Eosinophilic Infiltration in Korea: Idiopathic?

Eosinophilia is defined as the presence of more than 500 eosinophils/µL in the peripheral blood, and may be accompanied by eosinophil infiltration in tissues. Focal eosinophilic infiltration in the lungs and liver is relatively common and is often associated with a parasitic infection, drug hypersensitivity, allergic diseases, collagen vascular diseases, and internal malignancies such as Hodgkin's disease, as well as cancer of the lung, stomach, pancreas or ovary. An eosinophilic abscess refers to a lesion of massive eosinophil infiltration and associated destroyed tissue, and an eosinophilic granuloma refers to a lesion consisting of central necrosis and mixed inflammatory cell infiltrates with numerous eosinophils, a number of neutrophils and lymphocytes, and a palisade of epithelioid histiocytes and/or giant cells.

The imaging findings of eosinophilic infiltration in the lungs and liver have mainly been reported by Korean investigators (1-9). There have only been a few case reports (10-13) from Western countries. It is unclear why this is the case and why eosinophilic disease appears to be prevalent only in Korea. Moreover, it is unclear if there are any particular parasitic, allergic, or malignant diseases prevalent in Korea only.

Korean authors have addressed the possible causes of eosinophilic infiltration such as idiopathic hypereosinophilia (1, 2, 4, 6) and malignant tumors through the tumor-associated eosinophilotactic factor (3, 5, 7-9), whereas some authors have offered no explanation (3, 9). Idiopathic hypereosinophilia is a grave disease that is characterized by persistent eosinophilia of 1,500 eosinophils/µL for more than six months, and death before six months due to congestive heart failure (14). However, the course of these patients in our clinical practice is invariably benign. Eosinophilic infiltration of the liver is often associated with cancer of the stomach, liver, etc, but only few of those patients have malignancies (3, 7, 9). Extensive investigations have been to determine if a parasitic infection is the cause of eosinophilic infiltration (9) including Taenia solium (cysticercosis), Paragonimus westermani, Clonorchis sinensis, Sparganum mansoni, Anisakis simplex, Fasciola hepatica, Schistosoma, and Toxoplasma gondi. However none of their patients gave positive results.

The terminologies are variable and confusing, and include "focal eosinophilic infiltration", "focal eosinophilic necrosis", "focal eosinophilic abscess", "eosinophilic granuloma", and "foci of eosinophil-related necrosis", etc. However, these terms do not refer to a disease entity but to the histopathologic findings of some diseases with an unknown etiology. Moreover, it is unclear if the phenomenon is idiopathic or a syndrome caused by various etiologies.

Chang et al., in a study of eosinophilic infiltrative disease of the liver and lung, reported that a Toxocara canis larval infection is the cause of the hepatic or pulmonary eosinophilic infiltration in dog ascaris (15). Of 103 patients with peripheral eosinophilia, 70 were diagnosed with a Toxocara canis infection based on an enzyme linked immunoabsorbent assay (ELISA). Of these 70 patients, 54 (77%) showed evidence of a hepatic abnormality on sonography or CT, and 42 (60%, 42/70) had a history of ingesting uncooked cow liver, which is known to be a reservoir of the encapsulated larva of Toxocara canis. The CT and sonographic findings were the same as previous reported by Korean investigators (1-8), appearing as multiple, small, oval or round, ill-defined nodules on the sonography, CT and MR images (Fig. 1).

Fig. 1.

Hepatic and pulmonary toxoplasmosis in a 53-year-old man. The patient had a left nephrectomy for a renal cell carcinoma three years ago and visited a hospital for a periodic regular check up. He used to eat chops of uncooked cow liver two or three times a year, and three months before the hospital visit, he ate eight chops of uncooked cow liver at a meat restaurant. The peripheral blood showed leucocytosis (15,200 µL) with 18% eosinophils (2,736 eosinophils/µL). The ELISA test for Toxocara canis was strongly positive.

A. Contrast-enhanced transverse CT scan of the liver in the portal venous phase shows multiple, small, ill-defined, oval or round, low-attenuating nodules in the liver.

B, C. Transverse CT scan with the lung window setting shows three round or oval nodules with a peripheral halo of ground-glass opacity in the left lower lobe.

A human infection of Toxocara canis occurs in two ways, by ingesting eggs in soil or by eating uncooked animal liver containing encapsulated larvae. Dog hair and soil contains infective stage eggs, and an infection occurs when eggs containing fully developed larva are swallowed. After hatching in the human intestine, the larva penetrate the intestinal wall, flow through the portal vein, and reach the liver, lungs, orbit and brain. Some larvae move slowly in the liver (visceral larva migrans) or become encapsulated and remain in that state with no further growth for an indefinite period (16). Children who come in contact with infected dogs are prone to be infected in this way (17).

Alternatively, adults can be infected by eating uncooked animal liver, mainly cow liver, containing encapsulated larvae (15, 18). After swallowing the uncooked liver, the encapsulated larvae are released in the human intestine. The larvae penetrate the intestinal wall and reach the liver through the portal vein. From there, they migrate to the lungs, and other parts of the body. Toxocariasis is usually asymptomatic and self-limiting in a light infection and does not require treatment. In severe infections due to the heavy worm burden, anthelmintic treatment is effective. The administration of steroid hormone may be deleterious to patients.

Some ethnic populations have a custom of eating raw animal tissue. Many Koreans and Japanese eat raw seafood, and some prefer to eat raw freshwater fish, which is the route of a Clonorchis sinensis infection. Others have a habit of eating raw cow, pig, goat, chicken or goose liver, which is based on the belief that it is a "health-promoting food". Slices of cow liver served as a gratis are a popular dish in meat restaurants. Uncooked cow (15, 18), pig (19), lamb (20), and chicken (21) liver are a source of human Toxocara canis infections. The association between toxocariasis and malignant tumors in some patients may be explained by the propensity of those patients to eat "health-promoting food." Some people believe that animal liver is a good supply of nutrients for those with malignant diseases, and families or neighbors persuade these patients eat these foods.

In summary, many patients suffering from peripheral eosinophilia with eosinophilic infiltration in the lungs and liver have toxocariasis caused by the ingestion of uncooked liver, mainly cow liver. A diagnosis of toxocariasis is made by a serologic test for the Toxocara excretory/secretory antigen (ELISA test) because the histological proof of Toxocara larva in tissue is extremely difficult. However, an ELISA kit for this disease is not widely available. The clinical triad of toxocariasis is unexplained eosinophilia, liver or lung nodules on the imaging studies, and a history of eating animal liver. Based on the clinical diagnosis, physicians may try a conservative approach, thereby reducing the necessity of expensive diagnostic tests such as MR (9) or PET imaging (22), which are used for differentiation from a metastatic tumor, thus obviating unnecessary diagnostic procedures such as biopsy or surgery (23), and aggressive treatment.