Journal of the Louisiana State Medical Society Clinical Case of the Month

Hypereosinophilia in a Young Woman with a History of Childhood Asthma

William Varnado, MD; Angela Johnson, MD; Catherine O’Neal, MD; Anthony Harton, MD; Fred A. Lopez, MD

Hypereosinophillia is a rare clinical entity. It is associated with a wide differential diagnosis including neoplasm, infection, and allergic etiologies. Clinicians should have a well defined approach to hypereosinophilia in order to find treatable causes. We present a case of hypereosinophillia caused by parasitic infection with Toxocara canis. We also review epidemiology, transmission, microbiology, and management of Toxocara canis.

CASE PRESENTATION

A 39-year-old woman with a past medical history of childhood asthma presented to the emergency department with com- plaints of five days of back and right upper quadrant pain, nau- sea, vomiting, and shortness of breath. She had taken over the counter acetaminophen but was on no other medications. She denied any drug use and endorsed intermittent alcohol use. She stated she grew up near a farm and was exposed to wildlife and house pets. The patient reported her mother had thyroid disease and her father had hypertension.

Upon arrival to the emergency department, her temperature was 99.7°F, respirations were 20 breaths/minute, pulse was 95 beats/minute, blood pressure was 131/71 mmHg, and oxygen saturation was 100%. On physical exam, she was in mild dis- tress, but alert and oriented. There was no cervical or axillary lymphadenopathy. On lung exam she exhibited mild wheezes but no crackles. Her abdomen was tender to palpation in the right upper quadrant but without rebound tenderness, disten- tion, or rigidity.

Other significant test results included 3,900/ul (0.0-700/ul), al- kaline phosphatase (ALP) of 363 U/L (40-150 U/L), aspartate Figure 1. A computed tomograph of the thorax (lung window) reveals transaminase (AST) of 94/U/L (10-58 U/L), and an alanine bilateral pulmonary nodules as well as bilateral axillary, mediastinal, transaminase (ALT) of 78/U/L (5-50 U/L). Abdominal ultra- and hilar lymphadenopathy. sound showed hepatic steatosis, and chest radiograph (CXR) showed small bilateral lower lobe infiltrates. Computed tomog- raphy (CT) of the abdomen revealed gastric thickening and pertensive. She continued to have wheezing. Follow-up stud- patchy infiltrates in the lower lung lobes. She was treated with ies including flow cytometry and chromosomal analyses were piperacillin-tazobactam and azithromycin. Over the next week, negative for a monoclonal process or karyotypes associated her white blood cell count (WBC) continued to rise reaching a with an eosinophilic neoplasm. maximum of 42,200/ul. This was accompanied by a synchro- nous rise in her absolute eosinophil count reaching a maximum She underwent esophagogastroduodenoscopy (EGD) with of 34,700/ul. Her liver enzymes along with ALP remained el- biopsies which demonstrated mild scattered eosinophils evated. Throughout this time, she was afebrile and mildly hy- throughout the esophagus and an increased number of eosino-

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On initial follow-up (two weeks later) her WBC had risen back to 20,200/ul and absolute eosinophils to 10,000/ul. Over the next month her WBC remained between 16,800/ul and 13,000/ ul with an absolute eosinophil count approximately 9,000/ul. A decision was made to treat her again with albendazole. Af- ter the second round of therapy her symptoms improved with complete resolution of shortness of breath and abdominal pain. Her WBC and eosinophils continue to trend down.

Epidemiology

Toxocara canis is a parasite that causes infection when humans ingest contaminated soil or infected animal meat. Approxi- mately 14 percent of the population in the United States is se- ropositive for toxocariasis, with the highest incidence in young, non-Hispanic African Americans. Other risk factors include low socio-economic status, an occupation involving soil han- dling, and young age.1 Though larvae can survive in freezing temperature, the ideal climate is between 20 and 30 degrees Celsius.2 The average Louisiana temperature approximates 20.83 degrees Celsius,3 making Louisiana a high prevalence en- vironment for toxocara to embryonate. Firgure 2: A computed tomograph of the abdomen (post contrast view) with hypodensities seen throughout the liver and borderline The full life cycle of toxocara only occurs in dogs and cats (de- splenomegaly. finitive host). However adult worms can live in stools or tissues of multiple animals including rabbits, chicken or small rodents phils in the body of the stomach. CT scan of the chest revealed (paratenic host).4 Toxocara is passed through the stool of these numerous ill-defined small pulmonary nodules throughout all animals and contaminates the soil. Ingestion of the stool in con- lobes measuring 3mm up to 1.4cm in size, along with bilater- taminated soil or the meat of a paratenic host can transmit the al enlarged axillary, mediastinal, and hilar lymph nodes, and larvae to humans. small bilateral pleural effusions. This CT also noted numerous small hypodensities throughout the liver, which measured 5 to Toxocara larvae act the same way in humans as in other hosts. 22mm in width (not noted on the first CT scan). Bronchoscopy Ingestion of eggs allows embryosis to occur in the intestine with alveolar lavage returned with significant eosinophils but which produces larvae that penetrate through the gut wall and biopsies and cultures were negative for an identifiable organ- migrate to other organs (most commonly lung and liver). ism. CT-guided biopsy of liver lesions showed significantly in- creased eosinophils along portal tracks, lobules, and sinusoids. Most transmission of toxocara occurs via ingestion. There is Other tests including cortisol levels, anti-nuclear antibody some thought that toxocara in the coats of dogs may be able to (ANA) profile, thyroid studies, HIV, antineutrophil cytoplas- be transmitted, though this would be very rare. Glickman was mic antibody (ANCA) survey, acid fast bacillus (AFB) sputum not able to show a direct link between pet ownership and sero- stains, blood and sputum cultures, stool studies, and fungal se- positive humans.5 However, his study did show that of the 14 rology were normal. IgE levels were found to be immeasurable participants who denied past or present dog ownership, none at >26,000 intl. units/ml (0.0-100 intl. units/ml). The patient of them were antibody positive. had a positive Toxocara antibody level and toxoplasmosis IgG, both measured via enzyme-linked immunosorbent assay (ELI- Immunology SA). The first clue of a Toxocara infection other than symptoms may Given her hypereosinophila, liver abnormalities, lung imaging be marked eosinophillia. Eosinophils are tissue dwelling cells abnormalities, wheezing, and other possibilities reasonably ex- and the absolute number of eosinophils seen in the blood does cluded, the decision was made to treat the patient for visceral not necessarily correlate to the activity within tissues. Stimula- larva migrans due to Toxocara canis. The ophthalmology de- tion of the marrow to produce eosinophils is triggered by three partment was consulted to ensure there was no evidence of oc- main factors: interleukin (IL) -5, IL-3, and granulocyte macro- ular larva migrans. She was started on albendazole and predni- phase-colony stimulating factor (GM-CSF). Of these, IL-5 is sone. Her symptoms quickly improved with a substantial drop the most specific and provokes the largest response from bone in WBC to 14,800/ul and absolute eosinophils to 10,800/ul. She marrow. IL-5 is produced by Th2 cells which are lymphocytes was discharged from the hospital to complete her course of activated in response to helminth infections.6 Not only does therapy and received follow up in the outpatient setting. this stimulate production of eosinophils, but it also activates already circulating eosinophils to become more cytotoxic and immuno-active.7

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The microbiology of eosinophils makes them uniquely equipped to fight helminth infections. First, they have a high affinity for IgA antibodies which exist near mucosal surfaces, where helminths typically enter the body. Activation of eosin- ophils via IgA or Th2 cell mediation stimulates production and degranulation of the marrow and existing eosinophils. Since eosinophils are not particularly effective phagocytes, unicel- lular protozoan infection typically cause a macrophage and neutrophil response. However, eosinophils contain specific en- zymes which are cytotoxic to multicellular helminths that are too large for phagocytosis. These proteins include major basic protein (MBP), eosinophillic cationic protein, eosinophil de- rived neurotoxin, and eosinophil peroxidase. Degranulation of eosinophils leads to release of these proteins and a hypodense appearance of eosinophils in the periphery. The exact mecha- nism of these proteins is not known, but they have been shown to be toxic to parasites, certain types of cancers, and host tis- Figure 3. Liver biopsy significant for increased eosinophils within sues.8 portal tracts, lobules, and sinusoids.

Once there is infestation of tissues with embryos of Toxocara there is migration of eosinophils to that tissue by the aforemen- tioned mechanisms. The enzymes released by the now activat- ed eosinophils are not specific to the pathogen. They also have the ability to destroy and inflame host tissues, providing the basis for tissue damage and symptoms which occur with Toxo- cara infection.9 The organism itself does not cause damage per se; rather the invoked inflammatory response can cause severe and permanent damage if left untreated.

Clincial Presentation

Toxocariasis can have several different clinical manifestations. The most common are visceral larva migrans (VLM) and less common, occuring ocular larve migrans (OLM).

The organs usually involved in visceral larva migrans are the Figure 4. Bronchial lavage from multiple lung lobes showing numer- liver and lung. This correlates with the circulation pattern of the ous eosinophils and pulmonary macrophages. parasite as it burrows through the intestinal wall and circulates through the hepatic and pulmonary vasculature. Though lar- into the posterior portion of the eye, leading to granulomatous vae often cause objective liver-associated findings, more often inflammation. An opthomology evaluation for ocular larva mi- patients present with pulmonary complaints such as wheezing, grans is necessary if treatment is being considered. A dreaded dry cough, and dyspnea.10 Other patients may present with consequence of OLM is retinal infiltration leading to dragging vague flu-like complaints such as fatigue, mild fevers, or joint and eventual retinal detachment.13 pain. The most common laboratory finding associated with toxoca- With the increasing incidence of childhood asthma, Toxocara riasis is hypereosinophillia. The degree of elevation can vary canis has potentially increased importance. Wheezing with an from mild to dramatically elevated, as seen in our case. Hepatic increased eosinophil count is a hallmark of childhood asthma. granuloma formation can present with signs of transaminitis It has been postulated that helminth infections may be a risk along with elevations in ALP. Hypergammaglobulinemia may factor or predisposition to future reactive airway disease and also be present in the setting of symptomatic patients, as was asthma. This would likely be due to the large Th2 response to also seen in our patient. the parasite, causing some cross-reactivity and stimulating the symptoms of asthma.11 A pediatric study in Hungary showed Imaging is also variable with VLM. Ultrasonography, CT, and improvement in children with both seropositivity for ascariasis magnetic resonance imaging have been evaluated. In Lim’s re- and asthma who recieved therapy directed at asthma and one view in 2008, liver imaging typically showed multiple ill-de- course of anti-helminthic drugs.12 fined lesions that measured from 1.-1.5 cm. It is important to note that these lesions are best seen in the venous phase of CT Ocular larve migrans (OLM) involves the migration of the larva liver images, differentiating it from most metastatic cancers.14

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Pulmonary imaging is similar in that there are multifocal nob- REFERENCES: ules with ill-defined margins.15 1. Kimberly Y. Won, Kdusaon-Moran D, Schantz PM, jones JL. National seroprevalence and risk factors for zoonotic toxocara spp. infection. Am Diagnosis and Treatment J Trop Med Hyg. 2008;79:552-557. 2. Azam D, Ukpai OM, Said A, Abd-Allah GA, Morgan ER. Temperature Diagnosis of Toxocara infection relies heavily on the clini- and the development and survival of infective toxocara canis larvae. Par- cal scenario and epidemiology. A thorough history including asitology Res. 2012;110:649. childhood exposures, animal exposures, family history, and 3. Usclimatedata.com:usclimatedata.com/climate/louisiana/unit- ed-states/3188. work environment should be obtained before pursuing the 4. Hotez PJ, Wilkins PP. Toxocariasis: America’s most common neglected diagnosis. Clinical symptoms, leukocytosis, eosinophilia, and infection of poverty and a helminthiasis of global importance? 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As with many parasitic infections, the best approach to toxoca- Curr Opin Allergy Clinical Immunology. 2009;9:29-37. riasis is prevention. Given its prevalence for infecting children 13. Bede O, Szenasi Z, Danka J, Gyurkovits K, Nagy D. Toxocariasis assoi- it is important to teach proper hand washing and hygeine in cated with chornic cough in childhood: a longitudinal study in Hunga- high risk areas. Avoiding intake of soil and properly disposing ry. J of Helminthol. 2008;82:357. of pet feces can also help limit exposure. 14. Suh LH, Sweeney DA, Jun AS. A 33-year-old man with a white pupil. Clin Infect Dis. 2006;43:1043. 15. Lim JH. Toxocariasis of the liver: visceral larva migran. Abdom Imag- Therapy for toxocariasis is determined by symptom and dis- ing. 2008;33:151-156. ease burden. Patients with less severe disease respond well 16. Sakai S, Shida Y, Takahashi N, Yabuuchi H, Soeda H, Okafuji T, Hatak- to albendazole therapy for two weeks.18 There are instances of enaka M, Honda H. Pulmonary lesions associated with visceral larva patients with mild disease resolving without therapy which migrans due to Ascaris sujm or Toxocara canis: imaging of six cases. AJR AM J Roentgenol. 2006; 186:1697. would be optimal given the price of albendazole. Severe dis- 17. Jones WE, Schantz PM, Foreman K, Smith LK, Wittle EJ, Schooley DE, ease should be treated with concomitant steroids in order avoid Juranek DD. Human toxocariasis in a rural community. Am J of Dis the robust inflammatory response that will likely occur as lar- Children. 1980;134:967-969. vae die. Prednisone is also cytotoxic to eosinophils. 18. Glickman L, Schantz P, Dombroske R, Cypess R. Evaluation of serodi- agnostic tests for visceral larva migrans. Am J Trop Med andHygiene. 1978;27:492-498. Definitive cure for toxocaris infection is not well defined. Treat- 19. Sturchler D, Schubarth P, Gualzata M, Gottstein B, Oettli A. Thiabenda- ment studies for toxocara infection have used clinical resolu- zole vs. albendazole in treatment of toxocariasis: a clinical trial. Annals tion of symptoms to define cure.19 Symptom relief is typically of Trop Med Parasitol. 1989;83:473. accomplished before resolution of eosinophilia, which may take weeks. However, prednisone plus albendazole therapy results in a more dramatic decrease in eosinophils than therapy with albendazole alone. The eosinophil count should be rechecked after steroid therapy is completed. Dr. Varnado is an internal medicine resident and Dr. O’Neal is an Assistant Pro- fessor of Clinical Medicine and Infectious Disease at the LSU Internal Medicine Ocular larva migrans should be ruled out prior to initiation of Program in Baton Rouge, LA. She also serves as Medical Director of Quality and therapy as steroid use is always recommended for treatment of Infection Control and Prevention for Our Lady of the Lake Regional Medical Center. Dr. Johnson is Associate Program Director for the LSU Internal Medi- this presentation. cine Residency in Baton Rouge and an Associate Professor of Clinical Medicine. She serves as the Ambulatory Clinic Director for the primary care and medicine In summary, toxocariasis is a rare clinical entity despite a high sub-specialty clinics at LSU Health in Baton Rouge. Dr. Harton is the Director seroprevalence within our population. Suspicion for the disease of Laboratories for Our Lady of the Lake Regional Medical Center. Dr. Lopez is should be increased in patients with hypereosinophilia and the a Professor and Vice Chair in the LSUHSC-NO Department of Medicine. appropriate epidemiologic history.

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