Tag Archives: Clinical trial

Can I Prevent an Allergy Shot Reaction?

Risk Factors for Systemic Reactions to Allergen Immunotherapy

Alfredo Iglesias-Cadarso; Pilar Hernández-Weigand

Purpose of review To update safety information regarding allergen-specific immunotherapy (ASIT) in clinical practice and highlight the risk factors associated with the adverse reactions, product and each dose.
Recent findings Efforts in recent years have focused on increasing our understanding of the efficacy and safety of ASIT, especially the sublingual variety (SLIT), in multicenter studies. Moreover, new Clinical Practice Guidelines (CPGs) and an international consensus concerning ASIT have been published recently. Although no deaths as a result of subcutaneous immunotherapy or SLIT have been reported in the last 2 years, systemic reactions mainly arising from administration errors still appear. Recent studies support the safety of new forms of specific immunotherapy.
Summary An understanding of the risk factors for each patient, product and dose, and the implementation of CPGs are the main factors that could improve the safety of ASIT. The standardization of all procedures for prescribing and administering ASIT, and the systematic collection of standardized safety data in a multicenter database (postmarketing surveillance), may be required to generate new information on the safety of ASIT.

Why Do We Even Care About Safety of Allergy Shots?

Allergen-specific immunotherapy (ASIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), has been shown to be effective for the treatment of allergic respiratory disease in randomized controlled trials and meta-analyses.  Indeed, SCIT is the treatment of choice for preventing anaphylaxis in patients with systemic reactions to hymenoptera (bee stings).

The greatest drawback to the more widespread use of ASIT is the associated risk of severe side-effects, as the dose which has been shown to be well tolerated and effective in a group of patients may not be so for a specific patient. Here again, everyone is different and what may be the best dose for one patient, may cause an adverse reaction for someone else.

Systemic reactions are those which produce symptoms and signs far from the administration site. They may be immediate systemic reaction (ISR), appearing in the first 30 min postadministration, or delayed systemic reaction (DSR), occurring after the first 30 min, with the former tending to be more severe.

The incidence of systemic reactions has been estimated at between 1 and 34% of patients and around 0.2–0.3% of doses, depending on the type of study, patient, diagnosis, extract or treatment scheme.  

Historical reviews of ASIT-related mortalityhighlighted severe or poorly controlled asthma and administration errors as the main causes of fatal systemic reactions. These findings led to the drafting of Clinical Practice Guidelines (CPGs) for ASIT treatment,and their subsequent updates, in the 1990s. Adherence to such guidelines is the main reason behind the reduced frequency and severity of systemic reactions in the past 20 years. The statistics regarding mortality and systemic reactions prior to these CPGs are no longer applicable.

Let’s look at some individual factors that increase your chances of a systemic reaction to an allergy shot!

  • What do you put in my serum? No specific allergen is currently thought to produce higher mortality or a greater chance of a large local reaction.
  • Very few fatal reactions to pure hymenoptera venom immunotherapy (VIT) have been reported. Indeed, several studieshave found a lower incidence of systemic reactions with hymenoptera vaccines, with bee vaccines being tolerated worse than wasp vaccines.
  • Systemic reactions appear to be more frequent when aqueous extracts are used.  This is presumably due to the fact that the allergen is absorbed very quickly after it’s injected.

Dose-related Risk Factors

  • Administration errors are the main identifiable and avoidable cause of ASIT-related systemic reactions, including SLIT. (SLIT is the oral allergy drops)
  • Any delay in the treatment of a systemic reaction increases its severity. This is why I instruct my nurses to give epinephrine first, then call.
  • Although CPGs provide recommendations to avoid such errors, they continue to occur with a greater than expected frequency. 
  • I could write a book on the types of errors that occur with the dose of allergy shots.  Would this be a best-seller or what?
  • Research has shown that a large local reaction does not predict the occurance of a more severe systemic reaction; a concept that can be difficult to grasp for patients.  (see below)

Dosing Scheme

In the case of SCIT with airborne allergens, the use of fast regimens (rush and cluster) has been associated with a higher number of systemic reactions, although more recent studies have shown their safety to be similar to that of conventional schemes. Patients tend to like the rapid schedule because they can avoid the prolonged build-up of conventional treatment. 

Omalizumab (Xolair) has been used to reduce the systemic reaction incidence in patients receiving SCIT with inhaled allergens and VIT (venom shots),  with good results.

It is possible, but not confirmed, that systemic reactions increase during the pollen season, but patients generally do not decrease their dose at this time.

Prior Reactions

Together with poorly controlled asthma, the presence of a prior systemic reaction during AIT is the main risk factor associated with a new systemic reaction. 

There is currently no evidence that the dose adjustments recommended in clinical guidelines reduce recurrent systemic reaction in a patient.

Premedication with antihistamines or omalizumab has been shown to be useful in some studies, although such treatment is not recommended as standard.

Local reactions do not predict the appearance of a systemic reaction, although some studies have suggested them to be a risk factor.  The dose adjustments subsequent to major local reactions recommended in the clinical guidelines do not reduce the frequency of future systemic reactions. For additional information regarding the safety of allergy shots, refer to the reference below:

  • Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011; 127:S1-S55.
    •• Latest and extended update of the Joint Task Force (AAAAI-ACAAI) on Practice Parameters concerning all aspects of allergen-specific immunotherapy.

Provocative study!

 Or at least as sexy as you can get for a vitamin.  Of all the vitamins out there, vitamin D has the most PROVEN benefit for allergies & asthma.  Remember the cod liver oilWhat we grew up on for Vit D!Of course you don’t….you’re not that old!

Curr Opin Allergy Clin Immunol. 2012;12(1):13-17. © 2012

The importance of vitamin D as an essential nutrient is well known, given its role in calcium and phosphate homeostasis. Over the past two decades, the influence of vitamin D on the immune system has become increasingly clear.  Recent work has elucidated that vitamin D harbors actions more akin to hormones and pro-hormones. The discovery of the vitamin D receptor (VDR) has stimulated more research into the nature of this vitamin which has, subsequently, been shown to be a steroid hormone. This steroid constitutes a component of a complex endocrine pathway termed the ‘Vitamin D endocrine system’.  Investigators have found that vitamin D plays an integral role in the induction of cell differentiation, inhibition of cell growth, immunomodulation, and regulation of other hormonal systems.  This review seeks to highlight the recent research with respect to vitamin D and its role in chronic rhinitis and chronic rhinosinusitis (CRS).  The results show higher levels of Vit D are associated with fewer problems with allergy and sinusitis.

The effects of Vitamin D

Although these results are extremely compelling, the Mulligan study suffers from a small sample size. Future work may extrapolate these data to a larger patient set, ideally through a prospective study, which would help clarify the role of vitamin D in the pathophysiology of CRS. Systemic vitamin D levels could, potentially, be added to the routine workup of patients suffering from CRS and these data could be used to help determine the disease severity and possibly even treatment. To this end, a recent Polish study evaluated the role of vitamin D in the reduction of fibroblast proliferation in vitro from nasal polyps in patients with CRS.  A statistically significant decrease in fibroblast proliferation was noted with calcitriol and tacalcitol treatment. Furthermore, increasingly higher doses induced a greater suppressive effect on fibroblast proliferation. This study is a first step towards investigating the utility of topical vitamin D analogs for the treatment of CRS.  Wow–topical Vitamin D for treatment of sinusitis?!

Conclusions from this work:

  • Early research suggests that vitamin D is involved in the pathophysiology of chronic rhinitis and chronic rhinosinusitis (CRS).
  • It is intriguing to consider the possibility that abnormal vitamin D blood levels – or even the local tissue concentration of vitamin D – could be a critical influencing factor in chronic rhinitis and CRS pathophysiology.
  • The concept of the unified airway “one airway, one disease” would suggest that similar associations from the asthma literature will be found with regards to allergic rhinitis, chronic rhinitis, and CRS.
  • Randomized controlled trials are needed to further evaluate vitamin D and its relationship to allergic rhinitis, chronic rhinitis, and CRS.
  • These findings may then direct researchers to pursue clinical trials aimed at evaluating vitamin D and its analogs as potential therapeutic interventions.

So…..in other words, OPEN UP! 

How to Cure Milk Allergy!

Milk allergy may cause life-threatening anaphylaxis in children & adults.  Wouldn’t it be nice if milk allergy could be “cured?” 

The adverse immune reactions to cow’s milk proteins can range from immediate, potentially life-threatening reactions to chronic disorders. Cow’s milk allergy (CMA) is the most common food allergy in infants and young children, affecting 2–3% of general population.  That’s a lot of kids! Most studies have shown the prognosis for developing tolerance to cow’s milk to be good, with the majority outgrowing their allergy by age 3 years. 

Because no treatments are available to cure or provide long-term remission from food allergy, allergen-specific treatments and strategies that attempt to alter the allergic response to specific food allergens are expected. The approach that attracts a significant interest in the scientific community, as well as the public and media, is oral immunotherapy (OIT).

To begin treatment for food allergy, your doctor should do the following:

  • IgE must be demonstrated to the food in question.  That means skin testing or blood tests.
  • Who wants to be cured?  That’s what desensitization accomplishes.  If you gradually increase the amount of offending food (milk powder for instance), sensitive patients will no longer react to an accidental ingestion.  Pretty cool…but wait, that’s not all!
  • Permanent tolerance, as illustrated, means are you protected from ingestion of milk when you haven’t had exposure for say 2 months?  Because it’s not known how to predict whether patients develop tolerance, this procedure of OIT is not recommended for clinical use at this time. 

Almost all children receiving oral desensitization (OIT) experienced allergic symptoms during the protocol that primarily involved urticaria and angioedema. That’s mild and treatable.

Table 1. Oral food desensitization for IgE-mediated cow’s milk allergy

Study Patients (N) Success rate Comments
Staden et al. [15], CM and egg CM 14; egg 11; control group 20; age 0.6–12.9 years 9/35 (36%) permanent tolerance; 3/25 (12%) tolerance with regular intake (desensitization); 4/25 (16%) achieved partial tolerance The first randomized clinical trial of OIT. The rate of spontaneous food allergy resolution in the control group (7/29, 35%) was similar to the treatment group.
Longo et al. [16], CM CM 60; 30 active group; 30 control group; age 5–17 years 11/30 (37%) tolerated 150 ml f CM; 13/30 (53%) tolerated 5–150 ml The first study including children with previous anaphylaxis to cow’s milk; 3 children 10% discontinued the study because of severe systemic reaction. 17/30 children of active group reported side-effects at home.
Skripak et al. [17], CM CM 20; active to placebo; ratio 2 : 1; age 6–21 years 12 (92%) of active group reached the dose 5140mg of CM (range 2540–8140 mg); no change in the placebo group The first double-blinded, placebo-controlled clinical trial for OIT; the median frequency of side-effect was 35% in the active group compared with 1% of the placebo group.
Pajno et al. [19•], CM CM 30; active to placebo; ratio 1 : 1; age 4–13 years 10 (76%) of active group tolerated 200 ml CM; no change in the placebo group The first blinded trial with the weekly up-dosing regimen carried out in 18 weeks. Two children (15%) of active group discontinued the trial because of systemic reaction.

Legend for the above table:  CM, cow’s milk; OIT, oral immunotherapy.

Desensitization state can be achieved by approximately 36–92% of the children treated with specific immunotherapy; the rate of permanent tolerance is unknown.

An alternative route of allergen delivery is through an epicutaneous patch (EPIT). CMA was confirmed by an oral food challenge at baseline. Children received three 48-h applications (1mg of skimmed milk powder or 1mg of glucose as placebo) through a skin patch each week for 3 months. EPIT-treated children had a trend toward an increased threshold dose in the follow-up oral milk challenge. There was no change in the placebo group. The most common side-effects were local pruritus and eczema at the site of EPIT application.

The possibility of the appearance of adverse events or reactions during OIT is quite frequent. Side-effects have been reported by patients in all trials.

Severe systemic side-effects have been reported with either rush schedule or weekly up-dosing regimen.  The frequency of serious events and the severity of reactions are greatest on the initial days and least on the days following desensitization when high doses of cow’s milk intake are reached by patients.

Mild reactions such as abdominal pain, throat pruritus, gritty eyes, watery eyes, transient erythema and sneezing usually do not require stopping desensitization. On the contrary, when rhinitis, dyspnea, asthma, generalized urticaria and hypotension occur as a single symptom or in combination, OIT should be postponed or stopped.

A life-threatening asthma reaction caused by desensitization to milk was described by Nieto et al.  Adverse events are largely unpredictable, and they can occur during home dosing. Several systemic reactions have occurred at previously tolerated doses in the setting of exercise,viral illness and suboptimally controlled asthma.

Of note, these reactions had been well controlled by antihistamines, steroids or epinephrine. Because desensitization( s) place patients at risk for systemic reactions, it is not appropriate to implement OIT in clinical practice settings at this time. Therefore, OIT can be performed for research purposes or as ‘avant-garde’ and modern therapy for IgE-mediated food allergy in specialized pediatric centers.

  • Patriarca G, Nucera E, Roncallo C,et al. Oral desensitizing treatment in food allergy: clinical and immunological results. Aliment Pharmacol Ther 2003; 17:459–465.
  • Nieto A, Fernandez-Silveira L, Mazon A, Caballero L. Life-threatening asthma reaction caused by desensitization to milk. Allergy 2010; 65:1342–1343.

Best Immunotherapy for Allergic Rhinitis and Asthma?: Conclusion & Future Perspective

I didn’t think that all of you wanted to read the full article so here’s the link for the “brainiacs” in the group! Comparing drops to shots!

Conclusion & Future Perspective

The  clinical efficacy of SCIT (typical shots)  is well established for both rhinitis and asthma.  SLIT (sublingual drops) has also been validated in regards to rhinitis and asthma.   Two recent meta-analyses in children showed that sublingual delivery of allergen vaccination constitutes a safe and effective alternative to the injectable route to reduce allergic respiratory symptoms and drug intake.  Assessment of possible long-term benefits, including long-term disease remissions, suppression of new allergic sensitizations, and reduction of progression from rhinitis to asthma in children, as has been shown for the subcutaneous route, are future requirements for “proof” of benefits for sublingual drops. 

The immunological effects of SLIT and how these relate to clinical efficacy are yet incompletely understood. Large-scale trials have confirmed the induction of allergen-specific IgG antibodies to be dose dependent. There is no early suppression of allergen-specific IgE antibodies and a transient early increase in specific IgE antibodies as in SCIT.

Current models of SCIT propose the induction of antigen-specific Tregs (cell type in the body), which then orchestrate the observed antibody and mucosal changes observed during treatment. As of yet there is only scarce evidence that such mechanisms operate during SLIT. Comparative clinical studies of sublingual and subcutaneous treatment yielded heterogeneous results demonstrating efficacy of both modes, but SLIT to be a safer approach.

In conclusion, understanding of the interaction of allergen and antigen-presenting cells within the oral mucosa may allow improved targeting of SLIT vaccines. In the near future the combination of allergen products with adjuvants may improve efficacy of immunotherapy via the sublingual route.

So here’s the bottom line:

  • Sublingual drops are not yet approved by the FDA and I can’t bill insurance for the product like allergists now do for subQ shots. 
  • Why not use Rapid immunotherapy to achieve maintenance in ONE month, followed by MONTHLY shots instead of weekly?  With this method, you get the best of both worlds–good, proven benefits at a convenient dosing schedule. 
  • Sublingual drops have to be given multiple days per week and compliance isn’t all that impressive. 

This issue isn’t going away, so stay tuned!