The multidisciplinary approach to eosinophilia

Abstract

Eosinophilic granulocytes are normally present in low numbers in the bloodstream. Patients with an increased number of eosinophilic granulocytes in the differential count (eosinophilia) are common and can pose a clinical challenge because conditions with eosinophilia occur in all medical specialties. The diagnostic approach must be guided by a thorough medical history, supported by specific tests to guide individualized treatment. Neoplastic (primary) eosinophilia is identified by one of several unique acquired genetic causes. In contrast, reactive (secondary) eosinophilia is associated with a cytokine stimulus in a specific disease, while idiopathic eosinophilia is a diagnosis by exclusion. Rational treatment is disease-directed in secondary cases and has paved the way for targeted treatment against the driver in primary eosinophilia, whereas idiopathic cases are treated as needed by principles in eosinophilia originating from clonal drivers. The vast majority of patients are diagnosed with secondary eosinophilia and are managed by the relevant specialty-e.g., rheumatology, allergy, dermatology, gastroenterology, pulmonary medicine, hematology, or infectious disease. The overlap in symptoms and the risk of irreversible organ involvement in eosinophilia, irrespective of the cause, warrants that patients without a diagnostic clarification or who do not respond to adequate treatment should be referred to a multidisciplinary function anchored in a hematology department for evaluation. This review presents the pathophysiology, manifestations, differential diagnosis, diagnostic workup, and management of (adult) patients with eosinophilia. The purpose is to place eosinophilia in a clinical context, and therefore justify and inspire the establishment of a multidisciplinary team of experts from diagnostic and clinical specialties at the regional level to support the second opinion. The target patient population requires highly specialized laboratory analysis and therapy and occasionally has severe eosinophil-induced organ dysfunction. An added value of a centralized, clinical function is to serve as a platform for education and research to further improve the management of patients with eosinophilia. Primary and idiopathic eosinophilia are key topics in the review, which also address current research and discusses outstanding issues in the field.

Keywords: clinical; diagnosis; eosinophilia; multidisciplinary; review; treatment; trial.

Figure 1

Eosinophil granulocytes in peripheral blood smear. Giemsa stain, 400×. Upper panel illustrates one eosinophil, neutrophil granulocytes (/), and aggregates of platelets (>). Lower panel shows eosinophil granulocytes, a mononuclear cell (/ lymphocyte), a polynuclear granulocyte (/ neutrophil), and thrombocytes (not marked).

Figure 2

Pathophysiological algorithm and examples of diagnostic entities in patients with (moderate) eosinophilia. The diagram is not exhaustive. ABPA, allergic bronchopulmonary aspergillosis; BCR-ABL, breakpoint cluster region—abelson1; CBF, core binding factor; CML, chronic myeloid leukemia (t9;22) positive; DRESS, drug reaction eosinophilia systemic symptoms; EGPA, eosinophil granulomatous polyangiitis; ETV6, ETS variant transcription factor 6; FGFR1, fibroblast growth factor receptor 1; FLT3, Fms-related tyrosine kinase 3; HES, hypereosinophilic syndrome; ICI, immune checkpoint inhibitor; Ig, immunoglobulin; iHE, idiopathic hypereosinophilia; iHES, idiopathic hypereosinophilic syndrome; inv, inversion; JAK2, Janus kinase 2; MC, mixed cellularity; MDS, myelodysplastic neoplasm; MPN, myeloproliferative neoplasm; NS, nodular sclerosis; PDGFRA/B, platelet-derived growth factor A or B; t, translocation.

Figure 3

Diagnostic workup in patients with (moderate) eosinophilia. ALAT/ASAT, alanine aminotransferase/aspartate aminotransferase; ALP, alkaline phosphatase; ANA, antinuclear antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; BAL, bronchoalveolar lavage; BUN, blood urea nitrogen; CK-MB, creatine kinase—myocardial band; CRP, C-reactive protein; CSF, cerebrospinal fluid; ECG, electrocardiogram; EEG, electroencephalogram; ESR, erythrocyte sedimentation rate; FISH, fluorescence in situ hybridization; GI, gastrointestinal tract; Ig, immunoglobulin; INR, international normalized ratio; K+, potassium; LDH, lactate dehydrogenase; M-protein, monoclonal protein; Na+, sodium; PET, positron emission tomography; pro-BNP, pro-b-type natriuretic peptide; UT, urinary tract. ⋆ See information provided in Supplementary Table 2 . ⋆⋆ Skin, lung, lymph node, nasal polyp, liver, mucosa (GI, UT), muscle, myocardial, kidney, and brain. ⋆⋆⋆ For microscopy, culture, and other diagnostic tests (e.g., Mantoux in the skin). Proposals for blood samples and other tests to be adapted to pre-planned procedures at the department (e.g., routine laboratory packages). Proposals are not prioritized but must be selected and customized to the individual patient.

Figure 4

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions (MLN-TK). One disease with a specific rearrangement occurring in the MLN-TK is described briefly. ABL1, abelson1; ALL, acute lymphocytic leukemia/lymphoblastic lymphoma; AML, acute myeloid leukemia; BM, bone marrow; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; MPN, myeloproliferative neoplasm; CS, corticosteroid; del, deletion; EMD, extramedullary disease; ETV6, ETS variant transcription factor 6; FGFR1, fibroblast growth factor receptor 1; FIP1L1, Factor interacting with PAPOLA and CPSF1; FISH, fluorescence in situ hybridization; FLT3, fms-related receptor tyrosine kinase 3; HSCT hematopoietic stem cell transplantation; incl, including; JAK2, Janus kinase 2; LDH, lactate dehydrogenase; M, male; MDS, myelodysplastic neoplasm; MPAL, mixed-phenotype acute leukemia; PCM1, Pericentriolar material 1; PDGFRA/B, platelet-derived growth factor A or B; RT-PCR, reverse transcription polymerase chain reaction; t, translocation; TKI, tyrosine kinase inhibitor, here: imatinib, dasatinib, and ponatinib; WBC, white blood cell count; ZMYM2, Zinc Finger MYM-Type Containing 2; *eosinophilia, mild–severe, almost always present.

Figure 5

Multidisciplinary team flowchart in eosinophilia. MDT multidisciplinary team.