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Schistosoma mansoni granuloma in immunosuppressed man. Report of a case
331 TRANSACTIONS OF THE ROYAL Socm’y
Schistosoma
OF TROPICAL MEDICINE AND HYGIENE, VOL. 73, No. 3, 1979
mansoni
granuloma
in immunosuppressed
man.
Report of a case GEORGE V. HILLYER* AND Josh L. CANGIANOi’ * Department of Biology, University of Puerto Rico, Rico Piedras, Puerto Rico 00931, USA and Department of Pathology, UPR Medical Sciences Campus, SanJuan, Puerto Rico 00936, USA t General Medical Research Laboratory, Veterans Administration Center, San Juan, Puerto Rico 00936, USA
In humans with schistosomiasis mansoni a granulomatous response to eggs is a common finding in liver biopsies. Indeed, this response may be found practically in every organ (ANDRADE & CHEEVER, 1967). Little is known, however, about the granulomatous response in immunosuppressed humans. The purpose of this communication is to report the granulomatous response to S. mansoni eggs in a patient on maintenance immunosuppression after renal transplantation. Patient and Methods A 26-year-old Puerto Rican male with schistosomiasis mansoni of 14 years duration developed nephrotic syndrome and immune complex glomerulonenhritis. He was treated with diuretics for six years when end stage renal failure ensued. He then underwent a bilateral nephrectomy followed by renal transplantation. After his general health improved he was treated with a total dose of 6.25 g niridazole (AmbilharR) over a seven-day period and S. mansoni eggs disappeared from the faeces three weeks after start of therapy (FALCAO & GOULD, 1975). In addition, the patient was kept on maintenance immunosuppression consisting of prednisone (20 mg/day) and azathioprine (50 mg/day) for the next four years. In January 1977, the patient was hospitalized complaining of general malaise and generalized joint swelling with pain and stiffness. Within a month he developed septicaemia, respiratory distress, lactic acidosis, graft rejection and finally died after cardiorespiratory arrest. Sections of liver, colon, small intestine, lung, spleen and kidney obtained at autopsy were examined for the presence of eggs of S. mansoni. Results and Discussion Examination of sections of liver, colon, small intestine, lung, spleen and kidney revealed that eggs of S. mansoni were present only in the liver and colon. In a liver section 3 cm2 ten eggs of S. mansoni were observed trapped in the portal regions (Fig. 1). With the exception of an occasional lymphocyte in the vicinity of the eggs, it was noted that no granulomata or macrophages were present around the eggs. In the portal spaces a modest fibrosis was evident, with a few interspersed inflammatory cells. The liver presented a patchy fatty change of modest nature. Several small isolated areas of feathery and eosinophilic degenera-
tion of hepatocytes were observed, particularly in a centrilobular localization. In a section of colon, 0.3 cm2, 40 eggs or portions of eggs were seen, also with no noticeable inflammation (Fig. 2). The presence of S. mansoni eggs in the liver and colon of our patient suggests that the treatment with niridazole did not result in complete eradication of the parasite. Temporary cessation of egg-laying by the female schistosome after chemotherapy has been observed for years. WARREN et al. (1974) treated Yemeni immigrants in California (USA) who were heavily infected with S. mansoni with niridazole. In their studies they were able to follow nine patients for three to seven months after treatment. They observed that, despite treatment, more than half of the patients were still passing eggs in their faeces. Thus the presence of schistosome eggs in our patient who had also been treated with niridazole was not surprising. It has been demonstrated that when drugs which block the function of immunocompetent T cells are administered, granulomata fail to develop (WARREN, 1977). Further evidence of thymic dependency of granuloma formation was the observation that athymic (nude) mice exhibit a marked impairment in the development of hepatic granulomata to S. mansoni eggs, due in large measure to the selective depletion-ofeosinophils (PHILLIPS ef al., 1977; BYRAM & LICHTENBERG. 1977; Hsu et al.. 1976). However, in these smaller granblomata ne&ophils, macrophages, lymphocytes, epithelioid cells and pigments were usually present. In addition, granulomata to S. mansoni eggs were found to develop normally in B-cell deficient mice (S. MADDISON, personal communication). This patient was chronically treated with azathioprine and prednisone, both suppressors of cell-mediated immune responses and anti-inflammatory agents. Impaired delayed hypersensitivity responses were observed in this patient through negative intradermal reactions to PPD, Candida, Trichophytin, streptokinase and mumps antigens. His serum immunoglobulin levels were near normal for IgG (750 mg%), below normal for IgA (110 mg %) and above normal for IgM (260 mg %). Serum C3 and C4 levels were decreased (70 and 26 mg% respectively). Antibody responses to S. mansoni eggs (COP test) or egg extracts (Ouchterlony) were negative, but antibodies to adult worms as seen by immunofluorescence were present. Anti-nuclear (IIF) and anti-DNA (Ouchterlony)
332
s. t?ZUnSO?Z~GRANULOMA
IN IMMUNOSUPPRESSED
MAN
with prednisone and azathioprine for four years. Note Fig. 1. Egg of Schistosomo mansoni in liver of human treated for immunosuppression NO response to the egg. Cells in the vicinity of the egg include hepatocytes, fibroblasts and lymphocytes.
plete absence of granulomatous 50tn] emitlophils are evident.
Fig. 2. S. mans& egg in section of colon from patient with chronic schistosomiasis cell1liar response to this egg is observed.
and immunosuppression.
Complete absence of erg: lnized
G. V. HILLYERANDJ. L. CANGIANO antibodies, as well as circulating DNA, were present in the serum. Azathioprine, a purine analogue, is a powerful immunosuppresant, particularly of T cell function, often being used to prevent the rejection of transplanted organs (STARZL81 PUTNAM, 1969; THOMPSON, 1976). The patient under consideration received 100 mg of azathioprine per day for four years. We postulate that the granulomata surrounding the eggs of S. mansoni failed to develop once the clinical immunosuppression aimed at preventing transplant rejection was imposed. This could have been due to the suppression of the regulatory cells that sustained the granuloma: the immunocompetent T-lymphocytes responding to schistosomal egg antigens by, among other things, secreting MIF. Once MIF was absent, no further recruiting of cells to sustain the granuloma was possible. Studies with 6-mercaptopurine (6-Ml?), from which azathioprine is the 6-imidazole-substituted derivative, have suggested that suppression of delayed hypersensitivity is through its action on effector cells (PHILLIPS & ZWEIIMAN,1973). Thus the interpretation that azathioprine treatment in a human with chronic schistosomiasis mansoni results in diminished granulomatous response to the parasite eggs is in agreement with similar results obtained with the murine model of schistosomiasis mansoni (DOMINGO et al., 1967).
In conclusion, the significance of this study is the demonstration that suppression of cell-mediated immunity in man with schistosomiasis mansoni also results in suppression of granuloma formation. Acknowledgements
These studies were supported in part by NIH Grant No. RR-8102-06 administered by the Division of Research Resources. The help and encouragement of Angel Roman France, Chairman, Department of Pathology, University of Puerto Rico, Medical Sciences Campus is greatly appreciated.
333
Brazil. In: Bilharziasis, F. K. Mostofi (Editor), New York: Springer-Verlag, pp. 157-166. Byram, J. E. & Lichtenberg, F. V. (1977). Altered schistosome granuloma formation in nude mice. American Yournal of Hygiene, 26, 944-956:
TroPical -
Medicine
Domingo, E. O., Cowan, R. B. T. Sr Warren, K. S. (1967). The inhibition of granuloma formation around schistosoma mansoni eggs. I. Immunosuppressive drugs. American Journal of Tropical Medicine and Hygiene, 16, 284-292.
Falcao, H. A. & Gould, D. B. (1975). Immune complex nephropathy in schistosomiasis. Annals of Internal Medicine, 83, 148-154. Hsu, C. K., Hsu, S. H., Whitney, R. A. & Hanson, C. T. (1976). Immunopathology of schistosomiasis in athymic mice. Nature, 262, 397-399. Phillips, S. M., Di Conza, J. J., Gold, J. Q. 81 Reid, W. A. (1977). Schistosomiasis in the congenitally athymic (nude) mouse. I. Thymic dependency of eosinophilia, granuloma formation, and host morbidity. Journal of Immunology, 118, 594-599.
Phillips, S. M. & Zweiman, B. (1973). Mechanisms in the suppression of delayed hypersensitivity in the guinea pig by 6-mercaptopurine. Journal of Experimental Medicine, 137, 1494-1510. Starzl, T. E. & Putnam, C. W. (1969). Experience in hepatic transplantation. Philadelphia: W. B. Saunders Co. Thompson, D. M. (1976). Immunotherapy and immunosuppression. In: Clinical Immunology, S. 0. Freedman & I’. Gold(Editors). Hagerstown, Maryland: Harper and Rowe, Publ. Warren, K. S. (1977). Worms. In: Immunological Diseases, Samter, M. (Editor). Boston, USA.: Littel, Brown & Co. Warren, K. S., Mahmoud, A. A. F., Cummings, P., Murphy, D. J. & Houser, H. B. (1974). Schistosomiasis mansoni in Yemeni in California: duration of infection, presence of disease, therapeutic management. American Journal of Tropical Medicine and Hygiene, 23, 902-909.
References
Andrade, Z. A. & Cheever, A. W. (1967). Clinical and pathological aspects of schistosomiasis in
and
Accepted for publication
1st November, 1978.
Schistosoma
OF TROPICAL MEDICINE AND HYGIENE, VOL. 73, No. 3, 1979
mansoni
granuloma
in immunosuppressed
man.
Report of a case GEORGE V. HILLYER* AND Josh L. CANGIANOi’ * Department of Biology, University of Puerto Rico, Rico Piedras, Puerto Rico 00931, USA and Department of Pathology, UPR Medical Sciences Campus, SanJuan, Puerto Rico 00936, USA t General Medical Research Laboratory, Veterans Administration Center, San Juan, Puerto Rico 00936, USA
In humans with schistosomiasis mansoni a granulomatous response to eggs is a common finding in liver biopsies. Indeed, this response may be found practically in every organ (ANDRADE & CHEEVER, 1967). Little is known, however, about the granulomatous response in immunosuppressed humans. The purpose of this communication is to report the granulomatous response to S. mansoni eggs in a patient on maintenance immunosuppression after renal transplantation. Patient and Methods A 26-year-old Puerto Rican male with schistosomiasis mansoni of 14 years duration developed nephrotic syndrome and immune complex glomerulonenhritis. He was treated with diuretics for six years when end stage renal failure ensued. He then underwent a bilateral nephrectomy followed by renal transplantation. After his general health improved he was treated with a total dose of 6.25 g niridazole (AmbilharR) over a seven-day period and S. mansoni eggs disappeared from the faeces three weeks after start of therapy (FALCAO & GOULD, 1975). In addition, the patient was kept on maintenance immunosuppression consisting of prednisone (20 mg/day) and azathioprine (50 mg/day) for the next four years. In January 1977, the patient was hospitalized complaining of general malaise and generalized joint swelling with pain and stiffness. Within a month he developed septicaemia, respiratory distress, lactic acidosis, graft rejection and finally died after cardiorespiratory arrest. Sections of liver, colon, small intestine, lung, spleen and kidney obtained at autopsy were examined for the presence of eggs of S. mansoni. Results and Discussion Examination of sections of liver, colon, small intestine, lung, spleen and kidney revealed that eggs of S. mansoni were present only in the liver and colon. In a liver section 3 cm2 ten eggs of S. mansoni were observed trapped in the portal regions (Fig. 1). With the exception of an occasional lymphocyte in the vicinity of the eggs, it was noted that no granulomata or macrophages were present around the eggs. In the portal spaces a modest fibrosis was evident, with a few interspersed inflammatory cells. The liver presented a patchy fatty change of modest nature. Several small isolated areas of feathery and eosinophilic degenera-
tion of hepatocytes were observed, particularly in a centrilobular localization. In a section of colon, 0.3 cm2, 40 eggs or portions of eggs were seen, also with no noticeable inflammation (Fig. 2). The presence of S. mansoni eggs in the liver and colon of our patient suggests that the treatment with niridazole did not result in complete eradication of the parasite. Temporary cessation of egg-laying by the female schistosome after chemotherapy has been observed for years. WARREN et al. (1974) treated Yemeni immigrants in California (USA) who were heavily infected with S. mansoni with niridazole. In their studies they were able to follow nine patients for three to seven months after treatment. They observed that, despite treatment, more than half of the patients were still passing eggs in their faeces. Thus the presence of schistosome eggs in our patient who had also been treated with niridazole was not surprising. It has been demonstrated that when drugs which block the function of immunocompetent T cells are administered, granulomata fail to develop (WARREN, 1977). Further evidence of thymic dependency of granuloma formation was the observation that athymic (nude) mice exhibit a marked impairment in the development of hepatic granulomata to S. mansoni eggs, due in large measure to the selective depletion-ofeosinophils (PHILLIPS ef al., 1977; BYRAM & LICHTENBERG. 1977; Hsu et al.. 1976). However, in these smaller granblomata ne&ophils, macrophages, lymphocytes, epithelioid cells and pigments were usually present. In addition, granulomata to S. mansoni eggs were found to develop normally in B-cell deficient mice (S. MADDISON, personal communication). This patient was chronically treated with azathioprine and prednisone, both suppressors of cell-mediated immune responses and anti-inflammatory agents. Impaired delayed hypersensitivity responses were observed in this patient through negative intradermal reactions to PPD, Candida, Trichophytin, streptokinase and mumps antigens. His serum immunoglobulin levels were near normal for IgG (750 mg%), below normal for IgA (110 mg %) and above normal for IgM (260 mg %). Serum C3 and C4 levels were decreased (70 and 26 mg% respectively). Antibody responses to S. mansoni eggs (COP test) or egg extracts (Ouchterlony) were negative, but antibodies to adult worms as seen by immunofluorescence were present. Anti-nuclear (IIF) and anti-DNA (Ouchterlony)
332
s. t?ZUnSO?Z~GRANULOMA
IN IMMUNOSUPPRESSED
MAN
with prednisone and azathioprine for four years. Note Fig. 1. Egg of Schistosomo mansoni in liver of human treated for immunosuppression NO response to the egg. Cells in the vicinity of the egg include hepatocytes, fibroblasts and lymphocytes.
plete absence of granulomatous 50tn] emitlophils are evident.
Fig. 2. S. mans& egg in section of colon from patient with chronic schistosomiasis cell1liar response to this egg is observed.
and immunosuppression.
Complete absence of erg: lnized
G. V. HILLYERANDJ. L. CANGIANO antibodies, as well as circulating DNA, were present in the serum. Azathioprine, a purine analogue, is a powerful immunosuppresant, particularly of T cell function, often being used to prevent the rejection of transplanted organs (STARZL81 PUTNAM, 1969; THOMPSON, 1976). The patient under consideration received 100 mg of azathioprine per day for four years. We postulate that the granulomata surrounding the eggs of S. mansoni failed to develop once the clinical immunosuppression aimed at preventing transplant rejection was imposed. This could have been due to the suppression of the regulatory cells that sustained the granuloma: the immunocompetent T-lymphocytes responding to schistosomal egg antigens by, among other things, secreting MIF. Once MIF was absent, no further recruiting of cells to sustain the granuloma was possible. Studies with 6-mercaptopurine (6-Ml?), from which azathioprine is the 6-imidazole-substituted derivative, have suggested that suppression of delayed hypersensitivity is through its action on effector cells (PHILLIPS & ZWEIIMAN,1973). Thus the interpretation that azathioprine treatment in a human with chronic schistosomiasis mansoni results in diminished granulomatous response to the parasite eggs is in agreement with similar results obtained with the murine model of schistosomiasis mansoni (DOMINGO et al., 1967).
In conclusion, the significance of this study is the demonstration that suppression of cell-mediated immunity in man with schistosomiasis mansoni also results in suppression of granuloma formation. Acknowledgements
These studies were supported in part by NIH Grant No. RR-8102-06 administered by the Division of Research Resources. The help and encouragement of Angel Roman France, Chairman, Department of Pathology, University of Puerto Rico, Medical Sciences Campus is greatly appreciated.
333
Brazil. In: Bilharziasis, F. K. Mostofi (Editor), New York: Springer-Verlag, pp. 157-166. Byram, J. E. & Lichtenberg, F. V. (1977). Altered schistosome granuloma formation in nude mice. American Yournal of Hygiene, 26, 944-956:
TroPical -
Medicine
Domingo, E. O., Cowan, R. B. T. Sr Warren, K. S. (1967). The inhibition of granuloma formation around schistosoma mansoni eggs. I. Immunosuppressive drugs. American Journal of Tropical Medicine and Hygiene, 16, 284-292.
Falcao, H. A. & Gould, D. B. (1975). Immune complex nephropathy in schistosomiasis. Annals of Internal Medicine, 83, 148-154. Hsu, C. K., Hsu, S. H., Whitney, R. A. & Hanson, C. T. (1976). Immunopathology of schistosomiasis in athymic mice. Nature, 262, 397-399. Phillips, S. M., Di Conza, J. J., Gold, J. Q. 81 Reid, W. A. (1977). Schistosomiasis in the congenitally athymic (nude) mouse. I. Thymic dependency of eosinophilia, granuloma formation, and host morbidity. Journal of Immunology, 118, 594-599.
Phillips, S. M. & Zweiman, B. (1973). Mechanisms in the suppression of delayed hypersensitivity in the guinea pig by 6-mercaptopurine. Journal of Experimental Medicine, 137, 1494-1510. Starzl, T. E. & Putnam, C. W. (1969). Experience in hepatic transplantation. Philadelphia: W. B. Saunders Co. Thompson, D. M. (1976). Immunotherapy and immunosuppression. In: Clinical Immunology, S. 0. Freedman & I’. Gold(Editors). Hagerstown, Maryland: Harper and Rowe, Publ. Warren, K. S. (1977). Worms. In: Immunological Diseases, Samter, M. (Editor). Boston, USA.: Littel, Brown & Co. Warren, K. S., Mahmoud, A. A. F., Cummings, P., Murphy, D. J. & Houser, H. B. (1974). Schistosomiasis mansoni in Yemeni in California: duration of infection, presence of disease, therapeutic management. American Journal of Tropical Medicine and Hygiene, 23, 902-909.
References
Andrade, Z. A. & Cheever, A. W. (1967). Clinical and pathological aspects of schistosomiasis in
and
Accepted for publication
1st November, 1978.