Lymphocyte-variant hypereosinophilia

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Lymphocyte-variant hypereosinophilia
Other namesLymphocyte variant eosinophilia

Lymphocyte-variant hypereosinophilia is a rare disorder in which eosinophilia or hypereosinophilia (i.e. a large or extremely large increase in the number of eosinophils in the blood circulation) is caused by an aberrant population of lymphocytes. These aberrant lymphocytes function abnormally by stimulating the proliferation and maturation of bone marrow eosinophil-precursor cells termed colony forming unit-eosinophils or CFU-Eos. [1]

Contents

The overly stimulated CFU-Eos cells mature to apparently normal appearing but possibly overactive eosinophils which enter the circulation and may accumulate in and damage various tissues. The disorder is usually indolent or slowly progressive but may proceed to a leukemic phase sometimes classified as acute eosinophilic leukemia. Lymphocyte-variant hypereosinophilia can therefore be regarded as a precancerous disorder. [1]

The disorder merits therapeutic intervention to avoid or reduce eosinophil-induced tissue injury and treat its leukemic phase. The latter phase is aggressive and typically responds relatively poorly to anti-leukemia chemotherapeutic drug regimens. [2]

Presentation

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Splenomegaly

The typical patient with lymphocyte-variant hypereosinophilia presents with an extended history of hypereosinophilia and cutaneous allergy-like symptoms. [3] Skin symptoms, which occur in >75% of patients, include erythroderma, pruritus, eczema, poikiloderma, urticarial, and episodic angioedema. [3] [2] The symptom of episodic angioedema (i.e. soft tissue swelling of the face, tongue, larynx, abdomen, arms, or legs) 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; this involvement of the latter cell types supports the notion that Gleich's syndrome is a subtype of lymphocyte-variant hypereosiophilia. [3] [2] Biopsies of skin lesions commonly find prominent accumulations of eosinophils. [2] Other presentations include:

Cardiovascular complications such as various types of heart damage due to eosinophilic myocarditis and vascular disorders due to eosinophil infiltration of the vascular wall that lead to vascular thrombosis are often critical components of persistent hypereosinophilia syndromes; [6] These complications are not a prominent component of lymphocyte-variant hypereosionophilia, occurring in <10% of patients. [4] [5]

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. [3]

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] [2] These and other studies support the view that lymphocyte-variant hypereosinophilia is 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 one or more aberrant clones of T cells. [3] [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. [3] [2] [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. [2]

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. [3] [2] [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 hypereosinophilia (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). [2] [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. [3] [9]

Treatment

Hydroxyurea (Hydroxycarbamide) Hydroxyurea-3D-balls.png
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 (an 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 initial 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. [3] [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. [2] [12]

History

For years, lymphocyte-variant hypereosinophilia was used to describe hypereosinophilia associated with any one of several aberrant T cell lymphoproliferative disorders. [3] In 1987, however, a 42-year-old male patient was described who presented with cardiac failure, mitral heart valve regurgitation, pericardial effusion, splenomegaly, kidney dysfunction, non-specific skin lesions, a six-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]

Related Research Articles

<span class="mw-page-title-main">Eosinophil</span> Variety of white blood cells

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply. They form about 2 to 3% of white blood cells in the body.

<span class="mw-page-title-main">Eosinophilia</span> Blood condition

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

Hypereosinophilic syndrome is a disease characterized by a persistently elevated eosinophil count in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous system, or bone marrow.

<span class="mw-page-title-main">Eosinophilic granulomatosis with polyangiitis</span> Medical condition

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis, is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy).

<span class="mw-page-title-main">POEMS syndrome</span> Paraneoplastic syndrome

POEMS syndrome is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the disease's major signs and symptoms, as is PEP.

Eosinophilic pneumonia is a disease in which an eosinophil, a type of white blood cell, accumulates in the lungs. These cells cause disruption of the normal air spaces (alveoli) where oxygen is extracted from the atmosphere. Several different kinds of eosinophilic pneumonia exist and can occur in any age group. The most common symptoms include cough, fever, difficulty breathing, and sweating at night. Eosinophilic pneumonia is diagnosed by a combination of characteristic symptoms, findings on a physical examination by a health provider, and the results of blood tests and X-rays. Prognosis is excellent once most eosinophilic pneumonia is recognized and treatment with corticosteroids is begun.

Loeffler endocarditis is a form of heart disease characterized by a stiffened, poorly-functioning heart caused by infiltration of the heart by white blood cells known as eosinophils. Restrictive cardiomyopathy is a disease of the heart muscle which results in impaired diastolic filling of the heart ventricles, i.e. the large heart chambers which pump blood into the pulmonary or systemic circulation. Diastole is the part of the cardiac contraction-relaxation cycle in which the heart fills with venous blood after the emptying done during its previous systole.

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

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T-cell-prolymphocytic leukemia (T-PLL) is a mature T-cell leukemia with aggressive behavior and predilection for blood, bone marrow, lymph nodes, liver, spleen, and skin involvement. T-PLL is a very rare leukemia, primarily affecting adults over the age of 30. It represents 2% of all small lymphocytic leukemias in adults. Other names include T-cell chronic lymphocytic leukemia, "knobby" type of T-cell leukemia, and T-prolymphocytic leukemia/T-cell lymphocytic leukemia.

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<span class="mw-page-title-main">FIP1L1</span> Protein-coding gene in the species Homo sapiens

Factor interacting with PAPOLA and CPSF1 is a protein that in humans is encoded by the FIP1L1 gene. A medically important aspect of the FIP1L1 gene is its fusion with other genes to form fusion genes which cause clonal hypereosinophilia and leukemic diseases in humans.

Gleich's syndrome is a rare disease in which the body swells up episodically (angioedema), associated with raised antibodies of the IgM type and increased numbers of eosinophil granulocytes, a type of white blood cells, in the blood (eosinophilia). It was first described in 1984.

Acute eosinophilic leukemia (AEL) is a rare subtype of acute myeloid leukemia with 50 to 80 percent of eosinophilic cells in the blood and marrow. It can arise de novo or may develop in patients having the chronic form of a hypereosinophilic syndrome. Patients with acute eosinophilic leukemia have a propensity for developing bronchospasm as well as symptoms of the acute coronary syndrome and/or heart failure due to eosinophilic myocarditis and eosinophil-based endomyocardial fibrosis. Hepatomegaly and splenomegaly are more common than in other variants of AML.

<span class="mw-page-title-main">Lutzner cells</span>

Lutzner cells were discovered by Marvin A. Lutzner, Lucien-Marie Pautrier, and Albert Sézary. These cells are described as the smaller forms of Sézary cells, or Sézary-Lutzner cells, and the two variants are recognised as being morphologically different. Aggregates of these cells in mycosis fungoides are known as a Pautrier's microabscesses. They are a form of T-lymphocytes that has been mutated This atypical form of T-lymphocytes contains T-cell receptors on the surface and is found in both the dermis and epidermis layers of the skin. Since Lutzner cells are a mutated form of T-lymphocytes, they develop in bone marrow and are transported to the thymus is order to mature. The production and maturation stages occur before the cell has developed a mutation. Lutzner cells can form cutaneous T-cell lymphoma, which is a form of skin cancer.

<span class="mw-page-title-main">White blood cell</span> Type of cells of the immunological system

White blood cells, also called leukocytes or immune cells also called immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. White blood cells include three main subtypes; granulocytes, lymphocytes and monocytes.

Eosinophilic myocarditis is inflammation in the heart muscle that is caused by the infiltration and destructive activity of a type of white blood cell, the eosinophil. Typically, the disorder is associated with hypereosinophilia, i.e. an eosinophil blood cell count greater than 1,500 per microliter. It is distinguished from non-eosinophilic myocarditis, which is heart inflammation caused by other types of white blood cells, i.e. lymphocytes and monocytes, as well as the respective descendants of these cells, NK cells and macrophages. This distinction is important because the eosinophil-based disorder is due to a particular set of underlying diseases and its preferred treatments differ from those for non-eosinophilic myocarditis.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

Familial eosinophilia is a rare congenital disorder characterized by the presence of sustained elevations in blood eosinophil levels that reach ranges diagnostic of eosinophilia or, far more commonly, hypereosinophilia. Although high eosinophil levels are associated with certain diseases and thought to contribute to the tissue destruction found in many other eosinophilia-related diseases, clinical manifestations and tissue destruction related to the eosinophilia in familial eosinophilia is uncommon: this genetic disease typically has a benign phenotype and course compared to other congenital and acquired eosinophilic diseases.

Indolent T cell lymphoproliferative disorder of the gastrointestinal tract or Indolent T cell lymphoproliferative disorder of the GI tract (ITCLD-GT) is a rare and recently recognized disorder in which mature T cell lymphocytes accumulation abnormally in the gastrointestinal tract. This accumulation causes various lesions in the mucosal layer lining the GI tract. Individuals with ITCLD-GT commonly complain of chronic GI tract symptoms such as nausea, vomiting, diarrhea, abdominal pain, and rectal bleeding.

Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL) is an extremely rare peripheral T-cell lymphoma that involves the malignant proliferation of a type of lymphocyte, the T cell, in the gastrointestinal tract. Over time, these T cells commonly spread throughout the mucosal lining of a portion of the GI tract, lead to GI tract nodules and ulcerations, and cause symptoms such as abdominal pain, weight loss, diarrhea, obstruction, bleeding, and/or perforation.

References

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  6. ↑ Roufosse F (2013). "L4. Eosinophils: how they contribute to endothelial damage and dysfunction". Presse Médicale. 42 (4 Pt 2): 503–7. doi:10.1016/j.lpm.2013.01.005. PMID   23453213.
  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" (PDF). British Journal of Haematology. 176 (4): 553–572. doi: 10.1111/bjh.14488 . PMID   28112388. S2CID   46856647.
  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. doi:10.1016/j.iac.2015.04.001. PMID   26209891.
  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. doi:10.1146/annurev-pharmtox-010814-124407. PMC   4924608 . PMID   25340931.
  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. doi:10.1007/s11899-015-0280-3. PMID   26404639. S2CID   36630735.
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  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. 139 (11): 3753–8. doi:10.4049/jimmunol.139.11.3753. PMID   3500229. S2CID   23949209.
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