State of the Art: The Hypereosinophilic Syndromes
J. L. Liesveld, C. N. Abboud S UMMA R Y. Many disease states such as parasitic infestations, malignancies, collagen vascular diseases, and allergies are associated with eosinophilia. The diagnosis of idiopathic hypereosinophilic syndrome (HES) requires a persistent elevation in the total eosinophil count (> 1500/mm3) for over 6 months, associated organ damage and no detectable underlying cause. This review provides an updated summary of the cytohine cascade that controls eosinophil production and delineates our current understanding of the clinical features of hypereosinophilic states. We also examine the central role of T-lymphocyte activation in eosiuophilia, and have attempted to integrate current treatment strategies for HES with the physiology of eosinophilopoiesis.
Eosinophil Granules and Activation
The eosinophil has been the subject of continued scrutiny since its initial description by Paul Ehrlich in 1879,’ and new interest in the eosinophil has been recently sparked by description of the eosinophiliamyalgia syndrome. ’ The eosinophil is a type of granulocyte, the specific granules of which become apparent at the early myelocyte stage of development. Eosinophilic granules are membrane-bound and are resolvable with the light microscope. The eosinophil and its granule substances have been the subjects of many comprehensive reviews. 3-5 Granular substances produced by eosinophils include: 1) major basic protein, an alkaline core protein capable of damaging schistosomula and tumor cells, 2) eosinophi1 peroxidase, a matrix protein involved in halide and H,O,-producing interactions, 3) eosinophil cationic protein which is involved in fibrinolysis and is toxic to Schistosomula, 4) eosinophil-derived neurotoxin, and 5) lysophospholipase, the Charcot-Leyden crystal protein. In addition to their role in helminthotoxicity and in damping hypersensitivity reactions J. L. Liesvebd, C. N. Abboud MD,, Hematology Unit, PO Box 610, University of Rochester Medical Center, 601 Mmwood Avenue, Rochester, NY 14642, USA. Blood Reviews (1991) 5.029-037 0 1991 Longman Group UK Ltd
by enzyme neutralization of slow releasing substance of anaphylaxis, histamine, and platelet activating factor; eosinophil granules have been shown in vitro systems to be damaging to normal tissues. As examples, major basic protein causes exfoliation of respiratory epithelial cells and impairment of ciliary function, and cationic eosinophil proteins have been shown to have myocardial toxicity. Tumor necrosis factor alpha/cachectin has also been shown to stimulate eosinophil oxidant production and toxicity toward human endothelium. This toxicity was thought to be possibly mediated by eosinophil peroxidase.6 There is a large reserve pool of eosinophils with a high turnover rate so that rapid changes can occur in the number of circulating eosinophils. Eosinophil egress into the circulation and tissue migration are influenced by many factors. These include eosinophil chemotactic factor of anaphylaxis, histamine, C5a, antigen-antibody complexes, the chemotactic peptide, FMLP, leukotriene Bq, and platelet activating factor (PAF).7 Platelet activating factor can cause eosinophils to adhere to vascular endothelial cells. It is an alkyl phospholipid produced at inflammatory sites by endothelial cells, platelets, granulocytes, and monocytes. PAF also induces the release of eosinophil major basic protein, leukotriene Cq, and superoxide.
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STATE OF THE ART: THE HYPEREOSINOPHILIC
SYNDROMES
Cytokines such as granulocyte-macrophage colonystimulating factor (GM-CSF) and interleukin 5 (IL-5) can mediate eosinophil activation.’ IL-5 in addition is a selective eosinophil chemoattractant.g Furthermore, HILDA, human interleukin for DA-2 cells (murine IL-3 dependent cell line) is a chemoattractant for and activator of mouse and human eosinophils. lo Taken together, all these factors may participate in the local inflammatory responses and eosinophilmediated tissue damage.
murine marrow, synergistic interactions between IL-l, IL-3, and IL-5 are required for in vitro production of eosinophils from primitive hemopoietic cells. IL-l and IL-3 act early whereas IL-5 acts on already committed progenitors. l4 Preincubation of human marrow cells with granulocyte CSF (G-CSF) for 24-72 h followed by IL-5 indicates that G-CSF acts on early stage progenitors to increase eosinophilic commitment.’ 5 These synergistic interactions are illustrated in Figure 1.
Normal Eosinophilopoiesis
Hypereosinophilic Syndromes
The role of hemopoietic growth factors and interleukins in the regulation of eosinophil production, progenitor amplification and precursor maturation is illustrated in Figure 1. Synergistic interactions apply to early eosinophil progenitors while lineage specific factors act on later committed progenitors and eosinophil precursors. Using human marrow null cells, it has been found that interleukin 3 (IL-3) or granulocyte-macrophage colony stimulating factor (GM-CSF) are able to support eosinophil colony formation independently from one another. l1 Some of the resultant colonies are of mixed lineage, and many of them contain promyelocytes, myelocytes, and metamyelocytes. IL-5 alone gave rise to small numbers of pure eosinophilic colony forming units (CFU-Eo) consisting of mature cells. When IL-5 was combined with IL-3 or GM-CSF, larger eosinophil colonies of intermediate differentiation were seen. This was interpreted to mean that targets for IL3/GM-CSF are earlier in eosinophilipoiesis, whereas IL-5 acts on terminal, mature cells.” Clutterback et al” have shown that IL-5, IL-3, and GM-CSF stimulate the appearance of eosinophilic colonies in the same time course. IL-5 was additive but not synergistic with IL-3 or GM-CSF indicating that it may stimulate a smaller and possible different subset of progenitors and that it appears to have little or no effect on commitment. In vitro eosinophil production in response to IL-5 was maximal by 21 days.13 In
Disease states associated with eosinophilia are many and include parasitic infestation with tissue-invasive organisms, extrinsic (allergic) bronchial asthma, allergic rhinitis, pulmonary aspergillosis, vasculitides, miscellaneous collagen vascular diseases and neoplasms. l6 In humans, eosinophil counts >500/mm3 warrant investigation, and it must be kept in mind that blood eosinophils are only a small fraction of the total pool with the skin, gastrointestinal tract, lung, and marrow serving as prime tissue sites. In some cases of eosinophilia, despite extensive search, an underlying cause for eosinophilia cannot be found, in which case a diagnosis of idiopathic hypereosinophilic syndrome (HES) is made. Specific criteria for this disorder which encompasses a heterogeneous group of disorders were put forward by Chusid and others.” These are: 1) Persistent eosinophilia greater than or equal l,500/mm3 for > 6 months or death before 6 months with signs and symptoms of HES, 2) no underlying cause for eosinophilia, and 3) signs and symptoms of organ involvement.
EARLY
PRIMITIVE
MATURE
EOSINOPHIL
EOSINOPHIL PROGENITOR
EOSINOPHIL
PROGENITOR CFU-Ea
Syneralstlc factors IL-I
+ IL-3
IL-5
IL-5
GM-CSF
GM-CSF
_
GM-CSF
t
n
+ IL-5
IL-3
+ IL-5
G-CSF
+ IL-5
Fig. 1 A schema of eosinophil maturation illustrating site of hemopoietic growth factor action. IL= Interleukin, G-CSF= granulocyte colony stimulating factor, GM-CSF= granulocytemacrophage colony stimulating factor, CFU-Eo= eosinophil colony forming unit.
Properties of Eosinophils in HES
Studies of eosinophils from eosinophilic states have shown several altered properties. The eosinophils are often hypodense as compared to normal eosinophils. They are degranulated with low eosinophil cationic protein levels, and they demonstrate higher 0, consumption. l8 Some studies have shown that these hypodense eosinophils have increased Fc IgG receptorsl’ and others have shown no change in Fc gamma expression. lg It has been found that eosinophils from patients with eosinophilia of diverse causation demonstrate increased adherence to and functional capacity in an antibody dependent cytotoxicity (ADCC) assay against helminths in vitro.20,21 The eosinophils in HES have been found to release normal amounts of 5-lipooxyenase and 15-lipooxygenase and to be capable of degranulation after calcium ionophore A23 187 and opsonized zymosan particle exposure.22 The vacuolated cytoplasmic granules seen in HES states are thought to indicate prior activation and degranulation. Several cytokines have been found to activate eosinophils and to result in production of hypodense cells. Granulocyte-monocyte colony stimulating fac-
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tor (GM-CSF) has been shown in vitro to enhance eosinophil cytotoxicity and leukotriene synthesis.23 When normodense human peripheral blood eosinophils are cultured with recombinant human GM-CSF in the presence of mouse 3T3 cells, they are capable of surviving for 14 days, and they become hypodense and demonstrate increased LTC4 generation and &histosoma mansoni larvae cytotoxicity.24 Similarly, IL-3 can increase eosinophil viability, cause increased eosinophil LTC4 production in response to calcium ionophore, increase eosinophil Schistosoma killing, and cause eosinophils to become hypodense.25 Interleukin-5 in both human and murine systems has been found to have effects on eosinophil activation. In mice, IL-5 has been found to maintain viability, induce superoxide production, and exert a chemokinetic effect on normal eosinophils.26 In humans, IL-5 causes appearance of hypodense eosinophils, membrane ruffling and polarization, increased anti-tumor ADCC, and stimulation of O,-production.*’ Normal eosinophils have also been reported to become hypodense in the presence of platelet activating factor and to demonstrate increased adherence to normal endothelium mediated through increased CD18 (the p2 adhesion receptor of LFA-1, Mol , and pl50,95) expression. 28 IL-3, IL-5, and GM-CSF have also been found to augment synthesis of a sulfated proteoglycan from human eosinophils.29 Thus, exposure of normal eosinophils to IL-3, IL-5, and GM-CSF in vitro causes appearance of hypo-dense eosinophils which demonstrate increased anti-helminthic ADCC and increased calcium ionophore-mediated LTC, production. In 3 patients with HES unresponsive to corticosteroids, a population of hypodense eosinophils was found to be most effective in anti-helminth ADCC and to survive best in culture. When normodense normal eosinophils were cultured with serum from these HES patients, a dose-dependent increase in viability occurred, and the cells were converted to hypodense. Anti-IL-5 neutralized these serum effects while anti-GM-CSF and anti-IL-3 had no effect.30 It was thus postulated that excess IL-5 may account for the activated hypodense eosinophil morphology seen in hypereosinophilia. An example of a culture-derived hypodense eosinophil is shown in the transmission electron micrograph in Figure 2. Mechanisms for Increased Eosinophil Production in Hypereosinophilic Syndromes Role of T-Lymphocytes and Interleukins When eosinophilopoiesis has been studied in patients with HES31 approximately half (7 out of 13) were found to have normal numbers of CFU-Eo. Five out of 13 patients had increased numbers of CFU-Eo, and some of these cases showed evidence of increased eosinophil CSF while others demonstrated excess commitment to eosinophil differentiation. In bone marrow of mice parasitized with Nippostryongylus brasiliensis, marrow contains elevated numbers of
31
Fig. 2 A transmission electron micrograph showing human marrow-derived eosinophils obtained from methylcellulose cultures at 14 days. Note the many incomplete ‘hypodense’ granules in the cytoplasm.
eosinophils as early as 4 days after infection. Also, progenitors that form eosinophil colonies in soft agar cultures are increased. These marrow eosinophils and eosinophil precursors can be eliminated by infusion with anti-IL-5 antibodies at the time of infection, indicating a regulatory role for IL-5 in parasiteinduced eosinophilia.32 T-Lymphocyte Role in Eosinophilia
Early studies of Basten and Beeson demonstrated that lymphocytes sensitized to Trichinella were able to produce a soluble substance which resulted in selective marrow production of eosinophils when administered to mice in vivo. The importance of T-lymphocytes for the eosinophilic response of rats to Trichinella spiralis infection was shown by inhibition of the response with anti-thymocyte serum or neonatal thymectomy. 33 Unlike their neutrophil counterparts, mature human eosinophils become HLA-DR positive when cultured in the presence of 3T3 fibroblasts and GM-CSF.34 Thus activated eosinophils may interact closely with CD4+ T-lymphocytes through the DR locus. Enokihara et a13’ reported that when aspergillus extract was added to sensitized T-cells from a patient with allergic aspergillosis, conditioned medium from such cells had specific Eo-CSF activity. This effect was not elicited with patient non-T-cells or with mononuclear cells from normal subjects. Later, it was shown that IL-2 could substitute for the specific antigenic stimulation,36 and that effects of IL-2 could be neutralized with antibody to IL-5, the mRNA of which was induced by IL-2.37 In HES, where the antigenic stimulus for eosinophilia is unknown, it has been found that when T-cell clones are propagated with mitogen and IL-2, a subset can stimulate pure CFU-Eo marrow progenitor growth. The release of Eo-CSF from these clones can be inhibited by hydrocortisone or cyclosporine
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A. These T-cell clones were phenotypically T4 + T8 and produced IL-2. Furthermore, each clone had a different T-cell receptor beta chain rearrangement indicating a polyclonal activation.38 Taken together, these observations underscore the central role of T-cell activation in disorders associated with hypereosinophilia. Role of Interleukin-2 and T-cell Activation
It is of interest that in patients treated with interleukin-2/Lymphocyte Activated Killer Cell (LAK cell) administration, where reversible eosinophilia is noted, nearly all eosinophils become hypodense by the end of treatment.39 In one series of such patients, 12% demonstrated eosinophil counts greater than 10 OOO/mm3.4o It has been shown that these eosinophils also have eosinophil cationic protein in the secretory vs. storage form and increased ability to kill Schistosoma mansoni through antibody dependent cellular cytotoxicity mechanisms. IL-2 itself has no effect on eosinophils, and their progenitors but LAKcell conditioned medium could mediate these effects possibly through release of gamma interferon, lymphotoxin, or tumor necrosis factor alpha.41 Hypereosinophilia occurs also in AIDS patients receiving IL-2.42 The increase in eosinophils in this setting is preceded by a detectable eosinophilic factor in the sera of these patients. 42 These findings may be explained by the ability of IL-2 to mediate the release of IL-3 activity by human T-cells43 and enhance IL-5 mRNA expression in murine spleen cells.44 The eosinophilia which developed during IL-2 therapy could be eliminated by injection of a monoclonal antibody against murine IL-5.44 Interleukin-S and Eosinophil Regulation
Interleukin-5 has been identified as the principal eosinophilic regulatory factor.45 In addition to its effects on eosinophils, IL-5 induces differentiation of immature precursors into cytotoxic T-lymphocytes46 and induces maturation of IgA-producing B-cells.47 Murine IL-5 induces the expression of IL-2 receptor on splenic B-lymphocytes and PNA + thymocytes.48 IL-5 has also been found to enhance LAK activity in the presence of IL-2. 49 IL-5 maps to human chromosome 5 and is deleted in the Sq-syndrome.” Evidence has accumulated indicating that IL-5 mediates murine helminth-induced eosinophilia. In rodents with eosinophilia due to Nippostrongylus brasiliensis, injection of monoclonal antibody to IL-5 suppressed blood eosinophilia and infiltration of eosinophils into the lungs. The extent of infiltration with organisms and neutrophils was unchanged, however. Antibody to IL-4 inhibited only IgE production but not eosinophilia. The effect of IL-5 was mediated through TH2CD4 + cells. ” Also, antibody to IL-5 prevented blood and tissue eosinophilia in mice infected with Schistosoma mansoni but did not affect
granuloma formation or organism burden.52 It was postulated that lymphocytes belonging to the IL-5secreting subset predominate during the acute infection and may induce granuloma formation by the production of other cytokines. When 7 patients with helminth-induced eosinophilia were compared to 11 normals, levels of IL-3 and GM-CSF were similar between groups whereas IL-5 was increased at the protein and mRNA level in those with eosinophilia.53 Taken together, these findings underscore the central role of IL-5 in eosinophil regulation. Clinical Manifestations of HES Clinical features of the hypereosinophilic syndromes have been reviewed previously.’ 7*54*55The disease has male predominance and peak age of onset in the fifth decade. Some cases are diagnosed incidentally based on blood counts, and often the presenting symptoms are either nonspecific (e.g., fever, weight loss) or are related to specific organ involvement. Physical findings may include hepatosplenomegaly while lymphadenopathy is uncommon. In addition to blood eosinophilia, anemia and thrombocytopenia may be seen. Red cell poikilocytosis (teardrop forms) has been seen, and the eosinophils may be vacuolated and abnormally granulated. On marrow examination, an eosinophilia of > 30% is usually seen. Cytogenetic abnormalities described have been nonspecific. Involvement of almost all organ systems has been reported. The organs most commonly involved include heart, lungs, skin, and the nervous system. Cardiac Disease
The heart is involved in over 90% of HES cases, and cardiovascular disease is a principal cause of death in patients with HES. Cardiac dysfunction can also occur with eosinophilia of known cause, and there is evidence that eosinophil products are damaging to the myoendocardium. 56s7 Degranulated eosinophils may be found in the endomyocardium, and eosinophilic cationic protein blood levels are often elevated. Such proteins have been shown to damage isolated mammalian heart muscle cells in vitro and to have a toxic effect on enzyme complexes involved in mitochondrial respiration.56 Histologically, the primary site of damage is the endocardium. Fibrotic thickening of the endocardium ensues which may involve the posterior mitral and/ or tricuspid valve leaflets. Mural thrombi are also often seen as are thrombosis and inflammation of small intramyocardial vessels.55 Infiltration of eosinophils is usually not seen in the late stages of cardiac involvement which are characterized by fibrosis and thrombosis. Eosinophils can be seen during early necrotic stages.56 M-mode and 2-D echocardiography are abnormal in the majority of these cases studied.5B,5g Findings often include increased left ventricular wall thickness,
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abnormal motion of the posterior mitral valve leaflet, and left ventricular thrombi. Some cases of right ventricular thrombus have been seen, and dense endocardial fibrosis of papillary muscles, chordae, and valves can occur. Cardiac dysfunction in HES is most commonly produced by combined effects of endocardial fibrosis resulting in restriction to inflow and intracavitary thrombosis with outflow tract obliteration, Mitral regurgitation and tricuspid regurgitation occur secondary to involvement of the posterior papillary muscle with endocardial fibrosis, Aortic and mitral valve stenosis have also been reported in HES.60 It is recommended that patients with cardiac manifestations be managed with inotropic, diuretic, and afterload reduction therapy as required. Many patients with A-V valvular insufficiency show improvement after valve replacement. Because of the tendency for acute prosthetic valve stenosis due to the eosinophilia, 6o it is recommended that bioprotheses with long-term anticoagulation be used in these patients. The role of eosinophil reduction is uncertain in terms of preventing evolution of cardiac disease but is presumed beneficial.55
Pulmonary Disease
The most common symptoms related to eosinophil infiltration of the lungs are cough and dyspnea. NonHES related causes of pulmonary eosinophilias include Loeffler’s syndrome which is self-limited, PIE which is chronic, and hypersensitivity pneumonitis in which a known allergen is involved (e.g. allergic bronchopulmonary aspergillosis). In patients with chronic eosinophilic pneumonia, 89% will have blood eosinophilia. ‘l In their absence, lung biopsy is required to make a definitive diagnosis. Gas exchange may be impaired in these cases, and peripheral infiltrates are the most common chest x-ray finding. These are often bilateral and involve the upper zones. Many patients with chronic pulmonary involvement have rapid response to corticosteroid therapy, but many require prolonged treatment for disease control.61
Skin Disease
Approximately 50% of cases of HES have skin manifestations.62 Skin involvement may be the only manifestation of HES, and skin lesions often improve with treatment. The two types of involvement most commonly seen are: 1) erythematous pruritic papules and nodules of the trunk and extremities and 2) urticaria/angioedema. Biopsy often shows a mixed inflammatory infiltrate with a high proportion of eosinophils. 63 In some cases of dermal eosinophil infiltration, deposition of major basic protein in the extracellular matrix has been seen.64 PUVA treatment has been found to have efficacy when skin disease is the sole manifestation of HES.65
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33
Neurologic Disease
Over half of the patients with hypereosinophilic syndrome have neurologic involvement.66 This involvement may take the form of a generalized encephalopathy, peripheral neuropathy, or focal deficits from emboli or hemorrhage. CSF and CT findings are often normal in patients presenting with encephalopathy, but cases of CSF eosinophilia have been reported. 67 Most cases of CSF eosinophilia involve parasitic infiltration with Taenia solium or Angiostrongylus cantonensis. Reversible dementia responsive to steroids has also been reported in HES.68 Most commonly, the peripheral neuropathy seen in these syndromes is a symmetrical sensory polyneuropathy. Patients often complain of peripheral paresthesias or numbness. This peripheral involvement can take the form of radiculopathy or motor neuropathy. Electrodiagnostic studies often show an axonal pattern of denervation but may be norma1.70*71The prognosis of the sensory polyneuropathy is variable but many patients have residual disability even after eosinophilia is controlled with medical therapy. Muscle biopsies may show type II atrophy and eosinophilic infiltrates. On nerve biopsy, demyelination or axonal dropout may be seen.@j The mechanism of neurologic damage in eosinophilia may relate to direct infiltration or to production of eosinophil-derived neurotoxin, a cationic protein with ribonuclease function.72 Other Organ Involvement
Patients with HES may present anywhere on a continuum ranging from eosinophilic leukemia to an isolated skin rash. Survival in these cases seems more related to extent of organ involvement than to eosinophi1 counts. Other organs which have been reported to be involved in these syndromes include the eyes (retina), gastrointestinal tract (colitis with diarrhea73), liver, spleen, kidneys, muscle,74 and rarely, lymph nodes. Thromboembolic disease can also involve diffuse organs; e.g., hepatic vein obstruction. Some patients seem prone to recurrent thromboemboli despite adequate anticoagulation. In one reported series 5 out of 21 cases of HES studied had peripheral embolization.59 Other Eosinophilic States HES and Malignancy
Eosinophilia has been associated with many malignancies, although these cases with underlying causation do not qualify as HES. In contrast, true eosinophilic leukemia is often considered one part of the spectrum of diseases encompassed by the term HES.75 The secondary eosinophilias seen with solid tumors are often the result of tumor-derived eosinophilopoietic activity. This has been reported for tumors as diverse as pulmonary tumors,76 medullary
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STATE OF THE ART: THE HYPEREOSINOPHILIC SYNDROMES
carcinoma of the thyroid” and malignant fibrous histiocytoma. 78 Eosinophilia can also be seen in cases of AML, ALL, and CML, and idiopathic HES has been reported to evolve to AML79 and to occur in the setting of plasmacytoma.*’ In many cases of eosinophilia associated with ALL*’ or AML,*’ the eosinophil proliferation has appeared to be reactive based upon either resolution with treatment of the underlying leukemia or on cytogenetic analysis. In some cases, Calla positive acute leukemias have been associated with substantial leukocytosis and eosinophilia with a t(5q;l4q) translocation.83 It has been found that involved bands are 5q31.1 and 14q32.3 with GM-CSF and immunoglobulin heavy chain association, respectively. It is also of interest that IL-5 is located at 5q31. In some cases of acute myelomonocytic leukemia, abnormalities of chromosome 16 have been noted in association with eosinophilia. The most commonly seen abnormality is inv( 16)(pl3q22), but deletions and translocations involving 16q22 have also been reported. The marrow eosinophils are dysplastic or abnormal in morphology making this distinct from HES or eosinophilic leukemia.84 Trisomy 22 has been seen with monocytic leukemias with eosinophilia.85 In contrast to secondary eosinophilic proliferation with malignancy, cases of primary eosinophilic leukemia are also seen. Various cytogenetic abnormalities have been associated with eosinophilic leukemia including 12~13,~~ t(lOp+,llq-),*’ and trisomy 8.** Tryptophan-induced Eosinophilia-myalgia Syndrome
The eosinophilia-myalgia syndrome, characterized by peripheral eosinophilia and scleroderma-like features, was first reported in late 1989 by physicians in New Mexico and Minnesota. 89 An epidemiologic association between the syndrome and tryptophan consumption was soon confirmed. Tryptophan is an essential amino acid which is metabolized to serotonin and has been used to treat insomnia, depression, and other symptoms. Tryptophan-containing products have now been recalled from retail markets in the United States with a concomitant drop in the numbers of reported cases. As of July 1990, approximately 1,500 cases had been reported nationwide.” Numerous symptoms other than myalgia have been reported in this syndrome including muscle tenderness, fatigue, edema, arthralgia, neuropathy, rash, cough, and dyspnea. Deaths due to ascending polyneuropathy were also noted. HPLC of tryptophan from lots associated with the syndrome have shown a chemical constituent thought to contribute to the pathogenesis of the eosinophilia. 91 Some of these products have been contaminated with the di-tryptophan aminal of acetaldehyde (DTAA). 92 The relationship of this compound to eosinophilia is unknown. Other investigators have suggested that tryptophan itself or its metabolites contribute directly to the syndromeg3 but this does not explain the absence of cases prior to 1989.
The syndrome is defined by debilitating myalgias and absolute eosinophilia greater than or equal to 1.0 x lo9 cells/L with other causes of eosinophilia such as infections or neoplasia excluded.90 Most patients with this syndrome have absolute eosinophil counts >2,000/mm3. Bone marrow usually shows hyperplasia of eosinophilic precursors. Muscle biopsy often shows perivascular inflammatory infiltrates with eosinophilia, round cells, and sparing of the interstitium. Often, the syndrome improves with discontinuation of tryptophan but in other cases worsens despite discontinuation of the medication. Glucocorticoids have been reported to be of benefit. Many patients are left with residual neural or muscular deficits. Treatment of HES HES has a poor natural history with a median survival time in untreated cases of 12 months.94 Both effective cytoreductive agents and treatment of cardiac disease are required. In the largest series of HES patients thus far reported,95 6 out of 33 required no specific treatment. These patients had significantly less organ involvement at diagnosis. Blood eosinophil counts were less predictable regarding need for eventual treatment. High white cell count, blasts, and conjestive heart failure at diagnosis indicate a poor prognosis, but with appropriate treatment, mortality at 3 years was only 4% in the NIH series. Nine out of 24 cases responded to prednisolone alone. Angioedema, high serum IgE levels, and eosinopenia in response to a challenge dose indicated positive prednisone response. Figure 3 illustrates potential sites of action of steroids (hydrocortisone) including negative regulation of macrophages and activated T-cells which secrete IL-2 or express the IL-2 receptor. The lack of response to steroids has been correlated with absence of detectable receptors on eosinophils,96 so steroids may also have a direct suppressive effect on these cells. Also, it has been demonstrated that interleukin 5 activity is increased in sera from patients with eosinophilia and that administration of prednisolone decreases IL5 and IL-2 activity in these sera.97 In those not responding to prednisone, hydroxyurea gives a significant response in the majority of cases. Figure 3 illustrates the inhibition of CFU-Eos by hydroxyurea. Other treatment modalities of anecdotal benefit in HES include leukapheresis, PUVA treatment for skin disease,65 vincristine,98 vincristine plus 6-mercaptopurine,99 allogeneic bone marrow transplantation,ioO recombinant alpha-interferon”’ and cyclosporine Ae3* Cyclosporine A acts to suppress activation of T-lymphocytes”’ and also acts to decrease the output of regulatory cytokines which stimulate eosinophil production from these lymphocytes. lo3 Such factors include GM-CSF, IL-5, and IL-2 as shown in Figure 3. Afterload reduction treatment and appropriate surgical intervention are indicated for cardiac involvement. The treatment
BLOOD REVIEWS
Fig. 3 A model for increased CFU-Eo growth in eosinophilia showing interaction between antigen, monocytes/macrophages, IL-2 producing T cells and IL-2 responding T cells. Cytokine roles in mediating these interactions are indicated. Known sites of hydrocortisone, cyclosporine A, and hydroxyurea inhibition are illustrated. Action at all these sites leads to a decrease in eosinophil growth. y-IFN = gamma interferon, other abbreviations are as defined in the text.
modalities outlined here can be of benefit in both reactive and constitutive hypereosinophilic states. Acknowledgements This work was supported in part by PHS grant PO1 HL-18208 from the National Heart, Lung and Blood Institute. JLL is a Special Fellow of the Leukemia Society of America and the recipient of a James P. Wilmot postdoctoral cancer research award. We thank Dr. Marshall A. Lichtman for his helpful discussions and Carol B. Weed for her excellent assistance in the preparation of this manuscript.
References 1. Butterworth A E, David J R 1981 Current concepts. Eosinophil function. New England Journal of Medicine 304: 154-156 2. Flannery M T, Wallach P M, Espinoza L R, Dohrenwend M P, Moscinski L C 1990 A case of the eosinophiliamyalgia syndrome associated with use of an L-tryptophan product. Annals of Internal Medicine 112: 300-301 3. Mahmoud A A F 1980 Eosinophilopoiesis. In: Mahmoud A A F. Austen K F, eds. The eosinophil in health and disease. Orlando: Grune and Stratton, 61-75 4. Zucker-Franklin D 1990 Eosinophils: morphology, production, chemistry and function. In Williams W J, Beutler E, Erslev A J, Lichtman M A, eds. Hematology, 4th edn, McGraw-Hill, Ch 89, p 835-839 5. Spry C J F 1985 Synthesis and secretion of eosinophil granule substances. Immunology Today 6: 332-335 6. Slungaard A, Vercellotti G M, Walker G, Nelson R D, Jacob H S 1985 Tumor necrosis factor alpha/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium. Journal of Experimental Medicine 171: 2025-2041 7 Silberstein D S, Austen K F, Owen W F 1989 Hemopoietins for eosinophils: Glycoprotein hormones that regulate the development of inflammation in eosinophiliaassociated disease. Hematology/Oncology Clinics of North America 3: 51 l-533
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8. Wardlaw A J, Moqbel R, Cromwell 0, Kay A B 1986 Platelet activating factor: A potent chemotactic and chemokinetics factor for human eosinophils. Journal of Clinical Investigation 78: 1701-1706 9. Wang J M, Rambaldi A, Biondi A, Chen Z G, Sanderson C J, Mantovani A 1989 Recombinant human interleukin 5 is a selective eosinophil chemoattractant. European Journal of Immunology 19: 701-705 10. Moreau J-F, Bonneville M, Godard A, Gascon H, Gruart V, Moore M A, Souliiloui J P 1987 Characterization of a factor produced by human T-cell clones exhibiting eosinophil-activating and burst-promoting activities. Journal of Immunology 87: 3844-3849 11. Sonoda Y. Arai N, Ogawa M 1989 Humoral regulation of eosinophilopoiesis in vitro: analysis of the targets of interleukin-3, granulocyte/macrophage colony-stimulating factor (GM-CSF), and interleukin 5. Leukemia 3: 14-18 12. Clutterbuck E J, Hirst E M A, Sanderson C J 1989 Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-l, IL-3, IL-6, and GM-CSF. Blood 73: 1504-1512 13. Clutterbuck E J, Sanderson C J 1988 Human eosinophil hematopoiesis studies in vitro by means of murine eosinophil differentiation factor (IL-5): Production of functionally active eosinophils from normal human bone marrow. Blood 71: 646-651 14. Warren D J, Moore M A S 1988 Synergism among interleukin 1, interleukin 3, and interleukin 5 in the production of eosinophils from primitive hemopoietic stem cells. Journal of Immunology 140: 94-99 15. Enokihara H, Nagashima S, Noma T, Kajitani H, Hamaguchi H, Saito K, Furusawa S, Shishido H, Honjo T 1988 Effect of human recombinant interleukin 5 and G-CSF on eosinophil colony formation. Immunology Letters 18: 73-76 16. Kay A B 1976 Functions of the eosinophil leukocyte. British Journal of Haematology 33: 313-318 17. Chusid M J, Dale D C, West B C, Wolff S M 1975 The hypereosinophilic syndrome: analysis of 14 cases with review of the literature. Medicine 54: l-27 18. Winqvist I, Olofsson T, Olsson I, Persson A-M, Hallberg T 1982 Altered density, metabolism, and surface receptors of eosinophils in eosinophilia. Immunology 47: 531-539 19. Hartnell A, Moqbel R, Walsh G M, Bradley B, Kay A B 1990 Fcgamma and CD1 l/CD18 receptor expression on normal density and low density human eosinophils. Immunology 69: 264-270 20. David J R, Vadas M A, Butterworth A E, deBrito P A, Carvalhio E M, David R A, Bina J C, Andrade Z A 1980 Enhanced helminthotoxic capacity of eosinophils from patients with eosinophilia. New England Journal of Medicine 303: 1147-l 152 21. Prin L, Capron M, Tonne1 A-B, Bletry 0, Capron A 1983 Heterogeneity of human peripheral blood eosinophils: Variability in cell density and cytotoxic ability in relation to the level and the origin of hypereosinophilia. International Archives of Allergy and Applied Immunology 72: 336-346 22 Henderson W R, Harley J B, Fauci A S, Chi E 1988 Hypereosinophilic syndrome human eosinophil degranulation induced by soluble and particulate stimuli. British Journal of Haematology 69: 13-21 23 Silberstein D S, Owen W F, Gasson J C, DiPersio J F, Golde D W, Bina J C, Soberman R, Austen K F, David J R 1986 Enhancement of human eosinophil cytotoxicity and leukotriene synthesis by biosynthetic (recombinant) granulocyte-macrophage colony stimulating factor. Journal of Immunology 137: 3290-3294 24. Owen W F, Rothenberg M E, Silberstein D S, Gasson J C, Stevens R L, Austen K F, Soberman R J 1987 Regulation of human eosinophil viability, density, and function by granulocyte/macrophage colony-stimulating factor in the presence of 3T3 fibroblasts. Journal of Experimental Medicine 166: 129-141 25. Rothenberg M E, Owen W F, Silberstein D S, Woods J, Soberma R J. Austen K F, Stevens R L 1988 Human eosinophils have prolonged survival, enhanced functional properties, and become hypodense when exposed to human interleukin 3. Journal of Clinical Investigation 81: 19861992
36
STATE OF THE ART: THE HYPEREOSINOPHILIC
SYNDROMES
26. Yamaguchi Y, Hayashi Y, Sugama Y, Miura Y, Kasahara T, Kitamura S, Torisu M, Mita S, Tominaga A, Takatsu K, Suda T 1988 Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival. IL-5 as an eosinophil chemotactic factor. Journal of Experimental Medicine 167: 1737- 1742 27. Lopez A F, Sanderson C J, Gamble J R, Campbell H D, Young I G, Vadas M A 1988 Recombinant human interleukin 5 is a selective activator of human eosinophil function. Journal of Experimental Medicine 167: 219-224 28. Kimani G, Tonnesen M G, Henson P M 1988 Stimulation of eosinophil adherence to human vascular endothelial cells in vitro by platelet-activating factor. Journal of Immunology 140: 3161-3166 29. Rothenbere M E. Pomerantz J L. Owen W F. Avraham S. Soberman k J, Austen K F, Stevens R L 1988 Characterization of a human eosinophil proteoglycan, and augmentation of its biosynthesis and size by interleukin 3, interleukin 5, and granulocyte/macrophage colony stimulating factor. Journal of Cellular Biochemistry 263: 1390-1398 30. Owen W F, Rothenberg M E, Petersen J, Weller P F, Silberstein D, Sheffer A L, Stevens R L, Soberman R J, Austen K F 1989 Interleukin 5 and phenotypically altered eosinophils in the blood of patients with the idiopathic hypereosinophilic syndrome. Journal of Experimental Medicine 170: 343-348 31. Bjornson B H, Harley J B, Andre’-Schwartz J, Fauci A S, Desforges J F 1982 Peripheral blood myeloid progenitor cell cultures in patients with hypereosinophilic syndrome (CFU-Eos in hypereosinophilic syndrome). Blood 60: 721-726 32. Rennick D M, Thompson-Snipes L A, Coffman R L, Sevmour B W P. Jackson J D. Hudak S 1990 In vivo ad’ministration of antibody to interleukin-5 inhibits increased generation of eosinophils and their progenitors in bone marrow of parasitized mice. Blood 76: 312-316 33. Basten A, Beeson P B 1970 Mechanism of eosinophilia II. Role of the lymphocyte. Journal of Experimental Medicine 131: 1288-1305 34. Lucey D R, Nicholson-Weller A, Weller P F 1989 Mature human eosinophils have the capacity to express HLA-DR. Proceedings of the National Academy of Sciences USA 86: 1348-1351 35. Enokihara H, Hamaguchi H, Sakamaki H, Hazama S, Saito K, Furusawa S, Shishido H 1985 Specific production of eosinophil colony stimulating factor from sensitized T-cells from a patient with allergic eosinophilia. British Journal of Haematology 59: 85-91 36. Enokihara H, Furusawa S, Kajitani H, Hamaguchi H. Saito K, Fukuda T, Shishido H 1988 Interleukin 2 stimulates the T cells from patients with eosinophilia to produce CFU-Eo growth stimulating factor. British Journal of Haematology 69: 431-436 37. Enokihara H, Furusawa S, Nakakubo H, Kajitani H, Nagashima S, Saito K, Shishido H, Hitoshi Y. Takatsu K, Noma T, Shimizu A, Honjo T 1989 T cells from eosinophilic patients produce interleukin-5 with interleukin2 stimulation. Blood 73: 1809-1813 38. Raghavachar A, Fleischer S, Frickhofen N, Heimpel H. Fleischer B 1987 T lymphocyte control of human eosinophilic granulopoiesis. Journal of Immunology 139: 3753-3158 39. Sedgwick J B, Frick W E, Sondel P M, Hank J A, Borden E, Busse W W 1990 The appearance of hypodense eosinophils during interleukin-2 treatment. Journal of Allergy and Clinical Immunology 85: 557-566 40. Ettinghausen S E, Moore J G, White D E, Platanius L, Young N S. Rosenbera S A 1987 Hematolonic effects of immunotherapy with l-pphokine-activated killer cells and recombinant interleukin-2 in cancer patients. Blood 69: 1654-1660 41. Silberstein D S, Scoof D D, Rodrick M L, Tai P-C, Spry C J F, David J R, Eberlein T J 1989 Activation of eosinophils in cancer patients treated with IL-2 and IL-2-generated lymphokine-activated killer cells. J Immunol 142: 21622167 42. Kern P, Dietrich M 1986 Eosinophil differentiating activity in sera of patients with AIDS under recombinant IL-2 substitution. Blut 52: 249-254
43. Ythier A A, Abbud-Filho M, Williams J M, Loertcher R, Schuster M W, Nowill A, Hansen J A, Maltezos D, Strom T B 1985 Interleukin-2-dependent release of interleukin-3 activity by T4+ human T-cell clones. Proceedings of the National Academy of Sciences USA 82: 7020-7024 44. Yamaguchi Y, Suda T, Shiozakai H, Miura Y, Hitoshi Y, Tominaga A, Takatsu K, Kasahara T 1990 Role of IL-5 in IL-2 induced eosinophilia: in vivo and in vitro expression of IL-5 mRNA bv IL-2. Journal of Immunoloev 145: 873-877 45. Sanderson C J’1990 The biological role of interleukin 5. International Journal of Cell Cloning 8: 147-154, Suppl 1 46. Ramos T 1989 Interleukin 5 is a differentiation factor for cytotoxic T lymphocytes. Immunology Letters 21: 277-284 41. Matsumoto R. Matsumoto M. Mita S. Hitoshi Y. Ando M, Araki S, Yamaguchi N, Tdminaga ‘A, Takatsu’ K 1989 Interleukin-5 induces maturation but not class switching of surface &A-positive B cells into IgA-secreting cells. Immunology 66: 32-38 48. Loughnan M S, Takatsu K, Harada N, Nossal G J V 1987 T-cell replacing factor (interleukin-5) induces expression of interleukin 2 receptors on murine splenic B cells. Proceedings of the National Academy of Sciences USA 84: 5399-5403 49. Aoki T, Kikuchi M, Miyatake S-I, Oda Y, Iwasaki K, Yamasaki T, Kinashi T, Honjo T 1989 Interleukin 5 enhances interleukin-2-mediated lymphokine-activated killer activity. Journal of Experimental Medicine 170: 583-588 50. LeBeau M M, Lemons R S, Espinosa R, Larson R A, Arai N, Rowley J D 1989 Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemia with a Del (5q). Blood 73: 647-650 51. Coffman R L. Sevmour B W P. Hudak S. Jackson J. Rennick D 1989 Antibody to idterleukin-5 inhibits ’ helminth-induced eosinophilia in mice. Science 245: 308-310 52. Sher A, Coffman R L, Hieny S, Scott P, Cheever A W 1990 Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni. Proceedings of the National Academy of Sciences USA 87: 61-65 53. Limaye A P, Abrams J S, Silver J E, Ottesen E A, Nutman T B 1990 Regulation of narasite-induced eosinonhilia: selectively in&eased interleukin-5 production in ‘helminthinfected patients. Journal of Experimental Medicine 172: 399-402 54. Schooley R T, Flaum M A, Gralnick H R, Fauci A S 1981 A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. II. Clinical manifestations. Blood 58: 1021-1026 55. Fauci A S, Harley J B, Roberts W C, Ferrans V J, Gralnick H R. Biornson B H 1982 The idionathic hypereosinophilic syndrome: clinical, pathop’hysiologic, and therapeutic considerations. Annals of Internal Medicine 97: 78-92 56. Spry C J F, Tai P-C, Davies J 1983 The cardiotoxicity of eosinonhils. Posteraduate Medical Journal 59: 147-151 51. Olsen E G J, Spr’y C J F 1985 Relation between eosinophilia and endomyocardial disease. Progress in Cardiovascular Disease XXVII: 29-54 58. Presti C, Ryan T, Armstrong W F 1982 Two-dimensional and doppler echocardiographic findings in hypereosinophilic syndrome. American Heart Journal 114: 172-175 59. Gottdiener J S, Maron B J, Schooley R T, Harley J B, Roberts W C, Fauci A S 1983 Two-dimensional echocardiographic assessment of the idiopathic hypereosinophilic syndrome: anatomic basis of mitral regurgitation and peripheral embolization. Circulation 67: 572-578 60. Hendron W G, Jones E L, Smith M D 1988 Aortic and mitral valve replacement in idiopathic hypereosinophilic syndrome. Annals of Thoracic Surgery 46: 570-571 61. Jederlinic P J, Sicilian L, Gaensler E A 1988 Chronic eosinophilic pneumonia; a report of 19 cases and a review of the literature. Medicine 67: 154-162 62. Kazmierowski J A, Chusid M J, Parrillo J E, Fauci A S, Wolff S M 1978 Dermatologic manifestations of the hypereosinophilic syndrome. Archives of Dermatology 114: 531-535
BLOOD REVIEWS 63. Newton J A, Singh A K, Greaves A4 W, Spry C J F 1990 Aquagenic pnuitis associated with the idiopathic hypereosinophihc syndrome. British Journal of Dermatology 122: 103-106 64. Katzen D R, Leiferman K M, Weiler P F, Leung D Y M 1986 Hypereosinophilia and recurrent angioneurotic edema in a 2 l/2-year-old girl. American Journal of the Diseases of Children 140: 62-64 65. Van Den Hoogenband H M, Van den Berg W H H W, Van Diggelin 1985 PUVA therapy in the treatment of skin lesions of the hypereosinophilic syndrome. Archives of Dermatology 121: 450 66. Moore P M, Harley J B, Fauci A S 1985 Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Annals of Internal Medicine 102: 109-l 14 67. Weingarten J S, O’Shea1 S F, Margolis W S 1985 Eosinophilic meningitis and the hypereosinophilic syndrome. Case report and review of the literature. American Journal of Medicine 78: 674-676 68. Kaplan P W, Waterbury L, Kawas C, Bolla-Wilson K, Durack D 1989 Reversible dementia with idiopathic hypereosinophilic syndrome. Neurology 39: 1388-1391 69. Martin-Gonzalez E, Yebra M, Garcia-Merion A, Liano H 1986 Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Annals of Internal Medicine 104: 449-450 70 Monaco S, Lucci B, Laperchia N, Tezzon F, Curro-Dossi B, Nardelli E, Giannini C, Rizzuto N 1988 Polyneuropathy in hypereosinophilic syndrome. Neurology 38: 494-496 71. Dorfman L F. Ransom B R. Forno L S. Kelts A 1983 Neuropathy in the hypereosmophilic syndrome. Muscle and Nerve 6: 291-298 72 Rosenberg H F, Tenen D G, Ackerman S J 1989 Molecular cloning of the human eosinophil-derived neurotoxin. A member of the ribonuclease gene family. Proceedings of the National Academy of Science USA 86: 4460-4464 13. Shah A M, Joglekar M 1987 Eosinophilic colitis as a complication of the hypereosinophilic syndrome. Postgraduate Medical Journal 63: 485-487 14. Peison B, Benisch B, Lim M, Chin J A 1988 Idiopathic hypereosinophilic syndrome with polymyositis. Southern Medical Journal 81: 403-406 75. Hardy W R, Anderson R E 1968 The hypereosinophilic svndromes. Annals of Internal Medicine 68: 1220-1229 76. Shmgaard A, Ascensao J, Zanjani E, Jacob H S 1983 Pulmonary carcinoma with eosinophilia: demonstration of a tumor-derived eosinophilopoeitic factor. New England Journal Medicine 309: 778-781 77. Balducci L, Chapman S W, Little D D, Hardy C L 1989 Paraneoplastic eosinophilia: report of a case with in vitro studies of hemopoiesis. Cancer 64: 2250-2253 78. Serke S, Brenner M, Zimmermann R, Lobeck M 1986 Malignant fibrous histiocytoma associated with peripheral blood eosinophilia: in vitro studies demonstrating tumorderived eosinophilopoietic activity. Oncology 43: 230-233 79. Brown N J, Stein R S 1989 Idiopathic hypereosinophilic syndrome progressing to acute myelomonocytic leukemia with chloromas. Southern Medical Journal 82: 1303-1305 80. Franchi F, DeRosa F, Seminara P, Calvieri S, Carfagna G F, Bosman C 1984 Hypereosinophilic syndrome and plasmacytoma: report of a case and review of the literature. Acta Haematologica 72: 14-20 81. Troxell M L, Mills G M, Allen R C 1984 The hypereosinophilic syndrome in acute lymphocytic leukemia. Cancer 54: 1058-1061 82. Kimura H, Abe R, Shiga Y, Sato T, Kawaguchi M, Matsuda S, Uchida T, Kariyone S 1987 A case of acute myelogenous leukaemia associated with eosinophilia: cytogenetic study of eosinophilic colonies showing the origin of the normal clone. Acta Haematologica 77: 15-19 83. Baumgarten E, Wegner R D, Fengler R, Ludwig W D, Schulte-Overberg U, Domeyer C, Schuurmann J, Henze G 1989 Calla-positive acute leukemia with t(5q;l4q) translocation and hypereosinophilia-a unique entity? Acta Haematologica 82: 85-90 84. Hogge D E, Misaw A S, Parsa N Z, Pollak A, Testa J R 1984 Abnormalities of chromosome 16 in association with acute myelomonocytic leukemia and dysplastic bone marrow eosinophils. Journal of Clinical Oncology 2: 550-557
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85. Najfeld V, Seremetis S, Troy K, Uehlinger J, Schwartz P, Cuttner J 1986 Trisomy 22-A new abnormality found in acute leukemia characterized by eosinophilia and monocytoid blasts expressing immature differentiation antigens. Cancer Genetics and Cytogenetics 23: 105-l 14 86. Keene P. Mendelown B. Pinto M R, Bezwoda W, MacDodgall L, Falkson G, Ruff P, ‘Bernstein R 1987 Abnormalities of chromosome 12~13 and malignant proliferation of eosinophils; a nonrandom association British Journal of Haematoloev 67: 25-3 1 87. Broustet A, Bernard P, Dach&y D, David B, Marit G, Lacombe F, Issanchou A M, Reiffers J 1986 Acute eosinophilic leukemia with a translocation (1Op+ ; 11q - ), Cancer Genetics and Cytogenetics 21: 327-33 88. Parreira L, DeCastro J T, Hibbin J A, Marsh J C W, Marcus R E, Babapulle V B, Spry C J F, Goldman J M, Catovsky D 1986 Chromosome and cell culture studies in eosinophilic leukaemia. British Journal of Haematology 62: 659-669 89. Hertzman P A, Blevins W L, Mayer J. Greenfield B, Ting M, Gleich G J 1990 Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. New England Journal Medicine 322: 869-873 _ 90. Swvaert L A. Maew E F. Sewell L E. Miller L. Falk H. Kilbiume E ‘M 1990 Eosinophilia-myalgia syndrome: results of national surveillance. Journal of the American Medical Association 264: 1698-1703 91. Belongia E A, Hedberg C W, Gleich G J, White K E, Mayeno A N, Loegering D A, Dunnette S L, Pirie P L, MacConald K L. Osterholm M T 1990 An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. New England Journal of Medicine 323: 357-365 92. From the Centers for Disease Control. Analysis of L-tryptophan for the etiology of eosinophilia-myalgia syndrome 1990 Journal of the American Medical Association 264: 1656 93. Silver R M, Heyes M P, Maize J C, Quearry B, VionnetFuasset M, Sternberg E M 1990 Scleroderma, fascitis, and eosinophilia associated with the ingestion of tryptophan. New England Journal of Medicine 322: 874-881 94. Parrillo J E, Fauci A S, WolfI S M 1978 Therapy of the hypereosinophilic syndrome. Ann Int Med 89: 167-172 95. Schooley R T, Parillo J E, Wolff S M, Fauci A S 1980 Management of the idiopathic hypereosinophilic syndrome. In: Mahmoud A A F. Austen K F. eds. The eosinonhil in health and disease. Grune and Stratton, p 323-343 _ 96. Prin L, Lefebvre P, Gruart M, Capron M, Storme L, Formstecher P, Loiseau S, Capron A 1989 Heterogeneity of human eosinophil glucocorticoid receptor expression in hypereosinophilic patients: absence of detectable receptor correlates with resistance to corticotherapy. Clinical Experimental Immunology 78: 383-389 97. Enokihara H, Kajitani H, Nagashima S, Stunogake S, Takano N, Saito K, Furusawa S, Shishido H, Hitoshi Y, Takatsu K 1990 Interleukin 5 activity in sera from patients with eosinophilia. British Journal of Haematology 75: 458-462 98. Cofranesco E, Cortellaro M, Pogliani E, Boschetti C. Salvatore M, Polli E E 1984 Response to vincristine treatment in a case of idiopathic hypereosinophic syndrome with multiple clinical manifestations. Acta Haematologica 72: 21-25 99. Marshall G M, White L 1989 Effective therapy for a severe case of the idiopathic hypereosinophilic syndrome. American Journal of Pediatric Hematology Oncology 11: 178-183 100. Archimbaud E, Guyutat D, Guillaume C, Godard J, Fiere D 1988 Hypereosinophilic syndrome with multiple organ dysfunctions treated by allogeneic bone marrow transplantation. American Journal of Hematology 27: 3022303 101. Murphy P T, Fennelly D F, Stuart M, O’Donnell J R 1990 Alfa-interferon in a case of hvpereosinophilic svndrome. British Journal of Haematology 75: 6191620 _ 102. Dautrv-Varsat A. Hemar A. Comet V. Duorez V 1988 Autocrine growth of a human T-cell line is inhibited by cyclosporin A. Blood 72: 588-592 103. Palacios R 1982 Mechanism of T cell activation: Role and functional relationship of HLA-DR antigens and interleukins. Immunological Reviews 63: 73-l 10
J. L. Liesveld, C. N. Abboud S UMMA R Y. Many disease states such as parasitic infestations, malignancies, collagen vascular diseases, and allergies are associated with eosinophilia. The diagnosis of idiopathic hypereosinophilic syndrome (HES) requires a persistent elevation in the total eosinophil count (> 1500/mm3) for over 6 months, associated organ damage and no detectable underlying cause. This review provides an updated summary of the cytohine cascade that controls eosinophil production and delineates our current understanding of the clinical features of hypereosinophilic states. We also examine the central role of T-lymphocyte activation in eosiuophilia, and have attempted to integrate current treatment strategies for HES with the physiology of eosinophilopoiesis.
Eosinophil Granules and Activation
The eosinophil has been the subject of continued scrutiny since its initial description by Paul Ehrlich in 1879,’ and new interest in the eosinophil has been recently sparked by description of the eosinophiliamyalgia syndrome. ’ The eosinophil is a type of granulocyte, the specific granules of which become apparent at the early myelocyte stage of development. Eosinophilic granules are membrane-bound and are resolvable with the light microscope. The eosinophil and its granule substances have been the subjects of many comprehensive reviews. 3-5 Granular substances produced by eosinophils include: 1) major basic protein, an alkaline core protein capable of damaging schistosomula and tumor cells, 2) eosinophi1 peroxidase, a matrix protein involved in halide and H,O,-producing interactions, 3) eosinophil cationic protein which is involved in fibrinolysis and is toxic to Schistosomula, 4) eosinophil-derived neurotoxin, and 5) lysophospholipase, the Charcot-Leyden crystal protein. In addition to their role in helminthotoxicity and in damping hypersensitivity reactions J. L. Liesvebd, C. N. Abboud MD,, Hematology Unit, PO Box 610, University of Rochester Medical Center, 601 Mmwood Avenue, Rochester, NY 14642, USA. Blood Reviews (1991) 5.029-037 0 1991 Longman Group UK Ltd
by enzyme neutralization of slow releasing substance of anaphylaxis, histamine, and platelet activating factor; eosinophil granules have been shown in vitro systems to be damaging to normal tissues. As examples, major basic protein causes exfoliation of respiratory epithelial cells and impairment of ciliary function, and cationic eosinophil proteins have been shown to have myocardial toxicity. Tumor necrosis factor alpha/cachectin has also been shown to stimulate eosinophil oxidant production and toxicity toward human endothelium. This toxicity was thought to be possibly mediated by eosinophil peroxidase.6 There is a large reserve pool of eosinophils with a high turnover rate so that rapid changes can occur in the number of circulating eosinophils. Eosinophil egress into the circulation and tissue migration are influenced by many factors. These include eosinophil chemotactic factor of anaphylaxis, histamine, C5a, antigen-antibody complexes, the chemotactic peptide, FMLP, leukotriene Bq, and platelet activating factor (PAF).7 Platelet activating factor can cause eosinophils to adhere to vascular endothelial cells. It is an alkyl phospholipid produced at inflammatory sites by endothelial cells, platelets, granulocytes, and monocytes. PAF also induces the release of eosinophil major basic protein, leukotriene Cq, and superoxide.
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STATE OF THE ART: THE HYPEREOSINOPHILIC
SYNDROMES
Cytokines such as granulocyte-macrophage colonystimulating factor (GM-CSF) and interleukin 5 (IL-5) can mediate eosinophil activation.’ IL-5 in addition is a selective eosinophil chemoattractant.g Furthermore, HILDA, human interleukin for DA-2 cells (murine IL-3 dependent cell line) is a chemoattractant for and activator of mouse and human eosinophils. lo Taken together, all these factors may participate in the local inflammatory responses and eosinophilmediated tissue damage.
murine marrow, synergistic interactions between IL-l, IL-3, and IL-5 are required for in vitro production of eosinophils from primitive hemopoietic cells. IL-l and IL-3 act early whereas IL-5 acts on already committed progenitors. l4 Preincubation of human marrow cells with granulocyte CSF (G-CSF) for 24-72 h followed by IL-5 indicates that G-CSF acts on early stage progenitors to increase eosinophilic commitment.’ 5 These synergistic interactions are illustrated in Figure 1.
Normal Eosinophilopoiesis
Hypereosinophilic Syndromes
The role of hemopoietic growth factors and interleukins in the regulation of eosinophil production, progenitor amplification and precursor maturation is illustrated in Figure 1. Synergistic interactions apply to early eosinophil progenitors while lineage specific factors act on later committed progenitors and eosinophil precursors. Using human marrow null cells, it has been found that interleukin 3 (IL-3) or granulocyte-macrophage colony stimulating factor (GM-CSF) are able to support eosinophil colony formation independently from one another. l1 Some of the resultant colonies are of mixed lineage, and many of them contain promyelocytes, myelocytes, and metamyelocytes. IL-5 alone gave rise to small numbers of pure eosinophilic colony forming units (CFU-Eo) consisting of mature cells. When IL-5 was combined with IL-3 or GM-CSF, larger eosinophil colonies of intermediate differentiation were seen. This was interpreted to mean that targets for IL3/GM-CSF are earlier in eosinophilipoiesis, whereas IL-5 acts on terminal, mature cells.” Clutterback et al” have shown that IL-5, IL-3, and GM-CSF stimulate the appearance of eosinophilic colonies in the same time course. IL-5 was additive but not synergistic with IL-3 or GM-CSF indicating that it may stimulate a smaller and possible different subset of progenitors and that it appears to have little or no effect on commitment. In vitro eosinophil production in response to IL-5 was maximal by 21 days.13 In
Disease states associated with eosinophilia are many and include parasitic infestation with tissue-invasive organisms, extrinsic (allergic) bronchial asthma, allergic rhinitis, pulmonary aspergillosis, vasculitides, miscellaneous collagen vascular diseases and neoplasms. l6 In humans, eosinophil counts >500/mm3 warrant investigation, and it must be kept in mind that blood eosinophils are only a small fraction of the total pool with the skin, gastrointestinal tract, lung, and marrow serving as prime tissue sites. In some cases of eosinophilia, despite extensive search, an underlying cause for eosinophilia cannot be found, in which case a diagnosis of idiopathic hypereosinophilic syndrome (HES) is made. Specific criteria for this disorder which encompasses a heterogeneous group of disorders were put forward by Chusid and others.” These are: 1) Persistent eosinophilia greater than or equal l,500/mm3 for > 6 months or death before 6 months with signs and symptoms of HES, 2) no underlying cause for eosinophilia, and 3) signs and symptoms of organ involvement.
EARLY
PRIMITIVE
MATURE
EOSINOPHIL
EOSINOPHIL PROGENITOR
EOSINOPHIL
PROGENITOR CFU-Ea
Syneralstlc factors IL-I
+ IL-3
IL-5
IL-5
GM-CSF
GM-CSF
_
GM-CSF
t
n
+ IL-5
IL-3
+ IL-5
G-CSF
+ IL-5
Fig. 1 A schema of eosinophil maturation illustrating site of hemopoietic growth factor action. IL= Interleukin, G-CSF= granulocyte colony stimulating factor, GM-CSF= granulocytemacrophage colony stimulating factor, CFU-Eo= eosinophil colony forming unit.
Properties of Eosinophils in HES
Studies of eosinophils from eosinophilic states have shown several altered properties. The eosinophils are often hypodense as compared to normal eosinophils. They are degranulated with low eosinophil cationic protein levels, and they demonstrate higher 0, consumption. l8 Some studies have shown that these hypodense eosinophils have increased Fc IgG receptorsl’ and others have shown no change in Fc gamma expression. lg It has been found that eosinophils from patients with eosinophilia of diverse causation demonstrate increased adherence to and functional capacity in an antibody dependent cytotoxicity (ADCC) assay against helminths in vitro.20,21 The eosinophils in HES have been found to release normal amounts of 5-lipooxyenase and 15-lipooxygenase and to be capable of degranulation after calcium ionophore A23 187 and opsonized zymosan particle exposure.22 The vacuolated cytoplasmic granules seen in HES states are thought to indicate prior activation and degranulation. Several cytokines have been found to activate eosinophils and to result in production of hypodense cells. Granulocyte-monocyte colony stimulating fac-
BLOOD REVIEWS
tor (GM-CSF) has been shown in vitro to enhance eosinophil cytotoxicity and leukotriene synthesis.23 When normodense human peripheral blood eosinophils are cultured with recombinant human GM-CSF in the presence of mouse 3T3 cells, they are capable of surviving for 14 days, and they become hypodense and demonstrate increased LTC4 generation and &histosoma mansoni larvae cytotoxicity.24 Similarly, IL-3 can increase eosinophil viability, cause increased eosinophil LTC4 production in response to calcium ionophore, increase eosinophil Schistosoma killing, and cause eosinophils to become hypodense.25 Interleukin-5 in both human and murine systems has been found to have effects on eosinophil activation. In mice, IL-5 has been found to maintain viability, induce superoxide production, and exert a chemokinetic effect on normal eosinophils.26 In humans, IL-5 causes appearance of hypodense eosinophils, membrane ruffling and polarization, increased anti-tumor ADCC, and stimulation of O,-production.*’ Normal eosinophils have also been reported to become hypodense in the presence of platelet activating factor and to demonstrate increased adherence to normal endothelium mediated through increased CD18 (the p2 adhesion receptor of LFA-1, Mol , and pl50,95) expression. 28 IL-3, IL-5, and GM-CSF have also been found to augment synthesis of a sulfated proteoglycan from human eosinophils.29 Thus, exposure of normal eosinophils to IL-3, IL-5, and GM-CSF in vitro causes appearance of hypo-dense eosinophils which demonstrate increased anti-helminthic ADCC and increased calcium ionophore-mediated LTC, production. In 3 patients with HES unresponsive to corticosteroids, a population of hypodense eosinophils was found to be most effective in anti-helminth ADCC and to survive best in culture. When normodense normal eosinophils were cultured with serum from these HES patients, a dose-dependent increase in viability occurred, and the cells were converted to hypodense. Anti-IL-5 neutralized these serum effects while anti-GM-CSF and anti-IL-3 had no effect.30 It was thus postulated that excess IL-5 may account for the activated hypodense eosinophil morphology seen in hypereosinophilia. An example of a culture-derived hypodense eosinophil is shown in the transmission electron micrograph in Figure 2. Mechanisms for Increased Eosinophil Production in Hypereosinophilic Syndromes Role of T-Lymphocytes and Interleukins When eosinophilopoiesis has been studied in patients with HES31 approximately half (7 out of 13) were found to have normal numbers of CFU-Eo. Five out of 13 patients had increased numbers of CFU-Eo, and some of these cases showed evidence of increased eosinophil CSF while others demonstrated excess commitment to eosinophil differentiation. In bone marrow of mice parasitized with Nippostryongylus brasiliensis, marrow contains elevated numbers of
31
Fig. 2 A transmission electron micrograph showing human marrow-derived eosinophils obtained from methylcellulose cultures at 14 days. Note the many incomplete ‘hypodense’ granules in the cytoplasm.
eosinophils as early as 4 days after infection. Also, progenitors that form eosinophil colonies in soft agar cultures are increased. These marrow eosinophils and eosinophil precursors can be eliminated by infusion with anti-IL-5 antibodies at the time of infection, indicating a regulatory role for IL-5 in parasiteinduced eosinophilia.32 T-Lymphocyte Role in Eosinophilia
Early studies of Basten and Beeson demonstrated that lymphocytes sensitized to Trichinella were able to produce a soluble substance which resulted in selective marrow production of eosinophils when administered to mice in vivo. The importance of T-lymphocytes for the eosinophilic response of rats to Trichinella spiralis infection was shown by inhibition of the response with anti-thymocyte serum or neonatal thymectomy. 33 Unlike their neutrophil counterparts, mature human eosinophils become HLA-DR positive when cultured in the presence of 3T3 fibroblasts and GM-CSF.34 Thus activated eosinophils may interact closely with CD4+ T-lymphocytes through the DR locus. Enokihara et a13’ reported that when aspergillus extract was added to sensitized T-cells from a patient with allergic aspergillosis, conditioned medium from such cells had specific Eo-CSF activity. This effect was not elicited with patient non-T-cells or with mononuclear cells from normal subjects. Later, it was shown that IL-2 could substitute for the specific antigenic stimulation,36 and that effects of IL-2 could be neutralized with antibody to IL-5, the mRNA of which was induced by IL-2.37 In HES, where the antigenic stimulus for eosinophilia is unknown, it has been found that when T-cell clones are propagated with mitogen and IL-2, a subset can stimulate pure CFU-Eo marrow progenitor growth. The release of Eo-CSF from these clones can be inhibited by hydrocortisone or cyclosporine
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A. These T-cell clones were phenotypically T4 + T8 and produced IL-2. Furthermore, each clone had a different T-cell receptor beta chain rearrangement indicating a polyclonal activation.38 Taken together, these observations underscore the central role of T-cell activation in disorders associated with hypereosinophilia. Role of Interleukin-2 and T-cell Activation
It is of interest that in patients treated with interleukin-2/Lymphocyte Activated Killer Cell (LAK cell) administration, where reversible eosinophilia is noted, nearly all eosinophils become hypodense by the end of treatment.39 In one series of such patients, 12% demonstrated eosinophil counts greater than 10 OOO/mm3.4o It has been shown that these eosinophils also have eosinophil cationic protein in the secretory vs. storage form and increased ability to kill Schistosoma mansoni through antibody dependent cellular cytotoxicity mechanisms. IL-2 itself has no effect on eosinophils, and their progenitors but LAKcell conditioned medium could mediate these effects possibly through release of gamma interferon, lymphotoxin, or tumor necrosis factor alpha.41 Hypereosinophilia occurs also in AIDS patients receiving IL-2.42 The increase in eosinophils in this setting is preceded by a detectable eosinophilic factor in the sera of these patients. 42 These findings may be explained by the ability of IL-2 to mediate the release of IL-3 activity by human T-cells43 and enhance IL-5 mRNA expression in murine spleen cells.44 The eosinophilia which developed during IL-2 therapy could be eliminated by injection of a monoclonal antibody against murine IL-5.44 Interleukin-S and Eosinophil Regulation
Interleukin-5 has been identified as the principal eosinophilic regulatory factor.45 In addition to its effects on eosinophils, IL-5 induces differentiation of immature precursors into cytotoxic T-lymphocytes46 and induces maturation of IgA-producing B-cells.47 Murine IL-5 induces the expression of IL-2 receptor on splenic B-lymphocytes and PNA + thymocytes.48 IL-5 has also been found to enhance LAK activity in the presence of IL-2. 49 IL-5 maps to human chromosome 5 and is deleted in the Sq-syndrome.” Evidence has accumulated indicating that IL-5 mediates murine helminth-induced eosinophilia. In rodents with eosinophilia due to Nippostrongylus brasiliensis, injection of monoclonal antibody to IL-5 suppressed blood eosinophilia and infiltration of eosinophils into the lungs. The extent of infiltration with organisms and neutrophils was unchanged, however. Antibody to IL-4 inhibited only IgE production but not eosinophilia. The effect of IL-5 was mediated through TH2CD4 + cells. ” Also, antibody to IL-5 prevented blood and tissue eosinophilia in mice infected with Schistosoma mansoni but did not affect
granuloma formation or organism burden.52 It was postulated that lymphocytes belonging to the IL-5secreting subset predominate during the acute infection and may induce granuloma formation by the production of other cytokines. When 7 patients with helminth-induced eosinophilia were compared to 11 normals, levels of IL-3 and GM-CSF were similar between groups whereas IL-5 was increased at the protein and mRNA level in those with eosinophilia.53 Taken together, these findings underscore the central role of IL-5 in eosinophil regulation. Clinical Manifestations of HES Clinical features of the hypereosinophilic syndromes have been reviewed previously.’ 7*54*55The disease has male predominance and peak age of onset in the fifth decade. Some cases are diagnosed incidentally based on blood counts, and often the presenting symptoms are either nonspecific (e.g., fever, weight loss) or are related to specific organ involvement. Physical findings may include hepatosplenomegaly while lymphadenopathy is uncommon. In addition to blood eosinophilia, anemia and thrombocytopenia may be seen. Red cell poikilocytosis (teardrop forms) has been seen, and the eosinophils may be vacuolated and abnormally granulated. On marrow examination, an eosinophilia of > 30% is usually seen. Cytogenetic abnormalities described have been nonspecific. Involvement of almost all organ systems has been reported. The organs most commonly involved include heart, lungs, skin, and the nervous system. Cardiac Disease
The heart is involved in over 90% of HES cases, and cardiovascular disease is a principal cause of death in patients with HES. Cardiac dysfunction can also occur with eosinophilia of known cause, and there is evidence that eosinophil products are damaging to the myoendocardium. 56s7 Degranulated eosinophils may be found in the endomyocardium, and eosinophilic cationic protein blood levels are often elevated. Such proteins have been shown to damage isolated mammalian heart muscle cells in vitro and to have a toxic effect on enzyme complexes involved in mitochondrial respiration.56 Histologically, the primary site of damage is the endocardium. Fibrotic thickening of the endocardium ensues which may involve the posterior mitral and/ or tricuspid valve leaflets. Mural thrombi are also often seen as are thrombosis and inflammation of small intramyocardial vessels.55 Infiltration of eosinophils is usually not seen in the late stages of cardiac involvement which are characterized by fibrosis and thrombosis. Eosinophils can be seen during early necrotic stages.56 M-mode and 2-D echocardiography are abnormal in the majority of these cases studied.5B,5g Findings often include increased left ventricular wall thickness,
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abnormal motion of the posterior mitral valve leaflet, and left ventricular thrombi. Some cases of right ventricular thrombus have been seen, and dense endocardial fibrosis of papillary muscles, chordae, and valves can occur. Cardiac dysfunction in HES is most commonly produced by combined effects of endocardial fibrosis resulting in restriction to inflow and intracavitary thrombosis with outflow tract obliteration, Mitral regurgitation and tricuspid regurgitation occur secondary to involvement of the posterior papillary muscle with endocardial fibrosis, Aortic and mitral valve stenosis have also been reported in HES.60 It is recommended that patients with cardiac manifestations be managed with inotropic, diuretic, and afterload reduction therapy as required. Many patients with A-V valvular insufficiency show improvement after valve replacement. Because of the tendency for acute prosthetic valve stenosis due to the eosinophilia, 6o it is recommended that bioprotheses with long-term anticoagulation be used in these patients. The role of eosinophil reduction is uncertain in terms of preventing evolution of cardiac disease but is presumed beneficial.55
Pulmonary Disease
The most common symptoms related to eosinophil infiltration of the lungs are cough and dyspnea. NonHES related causes of pulmonary eosinophilias include Loeffler’s syndrome which is self-limited, PIE which is chronic, and hypersensitivity pneumonitis in which a known allergen is involved (e.g. allergic bronchopulmonary aspergillosis). In patients with chronic eosinophilic pneumonia, 89% will have blood eosinophilia. ‘l In their absence, lung biopsy is required to make a definitive diagnosis. Gas exchange may be impaired in these cases, and peripheral infiltrates are the most common chest x-ray finding. These are often bilateral and involve the upper zones. Many patients with chronic pulmonary involvement have rapid response to corticosteroid therapy, but many require prolonged treatment for disease control.61
Skin Disease
Approximately 50% of cases of HES have skin manifestations.62 Skin involvement may be the only manifestation of HES, and skin lesions often improve with treatment. The two types of involvement most commonly seen are: 1) erythematous pruritic papules and nodules of the trunk and extremities and 2) urticaria/angioedema. Biopsy often shows a mixed inflammatory infiltrate with a high proportion of eosinophils. 63 In some cases of dermal eosinophil infiltration, deposition of major basic protein in the extracellular matrix has been seen.64 PUVA treatment has been found to have efficacy when skin disease is the sole manifestation of HES.65
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Neurologic Disease
Over half of the patients with hypereosinophilic syndrome have neurologic involvement.66 This involvement may take the form of a generalized encephalopathy, peripheral neuropathy, or focal deficits from emboli or hemorrhage. CSF and CT findings are often normal in patients presenting with encephalopathy, but cases of CSF eosinophilia have been reported. 67 Most cases of CSF eosinophilia involve parasitic infiltration with Taenia solium or Angiostrongylus cantonensis. Reversible dementia responsive to steroids has also been reported in HES.68 Most commonly, the peripheral neuropathy seen in these syndromes is a symmetrical sensory polyneuropathy. Patients often complain of peripheral paresthesias or numbness. This peripheral involvement can take the form of radiculopathy or motor neuropathy. Electrodiagnostic studies often show an axonal pattern of denervation but may be norma1.70*71The prognosis of the sensory polyneuropathy is variable but many patients have residual disability even after eosinophilia is controlled with medical therapy. Muscle biopsies may show type II atrophy and eosinophilic infiltrates. On nerve biopsy, demyelination or axonal dropout may be seen.@j The mechanism of neurologic damage in eosinophilia may relate to direct infiltration or to production of eosinophil-derived neurotoxin, a cationic protein with ribonuclease function.72 Other Organ Involvement
Patients with HES may present anywhere on a continuum ranging from eosinophilic leukemia to an isolated skin rash. Survival in these cases seems more related to extent of organ involvement than to eosinophi1 counts. Other organs which have been reported to be involved in these syndromes include the eyes (retina), gastrointestinal tract (colitis with diarrhea73), liver, spleen, kidneys, muscle,74 and rarely, lymph nodes. Thromboembolic disease can also involve diffuse organs; e.g., hepatic vein obstruction. Some patients seem prone to recurrent thromboemboli despite adequate anticoagulation. In one reported series 5 out of 21 cases of HES studied had peripheral embolization.59 Other Eosinophilic States HES and Malignancy
Eosinophilia has been associated with many malignancies, although these cases with underlying causation do not qualify as HES. In contrast, true eosinophilic leukemia is often considered one part of the spectrum of diseases encompassed by the term HES.75 The secondary eosinophilias seen with solid tumors are often the result of tumor-derived eosinophilopoietic activity. This has been reported for tumors as diverse as pulmonary tumors,76 medullary
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STATE OF THE ART: THE HYPEREOSINOPHILIC SYNDROMES
carcinoma of the thyroid” and malignant fibrous histiocytoma. 78 Eosinophilia can also be seen in cases of AML, ALL, and CML, and idiopathic HES has been reported to evolve to AML79 and to occur in the setting of plasmacytoma.*’ In many cases of eosinophilia associated with ALL*’ or AML,*’ the eosinophil proliferation has appeared to be reactive based upon either resolution with treatment of the underlying leukemia or on cytogenetic analysis. In some cases, Calla positive acute leukemias have been associated with substantial leukocytosis and eosinophilia with a t(5q;l4q) translocation.83 It has been found that involved bands are 5q31.1 and 14q32.3 with GM-CSF and immunoglobulin heavy chain association, respectively. It is also of interest that IL-5 is located at 5q31. In some cases of acute myelomonocytic leukemia, abnormalities of chromosome 16 have been noted in association with eosinophilia. The most commonly seen abnormality is inv( 16)(pl3q22), but deletions and translocations involving 16q22 have also been reported. The marrow eosinophils are dysplastic or abnormal in morphology making this distinct from HES or eosinophilic leukemia.84 Trisomy 22 has been seen with monocytic leukemias with eosinophilia.85 In contrast to secondary eosinophilic proliferation with malignancy, cases of primary eosinophilic leukemia are also seen. Various cytogenetic abnormalities have been associated with eosinophilic leukemia including 12~13,~~ t(lOp+,llq-),*’ and trisomy 8.** Tryptophan-induced Eosinophilia-myalgia Syndrome
The eosinophilia-myalgia syndrome, characterized by peripheral eosinophilia and scleroderma-like features, was first reported in late 1989 by physicians in New Mexico and Minnesota. 89 An epidemiologic association between the syndrome and tryptophan consumption was soon confirmed. Tryptophan is an essential amino acid which is metabolized to serotonin and has been used to treat insomnia, depression, and other symptoms. Tryptophan-containing products have now been recalled from retail markets in the United States with a concomitant drop in the numbers of reported cases. As of July 1990, approximately 1,500 cases had been reported nationwide.” Numerous symptoms other than myalgia have been reported in this syndrome including muscle tenderness, fatigue, edema, arthralgia, neuropathy, rash, cough, and dyspnea. Deaths due to ascending polyneuropathy were also noted. HPLC of tryptophan from lots associated with the syndrome have shown a chemical constituent thought to contribute to the pathogenesis of the eosinophilia. 91 Some of these products have been contaminated with the di-tryptophan aminal of acetaldehyde (DTAA). 92 The relationship of this compound to eosinophilia is unknown. Other investigators have suggested that tryptophan itself or its metabolites contribute directly to the syndromeg3 but this does not explain the absence of cases prior to 1989.
The syndrome is defined by debilitating myalgias and absolute eosinophilia greater than or equal to 1.0 x lo9 cells/L with other causes of eosinophilia such as infections or neoplasia excluded.90 Most patients with this syndrome have absolute eosinophil counts >2,000/mm3. Bone marrow usually shows hyperplasia of eosinophilic precursors. Muscle biopsy often shows perivascular inflammatory infiltrates with eosinophilia, round cells, and sparing of the interstitium. Often, the syndrome improves with discontinuation of tryptophan but in other cases worsens despite discontinuation of the medication. Glucocorticoids have been reported to be of benefit. Many patients are left with residual neural or muscular deficits. Treatment of HES HES has a poor natural history with a median survival time in untreated cases of 12 months.94 Both effective cytoreductive agents and treatment of cardiac disease are required. In the largest series of HES patients thus far reported,95 6 out of 33 required no specific treatment. These patients had significantly less organ involvement at diagnosis. Blood eosinophil counts were less predictable regarding need for eventual treatment. High white cell count, blasts, and conjestive heart failure at diagnosis indicate a poor prognosis, but with appropriate treatment, mortality at 3 years was only 4% in the NIH series. Nine out of 24 cases responded to prednisolone alone. Angioedema, high serum IgE levels, and eosinopenia in response to a challenge dose indicated positive prednisone response. Figure 3 illustrates potential sites of action of steroids (hydrocortisone) including negative regulation of macrophages and activated T-cells which secrete IL-2 or express the IL-2 receptor. The lack of response to steroids has been correlated with absence of detectable receptors on eosinophils,96 so steroids may also have a direct suppressive effect on these cells. Also, it has been demonstrated that interleukin 5 activity is increased in sera from patients with eosinophilia and that administration of prednisolone decreases IL5 and IL-2 activity in these sera.97 In those not responding to prednisone, hydroxyurea gives a significant response in the majority of cases. Figure 3 illustrates the inhibition of CFU-Eos by hydroxyurea. Other treatment modalities of anecdotal benefit in HES include leukapheresis, PUVA treatment for skin disease,65 vincristine,98 vincristine plus 6-mercaptopurine,99 allogeneic bone marrow transplantation,ioO recombinant alpha-interferon”’ and cyclosporine Ae3* Cyclosporine A acts to suppress activation of T-lymphocytes”’ and also acts to decrease the output of regulatory cytokines which stimulate eosinophil production from these lymphocytes. lo3 Such factors include GM-CSF, IL-5, and IL-2 as shown in Figure 3. Afterload reduction treatment and appropriate surgical intervention are indicated for cardiac involvement. The treatment
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Fig. 3 A model for increased CFU-Eo growth in eosinophilia showing interaction between antigen, monocytes/macrophages, IL-2 producing T cells and IL-2 responding T cells. Cytokine roles in mediating these interactions are indicated. Known sites of hydrocortisone, cyclosporine A, and hydroxyurea inhibition are illustrated. Action at all these sites leads to a decrease in eosinophil growth. y-IFN = gamma interferon, other abbreviations are as defined in the text.
modalities outlined here can be of benefit in both reactive and constitutive hypereosinophilic states. Acknowledgements This work was supported in part by PHS grant PO1 HL-18208 from the National Heart, Lung and Blood Institute. JLL is a Special Fellow of the Leukemia Society of America and the recipient of a James P. Wilmot postdoctoral cancer research award. We thank Dr. Marshall A. Lichtman for his helpful discussions and Carol B. Weed for her excellent assistance in the preparation of this manuscript.
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