Idiopathic hypereosinophilic syndrome (IHES) is a group of myeloproliferative disorders with unknown etiology that is characterized by eosinophilia in peripheral blood and inflammatory damage of multiple organs, including the heart, lungs, skin, nervous system, and gastrointestinal tract.[1,2] The clinical manifestations include myocardial injury, heart failure, respiratory failure, intracardiac embolism, arrhythmia, pericarditis, and gastrointestinal mucosal injury. We report a unique case of IHES with multiple organ damage (MOD), including myocardial damage similar to acute myocardial infarction (AMI), cardiac tamponade, respiratory failure, skin damage, and gastrointestinal damage.
2 Case report
A 52-year-old male was admitted with chest pain for 1 week that was aggravated by dyspnea for 3 days. His medical history and family history of cardiovascular disease were unremarkable. His initial body temperature was 36.6°C, respiratory rate was 24 breaths/min, pulse rate was 112 beats/min, blood pressure was 111/87 mm Hg, and oxygen saturation in room air was 90%. An electrocardiogram (ECG) showed sinus tachycardia; T wave inversion in II, III, AVF, and V1 to V6; elevation of ST segment in I and AVL; and a poor increase of R wave in the thoracic leads (Fig. 1A). The initial laboratory tests indicated an absolute eosinophil count of 12,920/mm3, high-sensitivity troponin (hsTn) level of 2037.7 pg/mL (normal: <14 pg/mL), brain natriuretic peptide level of 758 pg/mL (normal: <100 pg/mL), and D-dimer level of 57 μg/dL (normal: <55 μg/dL). Arterial blood analysis also indicated hypoxemic respiratory insufficiency (pH 7.43, pCO2: 26.7 mm Hg, pO2: 72.6 mm Hg).
We considered AMI and performed coronary angiography immediately. There was no significant stenosis in the right coronary artery (Fig. 2A), left main artery, anterior descending artery, or circumflex artery (Fig. 2B). However, X-ray fluoroscopy indicated a bright band at the bottom of the heart, possibly due to pericardial effusion (Fig. 2A). An urgent bedside transthoracic echocardiogram demonstrated left ventricular endomyocardial thickening, and a dark area in the pericardial cavity. Thickness measurements indicated the anterior pericardium was 1.0 cm, the posterior pericardium was 1.4 cm, the left pericardium was 1.7 cm, and the apex was 1.0 cm. There was no valvular dysfunction, but the left ventricular systolic function was obviously reduced, with an estimated ejection fraction of about 31%.
We performed emergency pericardiocentesis, and drained about 100 mL of yellow, cloudy fluid. Examination of the pericardial effusate showed that the Rivalta test was positive (indicating an exudate). A chest computed tomography (CT) exam showed bilateral pleural effusion, scattered patches, and exudate in both lungs (Fig. 3A). We performed bilateral thoracentesis, and drained an additional 600 mL of yellow, cloudy fluid. Laboratory examination of his hydrothorax showed that Rivalta test was positive, the nucleated cell count was 9260/mm3 with 65% eosinophils (Fig. 5A), total protein was 34.9 g/L, lactate dehydrogenase was 201 IU/L, and adenosine deaminase was 4.8 U/L.
On the third day, the patient developed a bright red purpura-like rash on both lower limbs (Fig. 4A), which rose above the skin, fused partially, and then spread to the whole body (Fig. 4B). A second ECG indicated sinus tachycardia; pathological Q-wave formation in I and AVL; T-wave inversion in II, III, AVF, and V1-V6; and a poor increase of R wave in the thoracic leads (Fig. 1B). The patient was negative for male tumor markers (AFP, CA72–4, NSE, CYFRA21-1, TPSA, FPSA, CEA, CA-199), antinuclear antibody, thyroid dysfunction, and TB infection. We thus excluded causes of reactive eosinophilia (fungal infections, parasitic infections, hypersensitivity reactions, and malignant diseases). Antineutrophilic cytoplasmic antibodies were also negative. We administered oxygen, an anti-inflammatory agent (Piperacillin and Sulbactam, 4.5 g, every 8 hours), a diuretic (Furosemide, 40 mg, once a day), an anti-allergy medication (Loratadine, 10 mg, once a day), a proton pump inhibitor for acid suppression (Omeprazole, 40 mg, once a day).
On the fifth day, the patient developed gastrointestinal bleeding. Thus, we administered an intravenous infusion of somatostatin and omeprazole by micropump, performed fluid infusion, and provided other treatments to alleviate symptoms. A bone marrow examination indicated marked myelodysplastic activity and significantly increased eosinophils (42.5%). Flow cytometry showed there was “no significant abnormal phenotypic cell population,” and a biopsy showed that “bone marrow hematopoietic cells are proliferating and active, mainly eosinophils” (Fig. 5B). Examination of the peripheral blood using polymerase chain reaction indicated no abnormal expression of PDGFRA, PDGFRB, FGFRI or PCMI-JAK2, and no JAK2V617F point mutation. These results led to a clear diagnosis of IHES. High-dose methylprednisone (1 mg/kg/d), which began on the first day of admission, was apparently ineffective by itself, so we added hydroxyurea (days 1–2: 0.5 g per day; days 3–12: 0.5 g twice per day).
After 2 weeks, his eosinophil count dropped to normal and the rash subsided. Painless gastroenteroscopy showed multiple duodenal ulcers (stage A1), chronic nonatrophic gastritis with erosion, bile reflux, the presence of Helicobacter pylori, mild chronic mucosal inflammation of the terminal ileum, and focal lymphoid tissue hyperplasia. Antibiotic treatment (bismuth potassium citrate tablets 0.6 g, tinidazole tablets 0.5 g, clarithromycin tablets 0.25 g, twice a day) for H pylori was given. On day 20, we discharged the patient with a gradual tapering of corticosteroids.
A blood panel was reviewed once a week after discharge, and once a month after 2 months. The patient's eosinophil level remained within the normal range during follow-up. Two months later, a chest CT examination showed that the lung exudate was completely absorbed (Fig. 3B). A painless gastroscopy indicated chronic nonatrophic gastritis.
Hypereosinophilic syndrome (HES) was redefined in 2010 as more than 1500/mm3 eosinophils without a discernible secondary cause (eg, HIV infection, parasite or worm infection, allergic diseases, drug allergies, and nonhematologic malignancies). The eosinophil count in this patient was consistently higher than 1500/mm3, with a maximum of 12,920/mm3. To exclude secondary eosinophilia, we performed pretransfusion examinations with testing for tumor markers, antinuclear antibody, parasitic infections, allergic reactions, and abnormal expression of genes typical of other diseases associated with eosinophilia. We found eosinophilic infiltration in the pleural effusate and performed a bone marrow examination. The characteristics of our case coincide with the current diagnostic criteria for HES.
HES leads to organ dysfunction due to eosinophil infiltration and to various clinical manifestations which differ among individual patients. About 60% of patients with HES suffer from heart damage. Our patient had chest pain, an abnormal ECG, and elevated hsTn, suggestive of AMI, but the coronary angiography results were normal. Previous studies reported similar changes in ECG and hsTn in patients ultimately diagnosed with HES.[6–8] A small number of patients with HES are positive for PDGFRA or PDGFRB, and the transcribed proteins were sensitive to imatinib treatment, which may promote partial recovery of left ventricular function.
Although there are a variety of clinical manifestations in patients with IHES after cardiac injury, it is rare that pericardial tamponade occurs at disease onset.[10,11] Our patient was admitted with clinical manifestations of pericardial tamponade, including sinus tachycardia and a decreased pulse pressure difference (111/87 mm Hg). Pericardial puncture led to significant alleviation of the symptoms. The typical echocardiographic results in patients with IHES include decreased systolic and diastolic function, thickening of the myocardial intima, and thrombosis. Our patient had endocardial thickening and significant left ventricular dysfunction, but no intracardiac thrombosis.
Acute eosinophilic pneumonia is characterized by diffuse pulmonary parenchymal lesions. An X-ray examination can reveal pulmonary patches and exudation; excessive exudation can lead to pleural effusion, to gas exchange abnormalities, and eventually to severe respiratory failure.[12,13] Our patient had respiratory failure upon admission, with clinical manifestations of shortness of breath, dyspnea, and hypoxemia. Bilateral pleural effusion was evident in his chest CT results, and many lung patches had evidence of local exudation.
Wells et al first described eosinophilic cellulitis (Wells syndrome) in 1971. More recently, Caputo et al proposed classification of seven types of eosinophilic cellulitis: fixed drug eruption-like, plaque-type, bullous, annular granuloma-like, papulovesicular, papulonodular, and urticaria-like. Our patient began to develop loose red or dark red purpura-like rashes on both lower limbs, which rose above the skin, partially fused, and then spread to the whole body.
IHES is a rare disease characterized by damage to the entire gastrointestinal tract, including eosinophilic gastritis, gastroenteritis, and colitis. The mechanism is presumably related to the presence of dense mucosal eosinophilia. Our patient underwent painless gastroenteroscopy, and we detected erosive gastritis, multiple duodenal ulcers, and colitis.
The aim of IHES therapy is to reduce the eosinophilic granulocyte count in tissues, and glucocorticoids are often recommended. However, some patients with IHES do not respond to glucocorticoids, and cytotoxic drugs can be used as an alternative. Interferon and monoclonal immunomodulatory therapy may be considered in refractory cases. If an IHES patient has congestive heart failure, conventional therapy for heart failure should be administered. If IHES is accompanied by thrombosis, including thrombus in the heart or pulmonary artery thrombosis, anticoagulant therapy is necessary.
Our patient is still in follow-up. After nearly 5 months, his physical condition is basically normal. He continues to receive therapy for reversal of ventricular remodeling, including valsartan (80 mg/d), metoprolol tartrate (100 mg/d), and spironolactone (20 mg/d), as well as prednisone (10 mg/d).
We thank our parents and family for their support and encouragement, our teachers for their concern and guidance, and our patient for his trust and support.
Conceptualization: Peng Wu.
Data curation: Peng Wu.
Formal analysis: Peng Wu.
Funding acquisition: Peng Wu.
Investigation: Peng Wu, Yuanguo Chen.
Methodology: Peng Wu.
Project administration: Peng Wu.
Resources: Peng Wu.
Software: Peng Wu.
Supervision: Peng Wu, Haibo Zhang.
Validation: Peng Wu.
Visualization: Peng Wu.
Writing – original draft: Peng Wu.
Writing – review and editing: Peng Wu, Chen Li.
. Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975;54:1–27.
. Klion A. Hypereosinophilic syndrome: current approach to diagnosis and treatment. Annu Rev Med 2009;60:293–306.
. Akuthota P, Weller PF. Spectrum of eosinophilic end-organ manifestations. Immunol Allergy Clin North Am 2015;35:403–11.
. Simon HU, Rothenberg ME, Bochner BS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol 2010;126:45–9.
. Ogbogu PU, Rosing DR, Horne MK. Cardiovascular manifestations of hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007;27:457–75.
. Galiuto L, Enriquez-Sarano M, Reeder GS, et al. Eosinophilic myocarditis manifesting as myocardial infarction: early diagnosis and successful treatment. Mayo Clin Proc 1997;72:603–10.
. Enriquez A, Castro P, Gabrielli L, et al. Acute necrotizing eosinophilic myocarditis presenting as ST-elevation myocardial infarction: a case report. Can J Cardiol 2011;27:870e1–e3.
. Cooper LT, Zehr KJ. Biventricular assist device placement and immunosuppression as therapy for necrotizing eosinophilic myocarditis. Nat Clin Pract Cardiovasc Med 2005;2:544–8.
. Klion AD, Robyn J, Akin C, et al. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood 2004;103:473–8.
. Fernandez AB, Ahmed S, Duncan B, et al. Cardiac tamponade: a rare complication of idiopathic hypereosinophilic syndrome
. J Cardiovasc Med (Hagerstown) 2009;10:188–91.
. Kazama R, Okura Y, Hoyano M, et al. Therapeutic role of pericardiocentesis for acute necrotizing eosinophilic myocarditis with cardiac tamponade. Mayo Clin Proc 2003;78:901–7.
. Janz DR, O’Neal HR Jr, Ely EW. Acute eosinophilic pneumonia: a case report and review of the literature. Crit Care Med 2009;37:1470–4.
. Kalomenidis I, Light RW. Eosinophilic pleural effusions. Curr Opin Pulm Med 2003;9:254–60.
. Wells GC. Recurrent granulomatous dermatitis with eosinophilia
. Trans St Johns Hosp Dermatol Soc 1971;57:46–56.
. Caputo R, Marzano AV, Vezzoli P, et al. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol 2006;142:1157–61.
. Mehta P, Furuta GT. Eosinophils in gastrointestinal disorders: eosinophilic gastrointestinal diseases, celiac disease, inflammatory bowel diseases, and parasitic infections. Immunol Allergy Clin North Am 2015;35:413–37.