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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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The first four symptoms in Table 4 account for 35.9% of the complaints (37/103), and the first 5 symptoms account for 40.8% of the complaints (42/103). Itching/rash of the skin is by far the most common complaint, and it is not necessarily limited to the perioral area. In bold we have identified the complaints that are reported in the literature as "local reactions."2 The majority of the patients reported either 1 or 2 symptoms (see Table 5).

Table 5: Number of Reported Symptoms

1 symptom

2 symptoms

3+ symptoms


36 (58.1)

14 (22.6)

12 (19.3)


Total number (percentage)
3+ symptoms: patients who reported 3 or more symptoms

Symptom Groups
Given that symptoms were tabulated as described by the patient, and because many were clearly similar, we gathered the symptoms in groups that contain complaints belonging (anatomically or functionally) to the same body system with the exception of the group "constitutional," wherein we grouped somewhat disparate symptoms. These groups are presented in Table 6. Table 7 contains the groups arranged by frequency.

Table 6: Symptoms Arranged by Groups









Itchy Throat


Nasal Obstruction


Cold Sweat

Mood Changes

Itchy eyes

Lips tingling



Short of breath


Behavioral changes

Itchy face

Lips swelling

Stomach pain


Tight chest


Feels weird

Itchy lips

Lips dry/chapped





Smell perversion

Itchy skin

Sore throat






Rash face

Throat burning






Rash skin

Throat dryness






Swollen eye-lids

Throat tightness







Tongue burning







Tongue tingling






Table 7: Groups Arranged by Frequency

























#: Number of times a symptom pertaining to a group is reported
%: Percentage calculation based on a total of 103 complaints

The groups OP (17 cases) and GI (14 cases) hold what has been reported as local reactions for a total of 31 cases or 30.1%.2 The remaining AEs include 72 cases (skin: 38, respiratory: 14, constitutional: 11, psychoneurological: 6, and nasal: 3), or 69.9%. All these can be classified as systemic AEs. If GI symptoms were considered systemic AEs, the percentage would increase to 83.5%. We have classified itchy lips (1 case) in the skin group and taste-related complaints (2 cases) in the psychoneurological group. Even counting these 3 cases as local reactions, we would have a total of 34 cases, or 33.0%; therefore, it is clear that the majority of the reactions in this report are systemic (even more so if GI symptoms are counted as systemic reactions). The groups skin, OP, and GI hold the symptoms reported in the literature as the "common" or "usual" AEs, and the groups skin, nasal, and respiratory hold most of the symptoms reported as systemic.2,14,27-29 Symptoms grouped under constitutional and psychoneurological are not very prevalent. They are not commonly reported either, but they can clearly be classified as systemic.

Patient Management
Our management of the AEs has consisted primarily of dose adjustment, with occasional use of allergy medications. When medications were utilized, they were allergy medications. Spasmolytics or antiemetics were never utilized (GI symptoms in our experience resolved when treatment was discontinued), and it was never necessary to administer oral steroids or any parenteral medication.

The specific interventions for dose adjustment included:

  1. decreasing and subsequently increasing treatment dose
  2. discontinuing and restarting treatment
  3. diluting treatment bottle
  4. dividing treatment dose in smaller a.m.–p.m. doses

Decrease/Increase Number of Drops
The management for this group consisted of decreasing treatment dose and staying at the lower dose for two weeks before readvancing as per protocol.35

Discontinue and Restart
The management for this group consisted of stopping treatment until AE resolved. After this, treatment was restarted at 1 drop. When reaching the dose below the one that elicited the AE, the treatment dose was not advanced for 2 weeks. After this, it was readvanced as per protocol.

Diluting Treatment Bottle
In this group there were two different management circumstances:

  1. Symptoms developed upon administration of first drop; in this case the bottle was diluted immediately and treatment restarted at 1 drop of diluted bottle and advanced as per protocol.
  2. Symptoms occurred during dose advancement; in this case the dose was decreased and readvanced as in previous group. If AE repeated, bottle was then diluted and started at 1 drop of diluted bottle as above.

Divide Dose
The management for this group consisted of giving the total dose in 2 smaller doses administered twice a day (a.m. and p.m.) as follows: First dose was 1 drop per day; following week dose was advanced to 2 drops: 1 drop a.m. + 1 p.m.; following week 3 drops: 2 a.m. + 1 p.m.; following week 4 drops: 2 a.m. + 2 p.m.; following week 5 drops: 3 a.m. + 2 p.m.

The majority of the patients were managed with one intervention, but some required more (see Table 8).

Table 8: Number of Interventions for AE Management

# Int

 # (%)


36 (58.1)


18 (29.0)


 3 (4.8)


 1 (1.6)


 2 (3.2)


 2 (3.2)


62 (99.9)

# Int: Number of Interventions
# (%): Number of patients (percentage)
None: There was no need to intervene
?: No information on interventions used.

Final Outcome
We observed that many of the patients were not actively receiving treatment at the time of data collection. Defining "completion of the treatment" as 36 months, there were 9 patients who were either still active or had completed treatment at the time of data collection. The remaining patients were not active (see Table 9). Establishing an arbitrary limit of 3 months, we found that 23/62 (or 37.1%) patients had quit within 3 months of AEs onset and 18 after 3 months, and in 12 cases we did not have information on quitting date. In other words 53/62 (or 85.4%) of the patients did not complete the treatment after onset of AEs. Considering the total number (53) of patients who quit, 23/53 (or 43.4%) quit within 3 months of AE onset.

Table 9: Patients Who Quit After AE Onset

Treatment status



Completed RX



Quit RX



Quit RX <3 months



Quit RX >3 months



Information N/A



Total patients



Completed RX: Completed treatment.
Quit RX: Quit treatment.
<3 mo: quitting 3 months or less from AE onset.
>3 mo: quitting more than 3 months after AE onset.
Information N/A: Information when quitting occurred is not available.
%: percentage calculated over the total of 62 patients.

To further assess this finding, a group of 100 charts from patients on SLIT was randomly collected. Defining "quitting" as not ordering bottles for more than two consecutive cycles (6 weeks for each cycle during escalation), we found that 27 patients had quit and another 7 patients had an indeterminate status. Therefore in this group of 100 nonselected SLIT patients, 27.0% to 34.0% quit treatment for reasons not necessarily related to the development of AEs. Note that this number is similar to the 31% rate of treatment discontinuation reported in the literature.28

Special circumstances
Taste-related complaints
It has been reported that some patients complain about taste.42 This is not a common complaint. We found two patients who complained about taste; one eventually developed tolerance and the other changed treatment to SCIT, so no direct intervention was done in these cases.

Gastrointestinal symptoms
From the total sample of 62 patients, it was found that 15 had GI symptoms (nausea, vomiting, pain, and/or diarrhea) with or without other symptoms. This group will be referred to as the GI group. The remaining of the total sample will be referred to as the non-GI group (47 patients).

The patients in the GI group have somewhat different clinical characteristics than those in the non-GI group. This will be discussed in Tables 10 through 14. All comparisons will be done between the 2 subgroups extracted from the total sample: the GI group vs. the non-GI group. Table 10 shows that GI symptoms, in agreement with reported literature, occur with similar frequency in adults and children.9

Table 10: GI Demographics

GI Demographics


GI group






< 13


 Male <13


 Female <13


<13: Patients younger than 13 years

Table 11 analyzes the absolute numbers and the percentages of patients who are either active or have quit treatment. While 83.0% of the patients in the non-GI group have quit at the time of data collection, this percentage increased to 93.3% when considering the GI group (14 out of the 15). Considering the subgroup of patients who quit within 3 months, there also appears to be a difference with 40.0% of the GI group having quit within 3 months versus 34.0% in the non-GI group. However the results of a chi-squared (χ2 ) test revealed no statistical difference between these two results. The small sample size may influence the lack of statistical significance, but the different percentages may suggest that patients in the GI group are more likely to quit.

Table 11: Active and Nonactive Patients


TS # (%)

GI  # (%)

non-GI # (%)


 9/62 (14.5)

 1/15 (6.7)

 8/47 (17.0)


53/62 (85.5)

14/15 (93.3)

39/47 (83.0)

  < 3 mo

  22/62 (35.5)

   6/15  (40.0)

  16/47 (34.0)

  > 3 mo

  18/62 (29.0)

   4/15 (26.7)

  14/47 (29.8)


  13/62 (21.0)

   4/15 (26.7)

  9/47 (19.1)

TS: Total sample (62 cases)
GI: Subgroup of 15 patients who developed GI complaints
Non-GI: Subgroup that remains when GI group (15) is subtracted from total sample (62): 47cases
# (%): Number of patients (percentage)
<3 mo: Quitting occurs 3 months or less from AE onset
>3 mo: Quitting occurs 3 months or more from AE onset
N/A: Information when quitting occurred is not available

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