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. 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 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.
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 polymorphisms 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 eosinophilic 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 The idiopathic hypereosinophilic syndrome is a disorder characterized by hypereosinophilia 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. 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, (e.g.
Angiostrongylus cantonensis and
Hookworm infections),
ascariasis,
strongyloidiasis trichinosis,
visceral larva migrans,
Gnathostomiasis,
cysticercosis, and
echinococcosis;
2) filarioidea, e.g.
tropical pulmonary eosinophilia,
loiasis, and
onchocerciasis; and
3) flukes, e.g.
schistosomiasis,
fascioliasis,
clonorchiasis,
paragonimiasis, and
fasciolopsiasis. Other infections associated with increased eosinophil blood counts include:
protozoan infections, e.g.
Isospora belli and
Dientamoeba fragilis) and
sarcocystis);
fungal infections (e.g. disseminated
histoplasmosis,
cryptococcosis [especially in cases with
central nervous system involvement]), and
coccidioides); and viral infections, e.g.
Human T-lymphotropic virus 1 and
HIV.
Autoimmune diseases Hypereosinophilia 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. 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 accompanied by less severe (e.g. non-DRESS syndrome) symptoms include
tetracyclins,
doxycycline,
linezolid,
nitrofurantoin,
metronidazole,
carbamazepine,
phenobarbital,
lamotrigine,
valproate,
desipramine,
amitriptyline,
fluoxetine,
piroxicam,
diclofenac,
ACE inhibitors,
abacavir,
nevirapine,
ranitidine,
cyclosporin, and
hydrochlorothiazide. Allergic reactions to drugs are a common cause of eosinophilia, with manifestations ranging from diffuse
maculopapular rash, to severe life-threatening
drug reactions with eosinophilia and systemic symptoms (DRESS).
Primary immunodeficiency diseases Primary
immunodeficiency diseases are inborn errors in the immune system due to defective genes. Certain of these disorders are sometimes or often associated with hypereosinophilia. The list of such disorders includes
ZAP70 deficiency (defective
ZAP70 gene), CD3gamma chain deficiency (defective
CD3G gene),
MCHII deficiency (defective
RFXANK gene),
Wiskott–Aldrich syndrome (defective
WAS gene),
IPEX syndrome (defective
IPEX gene),
CD40 gene defect, and
autoimmune lymphoproliferative syndrome (defective
Fas receptor gene). More than 30 other primary immunodeficiency diseases are sometimes associated with modest increases in eosinophil counts, i.e. eosinophilia. The
hyperimmunoglobulin E syndrome is associated with hypereosinophilia or eosinophilia due to mutations in any one of the following genes:
STAT3, DOCK8, PGM3, SPINK5, and
TYK2 (see
mutations in the hymperimmoglobulin E syndrome).
Omenn syndrome is a severe combined
immunodeficiency disease characterized by skin rash,
splenomegaly, and lymphadenopathy due to a causative mutation in
RAG1, RAG2, or, more rarely, one of several other genes.
Angiolymphoid hyperplasia with eosinophilia Angiolymphoid hyperplasia with eosinophilia is a disorder initially classified as a form of IgG4-related diseases but now considered a distinct entity. The disorder involves inflamed benign tumors of the vasculature in skin and, less commonly, other tissues. The tumors consist of histiocytoid endothelial cells prominently infiltrated by lymphocytes and eosinophils and is associated with hypereosinophilia or eosinophilia.
Cholesterol embolism Transient, fluctuating hypereosinophilia occurs in 60–80% of individuals with
cholesterol embolisms. In this disorder, cholesterol crystals located in an
atherosclerotic plaque of a large artery dislodge, travel downstream in the blood, and clog smaller arteries. This results in obstructive damage to multiple organs and tissues. Affected tissues exhibit acute inflammation involving eosinophils,
neutrophils,
monocytes,
lymphocytes, and
plasma cells. The cause for this hypereosinophilic response is not known.
Adrenal insufficiency A class of
steroid hormones secreted by the
adrenal gland,
glucocorticoids, inhibit eosinophil proliferation and survival. In
adrenal insufficiency, low levels of these hormones allow increased eosinophil proliferation and survival. This leads to increases in blood eosinophil levels, typically eosinophilia and, less commonly, hypereosinophilia.
Organ-restricted hypereosinophilias Hypereosinophilia may occur in the setting of damage to a single specific organ due to a massive infiltration by eosinophils. This disorder is sub-classified based on the organ involved and is not considered to be a form of primary hypereosinophilia, secondary hypereosinophilia, or the idiopathic hypereosinophilic syndrome because:
a) the eosinophils associated with the disorder have not been shown to be clonal in nature;
b) a reason for the increase in blood eosinophils has not been determined;
c) organ damage has not been shown to be due to eosinophils; and
d) the disorder in each individual case typically is limited to the affected organ. Examples of organ-restricted hypereosinophilia include
eosinophilic myocarditis,
eosinophilic esophagitis,
eosinophilic gastroenteritis,
eosinophilic cystitis,
eosinophilic pneumonia,
eosinophilic fasciitis,
eosinophilic folliculitis,
eosinophilic cellulitis,
eosinophilic vasculitis, and
eosinophilic ulcer of the oral mucosa. Other examples of organ-restricted hypereosinophilia include those involving the heart, kidney, liver, colon,
pulmonary pleurae,
peritoneum, fat tissue,
myometrium, and
synovia. ==Pathophysiology==