Eosinophilia in a Patient From South America

DR PAGE: Mr R was referred to the infectious diseases clinic because of an incidental finding of eosinophilia on routine laboratory tests. Mr R, do you remember why you were referred to the clinic?

MR R: I went to my regular doctor for a checkup and she found that my cell count was abnormal. Over the next few months, I had blood work repeated twice and the blood counts were still abnormal, so she sent me to the infectious diseases clinic.

DR PAGE: Were you having any symptoms?

MR R: No, not really. I was working and I did not want to go to the specialist, but my regular doctor told me several times that I had to go, so eventually I went.

DR PAGE: So you were feeling well and not too worried about your doctor's concerns?

MR R: Not initially, but after the doctor told me I may have some kind of worm, I began to wonder and decided to take care of it.

DR PAGE: Could you tell us where you are from?

MR R: I am from Guyana in South America.

DR PAGE: When did you come to the United States?

MR R: Four years ago.

DR PAGE: Since then, have you returned to South America?

MR R: Yes, I go back every year.

DR PAGE: Have you traveled anywhere else outside the United States or Guyana?

MR R: I lived in Guyana until I was 18 years old, and then moved to Suriname until 4 years ago.

DR PAGE: Did you live in the city or in the country?

MR R: Mostly in the country. I worked for 24 years on a banana plantation.

DR PAGE: When you were in South America were you ever sick or in the hospital?

MR R: No, I was healthy and working.

DR PAGE: Since you arrived in the US, have you had any fevers, cough, or diarrhea?

MR R: No, none of that.

DR PAGE: How about rashes or fatigue?

MR R: No rashes, but I’m always a little tired because I have 2 jobs.

DR PAGE: What sort of work do you do?

MR R: I work in the hospital laundry room.

DR PAGE: In summary, Mr R is a 49-year-old man from Guyana with eosinophilia and an essentially negative review of systems. His physical examination at the clinic was unremarkable, and the only notable finding was his eosinophilia. He had a white blood cell count of 9700/μL, with 50% neutrophils, 26% lymphocytes, 6% monocytes, and 18% eosinophils. His absolute eosinophil count was 1740/μL. The rest of his laboratory test results, including liver enzyme and serum creatinine measurements, were normal. Previous laboratory tests showed that his eosinophilia had been present for at least 1 year.

Peripheral eosinophilia is often an incidental finding on routine laboratory examination in immigrants or travelers. A majority of such patients are asymptomatic, and routine evaluation of stool for the presence of ova and parasites is unrevealing. Although the workup of eosinophilia in immigrants or travelers may seem daunting for clinicians unfamiliar with parasitic diseases, most cases can be appropriately diagnosed and managed with a careful history and a directed evaluation. There are many information tools, such as the Centers for Disease Control and Prevention (CDC) travel medicine Web site (http://wwwn.cdc.gov/travel/), which provide a wealth of information to clinicians and allow correlation of travel to specific diseases/organisms and exposures.

Eosinophilia is defined as an absolute eosinophil count (AEC) of at least 500/μL of blood and is classified as primary, secondary, or idiopathic.¹ Primary eosinophilia is caused by expansion of eosinophils in the context of hematologic malignancies such as acute leukemia and mastocytosis. Patients with acute eosinophilic leukemia usually present with symptoms related to pancytopenia, such as fatigue, infections, and easy bleeding. Patients with systemic mastocytosis may have peripheral eosinophilia and present with evidence of mast cell proliferation and infiltration, such as hepatomegaly, splenomegaly, skin lesions, and hematologic abnormalities. Hypereosinophilic syndromes are disorders characterized by an AEC greater than 1500/μL for more than 6 months leading to end organ damage from infiltration of the heart, lung, skin, or nerve tissue. Although most hypereosinophilic syndromes are idiopathic, a subset of cases may have a defined molecular basis.² Examination of bone marrow for evidence of hematologic malignancy and cytogenetics should be performed in patients with peripheral eosinophilia associated with pancytopenia or evidence of end organ involvement.

Secondary eosinophilia can be caused by a variety of conditions, including allergic disorders, adrenal insufficiency, adverse reactions to medications, autoimmune conditions, and infections. With the exception of eosinophilia due to helminthic infection, secondary causes of eosinophilia rarely lead to an AEC greater than 1500/μL. Rarely, end organ damage occurs in patients with an AEC greater than 3000/μL in the setting of chronic parasitic infections.

Parasitic diseases account for most cases of eosinophilia due to infections. Several nonparasitic infectious diseases occasionally are associated with eosinophilia and need to be considered.³ Dysregulation of T_H1 responses in patients infected with human immunodeficiency virus (HIV) can sometimes exacerbate allergic conditions.⁴ Dermatologic conditions associated with HIV, such as eosinophilic folliculitis, atopic dermatitis, and prurigo nodularis, can be associated with peripheral blood eosinophilia.⁴ Eosinophilia in HIV-infected patients can also result from reactions to HIV-related medications, particularly sulfa drugs and nonnucleoside reverse transcriptase inhibitors. Adrenal insufficiency due to infection with cytomegalovirus, Histoplasma, Cryptococcus, or Mycobacteria can cause eosinophilia in HIV-infected patients. Eosinophilia is uncommon with tuberculosis but can be found in cases with adrenal involvement or in the setting of adverse drug reactions to medications in both HIV-infected and uninfected individuals. Peripheral blood eosinophilia has been reported in cases of coccidioidomycosis,^{5 - 6} but this finding is unusual.

Clinicians practicing in areas where parasitic infections are uncommon may be unfamiliar with the workup and manifestations of these diseases, but several useful tips can guide the diagnostic evaluation. Eosinophilia is usually associated with helminthic infections but not with common protozoal infections such as Giardia lamblia and Entamoeba histolytica.⁷ Peripheral blood eosinophilia occurs during the tissue-invasive phase of the helminthic cycle. Therefore, helminths such as tapeworms or the adult Ascaris roundworm cause peripheral eosinophilia only during the migratory phase of infection, not in the intestinal phase.⁷ Helminths that are antigenically sequestered within tissue, such as intact echinococcal cysts, can cause localized tissue eosinophilia but are not associated with peripheral blood eosinophilia unless there is disruption of sequestration or cyst rupture.¹ Eosinophil counts commonly are highest during the early stage of parasitic infection, when tissue invasion and larval migration are at their peak. Article shows the parasites associated with the highest level of eosinophilia.⁷

The majority of patients presenting with eosinophilia are asymptomatic and have normal physical examination findings. Initial laboratory assessment should include a comprehensive blood cell count with a manual differential to confirm eosinophilia and assess its severity, liver enzyme measurement, and serologic testing for HIV. A urinalysis should be performed to look for microscopic hematuria, which may be an initial sign of infection with Schistosoma hematobium. Stool samples must be evaluated for the presence of ova and parasites ( Article ).³

Patients diagnosed as having parasitic infections should be treated with the appropriate medication. However, many patients with asymptomatic eosinophilia remain without a diagnosis despite an appropriate workup with stool and serologic studies. Most of these patients may be monitored conservatively for 3 to 6 months to see if the eosinophilia spontaneously resolves. Patients with persistently elevated eosinophil counts should have repeated analysis of blood, stool, and urine studies. Empirical therapy with albendazole can be considered to treat occult hookworm infection.³ Patients with an AEC greater than 3000/μL or an AEC greater than 1500/μL for more than 6 months are at risk of end organ damage from eosinophilic infiltration and should be evaluated by a hematologist and referred to a center with expertise in tropical medicine.

How can this information help in the evaluation of the case presented? Mr R was asymptomatic and had persistent eosinophilia, unremarkable baseline laboratory results, a negative HIV test result, and 3 negative stool evaluations for ova and parasites. He was originally from Guyana, where strongyloidiasis and lymphatic filariasis are endemic.²³ Mr R was referred to the NIH Laboratory of Parasitic Diseases, where Strongyloides was found in his stool. Mr R also had a positive serologic finding for Strongyloides (performed at the CDC) and negative serologic finding for filaria infections. He was treated with 2 doses of ivermectin and within 6 months, his eosinophilia resolved.

Strongyloides is endemic in much of Latin America, Central Africa, India, Southeast Asia, and northern Australia. Sporadic cases have been reported in Europe²⁴ and the United States.^{25 - 26} Immunocompetent individuals are usually asymptomatic and present with eosinophilia, as occurred with Mr R. In contrast, immunocompromised individuals are at risk of hyperinfection syndrome, dissemination, and septic shock.

The life cycle of Strongyloides (Figure) illustrates 2 clinically important features of this parasite: autoinfection and persistence. Strongyloides is the only clinically important helminthic parasite that can complete its entire life cycle within a human host. Infection begins with penetration of the infective filariform larvae through the skin. The larvae hematogenously spread to the lung, where they migrate to the tracheobronchial tree and are swallowed. The female larvae invade the intestinal mucosa and deposit eggs, which release rhabditiform larvae. Most of the rhabditiform larvae are excreted in feces, but a small percentage mature into infective filariform larvae, which can invade through the colon and reinfect the host. This cycle of maturation and autoinfection within the host leads to a persistent infection that can last decades.¹⁸

The majority of patients have no specific symptoms associated with strongyloidiasis, which is frequently a chronic but unrecognized infection in immigrant populations. Nonetheless, larval migration can lead to specific clinical presentations. Larva currens, a pruritic serpiginous rash in the perianal area, is pathognomonic of strongyloidiasis but is rarely found on physical examination because of its transient nature.²⁷ However, on careful questioning, some patients with strongyloidiasis recall developing a pruritic perianal rash at some point. Infection of the gastrointestinal tract can lead to nonspecific symptoms such as nausea, intermittent loose stools, and chronic diarrhea. Transient pulmonary migration may cause a dry cough and, rarely, hemoptysis. Patients with chronic, recurrent pulmonary invasion with the parasite can present with recurrent pneumonitis, asthmalike symptoms, and even respiratory failure.

As with other chronic parasitic infections, a normal eosinophil count does not rule out infection. In one study, normal eosinophil counts were found in 12% of returning travelers with strongyloidiasis, 35% of patients with filariasis, and 55% of patients with schistosomiasis.¹⁴ The presence of eosinophilia may be even less sensitive in persons native to parasite-endemic areas, whose eosinophilic response may be down-regulated by long-term exposure.²⁸ A significant proportion of refugees from Africa and Asia with asymptomatic eosinophilia and negative stool studies have positive serologic results for Strongyloides (39%-85%), filaria (30%-51%), and Schistosoma (≈ 20%).^{8 - 10} The prevalence of these infections in immigrants without eosinophilia is unknown but may be substantial. In a study of Asian refugees with strongyloidiasis, 30% had normal eosinophil counts.²⁹

In immunocompromised hosts, hyperinfection syndrome can occur with repeated cycles of autoinfection, which lead to dissemination of the parasite to the lung, liver, heart, and central nervous system.³⁰ A sepsis syndrome can result from an overwhelming cytokine and chemokine response to parasitic tissue invasion. Patients with strongyloides are also at risk of recurrent gram-negative bacteremia or, rarely, candidemia from disruption of the gastrointestinal barrier during larval migration.³⁰ The main risk factor for hyperinfection syndrome is exposure to corticosteroids.^{30 - 32} Other risk factors include chemotherapy,³¹ coinfection with human T-cell lymphotropic virus type 1,^{33 - 34} hypogammaglobulinemia,³⁵ and use of tumor necrosis factor α inhibitors.³⁶ There are a few reports of hyperinfection syndrome associated with HIV infection, but strongyloidiasis has not been an important opportunistic infection in HIV-infected patients.^{30 ,37} The prognosis of patients with hyperinfection syndrome is poor because it usually affects individuals with serious comorbidities. The mortality rate for patients hospitalized with Strongyloides hyperinfection is approximately 17%.³⁸

The diagnosis of Strongyloides is facilitated by serologic testing. Because small numbers of Strongyloides larvae are shed in feces, conventional stool ova and parasite examination has low sensitivity, even with repeated evaluation.³⁹ Sensitivity can be improved with concentration techniques or fecal culture on agar, but these techniques are time-consuming and performed only in specialized laboratories.⁸ In contrast, the sensitivity of the CDC serologic test is greater than 95%.¹⁸ In immunocompromised hosts, sensitivity declines to approximately 70%.⁴⁰ The test has a negative predictive value of greater than 95%, so a negative serologic finding is useful in excluding the diagnosis. Published sensitivities for commercial serologic assays range from 83% to 93% with specificity greater than 95%.⁴¹ However, commercially available tests use different antigen preparations and may be unreliable. Therefore, results obtained from one laboratory should be confirmed by another independent laboratory. The Division of Parasitic Diseases at the CDC serves as a reference laboratory for Strongyloides serologic testing. Clinicians and laboratory personnel can obtain diagnostic assistance through their consultation service (http://www.dpd.cdc.gov/dpdx).

Treatment with 2 doses of ivermectin (200 μg/kg) cures more than 95% of cases, while albendazole (400 mg twice daily for 3 days) has lower efficacy (78% cure rate).^{42 - 43} Some experts recommend administering the 2 doses of ivermectin 2 weeks apart to allow enough time for migration of tissue forms that are unresponsive to ivermectin to the gut.⁴³ Therapeutic failures are more common in immunosuppressed patients, and some experts recommend longer courses in this population. Serial serologic monitoring can be used to assess response to therapy, since antibody titers usually decrease within 6 months of therapy.^{8 ,18 ,44 - 46} Eosinophilia may take several months to resolve, but persistent eosinophilia 6 months after therapy suggests another etiology or therapeutic failure, usually from nonadherence to the prescribed regimen.^{7 ,18}

Although there are no standard recommendations for screening patients at high risk of strongyloidiasis, it seems reasonable to screen patients at high risk of hyperinfection syndrome. Patients who have unexplained eosinophilia or who originate from endemic areas (regardless of eosinophil count) should be screened with serologic testing for strongyloides prior to initiating immunosuppressive therapy. Patients with positive serologic findings can be treated empirically with ivermectin.³⁰

In the United States, there is no standard practice for screening and treatment of parasitic diseases in immigrants at risk. Refugees usually receive a domestic assessment at a health department after arrival to the United States. However, the postarrival assessment varies in different states and local clinics. Nonrefugee immigrants and undocumented immigrants are unlikely to have a medical evaluation after arrival to the United States. The CDC recommends predeparture treatment for intestinal parasites with a single dose of albendazole for refugees coming from Africa and Southeast Asia.⁴⁷ This therapy is effective against Ascaris, hookworm, and Trichuris but does not adequately treat schistosomiasis, filarial infections, or strongyloidiasis. Currently available drug regimens can target several parasitic infections simultaneously, but the implementation of a simple strategy would require better characterization of the burden of parasitic infection in specific immigrant populations.⁴⁸ Very high prevalences of schistosomiasis (44%) and strongyloidiasis (49%) have been found in a Sudanese refugee group, and the CDC has recommended empirical therapy in this refugee population.⁴⁷ Recommendations for other foreign-born populations require further evaluation.

Asymptomatic eosinophilia is a common presentation in travelers and immigrants. Evaluation should include careful history and physical examination, basic laboratory tests, including liver enzymes, urinalysis, and HIV serology, and 3 stool evaluations for ova and parasites. Serologic evaluation for strongyloidiasis, filariasis, and schistosomiasis should be considered in patients with a relevant travel or exposure history. Coinfection with several parasites can occur in immigrants from endemic areas, and a comprehensive initial evaluation can expedite therapy at the follow-up visit. Approximately 50% of all travelers and immigrants with asymptomatic eosinophilia have negative workups. These patients can be conservatively managed with regular monitoring of eosinophil counts or empirically treated for occult hookworm infection. However, patients with an AEC greater than 3000/μL or persistent elevations (AEC >1500/μL for >6 months) are at risk of end organ damage and should have additional hematologic evaluation. All patients from Strongyloides-endemic areas and patients with unexplained eosinophilia should have serologic testing for strongyloidiasis prior to receiving immunosuppressive therapy.