High levels of these white blood cells produce a condition called eosinophilia, this condition represents a greater number of these cells in tissues and / or blood.
Eosinophils are bone marrow- derived cells of the granulocyte lineage. They have an approximate half-life of 8 to 18 hours in the bloodstream, and mostly reside in tissues, where they can persist for at least several weeks.
Its functions are multifaceted and include:
- The presentation of antigens.
- The release of lipid, peptide, and cytokine-derived mediators for acute and chronic inflammation.
- Responses to the elimination of helminths and parasites through degranulation.
- Ongoing homeostatic immune responses.
They can be part of the general cellular environment in malignant neoplasms and autoimmune diseases, and connective tissue disorders, and are also found in less well characterized entities, as described elsewhere in this document.
The approach to eosinophilia relies heavily on medical history. Often, some aspects of a case alert the clinician to the possible underlying cause of abnormally elevated eosinophils.
However, sometimes more extensive investigations must be conducted to more clearly define the cause of its presence and its possible role in the presentation of the disease.
Symptoms of High Eosinophils
The symptoms of eosinophilia are those of the underlying condition . For example, eosinophilia due to asthma is marked by symptoms such as wheezing and shortness of breath, while parasitic infections can lead to abdominal pain, diarrhea, fever, or cough and rashes.
Drug reactions often lead to skin rashes, and they often occur after taking a new drug.
The most common symptoms of eosinophilia can include:
- Night sweats.
- Enlarged lymph nodes.
- Other skin rashes and numbness and tingling due to nerve damage.
Causes and diseases associated with High Eosinophils
Mild eosinophilia is often present in patients with allergic disease (<1500 cells / μL will be used for the definition of mild, whereas hypereosinophilic syndromes are generally considered with sustained eosinophilia> 1500 cells / μL).
Allergic rhinitis and asthma often produce mild eosinophilia. Atopic dermatitis can produce more significant eosinophilia if it affects a large part of the body and is associated with significant atopy.
Eosinophilic esophagitis and other eosinophilic gastrointestinal diseases can cause mild peripheral eosinophilia.
Chronic sinusitis, especially of the polypoid variety seen in respiratory disease aggravated by aspirin, produces a more robust eosinophilic response that can be in the mild to moderate range.
Often these patients begin with nasal allergies and asthma, but then develop abnormal arachidonic acid metabolizing cascades and thus have a more dramatic presentation of both their disease entity and eosinophilia.
Allergic bronchopulmonary aspergillosis, associated with a fungus (Aspergillus) and with sensitization in an allergic / asthmatic host, can also produce varying and sometimes significant degrees of eosinophilia and also an elevated immunoglobulin (Ig) E.
Chronic eosinophilic pneumonia often begins in a sensitized asthmatic host. Although these patients may have milder peripheral eosinophilia early in the disease, they often have more moderate-range eosinophilia later in the course.
They also have a bronchoalveolar lavage fluid that contains at least 40% eosinophils in up to 80% of cases.
This form of eosinophilic pneumonia may be premonitory for the subsequent development of eosinophilic vasculitis, eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss vasculitis.
Drug allergy can cause mild to severe eosinophilia, often waxing quickly and tapering off slowly; It can take months for drug allergy eosinophilia to go away.
Usually, but not always, there is an associated drug eruption of the diffuse / maculopapular variety. Patients may also have asymptomatic eosinophilia due to medications, especially penicillins, cephalosporins, or quinolones.
Pulmonary infiltrates and peripheral eosinophilia have been associated with a variety of medications, including non-steroidal anti-inflammatory drugs, sulfa drugs, and nitrofurantoin.
Drug-induced diseases of other organs can also cause tissue and blood eosinophilia (eg, drug-induced interstitial nephritis).
Causes of allergy-associated eosinophilia
Take a degree of eosinophilia:
- Allergic rhinitis.
- Atopic dermatitis.
- Esofagitis eosinofílica.
- Allergy to a drug.
Moderate to severe degree of eosinophilia:
- Chronic sinusitis (especially polypoid and respiratory disease aggravated by aspirin).
- Aspergilosis broncopulmonar alérgica.
- Chronic eosinophilic pneumonia .
- Drug allergy (drug rash with eosinophilia and systemic symptoms or also called DRESS syndrome).
Drug eruption with eosinophilia syndrome and systemic symptoms (DRESS) often produces significant elevations of eosinophils in addition to abnormal liver function, temperature dysregulation, and lymphadenopathy.
According to some review studies, DRESS syndrome was mainly caused by:
- Anti-gout regimes.
- Non-steroidal anti-inflammatory drugs.
Stevens-Johnson syndrome and toxic epidermal necrolysis, severe and life-threatening forms of drug allergy, generally do not cause eosinophilia, but rather neutrophilia and lymphocytopenia.
Pharmaceuticals commonly implicated in drug eruption with eosinophilia syndrome and systemic symptoms (DRESS).
- Antibiotics : penicillins, cephalosporins, dapsone, sulfa-based antibiotics.
- Xanthine oxidase inhibitor : allopurinol.
- Antiepileptics : carbamazepine, phenytoin, lamotrigine, valproic acid.
- Antiretrovirales : nevirapine, efavirenz.
- Non-steroidal anti-inflammatory drugs : Ibuprofen.
Parasite-related eosinophilia and infection
Tissue-dwelling helminths (“worms”) are parasitic infections that often cause mild to moderate eosinophilia. Strongyloides infection is a common cause, while Giardia, a luminal parasite, does not cause eosinophilia.
Parasitic infections that cause eosinophilia:
- Helminth infections.
- Angiostrongyliasis costaricensis.
- Hookworm infection.
- Larva migrans visceral.
Tropical pulmonary eosinophilia:
- Isospora belli.
- Dientamoeba fragilis.
EGPA, formerly known as Churg-Strauss syndrome, generally occurs in an atopic individual and produces varying degrees of sinus disease, lung disease, and kidney disease and can cause mononeuritis multiplex and vascular disease as well.
EGPA is associated with significant eosinophilia, increased inflammatory markers, and tissue eosinophilia in affected areas. It carries in its differential diagnosis and shares many aspects with hypereosinophilic syndromes.
Vasculitis is often identified late in the course of the disease, especially if the kidney is not involved.
EGPA with eosinophilia and predominantly non-hemorrhagic pulmonary manifestations has a significantly lower prevalence of positivity for antineutrophil cytoplasmic antibodies (perinuclear antineutrophil cytoplasmic antibody) than EGPA with renal involvement.
EGPA produces eosinophilia and symptoms disproportionate to the usual allergic complications, affecting the sinuses, lungs, and other organs.
Connective tissue / autoimmune diseases to a variable extent can be associated with peripheral eosinophilia. Eosinophilia associated with connective tissue, rheumatologic, and autoimmune disease.
- Fascitis eosinofílica.
- Granulomatosis eosinofílica con poliangitis (vasculitis de Churg-Strauss).
- Severe rheumatoid arthritis
- Progressive systemic sclerosis.
- Sjogren’s syndrome.
- Obliterative thromboangiitis with temporal artery eosinophilia.
- Granulomatosis with polyangiitis (Wegener syndrome).
- Systemic lupus erythematosus.
- Behçet’s syndrome.
- IgG4-related disease.
- Inflammatory bowel disease
- Penfigoide bulloso.
- Dermatitis herpetiformis (celiac disease).
Hypereosinophilic syndromes (idiopathic, myeloproliferative, and lymphocytic variant) are a group of disorders in which eosinophilia is always present and can be moderate to severe. The underlying cause may have a definite etiology or be completely idiopathic.
Organs affected may include the lungs, skin, heart, blood vessels, sinuses, kidneys, and brain. Patients with idiopathic disease may present asymptomatic or with ongoing fatigue, myalgia, weakness, and malaise.
Treatment may be non-revealing, except for eosinophilia, which can be recalcitrant even for corticosteroid treatment.
Often patients with a lymphocytic variant have diffuse skin manifestations (pruritus, continuous erythema, rash). They often have a population of CD3 – CD4 + T cells and / or abnormal clonality of the T cell receptor.
They are at risk of developing T-cell lymphomas. They can be especially difficult to control with ongoing monitoring for neoplasm development and the continued need for oral (responsive) corticosteroids and other disease-modifying medications.
Patients with a myeloproliferative variant often have heart disease or thrombotic complications (endomyocardial inflammation and stroke), splenomegaly, elevated tryptase level, elevated lactate dehydrogenase, and increased vitamin B 12 level.
They may have FIP1L1-PDGFRA and other related chromosomal mutations and respond to imatinib. Imatinib may be useful in some who lack the FIP1L1-PDGFRA mutation if they have myeloproliferative features.
Episodic angioedema associated with eosinophilia (Gleich syndrome) is associated with marked episodic eosinophilia, angioedema, urticaria, pruritus, fever, weight gain, and often elevated IgM levels.
These patients have an underlying immune dyscrasia that drives their presentation, with elevated eosinophils associated with a prior increase in interleukin-5 cytokine levels. Many also have an aberrant CD3 – CD4 + T cell population and T cell receptor clonality as well.
In 25% of patients with mastocytosis, there is an associated eosinophilia, generally in the mild to moderate range.
It is believed that there is significant cross-interference between mast cells and eosinophils. Most patients have a mutation (D816V) in the c-KIT gene.
Systemic mastocytosis patients with D816VKIT mutations have co-presented with FIP1L1-PDGFRA mutations and chronic eosinophilic leukemia, although this is a rare event.
Bone marrow biopsy in mastocytosis and chronic eosinophilic leukemia shows some common pathologic features, such as CD25 expression in mast cells and spindle-shaped mast cell morphology.
Probable disease-related pathogenesis
- Idiopathic hypereosinophilic syndrome: sustained peripheral eosinophilia at more than 1500 cells / μL with associated end-organ damage.
- Lymphoproliferative hypereosinophilic syndrome: sustained peripheral eosinophilia greater than 1500 cells / μL, often associated with a rash, aberrant immunophenotypic profile of T cells, often responsive to steroids.
- Myeloproliferative hypereosinophilic syndrome: sustained peripheral eosinophilia greater than 1500 cells / μL, often with splenomegaly, heart-related complications, and thrombosis. They can have associated FIP1L1-PDGFRA and other mutations, and are often resistant to steroids.
Patients can be considered to have a diagnosis of chronic eosinophilic leukemia.
Episodic eosinophilia associated with angioedema (syndrome G): cyclical fevers, swelling, urticaria, pruritus, marked eosinophilia, and elevated IgM. Aberrant T cell phenotypes often associated.
There are malignant tumors derived from eosinophils (acute and chronic eosinophilic leukemia) and malignant tumors in which eosinophils are increased as part of the general cellular environment.
Eosinophilia associated with malignancy:
- Blood-related neoplasms.
- Acute or chronic eosinophilic leukemia.
- Lymphoma (T and Hodgkin cells).
- Chronic myelomonocytic leukemia.
- Neoplasms associated with solid organs.
- Adenocarcinomas of the gastrointestinal tract (gastric, colorectal).
- Lung cancer.
- Squamous epithelium-related cancers (cervix, vagina, penis, skin, nasopharynx, bladder).
- Thyroid cancer.
Autosomal dominant hyper-IgE syndrome (Job’s syndrome), with recurrent abscesses, lung infections, and severe eczema, is associated with eosinophilia.
Wiskott-Aldrich syndrome, with eczema, thrombocytopenia, and recurrent X-linked infections, also causes peripheral and tissue eosinophilia.
Severe combined immunodeficiency with adenosine deaminase also has eosinophilic associations. Atopy is a common feature in this entity in addition to severe immunodeficiency with recurrent infections that begin in childhood.
Omenn syndrome causes profound peripheral eosinophilia, elevated IgE and abnormally elevated T cells, as well as autoimmunity and erythrodermic rash. Patients are often discovered in newborn screening and undergo transplantation.
Miscellaneous entities associated with eosinophilia
Rejection of transplanted solid organs, including the liver, pancreas, kidney, and heart, has been associated with peripheral and organ-specific eosinophilia. Eosinophilia can be moderate to severe.
Chronic graft versus host disease after hematopoietic stem cell transplantation has also caused peripheral eosinophilia.
The level of skin involvement and severity of graft-versus-host disease could not be reliably predicted based on the presence of eosinophilia in a cohort of patients.
Kimura’s disease is a disease of mostly Asian men.
It is defined as a massive lymph node or swelling of the subcutaneous tissue mainly in the head and neck, peripheral eosinophilia, elevated IgE and pathological eosinophilic infiltrates with follicular hyperplasia and proliferation of postcapillary venules in biopsies. Surgical excision and steroid therapy are often used.
Epithelioid hemangioma, also known as angiolymphoid hyperplasia with eosinophilia, also most commonly affects the head and neck, especially in and around the atria. It is seen in all races and in both sexes, affects the dermis or epidermis, and is considered a benign vascular proliferative disease.
Excision and laser therapy appear to be the most widely used treatment modalities, often for cosmetic reasons. Peripheral eosinophilia is variable, and elevated IgE is uncommon.
Eosinophils are sensitive even to endogenous corticosteroid production. Therefore, the absence of corticosteroids can induce peripheral eosinophilia. Such hypoadrenalism can occur in Addison’s disease or adrenal hemorrhage.
Irritation of serous surfaces can cause peripheral eosinophilia. Peritoneal dialysis catheters can cause peritoneal eosinophilia, which in turn can be detected peripherally.
Cholesterol embolization, due to instrumentation or other trauma to the aorta, can cause purplish discoloration of the toes, livedo reticularis, kidney disease, elevated inflammatory markers, and hypocomplementemia, along with mild to moderate transient eosinophilia.
Entities that can be associated with eosinophilia
- Rejection of a transplanted solid organ.
- Graft versus host disease after hematopoietic stem cell transplantation.
- Kimura disease and epithelioid hemangioma.
- Eosinophilia-myalgia syndrome / toxic acceptance syndrome.
- Suprarrenal insufficiency.
- Irritation of serous surfaces.
- Cholesterol embolus.
Treatment and Management of High Eosinophils
Eosinophilia is a disorder that can arise from a number of etiologies. Therefore, the first task in treatment is to find out whether the condition is primary or secondary. Secondary eosinophilia is due to parasitic infection or drug hypersensitivity in most cases.
The first step is to remove all medications that are not essential to the continued health of the patient. This is so because there is a wide range of drugs that are capable of causing hypersensitivity reactions, even months or years after starting treatment.
Even if a drug is indicated for the patient, it should be continued only as long as there are no signs of organ involvement, such as lung or kidney inflammation.
The appearance of fever, rash or arthralgia or other systemic symptoms justify the cessation of the suspected drug.
Another step is fecal and serological tests for parasitic infestation. Three consecutive stool samples should be tested for the presence of parasite eggs, in addition to specific blood tests, based on the patient’s travel history and place of residence, past and present.
If the patient has any possibility of having Strongyloides stercoralis infection, serological testing for this parasite is mandatory, which does not appear on microscopic examination of stool samples.
This is because strongyloidiasis has a tendency to flare up and spread throughout the body when glucocorticoid treatment is started.
If this condition is suspected but not confirmed, and if immediate initiation of treatment is necessary, ivermectin should be administered along with the steroid. In other conditions, once the diagnosis of parasitic infestation is established, an adequate and effective antiparasitic treatment must be administered.
Treatment of complications
If none of these underlying disorders are found, or if the eosinophil count remains high despite treatment, other possibilities should be considered.
Tests such as antibody tests for vasculitis and other connective tissue disorders, chest and abdominal imaging, and bone marrow aspiration for biopsy may be indicated, among others.
However, many of these tests are as concerned with detecting organic complications related to eosinophilia as with establishing the etiology.
For example, cardiac involvement may be indicated by high cardiac troponin, EKG variations, or cardiac dysfunction on echocardiography.
Other serious complications include hypoxia due to pulmonary infiltration and neurological deficits.
If any of these are present, high doses of corticosteroids are started immediately, with the previous condition that ivermectin must be added simultaneously in case strongyloidiasis is present.
Only if the patient does not respond to corticosteroids is specialized treatment with imatinibmesilate or vincristine necessary.
Other emergency situations that require immediate corticosteroid therapy include:
- DRESS syndrome with persistent hypereosinophilia despite withdrawal of the suspected drug.
- Hypereosinophilia due to the presence of tumors and manifested by heart damage or failure.
Treatment of Hypereosinophilic Syndromes (HES)
HES types need to be differentiated. Type F / P is first treated with imatinib to achieve remission.
Corticosteroids generally do not produce a reduction in eosinophils in this type, but are added in the event of cardiac involvement, to prevent the development of acute myocarditis.
The L-HES subtype is treated with corticosteroids, in contrast, while T-cell inhibitors such as interferon-α are added in refractory cases or if the corticosteroid dosage is to be reduced. Such patients also require careful monitoring for T-cell lymphoma.
Most other cases of HES respond to corticosteroids if indicated to reduce the eosinophil count. This depends on whether complications have been established and, if so, which organ is affected and to what extent.
Dosage varies widely from patient to patient. If corticosteroids must be taken in a high dose, or if the adverse effects are severe, agents such as hydroxyurea and interferon-α are effective.
Patients with myeloproliferative disease are often treated with imatinibmesilate. All of these drugs are also used in patients who do not respond to steroid therapy.
Mepolizumab is a more recent addition, antagonizing the action of interleukin 5, an important chemokine in the production of eosinophils.