CASE REPORT Two Boys, 13 Months and 15 Years of Age

Home , Opisthorchiasis, Visceral larva migrans

THE PATIENTS CASE REPORT Two boys, 13 months and 15 years of age

THE CLINICAL QUESTION

While both of these patients Conar R. O’Neil, MD; had eosinophilia, their diag- Sergio Fanella, MD, FRCPC noses ended up being quite Department of Internal different. What is the best Medicine, University of Calgary Cumming School approach to the diagnosis and of Medicine, Alberta, Canada (Dr. O’Neil); management of eosinophilia Department of Pediatrics in the ambulatory care setting? and Child Health and Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada (Dr. Fanella) CASE 1 Sergio.Fanella@ umanitoba.ca A 13-month-old boy who was recently adopted from Ethiopia presented to a primary care physician with a 3-week history of bloody diarrhea accompanied by flatulence and bloating. acknowledgement Stool cultures were positive for Campylobacter and Shigella. He was prescribed azithromycin The authors would like to acknowledge Dr. Charles but saw only moderate improvement. He was then referred to the Infectious Diseases Depart- Musuka, MBChB, FRCPC, ment. Neonatal, pregnancy, and immunization histories were unknown and a review of sys- Department of Pathology, tems was unremarkable. On exam, the child looked well; he weighed 9.6 kg (15th percentile), University of Manitoba, Winnipeg, Canada, for his was 69.5 cm long (<3rd percentile), and his head circumference was 45 cm (10th percentile). editorial assistance. Head and neck, cardiorespiratory, and abdominal examinations were unremarkable. A complete blood count (CBC) showed an elevated white blood cell (WBC) count of The authors reported no 9 9 9 potential conflict of interest 26 x 10 /L (normal: 4-10 x 10 /L) with predominant eosinophilia (10.4 x 10 /L or 40.1% of relevant to this article. WBCs; normal: <0.45 x 109/L or 0%-8%). Hemoglobin and platelets were within normal limits. Stool testing for ova and parasites showed Strongyloides stercoralis larvae. Strongyloides serology was negative and Filaria serology was equivocal.

CASE 2 A 15-year-old boy was assessed for a 3-week history of fever and eosinophilia. He had enlarged cervical lymph nodes, a new rash, and had lost 4 pounds. He denied gastrointestinal symptoms, dyspnea, headaches, or chest pain. His past medical and family histories were unremarkable and he reported no drug use or allergies. He had traveled to Cuba with his family for 15 days 3 months prior to presentation. He recalled diarrhea while traveling, which resolved spontane- ously. He and his family had traveled “off the beaten track,” eating foods prepared at local establishments and swimming in local rivers. He received pre-travel immunizations. On examination, he appeared unwell, though his vital signs were normal. He had diffuse lymphadenopathy and a petechial rash on his chest, back, upper buttocks, legs, and feet. Cardio- respiratory and abdominal examinations were unremarkable. A CBC revealed an elevated WBC count of 76.9 x 109/L with predominant eosinophilia (71.5 x 109/L or 92% of WBCs). Hemoglobin, platelets, electrolytes, and liver function tests were normal. The patient was referred to a tertiary care center and was admitted to the hospital. Stool testing for ova and parasites, as well as serology for parasitic infections, was negative. A bone marrow aspiration and biopsy were performed and revealed the diagnosis of acute lymphoblastic leukemia (ALL).

DISCUSSION These 2 cases highlight how the presentation of eosinophilia can vary and how important it is to maintain a broad differential diagnosis TABLE( 11-4). Causes of eosinophilia are nu-

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TABLE 1 merous and can be divided Differential diagnosis for eosinophilia1-4 into 3 categories: primary, secondary, and idiopathic.1,5 He- Cause* Examples† matologic malignancy, where Allergic Asthma eosinophilia is clonal, is an example of a primary etiol- Drug-related (see TABLE 2) ogy. Causes of secondary eo- Atopic dermatitis sinophilia include infectious Allergic rhinitis diseases, drugs (TABLE 25), auto- Connective tissue Eosinophilic granulomatosis with immune disorders, and allergic disorder/- polyangiitis (formerly Churg-Strauss conditions. Prolonged eosino rheumatologic Syndrome) philia that is >3 x 109/L is Sarcoidosis associated with end-organ damage. Dermatologic, pulmonary, Other vasculitis gastrointestinal, and cardiac Infectious Strongyloidiasis involvement is most common.2 Helminths Schistosomiasis Ascariasis Eosinophilia associated with parasitic infection Prolonged Hookworm eosinophilia In returning travelers and in- that is Trichuriasis ternational adoptees, multi- >3 x 109/L Toxocariasis cellular helminthic parasites is associated Trichinellosis are the most common causes of eosinophilia, with eosino- with end-organ Filarial infections (eg, lymphatic damage. filariasis, loiasis, onchocerciasis) philia occurring during tissue migration or penetration.1,3 Flukes (eg, fascioliasis, Clonorchis, z opisthorchiasis, paragonimiasis) Strongyloides stercoralis is found in tropical and Cutaneous larva migrans temperate areas. Its life cycle Protozoa Isospora involves both a parasitic and Sarcocystis free-living component. It has the ability to autoinfect the Dientamoeba fragilis host and can cause hyperinfec- Other infections Coccidioidomycosis tion in those who are immuno- HIV compromised. Acute infection Tuberculosis is often subclinical, but may include a skin rash or non- Neoplasia Leukemia specific intestinal symptoms.1 Lymphoma Patients commonly present Mastocytosis with asymptomatic eosinophilia. Diagnosis is most often Other Hypereosinophilic syndrome via serology, and the first-line Adrenal insufficiency treatment for uncomplicated Serum sickness cases is ivermectin 200 µg/kg/ 4 Erythema multiforme day orally for 2 days. z Schistosomiasis is a Solid organ transplant rejection chronic parasitic infection HIV, human immunodeficiency virus. of the human vascular sys- *Consider using the mnemonic “CHINA” as a memory aid for causes of tem. It is transmitted by con- eosinophilia (Connective tissue/rheumatologic, Helminths, Infections (other), Neoplasia, and Allergy). tact with contaminated fresh †Not an exhaustive list. water, where cercariae pen-

716 THE JOURNAL OF FAMILY PRACTICE | OCTOBER 2016 | VOL 65, NO 10 TABLE 2 Drugs most commonly associated with eosinophilia5

Drug class Examples Antibiotics Penicillins, cephalosporins, tetracycline NSAIDs Aspirin, other NSAIDs Antiepileptic agents Phenytoin,* carbamazepine* Antihypertensive agents Hydrochlorothiazide* Other Ranitidine, allopurinol,* sulfasalazine,* cyclosporine,* G-CSF, nevirapine*

G-CSF, granulocyte colony-stimulating factor; NSAIDs, nonsteroidal anti-inflammatory drugs. *Associated with drug rash with eosinophilia and systemic symptoms (DRESS syndrome). etrate the skin. High prevalence areas include Eosinophilia associated Africa and Southeast Asia. Acute infection with primary hematologic malignancy can result in Katayama fever—a febrile illness Eosinophilia is a rare presentation of hema- with prominent eosinophilia that occurs 4 to tologic malignancy. Acute myeloid leuke- 7 weeks after exposure.4 Diagnosis is primar- mia, acute lymphoblastic leukemia (ALL), Causes ily clinical with appropriate epidemiology, chronic myeloid leukemia, and myeloprolif- of secondary as serology may be negative early in infec- erative disorders have all been associated with eosinophilia tion. Praziquantel is the treatment of choice, eosinophilia. Hepatosplenomegaly, gener- include though dosing varies by species, so expert alized lymphadenopathy, and cytopenias infectious consultation should be considered. in other cell lines are often noted. Also, the diseases, drugs, z Soil-transmitted helminths, such as degree of eosinophilia is often more pro- autoimmune Ascaris (Ascaris lumbricoides), whipworm nounced (>5 x 109/L). Patients with suspected disorders, (Trichuris trichiura), and hookworm (Ancy- hematologic malignancy should be urgently and allergic clostoma duodenale and Necator americanus), referred for expert consultation.5 conditions. can also cause eosinophilia during larval tissue migration. Following infection by ingestion or A systematic approach skin penetration, an acute respiratory illness, to patients with eosinophilia termed Löffler’s syndrome, can develop with Consider the following approach in the associated eosinophilia.1 Once the helminths assessment of patients with eosinophilia seen reach the adult stage, eosinophilia subsides. in the ambulatory care setting. Inpatients or Patients are most commonly treated with patients being seen in developing areas may albendazole 400 mg orally for 3 days.4 require a modified approach. z Fascioliasis is common in sheep- z History. All patients with eosinophilia rearing areas. Humans are infected through should have a thorough history taken, with ingestion of aquatic plants (eg, watercress). particular attention paid to travel history. Parasitic migration through the duodenal A travel history should make note of dates, wall and liver parenchyma can lead to fever, duration and location of travel, and any rel- right upper quadrant pain, and eosinophilia. evant exposures, such as arthropod bites The incubation period is 6 to 12 weeks. Diag- or swimming in freshwater. Dietary habits, nosis during acute infection is by serology.4 such as ingestion of seafood, game, or under- z Filarial infections, eg lymphatic fila- cooked meat can also be helpful in making a riasis, loiasis, and onchocerciasis, can also diagnosis.3,4 cause eosinophilia. The rise in eosinophils z Physical exam. In addition to a gen- can be triggered by either the adult worms eral physical examination, the following or circulating microfilariae.4 Treatment of features may be helpful in determining the fascioliasis and filarial infections varies and etiology of eosinophilia. Wheeze is char- expert consultation is recommended. acteristic of parasites in a lung migration

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phase (eg, strongyloidiasis and ascariasis) nella. Further investigations for filiariasis, or asthma. Hepatomegaly can be seen with including blood films, eye exam, and skin liver flukes, visceral larva migrans, or schisto- snips will vary with filarial species, so expert somiasis. Periorbital edema can be observed consultation should be considered.3,4 with Trichinella infection. Loa loa, a type of z Our patients. The first patient with filarial infection, produces a transient, migra- strongyloidiasis was treated with ivermectin tory angioedema, often localized to the wrists 200 µg/kg/day orally for 2 days and experi- and large joints (termed Calabar swelling). enced symptomatic improvement and reso- Dermatitis of varying intensity may suggest lution of eosinophilia. The second patient filarial infection, schistosomiasis, or atopy. with ALL was admitted and referred to hema- Perianal dermatitis is observed with strongy- tology and received induction chemother- loidiasis. Cutaneous larva migrans is charac- apy. Treatment was well tolerated and the terized by a linear, serpiginous rash.3,4 patient was discharged one week later, with z Laboratory investigations. Investiga- appropriate follow-up. tion will vary depending on the patient’s history, exposures, exam findings, and degree of eosinophilia. Any patient who is unwell or THE TAKEAWAY has significant eosinophilia (≥3 x 109/L) may Eosinophilia is commonly encountered in In returning warrant more urgent referral to infectious primary care. The approach to eosinophilia travelers and disease, travel medicine, or hematology. and the differential diagnosis can be chal- international Basic laboratory investigations should lenging. The correct diagnosis was reached adoptees, include a CBC with differential, routine in both cases by maintaining a broad dif- multicellular serum chemistries, and liver enzymes. In the ferential diagnosis. Obtaining a travel and helminthic setting of significant eosinophilia, an elec- exposure history is fundamental, although parasites are trocardiogram, cardiac enzyme levels, and a noninfectious causes, including allergy, the most chest x-ray should be obtained to screen for malignancy, and drug reaction, must always common causes end-organ damage related to eosinophilia.3-5 be considered. JFP of eosinophilia. In patients in whom you suspect hematologic malignancy, bone marrow aspiration

and biopsy are often needed to make the References diagnosis.5 1. Moore TA, Nutman TB. Eosinophilia in the returning traveler. In- fect Dis Clin North Am. 1998;12:503-521. Parasitic infections are most often 2. Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and diagnosed on stool examination for ova and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010;85:158-164. parasites or by serology. Stool should be col- 3. Schulte C, Krebs B, Jelinek T, et al. Diagnostic significance lected on 3 separate days to increase diagnos- of blood eosinophilia in returning travelers. Clin Infect Dis. 2002;34:407-411. tic yield. Certain species of Schistosoma can 4. Checkley AM, Chiodini PL, Dockrell DH, et al; British Infec- also be diagnosed on direct microscopy of tion Society and Hospital for Tropical Diseases. Eosinophilia in returning travellers and migrants from the tropics: UK recom- urine specimens. Serologic assays are avail- mendations for investigation and initial management. J Infect. able for schistosomiasis, strongyloidiasis, 2010;60:1-20. 5. Tefferi A, Patnaik MM, Pardanani A. Eosinophilia: secondary, Toxocara, fascioliasis, filariasis, and Trichi- clonal and idiopathic. Br J Haematol. 2006;133:468-492.

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