I applaud the effort by Drs. Hurst and McDaniel to emphasize, through their paper “Diagnosis of the Pathophysiology of Chronic Mucosal Diseases of Allergic Rhinitis, Asthma, and Otitis Media as Seen by an Otolaryngologist,”¹ recently published in this magazine, very important issues pertaining to allergy management.

They bring to our attention the importance of which test is the one used for the diagnosis of the allergic condition. They also remind us that the allergic condition affects the whole body. There are many conditions, usually not associated with allergy etiologies that can therefore benefit from allergy management (allergy immunotherapy). Recognizing this will add to the patient’s wellbeing and avoid unnecessary surgeries—sometimes repeated surgeries. Incorporating these concepts to medical practice would not only add to patient’s comfort and health but also would help to decrease the burden of the ever-expanding cost of medical care.

It obviously follows, that in order to provide appropriate care to the allergy sufferer, an accurate diagnosis needs to be established. And this perhaps is the most important issue. What if the usual test, the one that is the most commonly used, is not accurate enough to make the allergic condition evident?

Drs. Hurst and McDaniel recently published another paper² where it was shown that patients with clear allergic disease were considered to be non-allergic if they had a negative skin prick test (SPT) so, treatment was not provided for these patients. They also showed that patients who were diagnosed as being allergic using the SPT and then received immunotherapy had poor results, as the number of allergens that the prick test diagnosed was not enough to provide appropriate clinical relief. In both circumstances, Dr. Hurst retested those patients with a different type of skin test obtaining different results:

1. The cases that were negative by SPT now showed reactivities to many allergens.
2. The cases where the SPT yielded a positive result but with few allergens, had upon retest, many more positive results. When adjusting treatment to this new level of reactivity, immunotherapy results were satisfactory.

This “different type of skin test” was the intradermal dilutional test (IDT). We already had the opportunity to discuss about the advantages of the IDT in this magazine.³ Our clinical impression also is that patients diagnosed with the IDT, will rarely be misdiagnosed as “non-allergic” and results of allergy immunotherapy will be much more relevant than when treating from a SPT because the IDT is able to diagnose the allergic condition much more accurately. This fact is not well known in the medical community, including the general allergy community. Only physicians that use this test are aware of this. When these practitioners encounter patients previously tested with a skin prick test, it is not a rare occurrence to observe that either these patients were told that they were not allergic (as the SPT was negative) or they were receiving immunotherapy; but treatment results were not good.

In my opinion, the reason why the IDT performs so much better than the SPT is related to the fact that the mast cells are found in the dermis. ⁴ The prick test applies the allergen on the surface of the skin. The allergen needs to permeate to the dermis in order to be able to trigger the mast cells. Injecting the allergen directly into the dermis places this allergen in the immediate vicinity of these cells. Therefore, if these mast cells are sensitized against such allergen, they will degranulate and become biologically active.

Drs. Hurst and McDaniel point out that on the updated practice parameters on allergy diagnostic testing published by AAAAI and ACAAI,⁵ the IDT is considered to be equivalent to the SPT only at high dilutions (meaning the 4^th to the 6^th dilutions); IDT uses six dilutions, each successive dilution carrying progressively less allergen. The allergen to be tested by IDT is diluted with 1:5 dilutions. The 4^th dilution contains allergen diluted 625 times. In the 6^th dilution the allergen is diluted 15,625 times.

This clearly suggests that in patients that are very sensitive (in other words their dermis is filled with sensitized mast cells), their skin will react to a minimal amount of allergen (very diluted). In these cases, depositing the allergen in the skin surface may be enough to stimulate the mast cells, as the skin may be overflowing with mast cells. It could be assumed that even the area immediately below the basal lamina, (area immediately “deeper” to the epidermis) will be filled with mast cells.

So, extrapolating from the information provided in the practice parameters above mentioned,⁵ in an allergic person that is not very sensitive, the SPT will not be reactive, therefore the diagnosis will not be done. In other words, unless the patient is very sensitive, the IDT will outperform the SPT.

I would like to address one more time the significance of this problem: labeling a negative-prick test patient as non-allergic will deprive this patient of the only possible treatment able to correct the immune dysfunction leading into the profuse allergic symptomatology. This treatment is allergy immunotherapy.⁶

A concept observed in clinical practice, that is somewhat counterintuitive, is that the sensitivity not necessarily correlates to the degree of clinical disease. The sensitivity of the patient depends on the number or sensitized (“primed”) cells. This means that a patient who, for example, has an IDT with all allergens reacting at dilutions 4-6 (meaning that very diluted allergen is sufficient to trigger the response) may not have very significant clinical disease, whereas another patient who, for example, reacts only to very strong allergen concentration (for example in the 2^nd dilution, meaning that the response is only triggered by a high concentration of the allergen) may have severe allergies, asthma, and eczema. This second patient, even though clearly symptomatic, for sure will not be diagnosed with the SPT.

The inability to correctly diagnose an allergic patient occurs also with the usual RAST-like blood tests, where only determination of IgE is done, disregarding other immunoglobulins that can be involved in the immunological reactions as described by Gell and Coombs.⁷

This leads to a common apparent contradiction mentioned by Drs. Hurst and McDaniel and easily observed by any clinician who orders those tests: some patients are clearly allergic (an easy example is the case of the patient who develops asthma when close to a cat, of that is triggered during the spring) but has a “RAST” test that is negative.

In agreement with these authors, it is also my opinion, that establishing a diagnosis of allergy using poor performance tests and not considering the clinical presentation is the basis for describing other syndromes like non-allergic rhinitis with eosinophilia syndrome, non-allergic rhinitis, local allergic rhinitis, or Idiopathic rhinitis (considered a subtype of nonallergic rhinitis). Just entering these terms in the internet will show multiple references, always in the same style. For example, nonallergic rhinitis with eosinophilia syndrome (NARES) is defined as symptoms consistent with allergic rhinitis with negative allergen skin testing, but with nasal cytology showing eosinophils.⁸ In other words, a skin prick test was non-reactive, and despite the patient having the clinical presentation consistent with allergic disease, the patient is called “NARES.”

Nonallergic rhinitis⁹ is defined as the presence of nasal symptoms consistent with the allergic condition but “without evidence of systemic allergic inflammation,” meaning with a negative allergy test.

Local allergic rhinitis (LAR)¹⁰ is considered to be a localized nasal allergic response with negative skin prick tests or specific IgE tests, characterized by local production of specific IgE when there is an exposure to an allergen, with a positive nasal allergen provocation test to the allergen being considered.

The common link to all these different syndromes is that the patients have clear allergic symptomatology but the workup is negative. This negative workup can only be a SPT (where the allergen has poor capability to reach the mast cells) or a RAST-type blood test that found no IgE (but did not evaluate for other immunoglobulins), and obviously neither test evaluated for the possibility of other different immunological mechanisms.

To add to this conundrum, it is acknowledged that the prevalence of nonallergic rhinitis can be up to more than 50.0% of the cases and conditions like asthma and eczema can be present with or without IgE.^9,11 It is even acknowledged that IgE sensitization is not the main causal mechanism of these diseases.¹¹

Allergens, like molds and dust mites (but also others), can involve complex reactions with no IgE. In these cases, an IgE RAST-type of test will be negative, but the IDT will show a reaction. A skin test should be thought of as a “biological assay” as a positive wheal can contain, besides IgE, immunocomplexes (Type III reaction of Gell and Coombs) and immunological cells that can make a wheal persistent for many days or even appear 24-48 hours after the test. These are called delayed reactions and involve cellular immunity (type IV reaction of Gell and Coombs). ¹²

In Summary

As already stated, Drs, Hurst and McDaniel are making a commendable effort to bring to the attention of any practitioners managing allergic patients that the clinical presentation of allergies is not only sneezing and runny nose. Many conditions like middle ear inflammation (leading to fluid accumulation and predisposing to infections), inflammation of tonsils and adenoids (leading to hypertrophy and also predisposing to infections), and inflammatory conditions in other parts of the body like the lower respiratory tree or the skin, have an allergic component.

The mismatch between the clear clinical presentation and the negative skin tests can only be understood when realizing that the skin tests are not all the same, the most commonly used skin test is unfortunately the least able to perform, and when understanding that an immunological response to an allergen can involve one or more of the immunological mechanisms described by Gell and Coombs, therefore a negative IgE “RAST” will not exclude an allergic etiology.

References

1. Hurst DS, McDaniel, AB. Diagnosis of the Pathophysiology of Chronic Mucosal Diseases of Allergic Rhinitis, Asthma, and Otitis Media as Seen by an Otolaryngologist. Townsend Letter. April 2022:39-40.
2. Hurst DS, McDaniel A. Clinical Relevance and Advantages of Intradermal Test Results in 371 Patients with Allergic Rhinitis, Asthma and/or Otitis Media with Effusion Cells 2021; 10:3224. https://www.mdpi.com/2073-4409/10/11/3224.
3. Saporta D, Hurst D. Management of the allergic patient: The role of different diagnostic tests. Townsend Letter. April 2018:52-55.
4. Janssens AS, et al. Mast cell distribution in normal adult skin. J Clin Pathol. 2005 Mar; 58(3): 285–289
5. Bernstein I.L, et al. Allergy diagnostic testing: An updated practice parameter. Ann Allergy Asthma Immunol. 2008, 100, S1–S148
6. Jacobsen L, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. Aug 2007;62(8):943-948.
7. Gell PGH, Coombs RRA, eds. Clinical Aspects of Immunology. Oxford, England: Blackwell; 1963.
8. Ellis AK, Keith PK. Nonallergic rhinitis with eosinophilia syndrome. Curr Allergy Asthma Rep. 2006 May;6(3):215-20.
9. Yum HY, Ha EK, Shin YH, Han MY. Prevalence, comorbidities, diagnosis, and treatment of nonallergic rhinitis: real-world comparison with allergic rhinitis. Clin Exp Pediatr. 2021;64(8):373-383.
10. Rondón C, et al. Local allergic rhinitis: concept, pathophysiology, and management. J Allergy Clin Immunol. 2012 Jun;129(6):1460-7.
11. Pinart M, et al. Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study. Lancet Respir Med. 2014 Feb;2(2):131-40.
12. Saporta D. Immunotherapy Management of the Allergic Patient with Asthma and Lower Airway Inflammation. Townsend Letter. April 2021:38-45. (References available online at www.townsendletter.com).