Eosinophilia, defined as an absolute eosinophil count (AEC) > 0.5  × 10⁹/L, is a rather common condition, with a 1%–2% prevalence in the general population (1). On the other hand, a finding of an AEC >1500 cell/mcl, or hypereosinophilia (HE), is rare, with an estimated incidence of 6.3/100,000/year in the United States and Europe (2).

Indeed, eosinophilia and hypereosinophilia frequently require allergy or immunology consultations due to their association with organ damage or as an incidental finding (2).

In most cases, the clinical manifestations associated with HE clearly depict the underlying diseases, so diagnostic bickering fades quickly. For example, the presence of HE with cytopenia or lymph node enlargement immediately raises the suspicion of an underlying hematological disease, and the patient is immediately referred to the proper specialist. On the other hand, a patient with HE, asthma with aspergillus sensitization, lung infiltrates, and an increase in total IgE is highly suggestive of allergic bronchopulmonary aspergillosis (ABPA). Finally, one with HE, severe asthma, chronic rhinosinusitis with nasal polyps, ground glass lung involvement, skin purpura, and multiplex mononeuritis is likely to be affected with eosinophilic granulomatosis with polyangiitis (EGPA). Table 1 shows the most common conditions and diseases that should be ruled out before considering a diagnosis of HES (non-exhaustive list).

In the case of no promptly identifiable systemic diseases, a thorough assessment of both the causes of HE and organ damage should be done. The presence of HE for more than four weeks, associated with end-organ damage and no other plausible causes of HE, is in fact conventionally defined as Hypereosinophilic Syndrome (HES) (3), a rare disorder (4) with a highly heterogeneous clinical presentation and a very bad prognosis that also includes exitus if not recognized or left untreated (5).

Even though the skin, lungs, and gastrointestinal tract are the most frequently involved, almost all organs can be a target of the effects of long-lasting sustained hypereosinophilia (6, 7). In addition, the eosinophilic involvement of many organs, such as the heart, can be completely asymptomatic for a long period and then suddenly manifest itself with a serious and intractable clinical picture (8).

Despite the fact that many attempts have been made to provide diagnostic and classification algorithms for HES (9–12), the diagnostic delay is still considerable, in some cases reported up to 20 years (13). In addition, due to the failure to share a rational approach to HES, many patients with HES are still misclassified as idiopathic HES.

Recently, many international consensus (12) focused on the need for a complete diagnostic workup based on a whole assessment of potential causes of HE and the systematic evaluation of organ damage starting from the beginning of the patient’s medical history. Nevertheless, the importance of a proper diagnosis and organ damage assessment has been known for many years (14, 15), even though to date, no data concerning the application of the algorithm in a real-world setting are available.

Hence, our study aimed to describe the real-world scenario of patients presenting with HE not associated with other diseases that were later diagnosed with HES in an Italian Immunology Excellence University Centre. Moreover, we also aimed at highlighting the feasibility of the aforementioned diagnostic assessment, which we defined as a “two-tailed approach” in improving the HES diagnosis and looking for early organ damage.

A retrospective observational single-center study was conducted. All the adult patients referred for hypereosinophilia (AEC > 1500 cells/mcl on two or more occasions) to the Advanced Unit of Immunology and Allergy of the A. O. Ordine Mauriziano, Turin, Italy, from 2010 to 2020, were included.

On the other hand, the lack of the release in the informed consent or the presence of an AEC < 1500 cell/mcl represented exclusion criteria. Moreover, all the patients referred with hypereosinophilia sustained by another clearly identified cause (i.e., EGPA, ABPA, IgG4-related disease, systemic mastocytosis, infections, inflammatory bowel disease, systemic vasculitis, immunodeficiency, and other autoimmune diseases) (16) were excluded from the analysis.

The study was approved by the local ethics committee (Comitato Etico Territoriale Interaziendale (CET) “A.O.U. Città della Salute e della Scienza di Torino”, protocol code 665.743—dated 10th November 2021), and completely conducted following the Declaration of Helsinki and the latest Best Clinical Practice guidelines. All the enrolled patients released their informed consent for publication.

A total of 247 patients with hypereosinophilia were enrolled. Due to either the presence of a straightforward underlying disease associated with HE or the lack of sustained hypereosinophilia, 168 patients (68.0%) were excluded from the study and not considered in the statistical analysis, as shown in Figure 2. Briefly, 45 patients were diagnosed with EGPA and 12 with ABPA. Twenty-seven patients had HE due to parasitic infection, with no organ damage and AEC normalization after treatment. Finally, in 84 patients, the levels of eosinophils were not sustained over time.

Therefore, 79 patients (31 females, 39.2%) with a mean age of 54.9 years (range, 14–83 years) were included in the study. The mean AEC at the diagnosis was 5328.2 ± 1032.3 cells/mcl. The median total IgE value was 1670 ± 1676 kU/L, and 21 patients were atopic (26%).

Hypereosinophilia is a pretty common reason for allergy and clinical immunology consultations. In most cases, HE is isolated and self-limiting, thus not representing any real challenge for diagnostic and therapeutic purposes.

In our real-world experience, more than two-thirds of the initially evaluated patients were excluded from the study, primarily because of a not-sustained HE, which aligns with what happens in other real-life scenarios (23).

In patients with sustained HE, a comprehensive search for potential organ damage is of the utmost importance due to the extremely high rate of organ damage and the risk of end-stage organ damage in the case of a diagnostic delay. About 80% of the enrolled cohort showed at least two damaged organs.

In the last few years, the routine use of a two-tailed approach for HES diagnosis and organ damage detection has become increasingly accepted and implemented (1, 24). Still, no studies have focused on the exact timing of the application of this approach, which is the novelty of our study.

In our experience, the two-tailed approach should be implemented from the first outpatient visit, simultaneously testing for diagnosis and organ damage.

The routine use of the two-tailed approach in our clinical practice, as suggested by many recommendations (15, 16), induced us to search for any possible underlying cause of HE. This led to a very low rate of idiopathic HES, diagnosed only in 10% of our patients, a percentage far below that reported in the published real-world data.

?>In about a fourth of our HES patients, the HE and the organ damage were sustained by an infection or a drug reaction, thus being classified as R-HES. This observation underlines the importance of our approach to HE, considering that the patients had been referred to our center for incidental findings of hypereosinophilia and not due to the suspicion of an underlying disease.

Moreover, 20% of our patients, despite a whole assessment, were diagnosed with single-organ HES, and about 12% showed no organ damage at all (HEus). These data are noteworthy, as it is widely known that many single-organ HES, mainly with gastrointestinal involvement, could then be diagnosed with multisystemic HES (12). Regardless, none of our single-organ HES patients showed any disease progression, but all the patients initially classified as HEus eventually developed organ involvement and were reclassified as i-HES or l-HES, a finding that raises the possibility that HEus may not represent a truly distinct clinical entity but rather an early, pre-symptomatic phase of HES. This observation underscores the need for vigilant long-term monitoring of patients with HEus and may prompt a reconsideration of current clinical approaches to this condition.

The high prevalence of organ damage progression in patients with HEus raises the question of the importance of a comprehensive diagnostic approach. Likewise, it may also justify, both from an economic and ethical point of view towards the patient, the invasive diagnostic tests that should be required at diagnosis and follow-up.

Finally, in terms of organ damage, systematically searching for any tissue involvement, regardless of clinical presentation, has led to early recognition of HE-related cardiac damage in 12% of our patients. This percentage is much higher than that reported in the literature, estimated at around 5% in asymptomatic patients, with a significant increase up to 20% during the follow-up (7).

Based on this finding, we can postulate that the early use of the two-tailed approach in clinical practice allowed us to detect organ damage at a very early stage. As a consequence of that, the early treatment could be a reasonable explanation for the excellent outcome we observed in our patients, as no deaths nor end-stage organ damage were seen in our ten-year period follow-up. This is a remarkable observation, as in much recently published data, the mortality rate was far higher, estimated to be up to 75% in the case of a diagnostic delay (25).

Regarding diagnostic delay, the HES diagnosis in our cohort was carried out in about 4 months, which is far shorter than observed in the literature (10), probably thanks to the comprehensive two-tailed approach we used since the first outpatient visit. On the other hand, no differences were seen between the time of symptom onset and the time of the outpatients’ clinic referral. This could be linked to the low global attention paid to hypereosinophilia and its related symptoms in many clinical settings, as well as the barriers patients often face when getting to a center with HE expertise (26–28).

However, our study has some limitations. First, the selection of the patients could be a critical point. The patients referred to our center came from hematologists, gastroenterologists, and oncologists, so patients with clearly depicted clinical pictures were already excluded. Furthermore, the relatively small sample size, although one of the most extensive European case series, may be responsible for some limitations in terms of statistical analysis and comparison between groups.

Finally, the lack of a control group for comparing the efficacy of the two-tailed approach could represent a confounder. The two-tails approach was implemented in all the patients as a clinical practice and wasn’t initially designed as a prospective collection study. Therefore, we assume that further prospective studies on a larger scale, including a control group, are necessary to determine the possible implications and effectiveness of the two-tailed method on early diagnosis and disease follow-up.

In conclusion, HE is a common reason for allergists’ and clinical immunologists’ consultations, and the two-tailed approach, testing at the same time for diagnosis and organ damage, should be implemented from the first evaluation of patients with HE. This will aim at reducing diagnostic delay and the risk of mistakes in the classification of HES subtypes, thus allowing prompt and tailored treatment, as well as better outcomes.