Ann Hematol (1992) 64: A152- A157
Annals of
Hematology 9 Springer-Verlag 1992
Prevention of viral infections after bone marrow transplantation U. Schuler and G. Ehninger Medizinische Klinik der Universit~tt Ttibingen, Abteilung lnnere Medizin II, Otfried Mtiller Strasse 10, W-7400 Ttibingen, Federal Republic of Germany
Summary. After bone marrow transplantation, a number of viral infections contribute to the morbidity and mortality of the procedure. Established preventive measures to avoid primary infection and reactivation of herpesand cytomegaloviruses are outlined. Possible future strategies against these viruses (e. g., monoclonal antibodies, transfer of T-lymphocytes) and the possible role of improved diagnostic tools are briefly discussed. Key words: Bone marrow transplantation - Viral infections - Cytomegalovirus - Immunoglobulins - acyclovir, - Gancyclovir
Introduction Infectious complications are still the major cause of treatment- related deaths in bone marrow transplantation (BMT). A m o n g these cytomegalovirus (CMV), herpes simplex (HSV), and varicella zoster (VZV) are of main interest for the clinician. Prophylaxis of infection or in the case of an already existent latency, prevention of symptomatic disease is one of the m a j o r issues in supportive care of bone marrow transplant patients. It has been observed for years that infections after BMT follow a distinctive pattern. Table 1 shows the most relevant viruses observed after BMT. During the phase of granulocytopenia predominantly bacterial infections are observed, but herpes simplex virus infections were also frequently seen in the first m o n t h after transplantation. CMV infections are usually seen between day 30 and 100; later occurrence is always associated with immunosuppression in the course of chronic GVHD. In the same time interval Epstein-Barr virus and adeno- and respiratory viruses are pathogens of less severe infections. However, life-threatening pneumonia was described in less than 1% of transplant recipients [65,671.
Address for correspondence: U. Schuler (as above)
Since the latter infections are transmitted hand-tohand, hand-to-face, the use of surgical masks and other standard hygiene procedures might effectively reduce these infections. A number of viruses have been isolated from the urine of patients with hemorrhagic cystitis [2,4, 14,47,65]. Obviously as the heavily transfused BMT patients may acquire all the infections which are transmitted this way [35,36,69], preventive measures include standard serological testing of blood donors. Although a high percentage of patients harbor Epstein-Barr virus, very few develop any form of symptomatic infection [18]. However, the genome of this virus is frequently found in lymphoproliferative disorders after BMT [63] in the context of heavy immunosuppression or T-cell depletion. Reactivation of herpesvirus-6 may be the cause of febrile illness with skin rashes without severe consequences [76].
Herpes simpex and varicella zoster virus Herpes simplex reactivates in 6 0 % - 8 0 % of seropositive recipients [39]; patients with higher pretransplant titers seem to have an increased risk. The prophylaxis with oral and i.V. acyclovir [26, 33, 56, 62, 64, 70] is well establish-
Table 1. Viral pathogens after BMT Virus
Most frequent time of reactivation / infection
Cytomegalovirus Herpes simplex Varicella zoster Epstein-Barr virus Adenoviruses Herpesvirus 6 BK and JK papovavirus Other viruses (HIV, hepatitis A - C etc.)
2 - 3 months 1 - 3 weeks 3 - 12 months 3 - 6 months (1 - ) 2 - 4 months 3 - 5 weeks ? Not specifically different in the BMT setting
A153 ed and prevents VZV infection as well. Failures were observed in around 10~ of patients in a previous study of this group [22]. Acyclovir was used in an oral dose of 1600 mg per day for 3 months. Herpes virus was detected in five of 46 patients in surveillance cultures. In these patients no acyclovir was measured in repeated blood samples. Three patients were noncompliant; two patients lost the ability to absord acyclovir during the conditioning regimen. Despite this experience, we still use oral acyclovir and switch to intravenous application when herpes simplex is detected in surveillance cultures. Varicella zoster reactivates when no special prophylaxis is given [60]. In high-risk groups, such as patients with chronic GVHD and ongoing immunosuppression, acyclovir prevents reactivation and is also effective in treating the disease. Costs of the drug and the possibility of inducing resistance limit prolonged use of acyclovir in prophylaxis.
CMV infection Symptomatic disease with cytomegalovirus is the most important viral infection after BMT because it is associated with a high case-fatality rate. Not all patients in whom CMV virus is detected or seroconversion ist observed are symptomatic. Disease manifestations may range from oligosymptomatic febrile illness with marrow suppression to lifethreatening interstitial pneumonitis (CMV-IP), other manifestations include gastroenteritis, hepatitis, encephalitis and retinitis. CMV disease occurs either as primary infection or as secondary reactivation of latent virus in the recipient. The risk of primary infection/reactivation is obviously related to the serologic status of donor and recipient before BMT (Table 2). The rates may not necessarily reflect the risk of an individual patient to develop symtomatic disease. It has been reported that immunity of the donor protects recipients from serious symptomatic disease [30, 57]. Unlike in the case of HSV, the level of pretransplant CMV-IgG antibodies is not predictive for the risk of infection [49,511 within subgroup of seropositive patients. Autologous transplants, even in seropositive patients, carry a lower risk o f reactivation and symptomatic disease. Underlying disease may also be a factor; patients with severe aplastic anemia seem to have a lower incidence of CMV-IP [71]. The hallmark of prophylaxis studies in this context is usually the prevention of CMV-IP. Before the introduction of combined therapy with gancyclovir and immunoglobulins (If) 8 0 % - 90% of patients with CMV-IP died. Diagnosis of CMV-IP requires the detection o f virus in a lung with a pulmonary infiltrate. Idiopathic pneumonia is assumed if no pathogen can be detected. Recent observations by Einsele et al. [23] at our institution show that occasionally, culture-negative lung biopsies may be CMV-DNA-PCR positive. As yet, the clinical implications of this observation are unclear; possibly an unknown number of "idiopathic" pneumonias are caused
by CMV. If either patient or donor is seropositive, viremia is associated with an increased relative risk (3.6-5.6) of
Table 2. Rate of virus excretion or seroconversion as a function of pretransplant serology Recipient seronegative Reference
Donor seronegative
Donor seropositive
[75]a [61] [58] [34] [51]
112/404 3/55 1/14 18/49 4/61
67/143 4/15 4/10 10/18
Total: Percent:
138/583
90/205
25.6 b
43.5
5/19
Recipient seropositive Reference
Donor seronegative
Donor seropositive
[75] [61] [58] [34] [51]
128/182 11/41 1/1 16/24 16/29
177/255 26/62 8/17 35/46 31/61
Total: Percent:
172/277 62.1
277/441 62.8
a Reference [75] summarizes the following reports: [1,40,42, 45, 49]. b In more recent studies using exclusively seronegative blood products the percentage is close to zero
CMV-IP [27, 59]. It has also been found that a reduction in pretransplant forced vital capacity is a strong predictor for CMV-IP in CMV-seropositive patients [9]. These factors may help to identify high risk patients.
Prophylaxis of primary infection In seronegative patients with seronegative donors the goal is to prevent primary infection. This can be achieved by the exclusive use of blood products from seronegative donors [37,46]. In cases of a seropositive patient or donor no benefit for this restrictive transfusion policy was demonstrated [8, 46]. Avoiding CMV-positive granulocyte transfusions seems especially important because they seem to carry an increased risk of infection [41, 72]. In seronegative recipients the use of leukocyte-poor blood products may be an alternative [68]. The use of both centrifugation techniques [12, 19] and filters [10, 19] has been investigated. Interestingly, in one study [3], despite filtration and significant reduction of the leukocyte count, CMV-DNA as measured by PCR was still detectable. The cost-effectiveness of these different policies has not been compared. It will vary from one center to another, e.g., because of differences in the percentage of seronegative blood donors locally.
A 154
Prophylaxis with drugs Adenine arabinoside [31] and interferon [43] have not been able to reduce the incidence of CMV disease. So far, the only drug with a proven effect in a nonrandomized study [44] was intravenous acyclovir, in a dose of 3 • 500 m g / m 2 per day. The design of that study was not accepted by several teams; therefore, an ongoing European multicenter study is addressing that question again. Gancyclovir was tested in study with historic controls [5]. Patients who were seropositive or had seropositive donors received gancyclovir 5 mg/kg for 3 days a week, beginning on day 21 after BMT until day 84. Seropositive patients were also given a 1-week course of 2 • 5 mg/kg during the week before transplantation. None of 25 patients developed CMV disease; a randomized study is under way at the University of California at Los Angeles [751.
Prophylaxis with immunoglobulins A number of randomized studies comparing passive immunoprophylaxis with controls have been published in the past decade (Table 3) [7, 8, 11, 16,24,41, 55, 66,72-74]. Two tried to compare hyperimmunoglobulins (HIG) with standard immunoglobulin (SIG) preparations (Table 4) [32, 48]. Results in the respective studies have been variable; differences might be caused by a number of known factors which influence the rate of reactivation and pneumonitis, such as serologic status of recipient and donor, age, disease status, conditioning regimen, H L A compatibility, GVHD. Excepting the study of Sullivan et al. [66], most studies lack the power to detect small differences between treatment and control group. The supportive care with blood products, e.g., use of CMV-screened donors, and degree and method of leukocyte depletion
may have been quite variable. The Ig preparations were different in dose, timing, potency, and half-lives. The diagnostic procedures for detecting viremia and pneumonitis differ. The incidence of pneumonitis varies between 5% and 50%. In six of ten studies the incidence of CMV pneumonitis is reduced in the Ig group. A meaningful metaanalysis would require the original data of all studies in order to take account of the censoring of data. Crosstabulation (with a correction for different sample sizes [38]) shows the reduction of the incidence from 18% to 10% to be significant (p < 0.05). The exact statistical estimate is questionable; however, it may be argued that it is conservative because censoring due to early mortality (before the time when most CMV infections occur) caused by GVHD or septic complications may primarily affect control groups [15,28, 50]. One concern is whether prevention of CMV disease is confined to subgroups e.g. seronegative patients. It is of interest that these patients have been excluded in the largest study [66], which showed a significant decrease of all interstitial pneumonias; proven CMV-IP was observed in 15% of controls vs. 10.4% of Ig-treated patients (p-value for CMV-IP not given). There are several questions which remain to be solved. Are H I G or SIG to be preferred? Based on 1991 rates, at our institution the price of 1 g H I G is about equivalent to that of 5 g SIG. How would a 5 times higher dose of a SIG affect overall outcome compared with the lower dose of a HIG? In both studies addressing this question (Table 4), the doses of SIG are relatively low, the dose intervals long. Apart from prevention of CMV disease, Ig shows a number of positive effects in the setting of BMT, like the reduction of GVHD and septicemias [15, 28, 50], which also have to be considered in this context. Related to this is the second question: What is the exact mode of action? Apart from neutralizing CMV, effects of anti-
Table 3. Incidence of CMV-IP in studies evaluating prophylactic immunoglobulins Author
Preparation and dosage
Winston et al. ~ 1982 [72] Condie et al. 1984 [16] Meyers et al. a 1983 [41]
HIP, 10 ml/kg, days 0,3,30,45,60,75,90, 120 HIG, 200 mg/kg days 25,50,75 HIG, 6 ml/m z, days -4, - 2 then 11 weekly doses HIG, 150 mg/kg days -5, -1,6,20,34 100 mg/kg days 48, 62 HIG, 4 ml/kg, days -7,-3,0,15,30,45,60 75, 90 SIG, 20 ml/kg weekly until day 120 HIP, 30 ml/kg (200 mg IgG/kg) days 3,25,50,75 HIG, 200 mg/kg days - 8, - 6, 7, 14, 21, 28, 42, 56, 70 SIG 500 mg/kg/week SIG, 500- 1000 mg/kg week
Bowden et al. 1986 [8] Bordigoni et al. 1987 [7] Winston et al. 1987 [74] Ringden et al. 1987 [55] Bowden et al. 1991 [11] Sullivan et al. 1990 [66] Elfenbein et al. 1990 [24] (retrospective)
Control
Patients with neg. serology (%) contr./Ig
9/18 8/22 1/19
1/17 0/13 0/17
79/83 45/76 100/100 donor neg: 26/17
1/20
1/21
100 donor neg: 62/68
4/30
4/30
50/10 (~)
12/37 3/27
6/38 3/27
83/84, donor neg: 83/82 18/15
8/60
9/60
100, donors 100 seropositive
23/154 6/27
16/154 3/32
SIG, standard immunoglobulin; HIG, hyperimmunoglobulin; HIP, hyperimmune plasma Patients with granulocyte transfusions excluded
a
Ig
No Not given
A155 Table 4. Studies evaluating SIG versus HIG
Reference
O'Reilly 1983 [481 Kubanek 1985 [32]
SIG
Donors selected for negativeCMV titer, 200 mg/kg days 25, 50, 75 Intraglobin 2 ml/kg days - 7 , 13,33,73,93
HIG
IP incidence SIG
H1G
3/18
0/17
6/23 Cytotect 1 mI/kg days - 7,13,33, 73,93
1/26
200mg/kg days 25, 50,75
bodies against endotoxin or other immunomodulators, M H C molecules or unspecific immunmodulation may be involved. The use of monovalent monoclonal antibodies (MoAB) may help to answer this question. In vitro results seem to predict that CMV-induced myelosuppression is amenable to treatment with MoAB [13]. The optimal dose and timing of any Ig prophylaxis must still be determined. In some of the earlier studies the dose interval seems to have been too long [48]. In a recent study the lack of effect of Ig substitution was correlated to low Ig trough levels [17].
Outlook
At present, the most promising strategy seems to be the early therapy of patients at high risk for symptomatic disease [27, 59]. Gancyclovir given to patients with CMV detected by bronchoalveolar lavage at day 35 after BMT or to any patients with virus shedding or viruria seems to improve the outcome of the respective subgroups. These studies at the (in this field) imaginary border of prevention and treatment are covered in more detail in another review in this volume (Gluckman). In our group, Einsele et al. [23] applied the P C R technique to detect CMV in weekly surveillance specimens. With this method it seems that viremia can be detected earlier than with the conventional culture technique. This may help to define more clearly the risk groups, as in both of the above-mentioned studies [27, 59] some patients developed CMV-IP despite being in the respective low-risk group. Foscarnet is another promising drug. Like gancyclovir, its effectiveness in monotherapy in IP is limited, but virus replication can be reduced [541. A case of successful therapy in a BMT recipient with a gancyclovir resistant strain of CMV has been described [21]. The role of foscarnet in prevention or - like gancyclovir - in combination therapies (+_ Ig, _+ gancyclovir) has to be determined. Some concern has arisen about the additive nephrotoxicity with cyclosporin. Monoclonal antibodies are tested in phase-I trials [6, 20]. P h a s e - I I / I I I trials may also help to elucidate the pathogenesis of CMV-IP. Given the beneficial effects of SIG on GVHD and infections other than CMV (see above
[15, 28, 50]), it is obvious that MoAB will not completely replace polyvalent Ig in prophylaxis. In vitro studies suggest that recovery of T-cell function, as measured in a lymphocyte proliferation test to CMV antigens, correlates with clinical outcome [9,25, 52]. A logical consequence would be to try an adoptive transfer of CD 8 + cytotoxic T lymphocytes [29, 53].
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62. Selby PJ, Powles RL, Easton D, Perren TJ, Stolle K, Jameson B, Fiddian AP, Tryhorn Y, Stern H (1989) The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation. Br J Cancer 59:434-438 63. Shapiro RS, McClain K, Frizzera G, Gajl-Peczalska K J, Kersey JH, Blazar BR, Arthur DC, Patton DF, Greenberg JS, Burke B, et al. (1988) Epstein-Barr virus-associated B-cell lymphoproliferative disorders following bone marrow transplantation. Blood 71:1234-1243 64. Shepp DH, Dandliker PS, Flournoy N, Meyers JD (1987) Sequential intravenous and twice-daily oral acyclovir for extended prophylaxis of herpes simplex virus infections in marrow transplant patients. Transplantation 43:654-658 65. Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD (1985) Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med 312:529-533 66. Sullivan KM, Kopecky K J, Jocom J, Fisher L, Buckner CD, Meyers JD, Counts GW, Bowden RA, Peterson FB, Witherspoon RP, et al. (1990) Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 323:705-712 67. Taylor CE, Sviland L, Pearson AD, Dobb M, Reid MM, Kernahan J, Craft AW, Hamilton PJ, Proctor S (1990) Virus infections in bone marrow transplant recipients: a three-year prospective study. J Clin Pathol 43:633-637 68. Verdonck LF, de Graan-Hentzen YC, Dekker AW, Mudde GC, de Gast GC (1987) Cytomegalovirus seronegative platelets and leukocyte-poor red blood cells from random donors can prevent primary cytomegalovirus infection after bone marrow transplantation. Bone Marrow Transplant 2:73-78 69. Vilhner E, Devergie A, Gluckman E (1986) Lymphadenopathy AIDS virus (LAV) infection after bone marrow transplantation. Bone Marrow Transplant [Suppl 1]: 37 70. Wade JC, Newton B, Flournoy N, Meyers JD (1984) Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med 100:823-828 71. Weiner RS, Horowitz MM, Gale RP, Dicke KA, van Bekkum DW, Masaoka T, Ramsay NK, Rimm AA, Rozman C, Bortin MM (1989) Risk factors for interstitial pneumonia following bone marrow transplantation for severe aplastic anaemia. Br J Haematol 71:535-543 72. Winston D J, Pollard RB, Ho WG, Gallagher JG, Rasmussen LE, Huang SN, Lin CH, Gossett TG, Merigan TC, Gale RP (1982) Cytomegalovirus immune plasma in bone marrow transplant recipients. Ann Intern Med 97:11-18 73. Winston DJ, Ho WG, Lin GH, Bartoni K, Budinger MD, Gale RP, Champlin RE (1985) Use of a polyvalent intravenous immunoglobulin or specific cytomegalovirus hyperimmunoglobulin for modification of cytomegalovirus infections and prevention of interstitial pneumonias following bone marrow transplantation. Immun Infekt 13:296-301 74. Winston DJ, Ho WG, Lin CH, Bartoni K, Budinger MD, Gale RP, Champlin RE (1987) Intravenous immune globulin for prevention of cytomegalovirus infection and interstitial pneumonia after bone marrow transplantation. Ann Intern Med 106:12-18 75. Winston DJ, Ho WG, Champlin RE (1990) Cytomegalovirus infections after allogeneic bone marrow transplantation. Rev Infect Dis 12 [Suppl 7]: $776-$792 76. Yoshikawa T, Suga S, Asano Y, Nakashima T, Yazaki T, Sobue R, Hirano M, Fukuda M, Kojima S, Matsuyama T (1991) Human herpesvirus-6 infection in bone marrow transplantation. Blood 78:1381-1384
Annals of
Hematology 9 Springer-Verlag 1992
Prevention of viral infections after bone marrow transplantation U. Schuler and G. Ehninger Medizinische Klinik der Universit~tt Ttibingen, Abteilung lnnere Medizin II, Otfried Mtiller Strasse 10, W-7400 Ttibingen, Federal Republic of Germany
Summary. After bone marrow transplantation, a number of viral infections contribute to the morbidity and mortality of the procedure. Established preventive measures to avoid primary infection and reactivation of herpesand cytomegaloviruses are outlined. Possible future strategies against these viruses (e. g., monoclonal antibodies, transfer of T-lymphocytes) and the possible role of improved diagnostic tools are briefly discussed. Key words: Bone marrow transplantation - Viral infections - Cytomegalovirus - Immunoglobulins - acyclovir, - Gancyclovir
Introduction Infectious complications are still the major cause of treatment- related deaths in bone marrow transplantation (BMT). A m o n g these cytomegalovirus (CMV), herpes simplex (HSV), and varicella zoster (VZV) are of main interest for the clinician. Prophylaxis of infection or in the case of an already existent latency, prevention of symptomatic disease is one of the m a j o r issues in supportive care of bone marrow transplant patients. It has been observed for years that infections after BMT follow a distinctive pattern. Table 1 shows the most relevant viruses observed after BMT. During the phase of granulocytopenia predominantly bacterial infections are observed, but herpes simplex virus infections were also frequently seen in the first m o n t h after transplantation. CMV infections are usually seen between day 30 and 100; later occurrence is always associated with immunosuppression in the course of chronic GVHD. In the same time interval Epstein-Barr virus and adeno- and respiratory viruses are pathogens of less severe infections. However, life-threatening pneumonia was described in less than 1% of transplant recipients [65,671.
Address for correspondence: U. Schuler (as above)
Since the latter infections are transmitted hand-tohand, hand-to-face, the use of surgical masks and other standard hygiene procedures might effectively reduce these infections. A number of viruses have been isolated from the urine of patients with hemorrhagic cystitis [2,4, 14,47,65]. Obviously as the heavily transfused BMT patients may acquire all the infections which are transmitted this way [35,36,69], preventive measures include standard serological testing of blood donors. Although a high percentage of patients harbor Epstein-Barr virus, very few develop any form of symptomatic infection [18]. However, the genome of this virus is frequently found in lymphoproliferative disorders after BMT [63] in the context of heavy immunosuppression or T-cell depletion. Reactivation of herpesvirus-6 may be the cause of febrile illness with skin rashes without severe consequences [76].
Herpes simpex and varicella zoster virus Herpes simplex reactivates in 6 0 % - 8 0 % of seropositive recipients [39]; patients with higher pretransplant titers seem to have an increased risk. The prophylaxis with oral and i.V. acyclovir [26, 33, 56, 62, 64, 70] is well establish-
Table 1. Viral pathogens after BMT Virus
Most frequent time of reactivation / infection
Cytomegalovirus Herpes simplex Varicella zoster Epstein-Barr virus Adenoviruses Herpesvirus 6 BK and JK papovavirus Other viruses (HIV, hepatitis A - C etc.)
2 - 3 months 1 - 3 weeks 3 - 12 months 3 - 6 months (1 - ) 2 - 4 months 3 - 5 weeks ? Not specifically different in the BMT setting
A153 ed and prevents VZV infection as well. Failures were observed in around 10~ of patients in a previous study of this group [22]. Acyclovir was used in an oral dose of 1600 mg per day for 3 months. Herpes virus was detected in five of 46 patients in surveillance cultures. In these patients no acyclovir was measured in repeated blood samples. Three patients were noncompliant; two patients lost the ability to absord acyclovir during the conditioning regimen. Despite this experience, we still use oral acyclovir and switch to intravenous application when herpes simplex is detected in surveillance cultures. Varicella zoster reactivates when no special prophylaxis is given [60]. In high-risk groups, such as patients with chronic GVHD and ongoing immunosuppression, acyclovir prevents reactivation and is also effective in treating the disease. Costs of the drug and the possibility of inducing resistance limit prolonged use of acyclovir in prophylaxis.
CMV infection Symptomatic disease with cytomegalovirus is the most important viral infection after BMT because it is associated with a high case-fatality rate. Not all patients in whom CMV virus is detected or seroconversion ist observed are symptomatic. Disease manifestations may range from oligosymptomatic febrile illness with marrow suppression to lifethreatening interstitial pneumonitis (CMV-IP), other manifestations include gastroenteritis, hepatitis, encephalitis and retinitis. CMV disease occurs either as primary infection or as secondary reactivation of latent virus in the recipient. The risk of primary infection/reactivation is obviously related to the serologic status of donor and recipient before BMT (Table 2). The rates may not necessarily reflect the risk of an individual patient to develop symtomatic disease. It has been reported that immunity of the donor protects recipients from serious symptomatic disease [30, 57]. Unlike in the case of HSV, the level of pretransplant CMV-IgG antibodies is not predictive for the risk of infection [49,511 within subgroup of seropositive patients. Autologous transplants, even in seropositive patients, carry a lower risk o f reactivation and symptomatic disease. Underlying disease may also be a factor; patients with severe aplastic anemia seem to have a lower incidence of CMV-IP [71]. The hallmark of prophylaxis studies in this context is usually the prevention of CMV-IP. Before the introduction of combined therapy with gancyclovir and immunoglobulins (If) 8 0 % - 90% of patients with CMV-IP died. Diagnosis of CMV-IP requires the detection o f virus in a lung with a pulmonary infiltrate. Idiopathic pneumonia is assumed if no pathogen can be detected. Recent observations by Einsele et al. [23] at our institution show that occasionally, culture-negative lung biopsies may be CMV-DNA-PCR positive. As yet, the clinical implications of this observation are unclear; possibly an unknown number of "idiopathic" pneumonias are caused
by CMV. If either patient or donor is seropositive, viremia is associated with an increased relative risk (3.6-5.6) of
Table 2. Rate of virus excretion or seroconversion as a function of pretransplant serology Recipient seronegative Reference
Donor seronegative
Donor seropositive
[75]a [61] [58] [34] [51]
112/404 3/55 1/14 18/49 4/61
67/143 4/15 4/10 10/18
Total: Percent:
138/583
90/205
25.6 b
43.5
5/19
Recipient seropositive Reference
Donor seronegative
Donor seropositive
[75] [61] [58] [34] [51]
128/182 11/41 1/1 16/24 16/29
177/255 26/62 8/17 35/46 31/61
Total: Percent:
172/277 62.1
277/441 62.8
a Reference [75] summarizes the following reports: [1,40,42, 45, 49]. b In more recent studies using exclusively seronegative blood products the percentage is close to zero
CMV-IP [27, 59]. It has also been found that a reduction in pretransplant forced vital capacity is a strong predictor for CMV-IP in CMV-seropositive patients [9]. These factors may help to identify high risk patients.
Prophylaxis of primary infection In seronegative patients with seronegative donors the goal is to prevent primary infection. This can be achieved by the exclusive use of blood products from seronegative donors [37,46]. In cases of a seropositive patient or donor no benefit for this restrictive transfusion policy was demonstrated [8, 46]. Avoiding CMV-positive granulocyte transfusions seems especially important because they seem to carry an increased risk of infection [41, 72]. In seronegative recipients the use of leukocyte-poor blood products may be an alternative [68]. The use of both centrifugation techniques [12, 19] and filters [10, 19] has been investigated. Interestingly, in one study [3], despite filtration and significant reduction of the leukocyte count, CMV-DNA as measured by PCR was still detectable. The cost-effectiveness of these different policies has not been compared. It will vary from one center to another, e.g., because of differences in the percentage of seronegative blood donors locally.
A 154
Prophylaxis with drugs Adenine arabinoside [31] and interferon [43] have not been able to reduce the incidence of CMV disease. So far, the only drug with a proven effect in a nonrandomized study [44] was intravenous acyclovir, in a dose of 3 • 500 m g / m 2 per day. The design of that study was not accepted by several teams; therefore, an ongoing European multicenter study is addressing that question again. Gancyclovir was tested in study with historic controls [5]. Patients who were seropositive or had seropositive donors received gancyclovir 5 mg/kg for 3 days a week, beginning on day 21 after BMT until day 84. Seropositive patients were also given a 1-week course of 2 • 5 mg/kg during the week before transplantation. None of 25 patients developed CMV disease; a randomized study is under way at the University of California at Los Angeles [751.
Prophylaxis with immunoglobulins A number of randomized studies comparing passive immunoprophylaxis with controls have been published in the past decade (Table 3) [7, 8, 11, 16,24,41, 55, 66,72-74]. Two tried to compare hyperimmunoglobulins (HIG) with standard immunoglobulin (SIG) preparations (Table 4) [32, 48]. Results in the respective studies have been variable; differences might be caused by a number of known factors which influence the rate of reactivation and pneumonitis, such as serologic status of recipient and donor, age, disease status, conditioning regimen, H L A compatibility, GVHD. Excepting the study of Sullivan et al. [66], most studies lack the power to detect small differences between treatment and control group. The supportive care with blood products, e.g., use of CMV-screened donors, and degree and method of leukocyte depletion
may have been quite variable. The Ig preparations were different in dose, timing, potency, and half-lives. The diagnostic procedures for detecting viremia and pneumonitis differ. The incidence of pneumonitis varies between 5% and 50%. In six of ten studies the incidence of CMV pneumonitis is reduced in the Ig group. A meaningful metaanalysis would require the original data of all studies in order to take account of the censoring of data. Crosstabulation (with a correction for different sample sizes [38]) shows the reduction of the incidence from 18% to 10% to be significant (p < 0.05). The exact statistical estimate is questionable; however, it may be argued that it is conservative because censoring due to early mortality (before the time when most CMV infections occur) caused by GVHD or septic complications may primarily affect control groups [15,28, 50]. One concern is whether prevention of CMV disease is confined to subgroups e.g. seronegative patients. It is of interest that these patients have been excluded in the largest study [66], which showed a significant decrease of all interstitial pneumonias; proven CMV-IP was observed in 15% of controls vs. 10.4% of Ig-treated patients (p-value for CMV-IP not given). There are several questions which remain to be solved. Are H I G or SIG to be preferred? Based on 1991 rates, at our institution the price of 1 g H I G is about equivalent to that of 5 g SIG. How would a 5 times higher dose of a SIG affect overall outcome compared with the lower dose of a HIG? In both studies addressing this question (Table 4), the doses of SIG are relatively low, the dose intervals long. Apart from prevention of CMV disease, Ig shows a number of positive effects in the setting of BMT, like the reduction of GVHD and septicemias [15, 28, 50], which also have to be considered in this context. Related to this is the second question: What is the exact mode of action? Apart from neutralizing CMV, effects of anti-
Table 3. Incidence of CMV-IP in studies evaluating prophylactic immunoglobulins Author
Preparation and dosage
Winston et al. ~ 1982 [72] Condie et al. 1984 [16] Meyers et al. a 1983 [41]
HIP, 10 ml/kg, days 0,3,30,45,60,75,90, 120 HIG, 200 mg/kg days 25,50,75 HIG, 6 ml/m z, days -4, - 2 then 11 weekly doses HIG, 150 mg/kg days -5, -1,6,20,34 100 mg/kg days 48, 62 HIG, 4 ml/kg, days -7,-3,0,15,30,45,60 75, 90 SIG, 20 ml/kg weekly until day 120 HIP, 30 ml/kg (200 mg IgG/kg) days 3,25,50,75 HIG, 200 mg/kg days - 8, - 6, 7, 14, 21, 28, 42, 56, 70 SIG 500 mg/kg/week SIG, 500- 1000 mg/kg week
Bowden et al. 1986 [8] Bordigoni et al. 1987 [7] Winston et al. 1987 [74] Ringden et al. 1987 [55] Bowden et al. 1991 [11] Sullivan et al. 1990 [66] Elfenbein et al. 1990 [24] (retrospective)
Control
Patients with neg. serology (%) contr./Ig
9/18 8/22 1/19
1/17 0/13 0/17
79/83 45/76 100/100 donor neg: 26/17
1/20
1/21
100 donor neg: 62/68
4/30
4/30
50/10 (~)
12/37 3/27
6/38 3/27
83/84, donor neg: 83/82 18/15
8/60
9/60
100, donors 100 seropositive
23/154 6/27
16/154 3/32
SIG, standard immunoglobulin; HIG, hyperimmunoglobulin; HIP, hyperimmune plasma Patients with granulocyte transfusions excluded
a
Ig
No Not given
A155 Table 4. Studies evaluating SIG versus HIG
Reference
O'Reilly 1983 [481 Kubanek 1985 [32]
SIG
Donors selected for negativeCMV titer, 200 mg/kg days 25, 50, 75 Intraglobin 2 ml/kg days - 7 , 13,33,73,93
HIG
IP incidence SIG
H1G
3/18
0/17
6/23 Cytotect 1 mI/kg days - 7,13,33, 73,93
1/26
200mg/kg days 25, 50,75
bodies against endotoxin or other immunomodulators, M H C molecules or unspecific immunmodulation may be involved. The use of monovalent monoclonal antibodies (MoAB) may help to answer this question. In vitro results seem to predict that CMV-induced myelosuppression is amenable to treatment with MoAB [13]. The optimal dose and timing of any Ig prophylaxis must still be determined. In some of the earlier studies the dose interval seems to have been too long [48]. In a recent study the lack of effect of Ig substitution was correlated to low Ig trough levels [17].
Outlook
At present, the most promising strategy seems to be the early therapy of patients at high risk for symptomatic disease [27, 59]. Gancyclovir given to patients with CMV detected by bronchoalveolar lavage at day 35 after BMT or to any patients with virus shedding or viruria seems to improve the outcome of the respective subgroups. These studies at the (in this field) imaginary border of prevention and treatment are covered in more detail in another review in this volume (Gluckman). In our group, Einsele et al. [23] applied the P C R technique to detect CMV in weekly surveillance specimens. With this method it seems that viremia can be detected earlier than with the conventional culture technique. This may help to define more clearly the risk groups, as in both of the above-mentioned studies [27, 59] some patients developed CMV-IP despite being in the respective low-risk group. Foscarnet is another promising drug. Like gancyclovir, its effectiveness in monotherapy in IP is limited, but virus replication can be reduced [541. A case of successful therapy in a BMT recipient with a gancyclovir resistant strain of CMV has been described [21]. The role of foscarnet in prevention or - like gancyclovir - in combination therapies (+_ Ig, _+ gancyclovir) has to be determined. Some concern has arisen about the additive nephrotoxicity with cyclosporin. Monoclonal antibodies are tested in phase-I trials [6, 20]. P h a s e - I I / I I I trials may also help to elucidate the pathogenesis of CMV-IP. Given the beneficial effects of SIG on GVHD and infections other than CMV (see above
[15, 28, 50]), it is obvious that MoAB will not completely replace polyvalent Ig in prophylaxis. In vitro studies suggest that recovery of T-cell function, as measured in a lymphocyte proliferation test to CMV antigens, correlates with clinical outcome [9,25, 52]. A logical consequence would be to try an adoptive transfer of CD 8 + cytotoxic T lymphocytes [29, 53].
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