Evaluating eosinophilia in the primary care setting

Don’t rely on specialists to do the tests that you should do before your patient is referred. Eosinophilia can accompany many and varied signs and symptoms, but assessment always begins with basic testing.

Herb Ridings, MA, PA-C; William M. Geisler, MD, MPH

Herb Ridings works in the Surgical Physician Assistant Program and William Geisler in the Division of Infectious Diseases, Department of Medicine, both at the University of Alabama at Birmingham. The authors have indicated no relationships to disclose relating to the content of this article.

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Approximately 30 diseases are capable of causing an eosinophilia of greater than 600/μL of blood. Some of these diseases are relatively common and within the realm of primary care evaluation, while others are rare and difficult to diagnose without referral to a specialist. Because of this variability and to avoid unnecessary tests, excessive health care costs, and treatment delays, a systematic approach to the workup of eosinophilia is necessary (see the algorithm). The following case illustrates this point and reminds PAs that specialists cannot be relied upon to repeat basic tests that should have been performed at the primary care level before referral.

 Case study

During a routine visit to his primary care physician in June 2004, an elderly man was found to have a blood eosinophil count of 2,860/μL (22% of 13,000 WBCs/μL). The patient had no complaints at the time, but his physician was following him regularly for diverticulosis, gastroesophageal reflux disease, osteoarthritis, primary hypertension, hyperlipidemia, osteoporosis, and chronic low back pain. His medications included acetaminophen, alendronate, baclofen, hydrochlorothiazide, and omeprazole. The patient had no history of allergies, respiratory disease, or malignancy, and he denied any rashes, fever, chills, chest pain, dyspnea, cough, abdominal pain, nausea, vomiting, or change in bowel habits or weight. Upon further questioning, the patient revealed that he grew up on a farm in Alabama and frequently walked barefoot as a child. Further, he related that as a child he had developed what he called “stomach worms” and was treated successfully with some form of anthelmintic medication. He also indicated that he continued to have contact with a variety of farm animals and that he was an avid gardener. His only travel outside the continental United States was a trip to Hawaii more than 10 years previously.

The examination did not reveal any abnormalities, and the physician referred the patient to a university hematology clinic for evaluation for a possible autoimmune disease or occult malignancy. The results of a bone marrow biopsy with cytology were unremarkable. A panel of rheumatologic studies, colonoscopy, and CT of the chest, abdomen, and pelvis were performed. With the exception of a small liver cyst and renal cyst noted on CT, the results of all tests were negative; and the patient was sent to an internal medicine provider for further evaluation.

In August 2004, the internist noted that neither the primary care clinician nor the hematology specialists had performed stool studies or serologies for the various parasites indigenous to the region. A serology (enzyme-linked immunosorbent assay) for Strongyloides IgG was positive at 5.56 (reference range: less than 1.00, not detected). The patient was treated with thiabendazole, the eosinophilia resolved, and the serology results for strongyloidiasis returned to less than 1.0 when the test was repeated 6 months later.  

Discussion

Parasitic infections are the most common cause of eosinophilia worldwide, although eosinophilia in the population of the United States is most often due to allergies.¹ Numerous parasitic infections are capable of causing eosinophilia; in this country parasites that are endemic to the Southeast may cause ascariasis, trichinellosis, strongyloidiasis, and cysticercosis (see Table 1). Schistosomiasis and leishmaniasis are also occasionally seen, although usually only in immigrants and international travelers (see Table 2).

Several of these infections are readily diagnosed by serologic and stool studies for parasites and ova, but a few pose diagnostic difficulties. Leishmaniasis requires identification of the protozoa within selected tissues of the body; schistosomiasis requires identifying the eggs in either urine or stool, depending on the particular species; and trichinellosis requires a combination of positive serology and muscle biopsy showing encysted larvae.^2,3 Strongyloidiasis is also somewhat difficult to diagnose because patients are often asymptomatic and the larvae required for diagnosis are frequently absent in the initial stool specimens.⁴ Moreover, while serology for strongyloidiasis is positive approximately 90% of the time with an acute infection, it does not distinguish between current and past infection.^3,4 Thus, a definitive diagnosis requires repeating stool studies until the larvae are identified. This usually requires stool studies performed over 3 to 4 consecutive days.

Treatment of parasitic infections is usually possible with synthetic benzimidazoles (eg, albendazole, mebendazole, and thiabendazole). Some infections do not respond to these agents, however. Leishmaniasis is treated with antimony, and the drug of choice for schistosomiasis is praziquantel.⁵ Given that strongyloidiasis is frequently difficult to diagnose, some practitioners who regularly see patients with the infection treat them empirically with either ivermectin or thiabendazole. Ivermectin is the preferred anthelmintic for strongyloidiasis because it has fewer side effects, although either drug is effective. Common side effects include headache, weakness, vomiting, abdominal pain, vertigo, dizziness, and decreased mental alertness.⁶ Depending on the study cited, cure rates for the two medications range from 64% to 100%.³ Both agents are classified as pregnancy category C and should be avoided when possible in treatment of pregnant women.⁶

The workup for eosinophilia

Allergic disease Allergy is the most common cause of eosinophilia in the population of the United States.^1,7 Hay fever, asthma, eczema, and reactions to drugs can all produce an eosinophilia in the mild to moderate range, with mild defined as 600 to 1,500 eosinophils/μL and moderate defined as 1,500 to 5,000 eosinophils/μL.^1,7 Medications involved include a wide range of antimicrobials, anti-inflammatory drugs, neuroleptics, antiseizure drugs, oral hypoglycemic medications, and some anticancer agents. Fortunately, only about 0.1% of patients taking these drugs develop allergic reactions, and most symptoms resolve fairly quickly after the medication is discontinued.⁷ Common signs and symptoms associated with drug allergies include fever, rash, adenopathy, and signs of hepatic, renal, or cardiac toxicity.⁷

Autoimmune disease and malignancy Less common causes of eosinophilia include some unusual pulmonary syndromes, such as Loeffler’s syndrome (fibroplastic endocarditis), chronic eosinophilic pneumonia, reactive eosinophilia, and some autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and lupus erythematosus.⁸ Malignancies can also cause eosinophilia; examples are some of the leukemias, lymphomas, plasma cell dyscrasias, myelodysplastic disorders, and cancers of the lung, colon, pancreas, or cervix.^7,9 With autoimmune diseases like rheumatoid arthritis, Crohn’s disease, ulcerative colitis, and eosinophilic gastroenteritis, eosinophilia tends to occur primarily in patients with long-standing disease.⁷ Note, however, that recent-onset eosinophilia in established cases of inflammatory bowel disease requires an evaluation for malignancy.

Neoplastic diseases are generally associated with a mild to moderate eosinophilia, but patients with lung cancer, lymphoma, or acute leukemia can occasionally produce a severe eosinophilia in the range of 5,000 eosinophils/μL or higher.⁷ Eosinophilic leukemia is a rare and poorly defined entity that overlaps with the myelogenous leukemias and with a poorly understood entity called idiopathic hypereosinophilic syndrome (HES).^2,7,8,10 A diagnosis of exclusion, HES is defined as at least 6 months of a moderate or severe eosinophilia that cannot be attributed to any other cause.^2,7,8,10 Most patients with HES present with constitutional symptoms such as fever, weight loss, malaise, and night sweats; however, diagnosis revolves around identifying eosinophilic infiltrates within several organs.^2,7,8,10 Because of these infiltrates, patients are at risk for heart, lung, and CNS failure. Chemotherapy appears to be the only treatment that is currently available to prolong life in these patients.⁷

Evaluation The initial evaluation of a patient with eosinophilia should include a comprehensive history addressing symptoms of allergy, including hay fever, asthma, atopic skin disease, food allergies, family history of allergies, and exposure to allergens or chemicals at work. Thorough drug and travel histories should follow, as well as details of animal exposure and exposure to rural soil. Look for constitutional symptoms like fever, chills, malaise, night sweats, and weight loss, along with GI symptoms such as diarrhea, abdominal pain, bloating, nausea, and vomiting.

After the history, perform a complete physical examination, placing emphasis on the skin, lungs, lymph nodes, and abdomen. Note that splenomegaly can be present with parasitic disease, leukemia, lymphoma, and drug reactions. Atopic dermatitis and asthma can also manifest as eczema and respiratory abnormalities.

Laboratory testing At the primary care level, tests should include fecal examination for ova and parasites (at least three stool specimens on consecutive days) and possibly serologic studies to evaluate for strongyloidiasis, trichinellosis, and ascariasis if these are suggested by the travel history. Next, consider testing for other infections, such as schistosomiasis. Order a chest film to look for signs of allergic disease or acute inflammation related to strongyloidiasis, ascariasis, hookworm infection, eosinophilic pneumonitis, or drug reactions.³ Skin tests for atopic disease may be performed if indicated by the history and physical examination, but a referral is recommended beyond this level of evaluation. Depending on the differential diagnosis, referral can be to a specialist in hematology/oncology, gastroenterology, internal medicine, or infectious disease.  

Conclusion

Most cases of eosinophilia that will be seen in persons in the United States will be due to either allergy or parasitic infections, and these diseases can usually be diagnosed with a thorough history and physical examination and a limited number of inexpensive laboratory tests. In the initial examination, the clinician should focus on a history of allergy, medication use, and infectious disease exposure. Subsequent laboratory tests may include three to four stool examinations for ova and parasites, parasitic serologies, and, possibly, allergy testing. If the results of all of these tests prove negative, patients should be referred to appropriate specialists for evaluation of a possible malignancy, autoimmune disease, or hypereosinophilic syndrome.  

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