Selection of allergen extract for immunotherapy in polysensitized allergic rhinitis patients

Abstract

Aim: To evaluate the criteria used by allergists in selecting an immunotherapy extract (allergen immunotherapy [AIT]-extract) in rhinitis patients with polysensitization. Methods: First, a cross-sectional study was carried out by evaluating different factors that influence the medical choice of AIT-extract. Second, a literature review was performed by evaluating the diagnostic performance of atopy tests. Results: A total of 419 patients were included (84 children, 149 adolescents and 186 adults). Anamnesis, atopy tests and exposure to pets were the main factors for choosing the AIT extract. The sensitivity and specificity of atopy tests were high for Dermatophagoides spp., (>80%), moderate for pets (60%) and indeterminate for Blomia tropicalis. Conclusion: NCTs could be necessary for AIT-extract selection in polysensitized allergic rhinitis patients.

Plain language summary

Allergen immunotherapy is an effective treatment for patients with allergic rhinitis. Atopy tests are used to identify possible substances in the environment that cause symptoms. A patient may sometimes have multiple substances which could be causing their allergic reactions, which makes it difficult to choose the appropriate immunotherapy for the patient. In this study, we identified some factors that might help to guide the criteria used by allergists when selecting the extract for immunotherapy.

Plain language summary

Summary points.

• To the knowledge of the authors, this is the first study evaluating allergist criteria for the selection of an allergen immunotherapy (AIT)-extract in polysensitized patients.

• The principal criteria for selection of AIT-extracts were atopy tests, local allergen prevalence, anamnesis and allergen exposure.

• The selection of an AIT-extract based only on anamnesis and the presence of pets in homes has poor diagnostic performance.

• According to the nasal challenge test (NCT), for the selection of the Dermatophagoides spp. AIT-extract, atopy tests have a high diagnostic performance.

• According to the NCT, for the selection of the Blomia tropicalis AIT-extract, atopy tests have an indeterminate diagnostic performance.

• According to the NCT, for the selection of pets (cat or dog), AIT-extract atopy tests have a moderate diagnostic performance.

• A systematic review supports the use of the NCT for evaluating clinical relevance and choosing the AIT-extract in polysensitized AR patients.

• Diagnosis by components can help improve the selection of the most appropriate extract for polysensitized patients; however, there is a lack of studies that evaluate the diagnostic performance of this test for some sources of allergens.

1. Introduction

Allergy is an unexpected abnormal or exaggerated reaction to an exogenous stimulus involving the immune system [1]. The anamnesis and evaluation of atopy (IgE sensitization) using the skin prick test (SPT) or serum-specific IgE (sIgE) are the first step in identifying to potential allergenic sources, an association with the symptoms and in choosing the allergen extract for allergen immunotherapy (AIT) [2–4]. Nevertheless, between 15 and 30% of the population may have atopy and not be clinically relevant and between 20 and 50% of allergic patients may have atopy to different allergenic sources (polysensitization) [5–8]. In allergic rhinitis (AR), the nasal challenge test (NCT) is the gold-standard in confirming whether the presence of atopy is clinically relevant (allergy), but it is not usually used because it takes time and has a latent risk of generating systemic reactions [9,10].

Despite the growing number of studies that evaluate different aspects of the effectiveness and safety of AIT [4,11–13], few have evaluated the selection criteria of the allergenic extract for AIT (AIT-extract) in polysensitized patients. An inefficient selection of the AIT-extract can cause financial costs and loss of time for the patient [4,12,14]. This risk is higher among patients with IgE sensitization to multiple sources (polysensitization) [15,16]. In some parts of Europe and USA, pollen grains are the main source of sensitization, while in countries located in tropical regions, house dust mites (HDM) are the main source (80–90% of patients), but 30–60% of patients are polysensitized to Blomia tropicalis, Canis familiaris and Felis domesticus [5,17,18]. While there are several studies that evaluate clinical factors predicting the clinical relevance of the different allergenic sources for grain-pollen polysensitized patients, this information is scarce for other allergenic sources [19,20].

Previous studies in this population suggest a greater response to immunotherapy among monosensitized versus polysensitized patients [11,21]. This may be due to a greater inflammation process among the polysensitized patients or perhaps due to the greater difficulty for selection of the correct AIT-extract in the polysensitized patients. The selection of multiple allergens from different sources for immunotherapy could solve the problem of choosing a specific extract; however, the best evidence regarding the efficacy and effectiveness of AIT has been demonstrated by applying a single allergenic extract or a group of phylogenetically related allergenic extracts [15,22]. Additionally, there is little information on the clinical and sociodemographic factors to consider when selecting an allergen extract for AIT in a polysensitized AR patient. Considering this gap in knowledge and the impact it has on clinical practice, the objective of this study was to carry out an evaluation of the selection criteria used by allergists to select an AIT-extract in AR patients with polysensitization to Dermatophagoides spp., B. tropicalis, C. familiaris and F. domesticus and to propose a step-by-step algorithm for AIT-extract selection in this population.

2. Materials & methods

2.1. Study design

This study comprises two steps. First, allergists and patients completed a survey to collected sociodemographic and clinical characteristics of patients who were about to start or had less than 12 months with AIT. The timeframe of less than 12 months was selected to avoid memory bias. Additionally, we review medical records for patients who accept to participate. With this information we identified critical factors in the real-life for the selection of the AIT-extract. The population was recruited from six cities in Colombia. This country is in the Latin American tropic region, where the frequency of asthma (10%) rhinitis (24%), other allergic diseases and the frequency of pets at home (one in every three households) has been previously studied [5,11].

Second, we did a literature review looking for studies in which the clinical relevance of atopy in patients with rhinitis was evaluated according to NCT for the five most frequent allergenic sources in tropical regions [5,17] (Dermatophagoides farinae (Der f), Dermatophagoides pteronyssinus (Der p), B. tropicalis (Blo t), C. familiaris (Can f), F. domesticus (Fel d). Due to the strong phylogenetic relationship between Der f and Der p, they were presented together (Der spp.).

With the information from the survey and the literature review, we created a step-by-step algorithm for the management of polysensitized allergic rhinitis patients based in a Delphi panel.

2.2. Evaluation of clinical practice according atopy results

The data collection was carried out through an electronic survey. Patients and allergist from 31 centers participated. In the case of patients under 18 years old, the parents assisted in completing the questionnaire. This questionnaire was anonymous to avoid bias in the responses (Attention or Hawthorne bias). The survey had different domains; sociodemographic characteristics, clinical characteristics, atopy tests (SPT, sIgE), healthcare insurances. When reviewing the medical records, we assessed the topics revised by the physician during the anamnesis; the items evaluated in the anamnesis were questions about sociodemographic characteristics (age, sex, presence of pets in the house), clinical characteristics (allergic diagnoses, comorbidities, severity, pharmacotherapy, age of onset of diseases, triggers reported by the patient). We also performed a literature review to review the accuracy of anamnesis in predicting clinical response according to the NCT. Based on this information, we identified the most frequent topics considered for the selection of AIT-extract.

2.3. Nasal challenge tests

NCTs were performed according to medical criteria with Der p, Blo t, Can f, Fel d. Allergen extracts at a concentration of 10,000 UB/ml was applied with a nasal spray at a measured dose of 100 ml/puff in each nostril according to the manufacturer's instructions (Laboratory Inmunotek, Spain). Previously, the presence of non-specific nasal hyperreactivity was ruled out by performing the same procedure with saline solution [23]. To define a positive NCT, the criteria proposed by the “European Academy of Allergy and Clinical Immunology” (EAACI) was used [24]. The accuracy, specificity, reproducibility and reliability of NPT-extracts has been evaluated in previous studies [10].

2.4. Systematic review

Once the main critical factors in choosing the AIT-extract have been identified, we did a comprehensive review of the literature to identify if these factors allowed the selection of the most useful AIT-extract according to clinical relevance. The research questions were defined as:

• What is the diagnostic performance of atopy tests (SPT or sIgE) in rhinitis patients to identify clinical relevance according to NCT with Der spp., Blo t, Can f, Fel d?

• What is the diagnostic performance of anamnesis data in rhinitis patients to identify clinical relevance according to NCT with Der spp., Blo t, Can f, Fel d?

• What is the risk factor of pet's exposure in the house (Can f, Fel d) in rhinitis patients for clinical relevance according to NCT with Can f, Fel d?

The review was carried out following the PRISMA recommendations [25] (Supplemental material). We systematically searched articles from January 2000 to August 2023 from the Medline, google scholar and LILACs databases. Titles and abstracts and subsequently full-text articles were screened in duplicate to assess eligibility. Articles in English, Spanish and Portuguese were reviewed.

Studies were included if they provided empirical data related to the panel staff questions (clinical trials, cohort studies, case-control studies). Systematic reviews or meta-analysis using NCT as gold standard were also included. We excluded narrative reviews and case reports. We circulated the bibliography collected among the members of the staff; In case any of the staff members considered it was necessary to include an additional reference, this was discussed. The keywords used for each bibliographic search were Question 1: atopy, allergy, NCT, nasal provocation test, pets IgE, specific IgE, Component diagnosis, Dermatophagoides, pteronyssinus, farinae, B. tropicalis, C. familiaris, F. domesticus. Question 2: atopy, anamnesis, allergy, clinical history, NCT, nasal provocation test, pets, IgE, specific IgE, Component diagnosis, Dermatophagoides, pteronyssinus, farinae, B. tropicalis, C. familiaris, F. domesticus. Question 3: atopy, allergy, exposure, NCT, nasal provocation test, house, pets, dog, cat, C. familiaris, F. domesticus.

For each question, we summarized all information including a concise description of diagnostic performance (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), negative likelihood ratio (LR-), accuracy) and practical application. The answers for each question were then reviewed by the panel staff, who provided feedback through by means of electronic communication.

2.5. Staff conformation & clinical recommendations

Considering the recommendations for the construction of a Delphi panel [26], and seeking to have a representative group of public and private institutions, urban and rural area, adult and pediatric patients, a panel of 12 participants was selected based in an open invitation to allergists registered from the ACAAI society (Colombian Association of Allergy and asthma Immunology).

Based in the results of the survey, medical records and the systematic review, the Delphi panel built the most efficient management algorithm focused on the clinical practice efficiency according to effectiveness, safety and time saved. Recommendations were decided by consensus.

2.6. Statistical analysis

To describe the results of the survey and medical registers we use measures of dispersion and central tendency such as range, interquartile range, median and mode, as well as percentages and absolute values according to the nature of each variable. When data from articles included in the systematic review allowed it, we calculated the diagnostic performance (sensitivity, specificity, PPV, NPV, LR+, LR-, accuracy). Based on the probability reasons set, raising from social networking analysis, exploration and linking networks and complex systems were performed. A p-value < 0.05 was considered significant. Statistical analyses were performed using the IBM SPSS Statistics version 26.0 (IBM Corp, NY, USA) and GraphPad Prism version 10.0 (MA, USA).

2.7. Ethical considerations

This study was approved by the technical and ethical committee of the Hospital ‘Alma Mater de Antioquia’ code IN29–2021 act 169–2021. All participants gave written consent.

3. Results

3.1. Patients' characteristics & immunotherapy selection

A total of 419 polysensitized AR patients to at least two allergenic sources (Der spp, Blo t, Can f and/or Fel d) and AIT prescription were included (Table 1). None of the patients was younger than 3 years. The main allergenic source was Der spp., (86%), follow up by Blo t (52%). Most patients received AIT with Der spp., or Der spp. / Blo t extract (Figure 1A). A total of 12% patients received two AITs; most of them received second AIT with some pet's extract after 6–12 months with AIT-mites and the principal reason was low clinical response with the first AIT. Only 1% received AITs with cat and dog extract without mites (Figure 1B). Among patients who received AIT-Can f or AIT-Fel d, 78% had a pet at home and component molecular diagnosis was requested in only 3% patients.

Table 1.

Patients' characteristics.

	Polysensitized allergic rhinitis patients
Age (years)	18 (range 4–67 years)
4 to 12 years	84 (20%)
13 to 18 years	149 (35.5%)
18 to 49 years	153 (36.5%)
Over 50 years	33 (7.8%)
Gender (Female)	222 (52.9%)
Atopy	419 (100%)
Dermatophagoides spp.	364 (86.8%)
Blomia tropicalis	222 (52.9%)
Canis familiaris	151 (36%)
Felis domesticus	71 (16.9%)
Others	38 (9%)
Houses´ pets
Dog	128 (30.5%)
Cat	69 (16.4%)

General characteristics of population.

Figure 1.

Allergen immunotherapy extracts. Frequency of AIT-extract used (A) and in blue points AIT with one extract and in range AIT with two extracts (B).

AIT: Allergen immunotherapy.

A total of 97 nasal challenge tests (NCT) were done in 73 patients for the selection of AIT-extract; This indicates that in 344 (82%) polysensitized AR patients the selection of the AIT-extract was based in the anamnesis information and atopy test (Figure 2). Most of NCT were with Blo t (34%), Dog (20.6%) or Cat (17%), only 15.4% with Der spp. There was not significant difference in sensitivity and specificity between skin test and serum sIgE. The results of SPT and sIgE with allergenic extracts had high agreement (97%) for positive and negative results. As exploratory analysis, when dividing by quartiles, we observed that patients with higher sIgE for cat and dog allergens could present a higher frequency of NCT-positive (p 0.05) but not for Blomia tropicalis (p 0.12). However, these results are exploratory and must be confirmed with new studies.

Figure 2.

Nasal challenge tests. A total of 97 NCTs were done in 73 patients. In blue points (n = 49) patients with one NCT and in orange (n = 24) patients with two NCT.

NCT: Nasal challenge test.

3.2. Factors for decision-making

Different factors were evaluated to define how they influenced the selection of AIT-extract (Figure 3A & B). According to more than 50% of the allergists, pharmacotherapy response and clinical history were ‘indispensable’ factors for the selection of AIT extract and ‘Allergy comorbidities’, ‘Clinical History’, ‘NCT’ and ‘House ´pets’, were very important (Figure 3A).

Figure 3.

Factor for allergen immunotherapy-extract selection. Different factors were evaluated to define how they influenced the selection of allergen extract for allergen immunotherapy. In (A) factors identified by allergist (n = 76). In (B) factors identified in medical registers.

NCT: Nasal challenge test; OR: Odds ratio.

The factors described by the allergists presented some differences from those what we identified in the patient records. For Der spp., extract selection, clinical history was the principal factor, followed by pharmacotherapy response and patient age. For AIT-pets and AIT-Blo t selection these factors were also important, but NCT was also important and for AIT-pets allergist’ selection the presence of pets in the house was the most important factor.

3.3. Review results & management algorithm proposal

The search results for each question are presented in the Supplementary material. The summary of articles identified and selected for the exhaustive review is presented in Table 2. For the first question “What is the diagnostic performance of atopy tests (SPT or sIgE) in rhinitis patients to identify clinical relevance according to NCT with Der spp., Blo t, Can f, Fel d?” The results with Dermatophagoides spp., extract were consistent: the sensitivity of the test had a median of 83% (range 79–100%) and the specificity 98% (range 95–100%). Atopy tests for Dermatophagoides spp., in patients with chronic rhinitis identifies more than 80% of patients with allergies to this mite. In three studies polysensitized patients were included and this variable does not seem to affect the performance of the test. Among AR patients a positive atopy test with Der spp., can correctly identify more than 80% of patients with clinical relevance. Therefore, provocative testing is not routinely necessary for AIT-Der p. For Blomia tropicalis, there was not enough information for calculated diagnostic performance. For Can f and Fel d, some studies suggest a sensitivity between 50 and 70%, however, there is no comparator group so the specificity of the atopy test could not be calculated with these extracts.

Table 2.

Systematic review.

Question #1: What is the diagnostic performance of atopy tests (SPT or sIgE) in rhinitis patients to identify clinical relevance according to NCT with Der spp., Blo t, Can f, Fel d?
#	Extract	References	Ref.
1	Der spp.	Santamaría L, et al. World Allergy Organ J. 2020 Sep 28;13(9):100461.	[10]
2	Der spp.	Matsumoto FY, et al. Am J Rhinol Allergy. 2017 Jan 1;31(1):7–11.	[27]
3	Der spp.	Joo SH, et al. Clin Exp Otorhinolaryngol. 2021 Nov;14(4):382-389.	[28]
4	Der spp.	Hao Xio, et al. Am J Rhinol Allergy. 2022 Mar;36(2):191–197.	[29]
5	Der spp.	Kirerleri E, et al. Asian Pac J Allergy Immunol. 2006 Jun-Sep;24(2–3):117-121. Asian Pac J Allergy Immunol. 2006 Jun-Sep;24(2-3):117-21. Evaluation of the nasal provocation test for its necessity in the diagnosis of nasal allergy to house dust mite E Kirerleri, N Guler, Z Tamay, U Ones	[30]
6	Der spp.	King MJ, et al. Ann Allergy Asthma Immunol. 2008 Jul;101(1):12-17.	[31]
7	Der spp.	Cheung EJ, et al. Otolaryngol Head Neck Surg. 2010 Aug;143(2):290-293.	[32]
8	Der spp.	Blay F, et al. Ann Allergy Asthma Immunol. 2015 Nov;115(5):385–390.e1.	[33]
9	Der spp.	Chusakul S, et al. Am J Rhinol Allergy. 2010 Mar-Apr;24(2):133-136.	[34]
10	Der spp.	Kim KS, et al. Clin Exp Otorhinolaryngol. 2017 Sep;10(3):254–258.	[35]
11	Can f and Fel d	Sánchez A, et al. Pulm Med. 2020 Jan 24;2020:6365314.	[36]
12	Can f	Käck U, et al. J Allergy Clin Immunol. 2018 Oct;142(4):1113–1120.e9.	[37]
13	Fel d	David Larson 1, et al. J Allergy Clin Immunol. 2020 Jun;145(6):1585–1597.	[38]
14	Fel d	Mona Al-Ahmad et al. Int Arch Allergy Immunol. 2019;179(2):108–113.	[39]
Der spp.: Several articles found a sensitivity and specificity greater than 80% for the atopy test. Blo t: We did not find articles to answer this question. Can f: Two articles found a sensitivity of 50–60% for the atopy test. Fel d: Three articles found a sensitivity of 50–70% for the atopy test.

What is the diagnostic performance of anamnesis data in rhinitis patients to identify clinical relevance according to NCT with Der spp., Blo t, Can f, Fel d?
#	Extract	References	Ref.
1	Der spp.	Anna S Englhard, et al. Eur Arch Otorhinolaryngol. 2022 Feb;279(2):801–810.	[40]
Der spp.: One article suggests a sensitivity of 63% for the anamnesis. Blo t: We did not find articles to answer this question. Can f: We did not find articles to answer this question. Fel d: We did not find articles to answer this question.

What is the risk factor of pet's exposure in the house (Can f, Fel d) in rhinitis patients for clinical relevance according to NCT with Can f, Fel d?
#	Extract	References	Ref.
1	Can f and Fel d	Sánchez A, et al. Pulm Med. 2020 Jan 24;2020:6365314.	[36]
2	Can f	Ekäck U, et al. J Allergy Clin Immunol. 2018 Oct;142(4):1113–1120.e9.	[37]
Can f: Two articles found that dog exposure is not a risk factor for NCT positive. Fel d: One article Two articles found that dog exposure is not a risk factor for NCT positive.

Summary of systematic review of literature from January 2000 to August 2023.

NCT: Nasal challenge test.

For the second question “What is the diagnostic performance of anamnesis data in rhinitis patients to identify clinical relevance according to NCT with Der spp., Blo t, Can f, Fel d?”A total of 2430 articles were reviewed but only one specifically evaluated specifically the accuracy of the anamnesis according to the NCT. Englard A, et al., evaluated 417 patients with NCT-Der spp., and concluded that clinical data were not sufficient to distinguish between silent sensitization and clinically relevant (sensitivity <30%).

For the third question “How well does the presence of pets in the house (Canis familiaris, Felis domesticus) correlate with NCT in patients with allergic rhinitis?” Three articles were identified: one included information for Can f and Fel d and two only for Fel d. In all articles it was not observed that having pets in the house was a risk factor for a NCT positive.

3.4. Panel recommendations

Based on the information available according to the systematic review and the principal decision factors observed, the panel staff proposed a management algorithm (Figure 3).

In polysensitized AR patients AIT-Der spp., should be considered the first option considering the diagnostic performance of atopy tests according NCT; it is not justified to routinely perform the NCT-Der spp.

For Blo t, Can f and Fel d, according to the search criteria, there is not enough evidence to adequately establish the sensitivity of atopy tests to identify clinical relevance according to the NCT. With Can f and Fel d, pets in the house were not a risk factor for the NCT-positive. With this information the panel suggest that AIT with these extracts in AR polysensitized patients should be done only after additional tests like NCT or molecular component diagnosis (MCD) (Figure 4).

Figure 4.

Management algorithm proposal. Scenario #1 represented polysensitized AR patients with sensitization to Der spp., Blo t, Can f, Fel d (A). Scenario #2 represented polysensitized AR patients with sensitization to Blo t, Can f, Fel d. Control should be defined according to Clinimetric tools. Suspension of AIT should be considered when clinical improvement is not observed despite performing the previous steps. Selection of immunotherapy for pets should considered direct and indirect exposure.

AIT: Allergen immunotherapy; HDM; House dust mite; NCT: Nasal challenge test.

4. Discussion

The evaluation of the factors that influence the clinical response to immunotherapy is an important outcome and requires a prospective design for its response. As the first step, the factors that influence the choice of AIT-extract in polysensitized patients must be identified; as far as we know, this is the first study evaluating this point through a cross-sectional design and a review of the literature. Multiple studies support the effectiveness of AIT in both clinical trials and real-life studies; AIT in AR improves the quality of life of patients, reduces pharmacotherapy and potentially prevents the development of allergic comorbidities such as asthma [13,41]. These studies support the use of AIT with a single allergenic source or a combination of phylogenetically related allergenic sources, for example, Dermatophagoides pteronysinus and Dermatophagoides farinae [42]. In regions with a high rate of polysensitization, the choice of the AIT-extract is difficult because of the common polysensitization to species that are not phylogenetically related, such Dermatophagoides spp., B. tropicalis, C. familiaris and F. Domesticus is frequent.

We found the following results from the survey and the literature review:

• Allergists considered different factors when choosing the AIT-extract, but several of these were not sufficiently accurate enough to properly choose the AIT-extract.

• For selection of AIT-Der spp., IgE sensitization has a high diagnostic performance according to the NCT.

• There is little research evaluating the diagnostic performance of atopy tests with B. tropicalis or pets.

• Factors such as anamnesis and the presence of pets in homes do not seem to be precise enough to properly select the AIT-extract.

• The NCT or MCD are rarely performed when choosing the AIT-extract in polysensitized AR patients.

Different guidelines have been published to identify candidate patients for AIT and ways to evaluate clinical response [43,44]. However, there is little information about criteria for choosing the best allergenic extract in polysensitized AR patients. Most allergists make decisions based on anamnesis data, atopic test results and evidence of exposure to an allergenic source. However, the usefulness of the anamnesis and a positive atopy test in predicting clinical relevance appears to vary according to the allergenic source. Recently, Englhard et al. observed that the accuracy of the anamnesis in establishing clinical relevance according to the NCT-Der spp., was low [45]. The literature review in our study indicates that the diagnostic performance of atopy tests or having a dog or cat in the home had a low specificity. The allergist needs to explore other clinical tools, as anamnesis, atopy tests and pets' exposure are not sufficient criteria to select the AIT-extract for B. tropicalis, C. familiaris and F. domesticus. We observed that MDC was used little in clinical practice, but according to different studies it could be useful in identifying patients with clinically relevant sensitization especially those with pets [36,37]. Käck et al. [37] reported that sensitization to multiple components increase the possibility of a positive NCT with a cat or dog extract. Similar results were observed by Sánchez J et al. [36],; more than two components improve sensitivity from 50 to 73%. Based on these results, in patients with pet IgE sensitization, MCD could be used for selection of an AIT-extract. Avoiding pets for diagnosis and treatment is a controversial topic. In populations where having pets is common, their avoidance becomes difficult due to indirect exposure [36,46,47]. Additionally, ‘remove the pet” as a diagnostic test or therapy is also complicated by emotional attachment [48–50]. Therefore, the recommendation to avoid pets must consider the intensity of indirect exposure and the feasibility of its application in each family.

According to the results of the systematic review, in the case of Der spp., patients with allergic rhinitis and a positive atopy test for Der spp. present a positive NCT in more than 80% of cases, and these results do not vary between monosensitized and polysensitized patients. Based on these results, we proposed that this allergenic extract is the first AIT-extract of choice among polysensitized patients in tropical regions because cost-effective considerations by avoiding the need for a prior NCT. However, in populations where IgE sensitization to Dermatophagoides spp. is low, it may be necessary to consider confirming its clinical relevance using the NCT.

Atopy tests (SPT, sIgE) have high accuracy in identifying patients with IgE sensitization, but this is not always clinically relevant. A negative test rules out an allergic component in most cases, but in the case of a positive test, the result must sometimes be confirmed by the gold test (NCT) [9,10]. According to the review of the literature, we observed that in the case of pets, the performance of these tests to predict clinical relevance is lower than for Der spp.; therefore, in case of a positive atopy test to these allergens in a polysensitized patient, it is necessary to consider performing a challenge test if there is direct or indirect exposure.

According to the systematic review criteria, we did not find B. tropicalis studies that evaluate the diagnostic performance of anamnesis and atopy tests that predict clinical relevance. In an open search, Stanaland et al., reported a high frequency of positive NCT among 12 patients sensitized to Blo t [51] in 1996; unfortunately, no other studies support these results. In our study, the results of the NCT tests with Der p spp. correspond to what was found in the systematic review, but with Blo t, the atopy tests had a performance of less than 60% in predicting a positive NCT. The co-sensitization of Blo t and Der spp. is common in tropical regions [52,53], so the application of the three mites in AIT is relatively common in some areas [11,54]. While new studies appear to evaluate the clinical relevance of IgE sensitization with Blo t through the NCT, these practices may be clinically efficient; however, we suggest performing NCT-Blo t if the patient is not sensitized with Der spp.

Molecular diagnosis by components is a test that has proven to be useful in food allergies and for the choice of immunotherapy in patients polysensitized to various pollens. With Blo t the clinical usefulness of MDC is not clear, since there are few studies that evaluate its diagnostic accuracy using nasal challenge tests. There are few studies that establish the clinical relevance of sensitization to Blo t 5 and Blo t 21, but since they are species-specific allergens, they could potentially enable the identification of sensitization that are not secondary to cross-reactivity with proteins from other mites and therefore could be useful in AIT-extract selection. In the case of pet allergy, some previous studies suggest that sensitization to various dog or cat components increases the probability of a positive nasal challenge test, which would help in appropriately selecting patients who could benefit from immunotherapy. However, more studies are required to confirm these findings.

Our study has some limitations; we did not evaluate the clinical effectiveness of AIT, which would have been practical to define the usefulness of the measures proposed in the algorithm. The proposed management algorithm needs to be validated in different populations since the impact of the recommendations on the clinical response to immunotherapy was not evaluated in this study. New information is necessary to validate the proposed steps in the algorithm or make modifications. However, it is a starting point that is supported by an exhaustive review and provides a synthesis of the best available information. Despite this limitation, we observed that most patients start with AIT-Der spp., and only 12% received another AIT after 6 to 12 months suggesting that a high number of patients had a good clinical response with to AIT-Der spp. Another weakness of this study was that we did not evaluate other sources such as pollen grains, because the frequency of sensitization found in our study population was low. Among the strengths of this study, we achieved the principal objective, which was to identify the factors that influence when selecting AIT in polysensitized AR patients, and with the literature review, the findings allowed us to develop the proposed management algorithm, offering better evidence. The applicability of our results to other regions must be evaluated considering factors such as the main allergenic sources; however, because the results of the systematic review, for example for Der spp., for example, include articles from different parts of the world, we consider that the proposed algorithm can be useful at a global level.

5. Conclusion

In conclusion, the results of this study suggest that we should reconsider the criteria we use to define the extract we use for AIT. Additionally, we make a proposal that could help guide us in selecting the extract. When we consider applying AIT with B. tropicalis, C. familiaris or F. domesticus, the anamnesis and atopic test must be complemented with additional clinical tools such as the MDC and the NCT may be necessary.

Funding Statement

This study was supported by the Universidad de Antioquia (IN29-2021 act 169-2021).

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/1750743x.2024.2342225

Author contributions

E García and J Sánchez proposed the central idea of the article and conducted the literature review for the systemic review. E García, J Sánchez, J-C Ardila, N Crespo, E Chapman, J Ocampo, M Olivares, A Acevedo, N Aguirre, S Abreu, A Calle, R Ramírez, contributed equally to data collection and writing the manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the technical and ethical committee of the Hospital “Alma Mater de Antioquia” code IN29–2021 act 169–2021. All participants gave written consent.