Successful ivermectin treatment of hepatic strongyloidiasis presenting with severe eosinophilia.

Abstract: A 49-year-old, previously healthy nurse presented with hepatic lesions and severe peripheral eosinophilia due to strongyloidiasis. Imaging studies of the abdomen showed predominantly peripheral, confluent hepatic lesions. The hepatic lesions and eosinophilia did not show any improvement with albendazole, but completely resolved with ivermectin treatment. Our findings suggest that Strongyloides stercoralis can present with isolated focal hepatic lesions and severe eosinophilia, and resolves with ivermectin treatment.

Key Words: diagnostic imaging, ivermectin, liver, Strongyloides stercoralis

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Strongyloidiasis is a parasitic disease caused by the intestinal nematode Strongyloides stercoralis. (1) The gastrointestinal tract is the common site of involvement, with predilection for the small intestine. (2) Distinctive characteristics of this parasite include its ability to persist and replicate within the host for decades, producing minimal or no symptoms. It has the potential to cause life-threatening infection (hyperinfection syndrome, disseminated strongyloidiasis) in a host with a compromised immune system. (1) We report a case of S stercoralis infection presenting with isolated hepatic lesions which resolved with ivermectin treatment. To the best of our knowledge, there has been no report in the literature of isolated hepatic lesions secondary to S stercoralis infection, and only a solitary case report that describes imaging features of hepatic lesions. (3)

Case Report

A 49-year-old, previously healthy female nurse with a 2-month history of pruritus on her body and legs was transferred to our hematology clinic for investigation of eosinophilia. She had undergone treatment with oral methylprednisolone and antihistamines for two weeks before admission, but her symptoms did not resolve. She had no history of travel to any other country, and had not been in contact with either cats or dogs. Her body temperature was 36.7[degrees]C. She had no gastrointestinal or pulmonary complaints. Skin examination revealed hyper-pigmented knuckles and nail beds. No lymphadenopathy was detected. The liver was slightly tender, and there was evidence of hepatosplenomegaly.

Laboratory data were as follows: hemoglobin: 14.9 g/dL; white blood cell count: 14,100/UL; platelet count: 238 X [10.sup.3]/UL; absolute neutrophil count: 2,700/UL; absolute eosinophil count: 10,400/UL; ferritin: 206 ng/mL; erythrocyte sedimentation rate: 38 mm/h; blood urea nitrogen: 9 mg/dL; creatinine: 0.59 mg/dL; total protein: 6.8 g/dL; albumin: 3.8 g/dL; aspartate aminotransferase: 19 U/L; alanine aminotransferase: 26 U/L; [gamma]-glutamyltransferase: 22 U/L; alkaline phosphatase: 356 U/L; total bilirubin: 0.55 mg/dL; direct bilirubin: 0.14 mg/dL; lactic dehydrogenase: 338; uric acid: 2.3 mg/dL; prothrombin time: 13.6 seconds (control 14 s); activated partial thromboplastin time: 24.6 seconds (control 26 s); fibrinogen: 382 mg/L, C-reactive protein: 0.245 mg/L; carbohydrate antigen 19-9: 15.2 U/mL (normal, 0-33); cancer antigen 15.3: 11.7 U/mL (normal, 6.4-58); carcinoembryonic antigen: 1.2 ng/mL (normal, 0-4.1); [alpha]-fetoprotein: 5.9 U/mL (normal, 0.5-5.5); carbohydrate antigen-125: 42.7 U/mL (normal, 0-21), human immunodeficiency virus: negative. Peripheral blood smear showed marked eosinophilia, no anisocytosis and poikilocytosis, no atypic cell. Increased eosinophilic precursors were observed at bone marrow aspiration. Serum total immunoglobulins and complement levels were within normal limits (IgG: 1,540 mg/dL; IgA: 71 mg/dL; IgM: 148 mg/dL; IgE: 340 mg/dL; [C.sub.3]; 137 mg/dL; [C.sub.4]: 588 mg/dL). Throat culture showed normal flora. S stercoralis larvae were detected in stool specimens twice. Allergy tests showed only egg allergy class 2. Immunophenotyping of lymphocytes showed CD3 + CD4+: 39%; CD3 + CD8+: 44%; [T.sub.H]/[T.sub.S]: 0.9; CD19: 6%; CD16/56+: 7%. Neutrophil function tests were normal.

Transabdominal ultrasonography (US) showed multiple, predominantly peripheral, confluent, hypo- or iso-echoic areas in the left lobe of the liver. A subsequent contrast-enhanced helical computed tomographic (CT) scan of the abdomen revealed these lesions as clusters of small, hypodense areas. These lesions remained hypodense in the portal phase (Fig. 1A). On magnetic resonance imaging (MRI), T1-weighted spin-echo (TR/TE, 600/17) images showed ill-defined hypointense lesions in the left lobe (Fig. 2A). T2-weighted turbo spin-echo (TR/TE, 3,000/90) images showed ill-defined hypo- or hyperintense nodular lesions, surrounded by ill-defined hyperintense areas (Fig. 2B). Multiphasic dynamic gradient echo (TR/TE, 11/4.2, flip angle, 10[degrees]) images showed peripheral contrast enhancement of the lesions. Chest radiograph was normal.

CT-guided percutaneous liver biopsy was done. Light microscopy revealed that some of the portal areas showed pronounced fibrous expansion, and a dense infiltrate of eosinophils and mononuclear cells. Inflammatory cells were also present in the sinusoids (Fig. 3A). Limiting plate was destroyed in the portal areas showing heavy infiltrate. There were some necrotic areas resulting from degeneration and degranulation of eosinophils. Some of the portal areas were replaced by granulation and fibrous tissue. An oblique section of a migrating larvae of S stercoralis was observed (Fig. 3B). Granulomatous inflammation was not seen in the serial sections.

The patient was treated with albendazole 400 mg orally for 3 days, and this treatment was repeated 2 weeks later. The eosinophilia nonetheless persisted, and the liver lesions on abdominal ultrasonography did not show any improvement. The patient was then administered ivermectin 200 [micro]g/kg for 2 days, and this was repeated two weeks later. The eosinophilia resolved (absolute eosinophil count: 300/UL). Repeat ultrasonography and contrast-enhanced CT studies showed that the lesions had disappeared (Fig. 1B). Repeat examinations of stool were negative.

Discussion

Strongyloidiasis is endemic in tropical and subtropical countries. Prevalence rates are as high as 40% in certain areas, especially West Africa, the Caribbean, and Southeast Asia. (1) In our country, there is no study documenting prevalence of strongyloidiasis, which we think is uncommon.

S stercoralis has the unusual property that rhabditiform larvae may develop into infective filariform larvae and be passed in the feces. Thus, reinfection of the patient and/or direct transmission to a new host may take place. (4) Person-to-person transmission of S stercoralis has been demonstrated in residents of institutions for the mentally retarded, and in families of patients with strongyloidiasis. (5) Also, the possibility of S stercoralis transmission from hospitalized patients to medical staff has been reported. (6) Our patient was a nurse. She was taking care of inpatients in the internal medicine department of a public hospital. She was, then, at risk. We considered the possibility of transmission from an infective larvae-excreting patient. Her initial urticarial symptoms were probably due to chronic strongyloidiasis. However, she had been misdiagnosed as having an allergic urticaria, and was given corticosteroids. We did not have any information about liver involvement at that time. It is probable that the patient was immunocompromised due to the corticosteroid, and that as a result she developed liver lesions.

Infection with S stercoralis may be asymptomatic, or may cause a few symptoms. Symptomatic patients typically complain of gastrointestinal symptoms. The usual gastrointestinal symptoms are abdominal pain, diarrhea, gastrointestinal bleeding, tenderness, vomiting, and weight loss. (2) There are two severe forms of strongyloidiasis: hyperinfection syndrome and disseminated strongyloidiasis. A massive infection of the gastrointestinal tract and lungs is termed hyperinfection syndrome. Disseminated strongyloidiasis occurs when other organs are involved. These forms of strongyloidiasis may be seen in patients with chronic diseases, in patients on corticosteroids, and those who are immunocompromised. (1,7) It is postulated that a large proportion of activated natural killer cells, perhaps producing interferon, suppressed the T-helper 2 response that controlled the strongyloides infection (8) in patients with natural killer lymphocytosis. However, our patient did not have natural killer lymphocytosis.

[FIGURE 1 OMITTED]

Hepatic manifestations of strongyloidiasis are exceedingly unusual. In the case with a S stercoralis hyperinfestation, US showed lesions with an inner hyperechogenic area and an outer hypoechogenic rim. The CT scan showed hypodense lesions with a central ring-like area of increased attenuation. (3) To our knowledge, the MRI features have not been described. In our case, multiple, predominantly peripheral, confluent hepatic lesions, which were clustered in some areas, were observed by US and CT. On MRI, lesions were hypointense on T1-weighted images, and hypo- or hyperintense surrounded by ill-defined, peripherally less hyperintense areas on T2-weighted images. These findings seem to suggest the presence of necrosis and necrotic debris, and a variable degree of fibrosis surrounded by mild inflammatory changes. The data obtained from a biopsy specimen seemed to be consistent with these findings.

[FIGURE 2 OMITTED]

The clinical differential diagnosis of hepatic strongyloidiasis includes other parasitic and malignant diseases which cause hypereosinophilia (eg, fascioliasis, echinococcosis, schistosomiasis). The radiologic differential diagnosis may be difficult, and includes liver abscess, hepatobiliary malignancies, fascioliasis, echinococcosis, other rare parasitic diseases, and cholangitis due to acquired immunodeficiency syndrome. Diagnosis is confirmed only by demonstrating the parasite or its larval forms in lesions and in stool. (3,9,10) Although serologic methods have high sensitivity and specificity, cross-reactions have been reported in other parasitic diseases with similar clinical symptoms (eg, fascioliasis, schistosomiasis). (11) In our case, larvae were detected both in hepatic lesions and in stools.

Uncomplicated cases may be treated with thiabendazole or albendazole, but ivermectin has proven the most useful and least toxic drug for the treatment of strongyloidiasis. (10,12) Severe strongyloidiasis has a high mortality rate because the diagnosis is often delayed due to nonspecific presentation and patients who are immunocompromised. A high incidence of liver dysfunction is observed with mebendazole, and the eradicating effect is not sufficient with albendazole. Our case did not respond to albendazole, but was cured by ivermectin treatment.

[FIGURE 3 OMITTED]

Conclusion

We propose that hepatic strongyloidiasis should be included in the differential diagnosis of focal hepatic lesions and peripheral eosinophilia in patients whose stools are positive for this organism, and should be treated by ivermectin.

Talent does what it can; genius does what it must.
--Edward George Bulwer-Lytton

Accepted September 4, 2003.

References

1. Mahmoud AA. Strongyloidiasis. Clin Infect Dis 1996;23:949-953.

2. Sun T. Opportunistic parasitic infection in patients with acquired immunodeficiency syndrome. Pathol Annu 1988;23:1-32.

3. Rawat B, Simons ME. Strongyloides stercoralis hyperinfestation: another cause of focal hepatic lesions. Clin Imaging 1993;17:274-275.

4. Genta RM. Dysregulation of strongyloidiasis: a new hypothesis. Clin Microbiol Rev 1992;5:345-355.

5. Braun TI, Fekete T, Lynch A. Strongyloidiasis in an institution for mentally retarded adults. Arch Intern Med 1988;148:634-638.

6. Maraha B, Buiting AGM, Hol C, et al. The risk of Strongyloides stercoralis transmission from patients with disseminated strongyloidiasis to the medical staff. J Hosp Infect 2001;49:222-224.

7. Kothary NN, Muskie JM, Mathur SC. Strongyloides stercoralis hyper-infection. Radiographics 1999;19:1077-1081.

8. Myers B, Speight EL, Huissoon AP, et al. Natural killer-cell lymphocytosis and strongyloides infection. Clin Lab Haem 2000;22:237-238.

9. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 2001;33:1040-1047.

10. Zaha O, Hirata T, Kinjo F. Strongyloidiasis-progress in diagnosis and treatment. Intern Med 2000;39:695-700.

11. Andresen B, Blum J, von Weymarn A, et al. Hepatic fascioliasis: report of two cases. Eur Radiol 2000;10:1713-1715.

12. Adenusi AA. Cure by ivermectin of a chronic, persistent, intestinal strongyloidosis. Acta Tropica 1997;66:163-167.

RELATED ARTICLE: Key Points

* Strongyloides stercoralis can present with isolated focal hepatic lesions and severe peripheral eosinophilia.

* The clinical diagnosis of hepatic strongyloidiasis may be delayed because the clinical findings are nonspecific. The presence of eosinophilia warrants a search for this nematode.

* Imaging features are helpful in the diagnosis of hepatic strongyloidiasis.

* Ivermectin is a useful drug for the treatment of hepatic strongyloidiasis.

* Hepatic strongyloidiasis is exceedingly unusual; this case serves to remind physicians that isolated hepatic involvement and eosinophilia are features of strongyloidiasis.

Zafer Gulbas, MD, Mahmut Kebapci, MD, Ozgul Pasaoglu, MD, and Eser Vardareli, MD

From the Departments of Hematology, Radiology, Pathology, and Gastroenterology, Osmangazi University Medical Faculty, Eskisehir, Turkey.

Reprint requests to Mahmut Kebapci, MD, Department of Radiology, Osmangazi University Medical Faculty, Meselik, 26480, Eskisehir, Turkey. Email: [e-mail]