KQ4- What is the evidence for the safety of sublingual immunotherapy (SLIT) in tablet and aqueous form, in the treatment of asthma?

Sandra Y Lin; Antoine Azar; Catalina Suarez-Cuervo; Gregory B. Diette; Emily Brigham; Jessica Rice; Murugappan Ramanathan, Jr.; Jessica Gayleard; Karen A. Robinson

Appendix G.KQ4- What is the evidence for the safety of sublingual immunotherapy (SLIT) in tablet and aqueous form, in the treatment of asthma?

(Organization in tables first by population; adults-mixed population- children. Within each category by comparator SCIT vs placebo- SCIT vs pharmacotherapy- SCIT vs SCIT. Within each subcategory by allergen; HDM-grass- weed- trees- animal-multiple allergen)

SECTION A SLIT SAFETY FOR RCTS

Table G1.A

Study Characteristics.

Table G2.A

Patient Characteristics.

Table G3.A

Intervention Characteristics.

Table G4.A

Local Reactions.

Table G5.A

Systemic Reactions.

Table G6.A

Anaphylaxis.

Table G7.A

Deaths.

Table G8.A

Other reactions.

SECTION B SLIT SAFETY FOR NON RCTS

Table G1.B

Study Characteristics.

Table G2.B

Patient Characteristics.

Table G3.B

Intervention Characteristics.

Table G4.B

Local Reactions.

Table G5.B

Systemic Reactions.

Table G6.B

Anaphylaxis.

Table G7.B

Deaths.

Publication Details

Copyright

Publisher

Agency for Healthcare Research and Quality (US), Rockville (MD)

NLM Citation

Lin SY, Azar A, Suarez-Cuervo C, et al. The Role of Immunotherapy in the Treatment of Asthma [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Mar. (AHRQ Comparative Effectiveness Reviews, No. 196.) Appendix G., KQ4- What is the evidence for the safety of sublingual immunotherapy (SLIT) in tablet and aqueous form, in the treatment of asthma?

Table G1.AStudy Characteristics

Population	Author Country	Comparators	Asthma Diagnosis	Allergy Diagnosis	Number and Type of Allergen to which Patients were Sensitized	Allergen Provided in AIT	Setting
Adults	Virchow, 2016⁵⁸ Europe	SLIT(T) 6 SQ-HDM SLIT(T) 12 SQ-HDM Placebo	Asthma diagnosis GINA criteria Moderate to severe Asthma Pulmonary tests (PFT reversibility) Poorly Controlled	SPT and IgE SPT ≥ 3 mm SIgE≥ 0.70 ku/L	Both Mono and Polysensitized “Patients could have multiple sensitization but no perennial asthma caused by other allergens”	Single allergen Dust mite (D pter-D far)	Home
	de Blay, 2014⁵⁹ Mosbech, 2014⁶⁰ Mosbech, 2015⁶¹ Europe	SLIT(T) 6 SQ-HDM SLIT(T) 3 SQ-HDM SLIT(T) 1 SQ-HDM Placebo	Asthma diagnosis GINA criteria (steps 2 and 3) Pulmonary tests (documented history of reversible airway obstruction) Mild persistent and moderate persistent Controlled (ACQ scores and ICS dose of 100 to 800 mg/d)	SPT and IgE wheal size >3mm to D farinae, D pteronyssinus, or both IgE NS	Both Mono (17%) and Polysensitized (83%)	Single allergen Dust mite (D pter-D far)	Not specified
	Maloney, 2016⁶² US	SLIT(T) 6 SQ-HDM SLIT(T) 12 SQ-HDM Placebo	Asthma diagnosis GINA criteria Severity not specified Controlled (FEV1 ≥70% predicted, no more than 2 symptoms per week, no more than 2 days of SABA use per week, no more than 2 awakenings per month due to asthma)	SPT and IgE wheal diameter ≥5mm larger than saline control; serum-specific IgE≥ 0.7 kU/L or at least class II (all against D pter or D far)	Both Mono and Polysensitized Dust mite (D pter-D far) Grass, cat, dog, mold, birch,mugwort	Single allergen Dust mite (D pter-D far)	Home
	Devillier, 2016⁶³ Wang, 2014⁶⁴ Multisite	SLIT (A) Placebo	Pulmonary tests (bronchial reversibility test and methacholine challenge) Mild persistent and moderate persistent	SPT and IgE wheal diameter ≥ 4 mm in an SPT after washout of antihistamines, specific IgE ≥ 0.70 kU/ l	Monosensitized Dust mites (D pter-D far)	Single allergen Dust mite (D pter-D far)	Clinic
	Gomez, 2004⁶⁵ Mexico	SLIT (A) Placebo	Asthma diagnosis GINA criteria Pulmonary tests (FEV change >14% after salbutamol) Mild persistent and moderate persistent Control status NS	SPT and IgE specific IgE ≥ 200IU	Mono vs Polysensitized unclear^* All patients sensitized to Dust mite (Ppter)	Single allergen Dust mite (D pter)	Not specified
	Dahl, 2006⁶⁶ Europe	SLIT (T) Placebo	Asthma diagnosis GINA critera Severity Mild to moderate Controlled asthma	SPT and IgE wheal >3mm IgE NS	Monosensitized Grass (Phleum pratense)	Single allergen Grass (Phleum pratense)	Home
	Calderon, 2006⁶⁷ Europe	SLIT (A) Placebo	Asthma diagnosis criteria NS Severity Mild persistent and moderate persistent Controlled asthma	SPT and IgE wheal >3mm IgE > class 2	Monosensitized Grass (Phleum pratense)	Single allergen Grass (Phleum pratense)	Not specified
	Marogna, 2013⁶⁸ Europe	SLIT Pharmacotherapy	Asthma diagnosis GINA criteria Pulmonary tests (Positive methacholine challenge -PD20 FEV1 <800g) Severity Mild persistent Control status Poorly controlled	SPT and IgE Skin test >5mm (does not specify if wheal or flare); and class II positivity to birch assessed with ImmunoCAP (Unicap)	Monosensitized Trees (Birch)	Single allergen Birch	Home
	Voltolini 2010⁶⁹ Europe	SLIT (A) Placebo	Asthma diagnosis GINA criteria Severity Mild to moderate Control status NS	SPT and IgE NS	Monosensitized Pollen (White birch)	Single allergen Birch	Not specified
	Shao, 2014⁸⁰ Asia	SLIT (A) Pharmacotherapy	Asthma diagnosis Global Initiative for Asthma Excluded severe asthma Controlled Asthma	SPT and IgE wheal size ≥3mm IgE ≥ 0.7	Polysensitized (D pter-D far), cat, dog, german cockroach, artemisia pollen, humulus pollen, and plantain pollen)	Single allergen Dust mite (D far)	Clinic
Mixed age	Corzo, 2014⁸¹ Europe	SLIT (T) SLIT	WHO/GINA criteria Mild persistent and moderate persistent Controlled	SPT and IgE wheal ≥3mm IgE ≥ class2	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Clinic
	La Grutta, 2007⁷⁴ Europe	SLIT (T) Pharmacotherapy	Asthma diagnosis criteria NS Severity NS Control status NS	SPT >3mm	Both mono and polysensitized Dust mite and Parietaria	Single allergen Dust mite (NS)	Home
	Pham-Thi, 2007⁷² Europe	SLIT (T) Control	Asthma diagnosis pulmonary tests (reversible bronchial obstruction – salbutamol inhalation) Severity Mild persistent and moderate persistent Control status NS	SPT and IgE SPT NS IgE level ≥ 2 CAP RAST	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Not specified
	Bahceciler, 2001⁷³ Asia	SLIT (A) Placebo	Asthma diagnosis criteria NS Severity Persistent (NS) Control status – ongoing respiratory symptoms despite HDM avoidance and ICS	SPT and IgE Wheal >5mm IgE class 2	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Not specified
	Bufe, 2009⁸² Europe	SLIT (T) placebo	Asthma diagnosis criteria GINA and FEV1<80% expected after treatment with ICS and SABA) Severity Mild persistent Control status NS	SPT and IgE wheal >3mm, serum specific IgE class 2	Monosensitized Timothy grass	Single allergen Timothy grass	NR
	Stelmach, 2009⁷⁵	SLIT (A) Placebo	Asthma diagnosis pulmonary tests (reversible bronchial obstruction – salbutamol inhalation ≥12%) Severity Excluded severe asthma Control status NS	SPT and IgE SPT NS IgE NS	Monosensitized Grass	Single allergen Grass mix	Not specified
Children	Lue, 2006⁷⁶ Asia	SLIT (A) Placebo	Asthma diagnosis GINA criteria – FEV>70%) Severity Mild- moderate persistent Control status controlled	SPT and IgE Wheal >5mm IgE > 3	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Not specified
	Niu, 2006⁷⁷ Asia	SLIT (A) Placebo	Asthma diagnosis GINA criteria – FEV>70%) Severity Mild- moderate persistent Control status controlled	SPT and IgE Wheal >5mm IgE > 3	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Not specified
	Ippoliti, 2003⁷⁸ Europe	SLIT (A) Placebo	Asthma diagnosis GINA criteria – FEV>70%) Severity Mild- moderate persistent Control status controlled	SPT and IgE Wheal >5mm IgE class 3	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Not specified
	Mosges, 2010⁸³ Europe	SLIT(A) OTHER	Asthma diagnosis criteria NS Severity Mild persistent and moderate persistent Control status NS	SPT and IgE SPT NS IgE ≥0.7 kU/L	Polysensitized tree pollens (birch alder and/or hazel)	Single allergen Birch	Not specified

: T: Tablet

: A: Aqueous

: SPT: Skin prick test

: IgE:ImmunoglobulinE

: NS: Not specified

: D pter: Dermatophagoides pteronyssinus

: D far: Dermatophagoides farina

*: Authors did not report sensitization status

Table G2.APatient Characteristics

Population	Study	Patients Randomized	Comparators	Age in years Mean +/- SD (range)	Sex (% Male/Female)	Patients Enrolled/ Dropouts	Duration of Disease (Mean Years Affected)
Adults	Virchow, 2016⁵⁸	834	SLIT 6 SQ HDM SLIT 12 SQ HDM Placebo	33.6 (12.2) 33.7 (11.6) 33 (12.2)	48/52 52/48 55/45	275/34 282/43 277/48	NR
	de Blay, 2014⁵⁹ Mosbech, 2014⁶⁰ Mosbech, 2015⁶¹	604	SLIT 6 SQ-HQM SLIT 3 SQ-HQM SLIT 1 SQ-HQM Placebo	32 (NR) 32 (NR) 32 (NR) 32 (NR)	NR	156/16 159/25 146/14 143/17	NR
	Maloney, 2016⁶²	68	HDM SLIT 6 SQ-HDM HDM SLIT 12 SQ-HDM Placebo	Range (12-17)	NR	NR	6 months
	Devillier, 2016⁶³ Wang, 2014⁶⁴	484	SLIT Placebo	31.2 (9) 31.3 (8.2)	46.8/53.2 41.4/58.6	308/23 157/8	12.8 years 13.7 years
	Gomez, 2004⁶⁵	60	SLIT (A) Placebo	22.8 20.6	53/47 33/67	30/NR 30/NR	3.8
	Dahl, 2006⁶⁶	114	SLIT (T) Placebo	36.5 (11) 34.1 (10)	71/29 60/40	74/13 40/8	14 years 12 years
	Calderon, 2006⁶⁷	43	SLIT 75000 SQ-T SLIT 150000 SQ-T SLIT 300000 SQ-T SLIT 500000 SQ-T Placebo	22.1 (3.2) 23.2 (2.8) 28 (9.5) 25.8 (5.5) 24.5 (5.5)	67/33 67/33 67/33 60/40 55/45	9/0 9/0 9/0 5/0 11/0	12.9 years 15.7 years 22.2 years 19.4 years 15.4 years
	Marogna, 2013⁶⁸	84	SLIT+ BUD 400 μg/day BUD 800 μg/day BUD 1600 μg/day BUD 400 μg/day + LTRA	NR	NR	21/NR 21/NR 21/NR 21/NR	NR
	Voltolini, 2010⁶⁹	24	SLIT (A) Placebo	44+/- 9 40 +/- 7	50/50 30/70	14/1 10/1	NR
	Shao, 2014⁸⁰	218	SLIT Pharmacotherapy	NR	NR	NR	NR
Mixed age	Corzo, 2014⁸¹ adults Corzo, 2014⁸¹ Peds	71	SLIT 1 DU SLIT 2 DU SLIT 4 DU SLIT 8 DU SLIT 16 DU SLIT 16 DU Placebo	30.7(10.4) 32.4 (14.1) 25.9 (5.3) 30 (11.2) 27.9 (6) 25.2 (7.6) 29 (9.7)	33/67 22/78 33/67 56/44 44/56 22/78 47/53	54/NR 17/NR	Range: 13.8 years 14.8 years 13 years 17.1 years 16.1 years 15.8 years 0.2 years
	La Grutta, 2007⁷⁴	56	SLIT Pharmacotherapy	15.4 (9) 21.8 (15)	22/11 13/10	33/0 23/0	NR
	Pham-Thi, 2007⁷²	111	SLIT Placebo	9.6 (5-14) 9.5 (5-16)	72/28 71/29	55/11 56/8	6.1 years 5.7 years
	Bahceciler, 2001	15	SLIT (A) Placebo	Median 12.4 (range 8-18) Median 12 (range 7- 15)	50/50 43/57	8/0 7/0	NR
	Bufe, 2009⁸²	105	SLIT Placebo	Range: 5-16	NR	253/19	NR
	Stelmach, 2009⁷⁵	50	SLIT (A) Placebo	9.1 +/-2.4 8.5 +/- 2.8	60/40 66/33	25/5 25/10	NR
Children	Lue, 2006⁷⁶	20	SLIT (A) Placebo	7.7 +/- 1.8 8.6 +/- 1.8	40/60 40/60	10/0 10/0	1
	Niu, 2006⁷⁷	110	SLIT (A) Placebo	7.9 +/- 1.6 (Range 5-11) 8.2+/- 1.7 (Range 5-12)	61/39 58/42	56/7 54/6	1
	Ippoliti, 2003⁷⁸	86	SLIT (A) Placebo	Median;9 (Range 5-12) Median;9 (Range 7-11)	60/41 56/44	47/0 39/0	2 2
	Mosges, 2010⁸³	116	SLIT Placebo	10.2 (2.64) 10.5 (2.55)	37/63 67/33	27/NR 27/NR	NR

: T: Tablet

: A: Aqueous

: NR: Not reported

: SQU: standard quality tablet

: SQ-HDM-T standard quality House dust mite tablet

Table G3.AIntervention Characteristics

Population	Study	Arms	Control/ Rescue Therapy	Maintenance Dose	Cumulative Dose	Maintenance Dosing Interval	Quantity of Major Protein (μg)	Treatment Duration
Adults	Virchow, 2016⁵⁸	SLIT 6 SQ HDM T SLIT 12 SQ HDMT Placebo	Both	Targeted: 6 SQ Actual: 6 SQ Targeted: 12 SQ Actual: 12 SQ	Targeted: 360 SQ/month Actual: 360 SQ/month Targeted: 720 SQ/month Actual: 720 SQ/month	Daily	NR	7-12 months
	de Blay, 2014⁵⁹ Mosbech, 2014⁶⁰ Mosbech, 2015⁶¹	SLIT 6 SQ-HQM SLIT 3 SQ-HQM SLIT 1 SQ-HQM Placebo	Rescue therapy	Targeted:6SQ Actual 6 SQ Targeted:3SQ Actual: 3 SQ Targeted:1SQ Actual: 1 SQ Targeted: NR Actual: NR	NR	Daily	NR	1 year
	Maloney, 2016⁶²	SLIT T 6 SQ-HDM SLIT T 12 SQ-HDM Placebo	Both	Targeted: 6 SQ-HDM Actual: 6 SQ-HDM Targeted: 12 SQ-HDM Actual: 12 SQ-HDM Targeted: NA Actual: NA	Targeted: 168 SQ Actual: 168 SQ Targeted: 336 SQ Actual:336 SQ Targeted: NR Actual: NR	Daily	NR	28 days
	Devillier, 2016⁶³ Wang, 2014⁶⁴	SLIT Placebo	Both	Targeted: 300 IR Actual: 300 IR	NR	Daily	28ug Der p 1 and 50 ug Der f 1 NR	52 weeks: 24 w active treatment, 16 w step- down, 20 w efficacy measurement phase (8 w’ overlap (between w 32 and 40)
	Gomez, 2004⁶⁵	SLIT (A) Placebo	Both BUT excluded systemic corticosteroids	710 UBE/ml	10469 UBE	3 times a week	NR	6 months
	Dahl, 2006⁶⁶	SLIT (T) Placebo	Both (NS)	7500 SQT	NR	Daily	15 phl p5	137 days (Ultrarush)
	Calderon, 2006⁶⁷	SLIT 75000 SQ-T SLIT 150000 SQ-T SLIT 300000 SQ-T SLIT 500000 SQ-T Placebo	NR	Targeted: 75000 SQ-T Actual: 75000 SQ-T Targeted: 150000 SQ-T Actual: 150000 SQ-T Targeted: 300000 SQ-T Actual: 300000 SQ-T Targeted:500000 SQ-T Actual: 500000 SQ-T Targeted: NR Actual: NR	NR	Daily	15 μg/dose 30 μg /dose 60 μg /dose 100 μg /dose NR	28 days
	Marogna, 2013⁶⁸	SLIT + BUD 400 μg/day BUD 800 μg/day BUD 1600 μg/day BUD 400 μg/day + LTRA	Both	Targeted: 1000 AU once a day for five days/week Actual: 1000 AU once a day for five days/week	Targeted: Annual average dose approximately 60,000 AU Actual: Annual average dose approximately 60,000 AU Targeted: NR Actual: NR Targeted: NR Actual: NR	Daily	214,200 μg of protein (Annual cumulative) NR NR NR	12 weeks
	Voltolini 2010⁶⁹	SLIT (A) Placebo	Conventional therapy	Targeted 300 IR Actual 300IR	13.8 IR per season	Daily	13.8 IR (6.9 μgBet v1 per season)	4 months
	Shao, 2014⁸⁰	SLIT aqueous Pharmacotherapy	NR	NR	Targeted: 0.15 ml Actual: 0.15 ml Targeted: NR Actual: NR	Weekly	49.95 μg/dose	12 months
Mixed age	Corzo, 2014⁸¹ adults Corzo, 2014⁸¹ Peds	SLIT 1 DU SLIT 2 DU SLIT 4 DU SLIT 8 DU SLIT 16 DU SLIT 16 DU Placebo	Both	Targeted: 1 to 32 DU Actual: NR Targeted: NR Actual: NR	NR	Daily	NR	28 days
	La Grutta, 2007⁷⁴	SLIT Pharmacotherapy	Conventional therapy	Targeted: 1,000 AU Actual: 1,000 AU	NR	Biweekly NR	NR	1 year
	Pham-Thi, 2007⁷²	SLIT Placebo	Both	Targeted: 300 IR Actual: 300 IR Targeted: NR Actual: NR	Targeted: NR Actual: 155,000 IR, corresponding to 6.9mg Der p 1 and 14.7mg Der f 1 Targeted: NR Actual: NR	Daily NR	Daily dose: DerP1 27μg, Der f1 57μg	18 months
	Bahceciler, 2001	SLIT (A) Placebo	Both	20 drops of 100 IR/mL	Average 7,000 IR	Twice a week	Average cumulative dose of 0.56 mg Der P and 0.98 mg Der F)	24 weeks
	Bufe, 2009⁸²	SLIT Placebo	Both	NR	NR	NR	NR	NA
	Stelmach, 2009⁷⁵	SLIT (A) Ultrarush Placebo	Conventional therapy BUT excluded systemic corticosteroids	120IR	43800 IR	3 times a week	3.65 mg of major allergens (5 grasses)	6 months
Children	Lue, 2006⁷⁶	SLIT (A) Placebo	Conventional and rescue as needed	20 drops of 300 IR/mL	41824 IR	Daily	3 mg Der F 1.7 mg Der P (Cumulative)	24 weeks
	Niu, 2006⁷⁷	SLIT (A) Placebo	Conventional and rescue as needed	20 drops of 300 IR/ml	41824 IR	Daily	3 mg Der F, 1.7 mg Der P (Cumulative)	24 weeks
	Ippoliti, 2003⁷⁸	SLIT (A) Placebo	Conventional therapy	5 drops of 10 BU/mL	NR	3 times a week	2.4 Der p1 1.2 Der p2 (per week)	6 months
	Mosges, 2010⁸³	SLIT Placebo	Both	Targeted: 300 IR within 90 minutes Targeted: NR Actual: NR	NR	NR	NR	6 months

: T: Tablet

: A: Aqueous

: BU: Biological units

: SQU: standard quality units

: PNU: Protein Nitrogen Unit

: AU Allergy unit

: μg: microgram

: Ag/ml: major protein unit

: TU: Treatment units

: wt/vol Weight to volume

: SE: Specific units of short-term immunotherapy

: IR: Index of reactivity unit

: NR: Not reported

: DU dosing unit

Table G4.ALocal Reactions

Category	Study	Allergen and Asthma Severity	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N (%)	Calculated risk difference (for AEs reported as patients)
Pruritis/swelling of mouth, tongue or lip	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 6 SQ HDM (T) SLIT 12 SQ HDM (T) Placebo	275 282 277	Oral pruritus Treatment related	37 (13) 55 (20) 8 (3)	45 78 8	-0.029
					Edema mouth Treatment related	24 (9) 28 (10) 0 (0)	26 35 0	0.0
					Tongue pruritus Treatment related	12 (4) 13 (5) 1 (1)	13 15 1	-0.004
					Lip edema Treatment related	3 (1) 9 (3) 0 (0)	3 10 0	0.02
					Lip pruritus Treatment related	0 (0) 7 (2) 0 (0)	0 8 0	0.01
					Lip swelling Treatment related	4 (1) 6 (2) 0 (0)	4 7 0	0.01
					Swollen tongue Treatment related	1 (1) 5 (2) 0 (0)	1 6 0	0.0
					Laryngeal edema [moderate, no airway obstruction or dyspnea]	0 1 0	NR	0.0
	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	322 162	Swollen tongue	85 (26.4%) 2 (1.2%)	NR NR	0.252
					Oral pruritus	75 (23.3%) 23 (14.2%)	NR NR	0.091
					Glossitis	64 (19.9%) 17 (10.5%)	NR NR	0.094
					Mouth Edema	26 (8.1%) 0 (0)	NR NR	0.081
	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	29 27 25 27	Mouth edema	8% 3% 2% 0%	NR NR NR NR	-0.001
	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	29 27 25 27	oral pruritus	19% 19% 12% 3%	NR NR NR NR	-0.001
	Pham-Thi, 2007⁷²	Dust mite Mild and Moderate asthma	SLIT tablet Placebo	54 55	mouth itching/lip swelling	NR NR	10 5	NA
	Stelmach, 2009⁷⁵	Grass mix Excluded severe asthma	SLIT (A) Ultrarush Placebo	20 15	Sublingual itching	35% 20%	NR	0.15
	Calderon, 2006⁶⁷	Grass Mild and Moderate asthma	SLIT 75000 SQ-T SLIT 150000 SQ-T SLIT 300000 SQ-T SLIT 500000 SQ-T Placebo	9 9 9 5 11	Mouth edema	3 (33) 1 (11) 2 (22) 0 0	3 1 4 NR NR	0.006
					Oral pruritus	6 (67) 9 (100) 8 (89) 5 (100) 4 (36)	13 49 96 77 5	-0.336
					Swollen tongue	1 (11) 0 1 (11) 1 (20) 0	1 NR 1 1 NR	0.003
	Dahl, 2006⁶⁶	Timothy Grass Mild and Moderate asthma	SLIT (T) Placebo	61 32	Oral pruritus	53% 5%	NR NR	0.007
	Corzo, 2014⁸¹ (adults) Trial 1	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 17	Oral pruritis	NR NR	277 0	NA
	Corzo, 2014⁸¹ (adults) Trial 1	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 17	Mouth edema	NR NR	90 0	NA
	Corzo, 2014⁸¹ (peds) Trial 2	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 18	Oral pruritis	NR NR	263 5	NA
	Corzo, 2014⁸¹ (peds) Trial 2	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 18	Mouth edema	NR NR	96 0	NA
	Niu, 2006⁷⁷	Dust mite Mild and Moderate asthma	SLIT (A) Placebo	56 54	Tongue disorder and circumoral paresthesia	5 0	10 0	NA
	Ippoliti, 2003⁷⁸	Dust mite Mild and Moderate asthma	SLIT (A) Placebo	47 39	No local side effects in 86 children	0	0	0.0
	Voltolini 2010⁶⁹	Birch Mild and Moderate asthma	SLIT (A) Placebo	14 10	at least one adverse event was reported by 75% of actively trea- ted and 44.4% of placebo treated patients, most defined slight/moderate and consisting of local reaction in the mouth.	NA	NA	NA
Throat Irritation	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	29 27 25 27	throat irritation	6% 4% 2% 1%	NR NR NR NR	0.0
	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	29 27 25 27	oral paresthesia	6% 3% 1% 0.5%	NR NR NR NR	0.0
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 6 SQ HDM (T) SLIT 12 SQ HDM (T) Placebo	275 282 277	Throat irritation Treatment related	21 (8) 27 (10) 4 (1)	26 32 4	-0.014
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 6 SQ HDM (T) SLIT 12 SQ HDM (T) Placebo	275 282 277	Pharyngeal edema Treatment related	0 (0) 5 (2) 0 (0)	1 6 0	0.008
	Calderon, 2006⁶⁷	Grass Mild and Moderate asthma	SLIT 75000 SQ-T SLIT 150000 SQ-T SLIT 300000 SQ-T SLIT 500000 SQ-T Placebo	9 9 9 5 11	Throat irritation	0 0 1 1 1	NR NR NR NR NR	-0.089
					Dry throat	2 (22) 0 0 1 (20) 0	4 NR NR 1 NR	0.003
					Oral Hypoesthesia	0 0 1 (11) 3 (60) 0	NR NR 4 11 NR	0.004
	Calderon, 2006⁶⁷	Grass Mild and Moderate asthma	SLIT 75000 SQ-T SLIT 150000 SQ-T SLIT 300000 SQ-T SLIT 500000 SQ-T Placebo	9 9 9 5 11	Odynophagia	0 0 1 (11) 0 0	NR NR 1 NR NR	0.001
					Dysphagia	0 0 1 (11) 0 0	NR NR 2 NR NR	0.001
					Pharyngitis	3 (33) 0 4 (44) 0 1 (9)	3 NR 9 NR 1	-0.084
	Dahl, 2006⁶⁶	Timothy Grass Mild and Moderate asthma	SLIT (T) Placebo	61 32	nasopharyngitis	36% 25%	NR NR	-0.02
	Dahl, 2006⁶⁶	Timothy Grass Mild and Moderate asthma	SLIT (T) Placebo	61 32	throat irritation	32% 25%	NR NR	-0.03
	Corzo, 2014⁸¹ (adults) Trial 1	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 17	Stomatitis	NR NR	8 0	NA
					Throat irritation	NR NR	151 0	NA
					Oral paresthesia	NR NR	0 0	NA
	Corzo, 2014⁸¹ (peds) Trial 2	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 18	Stomatitis	NR NR	195 0	NA
					Throat irritation	NR NR	234 1	NA
					Oral paresthesia	NR NR	105 2	NA
Abdominal pain, nausea, vomiting/ gastrointestinal complaints	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 6 SQ HDM (T) SLIT 12 SQ HDM (T) Placebo	275 282 277	Nausea Treatment related	0 (0) 8 (3) 0 (0)	0 8 0	0.0
	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT Placebo	322 162	Abdominal pain	81 (25.2%) 17 (10.5%)	NR	0.147
	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT Placebo	322 162	Gastrointestinal disorders	239 (74.2%) 58 (35.8%)	NR	0.384
	Pham-Thi, 2007⁷²	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 55	Gastrointestinal complaint	NR NR	19 2	NA
	Stelmach, 2009⁷⁵	Grass mix Excluded severe asthma	SLIT (A) Ultrarush Placebo	20 15	Stomach ache	5% 6.6%	NR	-0.0016
	Shao, 2014⁸⁰	Dust mite Mild asthma	SLIT (A) Pharmacotherapy	141 (54 AEs) 77 (11 AEs)	gastrointestinal intolerance	NR NR	2 (3.7%) 2 (18.18%)	NA
	Shao, 2014⁸⁰	Dust mite Mild asthma	SLIT (A) Pharmacotherapy	141 (54 AEs) 77 (11 AEs)	Oral intolerance	NR NR	1 (1.85%) 0 (0)	NA
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 12 SQ HDM (T) SLIT 6 SQ HDM (T) Placebo	282 275 277	erosive esophagitis	0 0 1	NR	-0.004
	Corzo, 2014⁸¹ (adults) Trial 1	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 17	vomiting	1 0	1 0	NA
Local rashes	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT Placebo	322 162	Chelitis	36 (11.2%) 8 (4.9%)	NR NR	0.62
	Shao, 2014⁸⁰	Dust mite Intermittent and Mild asthma	SLIT (A) Pharmacotherapy	141 77	Local rashes	NR	5 (9.2%) 0 (0)	NA
	Mosges, 2010⁸³	Tree Pollen Mild and Moderate asthma	SLIT Placebo	27 27	Most frequent symptoms were application site itching and application site paresthesia	NR	NR	NA

: T: Tablet

: A: Aqueous

: NR: Not reported

: NA: Not applicable

Table G5.ASystemic Reactions

Category	Study	Allergen and Asthma Severity	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N (%)	Calculated risk difference (for AEs reported as patients)
Lower Respiratory	Shao, 2014⁸⁰	Dust mite Mild asthma	SLIT (A) Pharmacotherapy	139 (54 AEs) 79 (11 AEs)	Aggravating asthma	NR NR	8 (14.82%) 0 (0)	NA
	Pham-Thi, 2007⁷²	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 55	Asthma exacerbations	NR NR	64 67	NA
	Calderon, 2006⁶⁷	Grass Mild and Moderate asthma	SLIT 75000 SQ-T SLIT 150000 SQ-T SLIT 300000 SQ-T SLIT 500000 SQ-T Placebo	9 9 9 5 11	Chest tightness/chest discomfort	0 0 2 (22) 0 0	NR NR 4 NR NR	0.002
					Asthma aggravated	1 (11) 0 1 (11) 0 0	1 NR 1 NR NR	0.002
					Wheezing	0 1 (11) 1 (11) 0 1 (9)	0 1 2 0 1	−0.089
					Cough	0 0 1 (11) 0 0	NR NR 1 NR NR	0.001
					Dyspnea NOS	0 1 (11) 1 (11) 0 1 (9)	NR 1 2 NR 1	−0.089
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 12 SQ HDM (T) SLIT 6 SQ HDM (T)t Placebo	282 275 277	asthma [moderate, alternative etiology was “recently viral infection”	1 0 0	NR	0.0
	de Blay, 2014⁵⁹ Mosbech, 2014⁶⁰ Mosbech, 2015⁶¹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	156 159 146 143	Bronchitis	1/134 (<1) 6/131 (5) 4/117 (3) 3/107 (3)	1 8 7 6	0.0
	de Blay, 2014⁵⁹ Mosbech, 2014⁶⁰ Mosbech, 2015⁶¹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	156 159 146 143	Asthma	12/134 (9) 12/131 (9) 6/117 (5) 5/107 (5)	19 17 7 6	0.03
	Maloney, 2016⁶²	Dust mite Severity NS	SLIT - 6 SQ-HDM (T) SLIT - 12 SQ-HDM (T) Placebo	22 24 33	Asthma worsening	1 0 1	1 0 1	−0.31
	Bufe, 2009⁸²	Timothy Grass Mild, Moderate and Severe asthma	SLIT (T) Placebo	55 50	Asthma, asthma exacerbation	2 (4) 1 (2)	3 1	0.01
	Corzo, 2014⁸¹ (adults) Trial 1 (peds)Trial 2	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 17	Asthma worsening or asthma exacerbations	7 total	9 total	NA
	Corzo, 2014⁸¹ (adults) Trial 1 (peds)Trial 2	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 18	Asthma worsening or asthma exacerbations	12 total	7 6	NA
Mucosal irritation (other than mouth or GI tract)	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT Placebo	322 162	Rhinitis	67 (20.8%) 28 (17.3%)	NR	0.035
	Shao, 2014⁸⁰	Dust mite Intermittent and Mild asthma	SLIT aqueous Pharmacotherapy	141 77	Eye itching	NR NR	1 (1.85%) 0 (0)	NA
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 12 SQ HDM (T) SLIT 6 SQ HDM (T) Placebo	282 275 277	Ear pruritus Treatment related	11 (4) 7 (3) 2 (1)	11 7 2	−0.07
	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM (T) SLIT 3-HQ HDM (T) SLIT 1-HQ HDM (T) Placebo	29 27 25 27	Ear pruritus	5% 3% 3% 0%	NR NR NR NR	0.0
	Corzo, 2014⁸¹ (adults) Trial 1 (peds) Trial 2	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 17	Ear pruritis	NR NR	150 0	NA
	Corzo, 2014⁸¹ (adults) Trial 1 (peds) Trial 2	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	54 18	Ear pruritis	NR NR	33 0	NA
Cutaneous	Marogna, 2013⁶⁸	Trees Mild asthma	BUD 400 μg/day + SLIT BUD 800 μg/day BUD 1600 BUD 400 μg/day + LTRA (Montelukast)	19 19 20 18	Generalized itching	0 0 2 0	NR NR NR NR	0.001

: T: Tablet

: A: Aqueous

: NR: Not reported

: NA: Not applicable

Table G6.AAnaphylaxis

Study	Allergen and Asthma Severity	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N (%)
Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 6 SQ HDM (T) SLIT 12 SQ HDM (T) Placebo	275 282 277	There were no anaphylactic reactions	0 0 0	0 0 0
Pham-Thi, 2007⁷²	Dust mite Intermittent, Mild and Moderate asthma	SLIT (T) Placebo	54 55	There were no anaphylactic reactions	0 0	0 0
Maloney, 2016⁶²	Dust mite Severity NS	SLIT - 6 SQ-HDM (T) SLIT - 12 SQ-HDM (T) Placebo	22 24 22	There were no anaphylactic reactions	0 0 0	0 0 0
de Blay, 2014⁵⁹ Mosbech, 2014⁶⁰ Mosbech, 2015⁶¹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM (T) SLIT 3-HQ HDM (T) SLIT 1-HQ HDM (T) Placebo	134 131 117 107	No systemic allergic reactions/requirement for epinephrine.	0 0 0 0	0 0 0 0
Shao, 2014⁸⁰	Dust mite Intermittent and Mild asthma	SLIT (A) Pharmacotherapy	141 77	There were no anaphylactic reactions	0 0	0 0
Mosges, 2010⁸³	Tree Pollen Mild and Moderate asthma	SLIT (A) (ultra-rush) Placebo	27 27	There were no anaphylactic reactions	0 0	0 0

: T: Tablet

: A: Aqueous

Table G7.ADeaths^*

Study	Allergen and Asthma Severity	Arms	N	Event Description
Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 6 SQ HDM (T) SLIT 12 SQ HDM (T) Placebo	275 282 277	There were no deaths reported
Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT (T) Placebo	322 162	There were no deaths reported
Bufe, 2009⁸²	Timothy Grass Mild, Moderate ad Severe asthma	SLIT (T) Placebo	126 127	There were no deaths reported

: T: Tablet

: A: Aqueous

*: Data abstracted ONLY if studies specifically reported on deaths

Table G8.AOther reactions

Category	Study	Allergen and Asthma Severity	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N (%)	Calculated risk difference (for AEs reported as patients)
No reactions reported	La Grutta, 2007⁷⁴	Dust mite Severity NS	SLIT Concomitant pharmacotherapy	33 23	No local or systemic relevant adverse events were observed	NR NR	0 0	NA
	Bahceciler, 2001⁷³	Dust mite Mild asthma	SLIT (A) Placebo	8 7	No local or systemic side effects reported	0 0	0 0	NA
	Lue, 2006⁷⁶	Dust mite Mild and Moderate asthma	SLIT (A) Placebo	10 10	No severe drug-related adverse event was reported	0 0	0 0	NA
	Ippoliti, 2003⁷⁸	Dust mite Mild and Moderate asthma	SLIT (A) Placebo	47 39	No systemic side effects in 86 children	0	0	0.0
	Mosges, 2010⁸³	Tree Pollen Mild and Moderate asthma	SLIT aqueous (ultra-rush) Placebo	27 27	No serious systemic effects were observed	0 0	NR	NA
	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT Placebo	322 162	AEs or Adverse Drug Reactions life-threatening or disabling	0 0	0 0	0
	Corzo, 2014⁸¹ (adults) Trial 1	Dust mite Mild and Moderate asthma	SLIT tablet Placebo	54 17	There were no serious adverse events	0 0	0 0	0
	Corzo, 2014⁸¹ (peds) Trial 2	Dust mite Mild and Moderate asthma	SLIT tablet Placebo	54 18	There were no serious adverse events	0 0	0 0	0
	Pham-Thi, 2007⁷²	Dust mite Intermittent, Mild and Moderate asthma	SLIT tablet Placebo	54 55	There were no multiple-organ life-threatening events	0 0	0 0	0
	Gomez, 2004⁶⁵	Dust mite Mild and Moderate asthma	SLIT (A) Placebo	30 30	No adverse events were observed	0 0	0 0	0
Reactions not specified	Calderon, 2006⁶⁷	Grass Mild and Moderate asthma	SLIT 75000 SQ-T SLIT 150000 SQ-T SLIT 300000 SQ-T SLIT 500000 SQ-T Placebo	9 9 9 5 11	Not specified	0 0 0 0 1 (9%)	NR NR NR NR NR	−0.091
	Pham-Thi, 2007⁷²	Dust mite Intermittent, Mild and Moderate asthma	SLIT T Placebo	54 55	total number of adverse events, local and systemic	0 4 (10%)	NR	−0.073
	Bufe, 2009⁸²	Timothy Grass Mild, Moderate and Severe asthma	SLIT (T) Placebo	126 127	the pattern of adverse events was similar for subjects with and without asthma symptoms.	109 (87%) 106 (83%)	426 278	0.030
	Maloney, 2016⁶²	Grass, Cat, Dog, Mold, Birch, Mugwort Severity NS	SLIT - 6 SQ-HDM T SLIT - 12 SQ-HDM T Placebo	22 24 22	Adverse events not specified (TEAEs)	68% 50% 46%	NR	0.013
	Maloney, 2016⁶²	Grass, Cat, Dog, Mold, Birch, Mugwort Severity NS	SLIT - 6 SQ-HDM T SLIT - 12 SQ-HDM T Placebo	22 24 22	Adverse events not specified (TRAEs)	55% 50% 32%	NR	0.009
	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT Placebo	322 162	Severe Adverse Drug Reaction SLIT vs placebo P NS	10 (3.1%) 3 (1.9%)	NR	0.013
					Moderate Adverse Drug Reaction SLIT vs placebo P =0.0003	96 (29.8%) 24 (14.8%)	NR	0.150
					Mild Adverse Drug Reaction SLIT vs placebo P<0.0001	228 (70.8%) 70 (43.3%)	NR	0.276
					Severe AE SLIT vs placebo P NS	17 (5.3%) 10 (6.2%)	NR	−0.009
					Moderate AEs SLIT vs placebo P NS	149 (46.3%) 63 (38.9%)	NR	0.074
					Mild AEs SLIT vs placebo P NS	259 (80.4%) 101 (62.3%)	NR	0.181
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 12 SQ HDM T SLIT 6 SQ HDM T Placebo	282 275 277	Serious AE	7 (2%) 10 (4%) 11 (4%)	10 (1%) 10 (1%) 12 (2%)	−0.40
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 12 SQ HDM T SLIT 6 SQ HDM T Placebo	282 275 277	AEs leading to discontinuation	25 (9%) 12 (4%) 8 (3%)	46 (6%) 23 (3%) 10 (2%)	−0.29
	Stelmach, 2009⁷⁵	Grass mix Excluded severe asthma	SLIT (A) Ultrarush Placebo	20 15	AEs leading to discontinuation	0 0	NR	0
	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM T SLIT 3-HQ HDM T SLIT 1-HQ HDM T Placebo	134 131 117 107	Serious adverse events	6 3 6 4	7 3 7 5	−0.37
Infection	Devillier, 2016⁶³	Dust mite Mild and Moderate asthma	SLIT Placebo	322 162	Infections and infestations	67 (20.8%) 10 (18.5%)	NR	0.146
Infection	Shao, 2014⁸⁰	Dust mite Mild asthma	SLIT (A) Pharmacotherapy	141 (54 AEs) 77 (11 AEs)	Upper respiratory tract infection	NR	23 (42.5%) 7 (63.6%)	NA
Unable to categorize					Nosebleed	NR	1 (1.85%) 1 (9.09%)	NA
					Headache	NR	0 (0) 1 (9.09%)	NA
	Stelmach, 2009⁷⁵	Grass mix Excluded severe asthma	SLIT (A) Ultrarush Placebo	20 15	Headache	0% 6.6%	NR	−0.066
	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	134 131 117 107	dizziness	0 1 0 0	NR	0.002
	de Blay, 2014⁵⁹	Dust mite Mild and Moderate asthma	SLIT 6-HQ HDM SLIT 3-HQ HDM SLIT 1-HQ HDM Placebo	134 131 117 107	migraine	0 0 1 0	NR	0.002
	Virchow, 2016⁵⁸	Dust mite Moderate to severe Asthma	SLIT 6 SQ HDM tablet SLIT 12 SQ HDM tablet Placebo	275 282 277	Accidental overdose Treatment related	4 (1) 15 (5) 9 (3)	5 16 12	−0.032
					Arthralgia	0 1 0	NR	0.001
					hepatocellular injury	0 0 1	NR	−0.004

: T: Tablet

: A: Aqueous

: TRAE: Treatment related adverse event

: TEAE: Treatment emergent adverse event

Table G1.BStudy Characteristics

Population	Author Country	Comparators	Asthma Diagnosis	Allergy Diagnosis	Number and Type of Allergen to which Patients were Sensitized	Allergen Provided in AIT	Setting
Adults	Dunsky, 2006⁸⁴ US	SLIT wo comparator	Asthma diagnosis criteria NR Severity NS Control status NS	SPT NS	Polysensitized perennial and seasonal tree nut and peanut allergy	Multiple allergens	Home
	Vovolis, 2013⁸⁵	SLIT (A) wo comparator	Asthma diagnosis criteria NR Severity NS Control status NS	SPT and IgE Not reported	Polysensitized Olea europaea pollen, Dust mite (D pter-D far)	Multiple allergens	Clinic
	Ventura, 2008⁸⁶ Europe	SLIT wo comparator	Asthma diagnosis criteria NR Severity Mild persistent and moderate persistent Control status NS	SPT and IgE Not reported	Polysensitized graminacee, olive, cypress, house dust mite, Anisakis	Single allergen Dust mite (D pter-D far)	NR
	Blazowski, 2008⁸⁷	SLIT wo comparator	Asthma diagnosis criteria NR Severity NS Control status NS	Not reported	Not reported	Multiple allergens	Home
	Moral, 2016⁸⁸	SLIT (A) wo comparator	Asthma diagnosis criteria NR Mild to moderate persistent Control status NS	SPT and/or IgE Wheal diameter ≥3mm; IgE > class 2	Both poly and monosensitized	Pollens or Dust mite	Not specified
Mixed age	Roger, 2011⁸⁹ Europe	SLIT wo comparator	Asthma diagnosis criteria NR Severity Mild persistent and moderate persistent Control status NS	SPT and IgE Positive SPT (size NS) plus specific IgE class 2 or greater (10.7 kU/l)	Mono vs Polysensitized unclear^* All patients sensitized to Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Clinic
Mixed age	De Castro, 2013⁹⁰	SLIT (T) Control	Asthma diagnosis criteria NR Mild persistent and moderate persistent Controlled	SPT and IgE Wheal diameter > 3mm; or IgE CAP class 3	Both poly and monosensitized	Single allergen Grass	Not specified
Children	Nuhoglu, 2007⁹¹	SLIT wo comparator	Asthma diagnosis criteria NR Severity Intermittent Controlled	SPT >3mm	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Home and Clinic
	Galip, 2015⁹² Europe	SLIT (A) wo comparator	Pulmonary tests (PFT with bronchodilator reversibility of 18%) persistent asthma controlled on daily ICS	SPT wheal 10x10mm	Monosensitized Dust mite (D pter-D far))	Single allergen Dust mite (D pter-D far)	Home Hospital after AE
	Bene, 2016⁹³ Europe	SLIT (A) wo comparator	Asthma diagnosis criteria NR Severity NS Control status NS	NR	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	Not specified

: T: Tablet

: A: Aqueous

: SPT: Skin prick test

: IgE:ImmunoglobulinE

: NS: Not specified

: D pter: Dermatophagoides pteronyssinus

: D far: Dermatophagoides farina

*: Authors did not report sensitization status

Table G2.BPatient Characteristics

Population	Study	Patients	Comparators	Age in years Mean +/− SD (range)	Sex (% Male/ Female)	Patients Enrolled/Dropouts	Duration of Disease (Mean years Affected)
Adults	Dunsky, 2006⁸⁴ US	1	SLIT wo comparator	31 years	NR/1	1/NA	NR
	Vovolis, 2013⁸⁵	1	SLIT wo comparator	25 years	NR/1	1/NA	15 years
	Ventura, 2008⁸⁶ Europe	1	SLIT wo comparator	39 years	NR/1	1/NA	NR
	Blazowski, 2008⁸⁷	1	SLIT wo comparator	16 years	NR/1	1/NA	NR
	Moral, 2016⁸⁸	93	SLIT wo comparator	NR	NR	NR	NR
Mixed age	Roger, 2011⁸⁹ Europe	77	SLIT wo comparator	20.4 (NR)	46/54	77/NA	4.84 years
Mixed age	De Castro, 2013⁹⁰ Europe	98	SLIT Control	NR NR	NR NR	NR NR	NR
Children	Nuhoglu, 2007⁹¹	39	SLIT wo comparator	8.8 (2.3)	23/16	39/NR	NR
	Galip, 2015⁹²	1	SLIT wo comparator	6 years	1/NR	1/NA	3 years
	Bene, 2016⁹³	1	SLIT wo comparator	10 years	NR/1	1/NA	NR

Table G3.BIntervention Characteristics

Population	Study	Arms	Control/Rescue Therapy	Maintenance Dose	Cumulative Dose	Maintenance Dosing Interval	Quantity of Major Protein (μg)	Treatment Duration
Adults	Dunsky, 2006⁸⁴	SLIT without comparator	NR	NR	NR	NR	NR	NR
	Vovolis, 2013⁸⁵	SLIT without comparator	NR	Targeted: NR Actual: 3 drops /day	NR	Daily	NR	NR
	Ventura, 2008⁸⁶	SLIT without comparator	NR	NR	NR	NR	NR	1 month
	Blazowski, 2008⁸⁷	SLIT without comparator	NR	Targeted: 10 drops, 100 IR/ml Actual: 60 drops, 100 IR/ml	NR	Daily	NR	3 years
	Moral, 2016⁸⁸	SLIT without comparator	NR	Targeted: 300 SRU/day	NR	daily	NR	At least 3 months
Mixed age	Roger, 2011⁸⁹	SLIT without comparator	NR	Targeted: 240 IR 3 times per week Actual: NR	Targeted: 450 IR at the end of ultra-rush induction Actual: NR	3 times per week	NR	2 weeks
Mixed age	De Castro, 2013⁹⁰	SLIT (T) Control	Both (SABAs ICS and oral corticosteroids)	Targeted: 2-5 weekly tablets of 1.000 UA each Actual: 2-5 weekly tablets of 1.000 UA each Targeted: NA Actual: NA	NR	Daily	NR	3 years
Children	Nuhoglu, 2007⁹¹	SLIT without comparator	NR	Targeted: NR Actual: NR	Targeted: NR Actual: 100	3 alternate days a week	NR	3 years
	Galip, 2015⁹²	SLIT without comparator	Both	Targeted: 300 IR/ml Actual: 300 IR/ml	NR	Daily	NR	3 years
	Bene, 2016⁹³	SLIT wo comparator	NR	300IR	NR	NR	NR	NR

: NR: Not reported

: IR: index reactivity units

Table G4.BLocal Reactions

Category	Study	Allergen and Asthma Severity	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N (%)
Abdominal pain, nausea, vomiting/Gastrointestinal complaints	Ventura, 2008⁸⁶	Dust mite NS	SLIT (A) wo comparator	1	abdominal pain, nausea, vomiting	1	NR
	Bene, 2016⁹³	Dust mite NS	SLIT (T) wo comparator	1	Eosinophilic esophagitis: Patient presented reflux and vomiting 6 weeks after starting SLIT. Did not respond to treatment. Histopathology confirmed diagnosis of eosinophilic esophagitis. Resolved after SLIT discontinuation	1	1
	Roger, 2011⁸⁹	Dust mite Mild to moderate asthma	SLIT (A) wo comparator	77	General malaise, vomiting	1 (1.3%)	1

Table G5.BSystemic Reactions

Category	Study	Allergen and Asthma Severity	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N (%)
Lower respiratory	Galip, 2015⁹²	Dust mite NS	SLIT aqueous wo comparator	2	Wheezing requiring beta agonists and dose reduction of SLIT	1	NA
	Nuhoglu, 2007⁹¹	Dust mite Mild and Moderate asthma	SLIT tablet wo comparator	39	Asthma attacks	NR	0.44
	De Castro, 2013⁹⁰	Grass and Dust mite Mild and Moderate asthma	SLIT Control	50 48	Worsening of asthma	2% 0	1 0
	Roger, 2011⁸⁹	Dust mite Mild asthma	SLIT (A) without comparator	77	Moderate dyspnea and asthma- causal relationship thought improbable	1 (1.3%)	1
	Blazowski, 2008⁸⁷	Dust mite Intermittent asthma	SLIT aqueous wo comparator	1	Self-resolving wheezing	1	2
Reactions not specified	De Castro, 2013⁹⁰	Grass and Dust mite Mild and Moderate asthma	SLIT Control	50 48	No systemic adverse effects were reported during the 3 years	0 0	0 0
	Roger, 2011⁸⁹	Dust mite Mild and Moderate asthma	SLIT aqueous rush wo comparator	77	Adverse events not specified A little under half the adverse events were reported in the 77 asthmatic patients included in the study, although the profile of adverse events was similar to the overall population of the study.	NR	NR
	Moral, 2016⁸⁸	Pollens and Dust mite	SLIT without comparator	93	Adverse reaction, not specified	26 (28%)	NR

Table G6.BAnaphylaxis

Study	Allergen and Asthma severity	Arms	N	Description	Reported as patients N (%)	Reported as events N (%)
Blazowski, 2008⁸⁷^*	Dust mite Intermittent asthma	SLIT aqueous	1	Anaphylactic shock	1	NR
Vovolis, 2013⁸⁵	Dust mite and Trees NS	SLIT aqueous	1	Flushing, hoarseness, dyspnea, dizziness and mild hypotension	1	NR
Dunsky, 2006⁸⁴	Mold, Animals, Grass, and Weeds NS	SLIT aqueous	1	Anaphylaxis	1	NR

*: caused by overdose

Table G7.BDeaths^*

No study reported on deaths.

*: Data abstracted ONLY if studies specifically reported on deaths