All systems red
Authors: Paras Karmacharya, Anthony A Donato, Madan Raj Aryal, Ranjan Pathak, Michael Goonewardene, Peter Valent
Journal: American Journal of Hematology (2014)

A 69-year-old female presented to the emergency department with a 1-week history of low-grade fever, progressive dyspnea on exertion, fatigue, and confusion. She denied headache, nausea, vomiting, weakness, numbness or tingling in her extremities, orthopnea, chest pain, or swelling of her legs. Although previously very active, she had become homebound over the same duration and was not able to perform her daily activities. Her medications included mometasone-formoterol inhaler and zafirlukast for chronic obstructive lung disease and ibuprofen as needed for joint pain for the past 2 years, none of which was newly prescribed. She had a history of allergy to nonspecific environmental allergens. She denied any history of rash or recent travel. Confusion is a common symptom in the elderly and can have multiple etiologies, including polypharmacy, infections, hypovolemia due to medications or poor oral intake, electrolyte imbalances, cardiovascular problems, allergies, and central nervous system lesions. However, the presence of low-grade fever, dyspnea on exertion, and fatigue suggest the presence of a systemic disease with multisystem involvement. Given the relatively acute onset of her symptoms, an infectious or inflammatory etiology seems likely. Common multisystem infections that can affect cardiac and neurologic systems should be considered, including subacute bacterial endocarditis which can cause peripheral embolization to the central nervous system. Bacterial pneumonias can explain her dyspnea as well as her confusion due to delirium, however, her subacute illness time course and absence of an underlying dementing illness make this scenario less likely. Alternatively, noninfectious etiologies such as acute pulmonary embolism, diabetes mellitus, or exacerbation of her reactive airways should be considered. However, confusion is atypical with these conditions unless accompanied by shock or in the presence of a systemic thrombotic condition. Systemic malignancy and vasculitis with central nervous system and pulmonary involvement would also be a consideration here, although unlikely with her acute presentation. Her past medical history was significant for two episodes of transient word-finding difficulties and left facial droop 1 year prior with normal magnetic resonance imaging (MRI) findings. Her family history was negative for any cardiopulmonary or immunological disorders. Vital signs, including orthostatic blood pressures, were normal. On examination, she appeared confused, sluggish, and slow to respond to questions, but demonstrated no focal neurological deficits. She did not have any rashes or palpable lymph nodes. She had bilateral expiratory rales. The cardiovascular examination was normal including absence of jugular venous distension or pedal edema. Her previous history of transient ischemic attacks and sudden onset makes a cerebrovascular event a possibility. However, the presence of constitutional and cardiopulmonary symptoms, as well as the lack of focal deficits in the distribution of a single vascular territory should lead us to broaden our differential diagnoses. Her exam is not consistent with congestive heart failure. Patient's electrocardiogram showed nonspecific ST and T wave changes. Troponin level was 15 ng/ml (<0.06 ng/ml) with a brain natriuretic peptide (BNP) of 1,045 pg/ml (0–100 pg/ml). Transthoracic echocardiogram showed preserved systolic function with ejection fraction of 65% and no evidence of valvular dysfunction or intramural thrombus. Prothrombin time was 13.2 sec (10.2–11.7 sec), with an international normalized ratio of 1.2 (0.9–1.1), partial thromboplastin time (PTT) was 31 sec (25–33 sec), D-dimer was 1,893 ng/ml (65–500 ng/ml), and lactate dehydrogenase was 251 IU/l (94–202 IU/l). She had a serum creatinine (Cr) of 2.49 mg/dl (baseline Cr-1.14 mg/dl, 2 months prior), with urinalysis showing many eosinophils and elevated protein (30 mg/dl). Computed tomography (CT) scan of the head revealed no acute abnormalities. A contrast-enhanced MRI of brain was not performed due to her renal insufficiency. The patient does not have any signs and symptoms consistent with heart disease. Her cardiac enzyme and BNP levels are alarming, but her nonspecific electrocardiographic abnormalities and absence of wall-motion abnormalities on echocardiogram argue against acute coronary syndrome (ACS). Troponin is highly specific marker for myocardial injury; however, it is nonspecific for ACS. Alternative causes such as myocarditis, pericarditis, sepsis, pulmonary embolism, cardiomyopathy, and systemic thrombotic disorders such as antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia (HIT) need to be considered here. However, the absence of previous vascular events or pregnancy losses, and a normal range PTT argue against APS. Similarly, patient had not received any heparin products, making HIT unlikely. Systemic vasculitides involving the central nervous system, kidney, and heart such as Behcet's disease and systemic lupus erythematosus should also be included in the differential. The absence of oral/genital lesions, photosensitivity and arthritis, and the presence of urine eosinophils argue against both. Finally, hypereosinophilic syndrome (HES) may present with thromboembolism and multisystem involvement. A complete blood count would be an important next step. The white cell count was 25,700/mm3 (Eosinophils: 59%, absolute eosinophilic count: 15,000/mm3), hemoglobin 11.2 g/dl, platelet count 107,000/mm3. Peripheral blood smear showed increased eosinophils with no blast forms. Erythrocyte sedimentation rate and C-reactive protein were raised at 67 mm/hr (0–20 mm/hr) and 12.4 mg/dl (0–0.7 mg/dl), respectively. Chest radiograph revealed no infiltrates. A V/Q scan of the lungs was indeterminate, and a Doppler ultrasound of bilateral lower extremities was negative. The patient has leukocytosis with marked peripheral eosinophilia which may present as “smudge cells” in the peripheral smear. Eosinophilia suggests a broad differential diagnosis. Causes of eosinophilia include secondary causes including parasitic infections, allergic diseases, drug reactions, neoplastic conditions, autoimmune diseases, vasculitic conditions, and adrenal insufficiency. Apart from these secondary causes, clonal and idiopathic variants exist as well. Among clonal conditions, chronic eosinophilic leukemia, systemic mastocytosis (SM), and other myeloproliferative neoplasms have to be considered. Marked eosinophilia and evidence of multisystem involvement (including neurologic, cardiac, and pulmonary systems) should point toward the possibility of HES. Here, it is important to evaluate the whole clinical picture to arrive at the final diagnosis of HES and to determine its underlying cause. In fact, HES can occur with several different underlying diseases and can cause hypereosinophilia (HE)-induced diffuse tissue injury, including encephalopathy and renal involvement. An MRI of the heart could further delineate the eosinophil-mediated heart damage and is becoming the gold standard. Similarly, MRI of the brain with diffusion-weighted images is helpful to detect neurological complications of HES. The differentiation of a secondary (reactive) from a primary (neoplastic) or idiopathic HES is important, as secondary disorders require specific interventions directed at the underlying cause in addition to the eosinophilia itself. Likewise, it is especially important to rule out infectious etiologies before starting corticosteroids, as their use can worsen conditions in which an infection is the driving factor behind the eosinophils present. Among the reactive causes of eosinophilia, allergic reactions remain the most-common cause in developed countries, comprising approximately 80% of cases. Our patient did have a history of allergies, but an allergic reaction causing such high levels of eosinophilia involving multiple systems has not been reported. She was not on any medications that could lead to be associated with eosinophilia. Parasitic infections are the second most-common cause of eosinophilia in developed nations. A thorough travel history is important because many parasites are endemic in tropical and subtropical regions. The causative organism is generally a helminth, such as Strongyloides stercoralis, Toxocara canis, Schistosomia haematobium, and less commonly Isospora belli and Coccidioidomycosis. Although there is typically a close temporal relationship between some parasitic infections and symptoms, protozoa such as Strongyloides can cause asymptomatic eosinophilia for decades, and may not present clinically until after chronic steroids or transplant immunosuppression is prescribed, at which time the patient may die due to hyper-infestation. Our patient denied any recent travel history and was not on immunosuppressants. Laboratory tests to identify ova or larvae/parasites in stools, urine, body fluids along with appropriate serology to exclude parasitic infections are important. Fecal samples must be “fresh,” that is, the patient should deliver the samples (optimally on three occasions) and it should be sent without delay for the specified examinations, to get a representative and reliable result from the microbiologist. An extensive work-up was done to rule out secondary causes of eosinophilia. Antibodies to Strongyloides, Schistosomiasis, and Toxocara canis were all negative. Stool examination for ova and parasites was negative. Pulmonary diseases with concomitant eosinophilia are an important consideration here, as the patient's presenting symptoms included dyspnea on exertion with expiratory rales on examination. Among these, eosinophilic granulomatosis with polyangiitis (EGPA) is associated with severe eosinophilia. Clinical features of EGPA include adult onset asthma, paranasal sinusitis, mononeuropathy multiplex, pulmonary infiltrates, vasculitis, and HE. In addition, one of the patient's chronic medications, zafirlukast, a leukotriene receptor inhibitor, has been described to have an association with EGPA. Although the sensitivity of antineutrophil cytoplasmic antibodies (ANCA) is around 40–60%, its presence may be diagnostically useful. Bronchoalveolar lavage, showing a high percentage of eosinophils and biopsy of skin or peripheral nerves revealing eosinophilic granulomatous inflammation and evidence of vasculitis can be helpful. Surgical lung biopsy is a gold standard, although not commonly done. Another cause of pulmonary eosinophilia that needs to be considered is allergic bronchopulmonary aspergillosis (ABPA). Patients typically have a history of asthma or cystic fibrosis with bronchiectatic changes on chest radiograph. Characteristic laboratory findings include elevated serum immunoglobulin (Ig) E and Aspergillus-specific immunoglobulins. Patient's methacholine challenge test done 6 months prior was negative. Aspergillus-specific antibodies were negative. CT scan of the chest was normal. Antinuclear antibodies and ANCA were negative. Her serum IgE level was markedly elevated (1,167 IU/ml, normal: 1-165 IU/ml), and all other Ig levels were within normal range. Serum tryptase level was 4.8 ng/ml (normal <11.5 ng/ml). Bone marrow (BM) aspiration and biopsy revealed hypercellular marrow with predominant eosinophil precursors without dysplasia, normal maturation of the myeloid (M), and erythroid (E) series, no excess of blasts, an M/E ratio of 5:1 and marked HE (39%) (Fig. 1A, B). Flow cytometry of the BM delineated prominent eosinophilic population (Fig. 2A, B) with no significant blasts (Fig. 2C, D). T-cells accounted for only 3–4% of events in the specimen and demonstrated appropriate surface expression of CD3. The CD4:CD8 ratio was appropriate at 2:1, and no significant loss or gain of expression of T-cell antigens CD2, CD5, and CD7 were detected. In addition, T-cell receptor gene rearrangement studies performed on peripheral blood did not demonstrate the presence of a clonal T-cell population. Cytogenetic test results revealed a normal 46, XX karyotype. Additionally, fluorescence in situ hybridization study was negative for the t (9;22) translocation, as well as the FIP1L1-PDGFRA and BCR/ABL mutations. Molecular studies failed to identify a JAK2 V617F and KIT D816V mutation. A and B. BM biopsy (40× and 100×) demonstrating a myeloid predominance with a preponderance of eosinophils and eosinophilic precursors with no increase in blast population. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Panel A and B. Flow cytometric analysis demonstrating a prominent population of eosinophilic elements. Panel A. Scattergrams of CD13 and CD16 expression demonstrating absent expression of CD16 with expression of CD13 (purple population). Panel B. Scattergrams of right angle light scatter (SS Lin) plotted against expression of CD45 showing increased right angle light scatter characteristics. Panel C and D. Flow cytometric analysis demonstrating no significant blast population. Panel C. A scattergram of right angle light scatter (SS Lin) plotted against expression of CD45 showing no significant blast population as indicated by low density CD45 expression and low right angle light scatter. Panel D. Scattergram showing blasts (dark blue population) accounting for less than 2% of events as indicated by expression of CD34 and absent expression of CD11b. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The patient's negative methacholine challenge test, absence of Aspergillus-specific antibodies, normal chest radiograph, and negative ANCA along with absence of clinical evidence of vasculitis would argue against both ABPA and EGPA. Also, our patient did not have any clinical signs or symptoms suggestive of SM such as flushing, pruritus, gastrointestinal symptoms, lymphadenopathy, or splenomegaly. Her BM did not reveal significant mast cell population and molecular studies were negative for KIT D816V mutation. In addition, no signs for a clonal T-cell population (including T-cell gene rearrangement by polymerase chain reaction) were found excluding T-cell neoplasm as well as the lymphoid variant of HES (HES-L). Although there are elevated levels of IgE, hyper IgE syndrome is unlikely with her age, absence of recurrent skin and pulmonary infections, eczematous dermatitis, coarse facies, or retained primary teeth. Finally, paraneoplastic eosinophilia from occult solid organ tumors should also be considered after ruling out all other possible causes described. Positron emission tomography–computed tomography scan may be considered to identify location of solid tumors or lymphoproliferative disorders accessible for biopsy. Treatment with oral prednisone should be started without delay to prevent further eosinophil-mediated tissue infiltration/injury after ruling out secondary infectious causes. A subset of patients with FIPILI-PDGFRA mutation is typically responsive to imatinib mesylate, which was negative in our case. The patient was treated with oral prednisone (1 mg/kg/day) which led to a dramatic decrease in white cell counts and serum eosinophil levels, with marked resolution of symptoms over the next 24 hr (Fig. 3). Graph showing normalization of eosinophil count post steroid treatment. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] After ruling out all the possible causes of HE, our patient was diagnosed as idiopathic HES, as she had peripheral eosinophilia, tissue HE, signs and symptoms of end-organ involvement with the exclusion of other secondary and neoplastic causes of eosinophilia, and absence of phenotypically abnormal and/or clonal T lymphocytes. Glucocorticoids are the treatment of choice for HES and treatment could be of prolonged duration. Prophylaxis against osteoporosis should be added during glucocorticoid treatment following individual evaluation. Her prednisone was slowly tapered from 60 to 20 mg over the course of 2 months, followed by a slower taper to 5 mg over the third month. At 3-month follow up, she reported substantial improvement of her symptoms with no residual respiratory or neurological symptoms. At that time, her complete blood count revealed a peripheral white blood cell level of 17,500/mm3 (Neutrophils-78%, Lymphocytes-13.2%, Monocytes-4.6%, Basophils-0.6%, and Eosinophils-2.5% with an absolute eosinophil count of 440/mm3), as well as a platelet count of 281/mm3. Her renal function is back to near baseline (Cr-1.41 mg/dl) with no eosinophils detected in her urine. This patient's multisystem presentation required consideration of a broad differential as well as ruling out infectious etiologies prior to therapy. Special attention to the organ systems involved, striking peripheral eosinophilia, BM biopsy findings, and ruling out other possible causes led the clinicians to a diagnosis of acquired HES, which would not be a part of routine differential diagnosis. HE has been defined as marked and persistent eosinophilia with peripheral blood eosinophil levels greater than 1,500 cells/mm3 on at least two occasions at interval of ≥1 month, except when the patient requires immediate therapy for HE related end-organ damage. Similarly, tissue HE means either a BM sample showing greater than 20% eosinophils of all nucleated cells, or a tissue sample showing extensive infiltration of tissue by eosinophils. Commonly observed morphologic abnormalities in eosinophils include hypogranularity, abnormal distribution of cytoplasmic granules, cytoplasmic vacuolization, and abnormal nuclear lobations, however, it is important to note that these abnormalities are not specific to neoplastic disorders and can be seen in reactive conditions. The term HES should apply when a patient has peripheral HE and evidence of organ involvement attributable to the tissue HE. Idiopathic HES can then be diagnosed when underlying diseases triggering HE have been excluded 1-4. Our patient fulfilled these criteria as she had peripheral and tissue HE (40% eosinophils in BM) and was suffering from end-organ damage (brain, lung, and kidney) probably secondary to HE, but no underlying neoplastic or non-neoplastic condition could be diagnosed. The rapid improvement of symptoms and laboratory parameters after administration of glucocorticosteroids favors tissue HE and consecutive HE-related end-organ damage, and thus HES. HES can present with diffuse encephalopathy manifesting as confusion, deterioration of cognitive function, memory loss, and seizures 5. Although the exact mechanism is unclear, it is believed that eosinophils can induce neurological damage by direct infiltration or release of basic proteins, neurotoxins, and eosinophil cationic proteins 6. A radiological and pathology-confirmed diagnosis would be required to elucidate the exact pathogenesis of cerebral lesions in HES. Although our patient presented with nonspecific ST changes and elevated cardiac enzymes, her echocardiography was normal, with an absence of atrial flutter/fibrillation, endocarditis, and thrombi. Cardiac involvement has been reported in more than 50% cases of HES 2, 3. Pulmonary involvement may be seen in up to 40% of the cases, the most commonly reported symptom being chronic cough. It may present similar to asthma with signs and symptoms of bronchial reactivity such as dyspnea, wheezing, nocturnal cough, and productive sputum 7, 8. Marginated eosinophils are thought to interfere with gas exchange and promote mucus secretion. Other reported pulmonary complications include pulmonary embolism, pleural effusion, and ground-glass pulmonary infiltrates 9. Renal involvement in idiopathic HES is rare. The exact pathogenesis of renal involvement is unclear and various histopathological changes including thickened glomerular basement membrane, interstitial nephritis with eosinophilic infiltrates, intrarenal thrombotic microangiopathy with ischemic changes to proliferative and crescentic glomerulopathy have been described 10, 11. The major goal of therapy for symptomatic HES is to reduce the blood and tissue eosinophil burden and hence the damage mediated by them 2. Oral prednisone is usually started at 1 mg/kg per day and continued for 1–2 weeks before tapering it in the following 2–3 months. Hydroxyurea or interferon alfa is used as a corticosteroid-sparing agent if symptoms recur with a prednisone dosage level of greater than 10 mg/d or if there is poor tolerance of tapering doses. In patients with the FIP1L1-PDGFRA mutation, imatinib is extremely effective in lowering eosinophil levels and inducing cytogenetic remission. Imatinib may also be useful in some FIP1L1-PDGFRA negative patients who do not respond to classical cytotoxic (e.g., cladribine) and noncytotoxic (e.g., cyclosporine) drugs. Newer monoclonal antibodies that can be used including mepolizumab (targeting anti-interleukin-5) can be tried in patients with refractory HES 2, 3, 12. Mepolizumab has been shown to be well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES patients such as ours 12. Although omalizumab (anti IgE antibody) is approved for the treatment of asthma, its use in other eosinophilic disorders is still investigational 13. Allogeneic hematopoietic cell transplantation is a final option for drug-refractory HES or clonal eosinophilia 2, 3. The differential of eosinophilia is broad. Although newer molecular tools for diagnosis have been available over the years, a graded approach to diagnosis is suggested. Management of idiopathic HES should not be delayed as it has a poor prognosis when left untreated. It is a chronic condition requiring life-long follow up and monitoring. The authors thank Florence Roufosse, MD, Erasme Hospital, Department of Internal Medicine Universite Libre de Bruxelles, Belgium for assistance with the case discussion for this manuscript. The authors also thank Sharon Swierczynski, MD, PhD, Department of Pathology, Reading Health System, PA for assistance with the interpretation of the pathology slides and flow cytometry. Authors PK and MRA conceived, designed, participated in abstraction, analysis, interpretation, and drafting of the initial manuscript. Authors AD, MG, RP, and PV analyzed, interpreted and provided intellectual content, edited subsequent draft and approved final manuscript. FR (mentioned in acknowledgment section) was involved in providing intellectual content and revision to the manuscript. PK is responsible as overall guarantor of the content.