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CORRESPONDENCE Prophylaxis of Cytomegalovirus Disease in Allogeneic Bone Marrow Transplantation To the Editor-Bowden et al. [I] reported on the use of cytomegalovirus (CMV)-specific intravenous immunoglobulin (IVIG) prophylaxis after bone marrow transplantation. A total of 200 mg/kg of CMV IVIG was given weekly from 8 days before to day 28 after transplant and then every 2 weeks until day 70; however, antibody prophylaxis was ineffective in reducing the incidence of CMV disease and graft versus host disease (GVHD). This contrasts with the results reported by Sullivan et al. [2] in which standard IVIG at a dose of 500 mg/kg given weekly was effective in reducing the incidence of acute GVHD and interstitial pneumonitis. There is controversy over the kinetics of infused antibody in allograft recipients, with the median half-life reported to vary between 1.5 and 20 days [3, 4]. The half-life may be shortened in patients with acute GVHD by increased protein catabolism and protein-losing enteropathy. It is possible, therefore, that to maintain "therapeutic" levels, more frequent antibody administration is required at a higher dose than was used by Bowden et al. The main risk factor for CMV disease is acute GVHD [5]. Because IVIG preparations are expensive, an abbreviated course of administration to coincide with the period of highest risk for GVHD may be more cost effective. We recently updated the results ofa protocol in which CMV IVIG was given to 53 allogeneic recipients who were either seropositive or had a seropositive donor [6]. Antibody was given weekly at a dose of 150 mg/kg, beginning at day 28 and continuing until day 63. CMV disease occurred in 8 patients, 2 during therapy and in 6 within 6 weeks of cessation of prophylaxis. The median time of onset of CMV
Reprints or correspondence (present address): Dr. Andrew Grigg, Hematology/Oncology Unit, Royal Melbourne Hospital, Grattan Street, Parkville, 3050, Victoria 3050, Australia. The Journal of Infectious Diseases 1992;165:972 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6505-0035$01.00
Reply To the Editor-In response to the questions raised by Grigg and Phillips [I] regarding the use and duration of cytomegalovirus (CMV) intravenous immunoglobulin (IVIG) prophylaxis after marrow transplantation, we offer the following considerations.
Reprints or correspondence: Dr. Raleigh A. Bowden, Infectious Diseases, Fred Hutchinson Cancer Research Center, 1124 Columbia St., Seattle, WA 98104-2092. The Journal of Infectious Diseases 1992;165:972-3 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6505-0036$01.00
disease was 76 days after transplant, compared with 64 days in the CMV IVIG-treated patients in the study by Bowden et al. [I]. Although not conclusive, these results suggest that delaying commencement ofCMV IVIG until early after engraftment may not compromise its putative benefit and, conversely, that it may be necessary to continue the CMV IVIG beyond 10 weeks after transplantation in patients at risk. Finally, ganciclovir has recently been shown to be an effective and relatively nontoxic agent in prevention of CMV infection and disease after allogeneic bone marrow transplantation [7]. The routine use of this agent may well mean that the administration of expensive hyperimmunoglobulin preparations for the specific purpose of CMV prophylaxis is not warranted. Andrew Grigg and Gordon Phillips Leukaemia Bone Marrow Transplantation Programme ofBritish Columbia, Vancouver, Canada
References I. Bowden RA, Fisher LD, Rogers K, Cays M, Meyers JD. Cytomegalovirus (CMV)-specific intravenous immunoglobulin for the prevention of primary CMV infection and disease after marrow transplant. J Infect Dis 1991; 164:483-7. 2. Sullivan KM, Kopecky KJ, Jocom J, et al. Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 1990;323:705. 3. Meyers JD. Cytomegalovirus infection following marrow transplantation: Risk, treatment and prevention. Birth Defects 1984;20: 101-17. 4. Reusser P, Osterwalder B, Gratama JW, The TH, Gratwohl A, Speck B. Kinetics of cytomegalovirus IgG antibody following infusion of a hyperimmune globulin preparation in allogeneic marrow transplant recipients. Bone Marrow Transplant 1989;4:267-72. 5. Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153:478-88. 6. Grigg AP, Phillips GL, Barnett MJ, et al. CMV hyperimmunoglobulin after allogeneic bone marrow transplantation. J Cell Biochem 1990; 14A(suppl)308. 7. Atkinson K, Downs K, Golenia, et al. Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection. Br J Haematol 1991;79:57-62.
First, the CMV IVIG used in the study by Bowden et al. [2] gave a higher CMV-specific antibody dose than any previously published trial [3-7], including studies showing a benefit in preventing CMV pneumonia. However, the total dose ofIVIG was lower than that used in a study by Sullivan et al. [8], so it may not be surprising that no impact was seen on graft-versus-host disease, especially if the total dose of IVIG is important [9]. Second, review of table 2 in the study by Winston et al. [5] in which a dose ofIVIG twice as large as that used by Sullivan et al. [8] (but in a similar weekly schedule) reveals that while IVIG reduced all cases of interstitial pneumonia, it did not significantly reduce the number ofCMV pneumonia cases. Sullivan et al. and Bowden et al. [2] used products made by the same manu-
CORRESPONDENCE Prophylaxis of Cytomegalovirus Disease in Allogeneic Bone Marrow Transplantation To the Editor-Bowden et al. [I] reported on the use of cytomegalovirus (CMV)-specific intravenous immunoglobulin (IVIG) prophylaxis after bone marrow transplantation. A total of 200 mg/kg of CMV IVIG was given weekly from 8 days before to day 28 after transplant and then every 2 weeks until day 70; however, antibody prophylaxis was ineffective in reducing the incidence of CMV disease and graft versus host disease (GVHD). This contrasts with the results reported by Sullivan et al. [2] in which standard IVIG at a dose of 500 mg/kg given weekly was effective in reducing the incidence of acute GVHD and interstitial pneumonitis. There is controversy over the kinetics of infused antibody in allograft recipients, with the median half-life reported to vary between 1.5 and 20 days [3, 4]. The half-life may be shortened in patients with acute GVHD by increased protein catabolism and protein-losing enteropathy. It is possible, therefore, that to maintain "therapeutic" levels, more frequent antibody administration is required at a higher dose than was used by Bowden et al. The main risk factor for CMV disease is acute GVHD [5]. Because IVIG preparations are expensive, an abbreviated course of administration to coincide with the period of highest risk for GVHD may be more cost effective. We recently updated the results ofa protocol in which CMV IVIG was given to 53 allogeneic recipients who were either seropositive or had a seropositive donor [6]. Antibody was given weekly at a dose of 150 mg/kg, beginning at day 28 and continuing until day 63. CMV disease occurred in 8 patients, 2 during therapy and in 6 within 6 weeks of cessation of prophylaxis. The median time of onset of CMV
Reprints or correspondence (present address): Dr. Andrew Grigg, Hematology/Oncology Unit, Royal Melbourne Hospital, Grattan Street, Parkville, 3050, Victoria 3050, Australia. The Journal of Infectious Diseases 1992;165:972 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6505-0035$01.00
Reply To the Editor-In response to the questions raised by Grigg and Phillips [I] regarding the use and duration of cytomegalovirus (CMV) intravenous immunoglobulin (IVIG) prophylaxis after marrow transplantation, we offer the following considerations.
Reprints or correspondence: Dr. Raleigh A. Bowden, Infectious Diseases, Fred Hutchinson Cancer Research Center, 1124 Columbia St., Seattle, WA 98104-2092. The Journal of Infectious Diseases 1992;165:972-3 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6505-0036$01.00
disease was 76 days after transplant, compared with 64 days in the CMV IVIG-treated patients in the study by Bowden et al. [I]. Although not conclusive, these results suggest that delaying commencement ofCMV IVIG until early after engraftment may not compromise its putative benefit and, conversely, that it may be necessary to continue the CMV IVIG beyond 10 weeks after transplantation in patients at risk. Finally, ganciclovir has recently been shown to be an effective and relatively nontoxic agent in prevention of CMV infection and disease after allogeneic bone marrow transplantation [7]. The routine use of this agent may well mean that the administration of expensive hyperimmunoglobulin preparations for the specific purpose of CMV prophylaxis is not warranted. Andrew Grigg and Gordon Phillips Leukaemia Bone Marrow Transplantation Programme ofBritish Columbia, Vancouver, Canada
References I. Bowden RA, Fisher LD, Rogers K, Cays M, Meyers JD. Cytomegalovirus (CMV)-specific intravenous immunoglobulin for the prevention of primary CMV infection and disease after marrow transplant. J Infect Dis 1991; 164:483-7. 2. Sullivan KM, Kopecky KJ, Jocom J, et al. Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 1990;323:705. 3. Meyers JD. Cytomegalovirus infection following marrow transplantation: Risk, treatment and prevention. Birth Defects 1984;20: 101-17. 4. Reusser P, Osterwalder B, Gratama JW, The TH, Gratwohl A, Speck B. Kinetics of cytomegalovirus IgG antibody following infusion of a hyperimmune globulin preparation in allogeneic marrow transplant recipients. Bone Marrow Transplant 1989;4:267-72. 5. Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153:478-88. 6. Grigg AP, Phillips GL, Barnett MJ, et al. CMV hyperimmunoglobulin after allogeneic bone marrow transplantation. J Cell Biochem 1990; 14A(suppl)308. 7. Atkinson K, Downs K, Golenia, et al. Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection. Br J Haematol 1991;79:57-62.
First, the CMV IVIG used in the study by Bowden et al. [2] gave a higher CMV-specific antibody dose than any previously published trial [3-7], including studies showing a benefit in preventing CMV pneumonia. However, the total dose ofIVIG was lower than that used in a study by Sullivan et al. [8], so it may not be surprising that no impact was seen on graft-versus-host disease, especially if the total dose of IVIG is important [9]. Second, review of table 2 in the study by Winston et al. [5] in which a dose ofIVIG twice as large as that used by Sullivan et al. [8] (but in a similar weekly schedule) reveals that while IVIG reduced all cases of interstitial pneumonia, it did not significantly reduce the number ofCMV pneumonia cases. Sullivan et al. and Bowden et al. [2] used products made by the same manu-
