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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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While respiratory symptoms are typically considered "dangerous," none of the patients who had respiratory symptoms in this review required hospital care, nor did the patients come to the office because of respiratory complaints. Many of these symptoms (as commonly occurs with SLIT) are described by the patient over the phone and often never verified by the physician. Despite the stated fact of having never encountered a serious reaction to SLIT, we recognize that not all the symptoms developed during an AE are the same. In this respect, we tend to consider some symptoms occurring during AEs as more significant. This is a deliberate choice of words that avoids "severe" or "serious." The list of symptoms that we consider "significant" is shown in Table 15.

Table 15: Significant AEs

 

 

Tight throat

Taste/smell complaints

Tight chest

Headaches

Shortness of Breath

Nausea

Wheezing

Vomiting

Severe Cough

Stomach pain

Palpitations

Diarrhea

Severe skin rash

Behavioral/mood changes

We propose that these symptoms should be treated more aggressively. From the four maneuvers described above, diluting the treatment bottle or dividing the dose in two smaller a.m.-p.m. doses are more involved maneuvers. In other words, we propose that management of an AE should start by decreasing the number of drops and stopping and restarting treatment if necessary, reserving the other two maneuvers (bottle dilution and b.i.d. dosing) for persistence or recurrence of symptoms, or for the presence of the above (significant) symptoms.

SLIT reactions do not exhibit a dose-response curve, which is the case with SCIT. That is, AEs do not appear to have a higher incidence when higher doses are attained. As shown in Table 2, the majority of the events occurred during a dose administered from the first bottle and over time the number of events decreased. This supports the findings in the literature, that the occurrence and severity of AEs gradually decrease in subsequent years of treatment and that they are more common with low doses.9,30 A lower dose implies that the patient is in the escalating phase of the treatment. The exceptions are the AEs that include GI symptoms. Literature reports that GI AEs (nausea, upper abdominal pain, vomiting, and diarrhea) are dose related. In other words, they occur more frequently with higher doses.9,33 It is also established that GI AEs are a cause for treatment discontinuation.9 In this review, the GI AEs clearly occurred more frequently at lower doses, but differently from other symptoms; they also developed during high doses or maintenance.

Common Characteristics of Patients Who Develop GI Symptoms (GI Group)
From our study it is clear that patients who develop GI AEs have the following characteristics:

  1. GI symptoms develop in adults and children with the same frequency.
  2. Patients with GI symptoms are more likely to quit treatment than the other patients with AEs: 93.3% GI vs. 83.0% non-GI.
  3. Considering early treatment interruption, it is more likely that patients with GI symptoms will discontinue within 3 months of AE onset: 40.0% GI vs. 34.0% non-GI.
  4. While the majority of the GI symptoms occurred with the administration of the first treatment bottle (same as with the non-GI patients), comparison of symptoms that occurred with higher (advanced) doses revealed that patients with GI symptoms appeared to develop more symptoms than non-GI patients: 26.7% GI vs. 8.5 % non-GI (p < 0.1).
  5. Patients with GI symptoms appear to require a higher number of interventions: Three or four interventions were required in 20.0% GI vs. 2.1% non-GI (p < 0.05).
  6. Patients with GI symptoms appear to have a tendency to develop multiple symptoms: 4 or more symptoms developed in 13.3% of the cases in the GI group vs. 8.5% in the non-GI group.

From an anecdotal point of view, we can add the following observations made over the years:

  1. Some patients clearly had a worsening of the GI side effects as dose increased; for example, the nausea or stomach pain getting worse with an increasing dose.
  2. Some patients developed symptoms upon administration of the first drop. In some of those cases, to our consternation, we observed that upon dilution of the bottle, some patients still continued to develop GI symptoms from the first drop. We found this with 5-fold and 25-fold dilutions of the allergens. This specific fact led us to suspect that the GI symptoms after SLIT administration may be related not to the allergens intended to treat the allergic disease but to a reaction to the diluent used for SLIT: glycerin.
  3. We have sometimes been able to overcome GI problems by diluting the drops in phenolated saline, or by administering the total dose in 2 smaller doses (b.i.d. dosing explained above). This fact may suggest that the amount of glycerin could be an issue.

The last two observations strongly suggested to us that glycerin might be the reason for the GI AEs. In other words, what we are proposing in this discussion is that when GI symptoms develop, these patients are actually reacting to the glycerin rather than to the involved allergens. In support of this point of view is the fact that GI AEs are not reported in studies that evaluate rapidly dissolving oral tablets.2,5 We do not consider GI symptoms local symptoms. Except for occasional complaints about taste, all of these symptoms develop in the stomach or lower segments of the GI tract and not in the area where the drops are applied. As discussed above, it is even more likely that the GI symptoms are not really reactions to the allergens but to the glycerin used as diluent. Overcoming this problem has proven very difficult for us, as the result was failure in the overwhelming majority of the cases (including those not part of this review).
The following is a summary of what we have done over time to manage the issue of glycerin sensitivity during SLIT administration:

  1. Diluting allergens in phenolated saline. Using phenolated saline instead of glycerin as a diluent has helped us on occasion but we realized that this maneuver works only when the allergens are still very weak (diluted). As dose advances allergens become more concentrated therefore the content of glycerin increases (manufacturer's extracts contain 50% glycerin). This is more pronounced when the number of allergens is large as commonly happens when treating from an intradermal dilutional test. Diluting allergens with phenolated saline is at best of transitory success.
  2. Dividing the total dose in b.i.d. dosing. This can help sometimes. Therefore this suggests that the total amount of glycerin plays a role. This is not true for all of the glycerin-sensitive patients, as some patients react immediately from the first drop, but others clearly react as the dose increases.
  3. Neutralizing the glycerin. Glycerin neutralization was attempted in several cases. Once the neutralizing dose (ND) was obtained, these patients would carry two bottles: One with the glycerin ND, the other with the "active solution" (which constitutes the "real treatment bottle"). The ND (that does not change over time) was given 5 minutes before the active one (that changes over time according to protocol).35 Even with this intervention, it is our experience that these patients ultimately quit.
  4. There is a fourth intervention that we are just incorporating into our practice consisting of spitting the dose after placing the drops in contact with the sublingual mucosa. This has been tried only a couple of times and we still do not have information as to whether it will be of any clinical value.

As stated above, there is some evidence in the published literature that GI symptoms occur with higher doses of SLIT. What we have found is that while the majority of the GI symptoms occur at the beginning of the treatment, a small percentage of patients develop GI symptoms as dose advances. In this case (high doses), the incidence of AEs is much higher in the GI group than in the non-GI group. Still we find it difficult to state that there is a dose dependency for GI symptoms. We found that GI symptoms occurred more frequently at high doses in the GI group (with or without other non-GI symptoms), but overall, GI AEs are clearly more frequent at the begging of the treatment; therefore we think that even for GI AEs there is no dose response. In this respect we think that the patients who develop AEs could be divided into two groups: in the first one (which contains the majority of the cases), patients are already sensitized and therefore they react immediately, or early on. In the other group (clearly the minority of patients with GI symptoms), there is a process of sensitization; therefore the dose will continue to advance during the time required to trigger symptoms.

For the reasons explained above, when we find patients on SLIT who develop GI symptoms, our approach is to try to change into another treatment modality (SCIT or LDA). An obvious solution to this problem would be to use glycerin-free allergens. In other words, we think that the symptoms related to skin, OP, and respiratory are the "real" AEs from SLIT, while the GI symptoms (and potentially the symptoms from the constitutional and psychoneurological groups) could be related to glycerin sensitivity. This is not a "black and white" situation. We have also seen diffuse skin rashes related to glycerin sensitivity. SLIT implies administering not only immunogenic allergens but also the diluent glycerin. It is known that some patients can react to the preservatives used in extract preparation. Glycerin is a very common chemical present in household and beauty supplies and other items, and it is not unusual to find patients who react to it.49 Certainly allergy tablets avoid this problem, as they do not contain diluent.
Interestingly, there is a relatively large number of cases in the GI group in which we lack information in reference to the total number of symptoms: 46.7% in the GI group vs. 27.2% in the non-GI group (Table 14). It is not clear why this happened. We could hypothesize that because many of these situations are handled over the phone, it is possible that these patients, after they called complaining of GI symptoms and were advised as to management, decided to quit. This could be due to symptoms' having been severe, or to failure of proposed intervention, and/or recurrence of symptoms that eventually led into quitting without any further follow-up. If this contention were correct, it could be assumed that the majority of the cases with no information in Table 14 probably developed symptoms with the first bottle, and were soon after that lost to follow-up.

Page 1, 2, 3, 4

Acknowledgement
Yassir Samra, PhD, was in charge of statistical analysis.
 
Notes

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  2. Passalacqua G, Baena-Cagnani CE, Bousquet J. Grading local side effects of sublingual immunotherapy for respiratory allergy: Speaking the same language. J Allergy Clin Immunol. 2013;132:93–98.
  3. Curtis HH. The immunizing cure of hay fever. Med News. 1900;77:16.
  4. Saporta D. Sublingual immunotherapy: a novel, albeit not so new, immunotherapy treatment modality. Am J Rhinol. 2008;22(3):253–257.
  5. Ibañez MD, Kaiser F, Knecht R, et al. Safety of specific sublingual immunotherapy with SQ standardized grass allergen tablets in children. Pediatr Allergy Immunol. 2007 Sep;18(6):516–522.
  6. Calderón M, Brandt T. Treatment of grass pollen allergy: focus on a standardized grass allergen extract – Grazax®. Ther Clin Risk Manag. 2008 Dec;4(6):1255–1260.
  7. Pajno GB, Peroni DG, Vita D, Pietrobelli A, Parmiani S, Boner AL. Safety of sublingual immunotherapy in children with asthma. Paediatr Drugs. 2003;5(11):777–781.
  8. Agostinis F, Foglia C, Landi M, et al. The safety of sublingual immunotherapy with one or multiple pollen allergens in children. Allergy. 2008 Dec;63(12):1637–1639. doi:10.1111/j.1398–9995.2008.01742.
  9. Gidaro GB, Marcucci F, Sensi L, Incorvaia C, Frati F, Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies. Clin Exp Allergy. 2005;35:565–571.
  10. Sheikh J. Prospective evaluation of rate of systemic reactions to immunotherapy as part of a comprehensive allergy practice quality improvement project. J Allergy Clin Immunol. 2011;127S:AB50.
  11. Cox L, Nelson H, Lockey R, et al. Allergen Immunotherapy: A practice parameter third update. J Allergy Clin Immunol.  2011;127:S1–S55.
  12. Melamed J, Mehra A, Ahuja-Malik A. A 5-year study of systemic reactions using both shared and patient specific vaccines. Allergy Rhinol. 2013;4(2):e88–e93. doi:10.2500/ar.2013.4.0057.
  13. Akçakaya N, Hassanzadeh A, Camcioğlu Y, Cokuğraş H. Local and systemic reactions during immunotherapy with adsorbed extracts of house dust mite in children. Ann Allergy Asthma Immunol. 2000 Oct;85(4):317–321.
  14. Ciprandi G, Marseglia GL. Safety of sublingual immunotherapy. J Biol Regul Homeost Agents. 2011 Jan–Mar.
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  16. Grosclaude M, Boillot P, Alt R, et al. Safety of various dosage regimens during induction of sublingual immunotherapy. A preliminary study. Int Arch Allergy Immunol. 2002;129(3):248–253.
  17. Passalacqua G. Non injection routes for immunotherapy. J Allergy Clin Immunol. 2003;111(3):437–448.
  18. Dunsky EH, Goldstein MF, Dvorin DJ, Belecanech GA. Anaphylaxis to sublingual immunotherapy. Allergy. 2006 Oct;61(10):1235.
  19. Blazowski L. Anaphylactic shock because of sublingual immunotherapy overdose during third year of maintenance dose. Allergy. 2008 Mar;63(3):374. Epub 2007 Dec 8.
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  21. Eifan AO, Keles S, Bahceciler NN, Barlan IB. Anaphylaxis to multiple pollen allergen sublingual immunotherapy. Allergy. 2007 May;62(5):567–568. Epub 2007 Feb 20.
  22. Windom HH and Lockey, RF. An update on the safety of specific immunotherapy. Curr Opin Allergy Clin Immunol. 2008;8(6):571–576.
  23. Borchers AT, Keen CL, Gershwin ME. Fatalities following allergen immunotherapy. Clin Rev Allergy Immunol. 2004;27(2):147–158.
  24. Cook PR, Bryant JL, Davis WE, et al. Systemic reactions to immunotherapy: the American Academy of Otolaryngic Allergy morbidity and mortality survey. Otolaryngol Head Neck Surg. 1995;110(6):487–493.
  25. Davis WE, Cook PR, McKinsey JP, Templer JW. Anaphylaxis in immunotherapy. Otolaryngol Head Neck Surg. 1992;107(1):78–83.
  26. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol. 1987;79(4):660–677.
  27. Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011;66:740–752.
  28. Chang H, Han DH, Mo JH, et al. Early compliance and efficacy of sublingual immunotherapy in patients with allergic rhinitis for house dust mites. Clin Exp Otorhinolaryngol. 2009;2:136–140.
  29. Fiocchi A, Pajno G, La Grutta S, et al. Safety of sublingual- swallow immunotherapy in children aged 3 to 7 years. Ann Allergy Asthma Immunol. 2005;95:254–258.
  30. Cox LS, Linnemann DL, Nolte H et al. Sublingual immunotherapy: A comprehensive review. AAAAI/ACAAI Task force report. J Allergy Clin Immunol. 2006;117(5):1021–1035.
  31. Didier A, Worm M, Horak F, Sussman G, de Beaumont O, Le Gall M, et al. Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis. J Allergy Clin Immunol. 2011;128:559–66.
  32. Pajno GB, Peroni DG, Vita D, Pietrobelli A, Parmiani S, Boner AL. Safety of sublingual immunotherapy in children with asthma. Paediatr Drugs. 2003;5(11):777–781.
  33. Passalacqua G, Guerra L, Fumagalli F, Canonica GW. Safety profile of sublingual immunotherapy. Treat Respir Med. 2006;5(4):225–234.
  34. Passalacqua G, Canonica GW. Sublingual immunotherapy for allergic respiratory diseases: efficacy and safety. Immunol Allergy Clin N Am. 2011;31:265–277. doi:10.1016/j.iac.2011.03.002.
  35. Saporta D, McDaniel AB. Efficacy comparison of multiple-antigen subcutaneous injection immunotherapy and multiple-antigen sublingual immunotherapy. Ear Nose Throat J. 2007;86(8):493–497.
  36. Mabry RL. Skin End Point Titration. AAOA Monograph Series. New York: Thieme Medical Publishers; 1994.
  37. Fornadley JA. Skin testing in the diagnosis of inhalant allergy. In: Krouse JH, Chadwick SJ, Gordon BR, Derebery MJ, eds. Allergy and Immunology: An Otolaryngic Approach. Philadelphia: Lippincott Williams & Wilkins; 2002:114–123.
  38. Saporta D. Efficacy of Sublingual Immunotherapy versus Subcutaneous Injection Immunotherapy in Allergic Patients. J Environ Public Health. 2012. Article ID 492405. doi:10.1155/2012/492405.
  39. Antigen Laboratories Inc. 30 South Main Street, Liberty, MO.
  40. Alk-Abello Inc.1700 Royston Lane, Round Rock, TX.
  41. Pan American Allergy Society [website]. www.paas.org.
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  43. What is a serious adverse event? [Web page]. FDA. http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm. Accessed Jan. 5, 2014.
  44. For anybody interested in learning more about LDA, a first step could be to consult Dr. Shrader's website: www.drshrader.com/lda_therapy.htm‎
  45. Antico A, Pagani M, Crema A. Anaphylaxis by latex sublingual immunotherapy. Allergy. 2006;61:1236–1237.
  46. Cochard MM , Eigenmann PA. Sublingual immunotherapy is not always a safe alternative to subcutaneous immunotherapy. J Allergy Clin Immunol. 2009; 124(2):378–379.
  47. Bernstein DI, Wanner M, Borish L, Liss GM; Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990–2001. J Allergy Clin Immunol. 2004;113(6):1129–1136.
  48. Saporta D. Changes in peak flow meter values during immunotherapy administration. J Environ Public Health. 2012. Article ID 21286. doi:10.1155/2012/212867.
  49. Rapp DJ. Is This Your Child's World? Bantam Books; 1966.

 

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