**2. Diseases and classification**

*Cells of the Immune System*

Identification and quantification.

philic count (AEC) of 350–500/mm3

hypereosinophilic disorders [1–5].

regulated by T lymphocytes (**Figure 1**) [1, 2, 6].

both lobes [1].

by P. Ehrlich in 1879 calling them eosinophils because their acidic granules in the cytoplasm were stained by their affinity dye aniline-eosin giving them the form of red-orange ammunition observed by optical microscopy: They are rounded cells from 8 to 15 μm in diameter, with a bilobed core with a fine nuclear bridge joining

Methodology: Manual count in Neubauer chamber and automatic hematol-

(FcƳRIII-CD16). Under normal conditions peripheral blood eosinophils represent 1–5% of total leukocytes, with an upper limit of 0.4 × 109 L,, the absolute eosino-

increasing the number of eosinophils (eosinophilia) to more than 3–5 times which is indicative of an activity of infectious, parasitic, allergic, and eosinophilic and

They originate in the bone marrow, by a process of maturation and differentiation that lasts approximately 8 days (hematopoiesis) from a pluripotential precursor cell (stem cell) differentiating itself as myeloid granulocytic line, under the influence of IL-3, IL-4 - granulocytic colony stimulation factor (GM-CSF) of eotaxin; evolving toward a mixed eosinophil-basophilic precursor and then differentiating toward eosinophils by action of IL-3, GM-CSF, and especially IL-5, they have a survival of 6–12 hours before moving to tissues where they remain between 2 and 5 days; once there is a stimulus, they respond by exercising their multiple functions

The text begins with: Its main functions are the defense against parasites, helminths, nematodes, participate in allergic responses, inflammatory processes, restoration, and tissue repair; since they have specific chemotactic receptors on their membrane, eotaxin, cytokines (IL-3 -IL-5 and GM-CSF), eosinophil chemotactic factor of anaphylaxis (ECF-A); and nonspecific such as f MLP (from the wall of bacteria), complement activation products (C3a, C5a, C6, and C7), plateletactivating factor (PAF), leukotrienes (LTB 4 and LTD 4), histamine and IL-8. Diapedesis is mainly performed by integrins to adhere to the vascular endothelium

*Scheme representing hematopoiesis, origin of eosinophil and its main functions associated with eosinophilic disorders. Molecules expressed on its surface (FcεRI-CD23-IgE). CCR4, CD88,H4R. Adhesion molecules:* 

*CD11b, CD11c, CD62L, and chemokines that attract eosinophils from blood to tissues [3, 7].*

and in children is greater than 0.75 × 109 L,

ogy analyzer using impedance and colorimetry and flow cytometry CD16

**154**

**Figure 1.**

The severity of eosinophilia has been arbitrarily divided into mild (AEC from the upper limit of normal to 1500/mm3 ), moderate (AEC 1500–5000/mm3 ), and severe (AEC >5000/mm3 ).

The classification of eosinophilic diseases was revised in 2008 and reaffirmed in 2016. In 2017 its diagnosis, risk stratification (prognosis), and management (treatment) proposed by the World Health Organization were covered [10].

Eosinophilic diseases can be classified in two types: primary, intrinsic hematology due to clonal disorders, and secondary, extrinsic or reactive disorders to an external cause that cause damage to different organs. Primary eosinophilias or clonal disorders can be diagnosed by studying the blood and bone marrow by the following methods: standard cytogenetics, molecular biology with monoclonal antibodies, flow cytometry, in situ hybridization, and evaluation of T cell clonality.

The major category of primary diseases corresponds to myeloid/lymphoid neoplasms with eosinophilia and rearrangements PDGFRA, PDGFRB, or FGR1; with PCMiJAK2 and MPN, a subtype of chronic eosinophilic leukemia or not specified by CEL-NOS, there is another lymphoid-eosinophilic variant of aberrant T cell clone.

The modern definition of hypereosinophilic syndrome (HES) is a vestige of the historical criteria outlined by Chusid and colleagues in 1975: The absolute eosinophil count is >1500/mm3 for more than 6 months, and tissue damage is present [10, 11].

The Working Conference on Eosinophil Disorders and Syndromes proposed a new terminology for eosinophilic syndromes. Hypereosinophilia (HE) for persistent and marked eosinophilia (AEC >1500/mm3 ) in turn, HE subtypes were divided into a hereditary (familiar) variant (HEfa); HE of undetermined significance (HEus), primary (clonal-neoplastic), HE produced by clonal/neoplastic eosinophils (HEn), and secondary (reactive) (HEr) can be considered a provisional diagnosis until a primary or secondary cause of eosinophilia is ascertained [12].

To have to a better understanding of the pathogenetic aspects of eosinophilia, other classifications of eosinophilic diseases were generated according to the site of eosinophilic infiltration associated with organ damage and dysfunction. The primary cause of eosinophilia located within the eosinophils (and/or eosinophil precursors) themselves or in other cells, similar to allergic diseases, can be divided in IgE-mediated (extrinsic) and non-IgE-mediated (intrinsic) diseases; the terms extrinsic and intrinsic eosinophilic disorders indicate whether the primary cause of eosinophilia is inside or outside the eosinophil lineage [11].

#### **2.1 Eosinophilic intrinsic disorders**

Chronic eosinophilic leukemias belong to a special group of chronic myeloid leukemias, in which eosinophil differentiation is dominant, resulting in blood eosinophil counts of greater than 1500/mm3 . However, other lineages are also affected, because the disease is the result of a mutation in a pluripotent hematopoietic stem cell. The chromosomal translocations related to breakpoints on chromosome 8p11 result in fibroblast growth factor receptor 1 fusion genes with increased kinase activity causing the so-called 8p11 syndrome. The increase in tyrosine kinase activity is caused by gene 1 and the growth factor, and this leukemia has a worse prognosis, which transforms chronic leukemia to an acute, 1–2 years. Another type of cause may be the increase in tyrosine kinase by fusion of the platelet growth factor alpha receptor genes (PDGFRA). PDGFRA is fused by the Fip1-like 1 (FIP1L1) gene as a result of a 4q12.9 chromosome damage. This is both in eosinophils and in other hematopoietic lineages such as neutrophils, monocytes, lymphocytes, and mast cells. This type of leukemia is pluripotent hematopoietic stem cell which responds to the tyrosine kinase inhibitor (imatinib) [10, 11].

Mutations in multipotent myeloid stem cells: In the chronic myeloid leukemias with eosinophilia, eosinophils are part of the clone. This is because eosinophil differentiation is often not as prominent as other myeloid cells, such as monocytes, which also show increased differentiation. Chromosomal translocations related to breakpoints on chromosome 5q33 are common and represent the basis for the formation of platelet-derived growth factor receptor b (PDGFRB) fusion genes; this result increases the tyrosine kinase activity. There are patients with positive Philadelphia chromosome who can develop chronic leukemia with eosinophilia due to two factors: fusion by breakpoint cluster region-Abelson (ABL) and fusion of transcription gene 6 (ETV6). Marked eosinophilia often associated with a cytogenetic evolution and other accelerated phases of ABL can occur during an acute transformation; ABL may be fused with the transcription factor E26 by means of variant ETV6 triggering chronic leukemia [10].

Myelodysplastic syndromes: During hematopoiesis there may be an inefficient process in the differentiation of stem cell by mutations, malignant clones producing myelodysplastic syndromes that lead to myeloproliferative diseases such as polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia. The exact molecular genetic abnormalities resulting in eosinophilia in these disorders remain to be determined [10, 11].

#### **2.2 Eosinophilic extrinsic disorders**

T cell-mediated eosinophilias: The common diseases are allergic rhinoconjunctivitis, bronchial asthma, drug allergic, eosinophilic esophagitis, and atopic dermatitis. Eosinophilia and IgE production due to the polarization of TH2 cells whose causes are extrinsic or external by stimulation of environmental immunogens or chemical compounds, which are presented by APC-MHC, stimulating the release of pro-inflammatory cytokines (IL4, IL5, and IL13), induce the increase in eosinophils of IgE survival, high affinity receptors with PKC activation, cross-linking and signaling for histamine release, as well as vasoactive amines that produce inflammatory processes and organ damage [10, 11].

Infectious diseases: TH2 inflammatory responses are induced by helminths; these responses are characterized by IgE antibody production and eosinophilia; both have been implicated in mediating protective immunity to the parasites. In contrast, there is little doubt that eosinophils contribute to tissue damage and therefore to the pathogenesis of these infections.

**157**

**Figure 2.**

*response to the genes involved [12].*

*Eosinophilic Disorders: Extrinsic and Intrinsic Immune Response, New Diagnostic Perspectives…*

Viral infections are not common; however, when virus-specific T cells are generated in a TH2 environment, they can also release IL-5 and therefore trigger eosinophilia. In chronic rhinosinusitis, eosinophilia is related to fungal infections with certain molds (e.g., Alternaria) which is present in the nasal and paranasal

Autoimmune diseases: Because these diseases are often associated with a TH1 associated inflammatory response, eosinophilia is not frequent, but in systemic sclerosis, levels of major basic protein and extracellular major basic protein depositions were observed in skin and lung tissues. In primary biliary cirrhosis, eosinophilia is a distinctive feature that might be useful in the diagnosis of the disease

Graft-versus-host diseases: When an allogeneic bone marrow transplant is carried out and there are differences in MHC molecule polymorphism, these can be recognized by the immune system, and responses can be made against the alloantigens, producing graft-versus- host-disease (GVHDs), carrying out a reaction antigen antibody, cellular or cytotoxic that produces lysis and destruction in specific

Drug-induced diseases: Hypersensitivity drug reactions may present in some cases increased eosinophils. The manifestations range from maculopapular rashes of the skin to severe life-threatening drug reactions with eosinophilia and systemic symptoms (DRESS). Drugs and their metabolites can produce hypersensitivity by means of mechanisms mediated by APC-MHC TCR pi concept, generating TH2

There are other subgroups of this syndrome as episodic angioedema and hereditary eosinophilia. Where there is evidence of mechanism mediated by IL-5-

*Diagnostic algorithm for patients with hypereosinophilia. Due to the fact that eosinophilia can occur in different pathologies, an exclusion of the unlikely causes for hypereosinophilia is performed, in addition to a three-step follow-up treatment with imatinib due to mutation processes that is considered. Laboratory tests would be at the discretion of the doctor according to the medical history and the search according to the type of* 

*DOI: http://dx.doi.org/10.5772/intechopen.89229*

organs (skin, liver, and gastrointestinal tract mainly).

polarity or TH1 with memory T cells [10, 11, 13].

cavities [5, 10, 11].

producing T cells [5].

[10, 11, 13].

*Eosinophilic Disorders: Extrinsic and Intrinsic Immune Response, New Diagnostic Perspectives… DOI: http://dx.doi.org/10.5772/intechopen.89229*

Viral infections are not common; however, when virus-specific T cells are generated in a TH2 environment, they can also release IL-5 and therefore trigger eosinophilia. In chronic rhinosinusitis, eosinophilia is related to fungal infections with certain molds (e.g., Alternaria) which is present in the nasal and paranasal cavities [5, 10, 11].

Autoimmune diseases: Because these diseases are often associated with a TH1 associated inflammatory response, eosinophilia is not frequent, but in systemic sclerosis, levels of major basic protein and extracellular major basic protein depositions were observed in skin and lung tissues. In primary biliary cirrhosis, eosinophilia is a distinctive feature that might be useful in the diagnosis of the disease [10, 11, 13].

Graft-versus-host diseases: When an allogeneic bone marrow transplant is carried out and there are differences in MHC molecule polymorphism, these can be recognized by the immune system, and responses can be made against the alloantigens, producing graft-versus- host-disease (GVHDs), carrying out a reaction antigen antibody, cellular or cytotoxic that produces lysis and destruction in specific organs (skin, liver, and gastrointestinal tract mainly).

Drug-induced diseases: Hypersensitivity drug reactions may present in some cases increased eosinophils. The manifestations range from maculopapular rashes of the skin to severe life-threatening drug reactions with eosinophilia and systemic symptoms (DRESS). Drugs and their metabolites can produce hypersensitivity by means of mechanisms mediated by APC-MHC TCR pi concept, generating TH2 polarity or TH1 with memory T cells [10, 11, 13].

There are other subgroups of this syndrome as episodic angioedema and hereditary eosinophilia. Where there is evidence of mechanism mediated by IL-5 producing T cells [5].

#### **Figure 2.**

*Cells of the Immune System*

**2.1 Eosinophilic intrinsic disorders**

phil counts of greater than 1500/mm3

to the tyrosine kinase inhibitor (imatinib) [10, 11].

variant ETV6 triggering chronic leukemia [10].

remain to be determined [10, 11].

**2.2 Eosinophilic extrinsic disorders**

tory processes and organ damage [10, 11].

therefore to the pathogenesis of these infections.

Chronic eosinophilic leukemias belong to a special group of chronic myeloid leukemias, in which eosinophil differentiation is dominant, resulting in blood eosino-

because the disease is the result of a mutation in a pluripotent hematopoietic stem cell. The chromosomal translocations related to breakpoints on chromosome 8p11 result in fibroblast growth factor receptor 1 fusion genes with increased kinase activity causing the so-called 8p11 syndrome. The increase in tyrosine kinase activity is caused by gene 1 and the growth factor, and this leukemia has a worse prognosis, which transforms chronic leukemia to an acute, 1–2 years. Another type of cause may be the increase in tyrosine kinase by fusion of the platelet growth factor alpha receptor genes (PDGFRA). PDGFRA is fused by the Fip1-like 1 (FIP1L1) gene as a result of a 4q12.9 chromosome damage. This is both in eosinophils and in other hematopoietic lineages such as neutrophils, monocytes, lymphocytes, and mast cells. This type of leukemia is pluripotent hematopoietic stem cell which responds

Mutations in multipotent myeloid stem cells: In the chronic myeloid leukemias with eosinophilia, eosinophils are part of the clone. This is because eosinophil differentiation is often not as prominent as other myeloid cells, such as monocytes, which also show increased differentiation. Chromosomal translocations related to breakpoints on chromosome 5q33 are common and represent the basis for the formation of platelet-derived growth factor receptor b (PDGFRB) fusion genes; this result increases the tyrosine kinase activity. There are patients with positive Philadelphia chromosome who can develop chronic leukemia with eosinophilia due to two factors: fusion by breakpoint cluster region-Abelson (ABL) and fusion of transcription gene 6 (ETV6). Marked eosinophilia often associated with a cytogenetic evolution and other accelerated phases of ABL can occur during an acute transformation; ABL may be fused with the transcription factor E26 by means of

Myelodysplastic syndromes: During hematopoiesis there may be an inefficient process in the differentiation of stem cell by mutations, malignant clones producing myelodysplastic syndromes that lead to myeloproliferative diseases such as polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia. The exact molecular genetic abnormalities resulting in eosinophilia in these disorders

T cell-mediated eosinophilias: The common diseases are allergic rhinoconjunctivitis, bronchial asthma, drug allergic, eosinophilic esophagitis, and atopic dermatitis. Eosinophilia and IgE production due to the polarization of TH2 cells whose causes are extrinsic or external by stimulation of environmental immunogens or chemical compounds, which are presented by APC-MHC, stimulating the release of pro-inflammatory cytokines (IL4, IL5, and IL13), induce the increase in eosinophils of IgE survival, high affinity receptors with PKC activation, cross-linking and signaling for histamine release, as well as vasoactive amines that produce inflamma-

Infectious diseases: TH2 inflammatory responses are induced by helminths; these responses are characterized by IgE antibody production and eosinophilia; both have been implicated in mediating protective immunity to the parasites. In contrast, there is little doubt that eosinophils contribute to tissue damage and

. However, other lineages are also affected,

**156**

*Diagnostic algorithm for patients with hypereosinophilia. Due to the fact that eosinophilia can occur in different pathologies, an exclusion of the unlikely causes for hypereosinophilia is performed, in addition to a three-step follow-up treatment with imatinib due to mutation processes that is considered. Laboratory tests would be at the discretion of the doctor according to the medical history and the search according to the type of response to the genes involved [12].*

#### *Cells of the Immune System*

Severe primary (IL-5) and secondary immunodeficiencies (HIV) are associated with eosinophilia when there is polarization of TH2 by the immunogen (allergen) or drug (antiretroviral); infections such as tuberculosis are the cause of infections and resistance to treatment (**Figure 2**) [11].

## **2.3 Treatment of HES and CEL-NOS**

Corticosteroids should be considered a first-line treatment, which are potent anti-eosinophil agents, effective in producing rapid reductions. Maximal dose was 1 mg × kg 2 months, with symptom control and reduction of the eosinophil count to below 1500/mm3 after 1 month of treatment.

Hydroxyurea is an effective first-line agent for HES which may be used in conjunction with corticosteroids or in steroid nonresponders. A typical starting dose is 500–1000 mg daily which can serve as effective palliative to control leukocytosis and eosinophilia but with no proven role in favorably altering the natural history of HES or CEL-NOS (**Figure 2**) [10, 12, 14].

IFN-a has demonstrated hematologic responses and reversion of organ injury in patients with HES and CEL-NOS refractory to therapies including prednisone and/or hydroxyurea. Remissions have been associated with improvement in clinical symptoms and organ disease, including hepatosplenomegaly, cardiac and thromboembolic complications, mucosal ulcers, and skin involvement [5, 10–12].

#### **Figure 3.**

*Diagnostic and treatment algorithm based on revised 2016 WHO classification of eosinophilic disorders. According to the algorithm, the type of eosinophilia can be monitored according to the cases where other drugs other than imatinib should be used, with three pathological options being present: chronic leukemia with eosinophilia, idiopathic hypereosinophilia, and lymphocyte variant, all share the administration of imatinib and corticosteroids (idiopathic hypereosinophilia and lymphocyte variant) [10].*

**159**

*Eosinophilic Disorders: Extrinsic and Intrinsic Immune Response, New Diagnostic Perspectives…*

binding of IL-5 chain of the IL-5 receptor expressed on eosinophils [5, 14].

Mepolizumab anti-IL-5 antibody is a fully monoclonal IgG antibody that inhibits

Alemtuzumab is an anti-CD52 monoclonal antibody that has been evaluated in idiopathic HES based on expression of the CD52 antigen on eosinophils. In patients with refractory HES, alemtuzumab was administered intravenously at a dose of

Bone marrow/peripheral blood stem cell allogeneic transplantation has been attempted in patients with aggressive disease; a disease-free survival ranging from

Imatinib is a small-molecule tyrosine kinase inhibitor 100 mg per day; it also shows activity against platelet-derived growth factor receptor (PDGF-R), c-Kit, Abl-related gene (ARG), and their fusion proteins while sparing other kinases

Mastocytosis: Develops from a neoplastic proliferation of mast cells. It develops from a neoplastic clonal proliferation of mastocytes that accumulate in one or more organ systems and are organize as compact cohesive aggregate groups or multifocal groups of abnormal mastocytes. This disorder is diverse; it can be found as cutaneous lesions that may naturally recede, to highly aggressive neoplasias related with multiple organ failure and short outliving. Mastocytosis subtypes are principally characterized by the clinical manifestations and the spread of the disease. When cutaneous mastocytosis (CM) occurs, mastocyte infiltration is restricted to the skin, whereas systemic mastocytosis (SM) includes at least one extracutaneous organ, with or without skin lesions. Mastocytosis must be distinguished from mastocyte hyperplasia or from the mastocyte activation states, without the morphological or molecular abnormalities that characterize neoplastic proliferation [15]. The WHO classification includes seven types:

c.Systemic mastocytosis with associated clonal, hematologic non-mast cell line-

Hypereosinophilic syndrome (HES): It has been described as a condition associated with persistent eosinophilia in the peripheral blood, organ damage, and exclusion of any other underlying disease or condition that may explain eosinophilia or organ damage [4, 16–18]. The diagnostic algorithm must begin with the evaluation of peripheral blood hypereosinophilia (HE), defined as a persistent increase of blood eosinophils, above 1.5 X 109/L blood [4, 16–18]. The term "tissue HE" has also been proposed, and it may be useful in the evaluation and the classification of the disorders related to HES [16, 19]. The establishment of an HES diagnosis must be

*DOI: http://dx.doi.org/10.5772/intechopen.89229*

5–30 mg once to thrice weekly.

a.Cutaneous mastocytosis

age disease (SM-AHNMD)

e.Mast cell leukemia (MCL)

f. Mast cell sarcoma (MCS)

g.Extracutaneous mastocytoma

b.Indolent systemic mastocytosis (ISM)

d.Aggressive systemic mastocytosis (ASM)

(**Figure 3**) [10].

8 months to 5 years has been reported.

**3. Hematologic and neoplastic diseases**

#### *Eosinophilic Disorders: Extrinsic and Intrinsic Immune Response, New Diagnostic Perspectives… DOI: http://dx.doi.org/10.5772/intechopen.89229*

Mepolizumab anti-IL-5 antibody is a fully monoclonal IgG antibody that inhibits binding of IL-5 chain of the IL-5 receptor expressed on eosinophils [5, 14].

Alemtuzumab is an anti-CD52 monoclonal antibody that has been evaluated in idiopathic HES based on expression of the CD52 antigen on eosinophils. In patients with refractory HES, alemtuzumab was administered intravenously at a dose of 5–30 mg once to thrice weekly.

Bone marrow/peripheral blood stem cell allogeneic transplantation has been attempted in patients with aggressive disease; a disease-free survival ranging from 8 months to 5 years has been reported.

Imatinib is a small-molecule tyrosine kinase inhibitor 100 mg per day; it also shows activity against platelet-derived growth factor receptor (PDGF-R), c-Kit, Abl-related gene (ARG), and their fusion proteins while sparing other kinases (**Figure 3**) [10].
