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Inability of oral bovine transfer factor to eradicate cryptosporidial infection in a patient with congenital dysgammaglobulinemia
CLINICAl.
IMMUNOLOGY
AND
IMMC~NOPATHOI~OGY
50.
‘to?-406
(i%y)
Inability of Oral Bovine Transfer Factor to Eradicate Cryptosporidial Infection in a Patient with Congenital Dysgammaglobulinemia’ HIOK
HEE CHNG,*.’
DONALD SHAW,* PHILLIP ANDREW SAXON*
KLESIUS,?
AND
*Department of Medicine, UCLA School of Medicine. Los Angeles. California 90024, and tAnimal Parasite Research Laboratory. United States Department of Agriculture, Agricultural Research Senice. Auburn, Alabama 36831 A 31-year-old man with dysgammaglobulinemia Type I (deficient IgG, IgA, and elevated IgM) and persistent cryptosporidiosis was treated over a 13-week period with oral bovine transfer factor from calves immunized with cryptosporidia. Spiramycin was added toward the end of the treatment period. This patient failed to show clinical response although there was a decrease in the stool oocyst count from the value just prior to therapy. Bovine transfer factor alone and in combination with spiramycin failed to eradicate the infection in this man with well-documented stable cryptosporidiosis. 0 1989 Academic
Press. Inc
INTRODUCTION Cryptosporidium parvum, an intestinal coccidial protozoan, is a well-established cause of diarrhea in humans and animals (1, 2). In the immunocompetent host, the protozoan causes either asymptomatic infection or self-limited diarrhea (3,4). In immunocompromised persons, the diarrhea may be profuse, cholera-like and debilitating and may follow a relentless or relapsing course (5-7). In addition to infecting the bowel, C. parvum has also recently been reported to be isolated from the respiratory tract, pancreatic duct, biliary tract, and gallbladder (8-l 1). At present there is no effective therapy for ongoing cryptosporidial infection although numerous chemotherapeutic agents have been tried. Isolated responses have been reported but true responses compared to natural remission/relapse of the disease have not been well established (12). Bovine transfer factor was recently reported to result in the eradication of intestinal cryptosporidiosis in four of eight patients with the acquired immunodeficiency syndrome (AIDS) although in two patients the infection relapsed following cessation of therapy (13). We now report the use of oral bovine transfer factor as therapy for refractory cryptosporidiosis in a very well-studied patient with congenital dysgammaglobu’ Supported in part by USPHS Grant CA-12800. Dr. Chng was the recipient of a training grant from the Ministry of Health, Republic of Singapore. * Present address: Department of Medicine IV. Tan Tack Seng Hospital, Moulmein Road, Republic of Singapore.
402 0090-1229/89
$1.50
Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.
BRIEF
403
COMMUNICATIONS
linemia. Since this patient was clinically stable in relationship to both his dysgammaglobulinemia and his cryptosporidiosis, this allowed us to evaluate any possible theraputic benefit without the changing physical status as occurs in patients with AIDS. CASE REPORT
(UCLA
NUMBER
062-01-66)
AND RESULTS
The patient is a 31-year-old man with congenital dysgammaglobulinemia Type I (elevated IgM of 550 mg%, low IgG of 41 mg%, and IgA of less than 5 mg% at time of diagnosis) diagnosed at age 10 years. Since then, he has been on various forms of replacement immunoglobulin therapy. He developed uncontrolled diarrhea and steatorrhea in 1980 and a diagnosis of large and small bowel cryptosporidiosis was made based on positive intestinal biopsies. Multiple stool cultures for bacterial and viral pathogens (including CMV) and repeated examinations for ova and parasites as well as small and large bowel biopsies which were cultured and examined histologically (including electron microscopy) failed to reveal any etiology other than cryptosporidiosis for the patient’s diarrhea. This infection failed to respond to all therapy including a 2-week course of spiramycin, high dose intravenous and also high dose oral gammaglobulin, and oral administration of bovine colostral anti-cryptosporidial antibody (14). The diarrhea was eventually symptomatically controlled with naprosyn although he continued to excrete oocysts in his stools. In addition, he has had mild cholangitis since 1983. This is attributed to cryptosporidiosis in view of recent reports of biliary tract infestation although no cannulation of his biliary tract for evidence of the protozoa has been performed. His liver function tests remain stable. In March 1988, following Institutional Review Board approval and obtaining informed consent, the patient was started on oral bovine transfer factor. The crude product was prepared as described from lymph nodes of young calves which had developed resistance to C. parvum (13). The lymph node extract was dissolved in sterile, pyrogen-free water and filter sterilized with a 0.22~p,m filter. Oral bovine transfer factor was started at a dose of 1 unit/week (5 x 10’ lymph node cell equivalents), the dose used by Louie et al. (13), and subsequently increased to 2 units/week at Week 7 when oocysts continued to be excreted and there had been no symptomatic improvement. Spiramycin at a dose of 3 g/day in two divided doses was added at Week 10 and continued for 3 weeks. The patient’s weight, bowel movements, stool consistency, CBC and platelet numbers, BUN and liver function tests, and stool oocyst count were monitored at regular intervals. The cryptosporidial oocysts in the patient’s stools were quantitated using monoclonal antibodies to the oocysts. Naprosyn was discontinued during this period of treatment. During this treatment period, his bowel movements and stool consistency remained unchanged. There was however a decrease in the stool oocyst count from that obtained the day prior to beginning the treatment (40/10X field) although oocysts continued to be present throughout (Fig. 1). The drop in the oocyst count with initiation of transfer factor therapy is difficult to interpret as a response as the counts in this patient tended to vary spontaneously over time as evidenced by stool oocyst subsequent to cessation of transfer factor therapy with counts vary-
404
BRIEF COMMUNIC’AT’IONS
n
WEEKS FIG. 1. Patient’s course while receiving therapy with oral administration of oral bovine transfer factor (BTF). The patient was started on BTF at 1 unit/week for 6 weeks and then increased to 2 units/week for 7 more weeks. Spiramycin was added for 3 weeks as noted. The total number of stools (III), the number of watery stools (El) per week, and the number of oocytes present per microscopic field in the stool (0) are shown.
ing between 5 and 35 oocysts/tield. In view of this and the lack of clinical improvement, the therapy was considered unsuccessful. The patient’s hemogram, white blood cell count, and differential and biochemical profile remained unaltered during the transfer factor and spiramycin treatment. No toxic effects were observed during the course of oral bovine transfer factor treatment. DISCUSSION
Bovine transfer factor, derived from calves immune to clinical coccidiosis, has been reported to provide partial immunity against this infection in calves and mice (15, 16). In these aminal studies, it conferred protection against the lethal effects of the infection as well as decreased the oocyst excretion. These effects were dose dependent with a limiting effective dose. In addition, protection was conferred only when it was given prior to exposure to these protozoa (16). Louie ef al. (13) suggested a possible role for the use of oral bovine transfer factor in the treatment of cryptosporidiosis in immunodeficient patients and specifically those with AIDS, a disease with both cellular and humoral immune defects but in which the cellular defects predominate. Our patient with congenital dysgammaglobulinemia has been receiving adequate replacement gammaglobulin therapy (400 mg/kg/month). He does not have
BRIEF COMMUNICATIONS
40.5
any known cellular immune deficiency or opportunistic infections besides the cryptosporidiosis. The failure of oral bovine transfer factor to eradicate cryptosporidial infection in this man with a primarily humoral immune deficiency may simply be due to the fact that the immune defect predisposing him to cryptosporidiosis is different from that in patients with AIDS where cell-mediated immunity is primarily defective. Futhermore, even within the AIDS patients, successful oral bovine transfer factor therapy appears to be dependent on yet unknown individual factors associated with the response to C. parvum. However, chronic cryptosporidiosis was first recognized in patients with humoral immunodeficiency in the pre-AIDS era (14). Attempts to provide humoral immunity against C. parvum in the form of oral bovine colostral antibodies and oral and intravenous high dose human immunoglobulin have also failed. Our patient has cholangitis, thought to be due to cryptosporidia, which might represent a reservoir of infection making eradication of the organism particularly problematic. ACKNOWLEDGMENT The authors thank Ms. Lynn Garcia of the UCLA Parasitology Laboratory for performing the quantitation of cryptosporidium oocysts.
REFERENCES I. Navin, T. R., and Juranek, D. D., Cryptosporidiosis: Clinical epidemiologic, and parasitologic review. Rev. Infect. Dis. 6, 313-327, 1984. 2. O’Donoghue, P. J., Cryptosporidium infections in man, animals, birds and fish. Aust. Vet. J. 62, 253-258, 1985. 3. Wolfson, J. S., Richter, J. M., Waldron, M. A., Weber, D. J., McCarthy, D. M., and Hopkins, C. C., Cryptosporidiosis in immunocompetent patients. N. Engl. J. Med. 312, 1278-1282, 1985. 4. Holley, H. P., Jr., and Dover, C., Cryptosporidium: A common cause of parasitic diarrhea in otherwise healthy individuals. J. Infect. Dis. 153, 365-368, 1986. 5. Meisel, J. L., Perera, D. R., Meligro, C., and Rubin, C. E., Overwhelming watery diarrhea associated with Cryptosporidium in an immunosuppressed patient. Gastroenterology 70, 1156-l 160, 1976. 6. Booth, C. C., Slavin, G., Dourmashkin, R. R., Doniach, I., Webster, D., Bird, R. G., Bryceson, A., Asherson, G. L., Black, D., Lambert, H., and Valman. B., lmmunodeficiency and cryptosporidiosis. Brit. Med. J. 281, 1123-1127, 1980. 7. Soave, R., Danner, R. L., Honig, C. L., Ma, P., Hart. C. C., Nash, T., and Roberts, R. B., Cryptosporidiosis in homosexual men. Ann. Intern. Med. 100, 504-511, 1984. 8. Forgacs, P., Tarshis, A., Ma, P., Federman, M., Mele, T., Silverman, M. L., and Shea, J. A., Intestinal and bronchial cryptosporidiosis in an immunodeticient homosexual man. Ann. Intern. Med. 99, 793-794, 1983. 9. Pitlik, S. D., Fainstein, V., Rios. A., Guarda, L., Manrell, P. W. A.. and Hersh, E. M., Cryptosporidial cholecystitis. N. Engl. J. Med. 308, 967, 1983. 10. Blumberg, R. S., Kelsey, P., Perrone, T., Dickersin, R., Laquaglia, M., and Femici, J., Cytomegalovirus and cryptosporidium associated acalculus gangrenous cholecystitis. Amer. J. Med. 76, 1118-1123, 1984. 1I. Gross, T. L., Wheat, J., Barlett, M., and O’Conner, K. W.. AIDS and multiple system involvement with Cryptosporidium. Amer. J. Gastroenterol. 81, 45w58, 1986. 12. Hart, A., and Baxby, D., Management of cryptosporidiosis. J. Antimicrob. Chemother. 15, 3-7, 1985. 13. Louie, E., Borkowsky, W., Klesius, P. H., Haynes, T. B., Gordon, S., Bonk, S.. and Lawrence, H. S., Treatment of cryptosporidiosis with oral bovine transfer factor. Clin. Immunol. Immunopathol. 44, 32%334, 1987.
406
BRIEF COMMUNICATIONS
14. Saxon, A., and Weinstein. W.. Oral administration of bovine colostrum anticryptosporidial antibody fails to alter the course of human cryptosporidiosis. J. Parusi~ol. 73, 413-415. 1987. IS. Klesius, D. H., and Kristensen. F., Bovine transfer factor: Effect on bovine and rahhit cocci& osis. C/in. Immunol. Immccnopatiwl. 7. 140~252. 1972. 16. Klesius, D. H.. Quails. D. F., Elston, A. I,., and Fudenberg. H. H., Effects of bovine transfer factor (TFd) in mouse coccidiosis (Eimmriu ferrisil. Clin. Immunol. Immttnoprrt/z~~/. 10. 214-Z I, 1978. Received September 20. 198X: accepted with revision November 22, 1988
IMMUNOLOGY
AND
IMMC~NOPATHOI~OGY
50.
‘to?-406
(i%y)
Inability of Oral Bovine Transfer Factor to Eradicate Cryptosporidial Infection in a Patient with Congenital Dysgammaglobulinemia’ HIOK
HEE CHNG,*.’
DONALD SHAW,* PHILLIP ANDREW SAXON*
KLESIUS,?
AND
*Department of Medicine, UCLA School of Medicine. Los Angeles. California 90024, and tAnimal Parasite Research Laboratory. United States Department of Agriculture, Agricultural Research Senice. Auburn, Alabama 36831 A 31-year-old man with dysgammaglobulinemia Type I (deficient IgG, IgA, and elevated IgM) and persistent cryptosporidiosis was treated over a 13-week period with oral bovine transfer factor from calves immunized with cryptosporidia. Spiramycin was added toward the end of the treatment period. This patient failed to show clinical response although there was a decrease in the stool oocyst count from the value just prior to therapy. Bovine transfer factor alone and in combination with spiramycin failed to eradicate the infection in this man with well-documented stable cryptosporidiosis. 0 1989 Academic
Press. Inc
INTRODUCTION Cryptosporidium parvum, an intestinal coccidial protozoan, is a well-established cause of diarrhea in humans and animals (1, 2). In the immunocompetent host, the protozoan causes either asymptomatic infection or self-limited diarrhea (3,4). In immunocompromised persons, the diarrhea may be profuse, cholera-like and debilitating and may follow a relentless or relapsing course (5-7). In addition to infecting the bowel, C. parvum has also recently been reported to be isolated from the respiratory tract, pancreatic duct, biliary tract, and gallbladder (8-l 1). At present there is no effective therapy for ongoing cryptosporidial infection although numerous chemotherapeutic agents have been tried. Isolated responses have been reported but true responses compared to natural remission/relapse of the disease have not been well established (12). Bovine transfer factor was recently reported to result in the eradication of intestinal cryptosporidiosis in four of eight patients with the acquired immunodeficiency syndrome (AIDS) although in two patients the infection relapsed following cessation of therapy (13). We now report the use of oral bovine transfer factor as therapy for refractory cryptosporidiosis in a very well-studied patient with congenital dysgammaglobu’ Supported in part by USPHS Grant CA-12800. Dr. Chng was the recipient of a training grant from the Ministry of Health, Republic of Singapore. * Present address: Department of Medicine IV. Tan Tack Seng Hospital, Moulmein Road, Republic of Singapore.
402 0090-1229/89
$1.50
Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.
BRIEF
403
COMMUNICATIONS
linemia. Since this patient was clinically stable in relationship to both his dysgammaglobulinemia and his cryptosporidiosis, this allowed us to evaluate any possible theraputic benefit without the changing physical status as occurs in patients with AIDS. CASE REPORT
(UCLA
NUMBER
062-01-66)
AND RESULTS
The patient is a 31-year-old man with congenital dysgammaglobulinemia Type I (elevated IgM of 550 mg%, low IgG of 41 mg%, and IgA of less than 5 mg% at time of diagnosis) diagnosed at age 10 years. Since then, he has been on various forms of replacement immunoglobulin therapy. He developed uncontrolled diarrhea and steatorrhea in 1980 and a diagnosis of large and small bowel cryptosporidiosis was made based on positive intestinal biopsies. Multiple stool cultures for bacterial and viral pathogens (including CMV) and repeated examinations for ova and parasites as well as small and large bowel biopsies which were cultured and examined histologically (including electron microscopy) failed to reveal any etiology other than cryptosporidiosis for the patient’s diarrhea. This infection failed to respond to all therapy including a 2-week course of spiramycin, high dose intravenous and also high dose oral gammaglobulin, and oral administration of bovine colostral anti-cryptosporidial antibody (14). The diarrhea was eventually symptomatically controlled with naprosyn although he continued to excrete oocysts in his stools. In addition, he has had mild cholangitis since 1983. This is attributed to cryptosporidiosis in view of recent reports of biliary tract infestation although no cannulation of his biliary tract for evidence of the protozoa has been performed. His liver function tests remain stable. In March 1988, following Institutional Review Board approval and obtaining informed consent, the patient was started on oral bovine transfer factor. The crude product was prepared as described from lymph nodes of young calves which had developed resistance to C. parvum (13). The lymph node extract was dissolved in sterile, pyrogen-free water and filter sterilized with a 0.22~p,m filter. Oral bovine transfer factor was started at a dose of 1 unit/week (5 x 10’ lymph node cell equivalents), the dose used by Louie et al. (13), and subsequently increased to 2 units/week at Week 7 when oocysts continued to be excreted and there had been no symptomatic improvement. Spiramycin at a dose of 3 g/day in two divided doses was added at Week 10 and continued for 3 weeks. The patient’s weight, bowel movements, stool consistency, CBC and platelet numbers, BUN and liver function tests, and stool oocyst count were monitored at regular intervals. The cryptosporidial oocysts in the patient’s stools were quantitated using monoclonal antibodies to the oocysts. Naprosyn was discontinued during this period of treatment. During this treatment period, his bowel movements and stool consistency remained unchanged. There was however a decrease in the stool oocyst count from that obtained the day prior to beginning the treatment (40/10X field) although oocysts continued to be present throughout (Fig. 1). The drop in the oocyst count with initiation of transfer factor therapy is difficult to interpret as a response as the counts in this patient tended to vary spontaneously over time as evidenced by stool oocyst subsequent to cessation of transfer factor therapy with counts vary-
404
BRIEF COMMUNIC’AT’IONS
n
WEEKS FIG. 1. Patient’s course while receiving therapy with oral administration of oral bovine transfer factor (BTF). The patient was started on BTF at 1 unit/week for 6 weeks and then increased to 2 units/week for 7 more weeks. Spiramycin was added for 3 weeks as noted. The total number of stools (III), the number of watery stools (El) per week, and the number of oocytes present per microscopic field in the stool (0) are shown.
ing between 5 and 35 oocysts/tield. In view of this and the lack of clinical improvement, the therapy was considered unsuccessful. The patient’s hemogram, white blood cell count, and differential and biochemical profile remained unaltered during the transfer factor and spiramycin treatment. No toxic effects were observed during the course of oral bovine transfer factor treatment. DISCUSSION
Bovine transfer factor, derived from calves immune to clinical coccidiosis, has been reported to provide partial immunity against this infection in calves and mice (15, 16). In these aminal studies, it conferred protection against the lethal effects of the infection as well as decreased the oocyst excretion. These effects were dose dependent with a limiting effective dose. In addition, protection was conferred only when it was given prior to exposure to these protozoa (16). Louie ef al. (13) suggested a possible role for the use of oral bovine transfer factor in the treatment of cryptosporidiosis in immunodeficient patients and specifically those with AIDS, a disease with both cellular and humoral immune defects but in which the cellular defects predominate. Our patient with congenital dysgammaglobulinemia has been receiving adequate replacement gammaglobulin therapy (400 mg/kg/month). He does not have
BRIEF COMMUNICATIONS
40.5
any known cellular immune deficiency or opportunistic infections besides the cryptosporidiosis. The failure of oral bovine transfer factor to eradicate cryptosporidial infection in this man with a primarily humoral immune deficiency may simply be due to the fact that the immune defect predisposing him to cryptosporidiosis is different from that in patients with AIDS where cell-mediated immunity is primarily defective. Futhermore, even within the AIDS patients, successful oral bovine transfer factor therapy appears to be dependent on yet unknown individual factors associated with the response to C. parvum. However, chronic cryptosporidiosis was first recognized in patients with humoral immunodeficiency in the pre-AIDS era (14). Attempts to provide humoral immunity against C. parvum in the form of oral bovine colostral antibodies and oral and intravenous high dose human immunoglobulin have also failed. Our patient has cholangitis, thought to be due to cryptosporidia, which might represent a reservoir of infection making eradication of the organism particularly problematic. ACKNOWLEDGMENT The authors thank Ms. Lynn Garcia of the UCLA Parasitology Laboratory for performing the quantitation of cryptosporidium oocysts.
REFERENCES I. Navin, T. R., and Juranek, D. D., Cryptosporidiosis: Clinical epidemiologic, and parasitologic review. Rev. Infect. Dis. 6, 313-327, 1984. 2. O’Donoghue, P. J., Cryptosporidium infections in man, animals, birds and fish. Aust. Vet. J. 62, 253-258, 1985. 3. Wolfson, J. S., Richter, J. M., Waldron, M. A., Weber, D. J., McCarthy, D. M., and Hopkins, C. C., Cryptosporidiosis in immunocompetent patients. N. Engl. J. Med. 312, 1278-1282, 1985. 4. Holley, H. P., Jr., and Dover, C., Cryptosporidium: A common cause of parasitic diarrhea in otherwise healthy individuals. J. Infect. Dis. 153, 365-368, 1986. 5. Meisel, J. L., Perera, D. R., Meligro, C., and Rubin, C. E., Overwhelming watery diarrhea associated with Cryptosporidium in an immunosuppressed patient. Gastroenterology 70, 1156-l 160, 1976. 6. Booth, C. C., Slavin, G., Dourmashkin, R. R., Doniach, I., Webster, D., Bird, R. G., Bryceson, A., Asherson, G. L., Black, D., Lambert, H., and Valman. B., lmmunodeficiency and cryptosporidiosis. Brit. Med. J. 281, 1123-1127, 1980. 7. Soave, R., Danner, R. L., Honig, C. L., Ma, P., Hart. C. C., Nash, T., and Roberts, R. B., Cryptosporidiosis in homosexual men. Ann. Intern. Med. 100, 504-511, 1984. 8. Forgacs, P., Tarshis, A., Ma, P., Federman, M., Mele, T., Silverman, M. L., and Shea, J. A., Intestinal and bronchial cryptosporidiosis in an immunodeticient homosexual man. Ann. Intern. Med. 99, 793-794, 1983. 9. Pitlik, S. D., Fainstein, V., Rios. A., Guarda, L., Manrell, P. W. A.. and Hersh, E. M., Cryptosporidial cholecystitis. N. Engl. J. Med. 308, 967, 1983. 10. Blumberg, R. S., Kelsey, P., Perrone, T., Dickersin, R., Laquaglia, M., and Femici, J., Cytomegalovirus and cryptosporidium associated acalculus gangrenous cholecystitis. Amer. J. Med. 76, 1118-1123, 1984. 1I. Gross, T. L., Wheat, J., Barlett, M., and O’Conner, K. W.. AIDS and multiple system involvement with Cryptosporidium. Amer. J. Gastroenterol. 81, 45w58, 1986. 12. Hart, A., and Baxby, D., Management of cryptosporidiosis. J. Antimicrob. Chemother. 15, 3-7, 1985. 13. Louie, E., Borkowsky, W., Klesius, P. H., Haynes, T. B., Gordon, S., Bonk, S.. and Lawrence, H. S., Treatment of cryptosporidiosis with oral bovine transfer factor. Clin. Immunol. Immunopathol. 44, 32%334, 1987.
406
BRIEF COMMUNICATIONS
14. Saxon, A., and Weinstein. W.. Oral administration of bovine colostrum anticryptosporidial antibody fails to alter the course of human cryptosporidiosis. J. Parusi~ol. 73, 413-415. 1987. IS. Klesius, D. H., and Kristensen. F., Bovine transfer factor: Effect on bovine and rahhit cocci& osis. C/in. Immunol. Immccnopatiwl. 7. 140~252. 1972. 16. Klesius, D. H.. Quails. D. F., Elston, A. I,., and Fudenberg. H. H., Effects of bovine transfer factor (TFd) in mouse coccidiosis (Eimmriu ferrisil. Clin. Immunol. Immttnoprrt/z~~/. 10. 214-Z I, 1978. Received September 20. 198X: accepted with revision November 22, 1988