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Introduction
Immunotherapy can be administered either by injections (subcutaneous injection immunotherapy, or SCIT) or as oral vaccines (sublingual immunotherapy, or SLIT). SLIT consists of administering the allergens under the tongue. These oral drops are held in the sublingual area for a variable time according to different protocols, and then swallowed. Despite the fact that SLIT is occasionally portrayed as a new development, treatment with oral vaccines is very old (earliest description dates back to the year 1900) potentially older than the first injection treatments.3 The last two to three decades witnessed a very significant development and understanding of this immunotherapy technique.1-4 Since the early 2000s, rapidly dissolving tablets have been manufactured to deliver allergens sublingually.5,6 The main difference between oral drops and rapidly dissolving tablets is that while the allergy drops can be prepared in a doctor's office according to test results (therefore including all the allergens that are necessary to control patient's allergic disease), the oral tablets (manufactured by pharmaceutical companies) have only one or a few allergens, usually provided with no updosing schedule.
There is a consensus in the literature that SLIT is considered safe, as reactions during administration are generally mild. SLIT reactions (SRs), also known as adverse events (AEs), appear to occur more frequently than reactions to injection immunotherapy. For example, SLIT AEs are reported with a variable rate of 9.6%, 20%, 23%, or even 78%, while systemic reactions after SCIT administration occur with a variable rate of 0.05 to 0.23 per 100 injections.5,7-12 Even children treated by injections had an incidence of reactions of less than 4%, most of them local arm reactions.13 It has been reported that SLIT AEs subside spontaneously, usually in a few days without any intervention.6,14 Unlike what happens with injections (SCIT), it has been suggested that the occurrence of SLIT AEs does not depend on the dose of allergen administered.9,15 This would imply that the AE does not develop upon advancing the dose. In support of this contention is the fact that the occurrence and severity of AEs gradually decrease in the subsequent years of treatment.9 It has also been suggested that regardless of the aggressiveness of the protocol used during dose induction, there are no differences in the rate of the AEs.16 Some authors have even proposed continuing with the same dose as the one that elicited the AE on the assumption that the AE will resolve during treatment continuation.17
In the last few years, several cases of severe reactions after SLIT administration have been reported wherein patients suffered asthma attacks, in some cases severe enough to require hospital care.18-21 Despite these reports, SLIT safety is undisputed. While SCIT carries a risk of severe reactions including mortality, there has not been a single report of mortality due to SLIT administration for the treatment of inhalant allergies.2,14,22-27 AEs that are usually reported include labial or buccolingual edema, itching in oral cavity or other parts of the face, throat irritation, rhinoconjunctivitis and gastrointestinal (GI) symptoms.14,27-29
Classifying SLIT reactions is difficult. There is still no universally accepted system to grade and classify AEs; however, severity and/or persistence of the AE can result in SLIT discontinuation.2 Classifications of AEs have been proposed according to site of origin (local vs. systemic) or to severity (mild, moderate, and severe, or mild, moderate, and serious).2,30 It has also been suggested to consider SRs as early or late, depending on whether they develop before or after 30 minutes of drop-administration.2 Local reactions are reported as frequent and systemic reactions are reported as rare. There is no uniform criteria for inclusion of symptoms, as different authors report different symptoms for each group (local vs. systemic).2,9 For example, local reactions are reported as oral itching and/or swelling and gastrointestinal (GI) complaints, or altered taste perception, itching of lips, swelling of lips, itching of oral mucosa, swelling of oral mucosa, itching of ears, swelling of tongue, glossodynia, mouth or tongue ulceration, throat irritation, uvular edema, nausea, stomach ache, vomiting, abdominal pain, and diarrhea.2,9 Systemic reactions are reported as cutaneous symptoms (urticaria and itching), ocular symptoms (redness, itching, tearing), nasal symptoms (itching, sneezing, rhinorrhea, obstruction), asthma symptoms (cough, wheezing, shortness of breath, chest tightness), or rhinitis, asthma, urticaria, angioedema, and hypotension.2,9 While systemic reactions are usually mild and their incidence is similar in active or placebo groups, oral and gastrointestinal reactions appear to be more frequent in active groups, occurring with a similar rate in adults and children.9,31,32 AE duration is reported not to exceed 10 days, and occurrence and severity gradually decrease in the subsequent years of treatment.2 GI complaints (nausea, stomach pain, vomiting, abdominal pain, and diarrhea) are usually included with the local reactions unless they occur with other systemic manifestations, in which case they are classified as systemic reactions.2,9 AE management usually involves dose adjustment or symptomatic treatment.2,15,30,32,33 Symptomatic treatment includes one or more of oral antihistamines, antiemetics, and/or spasmolytics.2
Treatment discontinuation because of SLIT reactions has been reported as less than 7% in several randomized controlled trials using oral tablets but as high as 31% despite symptomatic improvement in a clinical trial when using sublingual drops and appears to be related mainly to the development of local reactions.2,28,34 It is not clear if there is a dose-dependent relationship for the development of AEs except for the gastrointestinal complaints that are reported to occur more frequently with higher doses.9 Some reports suggest that the majority of AEs occur during the induction phase and with low doses of allergen.9,28,30
SLIT has been administered in our practice for more than 10 years by utilizing a previously published protocol.35 For a period of 5 years, records of cases where SLIT administration elicited any problems were kept. The analysis of all the AEs collected in this period is presented here. Due to the nature of this article, we cannot determine what percentage of SLIT patients develop AEs during the course of treatment, as what we have done is just to collect all the cases wherein patients developed AEs during the described period of time. By the nature of this treatment (home-based immunotherapy), we cannot be sure that all the reactions developed in that period of time were reported. Still, the present list is representative of our experience.
Methods
Patient Population
Patients were adults or children of either sex that presented with nasal allergy symptoms, with or without a diagnosis of asthma.
Testing
Most patients were tested using a 5-fold intradermal dilutional skin test (IDT) as taught by the American Academy of Otolaryngic Allergy (AAOA) and Pan American Allergy Society (PAAS).36,37,41 In our practice, this test includes the following panels: dust, epidermals, molds, and pollens for our geographic area.38 Standardized antigens were used for testing and treatment whenever these were available; otherwise weight/volume antigen extracts were used.39,40 This type of intradermal skin test characteristically diagnoses multiple reactivities; therefore, most of our patients have positive reactions to allergens in the dust-dander, and pollen panels, and some patients also have positive reactions in the mold panel.
Management of the Asthmatic Patient
Asthmatic patients are tested only when their asthma is well controlled. These patients are routinely treated with inhaled corticosteroids before testing. If a patient's asthma is so severe that it cannot be brought under control ("brittle" patient), this person will not be tested or treated. If a patient becomes symptomatic while receiving SLIT, treatment will be interrupted until the patient is stabilized.
SLIT Treatment
According to our protocol, patients are treated with an escalating dose and a maintenance dose.35 During escalation, the patient starts with 1 drop every day for one week, and once a week the dose increases by 1 drop until reaching 5 drops per day. Maintenance dose is attained when a patient takes 5 drops from a bottle mixed from the manufacturer's extract vials.35 In the overwhelming majority of our patients, the maintenance dose is attained uneventfully. Following the above techniques, a maintenance bottle (mixed from manufacturer's extracts) will have a 25-fold dilution of such extracts (1:5 dilutions are used, and 1/25 of the volume to be prepared is added to the treatment bottle).36,37,41 With an intradermal dilutional test, it is the norm that multiple positive results are obtained. To have an idea of the major allergen content in such solutions, if one of the allergens with which the patient is treated is for example dust mite (extract contains 10.000 AU/mL), 5 drops will provide 1700 AU, which means that such a patient will receive 620,500 AU per year. With our protocol, the cumulative oral dose per year is approximately 2.5 times larger than the injectable cumulative yearly dose.35
Adverse Event reporting
By the nature of this treatment (home-based immunotherapy), AEs are reported by patients. Each time a patient presented an AE during SLIT administration, the case was managed and recorded for future reference. Frequently the situation was managed over the phone. Information was gathered in this way for 5 years. All gathered information was subsequently analyzed. Data were recorded on a spreadsheet using only pertinent information: patient's age and sex, description of the AE, and how it was managed at the time. The patient's privacy was kept confidential at all times.
Results
Sixty-two patients were identified for analysis. See Table 1 for demographic information.
Table 1: Demographic Information
| Patients |
# |
% |
Male |
19/62 |
30.6 |
Female |
43/62 |
69.4 |
Total Patients |
62 |
100.0 |
< 13 |
20/62 |
32.3 |
< 13M |
9/20 |
45.0 |
< 13F |
11/20 |
55.0 |
Asthma |
16/62 |
25.8 |
Asthma M |
6/16 |
37.5 |
Asthma F |
10/16 |
62.5 |
#: Number of patients
%: percentage
<13: patients 13 years old and younger
<13M: male patients 13 years old and younger
<13F: female patients 13 years old and younger
Asthma M: Male patients with asthma
Asthma F: Female patients with asthma
AE Onset
AEs developed mainly during administration of the first treatment bottle. Two cases developed during the second bottle, seven during the third bottle, and six during maintenance. Table 2 shows all the AEs (without distinction as to whether the reaction was local or systemic), including information on the dose at which the AEs occurred: first drop, second drop, and so on. AEs that occurred during administration of second and third bottles are reported together in the table as advanced bottle (Adv B). The majority of the AEs (74.2%) occurred during the administration of the first bottle, and it appears that more reactions occur with the first, second, or third drop of any bottle, so again this may suggest that the AEs develop rather early in the treatment.
Table 2: Dose At the Time When AE Developed
| Bottle |
# |
% |
D1 |
D2 |
D3 |
D4 |
D5 |
? |
B-1 |
46 |
74.2 |
12 |
10 |
12 |
3 |
6 |
3 |
Adv B |
9 |
14.5 |
2 |
1 |
3 |
|
|
3 |
Maint |
6 |
9.7 |
1 |
|
1 |
2 |
|
2 |
No Info |
1 |
1.6 |
|
|
|
|
|
|
Total |
62 |
100.0 |
|
|
|
|
|
|
B-1: First treatment bottle
Adv B: Advanced bottle (other than maintenance)
Maint: Maintenance bottle
No Info: Not known when AE developed
#: Number of patients
%: Percentage of patients
D1 to D5: First, second … fifth drop
?: Number of drops that elicited the AE is unknown
Reported symptoms
Sixty-two patients reported 39 symptoms. Total number of complaints was 103. Symptoms are presented according to the patient's description; therefore, some complaints appear to be slight variations of the same symptom. While some of the patients reported 1 symptom, some reported 2, 3, or even more symptoms. The symptoms, as reported by the patients, are presented alphabetically in Table 3. Table 4 has the same symptoms but they are arranged according to incidence.
Table 3: Reported Symptoms, Alphabetically
| Behavioral changes |
Itchy eyes |
Palpitations |
Throat burn |
Cold sweat |
Itchy face |
Rash face |
Throat dry |
Cough |
Itchy lips |
Rash skin |
Throat tight |
Diarrhea |
Itchy skin |
Smell perversion |
Tight chest |
Dizziness |
Itchy throat |
Sneezing |
Tired |
Dry/chapped lips |
Lip tingling |
Shortness of breath |
Tongue burn |
Eczema |
Lips swollen |
Sore throat |
Tongue tingling |
Feels weird |
Mood Changes |
Stomach pain |
Vomiting |
Headaches |
Nasal obstruction |
Swollen eyes |
Wheezing |
Insomnia |
Nausea |
Taste |
|
Table 4: Reported Symptoms Arranged by Incidence
| Rash Skin |
14 |
Nausea |
3 |
Cold Sweat |
1 |
Mood Changes |
1 |
Itchy skin |
11 |
Rash face |
3 |
Diarrhea |
1 |
Nasal obstruction |
1 |
Itchy throat |
6 |
Shortness of breath |
3 |
Dizziness |
1 |
Smell perversion |
1 |
Stomach pain |
6 |
Throat tight |
3 |
Dry/chapped lips |
1 |
Sore throat |
1 |
Cough |
5 |
Swollen eyes |
2 |
Eczema |
1 |
Throat burn |
1 |
Tight chest |
5 |
Tired |
2 |
Feels weird |
1 |
Throat dry |
1 |
Headaches |
4 |
Taste |
2 |
Insomnia |
1 |
Tongue burn |
1 |
Vomiting |
4 |
Palpitations |
2 |
Itchy lips |
1 |
Tongue tingling |
1 |
Itchy eyes |
3 |
Sneezing |
2 |
Lip tingling |
1 |
Wheezing |
1 |
Itchy face |
3 |
Behavioral changes |
1 |
Lips swollen |
1 |
|
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