid‐filled cavities

Table 1. Glossary of unfamiliar terms

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Comparison 1. Immunotherapy versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐ or parent‐reported specific symptoms of eczema Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 SCORAD part C	2	184	Mean Difference (IV, Random, 95% CI)	‐0.74 [‐1.98, 0.50]
1.2 Severity of sleep disturbance	2	184	Mean Difference (IV, Random, 95% CI)	‐0.49 [‐1.03, 0.06]
2 Adverse events Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Any local reaction	7	484	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.89, 1.81]
2.2 Any systemic reaction	7	492	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.41, 1.49]
2.3 Tiredness	1	48	Risk Ratio (M‐H, Random, 95% CI)	5.08 [0.66, 39.02]
2.4 Headache	1	48	Risk Ratio (M‐H, Random, 95% CI)	2.56 [0.11, 59.75]
3 Investigator‐ or physician‐rated global disease severity Show forest plot	6	262	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.16, 1.88]

4 Participant‐ or parent‐rated eczema severity using a non‐published scale Show forest plot	2	158	Mean Difference (IV, Random, 95% CI)	‐1.12 [‐1.92, ‐0.32]

5 Investigator‐rated eczema severity assessed using a published scale Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 Total SCORAD	3	244	Mean Difference (IV, Random, 95% CI)	‐5.79 [‐7.92, ‐3.66]
6 Use of other medications for eczema Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 1. Immunotherapy versus control

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Comparison 2. Planned subgroup analyses: immunotherapy versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐ or parent‐reported specific symptoms of eczema ‐ SCORAD part C by route of immunotherapy Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Totals not selected

1.1 Subcutaneous immunotherapy	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Sublingual immunotherapy	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by route of immunotherapy Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Totals not selected

2.1 Subcutaneous immunotherapy	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Sublingual immunotherapy	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Participant‐ or parent‐reported specific symptoms of eczema ‐ SCORAD part C by allergen type Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Perennial inhalant	2	184	Mean Difference (IV, Random, 95% CI)	‐0.74 [‐1.98, 0.50]
4 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by allergen type Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Perennial inhalant	2	184	Mean Difference (IV, Random, 95% CI)	‐0.49 [‐1.03, 0.06]
5 Participant‐ or parent‐reported specific symptoms of eczema ‐ SCORAD part C by participant age Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

5.1 18 years or over	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Participant‐ or parent‐reported specific symptoms of eczema ‐ itch severity by participant age Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

6.1 18 years or over	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by participant age Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

7.1 18 years or over	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
8 Participant‐ or parent‐reported specific symptoms of eczema ‐ itch severity by severity at randomisation Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8.1 Moderate (SCORAD mean objective score 16 to 40)	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Severe (SCORAD mean objective score > 40)	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Participant‐ or parent‐reported specific symptoms of eczema ‐ severity of sleep disturbance by severity at randomisation Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

9.1 Moderate (SCORAD mean objective score 16 to 40)	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Severe (SCORAD mean objective score > 40)	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Adverse events: any local reaction by route of immunotherapy Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Subcutaneous	5	320	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.90, 1.55]
10.2 Sublingual	2	164	Risk Ratio (M‐H, Random, 95% CI)	9.76 [1.28, 74.26]
11 Adverse events: any systemic reaction by route of immunotherapy Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 Subcutaneous	5	328	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.34, 2.00]
11.2 Sublingual	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.29, 1.89]
12 Adverse events: any local reaction by allergen type Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12.1 Perennial inhalant	6	464	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.81, 2.13]
13 Adverse events: any systemic reaction by allergen type Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

13.1 Perennial inhalant	6	472	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.41, 1.49]
14 Adverse events: any local reaction by participant age Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

14.1 18 years or over	2	275	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.44, 4.23]
15 Adverse events: any systemic reaction by participant age Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

15.1 18 years or over	2	275	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.38, 1.47]

Comparison 2. Planned subgroup analyses: immunotherapy versus control

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