Tag Archives: Adverse drug reaction

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.
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What is the Best Method for Testing Allergy to Drugs?

I must have a drug allergy….what is the best method for testing?  Countless times I have reviewed skin biopsy results that state evidence of a drug allergy.  Obviously, this is not a very specific method of diagnosis, so what does work?  I’ll copy the entire abstract for you and make some comments below.  In the meantime, if you’re interested in what doctors learn about drug allergy, this is a lecture from University of Texas–Southwestern designed for allergy fellowship training.  It’s a little long unless you’re a doctor, but have at it!  And yes, I trained at Children’s Mercy Hospital with Dr. Portnoy. 

L.M. Heinzerling; D. Tomsitz; M.D. Anliker  The British Journal of Dermatology. 2012;166(1):107-114. 

Is Drug Allergy Less Prevalent than Previously Assumed?

Background Rashes are a frequent conundrum in clinical practice as they may be reactive, drug induced or disease specific. Identification of the culprit drug is important as re-exposure may be harmful or even life-threatening and unnecessary avoidance of ‘innocent’ drugs leads to limitations of treatment options.
Objective To objectify the cause of suspected cutaneous drug reactions in a large patient population.
Method Over 5 years (2006–10), 612 patients with suspected cutaneous drug reactions were evaluated. Histology was assessed. About 200 patients were invited for complete work-up with skin tests (prick/intracutaneous testing and scratch/patch as indicated) and, if necessary, lymphocyte transformation tests (LTT). In special cases, drug provocation tests were conducted.
Results A total number of 141 cases with suspected drug reaction underwent full work-up (age 6–86 years; 75% female, 25% male). In 107 cases (76%) a drug was identified whereas 34 (24%) were reactive rashes or had other causes. Mostly, cutaneous drug reactions were maculopapular rashes, urticaria/angio-oedema; less frequently, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, systemic drug-related intertriginous and flexural exanthema, toxic epidermal necrolysis and fixed drug eruptions were present. Of all the cutaneous drug reactions investigated, 39·8% were caused by antibiotics, 21·2% by anti-inflammatories, 7·6% by contrast media and 31·4% by others (oral antidiabetics, antimycotics, antipsychotics, antiepileptics and others).
Conclusion Clinical assessment overestimates the role of drug allergies in cutaneous reactions. Assessment of suspected drug reactions can be greatly improved by thorough evaluation including dermatological and allergological work-up with skin testing and assays such as LTT.

Out of a total of 612 patients, 141 cases with suspected drug allergy were fully evaluated with allergy testing. Interestingly, out of the tested subjects with suspected drug reaction one-quarter could not be confirmed by objective testing, and skin changes were tracked to another trigger. This agrees with data from other studies which also found that not all the suspected drug reactions were finally confirmed.

Thus, depending on prescreening, the role of drugs in sudden exanthema is overestimated. In plain English, all of these  cases would have been FALSELY attributed as drug reactions had it not been for the testing and work-up.

However, only rigorous testing (and provocation) can rule out or confirm the drug reaction and finally identify the culprit drug. Interestingly, it was by means of a lymphocyte transformation test (LTT) that one-fifth of the cases were identified, which thus represents an important tool shown to have a sensitivity of 78%, even though this methodology is often considered experimental.

Further studies are needed to specify the sensitivity and specificity of LTT in comparison with skin tests for each substance.

Are we harming ourselves?

“I’m allergic to everything!”  Ah, you’re smiling.  Is this really possible to be allergic to multiple drugs?  Evidently this is true according to a recent study published in Ann Allergy Asthma Immunol 108 (2012) 88–93.

Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management byEric Macy, MD and Ngoc J. Ho, PhD.

So what is this condition? Multiple drug intolerance syndrome (MDIS) is generally defined as intolerance to 3 or more unrelated medications.  This can be antibiotics, ibuprofen, or high blood pressure medication.  The problem with adverse drug reactions is that intolerances are typically recorded in the “allergy” field of the medical record. This makes doctors and patients alike worry about anaphylaxis with any accidental use.  Relax….most adverse drug reactions are not going to result in a severe reaction without warning.  The authors of this paper use the word “allergy” in quotes throughout this paper to remind us that most of the drug “allergy” reports in the medical record are not immunoglobulin (IgE)-mediated.  

Now don’t misunderstand, a true IgE-mediated allergy requires sensitization, and every systemic exposure in a sensitized individual can potentially result in anaphylaxis and death. But this is not the type of reaction we’re dealing with in this study.

If you have Multiple Drug Intolerance Syndrome, what can you do?

  1. Most individuals with a record of any drug “allergy” have only 1 implicated medication, and they simply avoid that drug or class of medication. Individuals with multiple drug “allergies” are a special case.
  2. Antibiotic overuse probably accounts for a significant proportion of the antibiotic “allergy” reported.  Not only should antibiotics be avoided to prevent resistance, but overuse of antibiotics contributes to MDIS.
  3. Challenge testing has typically shown tolerance to most medications in patients with MDIS. Schiavino et al performed 1,808 challenges on 480 patients, 84.4% female, most ages 40 to 60, with histories of ADRs to at least 3 unrelated medications.
  4. All of these patients were evaluated at a specialized drug allergy clinic in Rome between January 1, 2000 and December 31, 2005. Two hundred twenty-four (12.4%) positive challenges were seen. In virtually all patients, either the index medication was tolerated on rechallenge or an acceptable alternative was identified.  

Multiple drug “allergy” is relatively uncommon in children, and most adverse drug reactions (ADRs) in children are associated with antibiotic use. Park et al provided demographic information on 97 children with 2 or more antibiotic “allergies” seen in a specialized drug allergy center in Canada. The accompanying editorial concluded that rare individuals may truly have allergic reactions to unrelated antibiotics, but it also might just be opportunity and bad luck.

 One often may stop multiple medications safely in the elderly. This may be the most important way to reduce the incidence of MDIS. In the presence of a life-threatening condition that would benefit from a particular medication associated with a historical reaction, based on a careful history, one may possibly safely test or rechallenge most individuals with MDIS.

 So is there anyone who should NOT be challenged with a drug they suspect is causing MDIS?

  • Individuals who have experienced drug-associated toxic epidermal necrolysis, Stevens-Johnson syndrome, blistering, desquamation.  These reactions are usually MORE severe after the second exposure! 

    example of Stevens Johnson syndrome

    Here’s what this type of reaction looks like:

  • Severe hepatitis, nephritis, or hemolytic anemia should not be rechallenged.  The risk of inducing severe reactions is just too great.  Fortunately, these severe reactions are rare.

  • Angiotensin-converting enzyme inhibitor–associated angioedema can be lethal, and rechallenge is not recommended.

If I have MDIS, when would a challenge be appropriate?

  • Urticaria or angioedema associated with NSAID use outside of aspirin-exacerbated respiratory disease is often transient, and rechallenge often can be safely performed.
  • Individuals with aspirin-exacerbated respiratory disease can be challenged with aspirin and desensitized.
  • Appropriate skin testing or in vitro IgE measurements can be used to evaluate individuals with MDIS who experienced classic IgE-mediated reactions such as anaphylaxis, shortness of breath, or hives. If negative, they can be rechallenged under observation.
  • If positive, they can be desensitized for 1 therapeutic course.
  • Multiple drug intolerance syndrome subjects with most other mild ADRs such as macular papular rashes, fixed drug eruptions, nausea, vomiting, gastrointestinal upset, diarrhea, drug fevers, other mild symptoms, or unknown symptoms can generally be safely rechallenged.

In closing, what’s the bottom line for patients with multiple drug “allergies?”

  1. Multiple drug intolerance syndrome may be considered partially an iatrogenic condition.
  2. Multiple drug intolerance syndrome is most prevalent in elderly women with high overall health care and pharmaceutical utilization.
  3. Multiple drug intolerance syndrome is associated with anxiety but not with life-threatening illnesses or IgE-mediated allergy.
  4. Coordinated efforts to reduce poly-pharmacy may be helpful in reducing iatrogenic MDIS.
  5. Drug hypersensitivity testing or drug challenges can be used safely to help manage many individuals with MDIS.

Call me with questions; I’d be happy to help you out!