Eosinophils originate from a myeloid cluster of differentiation (CD) CD34+ precursors in the bone marrow and are part of the innate immune system (16, 21). Maturation takes a week on average and is influenced by a granulocyte-macrophage colony-stimulating factor (GM-CSF), IL3, and IL-5 and is driven by activation of transcription factor networks including PU.1, CCAAT/enhancer-binding protein (C/EBP), and GATA-binding protein 1 (GATA-1). All of the above are involved, but IL-5 and GATA-1 have key roles in eosinopoiesis and turnover; IL-5 is involved in egress from the bone marrow microenvironment into the bloodstream, promoting activation and survival and preventing apoptosis; and GATA-1 is a vital regulator of cell maturation (22–24).

The course of eosinophils subsequent to bone marrow release starts with circulation in the bloodstream for 8–18 h and terminates in peripheral organs for up to 12–14 days or longer (25, 26). At some point during circulation in the bloodstream, the eosinophil migrates through the lining of blood vessels and enters one of the numerous organs, possibly attracted by chemokines (27). Being mobile cells, they are distributed to the liver, lungs, skin, heart, reticuloendothelial system, glands, and digestive tract, but not to the esophagus, which is normally devoid of eosinophils. The cells remain in the organs as tissue-resident cells under homeostatic conditions. During this time, the cell may proliferate under inflammatory conditions and undergo terminal apoptosis (28, 29).

Eosinophils in the bloodstream or tissues are large, spherical cells, 12–17 μm in size with a bi-lobed nucleus, without a nucleolus, and exhibiting numerous coarse, rounded, and red-purple granules in the cytoplasm by routine staining (16, 24, 28). Figure 1 shows peripheral blood smears, illustrating mature eosinophil granulocytes from a patient with mild eosinophilia. Eosinophils can be compared morphologically to neutrophil granulocytes, lymphocytes, and platelets. Typically, less than one eosinophil granulocyte will be recognized in a field using light microscopy. Detection of more than one eosinophil in a 400× light microscopy field examination is an indication of eosinophilia, normally representing 1%–4% of all white blood cells (1, 2).

The cell is easily identified by light microscopy in a blood smear by the appearance of the nucleus and coarse granules, which distinguish the appearance of eosinophils from other leukocytes ( Figure 1 ). The cytoplasm contains not only the abundant and phenotypically characteristic-specific (also named secondary) granules, but also other organelles (not readily visible using light-microscopy) such as the smaller, azurophilic, and fewer primary granules. Both granules are lysosomes, storage sites for agents involved in tissue damage and inflammation. The secondary granules contain chemokines, growth factors, cytokines, and proteolytic enzymes such as the major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and eosinophil cationic protein (15, 23, 24, 26, 30). A predominant protein in eosinophils is galectin-10, which is now identified as a component of the peripheral cytoplasm. Upon secretion, it precipitates in tissues and body fluids as the Charcot–Leyden crystal protein, a lysophospholipase indicative of eosinophil granulocyte activity (31). The various proteases released from the specific granules contribute to the antimicrobial effect of the phagocytosing eosinophil granulocyte but may, at the same time, cause epithelial cell damage, and cytotoxicity, and contribute to fibrosis. The release of substances into tissues is damaging to microorganisms or bystander cells, causing organ damage. The concentration of proteases in body fluids may serve as a biomarker of inflammation involving eosinophils, reflecting a potential effect of circulating granule components (15, 28, 32).

Eosinophil granulocytes interact via their arsenal of surface-bound receptors (e.g., IgE, histamine, chemokine, cytokine, and adhesion) and the ability to secrete various proteins and other substances as mentioned above, that characterize both circulating and resident granulocytes (15, 23, 24, 33, 34). The dynamics are normally reflected in their ability to respond to infectious and inflammatory stimuli by increased numbers, eosinophilia in the blood and affected tissues, and activation. The release of preformed or stimulus-dependent chemokines, interleukins, leukotrienes, growth factors, and proteins behaves like a cascade, accompanied by a respiratory burst. The generation of reactive oxygen species upon assembly of the components of the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in the plasma membrane is higher per cell in eosinophils than in neutrophils (35, 36). Although the number of neutrophils is usually about 10 times higher, the increase in eosinophils in response to inflammatory or infectious stimuli contributes to the potential toxicity in the process, including harmful effects on bystander cells, through the release of granule content and reactive oxygen species. Like neutrophils, eosinophils are phagocytes that contribute to the direct control of helminth infections, and both granulocytes can form extracellular traps. This complex network of granule components and DNA is the ultimate contribution of the dying cell participating in parasitic infection and inflammation (15, 34, 37).

The phenotype of mature eosinophil granulocytes and precursor cells can be separated by the CD11b/CD62L expression, accompanied by upregulation and co-expression of various surface markers. These include C-C motif chemokine receptor 3 (CCR3, CD193), IL-5 receptor alpha (CD125), and sialic acid-binding Ig-like lectin 8 (siglec-8), a member of the CD33-related siglec subfamily, all of which are highly expressed on the surface of eosinophil granulocytes in blood and bone marrow (23, 28, 38, 39). Flow cytometry to identify eosinophils may be routinely performed, including a panel of monoclonal antibodies to detect myeloid proliferation according to Euroflow (40). However, flow cytometry may not be relevant if the eosinophil count is normal.

Being classified as an MPN, iHES carries the risk for vascular events both before and after diagnosis. The manifestations are almost always thrombotic, in both arterial and venous locations, and may be more frequently associated with clonal, primary eosinophilia. The thrombogenic potential of eosinophilia may be manifested in addition to other inherited or acquired risk factors for vascular events. The risk of bleeding may be minimal because severe thrombocytopenia or another-acquired hemorrhagic diathesis is very unusual in iHES. Retrospective analyses of HES cohorts report that 21%–24% of patients have experienced at least one event before diagnosis (41, 42). One study has linked increased expression of tissue factor (factor III or CD142), which is the initiator of thrombin generation, in eosinophil granulocytes examined in patients with iHES and secondary hypereosinophilia (43). In addition, eosinophils interact with platelets to promote atherosclerosis and thrombosis (44).

An increase in the number of eosinophils is common and can be arbitrarily divided into three levels: mild (0.5–1.5 × 10⁹/L), moderate (≥1.5 × 10⁹/L), and severe (>5 × 10⁹/L) eosinophilia. The term hypereosinophilia may be used to characterize all cases of moderate or severe eosinophilia (3–6).

The number of eosinophil granulocytes in the blood is routinely measured by automated machine analysis as part of the differential count. Minor variations in the normal threshold, defined as 0.4–0.5 × 10⁹/L blood, may be observed between different machines and laboratories, but a manual count of (mature) eosinophils in the blood is rarely if ever, needed (45). An association within the normal range of blood eosinophil counts in adults has been reported to be correlated with several demographic factors including age, biological sex, race, BMI, and smoking status (46, 47). A diurnal variation in eosinophil count in healthy individuals has been reported to be higher at night and lower in the morning (48). Despite these variations in normal subjects, no specific recommendation has been made or deemed relevant for the interpretation of cell counts in patients with eosinophilia.

The incidence of eosinophilia varies worldwide. Although due to a plethora of reactive causes, it is more likely due to infection in tropical areas and inflammation in industrialized regions. A hospital incidence of over 10% has been reported in South Korea (49) and India (50). The incidence of eosinophilia in subjects having a blood sample taken over 10 years in the primary sector of a Western capital city was reported to be 4% in adults, reflecting that eosinophilia is a common problem to be contextualized clinically (51). In contrast, the incidence of eosinophilia in a large Canadian island district was 0.1% (52). The elevated cell count is transient in almost all patients with secondary eosinophilia, due to the impact of treatment or the self-limiting nature of the reaction, and the prevalence of eosinophilia remains low.

The definition of HES was introduced in 1968 and required that patients presented moderate or severe blood eosinophilia of unknown origin for more than 6 months, and for it to be responsible for organ damage (53, 54). The term in its original meaning is no longer applicable due to the options for treatment, the risk of irreversible symptoms, and the improvements in the diagnostic tools. Today, according to the agreed-upon definitions, HES reflects a heterogeneous group of disorders, presenting with persistent peripheral blood eosinophilia ≥1.5 × 10⁹/L on two occasions, the absence of a secondary cause of eosinophilia, and evidence of eosinophil-associated end-organ damage, justified by excessive tissue eosinophilia (55, 56).

The incidence has been reported to be 0.036/100,000 for HES in the USA (57) and 0.018/100,000 specifically diagnosed with the most prevalent primary eosinophilia, a factor interacting with PAPOLA and CPSF1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)-positive neoplasms, in France (58). The reports underline the rarity of primary eosinophilia, and more precise estimates may be difficult to collect, although the WHO ICD system provides diagnostic registry codes for different subclasses of hypereosinophilia. The FIP1L1-PDGFRA primary myeloid neoplasm is more prevalent in male adults (58), but otherwise, iHES and clonal primary eosinophilia are overall not gender-specific and can be diagnosed at all ages. No valid data are available on the incidence in pediatric patients (59, 60).

Eosinophilia can be classified by diagnostic tests into congenital (familial) causes as primary (intrinsic, clonal) or secondary (extrinsic, reactive) (20, 55). The diagnosis by exclusion of iHES (with symptoms due to eosinophilia) may also be clinically sub-characterized as either a myeloid (mHES) or a lymphoid (lHES) phenotype (61, 62). The lymphoid HES subtype is driven by CD3⁻CD4⁺ IL-5, producing T cells and thus secondary, non-neoplastic eosinophilia that is glucocorticoid sensitive and often associated with, e.g., angioedema, skin lesions, pruritus, and fasciitis (63). Previously, concomitant manifestations such as cardiac involvement, hepatosplenomegaly, anemia, variable leuko- and thrombocyte counts, and steroid resistance were used to phenotypically characterize a myeloid HES (61, 62, 64), similar to other MPNs. Specific diagnostic tests are required to identify patients according to the updated criteria. The revisions of the WHO classifications of malignant eosinophilic disorders by molecular diagnostic markers since 2008 have established the cluster of MLN-TK identified by specific tyrosine kinase rearrangements (3–9).

The presentation of patients with eosinophilia varies considerably, in terms of symptoms and severity. Over days to months, most patients may gradually experience a worsening of symptoms related to the cause of eosinophilia, whereas symptom flares are characteristic of iHES. The presence of an increased eosinophil count in the blood may have been indolent for years, or manifestations may be due to a recent onset involving one or more organs simultaneously. The clinical context at presentation in patients with an increased blood eosinophil count is not related to the classification of primary, secondary, or iHES, because the symptoms due to eosinophilia may mimic or be involved in the diseases listed in Supplementary Table 1 concerning organ manifestations (65–86) and Supplementary Table 2 concerning parasitic causes (87, 88). An exception is iHE/iHE_US, which by definition is asymptomatic eosinophilia (4–7, 20, 55).

The considerable overlap in patients presenting with eosinophilia as a clinical clue in differential diagnostics reflects how complex the correct diagnosis may be. Nevertheless, common pathologic conditions not associated with eosinophilia may manifest with similar symptoms. The recurrent question is to decide whether eosinophilia is an independent causative factor or whether the presence of eosinophilia is an additional causative factor to disorders that may have been present before the eosinophilia was noticed. Symptoms due to eosinophilia may thus be manifest in all organ systems in addition to pre-existing conditions, masked as a worsening ( Supplementary Table 1 ).

B-symptoms, including weight loss, low-grade fever, and night sweats may occur in all patients with eosinophilia, whether primary, secondary, or iHES. In the individual patient, they may be attributed to cytokine signaling induced by eosinophils or other immunocompetent cells as part of a malignant, infectious, and inflammatory secondary cause ( Supplementary Tables 1 , 2).

Reports on cohorts with eosinophilia have been published describing manifestations in iHES (65) or cross-sectional symptom registries (66, 67). Studies from Western institutions cannot be compared due to methodological differences, but the institutional reports reflect the diversity of symptoms ascribed to primary or secondary eosinophilia ( Supplementary Tables 1 , 2). The most common organ involvement in patients with unexplained hypereosinophilia referred for examination involves dermatologic, respiratory, and gastrointestinal symptoms in approximately 45%, 35%, and 25%, respectively (65, 66). Registration of causes of unclassified eosinophilia identifies infection, allergy, and non-hematologic malignancy as common causes in different parts of the world (49, 50, 52, 61, 66, 67). These data support a multidisciplinary approach to patients who cannot be classified in a straightforward manner according to diagnostic guidelines or who do not respond adequately to proper treatment ( Supplementary Tables 1, 2 ).

The diagnostic entity “myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions” (MLN-TK) was introduced in the 2008 WHO classification (134). The dissection of the genetic aberrations has contributed to identifying and including more patients in this clinically heterogeneous group and added information relevant to prognosis and treatment (9, 95). The neoplasms in this group are driven by constitutively active domains in tyrosine kinase fusion genes and may carry additional mutations in other genes that promote an increase in the number and survival of malignant cells (19, 135–137). Consequently, the pathophysiology of the disease and the clinical presentation of the patients with MLN-TK are very heterogeneous, emphasizing the importance of establishing a correct diagnosis. The application of cytogenetic and molecular analysis can be guided by the history (acute or chronic), examination findings (lymphadenopathy and splenomegaly), and laboratory tests (tryptase, blasts) ( Figure 3 ) (138).

All the specific diagnoses included in the MLN-TK must be BCR-ABL1 negative and instead arise due to rearrangements and abnormal gene products in PDGFRA, PDGFRB, FGFR1, FLT3, ETV6, or JAK2 (9, 95, 135–137). The origin of fusion genes involves cryptic deletions or translocations of chromosomal regions during mitosis in hematopoietic stem cells, which result in dysregulated intracellular signaling and the development of distinct AML, MPN, MDS, overlapping forms, mixed phenotype acute leukemia, and T- or B-ALL or lymphoma.

Figure 4 provides examples of the clinical presentation and management of MLN-TK, representing the diversity of disease in primary, neoplastic (intrinsic) eosinophilia. The figure is not exhaustive, as the individual patient may present with variable symptoms from different organ systems ( Supplementary Table 1 ). The partner combinations of the fusion genes in MLN-TK influence the clinical presentation, and a more—in this context—common partner and the associated phenotype is presented as an example in each of the six categories ( Figure 4 ). Specific features that may be observed in blood samples, are indicated, but are not universally observed and may be influenced by variations in disease dynamics, patient comorbidity, and latency or initiation of treatment before referral for examination, e.g., anemia, thrombocytopenia, and related symptoms. In principle, all organs may be involved in MLN-TK ( Supplementary Table 1 ), and the manifestations and clinical course from the presentation may be similar to those of acute or chronic leukemia ( Figure 4 ).

Eosinophilia is a hallmark of patients with MLN-TK that develops de novo but may be absent in a minority of patients. The increase in blood eosinophils may be mild to severe, and variable within the same MLN-TK entity. This feature reflects the complexity of the perturbed cell biology and the importance of identifying the partner gene through different analyses for clonality to confirm the correct diagnosis and possibly initiate a targeted therapy ( Figures 3 , 4 ). The number of potential partners is different for each fusion gene, but one gene can be involved in different fusion gene relations, and the number of genes and related pathways involved is increasing, with at least 72 fusion gene combinations overall in MLN-TK (9, 19, 95, 135–138). A challenge in the diagnostic process is how to combine panels and methodologies with varying sensitivity and specificity in bone marrow samples ( Figures 3 , 4 ). The partner in a rearrangement may not always be identified at diagnosis. Tissue samples may also be taken from enlarged lymph nodes, skin, or organs, and samples may be stored in the freezer for additional analysis if needed later.

Eosinophilia is the dominant feature of blood cell analysis in CEL and the most frequent PDGFRA-associated MLN-TK (9, 58, 139). The entity CEL is characterized by persistent hypereosinophilia for at least 4 weeks, organ involvement due to eosinophilia, and evidence of both clonality and abnormal bone marrow morphology (e.g., erythroid or megakaryocytic dysplasia), but does not require increased blasts (≥2% in peripheral blood or 5%–19% in bone marrow). The former CEL “not otherwise specified (NOS),” has, by this revised description, been left out of the fifth WHO classification (9, 95, 134). The result of clonal analysis in patients with CEL must exclude the other MLN-TKs specifically as primary eosinophilia, and acute or chronic MPN in general, defined by cytogenetic or mutational criteria in the WHO classification (9, 95). The information provided by cytogenetic, mutational, and cytologic analysis justifies that CEL represents an independent MPN ( Figures 2 , 4 ), which often presents with organ involvement due to eosinophilia, and may share clinical features with PDGFRA-FIPL1 MLN-TK. CEL is different from iHE or iHES, both benign conditions, and is defined by persistent hypereosinophilia in the absence of a clonal or reactive cause, by clonality, and abnormal bone marrow morphology (140). Mutational analysis for a single or concurrent clonal driver in patients with CEL has been reported in a variety of genes involved in myeloproliferation, such as JAK2, additional sex combs like 1 (ASXL1), chaperonin containing TCP1 subunit 6B (CCT6B), tet methylcytosine dioxygenase 2 (TET2), enhancer of zeste homolog 2 (EZH2), Casitas B-lineage lymphoma (CBL), or signal transducer and activator of transcription (STAT). The clinical phenotype may therefore be differentially associated with different genotypes (141–144). Next-generation sequencing (NGS) or polymerase chain reaction (PCR) analysis can be performed in cases without clonality by other tests to examine the differential diagnosis of CEL and iHE_US or iHES, which may be therapeutically important, demonstrating a potential target ( Figures 2 – 4 ).

Eosinophilia may be observed in a minority of patients with MPNs such asPV, PMF, or ET. However, it may be difficult to disentangle eosinophilia as part of the neoplastic process in these cases and, alternatively, it is appropriate to consider eosinophilia in these patients to be secondary, reactive to another condition. The diagnosis of an infectious or inflammatory condition in a patient with classic Philadelphia-negative MPN is imperative for optimal management ( Supplementary Tables 1, 2 ; Figures 2 , 3 ).

The approach may be wait-and-watch or may include any symptomatic treatment pending diagnostic clarification, such as antibiotics, xanthine oxidase inhibition, and fluid replacement, as indicated by the clinical circumstances since the dynamics and manifestations in the conditions are variable ( Supplementary Table 1 ; Figures 2 , 4 ). Unless diagnostic information is available at an early stage, e.g., by flow cytometry in AML, CS may be part of a first-line treatment to reduce symptoms and the blood eosinophil count. The final treatment strategy is decided by shared decision-making with the patient, based on full information and a complete diagnostic analysis ( Figure 3 ). Participation in a clinical trial is recommended for all patients with primary eosinophilia and iHES, if possible. No treatment is indicated for eosinophilia in iHES.

Imatinib is authorized by the FDA and EMA for the treatment of advanced iHES and MLN-TK with FIP1L1-PDGFRA rearrangement, and mepolizumab is approved as an add-on treatment for adult patients with inadequately controlled iHES without an identifiable non-hematologic secondary cause. The administration of a tyrosine kinase inhibitor (TKI) or anti-IL5 monoclonal antibody (anti-IL5 mAB) is rational given the pathophysiology of iHES and MLN-TK with FIP1L1-PDGFRA, which involves the potential stimulation of eosinophils by IL-5 (23–27, 145, 146) and a highly sensitive constitutively active tyrosine kinase (58, 139, 147), respectively.

The treatment strategy in all patients other than MLN-TK with FIP1L1-PDGFRA in the first line is therefore based on established use and extrapolation, and a highly individual assessment. This includes information on the diagnosis of CEL, type of MNL-TK or iHES, symptoms, comorbidity, and patient preferences. Adverse events or a planned pregnancy may impact the decision during treatment (3–7, 20, 61, 62, 64, 65). Treatment of primary eosinophilia and iHES includes one or more drugs to reduce and preferably normalize the eosinophil count and any additional medications indicated to mitigate symptoms caused by eosinophilia and organ symptoms. Supportive treatment is highly individualized and may involve all internal medicine specialties ( Supplementary Table 1 ).

Figure 4 ; Table 1 present the treatment options in MNL-TK, CEL, and iHES. Given the pathophysiologic mechanisms in MLN-TK, information on the clonal nature may indicate the use of TKI, chemotherapy, high-dose cytotoxic regimens, and stem cell support, including allogeneic hematopoietic stem cell transplantation (HSCT), with variable outcomes. Treatment of FIP1L1-PDGFRA MLN-TK shows a very high rate of durable complete remissions to low-dose imatinib, including undetectable residual disease by FISH or quantitative reverse transcriptase (RT) PCR. The potential cure of the patient is reflected by the discontinuation of imatinib in a small group of FIP1L1-PDGFRA MLN-TK patients (58). In contrast, the diversity of the diagnoses is reflected by indications for AML or ALL regimens in other patients of the same entity ( Figure 4 ).

The treatment of CEL and iHES reflects the possible lymphoid or myeloid nature since the specific mechanism of the disease is not known in iHES and may not be translated from a clonal finding to a therapeutic agent in CEL ( Table 2 ). There are no randomized clinical trials (RCTs) or robust data to support international agreement on the first or subsequent lines of treatment, after CS, and the decision will depend on the evaluation of the individual patient and treatment options.

CS is the drug of choice when immediate treatment is indicated in CEL and iHES, until clarification. Maintenance treatment, if CS is effective, should include steroid-sparing agents, due to the chronic nature or repeated need for CS, while tapering CS. Lack of CS sensitivity may indicate a “myeloid” phenotype, supporting, for example, interferon-alpha or hydroxyurea as a non-targeting treatment as the next line of treatment. Access to serum IL-5 or other cytokine levels may guide treatment with an immunosuppressive drug. However, validated and robust prospective results are not available, and pretreatment with CS may impact the analysis (145). The decision to introduce methotrexate, azathioprine, cyclosporine, or mycophenolate, instead of, for example, interferon-alpha or hydroxyurea, remains a clinical one ( Table 1 ). The administration of these drugs is supported by case reports, small studies, retrospective analyses, and established use extrapolating from experience in lymphoproliferative and myeloproliferative diseases (63, 104, 148–151) ( Table 2 ).

The lowest dose of CS or any agent should be used, and combination treatment may be administered, as in selected cases with PV or PMF, to reduce adverse events and maintain optimal efficacy. Efficacy may last from weeks to 2 - 3 months, preferably introducing only one drug at a time. Prophylaxis against osteoporosis should be initiated at an early stage in CS-sensitive patients with risk factors for bone density reduction, as CS may be used for months and repeatedly. Prophylactic antimicrobials for Pseudomonas infection may be contemplated in selected patients with chronic lung disease and long-term therapy with immunosuppressive agents ( Table 1 ).

Imatinib is approved for advanced iHES, which is a heterogeneous group clinically identified with persistent symptoms due to eosinophilia, and unresponsive to administered lines of treatment. Imatinib may be effective in CEL or iHES because fusion genes, not detected by analysis, may be sensitive to TKI (152). A standard dose may be started and tapered if effective to the lowest effective dosage. Response to any treatment in CEL or iHES is variable ( Table 1 ).

There are no internationally agreed-upon definitions of response to treatment in primary eosinophilia or iHES. Reduction in symptoms, flares, eosinophil count (complete response requires durable normalization), and any biomarker, particularly the clonal marker, may reflect a satisfactory effect.

Irrespective of the choice of treatment in CEL or iHES, drug discontinuation may be planned after months to years of treatment. It may be reasonable to taper the dosage, considering the drug and being aware that relapse of symptoms, typically manifested at the time of diagnosis is a risk. Patients with rare diagnoses such as primary eosinophilia or iHES should continue to be monitored and treated in specialized departments.

A multidisciplinary team (MDT) in a hospital is a function specifically suited to cases with complex care needs due to the variable symptoms, diagnostic challenges, and individualized treatment. MDTs are appropriate for rare diseases because expertise is required to provide optimal care and coordinating work in professional MDTs also promotes improvement in patient management. This has been well described in the management of patients with benign or malignant surgical and medical disorders and in research (172–177). MDTs may also be called tertiary centers.

Establishing an MDT has to take into account the different facilities and disciplines at hand, and the effort necessary in an MDT requires a number of clinical and diagnostic facilities to join the collaboration. MDTs are most often organized in regional or university hospitals with centralized functions in several specialties, and thus with extensive and recurrent interaction with local/regional hospitals based on collaborating policies. This development is in line with the centralization of certain functions, to aim for and maintain the highest degree of competence. MDTs and centralized functions reflect the same interest but differ in—at least—the fact that centralized functions are often allocated to one department based on daily routines, whereas MDTs are only operational when several diagnostic and clinical departments have established and agreed to a manner in which to collaborate, as a local policy. The centralized function is expected to run 24/7, whereas MDTs typically have planned meetings at weekly intervals.

A tertiary center for eosinophilia is a specialized function serving a large population since the number of patients with a primary or idiopathic cause in need of specialized treatment at the department of hematology and the incidence of complex secondary cases is low. Inborn errors of immunity and familial cases are exceedingly rare ( Figure 2 ). The population of Denmark is 5.85 million (in 2021), and two MDTs were allocated by government decision in 2017 at two university hospitals, each in a different part of the country. One is in the capital region (at Rigshospitalet, in Eastern Denmark) and the other is in the Southern Denmark region (at Odense University Hospital). Both MDTs are open to referrals from all five regions of the country, primarily for adult patients. Individual patients with eosinophilia can decide which MDT is more convenient for them to attend, but the contact with local/regional departments can be continuous due to the collaboration between departments at different institutions. Similarly, tertiary centers for other rare diagnoses have been established at Danish university hospitals. The Center for Eosinophilia is physically located in the Department of Hematology and collaborates with the six other hematology departments in Denmark, which are routinely involved in the management of patients following an initial referral at a regional level. The Department of Hematology may be appropriate to host the MDT due to the special differential diagnosis, including idiopathic and primary eosinophilia, and also including secondary cases of histiocytosis, malignant lymphoma, and leukemia, whereas the majority of secondary eosinophilia cases are optimally treated at other specialized departments ( Supplementary Tables 1, 2 ; Figures 2 – 4 ).

Figure 5 shows the principles of patient flow and functions in an eosinophilia MDT. It is important that GPs are also aware of the tertiary centers, e.g., through the dissemination of knowledge at regional meetings and in national medical journals (67, 178) (level 1) and that the specialized departments at the MDT hospital all serve as a filter for a second opinion in the MDT (level 2). Furthermore, GPs should be aware that there are no formal criteria for listing a case for an upcoming conference, which is planned regularly every 4–6 weeks. The MDT program can be planned 6 months in advance, each meeting lasting 60–75 min. The upcoming conference is announced via a mailing list to the colleagues in the MDT network and is sent out in advance with anonymized information on usually three to five patients. More detailed information can be retrieved in the secure areas of the hospital’s electronic filing system, which can be shared with all other hospitals in the region. The email information includes a video link for virtual participation in the MDT, which has been a positive outcome of the COVID pandemic (179). In this way, videoconferencing facilitates participation. The two centers for eosinophilia in Denmark organize conferences together four times a year to disseminate knowledge. This activity is made possible due to the use of virtual rooms. In principle, these conferences are open to all interested colleagues (nationwide) and participation is optional. The schedule for the MDT can include fixed days or be a rolling sequence to accommodate the numerous other activities on the ward, in the outpatient clinic, and at other conferences.

A major benefit of the organization of an MDT in eosinophilia is that it allows for direct contact with colleagues participating in the MDT during normal working hours. Colleagues can be contacted via an MDT telephone list and are more familiar with the task, and thus are more likely to be able to provide a qualified opinion directly than can be expected from both junior and senior doctors who are generally on-call. Naturally, cases can be discussed in a department within the MDT network, between on-call colleagues and colleagues participating in an MDT, if this is more feasible. It is our experience that an option for personal contact, through telephone lists for the MDT, is one of the aspects facilitating the process when, for various reasons (clinical circumstances, time, and presence) a discussion cannot await the next scheduled MDT to make decisions.

Figure 5 illustrates that most patients are referred from highly specialized departments at the MDT hospital or from collaborating hematology departments (67). The individual patient is presented by the physician most familiar with the case (most often the treating specialist). The case presentation may be in PowerPoint format, which can support the educational dimension of MDT conferences. Patients can be discussed in the MDT either during admission to the hospital or during follow-up in the outpatient clinic, reflecting the wide range of symptoms and severity in the target population ( Supplementary Tables 1, 2 ; Figures 2 – 4 ). The purpose of discussing an eosinophilia case in the MDT is to agree on a second opinion, including the need for additional diagnostic tests, e.g., due to persistent eosinophilia and symptoms despite relevant treatment for secondary eosinophilia, and also to establish diagnoses of iHE and iHES per exclusionem. The next step is a treatment decision, according to the working diagnosis, to be implemented at the appropriate specialized department, either in the outpatient clinic or during admission to the ward. The scheduled conferences, both in the individual center and in the two national centers, must always include a plan for informing the patient (usually by phone) and any department or function involved (either by verbal information or by referral in writing). All decisions should be recorded as a conference note, and the next MDT will provide the opportunity for follow-up ( Figure 5 ).