Eosinophilia

Doctors may find eosinophilia in the blood or tissues, in a complete blood count with a differential white blood cell count, or in tissue pathology.

This article reviews the biology of eosinophils and the definitions of eosinophilia in blood. The difficulties in defining tissue eosinophilia as well as the conditions associated with eosinophilia are also discussed and a general approach to its evaluation is analyzed.

Future challenges include determining which eosinophil-associated diseases could benefit from eosinophil-targeted therapy, and identifying biomarkers for disease activity and diagnosis.

Eosinophils are myeloid cells, that is, they are cells that arise from the bone marrow and are released when mature, circulate in the periphery and become resident cells in the tissues. The development of eosinophils depends on several cytokines, including interleukin (IL) IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF).

IL-5 is also essential for the activation and survival of eosinophils. Although these are found in the circulation, they are believed to be primarily tissue-dwelling cells, where they are 100 times more abundant. In the blood, eosinophils have a half-life of 8-18 hours after leaving the bone marrow. It is unclear how long they live in different tissues and it is possible that their survival could be extended/maintained due to exogenous factors such as IL-5.

Electron micrographs reveal that eosinophils contain multiple types of granules: primary, secondary (eosinophil-specific), small, and microgranules (secretory vesicles).

The primary granules are round and uniformly dense, and are composed of Charcot-Leyden crystal protein (galectin-10), which forms the well-known Charcot-Leyden crystals associated with the sputum of asthma patients, described years before the discovery of eosinophils. Despite this known association, it is now appreciated that these crystals are not pathognomonic of asthma, and that they can form anywhere where there is excess eosinophil turnover.

The secondary or specific granules of eosinophils have an electron-dense core and are surrounded by an electrolucent matrix. These granules are made up of 4 proteins: major basic protein, integrated in the central part; eosinophil peroxidase; eosinophil-derived neurotoxin and eosinophil cationic protein. Also found within the specific granules of eosinophils are several preformed chemokines, growth factors and cytokines, such as IL-4, IL-2, GM-CSF, IL-5, IL-13, CCL5/regulated on activation, lymphocytes Normal expressed and secreted T and eotaxin.

The small granules contain acid phosphatase and arylsulfatase. On the other hand, secretory vesicles, also known as microgranules, are dumbbell-shaped and contain several receptors, adhesion molecules, and albumin.

Eosinophils also contain lipid bodies that differ from granules because they are surrounded by a monolayer of phospholipids. Lipid bodies are the sites of leukotriene synthesis and their formation is induced in various experimental inflammatory conditions as well as in response to different stimuli.

Eosinophils use a variety of degranulation processes to selectively or completely release their cellular contents. These processes include classical exocytosis (individual granules fusing with the plasma membrane and releasing their cargo); compound exocytosis (several granules fuse with each other and with the plasma membrane) and, little by little, degranulation occurs (small components of the granules detach and fuse with the plasma membrane) and finally, cytolysis of eosinophils. How these processes are regulated is still being investigated.

On the other hand, eosinophils also release networks or DNA traps with intact content of free granules, this being a regulated pathway of cell death in an extracellular trap mediated by eosinophils, known as ETosis. Recently, ETosis has been directly associated with the formation of Charcot-Leyden crystals.

Eosinophils are thought to be effector cells in the body’s defense against parasitic infections, although their mechanism of action may differ depending on the parasite. A proposed mechanism of action is the release of granular proteins from toxic eosinophils through ETosis. Other mechanisms include antibody-dependent cytotoxic cell death, which in schistosomiasis is carried out by both eosinophils and neutrophils.

Eosinophils may use similar mechanisms to cause tissue damage and inflammation in disease-associated eosinophils.

However, eosinophil-deficient mice can clear some parasitic infections, suggesting that at least there is redundancy in the body’s antiparasitic defenses.

More recently, eosinophils have been attributed roles in maintaining bone marrow plasma cells, in vaccine recovery responses, and in modulating a variety of T cell-mediated responses, as well as roles in tissue repair, glucose and fat metabolism, and perhaps tumor surveillance. Many of these studies have been done in animal models and the extension to humans has not yet been carried out. Murine studies also suggest that eosinophils can be divided into inflammatory or homeostatic subsets and it is unclear whether these exist in humans.

The authors attach great importance to the role played by eosinophils in the pathogenesis of allergic disease. They are physically present in the airways of patients with eosinophilic asthma, within the polyps of those with chronic rhinosinusitis with polyps, and in the gastrointestinal (GI) tract of those with eosinophilic GI disease (EGIE). They may also be present on the skin of patients with drug-related rashes.

> Blood eosinophilia

In general, the degree of eosinophilia is defined by the absolute eosinophil count (number of eosinophils circulating in peripheral blood). The absolute eosinophil count can be determined by multiplying the total white blood cell count by the percentage of eosinophils. Its normal range in blood is 0 to 500 cells/mm3 and the typical percentage is <5% of the leukocyte count. However, the presence of eosinophilia cannot be determined by percentage alone because leukopenia leads to a relative increase in the percentage of eosinophils, and vice versa.

Humans show diurnal variation in several hematological parameters, including blood eosinophil counts.

A recent study showed a median within-subject variability of 40 cells/mm3, or 20%, with a peak occurring at 1 AM, but in those with eosinophil counts within the normal range, the peak occurred at noon. The change in eosinophil count within the same subject over 24 hours in those with eosinophilia is unknown.

Eosinophilia is defined as >500 eosinophils/mm3. The degree of eosinophilia can be classified as mild (500–1500 cells/mm3), moderate (1500–5000 cells/mm3), or severe (>5000 cells/mm3). Hypereosinophilia is defined as moderate to severe eosinophilia (≥1500 cells/mm3). To meet the definition of HES, evidence of target organ damage caused by hypereosinophilia is required.

It is commonly believed that the degree of eosinophilia in the blood correlates with the severity of the disease, but there is no evidence to support this. End organ damage can occur with moderate levels of eosinophilia. A recent study describes a rare group of people with asymptomatic hypereosinophilia and no evidence of target organ damage despite thorough and regular evaluation.

Some medications (e.g., corticosteroids) and transient medical conditions (bacterial infection) may also mask a higher degree of eosinophilia by temporarily suppressing the absolute eosinophil count. Therefore, clinical assessment and context are important.

> Tissue Eosinophilia

Under homeostatic conditions, most eosinophils reside in tissues, mostly in the GI tract except the esophagus. They are also found in the thymus, mammary glands and uterus.

Tissue residency is regulated by the expression of eosinophil-recruiting cells in tissues, such as eotaxin 1. Under pathological conditions, eosinophils are recruited to other anatomical sites, including the lung, skin, and esophagus, and may increase further in sites that normally already contain eosinophils, such as the stomach. However, the thresholds for what is considered a pathological increase are not well defined.

The experience with esophageal eosinophilia shows how that could change. In 2007, for the purposes of research and clinical care, a multidisciplinary consensus standard of physicians interested in eosinophilic esophagitis was established. In the clinical setting and with appropriate symptoms, in the absence of response to a trial of high-dose proton pump inhibitors (PPIs) (to treat gastric reflux disease), tissue showing a maximum eosinophil count of 15 or more eosinophils/high-power field was agreed upon as the minimum standard for the diagnosis of eosinophilic esophagitis. This pattern was often accompanied by other histological features, such as hyperplasia of the basal zone, the degranulated appearance of eosinophils, and the presence of eosinophilic microabscesses. Subsequent studies revealed an entity described as sensitive to PPIs.

Esophageal eosinophilia and transcriptomic studies suggest that this entity is more similar to eosinophilic esophagitis than to gastric reflux disease. Therefore, most current guidelines suggest that a trial of high doses of PPIs is not necessary to establish a diagnosis of eosinophilic esophagitis if the correct clinical context is present. PPIs could be considered as an initial treatment for eosinophilic esophagitis, although it is not yet known whether patients with esophageal eosinophilia who respond to PPIs maintain their ability to respond to this treatment. Beyond the esophagus, eosinophils are typically found in the GI tract and may therefore play a role in maintaining homeostasis.

There are few studies describing eosinophil levels in normal GI tissue. Debrosse et al. conducted a study on children from a pediatric hospital who underwent endoscopy with biopsies and who ultimately turned out to be normal. As a threshold for tissue eosinophilia, it was proposed to use 2 times the maximum eosinophil count in each GI segment. This method results in different segments of the large intestine with different cuts, with the ascending colon having the highest threshold for diagnosis.

Currently, gastric eosinophilia is accepted if there are 30 eosinophils/high-power field in at least 5 high-power fields, for clinical history and natural study enrollment purposes, with a similar threshold for the small intestine. Further studies are needed to determine whether the number of eosinophils alone defines disease in each segment of the GI tract, and up to what threshold.

The clinical context is important. Is the abnormal value new? Is it persistent? What are the clinical symptoms and concomitant medications associated with the laboratory abnormality, and how does that change over time and/or treatment? Therefore, a complete history and detailed physical examination are essential in this setting.

Mild eosinophilia in a patient taking high doses of corticosteroids while febrile would be interpreted differently than a patient without symptoms but with moderate eosinophilia. Furthermore, whether eosinophils are pathogenic and disease-causing or whether they are part of the cellular milieu that are recruited to the site of disease remains an open question.

Eosinophilia is associated with several medical conditions, including allergic diseases and specific conditions, from the most common such as a reaction to a medication, to rare eosinophilic diseases, such as HES.

> Infections

Eosinophilia is classically associated with parasitic diseases (e.g., helminthiasis). One approach is to consider patient characteristics, previous travel, and exposure history, thereby providing a guide for evaluation. If a patient is suspected of having a parasitic infection, referral to an infectious disease specialist may be warranted. Human immunodeficiency virus (HIV) infection may be associated with eosinophilia, although there are confounding factors, such as the use of medications or concomitant opportunistic or parasitic infections.

In a case-control study, about 10% of previously untreated HIV patients had blood eosinophilia and a slightly higher HIV RNA viral load, with no differences in age, sex, race, or baseline CD4 count. compared to a group of control patients with HIV and without blood eosinophilia or previous treatment.

In that study, the presence of rash, including eosinophilic folliculitis (although not exclusive to it) was more likely in patients with blood eosinophilia (46% in the case group vs 25% in the control group). Tuberculous and nontuberculous mycobacterial infections are associated with eosinophilia. Of note, bacterial infections are associated with eosinopenia.

Treatment is directed at the underlying infection. Resolution of infection is usually associated with a decrease or resolution of eosinophilia, although this may not occur immediately. For example, after a single dose of diethylcarbamazine or treatment with ivermectin, loa loa infection and post-treatment eosinophilia may be observed, which may take days or weeks to resolve.

In a study of Strongyloides stercoralis infection in rural India, eosinophilia decreased 6 months after treatment and, in some cases, did not resolve. Rarely, HES may occur as a result of active parasitic infections while treatment in such cases is still directed at the underlying infectious cause.

> Medications

Medications are the most common cause of persistent eosinophilia in developed countries, but the laboratory finding is neither sensitive nor specific for a drug reaction. In a study of acute cutaneous drug reactions in hospitalized patients (n = 55), blood eosinophilia (defined as >700 cells/mm3) was observed in only 18%, and tissue eosinophils were observed in 24% of cases. .

Furthermore, only half of those with biopsy-proven tissue eosinophils (12% of cases) had concurrent blood eosinophilia. Therefore, the lack of eosinophilia in the blood or eosinophils detected in tissue biopsy should not be used to rule out allergy or eosinophilic reaction to drugs.

On the other hand, there are many allergic drug reactions that are not thought to be mediated or associated with eosinophils, including immunoglobulin (Ig) E-mediated hypersensitivity type 1, delayed hypersensitivity (contact dermatitis), serum sickness and toxic epidermal necrolysis/Stevens-Johnson syndrome.

Drug reactions associated with eosinophilia can range from benign, transient eosinophilia with or without rash to more severe involvement of internal organs as in drug reaction with eosinophilia and systemic symptoms (ESS).

In a single-center prospective study investigating eosinophilic drug reactions in hospitalized patients, the incidence of eosinophil-associated drug reactions was 16.67/10,000 admissions, with 56% asymptomatic, 13% with tissue reactions in the skin and soft tissues, 7% with visceral involvement and 23% with a clinical presentation consistent with ESS.

ESS is a life-threatening disease.

It presents late (weeks) after starting the drug, with symptoms that include fever (90 to 100%), often elevated, along with a morbilliform rash. There may also be facial swelling in the early phase. These symptoms may be followed or accompanied by visceral involvement. The 2 most common are liver involvement and lymphadenopathy, but it can include myocarditis, colitis, pneumonitis, and central nervous system disorders.

Medications commonly associated with this syndrome are: allopurinol, sulfasalazine, antibiotics (ß-lactams, minocycline, dapsone, sulfamethoxazole, vancomycin), anticonvulsants (lamotrigine, valproic acid, carbamazepine, phenobarbital, phenytoin), antiretroviral agents (abacavir, nevirapine, raltegravir, efavirenz) and strontium ranelate.

The cause of the disease is believed to be a combination of activated CD81 T cells directed against the drug and viruses. Laboratory findings include eosinophilia, changes in the T helper cytokine environment, and viral reactivation, as detected by human herpesvirus (HHV) 6 polymerase chain reaction.

Recently, the factors associated with drugs or specific causes have begun to be analyzed. Examples include the correlation of increased serum thymic factor and chemokine-regulated activation (TARC)/CCL17 levels in ESS patients with HHV6 reactivation, and clinical and laboratory differences between those with lamotrigine-induced ESS vs. other drugs. Although there have been studies that isolated T cells in blood and skin for specific drugs from patients with ESS, there is currently no evidence to determine which drug is responsible.

Diagnosis of ESS can be difficult due to an incomplete clinical picture or atypical presentation, which led to the development of diagnostic scoring systems to simplify the approach. An example is the RegiSCAR score. Treatment of mild cases of ESS includes discontinuation of the drug and supportive measures. Skin manifestations can be treated with topical corticosteroids. In patients with visceral involvement, high doses of corticosteroids are often used. Complete recovery after drug withdrawal may take weeks or months.

Previous retrospective studies report a mortality of 5-10%, while a recent prospective study reported 2 deaths among 117 participants, (1.7%) during the acute phase. While any medication can cause a reaction, it has been recognized that they are best known for causing specific reactions, such as those described above for ESS. In some cases, these reactions are caused by a genetic susceptibility. For example, serious cutaneous adverse reactions in response to abacavir, allopurinol, carbamazepine, and nevirapine are more likely to occur in people with specific human leukocyte antigen alleles. (HLA).

Testing for HLA alleles is currently recommended before initiating carbamazepine and abacavir. It is also important to ask the patient about the use of supplements and over-the-counter medications.

Eosinophilic myalgia syndrome was described after exposure to a contaminant in the supplement L-tryptophan in the late 1980s, causing skin thickening, myalgia, and other organ involvement. On the other hand, allergic reactions to medications that are not associated with eosinophilia or mediated by eosinophils also occur, such as Stevens-Johnson syndrome.

> Malignancy

An occult neoplasm may be associated with blood eosinophilia. In patients with new-onset persistent eosinophilia without a clear cause and appropriate age, evaluation for the presence of malignancy is warranted. A complete history and physical examination may reveal symptoms and signs, such as fever, chills, weight loss, lymphadenopathy, or splenomegaly, to direct specific evaluation.

Biochemical evaluation could reveal alterations in other hematologic parameters (e.g., cytopenias, dysplastic-appearing cells on smear). In these cases, a hematological cause of eosinophilia should be sought with referral to a specialist. Various forms of mastocytosis are also associated with significant eosinophilia, but in these cases, treatment is tailored to the mastocytosis. On the other hand, after the malignant tumor is removed or treated, eosinophilia usually resolves. In stem cell transplants for the treatment of malignancy, post-transplant eosinophilia can sometimes be observed as part of graft vs. host disease.

> Autoimmune disorders/immune dysregulation

Several autoimmune disorders are associated with mild to moderate blood eosinophilia. In some cases, eosinophils are also found at the site of disease, such as in eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss). It is not clear whether eosinophils cause direct damage; whether they are trying to resolve the inflammation or are innocent bystanders. In general, treatments for autoimmune diseases with or without blood eosinophilia are the same.

A recent phase 3 trial of anti-IL-5 therapy to treat GEPA suggests that eosinophils themselves play some pathogenic role, because there was a significant decrease in disease flares in treated patients, despite gradual reduction of concomitant corticosteroid therapy, which would target beyond eosinophils. Currently, anti-IL-5 therapy is considered approved for GEPA. It remains to be established whether eosinophil-targeted therapy would be useful in other autoimmune diseases.

> Diseases with associated blood eosinophilia

Primary immunodeficiencies ( PIDs) are associated with eosinophilia and, less commonly, this association may be more evident in adulthood, with a clinical presentation consisting of a variety of autoimmune disorders. One explanation for the correlation is that oligoclonal/restricted lymphocyte repertoires such as those seen in various PIDs lead to eosinophilia and this was demonstrated experimentally in a murine model. Once again, the definitive treatment is that directed at the underlying PID.

> Atopic disorders

Mild to moderate eosinophilia may be associated with a wide variety of atopic disorders, including atopic dermatitis, allergic rhinitis, and asthma. Eosinophilic gastrointestinal disease (EGD) such as eosinophilic esophagitis is diagnosed by tissue eosinophilia along with the clinical context. In eosinophilic esophagitis , there is usually very mild blood eosinophilia, while in eosinophilic gastroenteritis (involvement of the stomach or small intestine), moderate to severe blood eosinophilia has been found, but larger studies are being carried out and are necessary to confirm These data.

Many of these diseases are treated with corticosteroids (topical or systemic), which target both eosinophils and other immune cells, such as lymphocytes, which could be the inciting cell population. In the case of EGIE, empiric food elimination diets have also been used, particularly in the pediatric population, and in eosinophilic esophagitis they have an efficacy of 70-80%. More recently, treatment with eosinophil-targeted therapies in a subgroup of patients with eosinophilic asthma using anti-IL-5 or anti-IL-5R resulted in increased lung function and decreased disease flares.

Both types of biologics have now been approved for use as an adjunct to maintenance therapies in severe asthma with an eosinophilic phenotype (moderate to severe for anti–IL-5R). This finding suggests that eosinophils represent a direct pathogenic role, at least in certain endotypes of asthma.

In contrast, treatment with anti-IL-4RA (which blocks IL-4-IL-13 signaling) in those with moderate to severe asthma resulted in similar clinical improvement, but was accompanied by transient increases in peripheral eosinophil counts, as well as serum eosinophil granule protein levels. With some individual exceptions, the resulting eosinophilia did not appear to cause harm or affect efficacy, although this was not evident in a subgroup analysis that stratified patients with different degrees of increased peripheral blood eosinophils.

In other conditions, eosinophilia may be associated with cholesterol embolization, irradiation, and adrenal insufficiency. Eosinophilia may be associated with cholesterol embolization, irradiation, and adrenaline insufficiency.

HES comprises a group of rare diseases defined by having a persistent blood eosinophil count ≥1500 cells/mm3 (for at least 4 weeks, unless imminent treatment is necessary) and evidence of target organ damage resulting from this eosinophilia. . This definition has evolved over the years since Chusid first described the disease. One way to subdivide this group may be into clinical subtypes .

In myeloid HES there is a genetic aberration in the lineage of eosinophilic and/or myeloid cells, this is accompanied by a dysplastic appearance of the eosinophils, increased serum levels of vitamin B12 and tryptase and clinical signs that could include splenomegaly. In lymphoid HES there is an aberrant clonal population of T cells (often CD3dimCD4 positive) that secretes high levels of IL-5, thus promoting eosinophilia.

Sometimes, patients with single-organ restricted eosinophilia such as EGIE have peripheral blood eosinophilia and meet criteria for HES, and these patients are classified as superimposed HES or superimposed HES. This associated syndrome is a category used for HES that develops in the presence of a malignancy or parasitic infection, or a reaction to a medication. Familial HES consists of few families with autosomal dominant inheritance of blood eosinophilia, and often without many symptoms.

A small group of patients show hypereosinophilia but have no noticeable symptoms or target organ damage despite deliberate evaluation over several years. These people are considered to have hypereosinophilia of unknown significance and remain untreated but monitored over the years.

In addition to the history and physical examination, it would be helpful to obtain another complete blood count with differential (to look for eosinophilia), a basic metabolic panel, liver function test, and a peripheral blood smear to examine for cellular dysplasia. Depending on the clinical context (and urgency) and probable causes, workup for eosinophilia differs and referral to a subspecialist is sometimes warranted.

It would be reasonable to refer older patients with lymphadenopathy, fever, weight loss, and cytopenias to a hematologist/oncologist.

Patients with eosinophilia should be evaluated for the association with a long history of GI symptoms, such as dysphagia, especially by a gastroenterologist and an allergist/immunologist with experience in EGIE. Furthermore, young men with recent evidence of cardiac dysfunction and severe eosinophilia should be urgently evaluated to rule out myeloid HES, with bone marrow biopsy and testing for causative genetic changes, including the FIP1L1-PDGFRA translocation.

Screening tests include determination of serum tryptase, vitamin B12, serum IgE, and flow cytometry for aberrant T cells, as well as imaging, cardiac, and pulmonary testing, if indicated. There are no validated tests to determine dietary triggers of EGIE in GI disease, other than repeat invasive tissue sampling, and therefore it is not useful to measure a panel of specific IgE or IgG4 foods.

Measuring serum IL-5 has not so far been useful in determining the cause of eosinophilia, although it is a predictor of response to anti-IL-5 therapy in a subset of patients with hypereosinophilic syndrome. On the other hand, there is little data indicating that the serum level of IL-5 is affected by medications such as corticosteroids. The 4 eosinophil granular proteins (MBP, EDN, EPO, ECP) ​​can be measured in blood and other body fluids and tissues, but exact correlations, both with diagnosis and disease activity, are not yet have been determined. On the other hand, isolated and asymptomatic blood eosinophilia may be the earliest sign of HES.

Initial workup for HES should include evaluation for myeloid HES if the absolute eosinophil count is markedly increased (>5,000 cells/mm3) with blood testing (tryptase, vitamin B12), genetic testing for associated mutations such as FIP1L1/PDGFRA, and bone marrow evaluation. If the clinical context remains worrying (male patient with elevated tryptase/B12 levels, presence of splenomegaly and dysplastic eosinophils) despite negative genetic testing, it is worth referring to a HES specialist because false negatives have been found.

Because symptoms can occur without warning, it is useful to periodically monitor increased eosinophil counts in the absence of symptoms or evidence of end-organ damage, with history and quarterly or annual physical examination, accompanied by targeted testing. There are no published consensus recommendations regarding the interval and modalities of testing because patients can have very different types of target organs affected.

It is reasonable to perform annual blood tests, lung function tests, and echocardiography in those with hypereosinophilia, especially in the first 5 years. In those with superimposed HES (e.g., EGIE, eosinophilic granulomatosis with polyangiitis), increases in eosinophil counts may precede or accompany a disease flare and those counts often return to the patient’s baseline with treatment.

If the symptoms that accompany this disease outbreak are different or new, a specific evaluation of these findings must be made to elucidate whether they are caused by a new pathological process or related to eosinophils.

In recent years, eosinophil-targeted therapy has been shown to reduce disease flares and has gained US Food and Drug Administration (FDA) approval for severe eosinophilic asthma (anti-IL- 5, mepolizumab [100 mg subcutaneously] and reslizumab [established weight]; anti–IL-5R, benralizumab) and eosinophilic granulomaatosis with polyangiitis (mepolizumab 300 mg subcutaneously).

In cases of life-threatening refractory HES, high-dose mepolizumab (300 to 700 mg) may be appropriate by applying it to the compassionate use study (NCT00244686). A small phase 2 study of benralizumab (anti–IL-5R) for patients with severe HES showed suppression of peripheral eosinophilia and symptomatic improvement over 48 weeks in 74% of patients. Larger multicenter phase 3 trials are still needed for both biologics in the treatment of HES.

Drugs that target other eosinophil membrane receptors or that reduce eosinophil counts without a defined mechanism are being evaluated in various eosinophil-associated conditions.

Whether IL-5/IL-5R biologics or other eosinophil-targeting therapies will be useful in other acute or chronic eosinophil-associated diseases remains an enigma. For example, would they be useful in acute ESS cases? Could they block eosinophilia and post-treatment reactions during the treatment of certain helminthiases? These are unexplored questions.

There is more than a decade of safety data on the use of anti-IL-5 therapy for HES from a compassionate use study. However, the effects of long-term eosinophil depletion with anti-IL-5R therapy (benralizumab) are unknown and may be different because this therapy appears to result in a more complete depletion of eosinophils, including tissue-resident ones. .

On the other hand, eosinophils may not be pathogenic under all conditions with which they are associated. The authors hope that in the next decade, the use of these new biological products targeting eosinophils will reveal in which disease the reduction of the level of eosinophils is beneficial.