**First-line treatment: topical and/or systemic corticosteroid therapy** Corticosteroid therapy is generally the first-line treatment for idiopathic HES, and rapid response (complete or partial) is the norm.

Depending on the clinical manifestations, the use of locally active steroids (topical corticosteroids, orodispersible budesonide for esophagitis, gastro-resistant budesonide for lower GI manifestations and inhaled corticosteroid therapy or nasal spray) is encouraged to reduce the use of systemic corticosteroids.

When organs not accessible (or resistant) to topical corticosteroids are involved, systemic corticosteroids are the first-line treatment for idiopathic HES. The loading dose (0.5–1 mg/kg/day prednisone (off-label)), possibly preceded by pulses of methylprednisolone (15 mg/kg/day for 1–3 days) in case of organ- or life-threatening manifestations, should be tailored to the severity of symptoms before gradual tapering. Overall, the minimum effective dose should be used, and weaning should always be discussed: in acute forms, cessation of corticosteroid therapy may be attempted after a few weeks of treatment; in the case of chronic disease, a treatment period of approximately 12 months seems advisable before considering cessation.

**Second-line treatments** To minimize the potential adverse reactions of systemic corticosteroid therapy, steroid-sparing treatment may be considered in patients with high dose corticosteroid dependence, considering the patient's specific comorbidities).

To date, being the only drug having been assessed in prospective randomized controlled trials, we currently recommend mepolizumab (300 mg subcutaneous monthly) as the first-line steroid-sparing agent. Contrariwise, all other compounds are prescribed off-label based essentially on the available retrospective data.

Following two clinical trials that demonstrated the superiority of mepolizumab, an IgG1 kappa monoclonal antibody targeting IL-5, vs. placebo in terms of reduction of the number of clinical relapses and steroid-sparing effect, mepolizumab was approved by the FDA in September 2020, by the EMA in November 2021 [99, 100]. Conversely, although preliminary data suggest that mepolizumab could remain efficacious even at lower “asthma” doses (i.e. 100 mg subcutaneous monthly) in other eosinophil-associated diseases (e.g. EGPA or idiopathic chronic eosinophilic pneumonia), it should be emphasized that, to date, standard treatment of HES relies on a full dose regimen i.e. 300 mg mepolizumab subcutaneous monthly [101].

Specifically, we suggest using mepolizumab in the following settings:

* Chronic AND idiopathic AND oral-corticosteroid-dependent HES (meaning that the efficacy of oral corticosteroids has previously been established, and that an attempt to withdraw oral corticosteroids has been followed by both a clinical AND a hematological relapse)

* Relapsing (either single-organ OR systemic) HES with at least 3 yearly flares requiring short courses of oral costicosteroids.

Under treatment with mepolizumab, once that sustained clinical and hematological remission have been achieved, the tapering (or even withdrawal) of both oral corticosteroids and other cytotoxic-immunosuppressive drugs is strongly encouraged.

Contrariwise, it should also be emphasized that there is to date no rationale for the prescription of mepolizumab either as first-line therapy (even in the setting of organ or life-threatening HES—where systemic corticosteroids, along with antiparasitic treatments and anticoagulants are usually effective, as detailed in “Follow-up of F/P + HE/HES” Section). Likewise, in patients under low dose oral corticosteroids and with no treatment-related side effect, maintenance treatment with low dose oral corticosteroids monotherapy is acceptable.

In case of failure of mepolizumab, further-line steroid-sparing treatments include:

* Interferon alfa-2a, an immunomodulatory agent acting on both eosinophilia and Th2-polarized T cells [102]. Currently, only the pegylated form is available (Pegasys®). Although the reported efficacy is relatively high, its safety profile can be a barrier to its use and long-term maintenance [103]. It is therefore standard practice to start with the lowest possible dosage (e.g., 45 µg pegylated interferon alfa-2a weekly by subcutaneous injection) and to increase it gradually monthly if necessary, depending on tolerability. The practicalities of prescribing pegylated interferon alfa-2a are detailed in Box 9.

* Hydroxycarbamide, a non-specific myelotoxic agent with anti-eosinophilic activity. In practice, it is usually started at a low dosage (1 g/day in a single dose) and then increased if necessary (up to 2 g/day in a single dose) depending on effectiveness and tolerability [8]. The practicalities of prescribing hydroxycarbamide are detailed in Box 10.

* Although its primary indication is clonal HES (specifically F/P + chronic eosinophilic leukemia), imatinib (400 mg/day) may also be used empirically (and off label) in patients with laboratory and clinical findings suggestive of underlying myeloid malignancies (although by definition, idiopathic HES does
**Box 9** Prescribing guidelines for pegylated interferon alfa-2a

Pegylated interferon alfa-2a is administered by weekly subcutaneous injections. In HES, common practice is to start with low doses (e.g., 45 µg per week, less than those used for myeloid neoplasms or viral hepatitis) to promote tolerability and long-term adherence. Combination with prophylactic administration of paracetamol (1 g every 8 hours for 24–48 hours) should be offered to reduce flu-like symptoms that can sometimes be observed after injection.

Pegylated interferon alfa-2a is contraindicated in children under 3 years of age, in case of documented hypersensitivity to benzyl alcohol, severe decompensated liver failure, thrombocytopenia < 100 × 10⁹/L or progressive autoimmune disease (particularly systemic lupus erythematosus, dermatomyositis, other diseases mediated by interferon pathways and autoimmune hepatitis). Overall, if there is a history of preexisting autoimmune disease, the benefit/risk ratio of treatment with pegylated interferon alfa-2a should be weighed on a case-by-case basis. In patients with a history of mood and/or personality disorders, a psychiatrist should be consulted prior to initiation of treatment (and monitoring increased if necessary), as this drug may induce mood disorders.

In addition, regular laboratory monitoring (including CBC, serum electrolytes, creatinine, transaminases, TSH) is recommended. In the event of cytopenia, the intervals between injections of pegylated interferon alfa-2a may be increased and/or the dosages reduced.

**Box 10** Prescribing guidelines for hydroxycarbamide

Hydroxycarbamide is administered orally at a daily dosage of 15–30 mg/kg (in one or two daily doses). Outside of emergency settings (where the starting dose is typically 1500–2000 mg daily), the standard practice for HES is to start with a low dosage (e.g., 1000 mg daily) and then increase it as needed depending on treatment effectiveness and tolerability. Hydroxycarbamide is contraindicated in patients with lactase deficiency, pregnancy and severe cytopenia (neutropenia < 10 × 10⁹/L, thrombocytopenia < 100 × 10⁹/L and/or anemia < 10 g/dL).

Because the risk of bone marrow failure is higher in patients who have received prior radiation or chemotherapy, hydroxycarbamide should be administered with caution in this situation. Likewise, in case of renal failure and/or concomitant use of other myelosuppressive agents, a reduction in the dosages of hydroxycarbamide and increased monitoring are recommended.

In case of significant HE, significant splenomegaly and/or elevated uric acid levels, hydration is recommended at the start of treatment to prevent the possible occurrence of lysis syndrome.

Regular (e.g., every two weeks for two months after initiation of treatment, and then every three months thereafter) clinical (including screening for oral or photo-induced lesions, trophic skin disorders, skin neoplasia and/or fibrosing lung disease that may be promoted by treatment) and laboratory monitoring (including CBC, serum electrolytes, urea, creatinine, transaminases, etc.) is indicated in long-term treatment. Hydroxycarbamide treatment is known to be associated with an increase of erythrocytes' average globular volume of to up to 120 fL. Lastly, live attenuated vaccines are contraindicated in case of concomitant treatment with hydroxycarbamide.

not show the cytogenetic or molecular abnormalities characteristic of clonal HES) e.g. splenomegaly, elevated vitamin B12 or tryptase, presence of other CBC abnormalities, nonresponse to corticosteroid therapy (or corticosteroid dependence on more than 10 mg/day prednisone) [104]. In the absence of response at 1 month after initiation of imatinib, the latter should be discontinued and replaced by another steroid-sparing drug.

* Conventional immunosuppressive agents (cyclosporine, methotrexate, and mycophenolate mofetil): limited data are available regarding their benefit in HES. For the time being, their use in this indication is limited.

* Recent preliminary data suggest that benralizumab (a monoclonal antibody targeting the alpha subunit of IL-5 receptor, IL-5Rα) could be a promising treatment for HES [105], and a prospective randomized placebo-controlled trial is underway.

In daily practice, pegylated interferon alfa-2a is often favored in young patients because of the theoretical long-term leukemogenic risk of hydroxycarbamide,

and the need for male and female contraception during treatment and up to 3–6 months after cessation. However, the indications for treatment with pegylated interferon alfa-2a must be assessed on a case-by-case basis, particularly in patients with a significant psychiatric history, liver disease and/or a history of concurrent underlying autoimmune disease (particularly lupus).

**Therapeutic management of lymphocytic HES**

*Indications* If a close clinical and laboratory monitoring is performed, non-treatment is perfectly acceptable in asymptomatic patients with lymphocytic HE.

In the event of clinical manifestations attributable to eosinophil toxicity and/or to the abnormal T-cell population (lymphocytic HES), treatment strategies (with a preference for topical corticosteroids and short-term rather than long-term treatment) share similarities with those previously described for the management of idiopathic HES, with the noteworthy exception that there is solid data supporting the use of Interferon alfa-2a in this setting.
**Box 9** Prescribing guidelines for pegylated interferon alfa-2a

Pegylated interferon alfa-2a is administered by weekly subcutaneous injections. In HES, common practice is to start with low doses (e.g., 45 µg per week, less than those used for myeloid neoplasms or viral hepatitis) to promote tolerability and long-term adherence. Combination with prophylactic administration of paracetamol (1 g every 8 hours for 24–48 hours) should be offered to reduce flu-like symptoms that can sometimes be observed after injection.

Pegylated interferon alfa-2a is contraindicated in children under 3 years of age, in case of documented hypersensitivity to benzyl alcohol, severe decompensated liver failure, thrombocytopenia < 100 × 10⁹/L or progressive autoimmune disease (particularly systemic lupus erythematosus, dermatomyositis, other diseases mediated by interferon pathways and autoimmune hepatitis). Overall, if there is a history of preexisting autoimmune disease, the benefit/risk ratio of treatment with pegylated interferon alfa-2a should be weighed on a case-by-case basis. In patients with a history of mood and/or personality disorders, a psychiatrist should be consulted prior to initiation of treatment (and monitoring increased if necessary), as this drug may induce mood disorders.

In addition, regular laboratory monitoring (including CBC, serum electrolytes, creatinine, transaminases, TSH) is recommended. In the event of cytopenia, the intervals between injections of pegylated interferon alfa-2a may be increased and/or the dosages reduced.

**Box 10** Prescribing guidelines for hydroxycarbamide

Hydroxycarbamide is administered orally at a daily dosage of 15–30 mg/kg (in one or two daily doses). Outside of emergency settings (where the starting dose is typically 1500–2000 mg daily), the standard practice for HES is to start with a low dosage (e.g., 1000 mg daily) and then increase it as needed depending on treatment effectiveness and tolerability. Hydroxycarbamide is contraindicated in patients with lactase deficiency, pregnancy and severe cytopenia (neutropenia < 10 × 10⁹/L, thrombocytopenia < 100 × 10⁹/L and/or anemia < 10 g/dL).

Because the risk of bone marrow failure is higher in patients who have received prior radiation or chemotherapy, hydroxycarbamide should be administered with caution in this situation. Likewise, in case of renal failure and/or concomitant use of other myelosuppressive agents, a reduction in the dosages of hydroxycarbamide and increased monitoring are recommended.

In case of significant HE, significant splenomegaly and/or elevated uric acid levels, hydration is recommended at the start of treatment to prevent the possible occurrence of lysis syndrome.

Regular (e.g., every two weeks for two months after initiation of treatment, and then every three months thereafter) clinical (including screening for oral or photo-induced lesions, trophic skin disorders, skin neoplasia and/or fibrosing lung disease that may be promoted by treatment) and laboratory monitoring (including CBC, serum electrolytes, urea, creatinine, transaminases, etc.) is indicated in long-term treatment. Hydroxycarbamide treatment is known to be associated with an increase of erythrocytes' average globular volume of to up to 120 fL. Lastly, live attenuated vaccines are contraindicated in case of concomitant treatment with hydroxycarbamide.

not show the cytogenetic or molecular abnormalities characteristic of clonal HES) e.g. splenomegaly, elevated vitamin B12 or tryptase, presence of other CBC abnormalities, nonresponse to corticosteroid therapy (or corticosteroid dependence on more than 10 mg/day prednisone) [104]. In the absence of response at 1 month after initiation of imatinib, the latter should be discontinued and replaced by another steroid-sparing drug.

* Conventional immunosuppressive agents (cyclosporine, methotrexate, and mycophenolate mofetil): limited data are available regarding their benefit in HES. For the time being, their use in this indication is limited.

* Recent preliminary data suggest that benralizumab (a monoclonal antibody targeting the alpha subunit of IL-5 receptor, IL-5Rα) could be a promising treatment for HES [105], and a prospective randomized placebo-controlled trial is underway.

In daily practice, pegylated interferon alfa-2a is often favored in young patients because of the theoretical long-term leukemogenic risk of hydroxycarbamide,

and the need for male and female contraception during treatment and up to 3–6 months after cessation. However, the indications for treatment with pegylated interferon alfa-2a must be assessed on a case-by-case basis, particularly in patients with a significant psychiatric history, liver disease and/or a history of concurrent underlying autoimmune disease (particularly lupus).

**Therapeutic management of lymphocytic HES**

*Indications* If a close clinical and laboratory monitoring is performed, non-treatment is perfectly acceptable in asymptomatic patients with lymphocytic HE.

In the event of clinical manifestations attributable to eosinophil toxicity and/or to the abnormal T-cell population (lymphocytic HES), treatment strategies (with a preference for topical corticosteroids and short-term rather than long-term treatment) share similarities with those previously described for the management of idiopathic HES, with the noteworthy exception that there is solid data supporting the use of Interferon alfa-2a in this setting.
**First-line treatments** In general, lymphocytic HES is highly responsive to corticosteroids.

Topical corticosteroids can be effective on localized inflammatory lesions, keeping in mind the cumulative dose.

Inhaled corticosteroids are recommended for recurrent and/or persistent moderate respiratory manifestations.

Oral corticosteroid therapy is the usual first-line treatment of lymphocytic HES. The loading dose (0.5–1 mg/kg/day prednisone) should be tailored to the severity of the symptoms related to eosinophilia, before gradual tapering. Overall, the lowest effective dose should be used and weaning attempted as early as possible.

**Second-line treatments** Mirroring the fact that lymphocytic HES is usually highly sensitive to systemic corticosteroids, high-dose steroid dependence is also common (possibly due to high levels of serum IL-5 and/or persistent underlying T-cell lymphoproliferative disease). To minimize the potential adverse reactions of systemic corticosteroids, steroid-sparing treatment may be considered in steroid-dependent patients.

Currently mepolizumab and interferon alfa-2a are the preferred first-line steroid-sparing treatments for lymphocytic-HES patients with high-dose corticosteroid dependency.

* Interferon alfa-2a, an immunomodulatory agent acting on both eosinophils and Th2-polarized T cells. Retrospective of both series Both Belgian, Canadian, and French retrospective showed marked clinical and hematological efficacy [10, 11, 106]. Nevertheless, the drug tolerability can be a barrier to its use and long-term maintenance. In daily practice, to minimize potential side effects and to promote adherence to treatment, we suggest starting at the lowest possible dose of the pegylated form (e.g., weekly subcutaneous injections 45 µg pegylated interferon alfa-2a) and to increase it gradually based on tolerability.

* Mepolizumab has also showed efficacy and steroid-sparing effect in lymphocytic HES, with a presumed better safety profile than interferon [107]. Yet persistent symptoms (despite normal absolute eosinophil counts) have also been reported [11].

In case of failure of both mepolizumab and interferon, further-line steroid-sparing drugs may be discussed in expert centers. These include:

* A few cases of successful treatment of refractory lymphocytic HES with romidepsin have been reported [108]. However, the small number of cases (n<5) and short follow-up do not currently make it possible to

clearly define the place of this compound in the therapeutic arsenal against lymphoid variant of HES, the indication of which may be discussed in a multidisciplinary team meeting.

* The membrane expression of CCR4 by clonal T cells suggests that mogamulizumab may be of interest, but its relevance remains to be determined.

* Following the identification of acquired abnormalities in factors affecting the JAK-STAT signaling pathway (including gain-of-function mutations of STAT3) in lymphocytic HES [108, 109], the potential effectiveness of JAK inhibitors (ruxolitinib and tofacitinib) has been suggested in small case series, surprisingly even in the absence of gene mutations of the JAK/STAT pathway [110, 111].

* Despite an attractive rationale for their use, limited data are available on immunosuppressive agents that can target T cells, such as cyclosporine, methotrexate, and mycophenolate mofetil.

**Therapeutic management of reactive HES (other than lymphocytic)**

As a general rule, when an underlying factor is identified as the cause of HE/HES, its management is based on the etiological treatment of the underlying disorder ( discontinuation of the causal drug/antiparasitic treatment/ chemotherapy).

In addition, in the event of organ involvement related to eosinophil toxicity, oral corticosteroid therapy may be recommended at the acute phase, pending the effects of the etiological treatment, and with the aim of weaning the patient from systemic steroids within than three months, if possible.

**Management of HE of undetermined significance**

The management of HEUS is not standardized. Some teams have reported prolonged follow-up (several years) in patients with significant HE (sometimes > 5.0 × 10⁹/L in the absence of any treatment [12]. However, the time between the onset of HE and the first related clinical manifestation can also be prolonged. The therapeutic approach should therefore be discussed with patients on a case-by-case basis, depending on their possible comorbidities, their understanding of the situation and their compliance with follow-up. Although there is no strict correlation between the levels of blood HE and tissue HE, it is conceivable not to initiate treatment in patients with asymptomatic HE < 5.0 × 10⁹/L but to continue long-term monitoring as described in “Follow-up” section. In asymptomatic clonal (or presumed clonal) HE, a
**First-line treatments** In general, lymphocytic HES is highly responsive to corticosteroids.

Topical corticosteroids can be effective on localized inflammatory lesions, keeping in mind the cumulative dose.

Inhaled corticosteroids are recommended for recurrent and/or persistent moderate respiratory manifestations.

Oral corticosteroid therapy is the usual first-line treatment of lymphocytic HES. The loading dose (0.5–1 mg/kg/day prednisone) should be tailored to the severity of the symptoms related to eosinophilia, before gradual tapering. Overall, the lowest effective dose should be used and weaning attempted as early as possible.

**Second-line treatments** Mirroring the fact that lymphocytic HES is usually highly sensitive to systemic corticosteroids, high-dose steroid dependence is also common (possibly due to high levels of serum IL-5 and/or persistent underlying T-cell lymphoproliferative disease). To minimize the potential adverse reactions of systemic corticosteroids, steroid-sparing treatment may be considered in steroid-dependent patients.

Currently mepolizumab and interferon alfa-2a are the preferred first-line steroid-sparing treatments for lymphocytic-HES patients with high-dose corticosteroid dependency.

* Interferon alfa-2a, an immunomodulatory agent acting on both eosinophils and Th2-polarized T cells. Retrospective of both series Both Belgian, Canadian, and French retrospective showed marked clinical and hematological efficacy [10, 11, 106]. Nevertheless, the drug tolerability can be a barrier to its use and long-term maintenance. In daily practice, to minimize potential side effects and to promote adherence to treatment, we suggest starting at the lowest possible dose of the pegylated form (e.g., weekly subcutaneous injections 45 µg pegylated interferon alfa-2a) and to increase it gradually based on tolerability.

* Mepolizumab has also showed efficacy and steroid-sparing effect in lymphocytic HES, with a presumed better safety profile than interferon [107]. Yet persistent symptoms (despite normal absolute eosinophil counts) have also been reported [11].

In case of failure of both mepolizumab and interferon, further-line steroid-sparing drugs may be discussed in expert centers. These include:

* A few cases of successful treatment of refractory lymphocytic HES with romidepsin have been reported [108]. However, the small number of cases (n<5) and short follow-up do not currently make it possible to

clearly define the place of this compound in the therapeutic arsenal against lymphoid variant of HES, the indication of which may be discussed in a multidisciplinary team meeting.

* The membrane expression of CCR4 by clonal T cells suggests that mogamulizumab may be of interest, but its relevance remains to be determined.

* Following the identification of acquired abnormalities in factors affecting the JAK-STAT signaling pathway (including gain-of-function mutations of STAT3) in lymphocytic HES [108, 109], the potential effectiveness of JAK inhibitors (ruxolitinib and tofacitinib) has been suggested in small case series, surprisingly even in the absence of gene mutations of the JAK/STAT pathway [110, 111].

* Despite an attractive rationale for their use, limited data are available on immunosuppressive agents that can target T cells, such as cyclosporine, methotrexate, and mycophenolate mofetil.

**Therapeutic management of reactive HES (other than lymphocytic)**

As a general rule, when an underlying factor is identified as the cause of HE/HES, its management is based on the etiological treatment of the underlying disorder ( discontinuation of the causal drug/antiparasitic treatment/ chemotherapy).

In addition, in the event of organ involvement related to eosinophil toxicity, oral corticosteroid therapy may be recommended at the acute phase, pending the effects of the etiological treatment, and with the aim of weaning the patient from systemic steroids within than three months, if possible.

**Management of HE of undetermined significance**

The management of HEUS is not standardized. Some teams have reported prolonged follow-up (several years) in patients with significant HE (sometimes > 5.0 × 10⁹/L in the absence of any treatment [12]. However, the time between the onset of HE and the first related clinical manifestation can also be prolonged. The therapeutic approach should therefore be discussed with patients on a case-by-case basis, depending on their possible comorbidities, their understanding of the situation and their compliance with follow-up. Although there is no strict correlation between the levels of blood HE and tissue HE, it is conceivable not to initiate treatment in patients with asymptomatic HE < 5.0 × 10⁹/L but to continue long-term monitoring as described in “Follow-up” section. In asymptomatic clonal (or presumed clonal) HE, a
<figure><img src="image_4.png" /><figcaption>**Fig. 3** Proposed algorithm for the management of emergency situations related to HE. Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; HES, hypereosinophilic syndrome; IL, interleukin; IV, intravenous; PO, per os; TKI2, second-generation tyrosine kinase inhibitor</figcaption></figure>

multidisciplinary team meeting on whether treatment is indicated should be considered.

## Specific settings

### Organ or life-threatening HES involvement

In the context of blood HE, some specific eosinophilic-related organ manifestations can be organ or life-threatening and thus require immediate treatment intensification (as detailed in Fig. 3). These mainly include cardiac manifestations (e.g., eosinophilic myocarditis, intracavitary thrombosis with peripheral or cerebral embolic events, coronary artery spasm, acute heart failure), respiratory disorders (severe acute asthma or hypoxic lung disease), central nervous system manifestations (typically strokes of bilateral watershed distribution) and thrombotic (either arterial or venous) events [37–41]. Contrariwise, in the absence of overt clinical manifestations, very high eosinophil counts (e.g., >10 × 10⁹/L) are not per se an indication for emergency initiation of treatment.

In these emergency situations, while the etiologic workup is also urgent, it should never delay the initiation of treatment. Thus, whatever the underlying cause of HE (reactive, idiopathic, clonal, but most often not determined at this stage), the initial management of severe eosinophilic vascular, respiratory, cardiac or neurological involvement that is life-threatening or can

cause irreversible loss of function is based on corticosteroid therapy (prednisone: 1 mg/kg/day, preceded by intravenous pulses of methylprednisolone 15 mg/kg for 1–3 days, depending on the clinical picture), in combination with antiparasitic treatment (as detailed in “Antiparasitic treatment” Section).

In most cases, corticosteroids rapidly lower or normalize blood and tissue eosinophilia. In reactive HES, treatment should also include the management of the underlying disease or cessation of the culprit drug. In clonal eosinophilia, although corticosteroids generally do not normalize absolute eosinophil counts, they may reduce eosinophil activation and lower their cytotoxic potential pending a precise molecular diagnosis and onset of a specific treatment (as detailed in “Management of FIP1L1::PDGFRA-positive chronic eosinophilic leukemia” and “Management of non-F/P-associated clonal HES” Sections).

In case of steroid-resistant HES (defined as the absence of clinical and laboratory response after 3 days of corticosteroid therapy), the main etiologies to be investigated are as follow:

* Clonal HES (including F/P + chronic eosinophilic leukemia)

* Paraneoplastic eosinophilia
<figure><img src="image_6.png" /><figcaption>**Fig. 3** Proposed algorithm for the management of emergency situations related to HE. Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; HES, hypereosinophilic syndrome; IL, interleukin; IV, intravenous; PO, per os; TKI2, second-generation tyrosine kinase inhibitor</figcaption></figure>

multidisciplinary team meeting on whether treatment is indicated should be considered.

## Specific settings

### Organ or life-threatening HES involvement

In the context of blood HE, some specific eosinophilic-related organ manifestations can be organ or life-threatening and thus require immediate treatment intensification (as detailed in Fig. 3). These mainly include cardiac manifestations (e.g., eosinophilic myocarditis, intracavitary thrombosis with peripheral or cerebral embolic events, coronary artery spasm, acute heart failure), respiratory disorders (severe acute asthma or hypoxic lung disease), central nervous system manifestations (typically strokes of bilateral watershed distribution) and thrombotic (either arterial or venous) events [37–41]. Contrariwise, in the absence of overt clinical manifestations, very high eosinophil counts (e.g., > 10 × 10⁹/L) are not per se an indication for emergency initiation of treatment.

In these emergency situations, while the etiologic workup is also urgent, it should never delay the initiation of treatment. Thus, whatever the underlying cause of HE (reactive, idiopathic, clonal, but most often not determined at this stage), the initial management of severe eosinophilic vascular, respiratory, cardiac or neurological involvement that is life-threatening or can

cause irreversible loss of function is based on corticosteroid therapy (prednisone: 1 mg/kg/day, preceded by intravenous pulses of methylprednisolone 15 mg/kg for 1–3 days, depending on the clinical picture), in combination with antiparasitic treatment (as detailed in “Antiparasitic treatment” Section).

In most cases, corticosteroids rapidly lower or normalize blood and tissue eosinophilia. In reactive HES, treatment should also include the management of the underlying disease or cessation of the culprit drug. In clonal eosinophilia, although corticosteroids generally do not normalize absolute eosinophil counts, they may reduce eosinophil activation and lower their cytotoxic potential pending a precise molecular diagnosis and onset of a specific treatment (as detailed in “Management of FIP1L1::PDGFRA-positive chronic eosinophilic leukemia” and “Management of non-F/P-associated clonal HES” Sections).

In case of steroid-resistant HES (defined as the absence of clinical and laboratory response after 3 days of corticosteroid therapy), the main etiologies to be investigated are as follow:

* Clonal HES (including F/P + chronic eosinophilic leukemia)

* Paraneoplastic eosinophilia
* Hodgkin's lymphoma or high-grade peripheral T-cell lymphoma (especially angioimmunoblastic T-cell lymphoma)

* Solid neoplasms (particularly bronchopulmonary carcinoma and colorectal or prostate adenocarcinoma).

* Rare corticosteroid-resistant DRESS

In rare cases of life-threatening clinically and biologically corticosteroid-refractory HES, it is recommended to contact a member of the CEREO network to discuss how to proceed with gradual and rapid treatment escalation (pending the etiological workup), which may include the use (sometimes sequentially) of:

* Hydroxycarbamide (15–20 mg/kg/day).

* Imatinib (at a dosage of 400 mg/day pending molecular testing)

* JAK inhibitors (including ruxolitinib) if clonal HES is strongly suspected and imatinib 400 mg/day has failed.

* Although the usefulness of biologic therapies such as anti-IL5 and anti-IL5R has only seldom been assessed in the context of emergency, their potential usefulness cannot be ruled out [112].

* As a last resort, alemtuzumab (the rationale being that CD52 is expressed on the surface of eosinophils, and the potential rapid onset of action of this treatment) [113].

* Conversely, while older studies had described the use of leukapheresis in this situation, it has become rare since the advent of targeted therapies [114].

Finally, in case of massive eosinophilia and/or manifestations related to micro/macrovascular complications of HE, curative anticoagulation may be recommended in the acute phase until HE subsides.

## Vascular manifestations and HE

Eosinophils have significant proaggregatory and procagulant properties, which may lead to (venous or arterial) thrombosis, vasculopathy (sometimes mimicking thromboangiitis obliterans), eosinophilic vasculitis (outside the context of EGPA or periarteritis nodosa) or even coronary artery spasm in HES [41, 59, 60]. There are currently no expert recommendations for the management of vascular thrombosis secondary to HE.

**In the acute phase** In case of severe thrombosis, the "etiological" management of HE is similar to the procedure for the management of emergency situations involving HE detailed in "Follow-up of F/P + HE/HES" section.

Given the ability of corticosteroids to induce rapid normalization of the CBC in most situations, the initiation of systemic corticosteroid therapy at the acute phase should be considered on a case-by-case basis. To date, there is no scientific data favoring either vitamin K antagonists or direct anticoagulants.

**Long-term** The optimal duration of anticoagulant therapy is unknown. A multivariate analysis performed in a retrospective study of 54 patients with venous thromboembolism secondary to HE (regardless of the underlying etiology, but in the absence of any other major risk factor for thrombophilia) reported that persistent eosinophilia (> 0.5 × 10⁹/L) was the only factor associated with both the recurrence of venous thromboembolism as well as the occurrence of arterial thrombosis, suggesting that long-term normalization of the CBC (through effective control of the underlying disease) is crucial. Also, the fact that in this study the recurrence of venous thromboembolism occurred in only 1 of 16 patients who discontinued anticoagulants despite long-term normalization of the CBC also suggests that anticoagulant therapy may be discontinued on a case-by-case basis in patients with well-controlled HES (pending the fact that other underlying risk factors for thrombophilia and the anatomic site of thrombosis are also considered) [40]. Finally, given the high rates of arterial thrombosis reported in patients with venous thrombosis, non-specific management of cardiovascular risk factors also seems advisable in this situation.

## Pregnancy

In some patients, pregnancy and the postpartum period seem to be risk periods for initial episodes or relapses of HE/HES. However, to date, there is no convincing evidence of specific eosinophil-related obstetric (notably placental vascular pathology, thrombosis, etc.) or fetal complications.

In practice, and pending further data:

* HE or HES is not a contraindication to pregnancy.

* Patients with HE/HES should have access to standard delivery, anesthesia, and breastfeeding options.

* The decision to conceive should ideally be discussed in advance with the HES specialist, considering the severity of organ involvement, any history of thrombosis associated with HES and medication (particularly TKI, hydroxycarbamide and anti-IL5), which are potentially advised against or contraindicated in pregnancy (and sometimes require a washout period prior to pregnancy, including imatinib in men). For anti-IL5 and anti-IL5R biologics, in the absence of substantial data supporting the safety or toxicity of
* Hodgkin's lymphoma or high-grade peripheral T-cell lymphoma (especially angioimmunoblastic T-cell lymphoma)

* Solid neoplasms (particularly bronchopulmonary carcinoma and colorectal or prostate adenocarcinoma).

* Rare corticosteroid-resistant DRESS

In rare cases of life-threatening clinically and biologically corticosteroid-refractory HES, it is recommended to contact a member of the CEREO network to discuss how to proceed with gradual and rapid treatment escalation (pending the etiological workup), which may include the use (sometimes sequentially) of:

* Hydroxycarbamide (15–20 mg/kg/day).

* Imatinib (at a dosage of 400 mg/day pending molecular testing)

* JAK inhibitors (including ruxolitinib) if clonal HES is strongly suspected and imatinib 400 mg/day has failed.

* Although the usefulness of biologic therapies such as anti-IL5 and anti-IL5R has only seldom been assessed in the context of emergency, their potential usefulness cannot be ruled out [112].

* As a last resort, alemtuzumab (the rationale being that CD52 is expressed on the surface of eosinophils, and the potential rapid onset of action of this treatment) [113].

* Conversely, while older studies had described the use of leukapheresis in this situation, it has become rare since the advent of targeted therapies [114].

Finally, in case of massive eosinophilia and/or manifestations related to micro/macrovascular complications of HE, curative anticoagulation may be recommended in the acute phase until HE subsides.

## Vascular manifestations and HE

Eosinophils have significant proaggregatory and procagulant properties, which may lead to (venous or arterial) thrombosis, vasculopathy (sometimes mimicking thromboangiitis obliterans), eosinophilic vasculitis (outside the context of EGPA or periarteritis nodosa) or even coronary artery spasm in HES [41, 59, 60]. There are currently no expert recommendations for the management of vascular thrombosis secondary to HE.

**In the acute phase** In case of severe thrombosis, the "etiological" management of HE is similar to the procedure for the management of emergency situations involving HE detailed in "Follow-up of F/P + HE/HES" section.

Given the ability of corticosteroids to induce rapid normalization of the CBC in most situations, the initiation of systemic corticosteroid therapy at the acute phase should be considered on a case-by-case basis. To date, there is no scientific data favoring either vitamin K antagonists or direct anticoagulants.

**Long-term** The optimal duration of anticoagulant therapy is unknown. A multivariate analysis performed in a retrospective study of 54 patients with venous thromboembolism secondary to HE (regardless of the underlying etiology, but in the absence of any other major risk factor for thrombophilia) reported that persistent eosinophilia (> 0.5 × 10⁹/L) was the only factor associated with both the recurrence of venous thromboembolism as well as the occurrence of arterial thrombosis, suggesting that long-term normalization of the CBC (through effective control of the underlying disease) is crucial. Also, the fact that in this study the recurrence of venous thromboembolism occurred in only 1 of 16 patients who discontinued anticoagulants despite long-term normalization of the CBC also suggests that anticoagulant therapy may be discontinued on a case-by-case basis in patients with well-controlled HES (pending the fact that other underlying risk factors for thrombophilia and the anatomic site of thrombosis are also considered) [40]. Finally, given the high rates of arterial thrombosis reported in patients with venous thrombosis, non-specific management of cardiovascular risk factors also seems advisable in this situation.

## Pregnancy

In some patients, pregnancy and the postpartum period seem to be risk periods for initial episodes or relapses of HE/HES. However, to date, there is no convincing evidence of specific eosinophil-related obstetric (notably placental vascular pathology, thrombosis, etc.) or fetal complications.

In practice, and pending further data:

* HE or HES is not a contraindication to pregnancy.

* Patients with HE/HES should have access to standard delivery, anesthesia, and breastfeeding options.

* The decision to conceive should ideally be discussed in advance with the HES specialist, considering the severity of organ involvement, any history of thrombosis associated with HES and medication (particularly TKI, hydroxycarbamide and anti-IL5), which are potentially advised against or contraindicated in pregnancy (and sometimes require a washout period prior to pregnancy, including imatinib in men). For anti-IL5 and anti-IL5R biologics, in the absence of substantial data supporting the safety or toxicity of
these compounds in pregnancy [115, 116], the decision may be discussed on a case-by-case basis in a multidisciplinary team meeting.

* In the absence of a history of HE or exacerbation of HES during pregnancy (or postpartum) in a patient followed up for HES, a CBC should be performed (i) in preparation for the planned pregnancy (enhanced monitoring is advisable in case of HE); (ii) at diagnosis, and monthly during pregnancy; (iii) during the postpartum period.

* The following are recommended in patients with a history of exacerbation of HES and/or increased eosinophil counts during pregnancy or postpartum:

* Close collaborative follow-up (involving the obstetrician-gynecologist and referring physician).

* Monthly monitoring of the CBC during pregnancy and postpartum as well as to educate the patient on the symptoms that should prompt her to consult her general practitioner and perform a CBC whenever in doubt.

* No cessation of ongoing corticosteroid therapy before or during pregnancy, but maintenance of a low dose or the minimum effective dose known to the patient during pregnancy and postpartum (3 months), before considering gradual tapering with laboratory monitoring (monthly CBC).

* Multidisciplinary team meeting to discuss preventive anticoagulation (LMWH at prophylactic doses) in case of significant and/or rapidly progressive HE.

## Children

Some specific factors also need to be considered in this population. Physical growth and pubertal development should be monitored, as well as the psychological impact of the disease and its treatment. Attempts should be made to reduce corticosteroid exposure as much as possible to limit potential steroids-related side-effects e.g., by not exceeding the maximum dose of 2 mg/kg/day of prednisone or equivalent, by trying to reduce the dose whenever the clinical situation and laboratory results allow so, or by considering a rapid switch to a second-line steroid-sparing treatment. In addition, peginterferon alfa-2a, mepolizumab and benralizumab have not been assessed in children under 3, 6, and 12 years of age, respectively. For imatinib, the dose should be adjusted based on body surface area, and close monitoring of physical growth in treated children is recommended (there have been reports of stunted growth in children and preadolescents receiving imatinib). Although not

currently published, real-life data suggest that ciclosporin or JAK inhibitors (e.g., ruxolitinib) may also be useful in the context of pediatric HES. In adolescence, early contact with adult medical care teams, as well as collaborative management, is advisable to facilitate the transition to adulthood.

## Other drugs that can be used to treat HES

Given the variety of clinical manifestations that may be encountered in HES, various adjunctive symptomatic treatments may be offered as appropriate. These include (non-exclusive list):

* Antiplatelet agents in case of HES with a vascular phenotype requiring the management of cardiovascular risk factors.

* Antidepressant(s) in case of psychological complications of chronic HES, and/or neurogenic pain.

* Oral antidiabetics and/or insulin therapy in case of steroid-induced diabetes.

* Antihistamines for the treatment of urticaria.

* Bisphosphonates (when indicated) for the prevention of steroid-induced osteoporosis.

* Contraceptives: especially during treatment with hydroxycarbamide, TKI and anti-IL5 therapies.

* Beta-blockers, angiotensin converting enzyme inhibitors angiotensin receptor blockers, SGLT2 inhibitors and/or diuretics (in case of chronic heart failure).

* Asthma treatments (including short- and long-acting beta-2 agonists, anticholinergics and antileukotrienes).

* Annual influenza vaccination, prime-boost pneumococcal vaccination (13-valent conjugate vaccine followed at least 8 weeks later by a 23-valent polysaccharide vaccine) in patients receiving corticosteroids and/or immunomodulators. Vaccination against SARS-CoV-2 is also recommended.

## Surgical treatments

### Use of cardiac surgery

Since the advent of targeted therapies (TKI, biologic therapies targeting IL-5), end-stage heart failure (endomyocardial fibrosis, valvular insufficiency, etc.) secondary to poorly controlled chronic HE has become exceptional. Nevertheless, when it is diagnosed at a late stage and the patient fails to recover despite prolonged normalization of the CBC and well-managed treatment of cardiac symptoms, cardiac surgery (valve replacement and/or endocardial decortication, or even heart transplantation as a last resort) is an option that can be discussed on a case-by-case basis in the event of refractory heart failure [38, 117]. HES that is amenable to targeted therapy (e.g.,
these compounds in pregnancy [115, 116], the decision may be discussed on a case-by-case basis in a multidisciplinary team meeting.

* In the absence of a history of HE or exacerbation of HES during pregnancy (or postpartum) in a patient followed up for HES, a CBC should be performed (i) in preparation for the planned pregnancy (enhanced monitoring is advisable in case of HE); (ii) at diagnosis, and monthly during pregnancy; (iii) during the postpartum period.

* The following are recommended in patients with a history of exacerbation of HES and/or increased eosinophil counts during pregnancy or postpartum:

* Close collaborative follow-up (involving the obstetrician-gynecologist and referring physician).

* Monthly monitoring of the CBC during pregnancy and postpartum as well as to educate the patient on the symptoms that should prompt her to consult her general practitioner and perform a CBC whenever in doubt.

* No cessation of ongoing corticosteroid therapy before or during pregnancy, but maintenance of a low dose or the minimum effective dose known to the patient during pregnancy and postpartum (3 months), before considering gradual tapering with laboratory monitoring (monthly CBC).

* Multidisciplinary team meeting to discuss preventive anticoagulation (LMWH at prophylactic doses) in case of significant and/or rapidly progressive HE.

## Children

Some specific factors also need to be considered in this population. Physical growth and pubertal development should be monitored, as well as the psychological impact of the disease and its treatment. Attempts should be made to reduce corticosteroid exposure as much as possible to limit potential steroids-related side-effects e.g., by not exceeding the maximum dose of 2 mg/kg/day of prednisone or equivalent, by trying to reduce the dose whenever the clinical situation and laboratory results allow so, or by considering a rapid switch to a second-line steroid-sparing treatment. In addition, peginterferon alfa-2a, mepolizumab and benralizumab have not been assessed in children under 3, 6, and 12 years of age, respectively. For imatinib, the dose should be adjusted based on body surface area, and close monitoring of physical growth in treated children is recommended (there have been reports of stunted growth in children and preadolescents receiving imatinib). Although not

currently published, real-life data suggest that ciclosporin or JAK inhibitors (e.g., ruxolitinib) may also be useful in the context of pediatric HES. In adolescence, early contact with adult medical care teams, as well as collaborative management, is advisable to facilitate the transition to adulthood.

## Other drugs that can be used to treat HES

Given the variety of clinical manifestations that may be encountered in HES, various adjunctive symptomatic treatments may be offered as appropriate. These include (non-exclusive list):

* Antiplatelet agents in case of HES with a vascular phenotype requiring the management of cardiovascular risk factors.

* Antidepressant(s) in case of psychological complications of chronic HES, and/or neurogenic pain.

* Oral antidiabetics and/or insulin therapy in case of steroid-induced diabetes.

* Antihistamines for the treatment of urticaria.

* Bisphosphonates (when indicated) for the prevention of steroid-induced osteoporosis.

* Contraceptives: especially during treatment with hydroxycarbamide, TKI and anti-IL5 therapies.

* Beta-blockers, angiotensin converting enzyme inhibitors angiotensin receptor blockers, SGLT2 inhibitors and/or diuretics (in case of chronic heart failure).

* Asthma treatments (including short- and long-acting beta-2 agonists, anticholinergics and antileukotrienes).

* Annual influenza vaccination, prime-boost pneumococcal vaccination (13-valent conjugate vaccine followed at least 8 weeks later by a 23-valent polysaccharide vaccine) in patients receiving corticosteroids and/or immunomodulators. Vaccination against SARS-CoV-2 is also recommended.

## Surgical treatments

### Use of cardiac surgery

Since the advent of targeted therapies (TKI, biologic therapies targeting IL-5), end-stage heart failure (endomyocardial fibrosis, valvular insufficiency, etc.) secondary to poorly controlled chronic HE has become exceptional. Nevertheless, when it is diagnosed at a late stage and the patient fails to recover despite prolonged normalization of the CBC and well-managed treatment of cardiac symptoms, cardiac surgery (valve replacement and/or endocardial decortication, or even heart transplantation as a last resort) is an option that can be discussed on a case-by-case basis in the event of refractory heart failure [38, 117]. HES that is amenable to targeted therapy (e.g.,
with imatinib) leading to long-term remission (especially cases involving PDGFRA or PDGFRB rearrangements) is not a contraindication to heart transplantation. In this case, specific treatment of HES should be continued over the long-term after transplantation to prevent recurrence of HES in the transplant [118].

## Use of ENT surgery

In case of nasal polyposis refractory to topical and systemic corticosteroid therapy, it is recommended to seek specialist advice to discuss the indications for and modalities of surgical management (polypectomy or ethmoidectomy), if appropriate.

## Paramedical support

### Patient support group

The primary care physician or specialist may encourage the patient to contact a patient support group association (if available).

In France, APIMEO (Association Pour l'Information sur les Maladies à Eosinophiles—Association for Information on Eosinophilic Diseases) is a patient support group consisting of patients and their relatives, whose main tasks are to:

* Bring patients and their relatives out of isolation.

* Contribute to better management of the disease.

* Facilitate the sharing of experiences and information between patients at dedicated events.

* Promote and participate in therapeutic educational activities.

* Disseminate information validated by the scientific committee.

* Help promote research.

* Work together with public authorities to improve patient care and quality of life.

* Participate in mixed working groups (doctors/patients) to share experiences and facilitate the dissemination of information to improve patient quality of life.

* Represent patients in various healthcare institutions.

* Initiate local or national events to spread awareness about eosinophilic diseases.

## Therapeutic patient education

**a**Definition Therapeutic patient education (TPE) is offered to all people with chronic diseases who may feel the need for it. This approach is centered on patients and their immediate circles and is integrated into the care process. It aims to increase their knowledge about their condition and eventually to improve their independence and quality of life.

**Practicalities for HES** The French Healthcare Network for Rare Immune-Hematological Diseases (MaRIH, filière de Santé Maladies rares immuno-hématologiques) and CEREO teamed up to launch a TPE program focused on HES, organ-specific eosinophilic disorders and their treatment, entitled 'Les éosinos ... kézako' ("Eos-what?"). The program, which has been accredited by both the Regional Health Agencies of Ile-de-France and Hauts-de-France, is aimed at patients over 16 years of age (and their families) managed in a CEREO facility.

It is led by a multidisciplinary team specifically trained in TPE, including health professionals (internists, pulmonologists, gastroenterologists, dermatologists, and nurses), social workers, clinical research assistants, management assistants, nutritionists, and patients with expertise, in partnership with APIMEO, a patient association for eosinophilic disorders.

It takes the form of monthly workshops (lasting 1.5–2 h each), either face-to-face or remote by videoconference.

The program is divided into different phases:

1. A shared educational assessment (in person or by phone) to better understand the patient's needs, expectations, concerns, beliefs, and plans.

2. For each patient, a personalized course is defined involving participation in some or all of the 8 educational workshops offered as part of the program.

3. Delivery of TPE workshops, each dedicated to a specific topic (e.g. overview of eosinophil-associated diseases and their treatments, focus on respiratory, GI or skin manifestations, how to prevent steroids-induced side-effects...) and with a standardized structure and content.

4. Review and individual evaluation of the "skills" acquired by the patient at the end of the educational program, a summary of the patient's course being sent to his General Practitioner.

## Other

Depending on each person's situation, the following may be offered on a case-by-case basis (in a non-exhaustive manner) in situations related to HES and/or its treatment:

* Physical therapy: in case of motor or proprioceptive symptoms related to HES.

* Support from a nutritionist.

* Support from a psychotherapist.

* Support from a social worker.
with imatinib) leading to long-term remission (especially cases involving PDGFRA or PDGFRB rearrangements) is not a contraindication to heart transplantation. In this case, specific treatment of HES should be continued over the long-term after transplantation to prevent recurrence of HES in the transplant [118].

## Use of ENT surgery

In case of nasal polyposis refractory to topical and systemic corticosteroid therapy, it is recommended to seek specialist advice to discuss the indications for and modalities of surgical management (polypectomy or ethmoidectomy), if appropriate.

## Paramedical support

### Patient support group

The primary care physician or specialist may encourage the patient to contact a patient support group association (if available).

In France, APIMEO (Association Pour l'Information sur les Maladies à Eosinophiles—Association for Information on Eosinophilic Diseases) is a patient support group consisting of patients and their relatives, whose main tasks are to:

* Bring patients and their relatives out of isolation.

* Contribute to better management of the disease.

* Facilitate the sharing of experiences and information between patients at dedicated events.

* Promote and participate in therapeutic educational activities.

* Disseminate information validated by the scientific committee.

* Help promote research.

* Work together with public authorities to improve patient care and quality of life.

* Participate in mixed working groups (doctors/patients) to share experiences and facilitate the dissemination of information to improve patient quality of life.

* Represent patients in various healthcare institutions.

* Initiate local or national events to spread awareness about eosinophilic diseases.

## Therapeutic patient education

**a**Definition Therapeutic patient education (TPE) is offered to all people with chronic diseases who may feel the need for it. This approach is centered on patients and their immediate circles and is integrated into the care process. It aims to increase their knowledge about their condition and eventually to improve their independence and quality of life.

**Practicalities for HES** The French Healthcare Network for Rare Immune-Hematological Diseases (MaRIH, filière de Santé Maladies rares immuno-hématologiques) and CEREO teamed up to launch a TPE program focused on HES, organ-specific eosinophilic disorders and their treatment, entitled 'Les éosinos ... kézako' ("Eos-what?"). The program, which has been accredited by both the Regional Health Agencies of Ile-de-France and Hauts-de-France, is aimed at patients over 16 years of age (and their families) managed in a CEREO facility.

It is led by a multidisciplinary team specifically trained in TPE, including health professionals (internists, pulmonologists, gastroenterologists, dermatologists, and nurses), social workers, clinical research assistants, management assistants, nutritionists, and patients with expertise, in partnership with APIMEO, a patient association for eosinophilic disorders.

It takes the form of monthly workshops (lasting 1.5–2 h each), either face-to-face or remote by videoconference.

The program is divided into different phases:

1. A shared educational assessment (in person or by phone) to better understand the patient's needs, expectations, concerns, beliefs, and plans.

2. For each patient, a personalized course is defined involving participation in some or all of the 8 educational workshops offered as part of the program.

3. Delivery of TPE workshops, each dedicated to a specific topic (e.g. overview of eosinophil-associated diseases and their treatments, focus on respiratory, GI or skin manifestations, how to prevent steroids-induced side-effects...) and with a standardized structure and content.

4. Review and individual evaluation of the "skills" acquired by the patient at the end of the educational program, a summary of the patient's course being sent to his General Practitioner.

## Other

Depending on each person's situation, the following may be offered on a case-by-case basis (in a non-exhaustive manner) in situations related to HES and/or its treatment:

* Physical therapy: in case of motor or proprioceptive symptoms related to HES.

* Support from a nutritionist.

* Support from a psychotherapist.

* Support from a social worker.
Also, in case of progression to multiple disabilities (which remain exceptional in the context of HES), it may be necessary to adjust daily life, prescribe medical support devices and/or apply for social assistance from disability support organizations.

## Follow-up

### Aims

The objectives of follow-up are to:

* Monitor the effectiveness of treatment on the clinical manifestations of HES, which should be assessed based on absolute eosinophil counts.

* Screen for other organ dysfunctions potentially associated with persistent HE.

* Identify and treat exacerbations early.

* Identify and address potential factors that may contribute to poor treatment compliance.

* Prevent, identify and, if necessary, provide early management of potential treatment-related complications.

* Limit, identify and, if necessary, provide early management of disease sequelae.

* Assess the psychological, family, scholastic and social/professional impact of the disease and limit its consequences.

* Cover the transition from pediatric to adult medicine.

### Professionals involved

The consultations required during treatment depend on the baseline assessment and the clinical course. Follow-up is generally multidisciplinary and coordinated by a hospital physician.

It is carried out by the same professionals as those involved in the initial assessment, plus other allied health professionals and social assistance professionals, if necessary.

### Frequency and content of consultations

The monitoring frequency depends on the duration and severity of the disease. Two specialist consultations per year are usually sufficient when the disease is well controlled.

Monitoring consists of a complete physical examination and quarterly (or more frequent, if indicated) monitoring of CBC. If necessary, clinical and laboratory monitoring may be supplemented by other complementary examinations (radiological, endoscopic, etc.) depending on the clinical manifestations of HES or the type of HES (e.g., pulmonology consultation with lung function tests in case of asthma, chest CT in case of

eosinophilic pneumonia, transthoracic echocardiogram in case of eosinophilic heart disease, etc.) or treatment (dermatological monitoring in case of treatment with hydroxycarbamide).

As the blood eosinophil count is a relatively reliable marker of the degree of tissue eosinophilia, it is not recommended to repeat invasive and/or expensive examinations if the CBC is well controlled. Similarly, if eosinophilic infiltration has been documented at least once in the affected organ and differential diagnoses have been ruled out, the clear correlation between eosinophil counts and clinical symptoms in most patients justifies not repeating invasive examinations (e.g., GI endoscopy).

However, in the event of persistent HE > 1.5 × 10⁹/L in patients not under treatment or in partial remission under treatment, regular heart examinations (troponin and BNP assays and TTE) are recommended (at frequent intervals in the first months following the onset of HE due to the high risk of organ complications during this period, and at longer intervals, e.g., annually thereafter) are recommended even in the absence of any symptoms due to the risk of pauci-symptomatic disease.

To date, there is no validated quality of life scale for HES, but scales designed for the assessment of specific symptoms (such as the Asthma Control Test or the Sino-Nasal Outcome Test) may be used if necessary.

### Follow-up specificities according to the disease subtype

#### Follow-up of F/P + HE/HES

After initiation of imatinib, Patients are initially closely monitored, with:

* Weekly CBCs until levels return to normal (which typically occurs within the first month) and then every 3 months, plus serum electrolytes and complete liver function tests).

* Molecular testing for the *FIP1L1::PDGFRA* transcript: at 3 months after initiation of imatinib, then every 6 months for 2 years, then annually thereafter).

**If imatinib is discontinued** If imatinib treatment is discontinued (ideally after at least 5 years of treatment), in the same manner as when it is discontinued in chronic myeloid leukemia, close molecular monitoring (every 3 months for the first year and every 6 months thereafter) is required in the long-term (even in the absence of laboratory evidence of HE, to avoid missing a molecular relapse).

**Various other considerations** Imatinib is generally well tolerated, with an incidence of less than 5% of grade 3 or 4 adverse events in the French case series of F/P + chronic
Also, in case of progression to multiple disabilities (which remain exceptional in the context of HES), it may be necessary to adjust daily life, prescribe medical support devices and/or apply for social assistance from disability support organizations.

## Follow-up

### Aims

The objectives of follow-up are to:

* Monitor the effectiveness of treatment on the clinical manifestations of HES, which should be assessed based on absolute eosinophil counts.

* Screen for other organ dysfunctions potentially associated with persistent HE.

* Identify and treat exacerbations early.

* Identify and address potential factors that may contribute to poor treatment compliance.

* Prevent, identify and, if necessary, provide early management of potential treatment-related complications.

* Limit, identify and, if necessary, provide early management of disease sequelae.

* Assess the psychological, family, scholastic and social/professional impact of the disease and limit its consequences.

* Cover the transition from pediatric to adult medicine.

### Professionals involved

The consultations required during treatment depend on the baseline assessment and the clinical course. Follow-up is generally multidisciplinary and coordinated by a hospital physician.

It is carried out by the same professionals as those involved in the initial assessment, plus other allied health professionals and social assistance professionals, if necessary.

### Frequency and content of consultations

The monitoring frequency depends on the duration and severity of the disease. Two specialist consultations per year are usually sufficient when the disease is well controlled.

Monitoring consists of a complete physical examination and quarterly (or more frequent, if indicated) monitoring of CBC. If necessary, clinical and laboratory monitoring may be supplemented by other complementary examinations (radiological, endoscopic, etc.) depending on the clinical manifestations of HES or the type of HES (e.g., pulmonology consultation with lung function tests in case of asthma, chest CT in case of

eosinophilic pneumonia, transthoracic echocardiogram in case of eosinophilic heart disease, etc.) or treatment (dermatological monitoring in case of treatment with hydroxycarbamide).

As the blood eosinophil count is a relatively reliable marker of the degree of tissue eosinophilia, it is not recommended to repeat invasive and/or expensive examinations if the CBC is well controlled. Similarly, if eosinophilic infiltration has been documented at least once in the affected organ and differential diagnoses have been ruled out, the clear correlation between eosinophil counts and clinical symptoms in most patients justifies not repeating invasive examinations (e.g., GI endoscopy).

However, in the event of persistent HE > 1.5 × 10⁹/L in patients not under treatment or in partial remission under treatment, regular heart examinations (troponin and BNP assays and TTE) are recommended (at frequent intervals in the first months following the onset of HE due to the high risk of organ complications during this period, and at longer intervals, e.g., annually thereafter) are recommended even in the absence of any symptoms due to the risk of pauci-symptomatic disease.

To date, there is no validated quality of life scale for HES, but scales designed for the assessment of specific symptoms (such as the Asthma Control Test or the Sino-Nasal Outcome Test) may be used if necessary.

### Follow-up specificities according to the disease subtype

#### Follow-up of F/P + HE/HES

After initiation of imatinib, Patients are initially closely monitored, with:

* Weekly CBCs until levels return to normal (which typically occurs within the first month) and then every 3 months, plus serum electrolytes and complete liver function tests).

* Molecular testing for the *FIP1L1::PDGFRA* transcript: at 3 months after initiation of imatinib, then every 6 months for 2 years, then annually thereafter).

**If imatinib is discontinued** If imatinib treatment is discontinued (ideally after at least 5 years of treatment), in the same manner as when it is discontinued in chronic myeloid leukemia, close molecular monitoring (every 3 months for the first year and every 6 months thereafter) is required in the long-term (even in the absence of laboratory evidence of HE, to avoid missing a molecular relapse).

**Various other considerations** Imatinib is generally well tolerated, with an incidence of less than 5% of grade 3 or 4 adverse events in the French case series of F/P + chronic
eosinophilic leukemia. The main toxic effects are hepatic, muscular, and hematologic. Superficial edema (particularly periorbital), non-specific GI symptoms, hypopigmentation and photosensitization may also occur.

### Follow-up of non-F/P-associated clonal HE/HES

Clonal HES related to a tyrosine kinase rearrangement (other than F/P) Because of the rarity of cases, the clinical/molecular follow-up of this type of clonal HES is not standardized. For practical purposes, the modalities described for F/P + chronic eosinophilic leukemia may be used. Regular cytogenetic follow-up is therefore required, especially in the absence of a specific molecular test.

Chronic eosinophilic leukemia–NOS Due to the rarity of CEL-NOS, the modalities of follow-up have not been standardized. Since there is a potential for progression to acute myeloid leukemia, regular monitoring (at least annually and/or more frequently in the event of cytopenia/increased blast count suggestive of progression) of cytogenetic and molecular data (including by NGS-based gene panel tests) is recommended.

Other considerations Hydroxycarbamide may be associated with hematologic (cytopenia), dermatologic (oral ulcerations, non-melanocytic skin tumors, hyperpigmentation, hair loss) and hepatic (cytolysis) adverse effects that call for regular clinical and laboratory monitoring (e.g., every 2 weeks for 2 months after initiation of treatment, then monthly for 3 months, and then every 3 months thereafter).

The tolerability of TKI other than imatinib is generally good, although there are some issues worth noting. Besides the (non-specific) hepatic, muscular and hematologic toxicity of TKI:

* Nilotinib can be associated with dermatologic (rash, xosis, pruritus), hepatic (usually moderate cytolysis, but also hyperlipidemia and/or free hyperbilirubinemia) and cardiovascular adverse reactions (arterial obstruction).

* Ponatinib is associated with frequent cardiovascular adverse reactions (including hypertension and arterial obstruction) and should be used with caution in patients with a history of cardiovascular disease. An assessment of cardiovascular risk (and the implementation of preventive measures) prior to initiating treatment is also advisable.

* Treatment with dasatinib can be associated with GI bleeding (although this is not a formal contraindication, caution should be exercised in patients with a history of gastritis or ulcers and/or in patients with thrombocytopenia or receiving antiplatelet/

anticoagulant therapy) and pleural effusion (which is a contraindication to continuation of treatment).

### Follow-up of lymphocytic HE/HES

Although rare (about 5–10% of patients), screening for transformation into high-grade T-cell lymphoma should be done at each visit, especially in case of clinical (e.g., general symptoms, new-onset lymphadenopathy) and/or biological ones (e.g., laboratory evidence of inflammation, cytopenia, etc.) suggestive of the diagnosis. When in doubt, a new PET scan can be performed to guide a lymph node biopsy. In ambiguous cases, a bone marrow biopsy may also be performed. Some discriminating criteria are suggested in Box 5 and in case of doubt, the advice of a trained pathologist should be sought.

While data are limited (due to the rarity of lymphocytic HES), some authors have suggested that there might be some degree of correlation between the percentage of abnormal T cells (especially CD3–CD4+) and the clinical course (i.e., an increased percentage of abnormal T cells could be associated with poorer control of clinical manifestations). However, there is no evidence to date suggesting that increased abnormal T-cell populations may be an early warning sign of transformation into high-grade T-cell lymphoma. In general, until further data become available, annual monitoring of T-cell phenotype is not recommended routinely.

### Conclusion

Here, we provide practical recommendations for both the step-by-step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophil-associated disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Although this expert consensus is likely to inform and assist health professionals in the diagnostic and/or therapeutic management of patients with HE/HES, it is—due to the wide range of clinical conditions grouped under the term of HES—not a substitute for expert opinion on a case-by-case basis. Further updates will be mandatory as new validated information emerges.

### Abbreviations

CBC Complete blood count

CCL Chemokine ligand

CCR C-C chemokine receptor
eosinophilic leukemia. The main toxic effects are hepatic, muscular, and hematologic. Superficial edema (particularly periorbital), non-specific GI symptoms, hypopigmentation and photosensitization may also occur.

### Follow-up of non-F/P-associated clonal HE/HES

Clonal HES related to a tyrosine kinase rearrangement (other than F/P) Because of the rarity of cases, the clinical/molecular follow-up of this type of clonal HES is not standardized. For practical purposes, the modalities described for F/P + chronic eosinophilic leukemia may be used. Regular cytogenetic follow-up is therefore required, especially in the absence of a specific molecular test.

Chronic eosinophilic leukemia–NOS Due to the rarity of CEL-NOS, the modalities of follow-up have not been standardized. Since there is a potential for progression to acute myeloid leukemia, regular monitoring (at least annually and/or more frequently in the event of cytopenia/increased blast count suggestive of progression) of cytogenetic and molecular data (including by NGS-based gene panel tests) is recommended.

Other considerations Hydroxycarbamide may be associated with hematologic (cytopenia), dermatologic (oral ulcerations, non-melanocytic skin tumors, hyperpigmentation, hair loss) and hepatic (cytolysis) adverse effects that call for regular clinical and laboratory monitoring (e.g., every 2 weeks for 2 months after initiation of treatment, then monthly for 3 months, and then every 3 months thereafter).

The tolerability of TKI other than imatinib is generally good, although there are some issues worth noting. Besides the (non-specific) hepatic, muscular and hematologic toxicity of TKI:

* Nilotinib can be associated with dermatologic (rash, xerosis, pruritus), hepatic (usually moderate cytolysis, but also hyperlipidemia and/or free hyperbilirubinemia) and cardiovascular adverse reactions (arterial obstruction).

* Ponatinib is associated with frequent cardiovascular adverse reactions (including hypertension and arterial obstruction) and should be used with caution in patients with a history of cardiovascular disease. An assessment of cardiovascular risk (and the implementation of preventive measures) prior to initiating treatment is also advisable.

* Treatment with dasatinib can be associated with GI bleeding (although this is not a formal contraindication, caution should be exercised in patients with a history of gastritis or ulcers and/or in patients with thrombocytopenia or receiving antiplatelet/

anticoagulant therapy) and pleural effusion (which is a contraindication to continuation of treatment).

### Follow-up of lymphocytic HE/HES

Although rare (about 5–10% of patients), screening for transformation into high-grade T-cell lymphoma should be done at each visit, especially in case of clinical (e.g., general symptoms, new-onset lymphadenopathy) and/or biological ones (e.g., laboratory evidence of inflammation, cytopenia, etc.) suggestive of the diagnosis. When in doubt, a new PET scan can be performed to guide a lymph node biopsy. In ambiguous cases, a bone marrow biopsy may also be performed. Some discriminating criteria are suggested in Box 5 and in case of doubt, the advice of a trained pathologist should be sought.

While data are limited (due to the rarity of lymphocytic HES), some authors have suggested that there might be some degree of correlation between the percentage of abnormal T cells (especially CD3–CD4+) and the clinical course (i.e., an increased percentage of abnormal T cells could be associated with poorer control of clinical manifestations). However, there is no evidence to date suggesting that increased abnormal T-cell populations may be an early warning sign of transformation into high-grade T-cell lymphoma. In general, until further data become available, annual monitoring of T-cell phenotype is not recommended routinely.

### Conclusion

Here, we provide practical recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophil-associated disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Although this expert consensus is likely to inform and assist health professionals in the diagnostic and/or therapeutic management of patients with HE/HES, it is—due to the wide range of clinical conditions grouped under the term of HES—not a substitute for expert opinion on a case-by-case basis. Further updates will be mandatory as new validated information emerges.

### Abbreviations

CBC Complete blood count

CCL Chemokine ligand

CCR C-C chemokine receptor
<table><tr><td>DRESS</td><td>Drug reaction with eosinophilia and systemic symptoms</td></tr><tr><td>ECP</td><td>Eosinophil cationic protein</td></tr><tr><td>EGPA</td><td>Eosinophilic granulomatosis with polyangiitis</td></tr><tr><td>EPX</td><td>Eosinophil peroxidase</td></tr><tr><td>FGFR</td><td>Fibroblast growth factor receptor</td></tr><tr><td>FIP1L1</td><td>Factor interacting with PAPOLA and CPSF1</td></tr><tr><td>FISH</td><td>Fluorescence in situ hybridization</td></tr><tr><td>GI</td><td>Gastrointestinal</td></tr><tr><td>HE</td><td>Hypereosinophilia</td></tr><tr><td>HES</td><td>Hypereosinophilic syndrome</td></tr><tr><td>HEus</td><td>HE of undetermined significance</td></tr><tr><td>ICOG-Eo</td><td>International cooperative working group on eosinophil disorders</td></tr><tr><td>IL</td><td>Interleukin</td></tr><tr><td>ILC2</td><td>Type 2 innate lymphoid cells</td></tr><tr><td>JAK</td><td>Janus kinase</td></tr><tr><td>KIT</td><td>Mast/stem cell growth factor receptor</td></tr><tr><td>MBP</td><td>Major basic protein</td></tr><tr><td>NGS</td><td>Next-generation sequencing</td></tr><tr><td>NOS</td><td>Not otherwise specified</td></tr><tr><td>PDGFRA</td><td>Platelet-derived growth factor receptor A</td></tr><tr><td>PDGFRB</td><td>Platelet-derived growth factor receptor B</td></tr><tr><td>PCR</td><td>Polymerase chain reaction</td></tr><tr><td>PET</td><td>Positron emission tomography</td></tr><tr><td>STAT</td><td>Signal transducer and activator of transcription</td></tr><tr><td>TKI</td><td>Tyrosine kinase inhibitor</td></tr><tr><td>TPE</td><td>Therapeutic patient education</td></tr></table>

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13023-023-02696-4.

**Additional file 1:** Summary intended for general practitioners

**Additional file 2:** List of referral centers of the French Eosinophil Network

**Additional file 3:** Main cosmopolitan parasitic infections

**Additional file 4:** Main cytogenetic abnormalities that can lead to clonal hypereosinophilia

**Additional file 5:** Screening strategy for organ involvement in patients with hypereosinophilia

## Acknowledgements

We are grateful to the French Healthcare Network for Rare Immune Hematological Diseases (MARIH) for their technical and editorial assistance (Amélie Marouane and Nidal Haddioui).

## Author contributions

MG, NE, JR, GL and JEK drafted the first draft of the manuscript (writing group). WAC, AB, ACHW, CC, ICR, VC, MD, PDG, FD, ND, SF, FG, FH, TL, AM, TM, GM, AN, LP, AP, JRos, NS, JSD, DSS, BT, LT, JVF (multidisciplinary review group) substantially edited the final manuscript. All authors read and approved the final manuscript.

## Funding

The French Healthcare Network for Rare Immune Hematological Diseases (MARIH) is funded by the National Health Ministry.

## Availability of data and materials

Not applicable.

## Declarations

### Ethics approval and consent to participate

Not applicable.

## Consent for publication

Not applicable.

## Competing interests

MG reports consulting fees from GlaxoSmithKline and AstraZeneca; speaking fees from GlaxoSmithKline, AstraZeneca and Sanofi; JRoh reports consulting fees from GlaxoSmithKline; speaking fees from GlaxoSmithKline; VC reports consulting fees from CSL Behring and AstraZeneca; speaking fees from AstraZeneca; ND reports consulting fees from Bristol Myers Squibb; SF reports consulting fees from Abyonix Pharma, Novartis, GlaxoSmithKline, Sanofi-Genzyme, CSL Vifor, Alexion; speaking fees from Baxter, Sanofi-Genzyme, CSL-Vifor; FG reports consulting fees from Nestlé; MH reports consulting fees from GlaxoSmithKline and Blueprint; speaking fees from Novartis, GlaxoSmithKline and Sanofi. AM reports consulting fees from GlaxoSmithKline, AstraZeneca and Novartis; speaking fees from GlaxoSmithKline, AstraZeneca and Novartis; TM reports consulting fees from Amgen, Chugai, Boehringer; speaking fees from GlaxoSmithKline; JRos reports speaking fees from Novartis; JSD reports consulting fees from Novartis; DSS reports grants from AstraZeneca and Sanofi-Genzyme; consulting fees from AstraZeneca, Novartis, Sanofi; speaking fees from Novartis and Sanofi-Genzyme; JFV reports consulting fees from GlaxoSmithKline; GL reports consulting fees from GlaxoSmithKline and Astra-Zeneca; speaking fees from GlaxoSmithKline and AstraZeneca. JEK reports consulting fees from GlaxoSmithKline and AstraZeneca.

## Author details

¹Department of Internal Medicine, National Reference Center for Hypereosinophilic Syndromes (CEREO), Hôpital Foch, 40, Rue Worth, 92151 Suresnes, France. ²Department of Internal Medicine, Hôpital Foch, Suresnes, France.

³Inserm, U1286 - INFINITE - Institute for Translational Research in Inflammation, University of Lille, CHU Lille, Lille, France. ⁴Department of Internal Medicine, University of Sorbonne-Paris-Cité, APHP, CHU Bichat, Paris, France. ⁵Department of Infectious Diseases and Tropical Medicine, University of Sorbonne-Paris-Cité, APHP, CHU Necker-Enfants Malades, Paris, France. ⁶Department of Pediatric Hematology, University of Lille, CHU Lille, Lille, France. ⁷Department of Internal Medicine, CH Annecy Genevois, Metz-Tessy, France. ⁸Department of Pharmacology, Hôpital Foch, Suresnes, France. ⁹CNRS, Inserm, Institut Pasteur de Lille, U1019-UMR9017-CIII-Centre d'Infection et d'Immunité de Lille, University of Lille, CHU Lille, Lille, France. ¹⁰CRISALIS (Clinical Research Initiative in Severe Asthma: a Lever for Innovation and Science), F-CRIN Network, INSERM US015, Toulouse, France. ¹¹Association Pour l'Information sur les Maladies à Eosinophiles, Bourg-la-Reine, France. ¹²Department of Respiratory Medicine, Hôpital Louis Pradel, UMR754 INRAE, University of Lyon 1, Hospices Civils de Lyon, Lyon, France. ¹³Department of Cytogenetics, CHU de Caen, Caen, France. ¹⁴Department of Cardiology, University of Lille, CHU Lille, Lille, France. ¹⁵Nantes, France. ¹⁶Laboratory of Hematology, University of Lille, CHU Lille, Lille, France. ¹⁷CNRS, Inserm, IRCL, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France. ¹⁸Department of Nephrology and Organ Transplantation, University of Paul Sabatier Toulouse III, CHU Toulouse, Toulouse, France.

¹⁹Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Jeanne de Flandre Children's Hospital, University of Lille, CHU Lille, Lille, France. ²⁰Department of Cardiology, Hôpital Foch, Suresnes, France.

²¹Pediatric Hematology and Immunology Department, University Sorbonne-Paris-Cité, APHP, CHU Robert Debré, Paris, France. ²²Department of Respiratory Medicine, Hôpital Foch, Suresnes, France. ²³Department of Internal Medicine, CHU Strasbourg, Strasbourg, France. ²⁴Otorhinolaryngology-Head and Neck Department, University of Lille, CHU de Lille, Lille, France. ²⁵Department of Internal Medicine, CHU Nantes, Nantes, France. ²⁶Department of Parasitology and Mycology, Sorbonne Université, APHP, CHU Pitié-Salpêtrière, Paris, France. ²⁷Department of Hematology and Pediatric Oncology, Sorbonne Université, APHP, CHU Armand Trousseau, Paris, France. ²⁸Department of Hematology, University of Sorbonne-Paris-Cité, APHP, CHU Necker, Paris, France. ²⁹Department of Internal Medicine, APHM, CHU La Timone, Marseille, France. ³⁰Centre d'Investigation Clinique, University of Sorbonne-Paris-Cité, AP-HP, CHU St-Louis, Paris, France. ³¹Department of Dermatology, University of Lille, CHU de Lille, Lille, France. ³²Department of Internal Medicine, University of Sorbonne-Paris-Cité, AP-HP, Paris, France. ³³Department of Internal
DRESS Drug reaction with eosinophilia and systemic symptoms

ECP Eosinophil cationic protein

EGPA Eosinophilic granulomatosis with polyangiitis

EPX Eosinophil peroxidase

FGFR Fibroblast growth factor receptor

FIP1L1 Factor interacting with PAPOLA and CPSF1

FISH Fluorescence in situ hybridization

GI Gastrointestinal

HE Hypereosinophilia

HES Hypereosinophilic syndrome

HEus HE of undetermined significance

ICOG-Eo International cooperative working group on eosinophil disorders

IL Interleukin

ILC2 Type 2 innate lymphoid cells

JAK Janus kinase

KIT Mast/stem cell growth factor receptor

MBP Major basic protein

NGS Next-generation sequencing

NOS Not otherwise specified

PDGFRA Platelet-derived growth factor receptor A

PDGFRB Platelet-derived growth factor receptor B

PCR Polymerase chain reaction

PET Positron emission tomography

STAT Signal transducer and activator of transcription

TKI Tyrosine kinase inhibitor

TPE Therapeutic patient education

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13023-023-02696-4.

**Additional file 1:** Summary intended for general practitioners

**Additional file 2:** List of referral centers of the French Eosinophil Network

**Additional file 3:** Main cosmopolitan parasitic infections

**Additional file 4:** Main cytogenetic abnormalities that can lead to clonal hypereosinophilia

**Additional file 5:** Screening strategy for organ involvement in patients with hypereosinophilia

## Acknowledgements

We are grateful to the French Healthcare Network for Rare Immune Hematological Diseases (MARIH) for their technical and editorial assistance (Amélie Marouane and Nidal Haddioui).

## Author contributions

MG, NE, JR, GL and JEK drafted the first draft of the manuscript (writing group). WAC, AB, ACHW, CC, ICR, VC, MD, PDG, FD, ND, SF, FG, FH, TL, AM, TM, GM, AN, LP, AP, JRos, NS, JSD, DSS, BT, LT, JVF (multidisciplinary review group) substantially edited the final manuscript. All authors read and approved the final manuscript.

## Funding

The French Healthcare Network for Rare Immune Hematological Diseases (MARIH) is funded by the National Health Ministry.

## Availability of data and materials

Not applicable.

## Declarations

### Ethics approval and consent to participate

Not applicable.

## Consent for publication

Not applicable.

## Competing interests

MG reports consulting fees from GlaxoSmithKline and AstraZeneca; speaking fees from GlaxoSmithKline, AstraZeneca and Sanofi; JRoh reports consulting fees from GlaxoSmithKline; speaking fees from GlaxoSmithKline; VC reports consulting fees from CSL Behring and AstraZeneca; speaking fees from AstraZeneca; ND reports consulting fees from Bristol Myers Squibb; SF reports consulting fees from Abyonix Pharma, Novartis, GlaxoSmithKline, Sanofi-Genzyme, CSL Vifor, Alexion; speaking fees from Baxter, Sanofi-Genzyme, CSL-Vifor; FG reports consulting fees from Nestlé; MH reports consulting fees from GlaxoSmithKline and Blueprint; speaking fees from Novartis, GlaxoSmithKline and Sanofi. AM reports consulting fees from GlaxoSmithKline, AstraZeneca and Novartis; speaking fees from GlaxoSmithKline, AstraZeneca and Novartis; TM reports consulting fees from Amgen, Chugai, Boehringer; speaking fees from GlaxoSmithKline; JRos reports speaking fees from Novartis; JSD reports consulting fees from Novartis; DSS reports grants from AstraZeneca and Sanofi-Genzyme; consulting fees from AstraZeneca, Novartis, Sanofi; speaking fees from Novartis and Sanofi-Genzyme; JFV reports consulting fees from GlaxoSmithKline; GL reports consulting fees from GlaxoSmithKline and Astra-Zeneca; speaking fees from GlaxoSmithKline and AstraZeneca. JEK reports consulting fees from GlaxoSmithKline and AstraZeneca.

## Author details

¹Department of Internal Medicine, National Reference Center for Hypereosinophilic Syndromes (CEREO), Hôpital Foch, 40, Rue Worth, 92151 Suresnes, France. ²Department of Internal Medicine, Hôpital Foch, Suresnes, France.

³Inserm, U1286 - INFINITE - Institute for Translational Research in Inflammation, University of Lille, CHU Lille, Lille, France. ⁴Department of Internal Medicine, University of Sorbonne-Paris-Cité, APHP, CHU Bichat, Paris, France. ⁵Department of Infectious Diseases and Tropical Medicine, University of Sorbonne-Paris-Cité, APHP, CHU Necker-Enfants Malades, Paris, France. ⁶Department of Pediatric Hematology, University of Lille, CHU Lille, Lille, France. ⁷Department of Internal Medicine, CH Annecy Genevois, Metz-Tessy, France. ⁸Department of Pharmacology, Hôpital Foch, Suresnes, France. ⁹CNRS, Inserm, Institut Pasteur de Lille, U1019-UMR9017-CIII-Centre d'Infection et d'Immunité de Lille, University of Lille, CHU Lille, Lille, France. ¹⁰CRISALIS (Clinical Research Initiative in Severe Asthma: a Lever for Innovation and Science), F-CRIN Network, INSERM US015, Toulouse, France. ¹¹Association Pour l'Information sur les Maladies à Eosinophiles, Bourg-la-Reine, France. ¹²Department of Respiratory Medicine, Hôpital Louis Pradel, UMR754 INRAE, University of Lyon 1, Hospices Civils de Lyon, Lyon, France. ¹³Department of Cytogenetics, CHU de Caen, Caen, France. ¹⁴Department of Cardiology, University of Lille, CHU Lille, Lille, France. ¹⁵Nantes, France. ¹⁶Laboratory of Hematology, University of Lille, CHU Lille, Lille, France. ¹⁷CNRS, Inserm, IRCL, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France. ¹⁸Department of Nephrology and Organ Transplantation, University of Paul Sabatier Toulouse III, CHU Toulouse, Toulouse, France.

¹⁹Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Jeanne de Flandre Children's Hospital, University of Lille, CHU Lille, Lille, France. ²⁰Department of Cardiology, Hôpital Foch, Suresnes, France.

²¹Pediatric Hematology and Immunology Department, University Sorbonne-Paris-Cité, APHP, CHU Robert Debré, Paris, France. ²²Department of Respiratory Medicine, Hôpital Foch, Suresnes, France. ²³Department of Internal Medicine, CHU Strasbourg, Strasbourg, France. ²⁴Otorhinolaryngology-Head and Neck Department, University of Lille, CHU de Lille, Lille, France. ²⁵Department of Internal Medicine, CHU Nantes, Nantes, France. ²⁶Department of Parasitology and Mycology, Sorbonne Université, APHP, CHU Pitié-Salpêtrière, Paris, France. ²⁷Department of Hematology and Pediatric Oncology, Sorbonne Université, APHP, CHU Armand Trousseau, Paris, France. ²⁸Department of Hematology, University of Sorbonne-Paris-Cité, APHP, CHU Necker, Paris, France. ²⁹Department of Internal Medicine, APHM, CHU La Timone, Marseille, France. ³⁰Centre d'Investigation Clinique, University of Sorbonne-Paris-Cité, AP-HP, CHU St-Louis, Paris, France. ³¹Department of Dermatology, University of Lille, CHU de Lille, Lille, France. ³²Department of Internal Medicine, University of Sorbonne-Paris-Cité, AP-HP, Paris, France. ³³Department of Internal
Medicine and Clinical Immunology, University of Lille, CHU de Lille, Lille, France. ³⁴Department of Internal Medicine, CHU de Bordeaux, Bordeaux, France. ³⁵Institut d'Immunologie, University of Lille, CHU de Lille, Lille, France. ³⁶Department of Internal Medicine, University of Paris Saclay, APHP, CHU Ambroise Paré, Boulogne-Billancourt, France.

Received: 18 January 2023 Accepted: 2 April 2023

Published online: 30 April 2023

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Medicine and Clinical Immunology, University of Lille, CHU de Lille, Lille, France. ³⁴Department of Internal Medicine, CHU de Bordeaux, Bordeaux, France. ³⁵Institut d'Immunologie, University of Lille, CHU de Lille, Lille, France. ³⁶Department of Internal Medicine, University of Paris Saclay, APHP, CHU Ambroise Paré, Boulogne-Billancourt, France.

Received: 18 January 2023 Accepted: 2 April 2023

Published online: 30 April 2023

## References

1. Valent P, Klion AD, Horny H-P, Roufosse F, Gotlib J, Weller PF, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012;130(3):607-612.e9.

2. Valent P, Klion AD, Roufosse F, Simon D, Metzgeroth G, Leiferman KM, et al. Proposed refined diagnostic criteria and classification of eosinophil disorders and related syndromes. Allergy. 2023;78(1):47-59.

3. Kahn JE, Groh M, Lefèvre G. (A critical appraisal of) classification of hypereosinophilic disorders. Front Med. 2017;4:216.

4. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-14.

5. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-19.

6. Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-28.

7. Reiter A, Gotlib J. Myeloid neoplasms with eosinophilia. Blood. 2017;129(6):704-14.

8. Shomali W, Gotlib J. World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97(1):129-48.

9. Cogan E, Schandené L, Crusiaux A, Cochaux P, Velu T, Goldman M. Brief report: clonal proliferation of type 2 helper T cells in a man with the hypereosinophilic syndrome. N Engl J Med. 1994;330(8):535-8.

10. Lefèvre G, Copin M-C, Staumont-Sallé D, Avenel-Audran M, Aubert H, Taieb A, et al. The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3 - CD4 + aberrant T-cell phenotype. Medicine (Baltimore). 2014;93(17):255-66.

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39. Tennenbaum J, Groh M, Venditti L, Campos-Gazeau F, Chalayer E, De Broucker T, et al. FIP1L1-PDGFRA-associated hypereosinophilic syndrome as a treatable cause of watershed infarction. Stroke. 2021;52(10):e605–9.

40. Réau V, Vallée A, Terrier B, Plessier A, Abisror N, Ackermann F, et al. Venous thrombosis and predictors of relapse in eosinophil-related diseases. Sci Rep. 2021;11(1):6388.

41. Groh M, Pineton de Chambrun M, Georges J-L, Panel K, Lefèvre G, Kahn J-E, et al. Recurrent cardiac arrest due to eosinophilia-related coronary vasospasm successfully treated by benralizumab. J Allergy Clin Immunol Pract. 2021;9:3497–3499

42. Groh M, Lefèvre G, Ackermann F, Etienne N, Kahn J-E. Syndromes hyperéosinophiliques [Hypereosinophilic syndromes]. Rev Prat. 2019;767-773.

43. Roufosse F, Weller PF. Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol. 2010;126(1):39–44.

44. Ramírez E, Medrano-Casique N, Tong HY, Bellón T, Cabañas R, Fiandor A, et al. Eosinophilic drug reactions detected by a prospective pharmacovigilance programme in a tertiary hospital. Br J Clin Pharmacol. 2017;83(2):400–15.

45. Descamps V, Deschamps L, El Khalifa J, Groh M, Gibier J-B, Lefèvre G, et al. Eosinophilic vasculitis associated with persistent dupilumab-induced hypereosinophilia in severe asthma. Respir Med Res. 2021;79:100821.

46. Scanvion Q, Béné J, Gautier S, Grandvuillemin A, Le Beller C, Chenaf C, et al. Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database. Oncoimmunology. 2020;9(1):1722022.

47. Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071–80.

48. Huang L, Appleton JA. Eosinophils in helminth infection: defenders and dupes. Trends Parasitol. 2016;32(10):798–807.

49. Ma G, Holland CV, Wang T, Hofmann A, Fan CK, Maizels RM, et al. Human toxocariasis. Lancet Infect Dis. 2018;18(1):e14–24.

50. Pagnoux C, Groh M. Optimal therapy and prospects for new medicines in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Expert Rev Clin Immunol. 2016;12(10):1059–67.

51. Asano K, Hebisawa A, Ishiguro T, Takayanagi N, Nakamura Y, Suzuki J, et al. New clinical diagnostic criteria for allergic bronchopulmonary aspergillosis/mycosis and its validation. J Allergy Clin Immunol. 2021;147(4):1261-1268.e5.

52. Leiferman KM, Peters MS. Eosinophil-related disease and the skin. J Allergy Clin Immunol Pract. 2018;6(5):1462–82.

53. Zuelgaray E, Chevret S, Jachiet M, Cacoub P, Kahn J-E, Groh M, et al. Trunk involvement and peau d'orange aspect are poor prognostic factors in eosinophilic fasciitis (Shulman's disease): a multicenter retrospective study of 119 patients. J Am Acad Dermatol. 2020;88(1):160.

54. Abisror N, Mekinian A, Dechartres A, Groh M, Berezne A, Noel N, et al. Abnormal T-cell phenotype in episodic angioedema with hypereosinophilia (Gleich's syndrome): frequency, clinical implication and prognosis. J Am Acad Dermatol. 2019;50190-9622(19)30196-3

55. Bertrand V, Boccara O, Filhon B, Manca F, Lefèvre G, Groh M, et al. Episodic angioedema with eosinophilia (Gleich syndrome) in children: a clinical review. Pediatr Allergy Immunol. 2020;31(3):297–302.

56. Winchester RJ, Koffler D, Litwin SD, Kunkel HG. Observations on the eosinophilia of certain patients with rheumatoid arthritis. Arthritis Rheum. 1971;14(5):650–65.

57. Moussiegt A, Müller R, Ebbo M, Grados A, Graveleau J, et al. IgG4-related disease and hypereosinophilic syndrome: overlapping phenotypes. Autoimmun Rev. 2021;20(9):102889.

58. Click B, Anderson AM, Koutroubakis IE, Rivers CR, Babichenko D, Machicado JD, et al. Peripheral eosinophilia in patients with inflammatory bowel disease defines an aggressive disease phenotype. Am J Gastroenterol. 2017;112(12):1849–58.

59. Rohmer J, Groh M, Samson M, London J, Jachiet M, Rouzaud D, et al. Distal ischemia as the initial presentation of hypereosinophilic syndrome-related arterial involvement: a case study and literature review. Autoimmun Rev. 2019;18(8):828–30.

60. Lefèvre G, Leurs A, Gibier J-B, Copin M-C, Staumont-Sallé D, Dezoteux F, et al. « Idiopathic eosinophilic vasculitis »: another side of hypereosinophilic syndrome? a comprehensive analysis of 117 cases in asthma-free patients. J Allergy Clin Immunol Pract. 2020;8(4):1329-1340.e3.

61. Krahn M, Lopez de Munain A, Streichenberger N, Bernard R, Pécheux C, Testard H, et al. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol. 2006;59(6):905–11.

62. Leurs A, Chenivesse C, Lopez B, Gibier JB, Clément G, Groh M, et al. C-Reactive protein as a diagnostic tool in differential diagnosis of hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract. 2019;7(4):1347–51.

63. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608–19.

64. Chandesris M-O, Melki I, Natividad A, Puel A, Fieschi C, Yun L, et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore). 2012;91(4):e1-19.

65. Béziat V, Tavernier SJ, Chen Y-H, Ma CS, Materna M, Laurence A, et al. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. J Exp Med. 2020;217(6).

66. Fournier B, Balducci E, Duployez N, Clappier E, Cucciniu W, Arfeville C, et al. B-ALL With t(5;14)(q31;q32); IGH-IL3 rearrangement and eosinophilia: a comprehensive analysis of a peculiar <i>i>IGH</i>/<i>i</i>-rearranged B-ALL. Front Oncol. 2019;9:1374.

67. McPherson T, Cowen EW, McBurney E, Klion AD. Platelet-derived growth factor receptor-alpha-associated hypereosinophilic syndrome and lymphomatoid papulosis. Br J Dermatol. 2006;155(4):824–6.

68. Olsson-Arvidsson L, Norberg A, Sjögren H, Johansson B. Frequent false-negative FIP1L1-PDGFRA FISH analyses of bone marrow samples from clonal eosinophilia at diagnosis. Br J Haematol. 2020;188(5):e76–9.

69. Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003;102(9):3093–6.

70. Maric I, Robyn J, Metcalfe DD, Fay MP, Carter M, Wilson T, et al. KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol. 2007;120(3):680–7.

71. Lee J-S, Seo H, Im K, Park SN, Kim S-M, Lee EK, et al. Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing. PLoS ONE. 2017;12(10):e0185602.

72. Pardanani A, Lasho T, Wassie E, Finke C, Zblewski D, Hanson CA, et al. Predictors of survival in WHO-defined hypereosinophilic syndrome and idiopathic hypereosinophilia and the role of next-generation sequencing. Leukemia. 2016;30(9):1924–6.

73. Wang SA, Tam W, Tsai AG, Arber DA, Hasserjian JP, Geyer JT, et al. Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified. Mod Pathol. 2016;29(8):854–64.

74. Lefèvre G, Copin M-C, Roulier C, Aubert H, Avenel-Audran M, Grardel N, et al. CD3-CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder. Haematologica. 2015;100(8):1086–95.

75. Carpentier C, Schandené L, Dewispelaere L, Heimann P, Cogan E, Roufosse F. CD3-CD4+ lymphocytic variant hypereosinophilic syndrome: diagnostic tools revisited. J Allergy Clin Immunol Pract. 2021;6:2426-2439.e7.

76. Ledoult E, Groh M, Kahn J-E, Trauet J, Bouaziz J-D, Caristan A, et al. Assessment of T-cell polarization on the basis of surface marker expression: diagnosis and potential therapeutic implications in lymphocytic variant hypereosinophilic syndrome. J Allergy Clin Immunol Pract. 2020;8(3):1110-1114.e2.

77. Gleich GJ, Schroeter AL, Marcoux JP, Sachs MI, O'Connell EJ, Kohler PF. Episodic angioedema associated with eosinophilia. N Engl J Med. 1984;310(25):1621–6.
38. Bondue A, Carpentier C, Roufosse F. Hypereosinophilic syndrome: considerations for the cardiologist. Heart. 2022;108(3):164–71.

39. Tennenbaum J, Groh M, Venditti L, Campos-Gazeau F, Chalayer E, De Broucker T, et al. FIP1L1-PDGFRA-associated hypereosinophilic syndrome as a treatable cause of watershed infarction. Stroke. 2021;52(10):e605–9.

40. Réau V, Vallée A, Terrier B, Plessier A, Abisror N, Ackermann F, et al. Venous thrombosis and predictors of relapse in eosinophil-related diseases. Sci Rep. 2021;11(1):6388.

41. Groh M, Pineton de Chambrun M, Georges J-L, Panel K, Lefèvre G, Kahn J-E, et al. Recurrent cardiac arrest due to eosinophilia-related coronary vasospasm successfully treated by benralizumab. J Allergy Clin Immunol Pract. 2021;9:3497–3499

42. Groh M, Lefèvre G, Ackermann F, Etienne N, Kahn J-E. Syndromes hyperéosinophiliques [Hypereosinophilic syndromes]. Rev Prat. 2019;767-773.

43. Roufosse F, Weller PF. Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol. 2010;126(1):39–44.

44. Ramírez E, Medrano-Casique N, Tong HY, Bellón T, Cabañas R, Fiandor A, et al. Eosinophilic drug reactions detected by a prospective pharmacovigilance programme in a tertiary hospital. Br J Clin Pharmacol. 2017;83(2):400–15.

45. Descamps V, Deschamps L, El Khalifa J, Groh M, Gibier J-B, Lefèvre G, et al. Eosinophilic vasculitis associated with persistent dupilumab-induced hypereosinophilia in severe asthma. Respir Med Res. 2021;79:100821.

46. Scanvion Q, Béné J, Gautier S, Grandvuillemin A, Le Beller C, Chenaf C, et al. Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database. Oncoimmunology. 2020;9(1):1722022.

47. Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071–80.

48. Huang L, Appleton JA. Eosinophils in helminth infection: defenders and dupes. Trends Parasitol. 2016;32(10):798–807.

49. Ma G, Holland CV, Wang T, Hofmann A, Fan CK, Maizels RM, et al. Human toxocariasis. Lancet Infect Dis. 2018;18(1):e14–24.

50. Pagnoux C, Groh M. Optimal therapy and prospects for new medicines in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Expert Rev Clin Immunol. 2016;12(10):1059–67.

51. Asano K, Hebisawa A, Ishiguro T, Takayanagi N, Nakamura Y, Suzuki J, et al. New clinical diagnostic criteria for allergic bronchopulmonary aspergillosis/mycosis and its validation. J Allergy Clin Immunol. 2021;147(4):1261-1268.e5.

52. Leiferman KM, Peters MS. Eosinophil-related disease and the skin. J Allergy Clin Immunol Pract. 2018;6(5):1462–82.

53. Zuelgaray E, Chevret S, Jachiet M, Cacoub P, Kahn J-E, Groh M, et al. Trunk involvement and peau d'orange aspect are poor prognostic factors in eosinophilic fasciitis (Shulman's disease): a multicenter retrospective study of 119 patients. J Am Acad Dermatol. 2020;88(1):160.

54. Abisror N, Mekinian A, Dechartres A, Groh M, Berezne A, Noel N, et al. Abnormal T-cell phenotype in episodic angioedema with hypereosinophilia (Gleich's syndrome): frequency, clinical implication and prognosis. J Am Acad Dermatol. 2019;50190-9622(19)30196-3

55. Bertrand V, Boccara O, Filhon B, Manca F, Lefèvre G, Groh M, et al. Episodic angioedema with eosinophilia (Gleich syndrome) in children: a clinical review. Pediatr Allergy Immunol. 2020;31(3):297–302.

56. Winchester RJ, Koffler D, Litwin SD, Kunkel HG. Observations on the eosinophilia of certain patients with rheumatoid arthritis. Arthritis Rheum. 1971;14(5):650–65.

57. Moussiegt A, Müller R, Ebbo M, Grados A, Graveleau J, et al. IgG4-related disease and hypereosinophilic syndrome: overlapping phenotypes. Autoimmun Rev. 2021;20(9):102889.

58. Click B, Anderson AM, Koutroubakis IE, Rivers CR, Babichenko D, Machicado JD, et al. Peripheral eosinophilia in patients with inflammatory bowel disease defines an aggressive disease phenotype. Am J Gastroenterol. 2017;112(12):1849–58.

59. Rohmer J, Groh M, Samson M, London J, Jachiet M, Rouzaud D, et al. Distal ischemia as the initial presentation of hypereosinophilic syndrome-related arterial involvement: a case study and literature review. Autoimmun Rev. 2019;18(8):828–30.

60. Lefèvre G, Leurs A, Gibier J-B, Copin M-C, Staumont-Sallé D, Dezoteux F, et al. « Idiopathic eosinophilic vasculitis »: another side of hypereosinophilic syndrome? a comprehensive analysis of 117 cases in asthma-free patients. J Allergy Clin Immunol Pract. 2020;8(4):1329-1340.e3.

61. Krahn M, Lopez de Munain A, Streichenberger N, Bernard R, Pécheux C, Testard H, et al. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol. 2006;59(6):905–11.

62. Leurs A, Chenivesse C, Lopez B, Gibier JB, Clément G, Groh M, et al. C-Reactive protein as a diagnostic tool in differential diagnosis of hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract. 2019;7(4):1347–51.

63. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608–19.

64. Chandesris M-O, Melki I, Natividad A, Puel A, Fieschi C, Yun L, et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore). 2012;91(4):e1-19.

65. Béziat V, Tavernier SJ, Chen Y-H, Ma CS, Materna M, Laurence A, et al. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. J Exp Med. 2020;217(6).

66. Fournier B, Balducci E, Duployez N, Clappier E, Cucciniu W, Arfeville C, et al. B-ALL With t(5;14)(q31;q32); IGH-IL3 rearrangement and eosinophilia: a comprehensive analysis of a peculiar <i>≤>IGH</i>/*i>-rearranged B-ALL. Front Oncol. 2019;9:1374.

67. McPherson T, Cowen EW, McBurney E, Klion AD. Platelet-derived growth factor receptor-alpha-associated hypereosinophilic syndrome and lymphomatoid papulosis. Br J Dermatol. 2006;155(4):824–6.

68. Olsson-Arvidsson L, Norberg A, Sjögren H, Johansson B. Frequent false-negative FIP1L1-PDGFRA FISH analyses of bone marrow samples from clonal eosinophilia at diagnosis. Br J Haematol. 2020;188(5):e76–9.

69. Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003;102(9):3093–6.

70. Maric I, Robyn J, Metcalfe DD, Fay MP, Carter M, Wilson T, et al. KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol. 2007;120(3):680–7.

71. Lee J-S, Seo H, Im K, Park SN, Kim S-M, Lee EK, et al. Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing. PLoS ONE. 2017;12(10):e0185602.

72. Pardanani A, Lasho T, Wassie E, Finke C, Zblewski D, Hanson CA, et al. Predictors of survival in WHO-defined hypereosinophilic syndrome and idiopathic hypereosinophilia and the role of next-generation sequencing. Leukemia. 2016;30(9):1924–6.

73. Wang SA, Tam W, Tsai AG, Arber DA, Hasserjian JP, Geyer JT, et al. Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified. Mod Pathol. 2016;29(8):854–64.

74. Lefèvre G, Copin M-C, Roulier C, Aubert H, Avenel-Audran M, Grardel N, et al. CD3-CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder. Haematologica. 2015;100(8):1086–95.

75. Carpentier C, Schandené L, Dewispelaere L, Heimann P, Cogan E, Roufosse F. CD3-CD4+ lymphocytic variant hypereosinophilic syndrome: diagnostic tools revisited. J Allergy Clin Immunol Pract. 2021;6:2426-2439.e7.

76. Ledoult E, Groh M, Kahn J-E, Trauet J, Bouaziz J-D, Caristan A, et al. Assessment of T-cell polarization on the basis of surface marker expression: diagnosis and potential therapeutic implications in lymphocytic variant hypereosinophilic syndrome. J Allergy Clin Immunol Pract. 2020;8(3):1110-1114.e2.

77. Gleich GJ, Schroeter AL, Marcoux JP, Sachs MI, O'Connell EJ, Kohler PF. Episodic angioedema associated with eosinophilia. N Engl J Med. 1984;310(25):1621–6.
78. de Lavaille A, Roufosse F, Schmid-Grendelmeier P, Roumier A-S, Schandené L, Cogan E, et al. High serum thymus and activation-regulated chemokine levels in the lymphocytic variant of the hypereosinophilic syndrome. J Allergy Clin Immunol. 2002;110(3):476-9.

79. Kuang FL, Curtin BF, Alao H, Piligian B, Berry A, Holland-Thomas N, et al. Single-organ and multisystem hypereosinophilic syndrome patients with gastrointestinal manifestations share common characteristics. J Allergy Clin Immunol Pract. 2020;8(8):2718-2726.e2.

80. Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French vasculitis study group cohort. Arthritis Rheum. 2013;65(1):270-81.

81. Cottin V, Bel E, Bottero P, Dalhoff K, Humbert M, Lazor R, et al. Revisiting the systemic vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): a study of 157 patients by the Groupe d'Etudes et de Recherche sur les Maladies Orophariesques Pulmonaires et la European respiratory society taskforce on eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Autoimmun Rev. 2017;16(1):1-9.

82. Groh M, Masciocco G, Kirchner E, Kristen A, Pellegrini C, Varnous S, et al. Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). J Heart Lung Transplant. 2014;33(8):842-50.

83. Lyons PA, Peters JE, Alberici F, Riley J, Coulson RMR, Astle W, et al. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun. 2019;10(1):5120.

84. Nishi R, Koike H, Ohyama K, Fukami Y, Ikeda S, Kawagashira Y, et al. Differential clinicopathologic features of EGPA-associated neuropathy with and without ANCA. Neurology. 2020;94(16):e1726-37.

85. Dulohery MM, Patel RR, Schneider F, Ryu JH. Lung involvement in hypereosinophilic syndromes. Respir Med. 2011;105(1):114-21.

86. Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376(20):1921-32.

87. Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American college of rheumatology/European league against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79(1):77-87.

88. Puxeddu I, Ribatti D, Crivellato E, Levi-Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol. 2005;116(3):531-6.

89. Galdiero MR, Varrichi G, Seaf M, Marone G, Levi-Schaffer F, Marone G. Bidirectional mast cell-eosinophil interactions in inflammatory disorders and cancer. Front Immunol. 2017;4:103.

90. Kluin-Nelemans HC, Reiter A, Illerhaus A, van Anrooij B, Hartmann K, Span LFR, et al. Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM registry. Leukemia. 2020;34(4):1090-101.

91. Gerds AT, Gotlib J, Bose P, Deininger MW, Dunbar A, Elshoury A, et al. Myeloid/lymphoid neoplasms with eosinophilia and TK fusion genes, version 3.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2020;18(9):1248-69.

92. Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFR-A-positive chronic eosinophilic leukemia. Blood. 2007;109(11):4635-40.

93. Metzgeroth G, Schwaab J, Gosenca D, Fabarius A, Haferlach C, Hochhaus A, et al. Long-term follow-up of treatment with imatinib in eosinophilia-associated myeloid/lymphoid neoplasms with PDGFR rearrangements in blast phase. Leukemia. 2013;27(11):2254-6.

94. Metzgeroth G, Erben P, Martin H, Mousset S, Teichmann M, Walz C, et al. Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFR-A positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation. Leukemia. 2012;26(1):162-4.

95. Metzgeroth G, Schwaab J, Naumann N, Jawhar M, Haferlach T, Fabarius A, et al. Treatment-free remission in FIP1L1-PDGFR-A-positive myeloid/lymphoid neoplasms with eosinophilia after imatinib discontinuation. Blood Adv. 2020;4(3):440-3.

96. Schwaab J, Naumann N, Luebke J, Jawhar M, Somervaille TCP, Williams MS, et al. Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes. Am J Hematol. 2020;95(7):824-33.

97. Verstovsek S, Gotlib J, Vannucchi A, Rambaldi A, Reiter A, Shomali W, et al. FIGHT-203, an ongoing phase 2 study of pemigatinib in patients with myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement (MLNFGFR1): a focus on centrally reviewed clinical and cytogenetic responses in previously treated patients. Blood. 2022;140(Supplement 1):3980-2.

98. Ueno NT, Anagnostopoulos A, Rondón G, Champlin RE, Mikhailova N, Pankratova OS, et al. Successful non-myeloablative allogeneic transplantation for treatment of idiopathic hypereosinophilic syndrome. Br J Haematol. 2002;119(1):131-4.

99. Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon H-U, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008;358(12):1215-28.

100. Roufosse F, Kahn J-E, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, et al. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020;146(6):1397-405.

101. Delcros Q, Taillé C, Vallée A, Brun AL, Chenivesse C, Couture P. Targeting interleukin-5/5R for the treatment of idiopathic chronic eosinophilic pneumonia. J Allergy Clin Immunol Pract. 2022;52213-2198(22):01335-6.

102. Aldebert D, Lamkhioued B, Desaint C, Gounni AS, Goldman M, Capron A, et al. Eosinophils express a functional receptor for interferon alpha: inhibitory role of interferon alpha on the release of mediators. Blood. 1996;87(6):2354-60.

103. Butterfield JH, Gleich GJ. Response of six patients with idiopathic hypereosinophilic syndrome to interferon alfa. J Allergy Clin Immunol. 1994;94(6 Pt 2):1318-26.

104. Khoury P, Desmond R, Pabon A, Holland-Thomas N, Ware JM, Arthur DC, et al. Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome. Allergy. 2016;71(6):803-10.

105. Kuang FL, Legrand F, Makiya M, Ware J, Wetzler L, Brown T, et al. Benralizumab for PDGFRA-negative hypereosinophilic syndrome. N Engl J Med. 2019;380(14):1336-46.

106. Choi C, Moller D, Tan J, Dou C, Peterson EA, Medvedev N, et al. Pegylated interferon alpha 2a is an effective and well-tolerated treatment option for lymphocyte-variant hypereosinophilic syndrome. Br J Haematol. 2020;188(5):e68-72.

107. Roufosse FE, Kahn JE, Gleich GJ, Schwartz LB, Singh AD, Rosenwasser LJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol. 2013;131(2):461-7.

108. Fernandez-Pol S, Petersen B, Murphy J-E, Oak JS, Wang EBK, Rieger KE, et al. Two cases with features of lymphocyte variant hypereosinophilic syndrome with STAT3 SH2 domain mutations. Am J Surg Pathol. 2021;45(2):193-9.

109. Walker S, Wang C, Walradt T, Hong BS, Tanner JR, Levinsohn JL, et al. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood. 2016;127(7):948-51.

110. King B, Lee AI, Choi J. Treatment of hypereosinophilic syndrome with cutaneous involvement with the JAK inhibitors Tofacitinib and Ruxolitinib. J Invest Dermatol. 2017;137(4):951-4.

111. Faguer S, Groh M, Vergez F, Hunault-Berger M, Duployez N, Renaudineau Y, et al. JAK inhibition for CD3-CD4+ lymphocytic-variant hypereosinophilic syndrome. Clin Immunol. 2023. https://doi.org/10.1016/j.clim.2023.109275.

112. Mesli F, Dumont M, Soria A, Groh M, Turpin M, Voiriot G, et al. Benralizumab: a potential tailored treatment for life-threatening DRESS in the COVID-19 era. J Allergy Clin Immunol Pract. 2021;9(9):3529-3531.e1.

113. Pitini V, Teti D, Arrigo C, Righi M. Alemtuzumab therapy for refractory idiopathic hypereosinophilic syndrome with abnormal T cells: a case report. Br J Haematol. 2004;127(5):477.

114. Davies J, Spry C. Plasma exchange or leukapheresis in the hypereosinophilic syndrome. Ann Intern Med. 1982;96(6 Pt 1):791.
78. de Lavaille A, Roufosse F, Schmid-Grendelmeier P, Roumier A-S, Schandené L, Cogan E, et al. High serum thymus and activation-regulated chemokine levels in the lymphocytic variant of the hypereosinophilic syndrome. J Allergy Clin Immunol. 2002;110(3):476-9.

79. Kuang FL, Curtin BF, Alao H, Piligian B, Berry A, Holland-Thomas N, et al. Single-organ and multisystem hypereosinophilic syndrome patients with gastrointestinal manifestations share common characteristics. J Allergy Clin Immunol Pract. 2020;8(8):2718-2726.e2.

80. Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French vasculitis study group cohort. Arthritis Rheum. 2013;65(1):270-81.

81. Cottin V, Bel E, Bottero P, Dalhoff K, Humbert M, Lazor R, et al. Revisiting the systemic vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): a study of 157 patients by the Groupe d'Etudes et de Recherche sur les Maladies Orophariesques Pulmonaires et la European respiratory society taskforce on eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Autoimmun Rev. 2017;16(1):1-9.

82. Groh M, Masciocco G, Kirchner E, Kristen A, Pellegrini C, Varnous S, et al. Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). J Heart Lung Transplant. 2014;33(8):842-50.

83. Lyons PA, Peters JE, Alberici F, Riley J, Coulson RMR, Astle W, et al. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun. 2019;10(1):5120.

84. Nishi R, Koike H, Ohyama K, Fukami Y, Ikeda S, Kawagashira Y, et al. Differential clinicopathologic features of EGPA-associated neuropathy with and without ANCA. Neurology. 2020;94(16):e1726-37.

85. Dulohery MM, Patel RR, Schneider F, Ryu JH. Lung involvement in hypereosinophilic syndromes. Respir Med. 2011;105(1):114-21.

86. Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376(20):1921-32.

87. Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American college of rheumatology/European league against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79(1):77-87.

88. Puxeddu I, Ribatti D, Crivellato E, Levi-Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol. 2005;116(3):531-6.

89. Galdiero MR, Varrichi G, Seaf M, Marone G, Levi-Schaffer F, Marone G. Bidirectional mast cell-eosinophil interactions in inflammatory disorders and cancer. Front Immunol. 2017;4:103.

90. Kluin-Nelemans HC, Reiter A, Illerhaus A, van Anrooij B, Hartmann K, Span LFR, et al. Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM registry. Leukemia. 2020;34(4):1090-101.

91. Gerds AT, Gotlib J, Bose P, Deininger MW, Dunbar A, Elshoury A, et al. Myeloid/lymphoid neoplasms with eosinophilia and TK fusion genes, version 3.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2020;18(9):1248-69.

92. Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFR-A-positive chronic eosinophilic leukemia. Blood. 2007;109(11):4635-40.

93. Metzgeroth G, Schwaab J, Gosenca D, Fabarius A, Haferlach C, Hochhaus A, et al. Long-term follow-up of treatment with imatinib in eosinophilia-associated myeloid/lymphoid neoplasms with PDGFR rearrangements in blast phase. Leukemia. 2013;27(11):2254-6.

94. Metzgeroth G, Erben P, Martin H, Mousset S, Teichmann M, Walz C, et al. Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFR-A positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation. Leukemia. 2012;26(1):162-4.

95. Metzgeroth G, Schwaab J, Naumann N, Jawhar M, Haferlach T, Fabarius A, et al. Treatment-free remission in FIP1L1-PDGFR-A-positive myeloid/lymphoid neoplasms with eosinophilia after imatinib discontinuation. Blood Adv. 2020;4(3):440-3.

96. Schwaab J, Naumann N, Luebke J, Jawhar M, Somervaille TCP, Williams MS, et al. Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes. Am J Hematol. 2020;95(7):824-33.

97. Verstovsek S, Gotlib J, Vannucchi A, Rambaldi A, Reiter A, Shomali W, et al. FIGHT-203, an ongoing phase 2 study of pemigatinib in patients with myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement (MLNFGFR1): a focus on centrally reviewed clinical and cytogenetic responses in previously treated patients. Blood. 2022;140(Supplement 1):3980-2.

98. Ueno NT, Anagnostopoulos A, Rondón G, Champlin RE, Mikhailova N, Pankratova OS, et al. Successful non-myeloablative allogeneic transplantation for treatment of idiopathic hypereosinophilic syndrome. Br J Haematol. 2002;119(1):131-4.

99. Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon H-U, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008;358(12):1215-28.

100. Roufosse F, Kahn J-E, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, et al. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020;146(6):1397-405.

101. Delcros Q, Taillé C, Vallée A, Brun AL, Chenivesse C, Couture P. Targeting interleukin-5/5R for the treatment of idiopathic chronic eosinophilic pneumonia. J Allergy Clin Immunol Pract. 2022;52213-2198(22):01335-6.

102. Aldebert D, Lamkhioued B, Desaint C, Gounni AS, Goldman M, Capron A, et al. Eosinophils express a functional receptor for interferon alpha: inhibitory role of interferon alpha on the release of mediators. Blood. 1996;87(6):2354-60.

103. Butterfield JH, Gleich GJ. Response of six patients with idiopathic hypereosinophilic syndrome to interferon alfa. J Allergy Clin Immunol. 1994;94(6 Pt 2):1318-26.

104. Khoury P, Desmond R, Pabon A, Holland-Thomas N, Ware JM, Arthur DC, et al. Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome. Allergy. 2016;71(6):803-10.

105. Kuang FL, Legrand F, Makiya M, Ware J, Wetzler L, Brown T, et al. Benralizumab for PDGFRA-negative hypereosinophilic syndrome. N Engl J Med. 2019;380(14):1336-46.

106. Choi C, Moller D, Tan J, Dou C, Peterson EA, Medvedev N, et al. Pegylated interferon alpha 2a is an effective and well-tolerated treatment option for lymphocyte-variant hypereosinophilic syndrome. Br J Haematol. 2020;188(5):e68-72.

107. Roufosse FE, Kahn JE, Gleich GJ, Schwartz LB, Singh AD, Rosenwasser LJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol. 2013;131(2):461-7.

108. Fernandez-Pol S, Petersen B, Murphy J-E, Oak JS, Wang EBK, Rieger KE, et al. Two cases with features of lymphocyte variant hypereosinophilic syndrome with STAT3 SH2 domain mutations. Am J Surg Pathol. 2021;45(2):193-9.

109. Walker S, Wang C, Walradt T, Hong BS, Tanner JR, Levinsohn JL, et al. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood. 2016;127(7):948-51.

110. King B, Lee AI, Choi J. Treatment of hypereosinophilic syndrome with cutaneous involvement with the JAK inhibitors Tofacitinib and Ruxolitinib. J Invest Dermatol. 2017;137(4):951-4.

111. Faguer S, Groh M, Vergez F, Hunault-Berger M, Duployez N, Renaudineau Y, et al. JAK inhibition for CD3-CD4+ lymphocytic-variant hypereosinophilic syndrome. Clin Immunol. 2023. https://doi.org/10.1016/j.clim.2023.109275.

112. Mesli F, Dumont M, Soria A, Groh M, Turpin M, Voiriot G, et al. Benralizumab: a potential tailored treatment for life-threatening DRESS in the COVID-19 era. J Allergy Clin Immunol Pract. 2021;9(9):3529-3531.e1.

113. Pitini V, Teti D, Arrigo C, Righi M. Alemtuzumab therapy for refractory idiopathic hypereosinophilic syndrome with abnormal T cells: a case report. Br J Haematol. 2004;127(5):477.

114. Davies J, Spry C. Plasma exchange or leukapheresis in the hypereosinophilic syndrome. Ann Intern Med. 1982;96(6 Pt 1):791.
115. Manetz S, Maric I, Brown T, Kuang FL, Wetzler L, Battisto E, et al. Successful pregnancy in the setting of eosinophil depletion by benralizumab. J Allergy Clin Immunol Pract. 2021;9(3):1405-1407.e3.

116. Pfaller B, José Yepes-Nuñez J, Agache I, Akdis CA, Alsalamah M, Bavbek S, et al. Biologicals in atopic disease in pregnancy: an EAACI position paper. Allergy. 2021;76(1):71–89.

117. Schneider U, Jenni R, Turina J, Turina M, Hess OM. Long-term follow up of patients with endomyocardial fibrosis: effects of surgery. Heart. 1998;79(4):362–7.

118. Fassnacht F, Roumier M, Fouret P, Levy V, Varnous S, Russel S, et al. Successful heart transplantation for irreversible endomyocardial fibrosis related to FIP1L1-PDGFRA chronic eosinophilic leukemia. Transplantation. 2015;99(11):e176-177.

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115. Manetz S, Maric I, Brown T, Kuang FL, Wetzler L, Battisto E, et al. Successful pregnancy in the setting of eosinophil depletion by benralizumab. J Allergy Clin Immunol Pract. 2021;9(3):1405-1407.e3.

116. Pfaller B, José Yepes-Nuñez J, Agache I, Akdis CA, Alsalamah M, Bavbek S, et al. Biologicals in atopic disease in pregnancy: an EAACI position paper. Allergy. 2021;76(1):71-89.

117. Schneider U, Jenni R, Turina J, Turina M, Hess OM. Long-term follow up of patients with endomyocardial fibrosis: effects of surgery. Heart. 1998;79(4):362-7.

118. Fassnacht F, Roumier M, Fouret P, Levy V, Varnous S, Russel S, et al. Successful heart transplantation for irreversible endomyocardial fibrosis related to FIP1L1-PDGFRA chronic eosinophilic leukemia. Transplantation. 2015;99(11):e176-177.

**Publisher's Note**

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ready to submit your research? Choose BMC and benefit from:

* fast, convenient online submission

* thorough peer review by experienced researchers in your field

* rapid publication on acceptance

* support for research data, including large and complex data types

* gold Open Access which fosters wider collaboration and increased citations

* maximum visibility for your research: over 100M website views per year

At BMC, research is always in progress.

Learn more biomedcentral.com/submissions

<figure><img src="image_7.png" /></figure>