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1.  Hypereosinophilic syndromes 
Hypereosinophilic syndromes (HES) constitute a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia (> 1.5 × 109/L for more than six consecutive months) associated with evidence of eosinophil-induced organ damage, where other causes of hypereosinophilia such as allergic, parasitic, and malignant disorders have been excluded. Prevalence is unknown. HES occur most frequently in young to middle-aged patients, but may concern any age group. Male predominance (4–9:1 ratio) has been reported in historic series but this is likely to reflect the quasi-exclusive male distribution of a sporadic hematopoietic stem cell mutation found in a recently characterized disease variant. Target-organ damage mediated by eosinophils is highly variable among patients, with involvement of skin, heart, lungs, and central and peripheral nervous systems in more than 50% of cases. Other frequently observed complications include hepato- and/or splenomegaly, eosinophilic gastroenteritis, and coagulation disorders. Recent advances in underlying pathogenesis have established that hypereosinophilia may be due either to primitive involvement of myeloid cells, essentially due to occurrence of an interstitial chromosomal deletion on 4q12 leading to creation of the FIP1L1-PDGFRA fusion gene (F/P+ variant), or to increased interleukin (IL)-5 production by a clonally expanded T cell population (lymphocytic variant), most frequently characterized by a CD3-CD4+ phenotype. Diagnosis of HES relies on observation of persistent and marked hypereosinophilia responsible for target-organ damage, and exclusion of underlying causes of hypereosinophilia, including allergic and parasitic disorders, solid and hematological malignancies, Churg-Strauss disease, and HTLV infection. Once these criteria are fulfilled, further testing for eventual pathogenic classification is warranted using appropriate cytogenetic and functional approaches. Therapeutic management should be adjusted to disease severity and eventual detection of pathogenic variants. For F/P+ patients, imatinib has undisputedly become first line therapy. For others, corticosteroids are generally administered initially, followed by agents such as hydroxycarbamide, interferon-alpha, and imatinib, for corticosteroid-resistant cases, as well as for corticosteroid-sparing purposes. Recent data suggest that mepolizumab, an anti-IL-5 antibody, is an effective corticosteroid-sparing agent for F/P-negative patients. Prognosis has improved significantly since definition of HES, and currently depends on development of irreversible heart failure, as well as eventual malignant transformation of myeloid or lymphoid cells.
doi:10.1186/1750-1172-2-37
PMCID: PMC2045078  PMID: 17848188
2.  Diagnosis of Exclusion: A Case Report of Probable Glatiramer Acetate-Induced Eosinophilic Myocarditis 
Importance. Medication-induced eosinophilia is an acknowledged, often self-limiting occurrence. Glatiramer acetate, a biologic injection used in the management of relapsing-remitting multiple sclerosis, is widely regarded as a safe and effective medication and lists eosinophilia as an infrequent side effect in its package insert. Contrary to reports of transient, benign drug-induced eosinophilia, we describe a case of probable glatiramer acetate-induced eosinophilia that ultimately culminated in respiratory distress, shock, and eosinophilic myocarditis. Observations. A 59-year-old female was admitted to the hospital after routine outpatient labs revealed leukocytosis (43,000 cells/mm3) with pronounced hypereosinophilia (63%). This patient had been using glatiramer acetate without complication for over 10 years prior to admission. Leukocytosis and hypereosinophilia persisted as a myriad of diagnostic evaluations returned negative, ultimately leading to respiratory depression, shock, and myocarditis. Glatiramer acetate was held for the first time on day 6 of the hospital stay with subsequent resolution of leukocytosis, hypereosinophilia, respiratory distress, and shock. Conclusions and Relevance. Glatiramer acetate was probably the cause of this observed hypereosinophilia and the resulting complications. Reports of glatiramer-induced eosinophilia are rare, and few case reports regarding medication-induced hypereosinophilia describe the severe systemic manifestations seen in this patient.
doi:10.1155/2014/786342
PMCID: PMC4106067  PMID: 25105037
3.  Chromophobe renal cell carcinoma associated with eosinophilia: A report of three cases 
Eosinophilia is typically associated with allergic reactions, parasitic infestations, certain forms of vasculitis, the use of certain medications and hematologic malignancies. In addition to eosinophilia associated with gastrointestinal tumors, lung cancer and thyroid carcinoma in solid malignancies, there are a limited number of cases describing peripheral hypereosinophilia in urologic tumors. The present study reports three cases of eosinophilia in patients with chromophobe renal cell carcinoma (CRCC) and investigates the association between excessive eosinophilia and the recurrence and prognosis of renal carcinoma. This is the first report of CRCC associated with excessive eosinophilia. Eosinophilia following tumor resectioning may indicate a poor prognosis, tumor recurrence and rapid disease progression.
doi:10.3892/etm.2014.1725
PMCID: PMC4061223  PMID: 24944603
chromophobe renal cell carcinoma; eosinophilia; recurrence
4.  Clonal Hypereosinophilia with ETV6 Rearrangement Evolving to T-Cell Lymphoblastic Lymphoma: A Case Report and Review of the Literature 
Case Reports in Hematology  2013;2013:652745.
Hypereosinophilia, either clonal or reactive, has been described in association with multiple hematological malignancies. We describe a case of a patient presenting with hypereosinophilia that evolved into T-cell lymphoblastic lymphoma. Complete remission was achieved with chemotherapy; however, hypereosinophilia recurred 5 months later in association with myeloblastic bone marrow infiltration and without evidence of lymphoblastic lymphoma relapse. Cytogenetic analysis of the bone marrow showed a complex translocation involving chromosomes 7, 12, and 16. A rearrangement of ETV6 gene (12p13) was demonstrated by FISH studies, thus confirming the clonality of this population. The association of lymphoblastic lymphoma, eosinophilia, and myeloid hyperplasia has been described in disorders with FGFR1 rearrangements. We hypothesize that other clonal eosinophilic disorders lacking this rearrangement could behave in a similar fashion through different pathogenic mechanisms.
doi:10.1155/2013/652745
PMCID: PMC3654631  PMID: 23710385
5.  Production of a Low Molecular Weight Eosinophil Polymorphonuclear Leukocyte Chemotactic Factor by Anaplastic Squamous Cell Carcinomas of Human Lung 
Journal of Clinical Investigation  1978;61(3):770-780.
A peptide of approximately 300-400 daltons exhibiting in vitro chemotactic activity for human polymorphonuclear (PMN) leukocytes, with a preference for the eosinophil series, was isolated from extracts of anaplastic lung carcinomas of the large squamous cell type obtained from three patients with marked peripheral blood hypereosinophilia and eosinophilic infiltration of the tumors and surrounding normal pulmonary tissues. This chemotactic factor was termed ECF-LSC (eosinophil chemotactic factor of lung squamous cell carcinoma). ECF-LSC appeared in the urine of two of the patients in increasing quantities late in the course of their disease and was also elaborated by long-term cultures of dispersed tumor cells from the same two patients. Three anaplastic large cell bronchogenic carcinomas which were not associated with tumor tissue or peripheral blood eosinophilia, a bronchogenic adenocarcinoma from a patient with only peripheral eosinophilia, and a renal cell carcinoma metastatic to the lungs and associated with transient pleural tissue and fluid eosinophilia were all devoid of ECF-LSC. ECF-LSC from tumor tissue extracts, urine, and tumor cell culture medium was comparable to the mast cell-associated tetrapeptides of the eosinophil chemotactic factor of anaphylaxis (ECF-A) in size, but eluted from Dowex-1 at pH 5.0-3.5 in contrast to the more acidic ECF-A tetrapeptides which eluted at pH 3.2-2.2 ECF-LSC, like the tetrapeptides of ECF-A, had a secondary chemotactic activity for neutrophil PMN leukocytes, but not mononuclear leukocytes, and deactivated both eosinophil and neutrophil PMN leukocytes so that they would not respond to a subsequent in vitro chemotactic stimulus. Eosinophils from the two patients with urinary excretion of ECF-LSC and the highest concentrations in tumor extracts were hyporesponsive in vitro to homologous and heterologous chemotactic stimuli, suggesting that ECF-LSC had deactivated the eosinophils in vivo.
PMCID: PMC372592  PMID: 641154
6.  Hypereosinophilia Presenting as Eosinophilic Vasculitis and Multiple Peripheral Artery Occlusions without Organ Involvement 
Journal of Korean Medical Science  2005;20(4):677-679.
We report here a case with hypereosinophilia and peripheral artery occlusion. A 32-yr-old Korean woman presented to us with lower extremity swelling and pain. Angiography revealed that multiple lower extremity arteries were occlusive. The biopsy specimen showed perivascular and periadnexal dense eosinophilic infiltration in dermis and subcutaneous adipose tissue. Laboratory investigations revealed a persistent hypereosinophilia. She was prescribed prednisolone 60 mg daily. Her skin lesion and pain were improved and the eosinophil count was dramatically decreased. After discharge, eosinophil count gradually increased again. Cyanosis and pain of her fingers recurred. She had been treated with cyclophosphamide pulse therapy. Her eosinophilia was decreased, but the cyanosis and tingling sense were progressive. The extremity arterial stenoses were slightly progressed. Skin biopsy showed perivascular eosinophilic infiltration in the dermis and CD40 ligand (CD40L) positive eosinophilic infiltration. The serum TNF-α was markedly increased. These results suggest that CD40L (a member of TNF-α superfamily) could play a role in the inflammatory processes when eosinophil infiltration and activation are observed. We prescribed prednisolone, cyclophosphamide, clopidogrel, cilostazol, beraprost and nifedipine, and she was discharged.
doi:10.3346/jkms.2005.20.4.677
PMCID: PMC2782169  PMID: 16100465
Hypereosinophilic Syndrome; Vasculitis; Tumor Necrosis Factor-alpha; CD40 Ligand
7.  Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes 
Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.
doi:10.1016/j.jaci.2012.02.019
PMCID: PMC4091810  PMID: 22460074
Hypereosinophilic syndrome; eosinophilic leukemia; criteria; classification; hypereosinophilia of undetermined significance
8.  Clonal Hypereosinophilic Syndrome: Two Cases Report in Black Men from Sub-Saharan Africa and Literature Reviews 
ISRN Hematology  2011;2011:974609.
The first case is about a man of 60 years old suffering of hypereosinophilic syndrome (HES) developed since 1998. He presented chronic cough, insomnia, and negative parasitical test. We observed hypereosinophilia and fibroblastic hyperplasia at the bone marrow biopsy. Initially, hydroxyurea and α-interferon treatment failed. We proposed to him imatinib mesylate in May 2003. The FIP1L1-PDGFRA gene was detected. The second case is about a man of 34 years old seen in March 2002. First investigation concluded to CML. Progressively, eosinophil cells increased, and complications occurred as oedema syndrome, dyspnoea, and parietal chronic endocarditic fibrosis associated with pericarditis. In addition, a bowel obstruction happened and was cured by surgery. Bcr-abl fusion was negative, and FIP1L1-PDGFRA gene was detected after and imatinib mesylate was given. Actually, endocarditic fibrosis decreased. The two patients are in haematological and cytogenetic remission. We concluded that clonal HES is present in Africa, and imatinib mesylate is effective.
doi:10.5402/2011/974609
PMCID: PMC3226243  PMID: 22135755
9.  Chronic diarrhea, eosinophilic ascites, acute pancreatitis and deep venous thrombosis: A case report 
Background: Eosinophilic gastroenteritis (EG) is rare and is characterized by recurrent eosinophilic infiltration of the gastrointestinal tract and chronic diarrhea. In this report we present a case of EG with acute pancreatitis and deep vein thrombosis (DVT).
Case presentation: A 30 years old male was admitted to our hospital with the complaints of epigastric pain, vomitting and swelling of his left limb for the past six days. He was also having diarrhea for the last several months. He had been evaluated for chronic diarrhea and ascites before he sought the current consultation. Duplex color doppler of left limb showed DVT of distal calf vein. Contrast enhanced CT imaging of abdomen revealed thickening of duodenum, proximal jejunal wall and presence of ascites. Duodenal biopsy showed normal villous pattern with mild inflammation and eosinophilic infiltration. The constellation of clinical presentation, hypereosinophilia, CT and biopsy findings all is in consistence to EG. The patient was treated with prednisolone 20 mg/day for four weeks and tapered slowly. Acute pancreatitis was managed conservatively while DVT was treated with heparin and oral anticoagulants. The patient’s diarrhea settled and ascites resolved completely. At follow up, the absolute eosinophil count was 300/μl and the patient was doing well.
Conclusion: This case report emphasizes that one should consider these rare disorders during the differential diagnosis of unexplained gastrointestinal symptoms in the presence of hypereosinophilia.
PMCID: PMC4143743  PMID: 25202449
Eosinophilic gastroenteritis; Acute pancreatitis; Deep vein thrombosis
10.  A Hypereosinophilic Syndrome Presenting as Eosinophilic Colitis 
Clinical Endoscopy  2012;45(4):444-447.
Hypereosinophilic syndrome (HES) has three defining features: marked hypereosinophilia for at least 6 months, no confirmed etiology for the eosinophilia, and eosinophilia-related symptoms or organ dysfunction. However, a shorter period of hypereosinophilia with symptoms requiring eosinophil-lowering therapy is also acceptable. We report a case of HES presenting as eosinophilic colitis. Although hypereosinophilia was present for 3 months, this patient needed to be treated with eosionphil-lowering therapy for severe hematochezia. After systemic corticosteroid therapy, symptoms caused by organ involvement were dramatically improved.
doi:10.5946/ce.2012.45.4.444
PMCID: PMC3521952  PMID: 23251898
Hypereosinophilic syndrome; Colon; Steroids
11.  Autoimmune chorea in adults 
Neurology  2013;80(12):1133-1144.
Objectives:
To determine the characteristics of adult-onset autoimmune chorea, and compare paraneoplastic and idiopathic subgroups.
Methods:
Thirty-six adults with autoimmune chorea were identified at Mayo Clinic (Rochester, MN) from 1997 to 2012. Medical record and laboratory data were recorded. Nonparaneoplastic (n = 22) and paraneoplastic cases (n = 14) were compared.
Results:
Women accounted for 21 patients (58%). Median age at symptom onset was 67 years (range 18–87 years). We estimated the incidence for Olmsted County was 1.5 per million person-years. Symptom onset was subacute in all. Chorea was focal (20 patients) or generalized (16 patients). Although chorea predominated, other neurologic disorders frequently coexisted (29 patients); abnormal eye movements were uncommon (4 patients). No patient had NMDA receptor antibody or any immunoglobulin (Ig)G yielding a detectable immunofluorescence binding pattern restricted to basal ganglia. Two had synaptic IgG antibodies novel to the context of chorea (GAD65, 1; CASPR2, 1). In the paraneoplastic group, 14 patients had evidence of cancer. Of 13 with a histopathologically confirmed neoplasm, small-cell carcinoma and adenocarcinoma were most common; 6 patients had a cancer-predictive paraneoplastic autoantibody, with CRMP-5–IgG and ANNA-1 being most common. In the idiopathic group, 19 of the 22 patients had a coexisting autoimmune disorder (most frequently systemic lupus erythematosus and antiphospholipid syndrome); autoantibodies were detected in 21 patients, most frequently lupus and phospholipid specificities (19 patients). The paraneoplastic group was older (p = 0.001), more frequently male (p = 0.006), had more frequent weight loss (p = 0.02), and frequently had peripheral neuropathy (p = 0.008).
Conclusions:
Autoimmune chorea is a rare disorder with rapid onset. Male sex, older age, severe chorea, coexisting peripheral neuropathy, and weight loss increase the likelihood of cancer.
doi:10.1212/WNL.0b013e3182886991
PMCID: PMC3662307  PMID: 23427325
12.  A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report 
Introduction
Hypereosinophilic syndrome is defined as a prolonged state (more than six months) of eosinophilia (greater than 1500 cells/μL), without an apparent etiology and with end-organ damage. Hypereosinophilic syndrome can cause coagulation abnormalities. Among hypereosinophilic syndrome types, the lymphocytic variant (lymphocytic hypereosinophilic syndrome) is derived from a monoclonal proliferation of T lymphocytes. Here, we describe the case of a patient with lymphocytic hypereosinophilic syndrome who presented with a coagulation abnormality. To the best of our knowledge, this is the first such report including a detailed clinical picture and temporal cytokine profile.
Case presentation
A 77-year-old Japanese man presented to our facility with massive hematuria and hypereosinophilia (greater than 2600 cells/μl). His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL). Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor α, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality.
Conclusions
To the best of our knowledge, this is the first case in which lymphocytic hypereosinophilic syndrome and IgG4-related disease have overlapped. In addition, our patient is only the second case of hypereosinophilic disease that manifested with acquired hemophilia. Our patient relapsed with the coagulation abnormality alone, without eosinophilia. This report shows that the link between eosinophilia, IgG4, and clinical manifestations is not simple and provides useful insight into the immunopathology of hypereosinophilic syndrome and IgG4-related disease.
doi:10.1186/1752-1947-6-63
PMCID: PMC3292962  PMID: 22333532
13.  Anti-Yo and anti-glutamic acid decarboxylase antibodies presenting in carcinoma of the uterus with paraneoplastic cerebellar degeneration: a case report 
Introduction
Paraneoplastic cerebellar degeneration is a rare non-metastatic manifestation of malignancy. In this report, to the best of our knowledge we describe for the first time a diagnosis of paraneoplastic cerebellar degeneration several months prior to the diagnosis of clear carcinoma of the uterus.
Case presentation
A 75-year-old Caucasian woman manifested a rapidly progressive cerebellar syndrome with nystagmus, past-pointing, dysdiadochokinesis, dysarthria, truncal ataxia and titubation. The paraneoplastic cerebellar degeneration was associated with anti-Yo and anti-glutamic acid decarboxylase antibodies. 14-3-3 protein was detected in the cerebrospinal fluid. She was treated with intravenous immunoglobulin prior to laparotomy, hysterectomy and bilateral salpingoophorectomy. Our patient has survived for three years following diagnosis and treatment.
Conclusions
To the best of our knowledge this is the first report of an association of clear cell carcinoma of the uterus and paraneoplastic cerebellar degeneration with both anti-Yo and anti-glutamic acid decarboxylase antibodies. The findings imply that both antibodies contributed to the fulminating paraneoplastic cerebellar degeneration observed in our patient, and this was of such severity it resulted in the release of 14-3-3 protein in the cerebrospinal fluid, a marker of neuronal death.
doi:10.1186/1752-1947-6-155
PMCID: PMC3407694  PMID: 22691265
14-3-3 proteins; anti-Yo/anti-GAD antibodies; clear cell carcinoma of uterus; paraneoplastic cerebellar degeneration
14.  Eosinophil-induced chronic hepatitis. 
Journal of Korean Medical Science  1998;13(2):219-222.
Chronic hepatitis associated with hypereosinophilia has been very rarely reported worldwide. A 7-month-old male infant presented with a high fever, cough, non-projectile vomiting and hepatomegaly. The eosinophil count of the peripheral blood increased up to 21,500/mm3 (49% of WBC). The infant had a history of frequent contact with a neighbor keeping a pigsty. The pathologic examinations of the liver showed severe porto-periportal necroinflammation with marked eosinophilic infiltration, giant cell transformation and ballooning degeneration of hepatocytes, and degranulation of the eosinophils. Bone marrow showed increased eosinophils and decreased myeloid series. Pericardial effusion and bilateral pulmonary consolidation were noted. Corticosteroid aggravated the clinical symptoms of the infant. Anthelmintic treatment significantly normalized the eosinophil count and liver function tests, but cardiopulmonary manifestations continued.
PMCID: PMC3054484  PMID: 9610627
15.  Eosinophilic cystitis in a patient with hypereosinophila syndrome: A case report 
Hypereosinophilic syndrome (HES) is a rare disorder that is characterized by hypereosinophilia and organ damage, caused by the infiltration of eosinophils. In rare cases, the urinary bladder may also be involved. The current case report presented a 56-year-old male with gross hematuria and hypereosinophilia. The diagnosis of eosinophilic cystitis associated HES was established. Oral prednisone with a slow tapering regimen was administered as the primary treatment for the patient, which achieved partial hematological remission and complete relief of cystitis during a six-month follow-up period. Although eosinophilic cystitis is not commonly the primary manifestation of HES, eosinophilic cystitis should be taken into consideration following the onset of urinary symptoms in patients with HES.
doi:10.3892/etm.2014.1706
PMCID: PMC4061232  PMID: 24944595
hypereosinophilic syndrome; eosinophilic cystitis
16.  A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and α-enolase 
BMC Ophthalmology  2014;14:5.
Background
Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein (CRMP)-5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies.
Case presentation
A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient’s optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient’s serum detected autoantibodies against recoverin, CRMP-5, and α-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma.
Conclusions
The development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements.
doi:10.1186/1471-2415-14-5
PMCID: PMC3898010  PMID: 24428923
Neuroretinitis; Recoverin; Cancer-associated retinopathy; Collapsin response mediator protein-5; Outer retinitis
17.  A pseudoleukemic blood differentiation in a 13-year-old child: an extraordinary presentation of Churg-Strauss syndrome 
Clinical Rheumatology  2009;32(Suppl 1):7-9.
Churg-Strauss syndrome (CSS) is a rare systemic vasculitis of the small- and medium-size vessels. It is mostly seen in elderly patients presenting as de novo asthma, eosinophilia, and vasculitic organ involvement. In childhood, CSS is extremely rare. The course of pediatric CSS is usually severe and often lethal. We present a case of a 13-year-old girl with a short history of asthma, marked eosinophilia, and multiorgan involvement. The extremely high level of blood eosinophilic granulocytes (51.6 × 109/L) prompted a workup for eosinophilic leukemia before the diagnosis CSS could be made. Subsequently, the disease was successfully treated. This case report shows a classical case of childhood CSS, remarkable because of the presence of extreme hypereosinophilia. It underlines the importance of CSS as a life-threatening cause of hypereosinophilia in children.
doi:10.1007/s10067-009-1265-1
PMCID: PMC3594815  PMID: 19756836
Childhood; Churg-Strauss syndrome; CSS; Hypereosinophilia
18.  Churg-Strauss syndrome with critical endomyocardial fibrosis: 10 year survival after combined surgical and medical management 
Heart  2002;87(5):e5.
A case is presented of the Churg-Strauss syndrome with hypereosinophilia and severe cardiac involvement, namely biventricular endomyocardial fibrosis and gross encroachment of the right ventricular cavity. The clinical picture was similar to Loeffler's syndrome and the idiopathic hypereosinophilic syndrome. Combined aggressive surgical and medical management led to full recovery and survival at 10 years. The good long term outcome is attributed to strict control of peripheral eosinophil count by oral corticosteroids. This case illustrates the damaging effects of hypereosinophilia on the heart.
PMCID: PMC1767086  PMID: 11997435
Churg-Strauss syndrome; cardiac involvement; hypereosinophilia
19.  Renal cell carcinoma with bilateral synchronous adrenal gland metastases: a case report 
Cases Journal  2009;2:7298.
Introduction
Renal cell carcinoma is characterized by its potential of metastasizing widely and to unusual sites, with the metastases occasionally preceding clinical recognition of the primary tumor. Synchronous bilateral adrenal metastases from renal cell carcinoma, without other metastases, are rare and, to our knowledge, only 17 cases have been published in the literature to date. In general, patients with synchronous bilateral adrenal metastases from renal cell carcinoma have a poor prognosis.
Case presentation
We report a case of right-sided renal cell carcinoma with simultaneous bilateral adrenal metastases in a 58-year-old woman. The primary tumor was localized in the upper and mid pole of the kidney. The diagnosis was established preoperatively by abdominal ultrasound and computed tomography. Surgical treatment consisted of a right radical nephrectomy and bilateral adrenalectomy. Postoperative cortisone acetate replacement was instituted. The pathological findings of the right renal tumor showed clear cell carcinoma and both adrenal tumors showed the same pathology as the right renal tumor. There was no evidence of recurrence after 6 months of follow-up.
Conclusion
Patients with bilateral synchronous adrenal metastases should be considered to have disseminated metastatic disease. However, good performance status, the presence of paraneoplastic syndrome and the alleviation of refractory pain are important reasons make an urologist to consider radical nephrectomy in renal cell carcinoma patient with metastases.
doi:10.4076/1757-1626-2-7298
PMCID: PMC2769348  PMID: 19918518
20.  Platelet-derived growth factors and their receptors in normal and malignant hematopoiesis 
Platelet-derived growth factors (PDGF) bind to two closely related receptor tyrosine kinases, PDGF receptor α and β, which are encoded by the PDGFRA and PDGFRB genes. Aberrant activation of PDGF receptors occurs in myeloid malignancies associated with hypereosinophilia, due to chromosomal alterations that produce fusion genes, such as ETV6-PDGFRB or FIP1L1-PDGFRA. Most patients are males and respond to low dose imatinib, which is particularly effective against PDGF receptor kinase activity. Recently, activating point mutations in PDGFRA were also described in hypereosinophilia. In addition, autocrine loops have been identified in large granular lymphocyte leukemia and HTLV-transformed lymphocytes, suggesting new possible indications for tyrosine kinase inhibitor therapy. Although PDGF was initially purified from platelets more than 30 years ago, its physiological role in the hematopoietic system remains unclear. Hematopoietic defects in PDGF-deficient mice have been reported but appear to be secondary to cardiovascular and placental abnormalities. Nevertheless, PDGF acts directly on several hematopoietic cell types in vitro, such as megakaryocytes, platelets, activated macrophages and, possibly, certain lymphocyte subsets and eosinophils. The relevance of these observations for normal human hematopoiesis remains to be established.
PMCID: PMC3301440  PMID: 22432087
Receptor tyrosine kinase; hypereosinophilia; signal transduction; imatinib; myeloproliferative disorders; myeloid neoplasms; chronic eosinophilic leukemia; hypereosinophilic syndrome
21.  Practical approach to the patient with hypereosinophilia 
Markedly increased blood eosinophilia, ≥1.5 × 109/L, whether discovered fortuitously or found with signs and symptoms of associated organ involvement, commands diagnostic evaluation and often therapeutic interventions. This degree of hypereosinophilia is often, but not uniformly, associated with eosinophilic infiltration of tissues that can potentially lead to irreversible, life-threatening organ damage. Initial approaches focus on ascertaining that eosinophilia is not secondary to other underlying disease processes, including helminth parasite infections, varied types of adverse reactions to medications, and other eosinophil-associated syndromes, such as eosinophilic gastroenteritides, eosinophilic pneumonias and Churg-Strauss syndrome vasculitis. If evaluations exclude eosinophilia attributable to secondary etiologies or other eosinophil-related syndromes or organ-specific diseases, attention must be directed to considerations of varied other forms of the hypereosinophilic syndromes, that include myeloproliferative variants, lymphocytic variants and many of still unknown etiologies. Cognizant of the capacities of eosinophils to mediate tissue damage, the varied etiologies for hypereosinophilia are considered and a contemporary step-wise practical approach to the diagnosis and treatment of patients with hypereosinophilia is presented.
doi:10.1016/j.jaci.2010.04.011
PMCID: PMC2902584  PMID: 20538328
eosinophils; hypereosinophilic syndromes; FIP1L1-PDGFRA
22.  A Case of Uterine Cervical Cancer Presenting with Granulocytosis 
Granulocytosis occurs in 40% of patients with lung and gastrointestinal cancers, 20% of patients with breast cancer, 30% of patients with brain tumor and ovarian cancer and 10% of patients with renal cell carcinoma. Granulocytosis occurs because of production of G-CSF, GM-CSF and IL-6. Uterine cervical carcinoma with granulocytosis as a paraneoplastic syndrome, however, has been rarely reported. We recently witnessed a case of invasive squamous cell carcinoma of the uterine cervix with granulocytosis. Leukocytosis developed up to 69,000/µL, and then normalized after chemo-radiotherapy. There was no evidence of infection, tumor necrosis, glucocorticoid administration, or myeloproliferative disease by examination of a bone marrow aspirate when granulocytosis appeared. This phenomenon was probably associated with the secretion of hematopoietic growth factors such as G-CSF, GM-CSF and IL-6 by the tumor. We suggest that, like some other solid tumors, cervical cancer can present with granulocytosis as a paraneoplastic syndrome.
doi:10.3904/kjim.2005.20.3.247
PMCID: PMC3891161  PMID: 16295785
Leukocytosis; Paraneoplastic syndrome; Cervical cancer
23.  Control of hypereosinophilic syndrome-associated recalcitrant coronary artery spasm by combined treatment with prednisone, imatinib mesylate and hydroxyurea 
Uncontrolled hypereosinophilic syndrome is frequently associated with cardiovascular consequences that cause significant morbidity and mortality. The present article reports on a patient with hypereosinophilic syndrome in whom recurrent, recalcitrant coronary artery spasm and associated cardiac arrest were the predominant cardiac manifestations. No valvular abnormalities, evidence of mural thrombi or other cardiac findings commonly associated with hypereosinophilic syndrome were detected, and cardiac function remained normal. The serum tryptase level was normal, cysteine-rich hydrophobic domain 2 (CHIC2) deletion analysis of bone marrow cells was negative and no evidence of mastocytosis or other hematological disorder was found in the bone marrow. To allow for the reduction of prednisone, interferon-alpha-2b was added to the patient’s program, but caused aggravation of chest pain and was discontinued. However, a combination of reduced prednisone dosage, imatinib mesylate and hydroxyurea successfully controlled the eosinophilia, and thereafter, episodes of coronary artery spasm did not recur. The clinical features of the present case suggest that, in some patients, hypereosinophilia may manifest as resistant coronary artery spasm and that aggressive control of eosinophilia is necessary.
PMCID: PMC2274835  PMID: 18651015
Coronary artery spasm; Hydroxyurea; Idiopathic hypereosinophilic syndrome; Imatinib mesylate
24.  Chronic eosinophilic pneumonia with persistent decreased diffusing capacity for carbon monoxide 
BMJ Case Reports  2013;2013:bcr2012008238.
We report a 15-year-old girl presenting with dry cough, exertional dyspnoea, weight loss, fever and night sweats for over 1 month. Blood tests revealed hypereosinophilia, high IgE and antinuclear antibodies levels. Chest x-rays showed bilateral peripheral infiltrates mostly in the right upper lobe which was confirmed by a chest CT. Bronchoalveolar lavage showed hypercellularity with 28% of eosinophils. Idiopathic chronic eosinophilic pneumonia was confirmed after exclusion of other causes of eosinophilic pneumonia and systemic disease. The patient responded dramatically to oral corticosteroids. Oral corticotherapy was stopped after 4 months. At 8 months of follow-up, diffusing capacity for carbon monoxide (DLCO) remained moderately low (58%) with persistent mild exertional dyspnoea. Cardiopulmonary exercise testing showed muscular peripheral limitation. Even if in our patient, mild exertional dyspnoea can be partly correlated to peripheral deconditioning, DLCO should be systematically evaluated to determine follow-up studies standards, to correlate with subclinical disease, relapse risk and to codify therapeutic options.
doi:10.1136/bcr-2012-008238
PMCID: PMC3604399  PMID: 23417937
25.  Bromide-dependent toxicity of eosinophil peroxidase for endothelium and isolated working rat hearts: a model for eosinophilic endocarditis 
Eosinophilic endocarditis is a potentially lethal complication of chronic peripheral blood hypereosinophilia. We hypothesized that eosinophil peroxidase (EPO), an abundant eosinophil (EO) cationic granule protein, promotes eosinophilic endocarditis by binding to negatively charged endocardium, and there generating cytotoxic oxidants. Using an immunocytochemical technique, we demonstrated endocardial deposition of EPO in the heart of a patient with hypereosinophilic heart disease. Because EPO preferentially oxidizes Br- to hypobromous acid (HOBr) rather than Cl- to hypochlorous acid (HOCl) at physiologic halide concentrations, we characterized the Br(-)- dependent toxicity of both activated EOs and purified human EPO towards several types of endothelial cells and isolated working rat hearts. In RPMI supplemented with 100 microM Br-, phorbol myristate acetate- activated EOs, but not polymorphonuclear leukocytes, caused 1.8-3.6 times as much 51Cr release from four types of endothelial cell monolayers as in RPMI alone. H2O2 and purified human EPO, especially when bound to cell surfaces, mediated extraordinarily potent, completely Br(-)-dependent cytolysis of endothelial cells that was reversed by peroxidase inhibitors, HOBr scavengers, and competitive substrates. We further modeled eosinophilic endocarditis by instilling EPO into the left ventricles of isolated rat hearts, flushing unbound EPO, then perfusing them with a buffer containing 100 microM Br- and 1 microM H2O2. Acute congestive heart failure (evidenced by a precipitous decrement in rate pressure product, stroke volume work, aortic output, and MVO2 to 0-33% of control values) ensued over 20 min, which deletion of EPO, Br-, or H2O2 completely abrogated. These findings raise the possibility that EPO bound to endocardial cells might utilize H2O2 generated either by overlying phagocytes or endogenous cardiac metabolism along with the virtually inexhaustible supply of Br- from flowing blood to fuel HOBr-mediated cell damage. By this mechanism, EPO may play an important role in the pathogenesis of eosinophilic endocarditis.
PMCID: PMC2118758  PMID: 1985118

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