Three years of specific immunotherapy may be sufficientin house dust mite respiratory allergy

Ana I. Tabar, MD, PhD,a Esozia Arroabarren, MD,b Susana Echechip�ıa, MD, PhD,a Blanca E. Garc�ıa, MD, PhD,a

Santiago Martin, MS,c and Mar�ıa J. Alvarez-Puebla, MD, PhDa Pamplona, San Sebasti�an, and Madrid, Spain

Abbreviations used

AQLQ: Asthma Quality of Life Questionnaire

HDM: House dust mite

IT3: Patients receiving SIT for 3 years

IT5: Patients receiving SIT for 5 years

RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire

SIT: Specific immunotherapy

T0: Baseline evaluation

T1: 1-year follow-up

T3: 3-year follow-up

T5: 5-year follow-up

VAS: Visual analog scale

Background: Specific immunotherapy (SIT) duration forrespiratory allergy is currently based on individual decisions.Objective: To evaluate the differences in clinical efficacy of SITas a result of the duration between the current recommendedlimits (3-5 years).Methods: A 5-year prospective, controlled clinical trial of SITblind until the first year and randomization to a 3-year (IT3) or5-year (IT5) course was conducted. Of the 239 patients withrespiratory allergy caused by D pteronyssinus initially included,142 completed 3 years of SIT with good compliance. Twenty-seven controls were included at the third year. Efficacy of SITafter 3 (T3) and 5 (T5) years was assessed by using clinicalscores, visual analog scales (VASs), rhinitis (RQLQ) and asthma(AQLQ) quality of life questionnaires, skin tests, and serumimmunoglobulins.Results: At T3, significant reductions were observed in rhinitis(44% in IT3 and 50% in IT5;P <.001), asthma (80.9% in IT3 and70.9% in IT5; P < .001) scores, VAS (P < .001 in both), RQLQ(P <.001 in both) and AQLQ (P <.001 in both). At T5, the clinicalbenefit was maintained in both groups, and IT5 patientspresented additional decreases (19%; P5 .019) in rhinitis scores.At Tf, specific IgG4 measurements were lower in IT3 (P 5 .03)without detecting differences in IT5. An increase in asthma scoreof 133% was the only difference observed in controls.Conclusion: Clinical improvement is obtained with 3 years of Dpteronyssinus SIT. Two additional years of SITadd clinical benefitin rhinitis only. (J Allergy Clin Immunol 2011;127:57-63.)

Key words: Specific immunotherapy, duration, quality of life,asthma, rhinitis, house dust mite, clinical efficacy, compliance,children, immunotherapy relapses

Since the first clinical trial with specific immunotherapy (SIT)was carried out by Noon,1 its clinical efficacy has been demon-strated by means of several meta-analyses.2-4 In addition, its pre-ventive ability has been reinforced by several trials5-7 as well asthe maintenance of the clinical efficacy after its discontinua-tion.8-10 However, the duration of treatment is still arbitrarily

From athe Department of Allergy, Hospital Virgen del Camino, Pamplona; bthe Depart-

ment of Pediatrics, Hospital Universitario Donostia, San Sebasti�an; and cthe Clinical

Research Department, ALK-Abell�o, Madrid.

Supported by a research grant from the Regional Government of Navarra.

Disclosure of potential conflict of interest: S. Martin is an employee of ALK-Abell�o and

helped in the design and analysis of the study. The rest of the authors have declared that

they have no conflict of interest.

Received for publication July 6, 2010; revised October 13, 2010; accepted for publication

October 20, 2010.

Reprint requests: Ana I. Tabar, MD, PhD, Department of Allergy, Hospital Virgen del

Camino, CS Conde Oliveto, Plaza de la Paz s/n, 31002 Pamplona, Spain. E-mail:

ana.tabar.purroy@cfnavarra.es.

0091-6749/$36.00

� 2010 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2010.10.025

decided. Being able to establish the adequate duration of inhalantSITmay have important clinical implications, because itmay influ-ence the patient’s compliance, the efficacy of treatment, its safety,and expenses derived from treatment and the disease itself.11

Current immunotherapy guidelines12,13 recommend ceasingthe treatment on individual basis. The usual duration ranges be-tween 3 and 5 years, although it might be administered indefi-nitely for certain cases of Hymenoptera venom allergy.14 DesRoches et al15 observed a greater frequency of relapses relatedto shorter treatments.Most of the available information on when SIT should be

discontinued is based on Hymenoptera venom trials.14 In most ofthese patients, a 5-year course of SIT equals the risk of systemicreactions to the general population.14 Regarding inhalants, wehave indirect data from trials performed during variable periods,with different doses and allergens: pollen8-10 and house dust mite(HDM).16 These data suggest that SIT administration is effectivein the treatment of respiratory allergy, and its efficacy continuesafter treatment discontinuation. However, no trial has been specif-ically designed to address the topic of optimal duration of SIT.Our objective was to evaluate the possible differences in the

efficacy of HDM SIT in respiratory allergy as a result of theduration between the currently recommended limits.

METHODS

Study designThis was a 5-year, phase IV, prospective study, double-blind for the first

year, in which the initial phase (cluster or conventional) was blind. After the

first year, half the patients were randomized17 to 3 years (IT3) and the other

half to 5 years of SIT (IT5). At the third year (T3), a control group receiving

pharmacologic treatment exclusively was also included (Fig 1). Patients were

evaluated at baseline (T0), after the first year (published data18), and at the

third year (T3) and the fifth year (T5).

PatientsAt baseline, we invited patients age 5 to 45 years studied at our department

during the previous year and diagnosed with moderate-severe rhinitis and/or

asthma caused by sensitization to D pteronyssinus to participate. SIT was

57

FIG 1. Study design. T0 to T1: results published in Tabar AI, Echechip�ıa S,

Garc�ıa BE, Olaguibel JM, Lizaso MT, G�omez B, et al. Double-blind compar-

ative study of cluster and conventional immunotherapy schedules with

Dermatophagoides pteronyssinus. J Allergy Clin Immunol 2005;116:109-

18. Arrows, Randomization. Red triangle, STOP immunotherapy.

J ALLERGY CLIN IMMUNOL

JANUARY 2011

58 TABAR ET AL

indicated for all the patients according to the European Academy of Allergy

and Clinical Immunology recommendations.13 Diagnosis and pharmacologic

treatment of rhinitis and asthma were based on the International Consensus

Report on the Diagnosis andManagement of Rhinitis19 and National Institutes

of Health, National Heart, Lung and Blood Institute,20 respectively. All

patients had to show positive results to D pteronyssinus in skin prick test

(wheal diameter >_ 3 mm) and in serum specific IgE (>0.7 kU/L).The initial

sample size was 239 patients.

Once we completed the first year of SIT (T1) and determined the lack of

differences regarding efficacy and safety between the schedules,18 we per-

formed a new randomization17: half of patients would receive a 3-year course

and the rest a 5-year course of SIT.

At T3, patients who hadwithdrawn fromSITand thosewho had an irregular

compliance (defined below) were excluded. At T3, we also recruited the

control group among the patients who had come to our department for the first

time by using a randomized sequence17 and the same clinical criteria. All sub-

jects were evaluated at T5.

At each visit (baseline, T1, T3, and T5), patients underwent clinical

assessment and physical evaluation by the physician, skin prick tests, and

spirometry and fulfilled their analog scales and quality of life questionnaires.

A venous blood sample was also obtained.

Ethical issuesThis protocol was conducted in compliance with the principles established

in theWorldMedical Association Declaration of Helsinki21 and was approved

by the Hospital Clinical Research Ethics Committee and the Spanish Drug

Agency. All patients were provided with written information and signed an in-

formed consent that was specific for minors.

Allergen extractA biologically standardized D pteronyssinus extract quantified in micro-

grams of Der p 1 and Der p 2 (Pangramin Depot UM; ALK-Abell�o, Madrid,

Spain) was used for treatment. During themaintenance phase, 0.8 mL contain-

ing 3.6 mg Der p 1 was administered monthly.

Skin prick tests were madewith 4 dilutions of the sameD pteronyssinus ex-

tract in 50% glycerin (wt/vol) containing phenol 0.4% (wt/vol) and ClNa 0.9%

(wt/vol), with a biological activity of 500 biological unit/mL (225mg Der p 1),

stored at –208C to keep its biological activity throughout the study.

Administration of the immunotherapyDuring the initial phase, a cluster and a conventional initial schedule were

used.18 Patients were monitored for 30 minutes after the administration of

each dose. Doses administered were recorded in the Immunotherapy Unit

Management software INMUNOWIN (ALK-Abell�o).

AssessmentsCompliance. Compliance was assessed by reviewing the registries in

the INMUNOWIN program. In addition, a physician performed a telephone

survey of all patients who withdrew to ascertain reasons for withdrawal. An

irregular compliance with frequent delays (>_ 3 consecutive doses) or admin-

istration delays in the maintenance phase longer than 16 weeks were

considered noncompliance.

Efficacy assessment. Clinical efficacy was assessed by using

objective scales on symptoms and medication use, adding a lung function test

(forced spirometry) in patients with asthma patients, previously used by our

group.18,22-24 Rhinitis severity was explored by combined scales for symptoms

(0-12 points) andmedication (0-2 points) published byMeltzer.25 Asthmawas

evaluated by an asthma symptom scale modified from Aas26 assessing symp-

toms (0-5 points), medication (0-5 points), and lung function tests (0-2 points).

The extent of clinical efficacy was graded according to the parameters pub-

lished by Malling27 (see this article’s Tables E1 and E2 in the Online Repos-

itory at www.jacionline.org).

Changes in quality of life were assessed by using the standardized

Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)28,29 and the

Asthma Quality of Life Questionnaire (AQLQ)28-30 that patients themselves

fulfilled. They assessed the 3 months before each visit, and their values ranged

from 0 points (no impairment) to 6 points (greatest impairment) for rhinitis

and from 7 points (no impairment) to 0 points (greatest impairment) for

asthma. Patient-perceived severity was also measured by a visual analog scale

(VAS) that explored the week before the visit and whose values ranged from 0

(very good) to 10 (very bad).31

Pulmonary function tests. Patients with asthma underwent

forced spirometry with bronchodilation test according to the American

Thoracic Society guidelines.32 We used a Jaeger spirometer (MasterScope,

Jaeger Toennies; Erich Jaeger GMBH, Hoechberg, Germany).

Asthma-free patients. Patients asymptomatic, with normal lung

function, and without any pharmacologic treatment for at least the 3 months

before the assessments were considered asthma-free patients.15

Reactivity to D pteronyssinus. Skin prick tests. Imme-

diate skin reactivity was assessed by prick test with D pteronyssinus extract,

standardized in mass units to 225, 45, 9, and 1.8 mg of Der p 1 with histamine

hydrochloride positive at 10 mg/mL and saline as positive and negative con-

trols, respectively, according to the European Academy of Allergy and Clini-

cal Immunology Subcommittee on Skin Tests recommendations.33 The wheal

diameter was measured by a scanner. Data were transformed logarithmically

for analysis with parametric tests.

In vitro testing. Serum levels of D pteronyssinus–specific IgG,

IgG4, and IgE were determined by enzyme immunoassay following the

CAP System RAST FEIA method (Phadia, Uppsala, Sweden). Measurements

were made at the end of the study by using the same assay for each evaluated

parameter.

Statistical and computing methodologyFor statistical analysis, the statistical software SPSS 16.0 for Windows,

BMDP Statistical Software release 7, Star Xact (Cytel Software Corp, Ma-

drid, Spain), and the AIAS CRS-PLA software (ALK-Abell�o, Madrid,

Spain) were used. The differences in efficacy between groups at each visit

(asthma and rhinitis severity, VAS, and RQLQ and AQLQ scores) were

assessed by repeated-measures ANOVA. Changes in skin reactivity were

assessed by AIASA CRS-PLA software for individual data, estimating the

differences in the skin tolerance rate on each time point. The evolution of

both treatment groups was compared by a 1-way ANOVA (duration of

treatment).

In vitro endpoints were assessed at T5 versus T3 by using a 1-way ANOVA

(duration of immunotherapy).

All statistical tests had a significance level of .05.

FIG 2. Patients’ flowchart throughout the study.

TABLE I. Patients’ baseline characteristics

Patients’ characteristics

All SIT

patients

IT-5

group

IT-3

group

Control

group

Age, <15/>15 y 81/158 39/31 29 /43 6/21

Age, median

(interquartile)

18 (5,49) 12,5 (5,42) 19 (5,49) 24 (8,43)

Sex, female/male 145/93 21/49 40/32 14/13

Monosensitized,

yes/no

125/114 32/28 37/31 11/16

Diagnosis, asthma/

rhinitis/rhinitis

and asthma

30/64/145 11/15/44 9/21/42 3/16/8

TABLE II. SIT safety

Reactions IT5 group IT3 group

Local reactions 1 Late local reaction (M) 1 Local reaction (I)

1 Nodes (M) 1 Local reaction (M)

1 Local reaction (M) 1 Local reaction (M)

1 Local reaction (l)� 1 Local reaction (M)

1 Local reaction (M)

Systemic reactions 1 Anaphylaxis (M) 1 Nonspecific RS

symptoms (I)

1 Rhinoconjunctivitis (I) 1 Nonspecific RS

symptoms (M)

1 Asthma* (M) 1 Nonspecific RS

symptoms (M)*

1 Asthma� (M) 1 Asthma (M)

1 Rhinoconjunctivitis (M)

I, Reactions during initiation phase; M, reactions during maintenance phase; RS,

systemic reactions.

* And � correspond to reactions experienced by the same patient.

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TABAR ET AL 59

RESULTSTwo hundred thirty-nine patients initiated the study, and at T3,

142 of the 215 patients who completed the first year were still ontreatment with good compliance. Seventy patients were told tocontinue SIT for 2 more years (IT5 group) and 72 were told tocease the treatment (IT3 group) according to a randomizedsequence. At this time, the control group was recruited. Forty-nine (IT5) and 62 (IT3) patients came to all scheduled visits. Foranalysis, we used data from patients who had complete baseline,T3, and T5 data (Fig 2).

Patients’ baseline characteristics are detailed in Table I.

ComplianceFifty-three dropouts and 18 withdrawals for noncompliance

occurred between the first and third years of follow-up. Thereasons for withdrawal and/or dropouts are summarized in Fig 2(see detailed information in this article’s Results section in theOnline Repository at www.jacionline.org). No differences inage, sex, or initial diagnosis were found between patients whocomplied with the 5-year follow-up and those who withdrew.

SafetySafety data from baseline and first year of SIT have been

already published.18 During the 5-year follow-up, 9 systemic re-actions (3 unspecific, 2 rhinoconjunctivitis, 3 asthma attacks, and1 anaphylaxis; see detailed information in this article’s Results

section in the Online Repository) were recorded, involving0.07% of doses and 5.6% of patients, among patients using SIT(Table II).

Clinical efficacyCompared with baseline, we observed statistically significant

decreases (P <.01) in rhinitis and asthma scores as well as in sub-jective endpoints (VAS scores and quality of life measurements)at T3 (Fig 3).Rhinitis score. Compared with baseline, IT5 group scores

had a reduction of 50% (P < .001) at T3 and of 69.1% at T5 (P <.001). The difference between T3 and T5 scores was also signif-icant (P 5 .019).Alternatively, IT3 group scores decreased in 44% (P < .001) at

T3 and in 48% (P <.001) at T5. When both groups’ global scoreswere compared at T5, we observed no significant difference(P 5 .146). No difference was observed in rhinitis severity inthe control group (Fig 3, A).Asthma score. Compared with baseline, IT5 group patients

had a 70.9% (P <.001) reduction in the global asthma score at T3that grew to 79.9% (P < .001) at T5. IT3 patients had an 80.9%(P <.001) reduction in global asthma scores at T3 that was main-tained (80.9%; P < .001) at T5. When changes at T3 and at T5were compared, we observed no significant difference either inthe IT5 (P 5 .729) or in the IT3 (P 5 .302) groups. Neitherwere the differences were significant between IT3 and IT5 atT5 (P 5 .330; Fig 3, B).

FIG 3. A, Rhinitis severity (global score). B,Asthma severity (global score). C, VAS score. Mean values (blackline) (SEs).*P < .001. CO, Control group.

TABLE III. Symptom-free and asthma medication-free patients

IT randomization

3-year SIT course N (%) 5-year SIT course N (%)

Asthma-free T0

Asthma-free 0 0

Asthma 54 51

Asthma-free T3

Asthma-free 32 (62.7) 47 (74.6)

Asthma 18 (35.3) 16 (25.4)

Asthma-free T5

Asthma-free 40 (64.5) 46 (74.1)

Asthma 22 (35.5) 16 (25.9)

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60 TABAR ET AL

The asthma symptoms score increased in 133% from baselinein the control group.Asthma-free patients. All patients with asthma were

symptomatic and required antiasthmatic treatment at baseline.At T3, 70% of SIT patients were symptom-free and out oftreatment. At T5, neither apparent asthma relapses nor greaternumbers of symptom-free patients were detected (Table III).VAS. Compared with baseline, the VAS scores decreased in

the IT5 and IT3 groups at T3 (61.1% and 58.7%, respectively) andat T5 (67.6% and 64%, respectively).Differences seen in VAS scores between the third and fifth

years of SIT were not significant in IT3 (P 5 .256) or IT5(P 5 .283). The difference between VAS scores after 5 yearsbetween IT3 and IT5 were not significant either (P 5 1).The control group showed similar VAS scores throughout the

study (P > .05; Fig 3, C).Quality of life. Compared with baseline, both groups showed

significant changes in the domains explored by RQLQ (general,nasal, and ocular symptoms, practical issues, and emotionalfunction) and AQLQ (symptoms, emotion, activity limitations,and environment). These changes had clinical relevance,29,30 in-creases above 0.5 points for RQLQ and above 1.5 points forAQLQ. In none of the groups were differences observed when re-sults at T3 and T5 were compared (Fig 4).

In the control group, we observed significant changes (0.5points) in the RQLQ domains concerning activity and emotions.

Reactivity against D pteronyssinusSkin prick tests. No significant differences regarding HDM

skin reactivity were seen in any group in the 3 assessment timepoints (P > .05).In vitro parameters. At T5, significant decreases in seric

IgG (P 5 .025) and sIgG4 (P 5 .003) measurements were ob-served among IT3 patients compared with the IT5 group. Controlgroup measurements remained unchanged (Table IV).

DISCUSSIONThe recommended duration of SIT treatment relies on empiric

data and is not well documented. In our opinion, an adequate SITtreatment should guarantee clinical efficacy with significantreduction of the symptoms and medication needs, a good safetyprofile without unpredictable systemic reactions, and a long-termtherapeutic benefit after its completion.To date, few studies have addressed the identification of the

proper duration of SIT treatment needed to fulfill those require-ments.34 Some trials have shown that the clinical benefit can bemaintained up to 10 years after SIT is completed.9,10 Neverthe-less, trials15,35 specifically assessing SIT duration observed avarying percentage of relapses—in some cases, above 50%—2years after stopping SIT. These data could be attributed at leastin part to factors that were not directly considered in the resultsanalysis such as the low numbers of patients included in thesetrials, the extracts and doses administered, and the study design.To our knowledge, with the exception of recently published trialswith products under investigation performed with differentaims,36 this is the first trial that prospectively explores the cur-rently recommended duration limits of SIT.We tried to control those factors other than treatment duration

that might influence the efficacy, such as patient screening, thechoice of the allergen, the quality and profile of the extract, andthe patient’s compliance, among others. Dermatophagoides mite

FIG 4. RQLQ and AQLQ scores. A, IT5. B, IT3. C, Control group. Mean values (black line) (SEs). *P < .01.

TABLE IV. Evolution of specific IgE (kU/L), IgG (kU/L), and IgG4

(mcg/mL) levels against D pteronyssinus, median (interquartile)

T0 T3 T5

IT5

IgEe 34.3 (11.4-76.9) 31.8 (11.25-70.8) 28.35 (9.37-53.8)

IgGe 13.3 (7.6-19.87) 20.7 (15.1-28.55) 16.7 (11.9-29.3)

IgG4e 300.5 (150-689.5) 2650 (2020-4950) 2625 (1487-4222)

IT3

IgEe 41.5 (11.17-100) 30.9 (10.17-70.85) 25.7 (7.31-62.4)

IgGe 14.1 (8.77-21.67) 21.1 (16.45-25.5) 13.7 (11.15-19)

IgG4e 521.27 (161.25-621.5) 2935 (1837.5-5810) 1920 (1427.5-2805)

CO

IgEe 17.95 (5-31.92) 9.06 (3.53-36.22)

IgGe 10.4 (8.38-27.4) 12.45 (7.84-21.67)

IgG4e 0.01 (0.01-300) 0.01(0.01-200)

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TABAR ET AL 61

is the main cause of respiratory allergy in our environment. Dur-ing 1 year, we included the patients who had been consecutivelydiagnosed with HDM respiratory allergy and in whomSITwas in-dicated. Therefore, we are confident that demographic and diag-nosis characteristics of our sample mirror the profile of patientswho usually visit our department. We also had experience con-cerning optimal dose, efficacy, and safety of the treatment ex-tract.21-23 In addition, we knew the exact dose of the major

allergen (in micrograms) received by our patients. This shouldalso allow us to compare our results with other trials in whichthe composition is detailed.Because of the likelihood of disease progression, the long-term

design of our trial did not advise including a control group atbaseline. Therefore, and to avoid a possible limitation of theclinical benefit of a future SIT among these patients, the controlgroupwas added 4 years after the first vaccinated patients. Criteriafor inclusion of controls were the same that had been followedwith the treated patients. During data analysis, we could observethat both the percentage of asthma diagnosis and the severity ofrespiratory symptomswere lower among the control group. Thesedifferences may be attributed to the randomization itself but alsoto the ‘‘calling effect’’ of recent medical articles such as rhinitisguides37 that highlight the clinical relevance of the disease, andtrials demonstrating the prophylactic ability of SIT, previouslymentioned.9,10 All of themmay have influenced both an earlier de-mand of specialized care by the patient and an earlier clinical in-dication of SIT therapy by the specialist, leading to the lack ofcomparability observed between the SIT and control groups.However, this fact has not influenced either the evolution of thevaccinated patients regarding their initial clinical status or the pro-gression of the control group itself, as proven by the worsening ofasthma symptoms. Although we used a per-protocol analysis, wetried to limit bias by randomization and by checks for comparabil-ity of baseline characteristics of completers and withdrawals.

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62 TABAR ET AL

Compliance is a cornerstone for the efficacy of any medicaltreatment. As discussed, we excluded patients who had discon-tinued SIT but also those whose cumulative doses were too lowand could potentially compromise the efficacy of SIT. At 3 years,we observed a compliance rate of 66%. This rate is consistent withthe wide range of compliance rates reported among subjectsfollowing SIT, varying from 16%38 to 80%.39

According to the World Allergy Organization recommenda-tions,28 most of the parameters used to evaluate SIT efficacy wereclinical. Evaluation at T3 showed significant improvements in allthe treated patients before randomization. These changes weregreater than those observed at T118 and consisted of reductionsof rhinitis and asthma scores of 50% and 80%, respectively. Se-venty percent of the patients with asthma were symptom-freewithout any antiasthmatic medication.At T5, we confirmed again that SIT had induced significant

improvements in both treated groups. As detected at T3, im-provements seemed to be more relevant in asthma (70% of theasthma patients remained symptom-free, and asthma scorereductions remained unchanged), than in rhinitis (48% scorereduction in IT3 and 69% in IT5). The magnitude of theimprovement observed among patients with asthma at T3 hadindeed left a small margin of benefit for the 2 additional years ofSIT to make any difference. Both groups of patients had similarclinical status at T5 because we observed neither relapses in IT3patients nor increases in the rate of IT5 asthma-free patients.However, rhinitis scores varied from 48% in IT3 to 69% in IT5 atT5. It seemed that among IT5 patients, 2 further years of SIT hadadded clinical benefit to rhinitis severity. These changes reachedno statistical difference when comparing IT5 and IT3 scores, andwere under the minimum rate of 30% proposed by Malling.27

However, following the same author’s criteria, the overall efficacyof SIT in the reduction of rhinitis’ severity increased frommoder-ate at T3 (50%) to high at T5 (69.1%) among IT5 patients,whereas it was not modified among the IT3 group.Trials assessing SIT duration15-32 observed that most of re-

lapses happened within the first 2 years after treatment discontin-uation. According to that, our 2-year follow-up period should beappropriate to detect the relapses that may have occurred in ourIT3 group.In the last few years, the patient’s point of view has become

more important both in clinical practice and in therapeutic evalu-ation. Accordingly, quality of life questionnaires were included asprimary endpoints in the Cochrane meta-analysis testing SIT effi-cacy in rhinitis.4 In our study, we included 2 subjective endpoints:VAS and quality of life questionnaires. To date, there are no stan-dards to evaluate the modifications of VAS scores, but they offerus patients’ perceptions of their health status.We observed greaterimprovements in quality of life questionnaires among patientswith asthma compared with those who had only rhinitis symp-toms. Strikingly, we also observed that the improvement mea-sured by the physician matched the patient’s perception ofhealth status. These observations are in keeping with the clinicalobservation regarding patients diagnosed with rhinitis and asthmawho, after SIT treatment, become asymptomatic regardingasthma without needing of medication whereas they still have re-sidual symptoms of rhinitis that require treatment. It is notewor-thy that, in our study, 70% of the patients remained asthma-freeafter SIT, without relapses in those who had stopped 2 years be-fore (IT3). To our knowledge, this is the first time these observa-tions have been made.

Des Roches et al15 also described greater skin reactivity amongpatients who relapsed.We had observed changes in skin reactivityafter a year of SIT18 that were not maintained either at T3 or at T5.We attributed this fact to the irregular behavior of skin reactivityas an index to evaluate SIT efficacy8,10 but also, although lesslikely, to the fact that tests were performed by different techni-cians at the different visits (baseline and T1 vs T3 and T5).Specific IgG4 measurements increased significantly after 3

years of SIT. At T5, IgG4 decreased significantly in IT3 but notin IT5 patients. We cannot check these data with literature be-cause long-term efficacy trials9 usually lack in vitro parameters.The significance is far from clear, although serum immunoglobu-lins provide information about the activity of regulatory T cells inSIT.40 Therefore, it could be speculated that the relative decreasein IgG4 levels among patients from the IT3 groupmight be relatedto a likely relapse of the disease. To date, these markers did notcorrelate with current clinical status, and only a longer follow-up should allow us to test that hypothesis.We conclude that 3 years of SIT is an adequate duration for the

treatment of respiratory allergy caused by HDM because itinduces a significant reduction in the severity of the disease,especially asthma, as well as significant changes in the patient’squality of life, that remain 2 years after SIT discontinuation.Two additional years of SIT seem to add benefit in rhinitis. Longerobservation periods would be needed to assess whether a 5-yearcourse might be related to a more prolonged efficacy.

We thank Dr S. Quirce for his kind and generous review of the article.

Clinical implications: A 3-year course of mite SIT has shown ef-ficacy, inducing a long-lasting remission in rhinitis and asthma,and may improve the quality of life associated with long-termtreatment.

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RESULTS

Efficacy assessmentSee Tables E1 and E2.

Compliance of SITFour patients required changes on the adjuvant treatment or

route of administration and were excluded. Four patientsdiscontinued SIT because of nonimmunologic nonspecific reac-tions. Two patients discontinued SIT because of pregnancy, 5because of subjective spontaneous improvement, 4 because oflack of clinical improvement, and 1 because of an asthmaexacerbation unrelated to vaccination. Eighteen patients discon-tinued without a specific reason but without experiencing adverse

events and 7 because they moved. Twelve patients could not becontacted.

Safety of SITA31-year-old patientwithasthma,monosensitized toDpteronys-

sinus, whowas stable and onmaintenance treatment formore than 3years,without previous reactions, experienced ananaphylactic reac-tion 1 minute after the administration of the 61st dose of treatment.The reaction was rapidly resolved with subcutaneous epinephrine,intravenous methylprednisone, and nebulized salbutamol. It sup-poses 0.009%of the administered and 0.7%of the patients complet-ing the follow-up. SITwas discontinued at that point. Four patientsrequired changes in the adjuvant or route of administration becauseof local reactions and/or the presence of subcutaneous nodules.

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TABLE E1. Rhinitis severity: symptoms and medication score

Symptoms

Sneezing AND/OR nose itching 0 Absent

1 Mild

2 Moderate

3 Severe

Anterior rhinorrhea 0 Absent

1 Mild

2 Moderate

3 Severe

Nose obstruction 0 Absent

1 Mild

2 Moderate

3 Severe

Postnasal drip 0 Absent

1 Mild

2 Moderate

3 Severe

Medication

0 No medication needed

1 Topical steroids OR oral

antihistamines

2 Topical steroids AND

oral antihistamines

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TABLE E2. Asthma severity combined score: symptom score, medication score, and lung function

Symptoms

0 No symptoms

1 Less than 5 short episodes (<7 d long) without any symptoms between crisis

2 Five to 10 short episodes (<7 d long) without symptoms between crisis or airflow obstruction less than 12 wk per year

3 More than 10 short episodes without symptoms between crises or airflow obstruction less than 12 wk per year

4 Frequent symptoms and airflow limitation for more than 6 mo in 1 year; 2 or 3 emergency department attendances

5 Incapacitating and chronic asthma with severe and frequent exacerbations despite optimal treatment; more than 3 emergency

department attendances

Medication

0 No treatment

1 Intermittent short-acting b2-agonists

2 Cromones

3 Inhaled steroids

4 Inhaled steroids plus sustained release theophylline or 1-3 oral short glucocorticosteroid treatments

5 Regular oral steroid treatment (lowest dose) or more than 4 oral steroid courses

Lung function

0 Normal base spirometry (FEV1 >80%)

1 Complete reversible airflow limitation after inhaled bronchodilator

2 Partial reversible airflow limitation after inhaled bronchodilator

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