Sublingual Versus Subcutaneous Immunotherapy

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

Appendix H.Sublingual Versus Subcutaneous Immunotherapy

Publication Details

Table H4.

Asthma Control Asthma symptoms ACT Scores.

Table H7.

Asthma Exacerbations and Health care Utilization.

Table H8.

Pulmonary Physiology and Airway Responsiveness.

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 H., Sublingual Versus Subcutaneous Immunotherapy.

Table H1.Study Characteristics

Population	Author Country	Comparators	Asthma Diagnosis	Allergy Diagnosis	Number and Type of Allergen to which Patients were Sensitized	Allergen Provided in AIT	Study Design Setting
Adults	Mungan, 1999⁹⁴ Turkey	SCIT SLIT (A)	Asthma diagnosis per clinical criteria and pulmonary tests (reversibility and FEV >70%) Severity NS Control status NS	SPT and IgE NS	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	RCT Clinic
Mixed age	Li, 2016⁹⁵ Asia	SCIT SLIT (A)	Asthma diagnosis per Chinese medical association Pulmonary tests (bronchial provocation test or exercise test positivity) Severity NS Control status presence of symptoms despite optimal treatment and allergen avoidance uncontrolled asthma excluded	SPT and IgE wheal ≥0.25, IgE>0.35 kU/L	Mono vs Polysensitized unclear^* All patients sensitized to Dust mite (Unspecified dust mites)	Single allergen Dust mite (NS)	RCT Clinic
Mixed age	Yukselen, 2012⁹⁶ Yukselen, 2013⁹⁷^* Turkey	SCIT SLIT (A)	Asthma diagnosis per GINA criteria Mild persistent Control status NS	SPT and IgE SPT >3mm IgE classII or >0.70kU/l	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	RCT Clinic
Children	Keles, 2011⁹⁸ Turkey	SCIT SLIT (A)	Asthma diagnosis per GINA criteria and pulmonary tests (reversibility and FEV >70%) Mild persistent and moderate Control status NS	SPT and IgE NS	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	RCT Clinic
	Karakoc-Aydiner, 2015⁹⁹ Eifan, 2010¹⁰⁰ Europe	SCIT SLIT (A)	Asthma diagnosis per EPR and GINA criteria Mild persistent and moderate persistent Controlled asthma	SPT and IgE IgE >0.35 positive SPT (size not described)	Monosensitized Dust mite (D pter-D far)	Single allergen Dust mite (D pter-D far)	RCT Clinic
	Cochard, 2009¹⁰¹ Europe	SCIT SLIT (A)	Asthma diagnosis criteria NR Severity NS Control status NS	SPT and IgE NS	Polysensitized Patient 1: birch, hazel tree, grass mix, rye, plantain, ragweed pollens, Alternaria; Patient 2: grass and cereal pollens, dust mites, molds, cat dander	Multiple allergens	Case report Clinic for SCIT NR for SLIT

: SPT: Skin prick test

: IgE:ImmunoglobulinE

: NS: Not specified

: D pter: Dermatophagoides pteronyssinus

: D far: Dermatophagoides farina

: RCT Randomized controlled trial

*: Authors do not specify sensitization status

**: This is a second phase, Yukselen, 2013⁹⁷, not included because is an open phase Cohort

Table H2.Patient 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	Mungan, 1999⁹⁴	36	SLIT (A) SCIT Placebo	32+/− 7 (Range 18-41) 29 +/− 7 (Range 18-39) 33 +/− 8 (Range 18-46)	13/87 40/60 9/91	15/0 10/0 11/0	5.67+/−4.32 years 6.2 +/−2.97 years 7.27 +/−3.07 years
Mixed age	Li, 2016⁹⁵	90	SCIT + Seretide SLIT (A) + Seretide Seretide	7.6 +/− 1.5 7.4 +/− 1.3 7.1 +/− 1.2	63/37 60/40 63/37	27/3 30/0 30/0	1.7 1.6 1.6
Mixed age	Yukselen, 2012⁹⁶	32	SCIT + placebo drops SLIT (A) + placebo injections Placebo injections + drops	11+/− 3 9+/− 3 10+/− 3	60/40 50/50 60/40	10/0 11/1 10/1	1 year
Children	Keles, 2011⁹⁸	60	SCIT SLIT (A) SCIT + SLIT Pharmacotherapy	7+/−2 9+/−2 8+/−1 8+/−3	36/74 31/69 56/44 42/58	11/2 13/2 14/0 12/0	NR
Children	Karakoc-Aydiner, 2015⁹⁹ Eifan, 2010¹⁰⁰	48	SLIT (A) SCIT Pharmacotherapy	6 +/− 2 (Range 5-10) 7 +/− 2 (Range 5-10) 7 +/− 2 (Range 5-10)	47/53 38/62 44/56	16/1 16/2 16/2	2.1 years 2.5 years 2.4 years

Table H3.Intervention Characteristics

Population	Study	Arms	Control/Rescue Therapy	Maintenance Dose	Cumulative Dose	Maintenance Dosing Interval	Quantity of Major Protein (μg)	Treatment Duration
Adults	Mungan, 1999⁹⁴	SLIT (A) SCIT Placebo SLIT	conventional therapy	20 drops of 100 IR/ml 0.15−0.75 ml of 10 IR/ml	11316 IR 131 IR	2 times a week Monthly	NR NR	1 year
Mixed age	Li, 2016⁹⁵	SCIT + Seretide SLIT (A) + Seretide Seretide	Both	SCIT conventional 0.1−0.8 mL of 100000 SQ-U/Ml SLIT 3 drops of 333 μg/mL daily	NR	SCIT Weekly SLIT daily	NR	16 weeks
	Yukselen, 2012⁹⁶	SCIT (plus placebo sublingual drops) SLIT (A) (plus placebo subcutaneous injections) Placebo (sublingual and subcutaneous)	conventional therapy	0.2−0.8 ml of 5000 TU/ml 28 drops of 1000 TU/ml	43,770 TU (21,885 TU of Dpt and 21885 TU of Df) 173733 TU (86866.5 TU of Dpt and 86,866.5 TU of Df)	Every 4^th week Three times a week	NR NR	1 year
	Eifan, 2010¹⁰⁰	SLIT (A) SCIT Pharmacotherapy	Only rescue medication	5 drops STU (1000 STU/ml) 100000 SQ U/ml, 1cm³	73876.8 STU 1131540 SQU	3 times per week Monthly	295.5 Der p 1, 295.5 Der f 1(cumulative) 111 Der p 1, 156 Der f 1(cumulative)	1 year
Children	Keles, 2011⁹⁸	SCIT SLIT (A) SCIT (build-up) +SLIT (maintenance) Pharmacotherapy	Only rescue medication	44.12 μg of Der p1 and 62.1 μg of Df1 52.8 μg of Der p1 and 52.8 μg of Df1 43.2 μg of Der p1 and 43.2 μg of Df1	NR	Monthly 3 times a week 3 times a week	44.12 μg of Der p1 and 62.1 μg of Df1 52.8 μg of Der p1 and 52.8 μg of Df1 43.2 μg of Der p1 and 43.2 μg of Df1 (Maintenance phase)	1 year

: 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 H4.Asthma Control
Asthma symptoms ACT Scores

Study	Allergen	Arms	N	Time of Measure	Value pre Mean+/−SD	Value post	Comparative Values
Li, 2016⁹⁵ Asia	Unspecified Dust mites	SCIT + Seretide SLIT (A) + Seretide Seretide	27 30 30	NR	18.84 (3.11) 19.06 (3.51) 18.74 (3.33)	24.75 (1.82) 23.35 (2.13) 23.01 (2.66)	SCIT pre vs post P < 0.05 SLIT pre vs post P < 0.05 Seretide pre vs post P < 0.05

Table H5.Quality of Life

No study reported on quality of life.

Table H6.Medication Use

No study reported on medication use

Table H7.Asthma Exacerbations and Health care Utilization

No study reported on Asthma exacerbations or healthcare utilization.

Table H8.Pulmonary Physiology and Airway Responsiveness

Study	Allergen	Arms	Time of Measure	Outcome Description	Value pre	Value post	Comparative Values
Li, 2016⁹⁵	Unspecified Dust mites	SCIT + Seretide SLIT (A) + Seretide Seretide	16 weeks	Peak expiratory flow (PEF)	81.79 +/−8.60 80.65 +/−8.60 79.69 +/−8.02	89.56 +/− 4.21 88.77 +/− 6.42 89.95 +/− 5.59	SCIT pre vs post P < 0.01 SLIT pre vs post P < 0.05 Seretide pre vs post P NR
Li, 2016⁹⁵	Unspecified Dust mites	SCIT + Seretide SLIT (A) + Seretide Seretide	16 weeks	FEV1	77.25 +/−6.6 77.65 +/−5.71 75.66 +/−4.06	89.79 +/−9.55 87.35 +/−9.96 79.63 +/−7.05	SCIT pre vs post P < 0.05 SLIT pre vs post P < 0.05 Seretide pre vs post P NR
Mungan, 1999⁹⁴	Dust mites	SLIT SCIT Placebo	1 year	Methacholine bronchial provocation test	NR	NR	SLIT pre vs post P=NS SCIT pre vs post P=NS Placebo pre vs post P=NS
Yukselen, 2012⁹⁶	Dust mites	SCIT SLIT Placebo	1 year	HDM-Specific Bronchial provocation	NR	NR	SCIT pre vs post, P=0.03 SLIT pre vs post, P=0.56 Placebo pre vs post, P=0.78 SCIT vs SLI T P= 0.91

: PFT: Pulmonary Function Test

: NS: Not significant

: PEF: Peak Expiratory Flow

: FEV: forced expiratory volume

Table H9.Immunological Markers

A.IgE

Study	Allergen	Arms	Time of Measure	Outcome/Unit	Value pre	Value post	Comparative Values
Eifan, 2010¹⁰⁰	Dust mite	SLIT (A) SCIT Pharmacotherapy	1 year	IgE D.f/ D.pt specific IU/ml	51.1±38.9/ 59.4 ±42.9 63.6±37.7/ 69.8±45.3 60.4±37.7/ 72.4±29.5	NR NR NR	D far specific: SCIT pre versus post P=0.03 SCIT versus Pharmacotherapy P=0.03 SLIT pre versus post P=0.04 Pharmacotherapy pre versus post P=NS D pter specific: SCIT versus Pharmacotherapy P=0.03
Mungan, 1999⁹⁴	Dust mite	SLIT (A) SCIT Placebo	1 year	IgE D.f/ D.pt specific kU/ml	505.05 311.89 288.40	NR NR NR	No significant changes in all three arms at 12 months compared to baseline
Keles, 2011⁹⁸	Dust mites	SCIT SLIT (A) SCIT+SLIT Pharmacotherapy	1 year	Derp1 specific IgE IU/ml	62+/−52 67+/− 33 83+/−27 73+/− 37	61+/− 53 44+/−32 85+/−34 75+/−41	No significant differences pre vs post in all groups. No significant differences between IT groups and pharmacotherapy
2006 Li, 2016⁹⁵	Unspecified dust mite	SCIT + Seretide SLIT (A) + Seretide Seretide	NR	HDM specific IgE	17.02+/− 9.25 18.62 +/−8.32) 17.89 +/−8.78)	11.12 +/− 8.27 13.07 +/− 9.15 16.07 +/− 9.35	P < 0.01 P < 0.05 NR

B.IgG4

Study	Allergen	Arms	Time of Measure	Biomarker	Units	Value pre	Value post	Comparative Values
Keles, 2011⁹⁸	Dust mites (D.pt and D.f)	SCIT SLIT (A) SCIT+SLIT Pharmacotherapy	1 year	Derp1 specific IgG4	Ua/ML	0.21+/0.37 0.14+/−0.1 0.11+/−0.03 0.11+/−.11	0.22+/−0.41 5.74+/−4.43 0.70+/−0.45 0.09+/−0.08	SCIT vs Pharmacotherapy p<0.05 SCIT+SLIT vs Pharmacotherapy p<0.05

Table H10.Anaphylaxis

Study	Arms	N	Event description	Reported as patients N (%)	Reported as Events N (%)
Eifan, 2010¹⁰⁰	SLIT (A) SCIT	16	Flushing, wheezing and dyspnea requiring epinephrine -required treatment discontinuation (SCIT arm)	1 (0.06%)	−

Table H11.Local Reactions

Study	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N(%)
Mungan, 1999⁹⁴	SLIT (A) SCIT Placebo	15 10 11	Reaction at the injection site classified > 5cm (SCIT)	2 (13%)	−
Mungan, 1999⁹⁴	SLIT (A) SCIT Placebo	15 10 11	Buccal pruritus (SLIT)	1 (10%)	−
Eifan, 2010¹⁰⁰	SLIT (A) SCIT Pharmacotherapy	16	Oral cavity or Oropharynx Itching classified as mild (SLIT)	1 (0.06%)	−
Li, 2016⁹⁵	SCIT + Seretide SLIT (A) + Seretide Seretide	27 30 30	Local AEs grade 1	10 3 NR	NR NR NR
Li, 2016⁹⁵	SCIT + Seretide SLIT (A) + Seretide Seretide	27 30 30	Local AEs grade 2	1 1 NR	NR NR NR

Table H12.Systemic Reactions

Study	Arms	N	Event Description	Reported as Patients N (%)	Reported as Events N (%)
Eifan, 2010¹⁰⁰	SLIT (A) SCIT	16	Respiratory reaction- severe asthma symptoms- classified as severe – required treatment discontinuation (SCIT arm)	1 (6.2%)	−
Mungan, 1999⁹⁴	SLIT (A) SCIT Placebo	15 10 11	Respiratory events classified as mild (bronchospasm) in SCIT	1 (10%)	−
Mungan, 1999⁹⁴	SLIT (A) SCIT Placebo	15 10 11	Mild Nausea in SLIT	1 (10%)	−
Keles, 2011⁹⁸	SCIT SLIT (A) SCIT+SLIT Pharmacotherapy	11	Respiratory events classified as moderate- dyspnea and wheezing- required treatment discontinuation (SCIT arm)	2 (18.2%)	−
Li, 2016⁹⁵	SCIT + Seretide SLIT (A) + Seretide Seretide	27 30 30	Unspecified systemic reactions	2 (SCIT) 1 (SLIT)	−

Table H13.Reactions Reported in Non RCTs

Study	Allergen and Asthma severity	N	Arms	Event Description
Cochard, 2009¹⁰¹	Case 1 Multiple Athma severity NS	1	SCIT	Recurrent immediate itchy and painful large local reactions at the injection site lasting for 2 to 4 days, in the absence of any systemic side effects – Required treatment discontinuation and switched to SLIT
	Case 1 Multiple Athma severity NS	1	SLIT	SLIT ultrarush- Mouth itchiness during build up asthma attacks, during treatment progression- required discontinuation
	Case 2 Multiple Athma severity NS	1	SCIT	shortness of breath and was wheezing required treatment with antihistamine. AE recurred with second dose– Required treatment discontinuation and switched to SLIT
	Case 2 Multiple Athma severity NS	1	SLIT	SLIT ultrarush- heavy nasal congestion during build up only with dust mite preparation. Reocurred when intiated followed with increased symptoms of asthma during treatment progression- required discontinuation

Table H14.Deaths

No deaths reported.

Appendix H.Sublingual Versus Subcutaneous Immunotherapy

Publication Details

Copyright

Publisher

NLM Citation

Table H1.Study Characteristics

Table H2.Patient Characteristics

Table H3.Intervention Characteristics

Table H4.Asthma Control Asthma symptoms ACT Scores

Table H5.Quality of Life

Table H6.Medication Use

Table H7.Asthma Exacerbations and Health care Utilization

Table H8.Pulmonary Physiology and Airway Responsiveness

Table H9.Immunological Markers

A.IgE

B.IgG4

Table H10.Anaphylaxis

Table H11.Local Reactions

Table H12.Systemic Reactions

Table H13.Reactions Reported in Non RCTs

Table H14.Deaths

Table H4.Asthma Control
Asthma symptoms ACT Scores