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Hyperimmuneglobulin for cytomegalovirus prophylaxis following heart transplantation
Journal
of Hospital
Infection
12 (Supplement
(1988)
Hyperimmuneglobulin prophylaxis following H.-J.
D),
61-65
for cytomegalovirus heart transplantation
SchHfers, Th. Wahlers, M. Jurmann, H.-G. H. Milbradt,* J. Flik* and A. Haverich
Division of Thoracic and Cardiovascular *Department of Virology, Hannover Medical
Fieguth,
Surgical School, Hannover,
Center, and W. Germany
Surgery,
Summary:
Cytomegalovirus continues to be an important cause of morbidity and mortality following organ transplantation. In a series of 75 heart transplant patients, we have compared two protocols for prophylactic administration of CMV hyperimmuneglobulin. The first group of patients received immunoglobulin on the operative and on the tenth postoperative days. The second group of patients received immunoglobulins on the operative day, and repeatedly with each period of increased immunosuppression. With repeated doses of immunoglobulin prophylaxis, the incidence of CMV reactivation and the clinical severity of CMV infection were both significantly reduced. A reduction in the incidence of CMV infection in recipients who were seronegative preoperatively was also observed. (S/8 vs. 7/ 25 patients; P= 0.06). We conclude that repeated administration of specific hyperimmuneglobulin with each period of increased immunosuppression following heart transplantation has a beneficial effect on both CMV reactivation and infection. Keywords: immunoglobulin.
Heart
transplant;
immunosuppression;
cytomegalovirus;
Introduction Cytomegalovirus (CMV) represents an important cause of morbidity and mortality following organ transplantation (Jamieson et al., 1981; Baumgartner, 1983; Ho et al., 1983). The virus is frequently transmitted by blood transfusions or by the transplanted organ, resulting in postoperative primary infection (Peterson et al., Hakim et al., 198S), while endogenous reactivation of CMV may occur during immunosuppression. As yet no safe and reliable drug is available for the treatment of CMV, stressing the need for preventive measures in transplant recipients. A protocol with prophylactic administration of iv hyperimmuneglobulin was instituted in our heart transplant programme. The results in 75 patients are presented.
Correspondence Medizinische 01954701/88/060061+05
to:
PD
Hochschule
Dr
med.
Hannover,
A.
Haverich,
Klinik
Konstanty-Gutschow-Str.
$03.00,0
fiir
Thorax-,
Hem-
8, 3000 Hannover
und
GeWOchirurgie,
61, W. Germany.
0 1988 The Hospital
61
Infection
Socieq
62
H.-J. Shiifers
et al.
Patients and methods Between October 1985 and February 1987, 86 heart transplantations were performed in 82 patients. Patients who died early after transplantation ( < 20 days) were excluded (n = 7). The remaining 75 patients are the subject of the study. Immunosuppression consisted of a triple drug regimen with cyclosporin A, azathioprine, and prednisolone; rabbit-ATG was given prophylactically in the early postoperative period. Rejection treatment was based on the histological diagnosis from endomyocardial biopsy specimens. Moderate rejection was treated with iv methylprednisolone; after the first 6-12 postoperative months oral prednisolone was used. Severe rejection was treated with rabbit-ATG; horse-ALG or monoclonal antibodies (OKT 3) were used in selected cases. All blood transfusions were screened for the presence of CMV-IgG antibodies; only blood from CMV-seronegative donors was administered. Information on preoperative serological status of donor and recipient with respect to CMV was obtained in all instances. The patients were followed closely for signs of infection. Increased temperature (> 38°C) led to complete diagnostic work-up, including a chest X-ray, blood count with differential count; urinalysis was performed and sputum and urine were cultured. The urine was analysed by electron Screening for antiviral antibodies was microscopy for virus excretion. performed; the diagnosis of CMV infection and reactivation was made on CMV-specific IgM by ELISA or the basis of demonstrating immunofluorescence. Specific CMV hyperimmuneglobulin (Polyglobin R. Cutter-Tropon, Cologne, W. Germany) was used for prophylaxis. In the first 20 patients (group l), hyperimmuneglobulin (100 mg kg-‘) was given on the operative and on the tenth postoperative days. In the remaining 55 patients (group 2), hyperimmuneglobulin (100 mg kg-‘) was given immediately following transplantation and repeatedly with each course of rejection treatment up to 1 year post-transplantation. The results presented here are based on a retrospective analysis. Statistical analysis was performed using Fisher’s exact test and Student’s t-test where applicable. A P-value of less than 0.05 was considered significant. Results There was no significant difference between groups 1 and 2 with respect to age, sex, or recipient diagnosis (Table I). Immunosuppression was identical in both groups; there was no difference in the incidence of rejection episodes during the first 6 months (group 1: 4*4f 1.3; group 2: 4*7& 1.1). The preoperative incidence of CMV-IgG was similar in donors and recipients of both groups (Table II). A total of 12 episodes of primary CMV infection and 15 of CMV reactivation were observed in 27 patients between 24 and 334 days post-transplantation. All patients were symptomatic; some developed only
CMV
prophylaxis
Group
63
Group
I
20 1614 38.5f12.9
55 4718 41.1kl1.2
15 4 1
44 9 2
II
P (I-II)
Total 75 63112 40.6f11.9
NS NS NS
Rejections
during
first 4.4f
6 months 1.3
post-TX 4.7f 1.1
DCM: Dilatative cardiomyopathy. Endomyocardial fibrosis, hypertrophic
Table
transplant
I. Analysed patient population
Table
Patient Male/female Age (yr) Diagnosis DCM ICM Misc.
and heart
II.
Preoperative
4.6f
ICM: Ischaemic cardiomyopathy,
1.1
cardiomyopathy. Mist: ventricular dysplasia.
presence of specific CMV-antibodies recipients and donors Group
I
Group
II
12 (60%) 8 (40%) 20
30 (5.5%) 2.5 (45%) 55
42 (56%) 33 (44%) 75
Donor Positive Negative Total
12 (60%) 8 (40%) 20
35 (64%) 20 (36%) 55
47 (63%) 28 (37%) 75
(n)
(IgG)
in
Total
Recipient Positive (n) Negative (n) Total (n)
(n) (n)
NS
mild disease whereas others presented with severe illness including pulmonary infiltrates. There was no significant difference in the incidence of CMV reactivation between groups 1 and 2; the serological status of the donor did not have an influence on the incidence of reactivation (Table III). In 33 patients who were CMV-negative preoperatively, 12 (37%) developed CMV infection; the incidence was considerably lower in group 2 (7/25 = 28%) than in group 1 (S/8= 63%; P~0.06). With a few exceptions, infection occurred in recipients who had received the heart of a seropositive donor. With respect to severity of the disease, fewer patients in group 2 developed fever (P
Following heart transplantation, CMV primary and reactivation infections are the most frequent cause of virus-related disease and are associated with a
H.-J. Shiifers Table
III.
Incidence of CMV disease, including reactivation and infection, analysed by serological status of recipient and donor Group CMV/patients
Serological status Recipient/donor Positive/positive Positive/negative Negative/positive Negative/negative Total
3/7 2/S 4/s l/3 10/20
Table
IV.
I
8/22 (36%) 2/8 (25%) 7/13 (54%) o/12 (0%)
(43%) (40%) (80%) (33%)
17/s!?
(50%)
Symptoms of CMV
infiltrate liver enzymes
8/18 7/10 3/10 4/10
P value
Group II CMV/patients
NS NS XCNS NS
(31%)
disease (reactivation Group
Fever Leucopenia Pulmonary Elevated
et al.
(80%) (70%) (30%) (40%)
I
and infection)
Group
II
6/17 6/17 o/17 5/l 7
(35%) (35%) (0%) (29%)
P-value 0.05 0.1 0.05 NS
morbidity and mortality (Jamieson et al., 1981; Baumgartner, 1983). While only blood from CMV-seronegative donors may be used in heart transplantation, the organ often has to be transplanted regardless of the donor’s serological status, thereby representing an important source of infection (Peterson et al., 1980; Hakim et al., 1985). Endogenous reactivation of CMV in patients with pre-existent antibodies on the other hand is usually the result of increased immunosuppression. Hyperimmuneglobulin as well as Dihydroxypropoxy-methylguauine (DHPG) have been used therapeutically in clinically manifest CMV disease (Blacklock et al., 1985; Incenogle et al., 1986; Cremer et al., in press). Specific hyperimmuneglobulin has also been used for prophylaxis against CMV in bone marrow as well as organ transplantation (Preiksaitis et al., 1982; Winston et al., 1982; Meyers et al., 1983; O’Reilly et al., 1983; Winston et al., 1984; Gregor et al., 1985). In most series, repeated administration of immunoglobulin has led to a reduction in the severity of CMV disease, and in some patient populations there has also been a reduced incidence of CMV infection (Meyers et al., 1983; O’Reilly et al., 1983). In our series, it is probable that an insufficient prophylactic dose was used in the first 20 patients (Buckley, 1982). By contrast, we found that with the dosage regimen used in the second group of patients, with repeated administration of hyperimmuneglobulin, we were able to reduce the severity of CMV disease, both in infection and reactivation. Interestingly, no instance of pulmonary infiltrate has been observed since the introduction of the current protocol. The prophylaxis was further able to reduce the significant
CMV
prophylaxis
and heart
65
transplant
incidence of CMV infection in patients with preoperative negative serological status. Due to small numbers this difference was only marginally significant. The results indicate, however, that repeated administration of specific hyperimmuneglobulin during periods of increased immunosuppression following heart transplantation has a beneficial effect on both CMV infection and reactivation. References Baumgartner,
W.
(1983).
Infections
in cardiac
transplantation.
Journal
of Heart
Transplant
3, 75-80. Blacklock. H. A., Griffiths, P., Stirk, P. & Prentice, H. G. (1985). Successful treatment of cytomegalovirus pneumonitis after allogeneic bone marrow transplantation using high titre CMV immunoelobulin. Experimental Hematology 13. 76. Buckley, R. H. (1982). tong-term use of intravenous
Transplant
1, 86-91.
Meyers, J. D., Leszczynski, J., Zaia, J. A., Flournoy, N., Newton, B., Snydman, D. Wright, G. G., Levin, M. J. & Thomas, E. D. (1983). Prevention of cytomegalovirus infection by cytomegalovirus immune globulin after marrow transplantation. Annals
Internal
Medicine
of
98, 442-446.
O’Reilly, R. J. O., Reich, L., Gold, J., Kirkpatrick, D., Dinsmore, R. (1983). A randomized trial of intravenous hyperimmune of cvtomegalovirus infections following marrow transplantation.
15, i405-i4i
R.,
R., Kapoor, N. & Condie, globulin for the prevention
Transplant
Proceedings
I.
Peterson, P. K., Balfour, H. H., Marker, S. C., Fryd, D. S., Howard, R. J. & Simmons, R. L. (1980). Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine 59.
283-300. Preiksaitis, J. K., Rosno, S., Rasmussen, L. & Merigan, T. C. (1982). Cytomegalovirus infection in heart transplant recipients: preliminarv results of a controlled trial of intravenous gamma globulin. Journal of Clinical Immunology 2 (Suppl.), 36-41. Winston, D. J., Ho, W. G., Lin, C. H., Budinger, M. D., Champlin, R. E. & Gale, R. P. (1984). Intravenous immunoglobulin for modification of cytomegalovirus infections associated with bone marrow transplantation. Journal of the American Medical Association 250. 128-l 33. Winston, D. J., Pollard, R. B., Ho, W. G., Gallagher, J. G., Rasmussen, I,. E., Huang, S. N., Lin, C. H., Gossett, T. G., Merigan, T. C. & Gale, R. P. (1982). Cytomegalovirus immune plasma in bone marrow transplant recipients. Annals of Internal Medicine 97, llll8.
of Hospital
Infection
12 (Supplement
(1988)
Hyperimmuneglobulin prophylaxis following H.-J.
D),
61-65
for cytomegalovirus heart transplantation
SchHfers, Th. Wahlers, M. Jurmann, H.-G. H. Milbradt,* J. Flik* and A. Haverich
Division of Thoracic and Cardiovascular *Department of Virology, Hannover Medical
Fieguth,
Surgical School, Hannover,
Center, and W. Germany
Surgery,
Summary:
Cytomegalovirus continues to be an important cause of morbidity and mortality following organ transplantation. In a series of 75 heart transplant patients, we have compared two protocols for prophylactic administration of CMV hyperimmuneglobulin. The first group of patients received immunoglobulin on the operative and on the tenth postoperative days. The second group of patients received immunoglobulins on the operative day, and repeatedly with each period of increased immunosuppression. With repeated doses of immunoglobulin prophylaxis, the incidence of CMV reactivation and the clinical severity of CMV infection were both significantly reduced. A reduction in the incidence of CMV infection in recipients who were seronegative preoperatively was also observed. (S/8 vs. 7/ 25 patients; P= 0.06). We conclude that repeated administration of specific hyperimmuneglobulin with each period of increased immunosuppression following heart transplantation has a beneficial effect on both CMV reactivation and infection. Keywords: immunoglobulin.
Heart
transplant;
immunosuppression;
cytomegalovirus;
Introduction Cytomegalovirus (CMV) represents an important cause of morbidity and mortality following organ transplantation (Jamieson et al., 1981; Baumgartner, 1983; Ho et al., 1983). The virus is frequently transmitted by blood transfusions or by the transplanted organ, resulting in postoperative primary infection (Peterson et al., Hakim et al., 198S), while endogenous reactivation of CMV may occur during immunosuppression. As yet no safe and reliable drug is available for the treatment of CMV, stressing the need for preventive measures in transplant recipients. A protocol with prophylactic administration of iv hyperimmuneglobulin was instituted in our heart transplant programme. The results in 75 patients are presented.
Correspondence Medizinische 01954701/88/060061+05
to:
PD
Hochschule
Dr
med.
Hannover,
A.
Haverich,
Klinik
Konstanty-Gutschow-Str.
$03.00,0
fiir
Thorax-,
Hem-
8, 3000 Hannover
und
GeWOchirurgie,
61, W. Germany.
0 1988 The Hospital
61
Infection
Socieq
62
H.-J. Shiifers
et al.
Patients and methods Between October 1985 and February 1987, 86 heart transplantations were performed in 82 patients. Patients who died early after transplantation ( < 20 days) were excluded (n = 7). The remaining 75 patients are the subject of the study. Immunosuppression consisted of a triple drug regimen with cyclosporin A, azathioprine, and prednisolone; rabbit-ATG was given prophylactically in the early postoperative period. Rejection treatment was based on the histological diagnosis from endomyocardial biopsy specimens. Moderate rejection was treated with iv methylprednisolone; after the first 6-12 postoperative months oral prednisolone was used. Severe rejection was treated with rabbit-ATG; horse-ALG or monoclonal antibodies (OKT 3) were used in selected cases. All blood transfusions were screened for the presence of CMV-IgG antibodies; only blood from CMV-seronegative donors was administered. Information on preoperative serological status of donor and recipient with respect to CMV was obtained in all instances. The patients were followed closely for signs of infection. Increased temperature (> 38°C) led to complete diagnostic work-up, including a chest X-ray, blood count with differential count; urinalysis was performed and sputum and urine were cultured. The urine was analysed by electron Screening for antiviral antibodies was microscopy for virus excretion. performed; the diagnosis of CMV infection and reactivation was made on CMV-specific IgM by ELISA or the basis of demonstrating immunofluorescence. Specific CMV hyperimmuneglobulin (Polyglobin R. Cutter-Tropon, Cologne, W. Germany) was used for prophylaxis. In the first 20 patients (group l), hyperimmuneglobulin (100 mg kg-‘) was given on the operative and on the tenth postoperative days. In the remaining 55 patients (group 2), hyperimmuneglobulin (100 mg kg-‘) was given immediately following transplantation and repeatedly with each course of rejection treatment up to 1 year post-transplantation. The results presented here are based on a retrospective analysis. Statistical analysis was performed using Fisher’s exact test and Student’s t-test where applicable. A P-value of less than 0.05 was considered significant. Results There was no significant difference between groups 1 and 2 with respect to age, sex, or recipient diagnosis (Table I). Immunosuppression was identical in both groups; there was no difference in the incidence of rejection episodes during the first 6 months (group 1: 4*4f 1.3; group 2: 4*7& 1.1). The preoperative incidence of CMV-IgG was similar in donors and recipients of both groups (Table II). A total of 12 episodes of primary CMV infection and 15 of CMV reactivation were observed in 27 patients between 24 and 334 days post-transplantation. All patients were symptomatic; some developed only
CMV
prophylaxis
Group
63
Group
I
20 1614 38.5f12.9
55 4718 41.1kl1.2
15 4 1
44 9 2
II
P (I-II)
Total 75 63112 40.6f11.9
NS NS NS
Rejections
during
first 4.4f
6 months 1.3
post-TX 4.7f 1.1
DCM: Dilatative cardiomyopathy. Endomyocardial fibrosis, hypertrophic
Table
transplant
I. Analysed patient population
Table
Patient Male/female Age (yr) Diagnosis DCM ICM Misc.
and heart
II.
Preoperative
4.6f
ICM: Ischaemic cardiomyopathy,
1.1
cardiomyopathy. Mist: ventricular dysplasia.
presence of specific CMV-antibodies recipients and donors Group
I
Group
II
12 (60%) 8 (40%) 20
30 (5.5%) 2.5 (45%) 55
42 (56%) 33 (44%) 75
Donor Positive Negative Total
12 (60%) 8 (40%) 20
35 (64%) 20 (36%) 55
47 (63%) 28 (37%) 75
(n)
(IgG)
in
Total
Recipient Positive (n) Negative (n) Total (n)
(n) (n)
NS
mild disease whereas others presented with severe illness including pulmonary infiltrates. There was no significant difference in the incidence of CMV reactivation between groups 1 and 2; the serological status of the donor did not have an influence on the incidence of reactivation (Table III). In 33 patients who were CMV-negative preoperatively, 12 (37%) developed CMV infection; the incidence was considerably lower in group 2 (7/25 = 28%) than in group 1 (S/8= 63%; P~0.06). With a few exceptions, infection occurred in recipients who had received the heart of a seropositive donor. With respect to severity of the disease, fewer patients in group 2 developed fever (P
Following heart transplantation, CMV primary and reactivation infections are the most frequent cause of virus-related disease and are associated with a
H.-J. Shiifers Table
III.
Incidence of CMV disease, including reactivation and infection, analysed by serological status of recipient and donor Group CMV/patients
Serological status Recipient/donor Positive/positive Positive/negative Negative/positive Negative/negative Total
3/7 2/S 4/s l/3 10/20
Table
IV.
I
8/22 (36%) 2/8 (25%) 7/13 (54%) o/12 (0%)
(43%) (40%) (80%) (33%)
17/s!?
(50%)
Symptoms of CMV
infiltrate liver enzymes
8/18 7/10 3/10 4/10
P value
Group II CMV/patients
NS NS XCNS NS
(31%)
disease (reactivation Group
Fever Leucopenia Pulmonary Elevated
et al.
(80%) (70%) (30%) (40%)
I
and infection)
Group
II
6/17 6/17 o/17 5/l 7
(35%) (35%) (0%) (29%)
P-value 0.05 0.1 0.05 NS
morbidity and mortality (Jamieson et al., 1981; Baumgartner, 1983). While only blood from CMV-seronegative donors may be used in heart transplantation, the organ often has to be transplanted regardless of the donor’s serological status, thereby representing an important source of infection (Peterson et al., 1980; Hakim et al., 1985). Endogenous reactivation of CMV in patients with pre-existent antibodies on the other hand is usually the result of increased immunosuppression. Hyperimmuneglobulin as well as Dihydroxypropoxy-methylguauine (DHPG) have been used therapeutically in clinically manifest CMV disease (Blacklock et al., 1985; Incenogle et al., 1986; Cremer et al., in press). Specific hyperimmuneglobulin has also been used for prophylaxis against CMV in bone marrow as well as organ transplantation (Preiksaitis et al., 1982; Winston et al., 1982; Meyers et al., 1983; O’Reilly et al., 1983; Winston et al., 1984; Gregor et al., 1985). In most series, repeated administration of immunoglobulin has led to a reduction in the severity of CMV disease, and in some patient populations there has also been a reduced incidence of CMV infection (Meyers et al., 1983; O’Reilly et al., 1983). In our series, it is probable that an insufficient prophylactic dose was used in the first 20 patients (Buckley, 1982). By contrast, we found that with the dosage regimen used in the second group of patients, with repeated administration of hyperimmuneglobulin, we were able to reduce the severity of CMV disease, both in infection and reactivation. Interestingly, no instance of pulmonary infiltrate has been observed since the introduction of the current protocol. The prophylaxis was further able to reduce the significant
CMV
prophylaxis
and heart
65
transplant
incidence of CMV infection in patients with preoperative negative serological status. Due to small numbers this difference was only marginally significant. The results indicate, however, that repeated administration of specific hyperimmuneglobulin during periods of increased immunosuppression following heart transplantation has a beneficial effect on both CMV infection and reactivation. References Baumgartner,
W.
(1983).
Infections
in cardiac
transplantation.
Journal
of Heart
Transplant
3, 75-80. Blacklock. H. A., Griffiths, P., Stirk, P. & Prentice, H. G. (1985). Successful treatment of cytomegalovirus pneumonitis after allogeneic bone marrow transplantation using high titre CMV immunoelobulin. Experimental Hematology 13. 76. Buckley, R. H. (1982). tong-term use of intravenous
Transplant
1, 86-91.
Meyers, J. D., Leszczynski, J., Zaia, J. A., Flournoy, N., Newton, B., Snydman, D. Wright, G. G., Levin, M. J. & Thomas, E. D. (1983). Prevention of cytomegalovirus infection by cytomegalovirus immune globulin after marrow transplantation. Annals
Internal
Medicine
of
98, 442-446.
O’Reilly, R. J. O., Reich, L., Gold, J., Kirkpatrick, D., Dinsmore, R. (1983). A randomized trial of intravenous hyperimmune of cvtomegalovirus infections following marrow transplantation.
15, i405-i4i
R.,
R., Kapoor, N. & Condie, globulin for the prevention
Transplant
Proceedings
I.
Peterson, P. K., Balfour, H. H., Marker, S. C., Fryd, D. S., Howard, R. J. & Simmons, R. L. (1980). Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine 59.
283-300. Preiksaitis, J. K., Rosno, S., Rasmussen, L. & Merigan, T. C. (1982). Cytomegalovirus infection in heart transplant recipients: preliminarv results of a controlled trial of intravenous gamma globulin. Journal of Clinical Immunology 2 (Suppl.), 36-41. Winston, D. J., Ho, W. G., Lin, C. H., Budinger, M. D., Champlin, R. E. & Gale, R. P. (1984). Intravenous immunoglobulin for modification of cytomegalovirus infections associated with bone marrow transplantation. Journal of the American Medical Association 250. 128-l 33. Winston, D. J., Pollard, R. B., Ho, W. G., Gallagher, J. G., Rasmussen, I,. E., Huang, S. N., Lin, C. H., Gossett, T. G., Merigan, T. C. & Gale, R. P. (1982). Cytomegalovirus immune plasma in bone marrow transplant recipients. Annals of Internal Medicine 97, llll8.