Multi-system complications of hypereosinophilia
Authors: Maximilian Stahl, Amir M. Mohareb, Alfred I. Lee, Daniel G. Federman, Alexa J. Siddon, Juliette Spelman
Journal: American Journal of Hematology (2015)

A 60 year-old male Veteran with medical history of COPD, hypertension, and a 45 pack-year smoking history presented to his primary care provider. Routine lab work incidentally showed a 31% eosinophilia, corresponding to a total eosinophil count of 2000/μL. The remainder of a complete blood count at initial and subsequent presentations are shown in Table 1. He had no diarrhea, sick contacts, or recent travel. He did not report any food, drug, or seasonal allergies, and his physical exam was unrevealing. He did not have any Agent Orange exposure and had no family history of hematologic malignancy. A limited workup for his eosinophilia included negative stool testing for ova and parasites and a negative Strongyloides antibody. Eosinophilia is defined as an absolute eosinophil count (AEC) in the peripheral blood of ≥500 eosinophils/µL. Marked eosinophilia refers to a more significant increase in eosinophil counts to ≥1500 eosinophils/µL. The differential diagnosis for marked eosinophilia is broad and includes primary (clonal), secondary (reactive), and idiopathic causes 1. This patient's military history, and associated travel to endemic regions, puts him at risk for helminthic infections such as Strongyloidiasis, Toxocariasis, Trichinellosis, and Hookworm. In the general population, other secondary causes include allergic disorders (such as asthma, allergic rhinitis, allergic broncho-pulmonary aspergillosis, eosinophilic esophagitis), drug reactions, adrenal insufficiency, and a variety of rheumatologic diseases [such as dermatomyositis and eosinophilic granulomatosis with polyangiitis (EGPA)]. Worldwide, the most common causes of eosinophilia are parasitic diseases, while in developed countries, allergic processes are most frequent 2. Primary causes for hypereosinophilia are rare and are due to myeloproliferative or lymphoproliferative disorders. They should be considered when secondary causes have been ruled out. When a patient presents with marked eosinophilia, one should focus on ruling out the most common secondary causes without completing an extensive workup. Initial tests include a complete blood cell count (CBC), blood smear, as well as an assessment of allergies and parasites (with antibodies to Strongyloides and Schistosomiasis as well as stool ova and parasites, if indicated). Screening tests should be done to exclude organ involvement, with attention to cardiac and pulmonary involvement: basic metabolic panel, urinalysis, liver function tests, cardiac biomarkers, and chest radiography. For eosinophilia persisting beyond one month, more extensive diagnostic studies including flow cytometry and consultation with a hematologist are indicated. Our patient remained asymptomatic and presented four months later when he was admitted to an outside hospital with severe left upper quadrant abdominal pain. The pain was accompanied by nausea and non-bloody, non-bilious emesis. CT imaging of the abdomen revealed multiple wedge-shaped splenic infarcts. A workup for splenic infarcts was initiated and included a negative thromboembolic workup, without evidence for atrial fibrillation on ECG or valvular vegetations on echocardiogram. Hypercoagulability testing showed negative lupus anticoagulant, anticardiolipin antibodies, and beta-2 glycoprotein. Antinuclear antibody (ANA) was positive (1:160) and anti-neutrophil cytoplasmic antibody (ANCA) testing was negative. Anticoagulation was initiated, and he was eventually transitioned to aspirin. Labs were significant for leukocytosis, polycythemia, thrombocytosis, and worsening eosinophilia (WBC 21.4 K/μL, Hb 17.0 g/dL, Platelets 470 K/cmm, Eosinophils 25% (5350/μL). Persistent eosinophilia combined with erythocytosis and thrombocytosis in the absence of secondary causes raises the suspicion for lymphoproliferative or myeloproliferative conditions. This patient merits further evaluation for clonal disorders in the bone marrow, including chronic myeloid leukemia, essential thrombocytosis, polycythemia vera, eosinophilic leukemia, and mastocytosis. Historically, many cases of eosinophilia with no identifiable secondary cause were grouped under the umbrella category of HES, which is in fact a diagnosis of exclusion. More recently, however, there have been significant advancements in uncovering specific genetic rearrangements that contribute to the pathogenesis of primary eosinophilia. As such, precise diagnoses can now be assigned in many cases that were previously defined as primary idiopathic HES. HES can be classified in several variants including myeloproliferative (M-HES), T lymphocytic variants (L-HES), and idiopathic variants 4. M-HES variants display features more typical of myeloproliferative disorders, including increased serum vitamin B12 levels, chromosomal abnormalities, erythrocytosis, thrombocytosis, hepatomegaly, splenomegaly, and circulating leukocyte precursors 5. The most frequently observed chromosomal aberration in HES results in the fusion of two genes, those for Fip1-like1 (FIP1L1) and platelet-derived growth factor receptor alpha (PDGFRA). The FIP1L1-PDGFRA fusion displays constitutively active tyrosine kinase activity which can be therapeutically targeted with imatinib 6. L-HES variants are characterized by skin and soft tissue involvement, although other clinical manifestations of HES can be seen. At least a subset of these patients seem to have abnormal IL-5 producing T cells promoting eosinophilia 7. Mepolizumab, a monoclonal antibody targeting IL-5, has been shown to be beneficial in randomized controlled trial of such cases 8. Two months later, he was seen in Hematology clinic complaining of worsening abdominal pain and lack of appetite. He had arthalgias of elbows, hips, and knees. The patient had pain and swelling in both hands associated with morning stiffness >1 hr. He was admitted to the hospital for an expedited workup. On exam, his vital signs were within normal limits. He had bilateral swelling at the wrist and metacarpophalangeal joints, tightness of the skin with difficulty making a fist, but no erythema or warmth. A diffuse, non-blanching, erythematous macular rash was noted on his chest, back, and shins, as shown in Fig. 1. He denied itchiness, pain, blistering and involvement of mucous membranes. Labs were remarkable for erythrocyte sedimentation rate (ESR) 51, negative rheumatoid factor, urinalysis without evidence of hematuria or proteinuria. Further studies were sent including FIP1L1-PDGFRA (for primary neoplastic HES), JAK-2 (V617F and exon 12 mutation), epo, bcr-abl (for myeloproliferative diseases including polycythemia vera and chronic myelogenous leukemia), and tryptase (for mastocytosis), which were within normal limits. (a) Skin findings over lower extremities. (b) Skin findings over lower extremities. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] CT imaging of the chest demonstrated interval development of diffuse, patchy consolidation and, to lesser extent, subpleural reticulation. Also noted were enlarged bilateral axillary lymphadenopathy, measuring up to 3 cm, as well as prominent inguinal lymph nodes. Pulmonary function testing showed mild obstructive physiology and moderately reduced diffusing capacity: Forced vital capacity (FVC) 3.48 L, 84% of predicted; Volume exhaled at the first second of forced expiration (FEV1) 2.36 L, 76% of predicted; FEV1/FVC 68%; diffusion capacity of the lung for carbon monoxide (DLCO) 66%. He Underwent a Skin Biopsy Demonstrating a Patchy Mixed Dermal Infiltrate with Eosinophils but No Evidence of Sweet's Syndrome or Cutaneous Lymphoma. Our patient had involvement of his spleen, skin, joints, and lungs. In addition to HES, other diagnoses of consideration include sarcoidosis and EGPA, but the negative ANCA testing makes the latter unlikely. Regardless of the cause, end-organ manifestations may be seen in hypereosinophilia. Although complications of eosinophilia are more common in patients with higher eosinophil counts (>1,500 eosinophils/μL), a patient with mild peripheral blood eosinophilia may have significant organ involvement 9. Splenic infarcts in the setting of marked eosinophilia are either due to an underlying infiltrative myeloproliferative disease (MPD) that causes congestion of the splenic circulation, or secondary thromboembolic events that produce obstruction of larger vessels. On hospital day 2, he developed sub-sternal chest pain that radiated to the left side while lying in bed. He did not report any associated symptoms of nausea, vomiting, palpitations, dyspnea, diaphoresis, or lightheadedness. EKG was obtained that demonstrated new ST elevations > 1mm in II, III and aVF (see Figure 2a) and initial troponin I was 0.5 ng/mL which subsequently trended up to to 1.0 within 8 hr [upper limit of normal 0.03 ng/mL]. He was treated for acute coronary syndrome, but by the time of evaluation by cardiology consultants, his chest pain had resolved and the ischemic changes on EKG had reversed (see Figure 2b). Echocardiography showed abnormal left ventricular systolic function, with an ejection fraction of 50%. There was severe hypokinesis of mid to distal inferior, inferoseptal and mid inferolateral and anteroseptal segments. The patient was scheduled for an urgent cardiac catheterization. (a) EKG with active chest pain (a) and when chest pain free (b). (b) EKG with active chest pain (a) and when chest pain free (b). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Left heart catheterization did not show obstructive coronary disease. The patient underwent cardiac MRI, demonstrating edema in the mid inferolateral wall and mid septum. On delayed contrast enhanced images, multiple focal areas of enhancement, along with areas of mild heterogeneity, were noted to involve the mid septum, mid inferolateral wall, apical lateral wall, and apical anterior wall. This pattern was considered highly suggestive for necrotizing myocarditis. Necrotizing myocarditis is a particularly dangerous complication of hypereosinophilia. Patients who raise concern for necrotizing myocarditis should be examined for splinter hemorrhages and should have cardiac biomarkers [including Troponin, CK-MB, and Brain natriuretic peptide (BNP)] tested. Damage in necrotizing myocarditis typically occurs in 3 stages 10: Stage I: The acute necrotic stage is characterized by eosinophilic infiltration of the myocardium associated with myocardial necrosis due to release of toxic cationic proteins (eosinophil peroxidase and cationic protein) from degranulating eosinophils. Typically, the damage in this stage is asymptomatic but may occasionally be severe enough to cause angina-like symptoms. Stage II: The acute myonecrosis is followed by formation of mural thrombi. The most obvious stimulus for thrombosis is ventricular wall vascular damage and disruption of the normally anticoagulant endothelial lining exposes von Willebrand factor (vWf), collagen, and tissue factor (TF). VWf and collagen bind platelets, and TF binds activated factor VII to start the coagulation cascade forming fibrin thrombi. There is a paucity of data on the embolic risk in eosinophilia-mediated cardiac disease. One study showed that approximately a quarter of HES patients develop thromboembolic complications, and roughly 5–10% die of them 11. Autopsies performed on reported cases revealed cardiac mural thrombi, splenic infarcts, and more rarely, pulmonary emboli, microthrombi in cerebral arteries and renal arteries. Stage III: Thrombus formed on denuded myocardium is replaced by fibrosis which is mediated by Granulocyte macrophage-colony stimulating factor (GM-CSF) and Transforming growth factor beta (TGF beta). Scarring of the chordae tendinae and endocardium leads to endomyocardial fibrosis resulting in restrictive or dilated cardiomyopathy as well as progressive valvular incompetence. Our patient had evidence of at least severe stage I damage (inferior STEMI with evidence of myocardial necrosis on MRI). In these cases, cardiac catheterization and initiation of anti-platelet therapy do not address the underlying cause of myocardial necrosis. The exact cause of eosinophilia continued to be unclear. However the multi-organ involvement as well as significant weight loss raised the suspicion for malignancy, either primary HES, MPD, or lymphoma. Bone marrow biopsy was obtained and showed pronounced eosinophilia comprising approximately 50% of the cells. There was no evidence of increased plasma or mast cell population or myelofibrosis. Molecular studies were negative for BCR-ABL1, JAK-2 (both exon 12 and exon 13), and PDGFRA. While results from Fluorescence in situ hybridization (FISH) and molecular testing were still pending, he was started on a combination of prednisone 30 mg/day, hydoxyurea 500 mg/day and imatinib 200 mg/day, to treat presumptive primary HES vs. MPD. Two weeks of imatinib therapy did not correct his eosinophilia or thrombocytosis, so it was ultimately discontinued after these tests returned to be negative. The patient continued to be symptomatic with arthralgias, weight loss, and malaise. He underwent an Fluodeoxyglucose Positron Emission Tomography (FDG-PET) scan showing metabolically active lymphadenopathy in the right and left axillary nodes, mediastinal nodes, superficial inguinal nodes, and femoral nodes (maximum Standardized Uptake Value of FDG avid nodes was 7.1). He underwent lymph node biopsy of left groin, which was diagnostic of Classical Hodgkin Lymphoma, lymphocyte-rich subtype (see Figure 3). With disease above and below the diaphragm, involving the spleen and initial weight loss, he was considered to have Stage III Hodgkin Lymphoma. Hydroxyurea was stopped, prednisone was tapered off, and the patient was started on Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. After three cycles of ABVD, interim restaging PET scan showed a near complete remission and CBC demonstrated resolution of eosinophilia. Lymph node biopsy shows lymphocyte rich Hodgkin Lymphoma with rare eosinophil mixed in background of Reed-Sternberg cells and small lymphocytes. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] In summary, we discussed a case of a patient with 18 months of eosinophilia eventually manifesting in splenic infarcts, joint and skin symptoms, as well as cardiopulmonary involvement. Testing for infectious, allergic and rheumatologic causes for secondary hypereosinophilia was negative. Bone marrow biopsy showed significant eosinophilia as well as leukocytosis, thrombocytosis, and erythocytosis, so a primary bone marrow disorder, either HES or MPD was initially considered. The patient was treated with imatinib, hydroxyurea, and prednisone pending molecular confirmation of disease-specific translocations. After there was no significant improvement in symptoms, and as molecular studies ultimately returned negative, a PET scan was pursued, which showed FDG-avid lymphadenopathy. Lymph node biopsy demonstrated lymphocyte-rich Classical Hodgkin Lymphoma. The patient's symptoms and eosinophilia improved after initiation of ABVD chemotherapy and repeat PET scan showed interval regression of lymphadenopathy. Eosinophilia in Hodgkin Lymphoma is not uncommon, with an incidence of 15% 12. Even though the presence of a prominent tissue eosinophilia represents a common histopathologic feature of Hodgkin Lymphoma, eosinophils have been mainly regarded as ‘innocent' bystanders recruited and activated during the cellular reaction typical of Hodgkin Lymphoma. Recent research, however, challenges this notion 13, 14. Eosinophils may act as important elements in the pathology of Hodgkin Lymphoma by providing cellular ligands to the Tumor Necrosis Factor (TNF) superfamily receptors (CD40, CD30, CD95/Fas) expressed on the surface of both Hodgkin and Reed Sternberg cells. These receptors, once activated, are able to transduce proliferation and anti-apoptotic signals in these cells promoting tumor growth. Furthermore, T cell produced cytokines like IL-5 and IL-3, found to be present in at least a subset of L-HES, are capable of enhancing the cellular density of several TNF superfamily ligands at the surface of cultured eosinophils. These findings argue for a complex deregulated network of interactive signals between Hodgkin/Reed-Sternberg cells, T cells, and eosinophils 13. Interestingly, absolute eosinophilia count does not seem to predict outcomes, but prognosis and response to treatment is dependent on the specific setting in which eosinophilia is observed. Clinical studies by the British National Lymphoma Investigation (BNLI) examined 1290 Hodgkin Lymphoma patients, including 15% with eosinophilia 15. Patients who presented with selective eosinophilia (that is, without generalized leukocytosis) had a clear survival benefit. Patients with eosinophilia and leukocytosis have only a minor survival advantage. Within the group of selected eosinophilia, the benefit was found to be limited to patients with mixed cellularity and nodular sclerosis histology. The German Hodgkin Lymphoma study group further demonstrated that eosinophilia is of prognostic relevance in nodular sclerosis-subtype Classical Hodgkin Lymphoma patients, whereas in patients with mixed cellularity-subtype Hodgkin Lymphoma, the effect on survival was weaker 16. These observational findings suggest that the prognostic relevance of eosinophils in Hodgkin Lymphoma depends on the specific histological subtype, however, they are not able to offer an explanation for this finding 14. The main teaching point of this case is to keep a broad differential diagnosis when faced with a patient with unexplained eosinophilia. It is vital to exclude secondary causes for eosinophilia first and when these are excluded, to consider myeloproliferative and lymphoproliferative diseases before making the diagnosis of idiopathic HES. There has been significant improvement in the mechanistic understanding of clonal eosinophilia and a precise diagnosis is often attainable. Therefore, progressively fewer cases remain truly idiopathic HES. Clinicians should be cautious of the multi-system complications associated with hypereosinophilia, including necrotizing myocarditis, as seen in this case.