eosinophilia eosinophilia 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. eosinophiliaeosinophils in the peripheral blood of a patient with idiopathic eosinophiliaspecialtyinfectious disease, hematology eosinophils usually account for less than 7% of the circulating leukocytes. a marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. several causes are known, with the most common being some form of allergic reaction or parasitic infection. diagnosis of eosinophilia is via a complete blood count (cbc), but diagnostic procedures directed at the underlying cause vary depending on the suspected condition(s). an absolute eosinophil count is not generally needed if the cbc shows marked eosinophilia. the location of the causal factor can be used to classify eosinophilia into two general types: extrinsic, in which the factor lies outside the eosinophil cell lineage; and intrinsic eosinophilia, which denotes etiologies within the eosiniphil cell line. specific treatments are dictated by the causative condition, though in idiopathic eosinophilia, the disease may be controlled with corticosteroids. eosinophilia is not a disorder (rather, only a sign) unless it is idiopathic. informally, blood eosinophil levels are often regarded as mildly elevated at counts of 500–1,500/μl, moderately elevated between 1,500 and 5,000/μl, and severely elevated when greater than 5,000/μl. elevations in blood eosinophil counts can be transient, sustained, recurrent, or cyclical. eosinophil counts in human blood normally range between 100 and 500 per/μl. maintenance of these levels results from a balance between production of eosinophils by bone marrow eosinophil precursor cells termed cfu-eos and the emigration of circulating eosinophils out of the blood through post-capillary venules into tissues. eosinophils represent a small percentage of peripheral blood leucocytes (usually less than 8%), have a half-life in the circulation of only 8–18 hours, but persist in tissues for at least several weeks. eosinophils are one form of terminally differentiated granulocytes; they function to neutralize invading microbes, primarily parasites and helminthes but also certain types of fungi and viruses. they also participate in transplant rejection, graft-versus-host disease, and the killing of tumor cells. in conducting these functions, eosinophils produce and release on demand a range of toxic reactive oxygen species (e.g. hypobromite, hypobromous acid, superoxide, and peroxide) and they also release on demand a preformed armamentarium of cytokines, chemokines, growth factors, lipid mediators (e.g. leukotrienes, prostaglandins, platelet activating factor), and toxic proteins (e.g. metalloproteinases, major basic protein, eosinophil cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin). these agents serve to orchestrate robust immune and inflammatory responses that destroy invading microbes, foreign tissue, and malignant cells. when overproduced and over-activated, which occurs in certain cases of hypereosinophilia and to a lesser extent eosinophilia, eosinophils may misdirect their reactive oxygen species and armamentarium of preformed molecules toward normal tissues. this can result in serious damage to such organs as the lung, heart, kidneys, and brain. classification based on their causes, hypereosinophilias can be sorted into subtypes. however, cases of eosinophilia, which exhibit eosinophil counts between 500 and 1,500/μl, may fit the clinical criteria for, and thus be regarded as falling into, one of these hypereosinophilia categories: the cutoff of 1,500/μl between hypereosinophilia and eosinophilia is somewhat arbitrary. there are at least two different guidelines for classifying hypereosinophilia/eosinophilia into subtypes. the general haematoloy and haemato-oncology task forces for the british committee for standards in haematology classifies these disorders into a) primary, i.e. caused by abnormalities in the eosinophil cell line; b) secondary, i.e. caused by non-eosinophil disorders; and c) idiopathic, cause unknown. the world health organization classifies these disorders into a) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of pdgfra, pdgfrb, or fgfr1 (i.e. high eosinophil blood counts caused by mutations in the eosinophil cell line of one of these three genes), 'b) chronic eosinophilic leukemia, and c) the idiopathic hypereosinophiic syndrome. in the latter classification, secondary hypereosinophilia/eosinophilia is not viewed as a true disorder of eosinophils. here these two classifications are merged and expanded to include the many forms of secondary, i.e. reactive hypereosinophilia/eosinophilia, disorders and also includes another subtype, organ-restricted hypereosinophilias, a disorder in which eosinophil-mediated tissue damage is restricted to one organ and is often but not always associated with increased blood eosinophil counts. primary hypereosinophilia primary hypereosinophilia is due to the development of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a significantly mutated ancestor cell. the clone may prove to be benign, pre-malignant, or overtly malignant. the fundamental driver of these hypereosinophilic (or uncommonly eosinophilic) disorders is the mutation which increases the proliferation, survival, and further mutation of cells descendant from the originally mutated cell. there are several subtypes of primary hypereosinophilia. clonal hypereosinophilia main article: clonal hypereosinophilia clonal hypereosinophilia is hypereosinophilia caused by a pre-malignant or malignant clone of eosinophils that bear mutations in genes for pdgfra, pdgfrb, or fgfr1 or, alternatively, a chromosome translocation that creates the pcm1-jak2 fusion gene. these genes code for dysfunctional protein products capable of enhancing proliferation and/or survival of their parent cells which, in consequence, become an evolving and constantly growing clone of eosinophils. these mutations are recognized by the world health association as causing distinct entities differing from idiopathic hypereosinophilia and the idiopathic hypereosinophilic syndrome. presence of these clones may be associated with tissue injury but in any case suggests specific therapy be directed at reducing the size and suppressing the growth of the eosinophil clone. more recently, mutations in other genes have been described as causing a similar type of clonal hypereosinophilia but have not yet been recognized as entities distinct from idiopathic hypereosinophilia and the idiopathic hyperesoniphilic syndrome. these include gene mutations in jak2, abl1, and flt2 and chromosomal translocations that create the etv6-acsl6 fusion gene. chronic eosinophilic leukemia (nos) main article: chronic eosinophilic leukemia chronic eosinophilic leukemia, not otherwise specified (i.e. cel, nos), is a leukemia-inducing disorder in the eosinophil cell lineage that causes eosinophil blood counts greater than 1,500/μl. the most recent (2017) world health organization criteria specifically excludes from this disorder hypereosinophilia/eosinophilia associated with bcr-abl1 fusion gene-positive chronic myeloid leukemia, polycythemia vera, essential thrombocytosis, primary myelofibrosis, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, clonal eosinophilias involving gene rearrangements of pdgfra, pdgfrb, or fgfr1, and chromosome translocations that form pcm1-jak2, etv6-jak2, or bcr-jak2 fusion genes. for this diagnosis, immature eosinophil (e.g. myeloblast) cell counts in the bone marrow and peripheral blood must be less than 20% and the chromosomal alterations (inv(16)(p13.1q22)) and t(16;16)(p13;q22) as well as other features diagnostic of acute myelogenous leukemia must be absent. the latter diagnostic features include clonal cytogenetic abnormalities and molecular genetic abnormalities diagnostic for other forms of leukemia or the presence of myeloblast counts greater than 55% in bone marrow or 2% in blood. chronic eosinophilic leukemia may transform into acute eosinophilic or other types of acute myelogenous leukemia. familial eosinophilia main article: familial eosinophilia 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. it is an autosomal dominant disorder in which genetic linkage gene mapping family studies localize the gene responsible for it to chromosome 5 at position q31–q33, between markers d5s642 and d5s816. this region contains a cytokine gene cluster which includes three genes whose protein products function in regulating the development and proliferation of eosinophils viz., interleukin 3, interleukin 5, and colony stimulating factor 2. however, no functional sequence genetic polylmophisms are found within the promoter, exons, or introns, of these genes or within the common gene enhancer for interleukin 3 or colony stimulating factor 2. this suggests that the primary defect in familial eosinophilia is not a mutation in one of these genes but rather in another gene within this chromosome area. clinical manifestations and tissue destruction related to the eosinophilia in this disorder are uncommon: familial eosinophilia typically has a benign phenotype compared to other congenital and acquired eosinophilic diseases. idiopathic hypereosinophilia idiopathic hypereosinophilia (also termed hypereosinophilia of undetermined significance, i.e. heus) is a disorder characterized by an increase in eosinophil blood counts above 1,500/μl, as detected on at least 2 separate examinations. the disorder cannot be associated with eosinophil-based tissue damage or a primary or secondary cause of eosinophilia. that is, it is a diagnosis of exclusion and has no known cause. over time, this disorder can resolve into a primary hypereosinophilia, typically clonal hypereosinophilia, chronic eosinphilic leukemia, or an eosinophilia associated with another hematological leukemia. the disorder may also become associated with tissue or organ damage and therefore be diagnosed as the hypereosinophilic syndrome. idiopathic hypereosinophilia is treated by observation to detect development of the cited more serious disorders. idiopathic hypereosiophilic syndrome main article: hypereosinophilic syndrome the idiopathic hypereosinophilic syndrome is a disorder characterized by hypereosiophilia that is associated with eosinophil-based tissue or organ damage. while almost any organ or tissue may be damaged, the lung, skin, heart, blood vessels, sinuses, kidneys, and brain are the most commonly affected. the world health organization restrict this diagnosis to cases which have no well-defined cause. that is, all cases of secondary (i.e. reactive) eosinophilia (including lymphocyte-variant hypereosinophilia) and primary hypereosinophilia (including chronic eosinophilic leukemia (nos), clonal eosinophilia, and hypereosinophilia associated with hematological malignancies) are excluded from this diagnosis. secondary hypereosinophilia secondary (or reactive) eosinophilias are non-clonal increases in blood eosinophil levels caused by an underlying disease. the pathogenesis of the hypereosinophilia in these diseases is thought to be the release of one or more cytokines (e.g. granulocyte macrophage colony stimulating factor, interleukin 3, interleukin 5) that: a) cause bone marrow precursor cells, i.e. cfu-eos, to proliferate and mature into eosinophils; b) promote release of bone marrow eosinophils into the circulation, c) stimulate circulating eosinophils to enter tissues and release tissue-injuring agents. these cytokines may be released by the diseased cells or the diseased cells may cause the release of these cytokines by non-diseased cells. primary disorders associated with and known or presumed to cause hypereosinophilia or eosinophilia are given below. infections helminths are common causes of hypereosinophilia and eosinophilia in areas endemic to these parasites. helminths infections causing increased blood eosinophil counts include: 1) nematodes, (i.e. angiostrongylus cantonensis and hookworm infections), ascariasis, strongyloidiasis trichinosis, visceral larva migrans, gnathostomiasis, cysticercosis, and echinococcosis; 2) filarioidea, i.e. tropical pulmonary eosinophilia, loiasis, and onchocerciasis; and 3) flukes, i.e. schistosomiasis, fascioliasis, clonorchiasis, paragonimiasis, and fasciolopsiasis. other infections associated with increased eosinophil blood counts include: protozoan infections, i.e. isospora belli and dientamoeba fragilis) and sarcocystis); fungal infections (i.e. disseminated histoplasmosis, cryptococcosis ), and coccidioides); and viral infections, i.e. human t-lymphotropic virus 1 and hiv. autoimmune diseases hypereosiophilia or eosinophilia may be associated with the following autoimmune diseases: systemic lupus erythematosus eosinophilic fasciitis, eosinophilic granulomatosis with polyangiitis, dermatomyositis, severe rheumatoid arthritis, progressive systemic sclerosis, sjögren syndrome, thromboangiitis obliterans, behçet's disease, igg4-related disease, inflammatory bowel diseases, sarcoidosis, bullous pemphigoid, and dermatitis herpetiformis. allergic diseases eosinophilia and comparatively fewer cases of hypereosinophilia are associated with the following known diseases that are known or thought to have an allergic basis: allergic rhinitis, asthma, atopic dermatitis, eosinophilic esophagitis, chronic sinusitis, aspirin-exacerbated respiratory disease, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, and kimura's disease. certain types of food allergy disorders may also be associated with eosinophilia or, less commonly, hypereosinophilia. allergic eosinophilic esophagitis and the food protein-induced enterocolitis syndrome are commonly associated with increased blood eosinophil levels. drugs a wide range of drugs are known to cause hypereosinophilia or eosinophilia accompanied by an array of allergic symptoms. rarely, these reactions are severe causing, for example, the drug reaction with eosinophilia and systemic symptoms (dress) syndrome. drug- induced hepatitis marked by immunoallergic pathology, which has much bidirectional crossover with dress syndrome, is typically accompanied by some severity of eosinophilia. while virtually any drug should be considered as a possible cause of these signs and symptoms, the following drugs and drug classes are some of the most frequently reported causes: penicillins, cephalosporins, dapsone, sulfonamides, carbamazepine, phenytoin, lamotrigine, valproic acid, nevirapine, efavirenz, and ibuprofen. these drugs may cause severely toxic reactions such as the dress syndrome. other drugs and drug classes often reported to cause increased blood eosinophil levels