Index
It is a condition in which the peripheral blood contains an excessive amount of eosinophils, more than 500 / μL.
Eosinophils are a type of blood cell that help fight certain infections and participate in the body’s immune reactions.
Eosinophilia refers to an absolute peripheral blood eosinophil count of ≥500 eosinophils / microL; this is considered abnormal in most laboratories.
It can be classified as mild (500-1500 / μL); moderate (1500-5000 / μL); and severe (more than 5000 / μL).
The peripheral blood eosinophil count does not accurately predict the risk of organ damage in all patients. However, eosinophilia complications are more common in patients with higher eosinophil counts.
For example, a patient with mild peripheral blood eosinophilia may have significant organ involvement by eosinophils.
Therefore, it is also essential to consider the clinical status of the patient and determine if there is evidence of end-organ involvement.
Organ-specific eosinophilic disorders are presented separately.
The typical percentage of eosinophilia in an individual without eosinophilia is less than 5 percent, but the presence of eosinophilia cannot be determined based on the rate of eosinophilia.
This percentage is a relative number that varies with the total white blood cell count and the comparable rates of other WBCs (neutrophils, lymphocytes).
Historically, the terms “HES” and “idiopathic HES” have been used to describe eosinophilia ≥1500 / microL associated with end-organ dysfunction attributable to eosinophilia, in which the cause is unknown, from a practical point of view.
However, it is essential to recognize that:
- The end-organ manifestations of eosinophilia can be identical regardless of the cause.
- The etiology of eosinophilia may not be apparent at presentation but can be determined later.
- Some individuals with moderate to severe eosinophilia remain asymptomatic or develop signs of organ dysfunction many years after the first eosinophilia.
Additionally, with the availability of new diagnostic tests and targeted therapies, the ability to identify specific etiologies of HES continues to grow.
A more important distinction is whether treatment should target eosinophilia or another condition that stimulates eosinophil production (e.g., parasitic infection, drug hypersensitivity, and non-hematologic cancer) from a patient management perspective.
Pathophysiology
Eosinophils are primary cells that live in tissues; they are several hundred times more abundant in tissues than in blood.
Significantly, as mentioned above, the degree of peripheral blood eosinophilia does not always accurately predict the risk of organ damage.
Therefore, a high eosinophil count cannot predict organ involvement and end-organ damage, nor can they be excluded by a low eosinophil count.
Organs affected
Commonly affected organs of eosinophils in disease include the skin, lungs, and gastrointestinal tract.
However, heart and nervous system damage can also occur and be more concerning and life-threatening.
Causes
Peripheral blood eosinophilia can be caused by numerous allergic, infectious, and neoplastic disorders that require various treatments.
The degree of eosinophilia is rarely helpful in identifying the cause, except in extreme eosinophil counts; for example, very mild eosinophilia may be associated with asthma or allergic rhinitis.
Disorders that can cause eosinophilia are best distinguished by the patient’s history, clinical presentation, and specific laboratory tests. A more detailed discussion of the causes of eosinophilia was found separately.
The optimal evaluation of the asymptomatic or immigrant traveler with eosinophilia is uncertain. Despite a thorough review, up to 50 percent of these patients never identified a cause for their eosinophilia.
Kids
The possible causes of eosinophilia in children are identical to those in adults, with a few exceptions. Asthma and atopic disease remain the most common causes of mild to moderate eosinophilia in children.
However, careful attention must be paid to the frequency and etiology of infections, as immunodeficiency syndromes typically present in childhood and can be associated with atopic disease and peripheral eosinophilia in blood and tissue.
Food allergy and eosinophilic esophagitis are also more common causes of eosinophilia in the pediatric age group and can be missed if a good history is not obtained.
The only clue to diagnosing eosinophilic esophagitis in a child may be occasional vomiting.
Since helminth infections require adequate exposure, some conditions are more or less common in children.
For example, visceral larva migrans, which require the ingestion of eggs from soil contaminated with animal feces, are seen almost exclusively in young children.
While filariasis, which requires repeated exposure to infected insect vector bites, increases with age and is rare in children under four.
Some forms of leukemia and lymphoma are more common in childhood and can present with asymptomatic eosinophilia, sometimes several years before the malignancy is detected.
In contrast, solid tumors are rarely the cause of eosinophilia in children.
Although definitive data are lacking, the prevalence of other rare causes of eosinophilia include FIP1L1 / PDGFRA-positive myeloproliferative neoplasms and eosinophilic granulomatosis polyangiitis, and episodic angioedema and eosinophilia, appear to be comparable in children and adults.
In turn, eosinophilia can be caused by a series of conditions such as:
Clinic history
All patients should have a complete history that addresses symptoms of organ involvement, medical conditions, exposures (medications, foods, over-the-counter remedies, travel, and occupational and recreational exposures), and prior eosinophil counts.
Family history can also be helpful in rare cases of hematologic syndromes related to inheritance.
Exhibitions
Exposure history should include occupational and recreational activities, medications and supplements, food, and travel.
Examples include the risk of Strongyloides infection in miners, the risk of ascariasis in slaughterhouse workers, and the risk of schistosomiasis in river beams.
Over-the-counter medications and remedies
Eosinophilia can be caused by almost any prescription or over-the-counter medicine, herbal remedy, or dietary supplement. Therefore, a detailed review of past, current, and over-the-counter medications and treatments should be obtained.
The temporal relationship between the administration of the medication or the herbal remedy can be helpful, but the time course of eosinophilia does not always follow a consistent pattern.
Although drug-induced eosinophilia is often accompanied by fever, rash, or other clinical manifestations, signs, and symptoms may be absent.
In a prospective cohort study of 824 patients receiving long-term intravenous antibiotic therapy as outpatients, 25 percent developed eosinophilia after 15 days of treatment.
Patients with eosinophilia were significantly more likely to have a rash than patients without eosinophilia.
Liver injury was comparable between the two groups. DRES’s syndrome (rash with eosinophilia and systemic symptoms) occurred in seven patients, four of whom were receiving vancomycin.
Medication-associated eosinophilia per se does not require cessation of drug administration but requires careful consideration of the following questions:
- Are there clinical manifestations associated with eosinophilia that would dictate a change in medication?
- Are there alternative medications (antibiotics, seizure medications) that could be substituted, or is the likely medication the highly required preferred therapy?
It is also important to realize that eosinophilia may not resolve for weeks or months after the offending agent is discontinued.
Food
Dietary history should determine ingestion of raw or undercooked meat because incompletely cooked pork containing cystic larvae is a source of trichinellosis.
Ingesting soil or vegetables contaminated by infected dog or cat droppings can cause toxocariasis, and raw or undercooked crab or crab can transmit paragonimiasis.
Trip
A recent history of residence or travel to an endemic area for the parasite may help suggest a parasitic etiology of eosinophilia.
However, the lack of recent travel should not eliminate parasitic infection as a possible cause of eosinophilia, especially for helminths with a worldwide distribution and a long latency.
For example, foreign military service could be a source of infection by Strongyloides, which occurs through skin penetration in contact with soil or water contaminated by human feces. This story can be omitted unless specifically asked.
Since some helminth parasites have a limited geographic distribution, a detailed travel history is significant.
For example, Loa infection is endemic only in West and Central Africa, while gnathostomiasis has a worldwide distribution.
Consequently, a patient with migratory angioedema without a history of travel to Africa should be evaluated for some causes of migratory angioedema.
In contrast to helminthic parasites, most pathogens responsible for traveler’s diarrhea include bacteria.
Ozona parasites (Giardia, Entamoeba) generally do not cause eosinophilia. The exceptions are Dientamoeba fragilis, Isospora Belli, and the Sarcocystis species, which can cause eosinophilia.
These organisms have a worldwide distribution, with geographic concentrations (tropical and subtropical areas).
Previous eosinophil counts
The new onset of eosinophilia suggests a new diagnosis, although it does not help narrow the diagnosis.
Persistent eosinophilia without symptoms is reassuring and suggests that evaluation can be done with less urgency.
Eosinophilia can also be caused by the following:
- Steroid use can temporarily lower your eosinophil count.
- Intercurrent bacterial or viral infections may temporarily decrease the eosinophil count.
- Intermittent fluid leakage from walled echinococcal cysts may temporarily stimulate blood eosinophilia, although this is rare.
Family history
Cases of familial clustering of eosinophilic syndromes have been described, but familial clustering is rare in most cases of eosinophilia. Familial hypereosinophilia is rare but has been described.
Symptoms
Symptoms of specific organ system involvement may suggest a possible cause of eosinophilia and the consequences of eosinophil-induced tissue damage. Therefore, the following is evaluated:
- Fever, weight loss, fatigue.
- Rash / itching.
- She was gasping / coughing/and had chest congestion.
- Gastrointestinal involvement/diarrhea.
- Myalgia.
- Symptoms are attributable to lymphadenopathy or hepatosplenomegaly.
- Symptoms of cardiac dysfunction or myocarditis.
It is also necessary to know about the medical conditions associated with eosinophilia (Asthma, rheumatological diseases, malignancy).
In turn, if there has been a recent change in the symptoms of the disease, that could represent a progression of it or a new diagnosis.
Diagnosis
The most critical steps in evaluating an individual with eosinophilia are assessing the presence and degree of tissue/organ involvement, which determines the evaluation’s urgency, and the etiology, which has important implications for treatment.
A patient with acute illness or extremely high eosinophil count, a critically ill patient with eosinophilia, or an individual with a higher high eosinophil count, requires hospitalization and urgent evaluation to determine the cause of the eosinophilia; these cases are rare.
If the acute disease appears to be due to organ dysfunction (possibly caused by infiltration of eosinophils into the tissue), or if no suitable alternative therapy is identified, urgent treatment aimed at reducing the eosinophilia should be initiated.
Ideally, initial laboratory tests to determine the possible cause of eosinophilia are sent before urgent treatment begins, as treatment may hide the underlying cause.
However, urgent therapy should not be delayed while trying to obtain or wait for the results of this test.
Outpatients with signs of organ involvement
Peripheral blood eosinophilia does not correlate well with the extent of tissue damage, except at the extremes of absolute eosinophil counts.
Therefore, signs of organ dysfunction must be addressed promptly, regardless of the level of blood eosinophilia.
Helminth infections are among the most common causes. In the developed world, allergies and asthma predominate, and drug hypersensitivity is common in those with eosinophil counts> 1500 / microL.
For a patient with signs of organ involvement who is not seriously ill or hospitalized, the pace of evaluation and the need for a specialized referral depends on the specific organ involved and the degree of organ dysfunction.
In many cases, initial testing can be done in the outpatient setting.
Incidental finding, healthy individual
Eosinophilia discovered as an incidental finding on a complete blood count in an otherwise healthy person can be evaluated, outpatient. The initial evaluation should include a full history, physical examination, and baseline laboratory tests.
If signs of organ involvement are found during the initial evaluation or this evaluation, the patient may need more urgent care by a physician experienced in evaluating eosinophilic disorders and admitted to the hospital.
The patient without signs of organ involvement should undergo periodic monitoring to develop organ involvement at six-month intervals.
Physical exams
The physical examination should focus on identifying lesions that suggest a possible cause of eosinophilia and determining the presence of organ involvement.
The skin, eyes, nose, lymph nodes, gastrointestinal, cardiac, respiratory, and neurological systems, and the presence of splenomegaly are specifically evaluated.
Laboratory exams and other tests:
The initial etiology and organ involvement tests detailed below should be performed in the following patients:
- On two separate occasions, all patients with unexplained eosinophilia of ≥1500 eosinophils / microL.
- Patients with persistent eosinophils ≥500 / microL and signs or symptoms of organ involvement (e.g., skin rash, wheezing, abnormal chest radiograph, elevated troponin)
- Patients with eosinophilia between 500 and 1500 eosinophils / microL who have a history of traveling to a parasite endemic area, symptoms attributable to eosinophilia (except allergic symptoms), or other clinical findings of interest
- Patients who do not belong to these categories (asymptomatic, no travel history, mild eosinophilia) can be observed. The eosinophil count can be repeated to determine if it is increasing.
- An increased eosinophil count or the development of new signs or symptoms should prompt a reevaluation.
Initial tests
In the groups of patients mentioned above, the following initial tests are suggested to detect possible causes of eosinophilia and signs of organ involvement.
- Complete blood count with differential to determine abnormalities of other cell lines. The absolute numbers of different white blood cells must be selected because the relative percentages may be reduced in increased eosinophils.
- Peripheral blood smear review (for immature white blood cells, dysplastic features suggest a primary hematologic disorder).
- Serum chemistry, creatinine, urinalysis (to detect kidney failure and, in rare cases, adrenal failure).
- Serum B12 level (elevated in myeloproliferative neoplasms and autoimmune lymphoproliferative syndrome [ALPS])
- Liver function tests (for evidence of liver involvement).
- Troponin (for proof of eosinophil-associated subclinical myocarditis); those with elevated troponin should undergo electrocardiography and echocardiography.
- Chest X-ray (for evidence of lung involvement).
Serological tests for Strongyloides
Positive serology in an untreated patient is presumptive evidence of infection; however, serology remains positive after treatment, so it does not help document cure or reinfection.
Flow cytometry for lymphocyte subsets can show clonality in lymphocytic hypereosinophilic syndrome or lymphoid malignancy and selective deficiencies in immunodeficiency syndromes.
Evidence of organ dysfunction should prompt the initiation of therapy to reduce the risk of permanent and life-threatening organ damage in most patients. This is discussed in detail separately.
This test is repeated periodically for those without signs of organ involvement, along with the complete blood count and differential (e.g., at six-month intervals). Any temporal relationship to exposures or diseases should be taken into account.
Intermittent steroid administration can produce a false appearance of episodic eosinophilia.
Additional tests in selected patients
The following may also be appropriate in selected patients, depending on the individual characteristics of the patient and the results of the initial evaluation:
- Serological tests for Strongyloides should be performed in patients with a history of potential exposure, and empirical treatment with ivermectin should be considered if reliable serological tests are not available.
- Patients with risk factors for tuberculosis should also be screened for latent tuberculosis before glucocorticoid treatment due to the risk of reactivation.
- People with an appropriate exposure history should be tested for additional parasites and other infections.
- Patients with recurrent infections or clinical features suggestive of autoimmune disease or immunodeficiency should measure serum immunoglobulins, immunoglobulin isotypes, and other immune deficiencies based on clinical presentation.
- Individuals with features of the myeloproliferative disease (splenomegaly, anemia or thrombocytopenia, dysplastic eosinophils); skin lesions compatible with urticaria pigmentosa; or a history of anaphylaxis should measure serum vitamin B12 and tryptase levels at random.
- People with signs of adrenal dysfunction (malaise, weakness, weight loss, hypotension, skin hyperpigmentation) and those at risk of adrenal hemorrhage or necrosis should have early cortisol levels and dynamic cortisol tests.
- In patients with rhinosinusitis, asthma, and vasculitis, antineutrophil cytoplasmic antibody (ANCA) tests can evaluate eosinophilic granulomatosis with polyangiitis (EGPA), although the sensitivity of this test is low.
- People with suspected systemic disorders, such as lymphoma, should have an evaluation of peripheral blood lymphocyte subsets and clonality and computed tomography (CT) of the chest, abdomen, and pelvis; with a biopsy of an appropriate lymph node.
- Those with suspected vasculitis should undergo a chest CT scan, other studies appropriate to their symptoms, and a biopsy of the involved tissue if feasible.
- People with suspected hematologic malignancy should undergo a bone marrow evaluation with cytogenetic and molecular testing.
Testing for other parasites and infections
In addition to serologies for Strongyloides species, which should be performed in all patients, additional tests for parasitic or other infections may be indicated depending on the exposure history.
Toxocara serology
Toxocara Canis and cati are endemic worldwide and can be ingested with soil or food contaminated by cat or dog feces. This is often a concern for children who may eat contaminated soil.
Visceral larva migrans are almost exclusively a disease of children, and children with Toxocara are seriously ill.
Toxocara serology is not helpful in adults due to the high rate of seropositivity in the adult population.
Trichinella serology
Trichinella species have been reported worldwide; human infections are seen most frequently in China, Thailand, Mexico, Argentina, Bolivia, and parts of Central and Eastern Europe.
The infection results from the ingestion of undercooked meat, especially pork.
Other serologies
Depending on travel history, serology for other helminths may be appropriate.
Stool studies
People with a history of travel or exposure suggesting a possible helminth infection should also have stool tests for the presence of eggs and parasites.
The parasites’ eggs and larvae identified in feces include Strongyloides, hookworm (i.e., Ancylostoma duodenale, Necator americanus), and trematodes (ie, Fasciola, Clonorchis, Opisthorchis species). These generally do not cause diarrhea.
Stool studies should also be performed in individuals with watery stools or diarrhea to look for diagnostic trophozoites of D. fragilis and oocysts of I. Belli and Sarcocystis species, all of which can cause peripheral blood eosinophilia.
It should be noted that, although stool studies can be helpful in some cases and should be performed, they are neither sensitive nor specific, and the results can be highly variable depending on the laboratory. Repeating the tests can increase sensitivity.
Stool studies, including the following, cannot reliably identify several helminths:
- Strongyloides stercoralis.
- Schistosomes.
- Filariasis.
- Trichinella.
- Toxocara species.
Testing for these organisms is typically done by serology; in some cases, organisms can be identified on the tissue biopsy.
Viral Serologies: Depending on exposures, HIV serology, and HTLV-I and II screening may be indicated.
Body fluid tests
Urine sediment can be tested for Schistosoma haematobium if urinary symptoms and the exposure history are consistent.
Cerebrospinal fluid can be tested for eosinophils and serology if eosinophilic meningitis is suspected; infectious causes include helminths and coccidiomycosis.
Drug discontinuation test
If a cause of drug-induced eosinophilia is suspected based on an implicated drug and the lack of another explanation, a drug discontinuation trial, substituting an alternative if necessary, may be helpful.
The most likely drugs can be stopped first if the patient is not seriously ill; if the cause remains undetermined or develops an acute illness, it is appropriate to discontinue all non-essential drugs.
Blood eosinophilia itself does not necessitate cessation of drug therapy but should lead to an evaluation of the organs that may be involved in eosinophil-associated drug reactions.
If organ dysfunction develops, the stimulant drug must be discontinued. Notably, eosinophilia may take months to resolve after discontinuation of treatment.
Treatment
In some cases, eosinophilia resolves without treatment. Possible explanations for the resolution of eosinophilia include:
- Removal of an offending agent (i.e., transient exposure).
- Clearance of an infection.
- Downregulation of host responses.
The expected time course for resolution of eosinophilia after transient exposure is unknown. However, in the case of drug hypersensitivity and removal of the offending agent, resolution may take many months.
Refer to specialist
Referral to a specialist is appropriate for clinical evaluation and biopsy of the potentially affected tissue.
For example, pulmonary evaluation is appropriate for individuals with evidence of lung involvement; allergy testing is suitable for those with suspected eosinophilic esophagitis.
Referral to a physician specializing in eosinophilia is appropriate if a thorough evaluation has been performed and the cause of persistent eosinophilia has not been found.
Depending on the institution, it may be an infectious disease expert, hematologist, or allergist.
People with experience in tropical diseases should be consulted rather than attempting empirical anthelmintic therapy, which can delay appropriate diagnostic tests and lead to complications from treatment that was not indicated or misused.
Bone marrow examination
Hematologic evaluation with bone marrow examination (aspiration and biopsy) is appropriate for anyone with a possible primary hematologic cause of eosinophilia. The following cases include:
- Acute patient or eosinophil count> 100,000 / microL without an obvious causative condition.
- Eosinophil count ≥1500 / microL or signs of eosinophil organ involvement with no apparent cause identified from initial testing.
- Standard features on peripheral blood smear suggest an underlying hematologic condition (immature or dysplastic white blood cells, thrombocytopenia, unexplained anemia).
If indicated, bone marrow morphology should be evaluated for eosinophil precursor abnormalities, with special stains for reticulin and mast cells. The detection of mast cells in the bone marrow is analyzed separately.
The bone marrow should undergo cytogenetic and specific molecular tests for hematologic neoplasms associated with eosinophilia, including the following:
- Chronic myeloid leukemia testing by cytogenetics, fluorescent hybridization, or reverse transcriptase-polymerase chain reaction (RT-PCR) for the BCR-ABL fusion product.
- Testing for abnormalities of platelet-derived growth factor receptor (PDGFR) alpha or beta, fibroblast growth factor receptor 1 (FGFR1), and Fip1-like 1 (FIP1L1).
- Multicolor flow cytometry for evidence of clonal lymphocytic proliferation, including assays for (at a minimum) CD3, CD4, and CD8 (to detect CD3 negative, CD4 positive subsets).
- Peripheral blood and bone marrow T-cell receptor rearrangement studies (available from specialized academic centers) can be performed to diagnose HES lymphocyte variants.
Depending on the clinical presentation and the urgency to initiate therapy, investigations may be conducted sequentially, beginning with those that appear to be the most informative.
For example, if a patient has splenomegaly, ulcers of the oral cavity mucosa, and signs of heart failure, the FIP1L1 / PDGFRA fusion test indicates myeloproliferative hypereosinophilic syndrome (HES) is displayed.
Ideally, diagnostic tests for myeloproliferative or lymphocytic etiologies for HES should be performed before initiating therapies that can suppress clonal cell populations.
Summary and Recommendations
It is essential to consider the possibility of various causes of eosinophilia during the initial evaluation, as the timing and degree of eosinophilia can be pretty variable for many conditions.
The leading causes of eosinophilia include neoplastic disorders, parasitic and other infections, allergic disorders, adrenal insufficiency, and rheumatological conditions.
The most critical steps in evaluating an individual with eosinophilia are evaluating the presence and degree of tissue/organ involvement, which determines the urgency of the evaluation and choosing the etiology, which has important implications for treatment.
An acute patient with eosinophilia, or an individual with an extremely high eosinophil count (e.g., ≥ 100,000 eosinophils / microL), requires hospitalization and urgent evaluation to determine the cause of the eosinophilia.
For a patient with signs of organ involvement who is not seriously ill or hospitalized, the pace of evaluation and the need for specialized referral depend on the specific organ involved and the degree of organ dysfunction.
Eosinophilia discovered as an incidental finding on a complete blood count in an otherwise healthy person can be evaluated on an outpatient basis.
The probable causes of eosinophilia in children are identical to those in adults, with a few exceptions. Children are more likely to have asthma and atopic disease, immunodeficiency syndromes; food allergy and eosinophilic esophagitis; and some forms of leukemia.
Visceral larva migrans are seen almost exclusively in young children, while filariasis increases with age and is rare in children under four.
All patients should have a complete history that addresses symptoms of organ involvement, medical conditions, exposure medications, over-the-counter remedies, travel, food, occupational and recreational exposures, and previous eosinophil counts.
The physical examination should focus on the skin, eyes, nose, lymph nodes, gastrointestinal, cardiac, respiratory, and neurologic systems, and the presence of splenomegaly.
Additional testing or a drug discontinuation trial may be warranted in selected patients.
Referral to a physician who specializes in eosinophilia is appropriate if a thorough evaluation has been performed and the cause of persistent eosinophilia cannot be found.
Bone marrow aspiration and biopsy are appropriate for individuals with findings that suggest a possible primary hematologic cause of eosinophilia (e.g., hypereosinophilia, organ involvement, dysplastic or immature leukocytes on peripheral blood smear).
