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• Yes, an important place for depot triamcinolone in hay fever!
  J. Alexander de Ru, Ahmed B. Bayoumy
  Published on: 23 March 2020

• Published on: 23 March 2020

  Yes, an important place for depot triamcinolone in hay fever!

  • J. Alexander de Ru, otorhinolaryngologist Central Military Hospital
  • Other Contributors:
    • Ahmed B. Bayoumy, Resident

  We commend the author’s endeavours to present an unbiased review concerning depot triamcinolone. However, this review cannot be judged a total success; there are numerous flaws that cry out to be corrected. The most important issue is the excessive focus on potential side effects, that are generally regarded as of minor significance.
  We understand that this is a somewhat lengthy comment, but since the journal states that ‘critique and disagreement are important features of science’, we hope that we are allowed to express our opinion in order to be able to promote further debate.

  The title, negatively framed, states ‘Still no place for depot triamcinolone in hay fever?’ and we get the feeling that the author already skipped the question mark and directly continued with the key learning point that ‘in 1999, Drug and Therapeutics Bulletin (DTB) noted that despite the likelihood that a single injection of triamcinolone will relieve hay fever symptoms, there was uncertainty about the efficacy and safety of repeated administration’.1
  This notion is too easily repeated in the current conclusion. The first part of the first sentence of the conclusion section informs us again that a single injection of triamcinolone has likelihood that it will relieve hay fever symptoms. The fact that it probably causes symptom reduction should be enough reason to explore the possible indications for this therapy.
  Therefore, the only logical conclusion should have been that...

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  We commend the author’s endeavours to present an unbiased review concerning depot triamcinolone. However, this review cannot be judged a total success; there are numerous flaws that cry out to be corrected. The most important issue is the excessive focus on potential side effects, that are generally regarded as of minor significance.
  We understand that this is a somewhat lengthy comment, but since the journal states that ‘critique and disagreement are important features of science’, we hope that we are allowed to express our opinion in order to be able to promote further debate.

  The title, negatively framed, states ‘Still no place for depot triamcinolone in hay fever?’ and we get the feeling that the author already skipped the question mark and directly continued with the key learning point that ‘in 1999, Drug and Therapeutics Bulletin (DTB) noted that despite the likelihood that a single injection of triamcinolone will relieve hay fever symptoms, there was uncertainty about the efficacy and safety of repeated administration’.1
  This notion is too easily repeated in the current conclusion. The first part of the first sentence of the conclusion section informs us again that a single injection of triamcinolone has likelihood that it will relieve hay fever symptoms. The fact that it probably causes symptom reduction should be enough reason to explore the possible indications for this therapy.
  Therefore, the only logical conclusion should have been that in specific cases this therapy might be used, but that possible side effects - though rarely seen in a clinical relevant degree - should be taken into account. Specific cases being, some of those 10% patients who do not obtain enough relief with the current gold standard intranasal steroids and antihistamines. Each year we see patients who cannot get out of their houses because of the severity of their symptoms despite ‘modern, safe and effective treatments’. In our practice a single injection is all we need for patients suffering from severe hay fever.

  The second part however, states ‘there remains uncertainty about the efficacy and safety of repeated administration’. But, this is the answer to a completely different question – namely “place for repeated depot triamcinolone?” – that should not be used in the same sentence.

  Likewise DTB states that if ‘the patient experiences prolonged symptoms as a result of multiple allergies, several injections may be necessary, which increases the risk of severe adverse effects’. But, though that might be true, it again is not the answer to the question whether a place exists for triamcinolone in hay fever. The review question was not “does a place exist for multiple triamcinolone injections in patients with multiple allergies?”.
  And if the season is exceptionally severe, the other reason mentioned for prescribing several injections, we think that this circumstance would probably also lead to a higher prescription of oral steroids with the same profile of side effects.
  The DTB recommended a brief course of oral prednisolone in patients with severe hay fever as this allows flexibility in dosing and the option to stop treatment if unwanted effects occur. Recently, an article was published comparing the pharmacokinetics of intramuscular and oral betamethasone and dexamethasone. Based on these data we see that the pharmacokinetics and pharmacodynamics (effects on glucose and plasma cortisol) are similar for both the oral and intramuscular preparations for dexamethasone and betamethasone.2 Why expect more side effects for intramuscular corticosteroids as they show similar pharmacokinetic- and dynamic characteristics with oral preparations?

  Why not just follow the clinically most important question: how effective is a single intramuscular injection for hay fever? As recently described, in our military population we clearly see an indication in case of severe symptoms. Our patients are extremely satisfied with this therapy; therefore we concur with the notion that ‘continued interest by patients in using this treatment’ exists.
  The current review shows that in 1999 the DTB already described a double-blind placebo-controlled trial, which included 38 patients with severe symptoms of hay fever and reported an improvement or resolution of symptoms in 94% of patients given triamcinolone compared with 10% given a placebo.3 That was and is quite an effect and it is incomprehensible that the authors in 1999 and now come to a conclusion that there is no place for this therapy. Especially considering that DTB further quotes that in all the double-blind placebo-controlled trials, a statistically significant effect on symptom relief was shown.

  The DTB authors then and now, however, are obsessed with finding unwanted effects. Even though the 1999 review concluded that such side effects were not seen often, the DTB concluded that there was a marked lack of controlled trial data on the likelihood of such effects. However, side effects are preferably assessed in the total population instead of in trials. According to the DTB review 222,000 prescriptions for triamcinolone acetonide injection were dispended in primary care in England in 2018, and we suppose that this will have been about the same amount every year for the last few decades. Whether prescribed for hay fever or for other indications, major clinical side effects of this therapy would have surfaced by now with these amounts of injections, but they did not. Many articles in various disciplines such as dermatology and pulmonology conclude that the profile of side effects is not that disastrous.4,5
  Side effects are inherent to every therapy. The chance of occurrence and their severity is something that should be discussed with patients and should lead to well-informed patients and doctors performing shared decision-making. Side effects should be weighed against disease burden/decreased quality of life. Even severe side effects are not a reason to completely withhold or abandon the therapy if the medication is highly effective.
  Østergaard et al.6 noted that the data did not highlight any concerns regarding long-lasting suppression of plasma cortisol, the possibility of a longstanding influence on stress reaction, or the risk of serious tissue atrophy following a single intramuscular injection of corticosteroid for hay fever. And to quote Storrs: ‘there is good reason to believe that the marked and long-lasting hypothalamic-pituitary-adrenal axis suppression associated with even one 40-mg injection is of theoretical rather than practical importance’.

  According to Sackett et al.7 the practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. Why does DTB fail to see that the manuscript by Ostergaard et al.6 is the best available external evidence?
  The DTB review, in our opinion, creates ‘disinformation’ by putting the pro argument – based on a systematic review - by Østergaard et al. somewhat at the same level of evidence as two subsequent negative comments by Barnes & Kuitert8, and Bousquet9. The stake holding counter arguments by Østergaard to the comments by Bousquet, and Barnes & Kuitert are unfortunately completely ignored; it would have been only fair to mention these as well.
  As for the negative arguments the DTB further mentions Nasser10, and Scadding et al.11 We wonder if the DTB noticed that Bousquet, Nasser and Scadding is actually three occurrences of the same argument. The only reference to the fact that ‘adverse effects outweigh the demonstrated clinical benefit’ in the International Consensus Statement by Scadding et al. is the extremely rare case of avascular necrosis by Nasser. Also please note that this avascular necrosis case, also referenced by Bousquet, occurred in a patient with more than just a single 40 mg triamcinolone injection per year.

  Another point that is ignored is the fact that a single intramuscular injection is extremely cost-effective. The interested reader should look for the price of a single depot triamcinolone and compare this with nasal sprays, antihistamines, oral steroids and especially immunotherapy. Østergaard et al., in the response to Barnes and Kuitert, wrote that they think that the reason for the lack of studies remains unclear. We dare to suggest that the reason is quite simply financially. The alarming number of conflicts of interest disclosed by most authors of guidelines on this topic, in combination with the fact that the majority of clinical studies in allergy are supported by the pharmaceutical industry, should be a reason for grave concern.

  DTB also mentions the retrospective study based on Danish registry databases as a safety issue. DTB fails to note that according to Aasbjerg et al.12: 1) ‘rhinitis treatment with depot-steroid injections was defined as individuals receiving at least one depot-steroid injection ..’, so the study does not show if the patients developing diabetes and osteoporosis had one or more injection, and it does not show if one injection concerns 40 mg triamcinolone or 80 mg methylprednisolone; 2) ‘we do not know if the cumulative effect of several steroid injections plays a role’; 3) ‘among the cases diagnosed with diabetes based on the prescription of glucose lowering drugs, the number who remained on glucose lowering treatment decreased in both groups during the observation period, ending up at only 40% and 51% for steroids and SCIT respectively’ (e.g. more in the SCIT group!); 4) ‘a possible confounder in our study is that doctors might initiate – more? - screening for osteoporosis and/or diabetes following treatment with steroids compared to immunotherapy which is not associated with the same risk factors. Accordingly, more individuals might be diagnosed when treated with steroids as a result of the screening’.
  And the most relevant remark is that Aasbjerg compared depot-steroid to immunotherapy; that is comparing apples to oranges. Would the outcome be totally different if depot steroids were compared with oral steroids? We think not.

  Moreover, the DTB review stating that ‘immunotherapy may be an option for patients requiring frequent oral corticosteroid rescue’ makes it look like these therapies are mutually exclusive. But they are not. We offer immunotherapy to the same patient group with severe hay fever symptoms. This, because they visit us in the season at a moment they experience a lot of complaints, however we are unable to start immunotherapy since it is advised not to start during the pollen season. Furthermore, immunotherapy takes some years for optimal effect, so patients sometimes still have a couple of years of incapacitating complaints before the desensitisation works. Also, not all our military patients can adhere to the strict schemes of immunotherapy due to their professional duties.
  Last but not least, to get back to the topic of side effects, have the authors of the DTB reviews ever experienced a patient getting an anaphylactic shock due to immunotherapy? That is a truly scary situation! Unlike the avascular hip necrosis described by Nasser, it is one we meet on a yearly base.

  Before concurring that a short course of oral corticosteroids is recommended over a depot injectable preparation as DTB suggests, the trial that needs to be done is one that shows that oral steroids are superior with less side effects. At this point there is, to the best of our knowledge, no published evidence whatsoever that oral corticosteroids are more effective with less side effects than a single injection triamcinolone in case of severe hay fever.
  Therefore, we simply cannot agree with turning around the burden of proof as implied in the sentence that ‘this product should not be used, until clear evidence of its advantages over other hay fever treatments, including oral prednisolone, become available’.

  1. Any place for depot triamcinolone in hay fever? Drug and Therapeutics Bulletin. 1999;37(3):17-18.
  2. Jobe AH, Milad MA, Peppard T, Jusko WJ. Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India. Clinical and translational science. 2020;13(2):391-399.
  3. Axelsson A, Lindholm B. The effect of triamcinolone acetonide on allergic and vasomotor rhinitis. Acta oto-laryngologica. 1972;73(1):64-67.
  4. Thomas LW, Elsensohn A, Bergheim T, Shiu J, Ganesan A, Secrest A. Intramuscular Steroids in the Treatment of Dermatologic Disease: A Systematic Review. Journal of drugs in dermatology : JDD. 2018;17(3):323-329.
  5. Kirkland SW, Cross E, Campbell S, Villa-Roel C, Rowe BH. Intramuscular versus oral corticosteroids to reduce relapses following discharge from the emergency department for acute asthma. The Cochrane database of systematic reviews. 2018;6:Cd012629.
  6. Ostergaard MS, Ostrem A, Soderstrom M. Hay fever and a single intramuscular injection of corticosteroid: a systematic review. Primary care respiratory journal : journal of the General Practice Airways Group. 2005;14(3):124-130.
  7. Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ (Clinical research ed). 1996;312(7023):71-72.
  8. Barnes N, Kuitert L. Treatment of hay fever with a single intramuscular (i.m.) injection of corticosteroid. Primary care respiratory journal : journal of the General Practice Airways Group. 2005;14(6):320; author reply 321-322.
  9. Bousquet J. Primum non nocere. Primary care respiratory journal : journal of the General Practice Airways Group. 2005;14(3):122-123.
  10. Nasser SM, Ewan PW. Lesson of the week: Depot corticosteroid treatment for hay fever causing avascular necrosis of both hips. BMJ (Clinical research ed). 2001;322(7302):1589-1591.
  11. Scadding GK, Kariyawasam HH, Scadding G, et al. BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007). Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2017;47(7):856-889.
  12. Aasbjerg K, Torp-Pedersen C, Vaag A, Backer V. Treating allergic rhinitis with depot-steroid injections increase risk of osteoporosis and diabetes. Respiratory medicine. 2013;107(12):1852-1858.

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  Conflict of Interest:
  None declared.

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