Hypereosinophilic syndrome
http://www.100md.com
《美国医学杂志》
Departments of Pediatrics, Pediatric Gastroenterology and Pediatric Nephrology, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India
Abstract
Hypereosinophilic syndrome is a leukoproliferative disease characterised by sustained overproduction of eosinophils. The three diagnostic criteria for this disorder are (1) Eosinophilia of greater than 1500 cells/ml, persisting for longer than 6 months, (2) lack of another diagnosis to explain the eosinophilia and (3) signs and symptoms of organ involvement. We report a 15-year-old boy who was diagnosed as Hypereosinophilic syndrome based on these criteria.
Keywords: Eosinophilia; End organ damage
Hypereosinophilic syndrome, (HES) first described by Hardy and Anderson in 1968, is characterized by sustained overproduction of eosinophils. It is a rare disorder in children. The term Idiopathic Hypereosinophilic syndrome as defined by Chusid et al characterized by 3 criteria- eosinophil count greater than 1500 cells/mL persisting longer than 6 months and single or multiple organ system dysfunction attributable to cytotoxic injury by eosinophils, without an identifiable etiology to explain the eosinophilia.[1] The mortality in untreated patients 3years after diagnosis, can be as high as 75%.[2] Cardiac involvement is the most common cause of increased morbidity and mortality.[3] Early identification and aggressive therapy is of paramount importance in decreasing the morbidity and mortality associated with this condition.
Case Report
A 15-year-old previously healthy boy was brought for fever and malaise of two months duration, itchy papular skin rashes with scaling for one month, progressively increasing dyspnoea, with jaundice and decreased urine output of 1-week duration prior to admission. Earlier there was no puffiness of face, abdominal distension or pain, pedal edema, seizures, altered sensorium, hematemesis, malaena, arthralgia, arthritis or mucosal ulceration. His chest X-ray showed right basal pneumonitis, sputum culture had grown Staphylococcus aureus and was diagnosed to have staphylococcal pneumonia .He was treated with parenteral vancomycin, meropenem, netilmicin, oral cephalexin and doxycycline.
Clinically he was well built, afebrile with marked pallor, icterus and extensive exfoliative skin rashes with hyper pigmentation over his entire body. He had bilateral cervical lymphadenopathy of size 1-1.5 cm. His cardiovascular system examination was normal with blood pressure of 100/60 mm of Hg. The respiratory rate was 42/min with fine crackles and wheeze. There was a soft hepato-splenomegaly. The neurological examination was normal.
His investigations were as follows: Hemoglobin 6 gm%, PCV 18 %, total leukocyte count 27,600/mm 3 with shift to left (stab forms 20%), eosinophils 14%, absolute eosinophil count (AEC) 3864/mm 3, platelet count 1.2 lakhs/mm 3, ESR 150 mm in the 1st hour, reticulocyte count 4.7%, Direct Coomb's test was negative. Serum total bilirubin was 4.4mg/dL with direct fraction 3.8 mg/dl, SGOT 113 IU/L (5-45IU/L), SGPT 68 IU/L (5-45IU/L), serum alkaline phosphatase 1454 IU/L (130-525 IU/L), serum total protein 7.6 gm/dL, albumin 2.8gm/dL, increased globulin 4.8gm/dL, blood urea 75mg/dL, serum creatinine 3.1 mg/dL, and normal serum electrolytes. Urine showed 4+ proteinuria by dipstick and spot protein/creatinine ratio of more than 3.0 without cellular casts or erythrocyturia. C-reactive protein was 48mg/L, and cultures of blood and urine were sterile. Serology for hepatitis A, B and E, leptospirosi s and HIV were negative. Smear study for microfilaria and malarial parasite was negative and repeated stool microscopy for parasites did not reveal any ova, cysts or occult blood. Chest X-ray and echocardiogram were normal. Ultra sonogram of abdomen revealed hepatosplenomegaly and bilateral renomegaly (11.8&12cm) with normal echo texture and no free fluid in the abdomen.
Bone marrow aspiration revealed plasmacytosis and increased eosinophilic precursors. Karyotyping was normal. Serum protein electrophoresis revealed elevated gamma globulin of 3.5gm/dl and immunoglobulin profile showed elevated S.IgE>2000 IU/L (<87 IU/L) and IgG 31.49 gm/L (7-16 gm/L), with normal IgM 0.9gm/L (0.4-2.3gm/L) and IgA 3.85gm/L (0.7 -4.0 gm/L). Anti Nuclear Antibody (ELISA) was borderline positive but antibody to double stranded DNA, rheumatoid factor and Anti Neutrophilic Cytoplasmic Antibody were negative. Renal histology showed mild mesangial proliferation with significant IgA deposits with few tubules showing Periodic Acid Schiff (PAS) positive eosinophilic material.
The differential diagnosis included drug induced allergic reaction, hypereosinophilic syndrome and autoimmune disorder. In view of high AEC, multisystem involvement at onset and rapidly deteriorating renal function, hypereosinophilic syndrome was strongly suspected. He was started on intravenous methylprednisolone (30 mg/Kg/day) for 5 days, followed by oral prednisolone 1mg/Kg/day. Packed red cells were transfused for anemia. Within 10 days of initiation of corticosteroid therapy, his renal function improved and at one month of therapy, there was disappearance of skin rashes with clinical and subjective improvement of pulmonary symptoms with normal renal and hepatic functions.
In view of significant improvement in symptomatology with fully recovered renal and hepatic functions, he was discharged on oral prednisolone, which was tapered and stopped over a period of 6 months. However, his AEC continued to be over 1500/mm 3. and hence received di-ethyl carbamazine (DEC) for 6 weeks. At 8 months follow up his AEC was 3075/mm 3. At 10 months follow up, his AEC was 882/mm 3. His last AEC at 11 months follow up was 847/mm 3 and ESR was only 8mm in 1st hr. His repeat echocardiogram and follow up renal and liver function test continued to be normal and there was no proteinuria during this period. He continues to be symptom free till date. A diagnosis of Hypereosinophilic Syndrome was made in view of high AEC persisting for more than 6 months and multisystem (dermatological, hematological, renal, pulmonary and hepatic) dysfunction at onset.
Discussion
Hypereosinophilic syndrome is a rare disease in children and its exact incidence is uncertain. The presentation is heterogeneous. It can be asymptomatic or may present as a life threatening disease. The pathophysiology of this disease is centered around eosinophil mediated tissue damage causing organ dysfunction. Numerous cytokines especially IL3, IL5, GM-CSF and proinflammatory cytokines are involved in its pathogenesis. Eosinophilic infiltration is necessary to cause tissue damage. Two variants of this disease have been described recently, the myeloproliferative and the lymphocytic variants. Multiple organ systems are usually affected but cardiac involvement in the form of endomyocardial fibrosis, valvular regurgitation, mural thrombosis, ischemia and congestive cardiac failure results in significant morbidity in children.[4] Central nervous system involvement is seen with peripheral neuropathies, hemiplegia, paraplegia encephalopathy, memory loss and ataxia. Diarrhea, hepatosplenomegaly, hepatic dysfunction, ascites, chronic active hepatitis and sclerosing cholangitis are few gastrointestinal manifestations. Renal manifestations include acute renal failure, chronic renal failure, immunotactoid glomerulopathy, crescentic glomerulonephritis and membranous glomerulopathy. Anemia, thrombocytopenia and thrombotic episodes are the common hematological manifestations. Some have underlying malignancy while others progress to eosinophilic leukemia. Skin manifestations are nonspecific. The rashes can be macular, papulo-vesicular or maculopapular. Urticaria and angioedema may be seen. Mucosal ulcerations are common HES is difficult to differentiate from eosinophilic leukemia as both have common features at presentation. However, eosinophilic leukemia may be associated with clonality, abnormal karyotyping and presence of more than 5% blasts in the marrow and more than 25% immature eosinophils in peripheral smear or marrow.[4],[5] Treatment includes glucocorticoids, hydroxyureas, and cyclosporin and interferon alpha. Cardiac or neurological dysfunction at onset results in aggressive clinical course and treatment failure. Newer modalities of therapy include the use of imatinib mesylate, monoclonal anti IL5 antibody and stem cell transplantation after nonmyeloablative conditioning.[6],[7],[8],[9]
In the present case, multisystem dysfunction was present at the onset in the form of renal, hematological, cutaneous, pulmonary and hepatic dysfunctions. There was no cardiac or neurological involvement. The renal involvement seen in this patient has been reported in a patient with eosinophilic fasciitis and IgA nephropathy.[10] The favorable response to steroids seen can be due to absence of cardiologic or neurological dysfunction at onset.[3] However, the persistence of high AEC beyond six months of withdrawal of the suspected offending drug(s) makes this diagnosis less likely and further we were not able to identify any etiological factor in him. Although this patient had borderline ANA positivity, autoimmune disease was not considered in him because the clinical and laboratory features were more in favour of HES and did not fit into any known spectrum of autoimmune diseases.
Conclusion
HES is a multisystem disorder secondary to eosinophilic infiltration of unknown etiology. In the present case the above documented features fulfill the criteria for the syndrome of HES. What is interesting is not only the rarity of the case, but the rewarding response in freeing the child of symptoms and a possible cure.
References
1. Chusid MJ, Dale DC, West BC Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975; 54: 1-27.
2. Boxer LA. Hypereosinophilic syndrome. In Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of Pediatrics. 17th edn. Philadelphia; Saunders, 2004; 710.
3. Schooley RT, Flaum MA, Gralnick HR, Fauci AS. A clinico-pathologic correlation of the idiopathic hypereosinophilic syndrome II. Clinical manifestations. Blood 1981; 58 : 1021-1026.
4. Alfaham MA, Ferguson SD, Sihra B, Davies J. The idiopathic hypereosinophilic syndrome. Arch Dis Child 1987; 62 : 601-613.
5. Bain BJ, Eosinophilic leukemias and the idiopathic hypereosinophilic syndrome. Br J Haematol 1996; 95 : 2-9.
6. Roufosse F, Bartholome E, Schandene L, Goldman M, Cogan E.The idiopathic hypereosinophilic syndrome: Clinical presentation, pathogenesis and therapeutic strategies. Drugs Today (Barc) 1998; 34: 361-373.
7. Klion AD, Robyn J, Akin C, Noel P, Brown M, Law M, Metcalfe DD, Dunbar C, Nutman TB. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with myeloproliferative variant of hypereosinophilic syndrome. Blood 2004; 103 : 473-478.
8. Klion AD, Law MA, Noel P, Kim YJ, Haverty TP, Nutman TB. Safety and efficacy of monoclonal anti interleukin 5 antibody SCH 55700 in the treatment of patients with hypereosinophilic syndrome. Blood 2004; 103 : 2939-2941.
9. Juvonen E, Volin L, Koponen A, Ruutu T. Allogeneic blood stem cell transplantation following non-myeloablative conditioning for hypereosinophilic syndrome. Bone Marrow Transplantation 2002; 29: 457-458.
10. Takeda S, Takazakura E, Fukui Y. Tubulointerstitial nephritis in a patient with eosinophilic fasciitis and IgA nephropathy. Nephron 1995; 69 : 314-317.(Venkatesh C, Mahender E, )
Abstract
Hypereosinophilic syndrome is a leukoproliferative disease characterised by sustained overproduction of eosinophils. The three diagnostic criteria for this disorder are (1) Eosinophilia of greater than 1500 cells/ml, persisting for longer than 6 months, (2) lack of another diagnosis to explain the eosinophilia and (3) signs and symptoms of organ involvement. We report a 15-year-old boy who was diagnosed as Hypereosinophilic syndrome based on these criteria.
Keywords: Eosinophilia; End organ damage
Hypereosinophilic syndrome, (HES) first described by Hardy and Anderson in 1968, is characterized by sustained overproduction of eosinophils. It is a rare disorder in children. The term Idiopathic Hypereosinophilic syndrome as defined by Chusid et al characterized by 3 criteria- eosinophil count greater than 1500 cells/mL persisting longer than 6 months and single or multiple organ system dysfunction attributable to cytotoxic injury by eosinophils, without an identifiable etiology to explain the eosinophilia.[1] The mortality in untreated patients 3years after diagnosis, can be as high as 75%.[2] Cardiac involvement is the most common cause of increased morbidity and mortality.[3] Early identification and aggressive therapy is of paramount importance in decreasing the morbidity and mortality associated with this condition.
Case Report
A 15-year-old previously healthy boy was brought for fever and malaise of two months duration, itchy papular skin rashes with scaling for one month, progressively increasing dyspnoea, with jaundice and decreased urine output of 1-week duration prior to admission. Earlier there was no puffiness of face, abdominal distension or pain, pedal edema, seizures, altered sensorium, hematemesis, malaena, arthralgia, arthritis or mucosal ulceration. His chest X-ray showed right basal pneumonitis, sputum culture had grown Staphylococcus aureus and was diagnosed to have staphylococcal pneumonia .He was treated with parenteral vancomycin, meropenem, netilmicin, oral cephalexin and doxycycline.
Clinically he was well built, afebrile with marked pallor, icterus and extensive exfoliative skin rashes with hyper pigmentation over his entire body. He had bilateral cervical lymphadenopathy of size 1-1.5 cm. His cardiovascular system examination was normal with blood pressure of 100/60 mm of Hg. The respiratory rate was 42/min with fine crackles and wheeze. There was a soft hepato-splenomegaly. The neurological examination was normal.
His investigations were as follows: Hemoglobin 6 gm%, PCV 18 %, total leukocyte count 27,600/mm 3 with shift to left (stab forms 20%), eosinophils 14%, absolute eosinophil count (AEC) 3864/mm 3, platelet count 1.2 lakhs/mm 3, ESR 150 mm in the 1st hour, reticulocyte count 4.7%, Direct Coomb's test was negative. Serum total bilirubin was 4.4mg/dL with direct fraction 3.8 mg/dl, SGOT 113 IU/L (5-45IU/L), SGPT 68 IU/L (5-45IU/L), serum alkaline phosphatase 1454 IU/L (130-525 IU/L), serum total protein 7.6 gm/dL, albumin 2.8gm/dL, increased globulin 4.8gm/dL, blood urea 75mg/dL, serum creatinine 3.1 mg/dL, and normal serum electrolytes. Urine showed 4+ proteinuria by dipstick and spot protein/creatinine ratio of more than 3.0 without cellular casts or erythrocyturia. C-reactive protein was 48mg/L, and cultures of blood and urine were sterile. Serology for hepatitis A, B and E, leptospirosi s and HIV were negative. Smear study for microfilaria and malarial parasite was negative and repeated stool microscopy for parasites did not reveal any ova, cysts or occult blood. Chest X-ray and echocardiogram were normal. Ultra sonogram of abdomen revealed hepatosplenomegaly and bilateral renomegaly (11.8&12cm) with normal echo texture and no free fluid in the abdomen.
Bone marrow aspiration revealed plasmacytosis and increased eosinophilic precursors. Karyotyping was normal. Serum protein electrophoresis revealed elevated gamma globulin of 3.5gm/dl and immunoglobulin profile showed elevated S.IgE>2000 IU/L (<87 IU/L) and IgG 31.49 gm/L (7-16 gm/L), with normal IgM 0.9gm/L (0.4-2.3gm/L) and IgA 3.85gm/L (0.7 -4.0 gm/L). Anti Nuclear Antibody (ELISA) was borderline positive but antibody to double stranded DNA, rheumatoid factor and Anti Neutrophilic Cytoplasmic Antibody were negative. Renal histology showed mild mesangial proliferation with significant IgA deposits with few tubules showing Periodic Acid Schiff (PAS) positive eosinophilic material.
The differential diagnosis included drug induced allergic reaction, hypereosinophilic syndrome and autoimmune disorder. In view of high AEC, multisystem involvement at onset and rapidly deteriorating renal function, hypereosinophilic syndrome was strongly suspected. He was started on intravenous methylprednisolone (30 mg/Kg/day) for 5 days, followed by oral prednisolone 1mg/Kg/day. Packed red cells were transfused for anemia. Within 10 days of initiation of corticosteroid therapy, his renal function improved and at one month of therapy, there was disappearance of skin rashes with clinical and subjective improvement of pulmonary symptoms with normal renal and hepatic functions.
In view of significant improvement in symptomatology with fully recovered renal and hepatic functions, he was discharged on oral prednisolone, which was tapered and stopped over a period of 6 months. However, his AEC continued to be over 1500/mm 3. and hence received di-ethyl carbamazine (DEC) for 6 weeks. At 8 months follow up his AEC was 3075/mm 3. At 10 months follow up, his AEC was 882/mm 3. His last AEC at 11 months follow up was 847/mm 3 and ESR was only 8mm in 1st hr. His repeat echocardiogram and follow up renal and liver function test continued to be normal and there was no proteinuria during this period. He continues to be symptom free till date. A diagnosis of Hypereosinophilic Syndrome was made in view of high AEC persisting for more than 6 months and multisystem (dermatological, hematological, renal, pulmonary and hepatic) dysfunction at onset.
Discussion
Hypereosinophilic syndrome is a rare disease in children and its exact incidence is uncertain. The presentation is heterogeneous. It can be asymptomatic or may present as a life threatening disease. The pathophysiology of this disease is centered around eosinophil mediated tissue damage causing organ dysfunction. Numerous cytokines especially IL3, IL5, GM-CSF and proinflammatory cytokines are involved in its pathogenesis. Eosinophilic infiltration is necessary to cause tissue damage. Two variants of this disease have been described recently, the myeloproliferative and the lymphocytic variants. Multiple organ systems are usually affected but cardiac involvement in the form of endomyocardial fibrosis, valvular regurgitation, mural thrombosis, ischemia and congestive cardiac failure results in significant morbidity in children.[4] Central nervous system involvement is seen with peripheral neuropathies, hemiplegia, paraplegia encephalopathy, memory loss and ataxia. Diarrhea, hepatosplenomegaly, hepatic dysfunction, ascites, chronic active hepatitis and sclerosing cholangitis are few gastrointestinal manifestations. Renal manifestations include acute renal failure, chronic renal failure, immunotactoid glomerulopathy, crescentic glomerulonephritis and membranous glomerulopathy. Anemia, thrombocytopenia and thrombotic episodes are the common hematological manifestations. Some have underlying malignancy while others progress to eosinophilic leukemia. Skin manifestations are nonspecific. The rashes can be macular, papulo-vesicular or maculopapular. Urticaria and angioedema may be seen. Mucosal ulcerations are common HES is difficult to differentiate from eosinophilic leukemia as both have common features at presentation. However, eosinophilic leukemia may be associated with clonality, abnormal karyotyping and presence of more than 5% blasts in the marrow and more than 25% immature eosinophils in peripheral smear or marrow.[4],[5] Treatment includes glucocorticoids, hydroxyureas, and cyclosporin and interferon alpha. Cardiac or neurological dysfunction at onset results in aggressive clinical course and treatment failure. Newer modalities of therapy include the use of imatinib mesylate, monoclonal anti IL5 antibody and stem cell transplantation after nonmyeloablative conditioning.[6],[7],[8],[9]
In the present case, multisystem dysfunction was present at the onset in the form of renal, hematological, cutaneous, pulmonary and hepatic dysfunctions. There was no cardiac or neurological involvement. The renal involvement seen in this patient has been reported in a patient with eosinophilic fasciitis and IgA nephropathy.[10] The favorable response to steroids seen can be due to absence of cardiologic or neurological dysfunction at onset.[3] However, the persistence of high AEC beyond six months of withdrawal of the suspected offending drug(s) makes this diagnosis less likely and further we were not able to identify any etiological factor in him. Although this patient had borderline ANA positivity, autoimmune disease was not considered in him because the clinical and laboratory features were more in favour of HES and did not fit into any known spectrum of autoimmune diseases.
Conclusion
HES is a multisystem disorder secondary to eosinophilic infiltration of unknown etiology. In the present case the above documented features fulfill the criteria for the syndrome of HES. What is interesting is not only the rarity of the case, but the rewarding response in freeing the child of symptoms and a possible cure.
References
1. Chusid MJ, Dale DC, West BC Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975; 54: 1-27.
2. Boxer LA. Hypereosinophilic syndrome. In Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of Pediatrics. 17th edn. Philadelphia; Saunders, 2004; 710.
3. Schooley RT, Flaum MA, Gralnick HR, Fauci AS. A clinico-pathologic correlation of the idiopathic hypereosinophilic syndrome II. Clinical manifestations. Blood 1981; 58 : 1021-1026.
4. Alfaham MA, Ferguson SD, Sihra B, Davies J. The idiopathic hypereosinophilic syndrome. Arch Dis Child 1987; 62 : 601-613.
5. Bain BJ, Eosinophilic leukemias and the idiopathic hypereosinophilic syndrome. Br J Haematol 1996; 95 : 2-9.
6. Roufosse F, Bartholome E, Schandene L, Goldman M, Cogan E.The idiopathic hypereosinophilic syndrome: Clinical presentation, pathogenesis and therapeutic strategies. Drugs Today (Barc) 1998; 34: 361-373.
7. Klion AD, Robyn J, Akin C, Noel P, Brown M, Law M, Metcalfe DD, Dunbar C, Nutman TB. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with myeloproliferative variant of hypereosinophilic syndrome. Blood 2004; 103 : 473-478.
8. Klion AD, Law MA, Noel P, Kim YJ, Haverty TP, Nutman TB. Safety and efficacy of monoclonal anti interleukin 5 antibody SCH 55700 in the treatment of patients with hypereosinophilic syndrome. Blood 2004; 103 : 2939-2941.
9. Juvonen E, Volin L, Koponen A, Ruutu T. Allogeneic blood stem cell transplantation following non-myeloablative conditioning for hypereosinophilic syndrome. Bone Marrow Transplantation 2002; 29: 457-458.
10. Takeda S, Takazakura E, Fukui Y. Tubulointerstitial nephritis in a patient with eosinophilic fasciitis and IgA nephropathy. Nephron 1995; 69 : 314-317.(Venkatesh C, Mahender E, )