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From the Townsend Letter
August/September 2014

Reactions to Sub-Lingual Immunotherapy: An Analysis of a Group of Patients Who Developed Adverse Events over a Period of 5 Years
Does Glycerin play a role?
by Diego Saporta, MD
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Table 12 shows that the majority of the AEs occurred while administering the first treatment bottle (73.3% in the GI group vs.74.5% in the non-GI group). The occurrence of AEs during administration of more concentrated (advanced-dose) bottles drastically decreased for both groups which is in agreement with published literature, that AEs occur less frequently later on in the treatment.9 When comparing both groups, the incidence of AEs while administering advanced bottles (second and subsequent bottles, including maintenance bottles) patients in the GI group had an incidence of AEs of 26.7% vs. 8.5% in the non-GI group. The results of χ2 tests applied to these observations reveals that there is no significant difference for Bottle 1, but marginal significance when considering Advanced Bottles (χ2 = 3.34, p < 0.1). These findings support the suggestion that there is no dose response for SLIT-related AEs and that the incidence of AEs decrease as treatment progresses. In our series, GI symptoms are clearly more frequent at the beginning of the treatment (73.3% of the patients). This is in disagreement with published literature as GI AEs are reported to be more frequent at higher doses.9 Still, when considering only AEs that developed during administration of high (advanced) doses, these reactions were more frequent in the GI group (as stated before, results attain marginal statistical significance).

Table 12: Onset of Symptoms

Symptoms Developed During

Total sample (%)

GI subgroup (%)

Non GI (%)


Bottle 1

46 (74.2)

  11 (73.3)

 35 (74.5)


Bottle 2

 7  (11.3)


  7 (14.9)


Advanced Bottle (>2+M)

   8  (12.9)

  4 (26.7)

   4 (8.5)


? Bottle

 1  (1.6)


   1 (2.1)


Total Sample (%): 62 patients (% of 62)
GI subgroup (%): 15 patients (% of 15)
Non GI (%): 47 patients (% of 47)
p: Probability after χ2 (Chi-squared test)
NS: Not significant
Bottle 1: Symptoms developed while treating from first bottle
Advanced Bottle: Symptoms developed while treating from 3rd Bottle or Maintenance Bottle
? Bottle: No information during which bottle AE developed

Table 13 shows how many patients were managed with one, two, or more of the four interventions described above. The majority of the patients received one intervention (64.5% in the total sample). When comparing the GI patients vs. the non-GI patients managed with one intervention (53.3% GI vs. 61.7% non-GI), the χ2 results indicate that there is no significant difference between the groups. When analyzing the patients who required many interventions it was found that 20.0% of the patients (3/15) in the GI group were managed with 3 or 4 interventions vs. 2.1% of the patients (1/47) in the non-GI group. In this case while the number of observations may seem too few, the results of the χ2 analysis indicates that there is indeed a significant difference between these two groups (χ2 = 6.01, p < 0.05). This result may suggest that when patients developed GI AEs their cases were more complex to manage and required more interventions for AE management. Ultimately, as previously shown, management was not successful to control patient's symptoms as 93.3% of the patients eventually quit.

Table 13: Number of Interventions Done to Control AEs

Number of Interventions

Total sample (%)

GI (%)

Non GI (%)


1 intervention

  40/62 (64.5)

8/15 (53.3)

 29/47 (61.7)


2 interventions

  17/62 (27.4)

3/15 (20.0)

 15/47 (31.9)


3–4 interventions

   5/62 (8.1)

3/15 (20.0)

 1/47  (2.1)


No interventions

   3/62 (4.8)

1/15 (6.7)

 1/47  (2.1)





 1/47  (2.1)


Total sample (%): 62 patients (percentage of 62)
GI (%): GI group of 15 patients (percentage of 15)
non-GI: non-GI group of 47 patients (percentage of 47)
?: Intervention used is not known
p: Probability after χ2 (chi-squared test)
NS: Not significant

Table 14 shows how many patients had 1, 2, 3, or more symptoms. The patients in the GI group tend to have more symptoms than the non-GI patients. When comparing the GI vs. the non-GI groups, 13.3% GI vs. 29.8% non-GI had 1 symptom but 13.3% GI vs. 8.5% non-GI had 4 or more symptoms. The results of the χ2 test showed no significant differences between the two groups, probably due to the limited sample (mainly in the GI group); but this observation might suggest that patients with GI symptoms also develop other symptoms.

Table 14: Number of Symptoms

# S's

TS (%)

GI (%)

Non-GI (%)


17/62 (27.4)

2/15 (13.3)

 14/47  (29.8)


14/62 (22.6)

4/15 (26.7)

 11/47  (23.4)


5/62   (8.1)

0/15  (0.0)

  5/47  (10.6)


6/62   (9.7)

2/15 (13.3)

  4/47   (8.5)


29/62 (46.8)

7/15 (46.7)

 13/47  (27.7)

# S's: Number of symptoms
TS: Total sample (62 cases)
GI: Group with GI symptoms
Non-GI: Remaining group of 47 cases
(%): Percentage
4>: Four or more symptoms
?: How many symptoms developed is not known

1.  The most common complaints in this series occurred in the group Skin. The most common symptom is "itching" that developed not necessarily in the perioral region; rather, in the face and even more frequently in distant areas of the body beyond the face.

2. Symptoms pertaining to Skin, OP, and GI groups held 67% of the complaints, which is concordant with the AEs reported in the literature as "common" or "usual."

3. The large majority of the AEs occurred during the administration of the first bottle (74.2% in the total sample). As bottle concentration increased, the number of AEs tended to decrease. AEs occurred mainly with 1 to 3 drops from each bottle. Our findings would support the contention that there is no dose-response curve for AE development and that the AEs occur during the induction phase and with low doses of antigen.9,30

4. The majority of the reactions reported in our series can be considered as systemic reactions: 69.9% (or 83.5% if GI group is included). Local reactions occurred at a rate of 30.1% (or 16.5% if GI group is excluded).

5. Considering the classification of AEs according to severity, the majority of reactions in this study can be classified as moderate or severe according to one classification or as moderate according to another classification.2,30 No serious adverse events were identified in this series; in other words, there were no life-threatening events.

6. This review suggests who patients who develop an AE during SLIT administration will probably quit the treatment. In support of this contention, while a maximum of 34% of the patients in a nonselected group were found to quit for reasons other than the development of AEs, 85.5% of the patients who developed AEs quit. More than 1/3 of those quit within 3 months (37.1% of the total sample of 62 patients, or 43.4% of the 53 patients who quit). In other words, this study suggests that once an AE develops, it is highly likely the patient will quit treatment and this will occur within 3 months of the AE-onset for a large number of the patients. Our finding of "spontaneous quitting" in a non-selected group is in agreement with at least one report that evaluated clinical outcomes but it is different from figures obtained from results of randomized controlled trials.2,28

7. Patients who develop GI symptoms appear to have a higher rate of treatment interruption (93.3% vs. 83.0% of the patients in the non-GI group).

8. From the 4 interventions for dose modifications here described, 58% of patients required 1 intervention and 87% were managed with 1 or 2 interventions.

This is a retrospective analysis of all of the AEs that occurred during the 5-year period of this study. While most of the published literature addresses the issue that in a certain group of SLIT patients, a percentage will develop AEs, this appears to be the only report that analyzes a group of patients who had already developed AEs, as there is no information in the literature that we are aware of which evaluates ultimate outcome of the patients who developed AEs during SLIT treatment. This study strongly suggests that once an AE develops, chances of quitting treatment are high. Certainly financial, social, personality, or other circumstantial factors can determine that a patient stops SLIT treatment, but the AE itself appears to be a strong factor leading to SLIT discontinuation. In support of this statement is the different rate of 27% to 34% of "spontaneous" discontinuation versus almost 86% of AE-related discontinuation. Certainly not having a prospective study with a control group is a shortcoming, but it is interesting that in randomized control trials, less than 7% of patients quit treatment, while in a report on patients attending a clinic setting 31% had discontinued, a figure that, as we said, is similar to our discontinuation figures of 27% - 34%.2,28 It is possible that in clinical practice, the number of patients quitting the treatment is higher than the reported figures in reference #2. The reason may be that in randomized trials, enrolled patients are under stricter control. As opposed to that, in private practice, one or more of the above discussed factors will determine ultimate compliance. Since this analysis suggests that once an AE develops, the patient is highly likely to quit treatment, we think that it is important when an AE develops to promptly counsel the patient. The patient should be told that a serious reaction during SLIT administration is extremely unlikely. (A serious reaction implies a life-threatening event.43) If the patient is comfortable with the idea of managing the AE, then dose modifications and/or symptomatic treatment can be attempted. On the other hand, this is the moment to advise the patient that there are other treatment modalities available for management. Immunotherapy can also be administered with SCIT. SCIT requires patients to receive weekly injections for a rather long period of time. The "usual problems" with SCIT are that patients may not have the time or will to comply, or they may develop arm pain that renders treatment uncomfortable or even at times intolerable. With SCIT there is also the risk of severe reactions as explained above. This concern applies not only to the patient who has hyperreactivity of the lower airways but also for the patient with poor health who may not tolerate an injection of adrenaline should it be necessary. Another available modality is LDA (low dose allergen immunotherapy). It uses ultralow doses of allergens. At this time it is not understood how this treatment modality works, which is a drawback for physicians to incorporate it into their armamentaria.44

The symptoms reported in this article suggest that most of the AEs occur in the skin, face, OP and GI tract (pertaining to our Skin, OP, and GI groups), which is in agreement with published literature.14,27-29 If we consider individual symptoms rather than groups, our findings strongly suggest that itching of the skin is by far the most common complaint during SLIT administration. Published literature suggests that the most common AEs are local symptoms  usually related to the oral cavity, where itching is one of the symptoms that frequently occurs.2,30 Our findings in this respect are not in agreement with the reported literature as this itching occurs not necessarily in the lips or perioral area but rather on the face and other parts of the body (see Table 4). This is why we do not find it useful to classify SLIT AEs as "local or systemic reactions" because the majority of the events, while being by definition "systemic" are not "dangerous." We think that a severity-based classification has more clinical usefulness. In this respect, we favor the classification that involves the terminology mild, moderate, and serious.30 A serious AE is defined as an untoward reaction that is life-threatening (including death) or determines a hospital admission.43 Following this criterion of severity, none of our reactions were serious. This is in agreement with published literature and with our own overall experience of more than 10 years working with SLIT and supports the contention that SLIT is a very safe treatment modality. Certainly modifying the treatment dose would fit the criteria of a moderate reaction or severe reaction, according to both of the above-mentioned classifications.2,30  Given that we find decreasing the treatment dose more useful than observing if an AE resolves spontaneously despite dose progression or even while maintaining the same dose, we believe that for our type of clinical practice, a definition of severity correlates better with the concept "serious reactions" rather than a definition of severity related to modification of the treatment dose.2,30 In other words, we routinely modify the treatment dose each time we encounter an AE even if there are no serious reactions. We think that the concept of "moderate" or "severe" reaction should be used when more significant symptoms develop (see farther down), when there is a recurrence of the reaction, or when there is a need for medications other than usual allergy medications (for example if oral steroids or parenteral medications were required). The four interventions here described, in one way or another will decrease the dose that is administered to the patient.

We think that immunotherapy is a type of treatment that should be based in safety and not in speed. The results of an intradermal dilutional test will determine the initial level of reactivity for each of the reactive allergens for the particular patient being tested. The initial treatment doses based on this test will already be immunogenic (meaning the treatment will be effective from early on). In other words, when SLIT is administered based on the results of that (or similar) test, it is expected that patient's symptoms will start to improve soon after treatment initiation; therefore there should be no rush to increase the treatment dose. We think that when AEs develop, the treatment should be slowed down rather than rushed. Most reported severe reactions after SLIT administration occurred during rush protocols, overdosing, or treatments with no updosing protocol.19,20,45,46 Patients who developed severe reactions were often asthmatic.18,20,46 For this reason, we think that asthmatic patients should be considered "brittle" patients even when treated with SLIT. Their management should always be done with caution, advancing dose slowly and always paying attention to patient's respiratory symptoms. We believe that a practitioner should never rush to treat an asthmatic patient with any type of immunotherapy. Certainly not all asthmatic patients are the same. Asthma is a disease that covers a broad spectrum from barely perceptible to life threatening. However, once immunotherapy treatments are instituted, we think that careful management should be the norm. There is evidence that fatalities from immunotherapy, although rare, are more common in asthmatic patients, and we have found that a large percentage of immunotherapy patients have lower airway hyperreactivity without being aware of it.26,47,48 This is why we consider it important to determine if the patient has potential hyper reactivity of the lower airway before testing, as we know that these are the patients who can run into problems during testing or treatment. Although SLIT is much safer than SCIT, both modalities require the same diagnostic testing.

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