Lymphocyte-variant hypereosinophilia

Lymphocyte-variant hypereosinophilia
Classification and external resources
ICD-10 D47.5
Orphanet 314970

Lymphocyte-variant hypereosinophila, also termed lymphocyte variant eosinophilia, is a rare condition in which hypereosinophilia or eosinophilia is caused by aberrant lymphocytes that function abnormally to stimulate the proliferation of eosinophil precursor cells which subsequently mature to eosinophils. The condition is sometimes associated with sever tissue injury due to eosinophil infiltrations and, while usually indolent or slowly progressive, may proceed to a leukemic phase. Hence, lymphocyte-variant hypereosinophilia can be regarded as a precancerous disease.[1]

Clinical presentation

Splenomegaly

The typical patient with lymphocyte-variant hypereosinophilia presents with an extended history of hypereosinophilia and cutaneous allergy-like symptoms.[2] Skin symptoms, which occur in >75% of patients, include erythroderma, pruritis, eczema, Poikiloderma, urticarial, and episodic angioedema.[2][3] The symptom of episodic angioedema in lymphocyte-variant hypereosinophilia resembles that occurring in Gleich's syndrome, a rare disease that is accompanied by secondary hypereosinophilia plus a sub-population of CD3(-), CD4(+) T cells and therefore proposed, at least in many patients, a subtype of lymphocyte-variant hypereosiophilia.[2][3] Biopsies of these erythroderma and eczema skin lesions find prominent accumulations of eosinophils.[3] Other presentations include; a) lymphadenopathy occurring in ~60% of patients; b) eosinophil infiltrations in lung similar to, and often diagnosed as, eosinophilic pneumonia, occurring in ~20% of patients; c) episodic angioedema-related gastrointestinal symptoms that are sometimes similar to symptoms of the irritable bowel syndrome occurring in ~20% of patients; d) rheumatologic manifestations of inflammatory arthralgias in ~20% of patients; and e) splenomegaly occurring in ~10% of patients.[4][5] Cardiovascular complications such as various types of heart damage (see above History section) and vascular injuries due to eosinophil infiltration and eosinophil-induced thrombosis are often critical components of persistent hypereosinohilia syndromes;[6] These complications are not a prominent component of lymphocyte-variant hypereosionophilia, occurring in <10% of patients.[4][5]

Pathogenesis

Following the historical findings cited above, studies identified the cytokine, interleukin 5 (IL5), as the eosinophil growth-stimulating CFU made by T cells from patients suffering the idiopathic hypereosinophilic syndrome.[7] Subsequent studies likewise identified IL5 as a cytokine being overproduced by certain lymphocytes taken from patients with lymphocyte-variant eosinophilia.[1][3] In consequence of the initial 1987 study, these studies, and further studies, lymphocyte-variant hypereosinophilia is viewed as a unique disease characterized by hypereosinophilia secondary to the pathological production of eosinophil growth factors, particularly IL5 but possibly also IL4; IL13, and GM-CSF by aberrant clones of T cells.[2][8] The aberrant T cell clone, as defined by immunophenotyping their expression of certain cell surface molecules, the cluster of differentiation (i.e. CD) proteins, varies from patient to patient; furthermore, some of these clones also exhibit clonal rearrangements in their T-cell receptor gene. The most common immunophenotypes in lymphocyte-variant eosinophilia are: a) CD3(−), CD4(+) T cells, b) CD3(+), CD4+, CD8(−) T cells, c) CD3(+), CD4(+), CD7(−) T cells also bearing αβ+ T cell receptors, d) CD3(+), CD4(+), CD7(-) T cells, and e) CD3(+), CD4(+), CD2(-) T cells.[2][3][4] Chromosome abnormalities such as breakage of the long ("q") arm of chromosome 16, partial deletions in the q arm of chromosome 6 or short ("p") arm of chromosome 10, and trisomy of chromosome 7 are occasionally detected in these T cells. Regardless of immunophenotype, these T cells typically express CD45RO plus HLA-DR and/or IL2RA (also termed CD25} cell surface antigens. Expression of these antigens is characteristic of activated memory T cells.[3]

The underlying cause(s) for the origination and expansion of the phenotypically and clonally aberrant T cells in lymphocyte-variant hypereosinophilia remains unclear. In all events, these aberrant T cells are not, at least initially, malignant although they do exhibit pathological behavior. They produce, in addition to interleukin 5, another eosinophil-stimulating cytokine, Granulocyte macrophage colony-stimulating factor. The aberrant T cells also produce: IL4, a T cell-stimulating cytokine; interleukin 13, a cytokine mediator of allergic reactions, particularly those occurring in the lung; IL2, a t cell-stimulating cytokine, tumor necrosis factor alpha, a proinflammatory cytokine that regulates immune responses, and, at least in the aberrant T cells of certain patients, Interferon gamma (i.e. IFGγ), s cytokine that regulates innate and adaptive immunity. These cells also stimulate other, non-clonal lymphocytes to secrete chemokine (C-C motif) ligand 17 (also termed CC17 or TARC), a T cell-stimulating cytokine belonging to the CC chemokine family. While IL-5 is regarded as the principal mediator of the eosinophilia found in lymphocyte-variant hypereosinophilia, one or more of the other cited cytokines may also contribute to this eosinophilia as well as other pathological features of the disease.[2][3][5]

Diagnosis

Criteria for the clinically defined diagnosis of lymphocyte-variant hypereosinophilia have not been strictly set forth. Diagnosis must first rule out other causes of eosinophilia and hypereosinophilia, such as those due to allergies, drug reactions, infestations, and autoimmune diseases as well as those associated with eosinophilic leukemia, clonal eosinophilia, systemic mastocytosis, and other malignancies (see causes of eosinophilia). Criteria for the diagnosis include findings of: a) long term hypereosinophila (i.e. eosinophil blood counts >1,500/microliter) plus physical findings and symptoms associated with the disease; b) bone marrow analysis showing abnormally high levels of eosinophils; c) elevated serum levels of Immunoglobulin E, other immunoglobulins, and CCL17; d) eosinophil infiltrates in afflicted tissues; e) increased numbers of blood and/or bone marrow T cells bearing abnormal immunophenotype cluster of differentiation markers as defined by fluorescence-activated cell sorting (see above section on Pathogenesis); f) abnormal T cell receptor arrangements as defined by polymerase chain reaction methods (see above section on Pathogenesis); and g) evidence of excessive IL-5 secretion by lymphocytes (see above section on Pathogenesis).[3][4][5] In many clinical settings, however, studies on the T cell receptor and IL-5 are not available and therefore not routine parts of the diagnostic work-up or criteria for the disease.[5] The finding of T cells bearing abnormal immunophenotype cluster of differentiation markers is critical to making the diagnosis.[2][9]

Treatment

Hydroxyurea(Hydroxycarbamide)

Lymphocyte-variant hypereosinophilia usually takes a benign and indolent course. Long term treatment with corticosteroids lowers blood eosinophil levels as well as suppresses and prevents complications of the disease in >80% of cases. However, signs and symptoms of the disease recur in virtually all cases if corticosteroid dosages are tapered in order to reduce the many adverse side effects of corticosteroids. Alternate treatments used to treat corticosteroid resistant disease or for use as corticosteroid-sparing substitutes include interferon-α or its analog, Peginterferon alfa-2a, Mepolizumab (an antibody directed against IL-5), Ciclosporin (an Immunosuppressive drug), imatinib (an inhibitor of tyrosine kinases; numerous tyrosine kinase cell signaling proteins are responsible for the growth and proliferation of eosinophils {see clonal eosinophilia}), methotrexate and Hydroxycarbamide (both are chemotherapy and immunosuppressant drugs), and Alemtuzumab (a antibody that binds to the CD52 antigen on mature lymphocytes thereby marking them for destruction by the body). The few patients who have been treated with these alternate drugs have exhibited good responses in the majority of instances. Reslizumab, a newly developed antibody directed against interleukin 5 that has been successfully used to treat 4 patients with the hypereosinophilic syndrome, may also be of use for lymphocyte-variant eosinophilia.[4][5][10][11] Patients suffering minimal or no disease complications have gone untreated.[4]

In 10% to 25% of patients, mostly 3 to 10 years after initical diagnosis, the indolent course of lymphocyte-variant hypereosinophilia changes. Patients exhibit rapid increases in lymphadenopathy, spleen size, and blood cell numbers, some cells of which take on the appearance of immature and/or malignant cells. Their disease soon thereafter escalates to an angioimmunoblastic T-cell lymphoma, peripheral T cell lymphoma, Anaplastic large-cell lymphoma (which unlike most lymphomas of this type is Anaplastic lymphoma kinase-negative), or Cutaneous T cell lymphoma.[2][5] The malignantly transformed disease is aggressive and has a poor prognosis. Recommended treatment includes chemotherapy with Fludarabine, Cladribine, or the CHOP combination of drugs followed by bone marrow transplantation.[3][12]

History

For years, lymphocyte-variant hypereosinophilia was used to describe hypereosinophila associated with any one of several aberrant T cell Lymphoproliferative disorders.lymphocyte-variant hypereosinophilia[2] In 1987, however, a 42-yr-old male patient was described who presented with cardiac failure, mitral heart valve regurgitation, pericardial effusion, splenomegaly, kidney dysfunction, non-specific skin lesions, a 6-year history of eosinophilia, and, on admission, an eosinophil blood count of 7,150 per microliter (normal <500/microliter), a level that was 50% of total white blood cells (normal <5%). Blood smears revealed that these eosinophils as well as other white blood cells were mature and normal in appearance. Bone marrow examination revealed greatly increased eosinophils (60% of nucleated cells) in all states of maturation but with a normal karyotype; tissue biopsies revealed eosinophil infiltrates in liver and skin as well as eosinophilic vasculitis. Cell cultures from the patient's bone morrow grew an abnormally high percentage (52%) of eosinophil Colony-forming units (CFUs). Nine of 25 cell clones derived from the patient's blood T cells stimulated abnormally high (>60%) eosinophil CFUs when incubated with bone marrow cells taken from a non-identical donor; supernatant fluid taken from the patient's T cells was also active in inducing eosinophil CFUs from the non-identical donor's bone marrow cells. Immunophenotyping of these eosinophil CFU-stimulating T cells indicated that they expressed the CD4 but not CD8 cell surface Cluster of differentiation antigen, suggesting that they were cytokine-secreting helper T cells. Characterization of the T cell receptor on these T cell's revealed several patterns of rearrangement in the receptor's β chains. The eosinophilia in this patient, therefore, appeared due to the expansion of a clone of T cells that secreted a factor stimulating bone marrow precursor cells to differentiate into normal eosinophils.[13]

Other lymphoid disorders associated with eosinophilia

Lymphoid neoplasms can be associated with eosinophilia presumably because of the secretion of eosinophil/eosinophil precursor cell-stimulating cytokines by the malignant lymphoid cells. Most commonly, this is seen in cutaneous T cell lymphoma, Adult T-cell leukemia/lymphoma, and angioimmunoblastic T cell lymphoma. Less often, it is seen in B cell neoplasms such as Hodgkin's lymphoma, and B cell acute lymphoblastic leukemia, particularly forms of the latter disease associated with the t(5;9)(q31;p24) translocation creating gene fusion between the IL3 (at chromosome 5q31) and the JAK2 (at chromosome 9p24). The JAK2-IL3 fusion gene associated disease is accompanied by the overproduction of IL3, a simulator of eosinophil and eosinophil precursor cell growth, by the neoplastic cells.[2]

References

  1. 1 2 Gotlib J (2015). "World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management". American Journal of Hematology. 90 (11): 1077–89. PMID 26486351. doi:10.1002/ajh.24196.
  2. 1 2 3 4 5 6 7 8 9 10 Boyer DF (2016). "Blood and Bone Marrow Evaluation for Eosinophilia". Archives of Pathology & Laboratory Medicine. 140 (10): 1060–7. PMID 27684977. doi:10.5858/arpa.2016-0223-RA.
  3. 1 2 3 4 5 6 7 8 9 Roufosse F, Cogan E, Goldman M (2004). "Recent advances in pathogenesis and management of hypereosinophilic syndromes". Allergy. 59 (7): 673–89. PMID 15180753. doi:10.1111/j.1398-9995.2004.00465.x.
  4. 1 2 3 4 5 6 Carruthers MN, Park S, Slack GW, Dalal BI, Skinnider BF, Schaeffer DF, Dutz JP, Law JK, Donnellan F, Marquez V, Seidman M, Wong PC, Mattman A, Chen LY (2017). "IgG4-related disease and lymphocyte-variant hypereosinophilic syndrome: A comparative case series". European Journal of Haematology. 98 (4): 378–387. PMID 28005278. doi:10.1111/ejh.12842.
  5. 1 2 3 4 5 6 7 Lefèvre G, Copin MC, Staumont-Sallé D, Avenel-Audran M, Aubert H, Taieb A, Salles G, Maisonneuve H, Ghomari K, Ackerman F, Legrand F, Baruchel A, Launay D, Terriou L, Leclech C, Khouatra C, Morati-Hafsaoui C, Labalette M, Borie R, Cotton F, Gouellec NL, Morschhauser F, Trauet J, Roche-Lestienne C, Capron M, Hatron PY, Prin L, Kahn JE (2014). "The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3-CD4+ aberrant T-cell phenotype". Medicine. 93 (17): 255–66. PMC 4602413 Freely accessible. PMID 25398061. doi:10.1097/MD.0000000000000088.
  6. ↑ Roufosse F (2013). "L4. Eosinophils: how they contribute to endothelial damage and dysfunction". Presse Medicale (Paris, France : 1983). 42 (4 Pt 2): 503–7. PMID 23453213. doi:10.1016/j.lpm.2013.01.005.
  7. ↑ Schrezenmeier H, Thomé SD, Tewald F, Fleischer B, Raghavachar A (1993). "Interleukin-5 is the predominant eosinophilopoietin produced by cloned T lymphocytes in hypereosinophilic syndrome". Experimental Hematology. 21 (2): 358–65. PMID 8425573.
  8. ↑ Butt NM, Lambert J, Ali S, Beer PA, Cross NC, Duncombe A, Ewing J, Harrison CN, Knapper S, McLornan D, Mead AJ, Radia D, Bain BJ (2017). "Guideline for the investigation and management of eosinophilia". British Journal of Haematology. 176 (4): 553–572. PMID 28112388. doi:10.1111/bjh.14488.
  9. ↑ Curtis C, Ogbogu PU (2015). "Evaluation and Differential Diagnosis of Persistent Marked Eosinophilia". Immunology and Allergy Clinics of North America. 35 (3): 387–402. PMID 26209891. doi:10.1016/j.iac.2015.04.001.
  10. ↑ Radonjic-Hoesli S, Valent P, Klion AD, Wechsler ME, Simon HU (2015). "Novel targeted therapies for eosinophil-associated diseases and allergy". Annual Review of Pharmacology and Toxicology. 55: 633–56. PMC 4924608 Freely accessible. PMID 25340931. doi:10.1146/annurev-pharmtox-010814-124407.
  11. ↑ Gotlib J (2015). "Tyrosine Kinase Inhibitors and Therapeutic Antibodies in Advanced Eosinophilic Disorders and Systemic Mastocytosis". Current Hematologic Malignancy Reports. 10 (4): 351–61. PMID 26404639. doi:10.1007/s11899-015-0280-3.
  12. ↑ Roufosse F (2015). "Management of Hypereosinophilic Syndromes". Immunology and Allergy Clinics of North America. 35 (3): 561–75. PMID 26209900. doi:10.1016/j.iac.2015.05.006.
  13. ↑ Raghavachar A, Fleischer S, Frickhofen N, Heimpel H, Fleischer B (1987). "T lymphocyte control of human eosinophilic granulopoiesis. Clonal analysis in an idiopathic hypereosinophilic syndrome". Journal of Immunology (Baltimore, Md. : 1950). 139 (11): 3753–8. PMID 3500229.
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