Diego Saporta, MD

Abstract

Administration of immunotherapy is rewarding but challenging. The reward is observing how a patient exhibits progressive symptom improvement while at the same time requiring less medication, even to the point of not requiring medications any more. The problem is the specter of a reaction to the immunotherapy injections. Even though the frequency of reactions to testing or immunotherapy administration is low, if a severe reaction were to develop it could have devastating consequences. The patient most at risk for this type of reaction is the asthmatic patient. 

The purpose of this article is to bring awareness, both to patients and practitioners, that there are patients with allergy symptoms that are not considered to be allergic because their tests are negative; that there is a large group of patients that have evidence of inflammation of the lower airway but that usually are not identified as asthmatics. Their management should include the same precautions taken to manage the asthmatic patients. Lastly, perceptions of the significance of immunotherapy for the management of the allergic patient, mainly the asthmatic one, will be presented and a discussion about the management of such patient will follow.

Introduction

Allergy, a word derived from two Greek words meaning “different” (Allos) and “mechanism” (Ergos) describes the reactivity of an organism to the surrounding environment. Certainly, since the discovery of IgE in 1965,¹ the word “allergy” has been redefined as a phenomenon exclusively mediated by IgE even though Gell and Coombs had previously described four mechanisms by which the immunological system can react. ²

Type I reactivity or hypersensitivity reaction is the mechanism that involves IgE. It is logical to think that the immunological system reacts as a whole, rather than with only one of its components. This common-sense thought is backed by multiple clinical observations of patients with clear symptoms of allergic disease but with negative RAST tests for IgE and/or negative prick tests. Is it possible that terms like “non-allergic rhinitis,”³ described as a chronic nasal inflammation not caused by systemic IgE-dependent mechanisms, or Non-Allergic Rhinitis with Eosinophilia Syndrome (NARES) described as a syndrome consisting of allergic rhinitis (AR) symptoms with negative tests and nasal cytology showing greater than 20% eosinophils,⁴ have been coined to describe these cases of clear allergic symptoms with a test that is negative?

Published evidence suggests that there is allergic reactivity not mediated by IgE. In this regard, IgG with its subclasses and IgA are currently being investigated for their role in allergic disease.⁵ Allergic reactions induced by IgG, including anaphylaxis mediated by IgG, were studied in mice.⁶ Mast cells and basophils can be activated in vitro independently of the presence of IgE, again suggesting that non-IgE pathways for hypersensitivity reactions exist. ⁷ Also, bronchial hyperreactivity and airway inflammation can develop via activation of mast cells without involving IgE.⁸ The patient with inhalant allergies frequently develops reactivity to multiple foods. In this case the role of IgG is more significant.⁹

Mainstream medicine continues to define “allergy” as a phenomenon solely mediated by IgE. Sensitization is defined by the results of a positive test and the most common tests used for diagnosis are a blood test for IgE (usually known as “RAST” test even though in most cases ELISA technology is used) or skin prick test. Often times these tests will be negative, either because the patient has reactivity that is not mediated by IgE, therefore the IgE-RAST will be non-reactive, or because the prick test lacks the sensitivity of an intradermal test.¹⁰

This produces an apparently contradictory situation: a patient with clear allergic symptoms and negative tests can be diagnosed as being non-allergic or having “non-allergic rhinitis” or similar. All this, despite evidence that in these “non-allergic” events there is inflammation³ which is the hallmark of the allergic disease. Cases like NARES have an increase in eosinophils, cells that are always involved in the allergic response.  

“Allergy” should be defined as the reactivity of the individual to the surrounding environment. This is a complex process that not only affects the whole body¹¹ but also involves one or more of the immunological mechanisms described by Gell and Coombs. For management of the allergic patient, I rely mostly on the Intradermal Dilutional Test or IDT (previously known as Skin End Point Titration or SET) to determine which are the involved allergens. I evaluate not only the immediate skin response (ISR), but also the delayed skin response (DSR) that develops 24 or more hours after the injection of the allergen being tested. ¹²

A skin response that occurs many hours after the injection of the allergen is, in all probability, not related to an IgE-dependent mechanism, rather to other immunological mechanisms. The papules of the DSRs are indurated, not well defined, often with significant erythema and they can persist for days and even weeks.¹² Delayed reactivity has clinical significance. For example, asthma can occur as a delayed response, and clinical improvement and decrease in the need for controlling medication can be attained if immunotherapy is administered.¹³

The ISR starts developing usually about 5-10 minutes after the prick or intradermal skin tests. The main allergy community defines these ISRs as being exclusively mediated by IgE. To be able to make that assertion would require histological studies of the papule developed after the skin test, for cellular and immuno-electrophoresis analysis. Otherwise, it cannot be asserted that the skin reactivity was mediated by one or another of the potential mechanisms by which the immunological system can respond to a stimulus.

Management of the Allergic Patient -The Role of Immunotherapy

Allergen Specific Immunotherapy (SIT) is the only treatment capable of modifying the inflammatory response¹⁴ characteristic of the allergic conditions.  Not only can it have a preventative effect on AR and asthma, but also can prevent further development of new sensitizations, progression of AR into asthma, and can even alter the natural history of asthma itself. ^14,15,16,17 SIT was found to promote asthma resolution, and this effect was more pronounced with higher doses of allergen-immunotherapy.¹⁸

In the best of cases. immunotherapy administration can lead to a cure of the allergic condition affecting the whole body. In the worst of cases, it will produce an incomplete response. In general, it should be expected that some improvement will always occur when immunotherapy is administered.

Complications of Immunotherapy

Immunotherapy uses extracts of the same allergens responsible for patient’s symptoms; therefore the extracts contain only natural proteins. This explains why immunotherapy has no side effects from the injected allergens themselves. This does not mean the patient cannot have an immunological reaction to the injected allergens. It is a fact that administration of allergens to which one is sensitized can trigger symptoms. Allergic disease is characterized by reactivity. Symptom development will follow exposure to the reactive allergens present in the environment. This “natural reactivity” triggers the usual allergy symptoms, which can be mild or severe. Occasionally, a serious reaction can develop. Example: the case of a cat-allergic patient that develops a bad asthma attack just by entering a home where there is a cat.

So, it is not surprising that when administering extracts from these allergens, symptoms can be triggered. In this case, these symptoms are called “reactions.” When the administration is by injection, the reaction has the potential for severity. Most reactions develop at the injection site. They are known as local arm reactions, consisting of inflammation, swelling, and pain. They may alter the course of immunotherapy treatment, but usually they resolve without intervention. An injected allergen can also trigger systemic symptoms, which can be mild or severe. Severe systemic reactions are rare, but they can lead to anaphylaxis of which mortality, an infrequent outcome, is unfortunately a possibility. There are reports of mortality due to the administration of injectable immunotherapy (properly known as Subcutaneous Injection Immunotherapy or SCIT) or even during intradermal testing. It has been observed that severe reactions that required emergency intervention or that produced mortality occurred more frequently in asthmatic patients.^19,20,21,22 This is why it is of extreme importance for the allergy practitioner to become proficient in identifying and managing patients with potential inflammation of the lower airway. These severe reactions are rare; therefore, publishing a series as in the references above, requires reviewing reports in the literature over the span of several years.