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Prevention and treatment of viral infections in stem cell transplant recipients

2002; Wiley; Volume: 118; Issue: 1 Linguagem: Inglês

10.1046/j.1365-2141.2002.03515.x

1365-2141

Per Ljungman,

Polyomavirus and related diseases

Viral infections are important causes of morbidity and mortality after allogeneic stem cell transplantation (SCT). Although viral infections are also common after autologous SCT, the risk for severe disease is lower. The main explanation for this tendency is that T cell-mediated immune responses are the main factors for controlling viruses in the immune competent state and these responses are more severely depressed after allogeneic transplantation. However, the immune defect is frequently complex, with defects in both cytotoxic T-lymphocyte, helper T-lymphocyte, and B-lymphocyte functions. The cytotoxic T-cells are most important in the control of viruses that can cause latency and thus reactivate in an immunocompromised individual. Specific antibodies are important for preventing reinfections with exogenous viruses and the loss of these antibodies in many allogeneic SCT patients over time will also increase the risk for reinfections. This review considers the preventive and therapeutic options for some of the more important viruses implicated as pathogens after allogeneic SCT. The herpesvirus group consists currently of eight members, six of which have been implicated as important pathogens in SCT recipients. During recent years, development of antiviral agents with anti-herpesvirus efficacy has resulted in a number of drugs that can be considered for prevention or therapy in SCT patients. Currently available drugs with anti-herpesvirus efficacy are acyclovir with its prodrug valacyclovir, penciclovir with the prodrug famciclovir, ganciclovir with the prodrug valganciclovir, cidofovir and foscarnet. All the available drugs, except foscarnet, are nucleoside analogues and require phosphorylation by viral or cellular enzymes to become activated (Table I). The first controlled studies of prophylaxis and therapy of HSV in allogeneic SCT patients were performed more than 20 years ago, showing that effective antiviral agents can make an important impact on morbidity and mortality. The results from these early trials are also relevant today (Saral et al, 1981; Hann et al, 1983; Ljungman et al, 1986). The results showed that acyclovir prophylaxis is indicated in all HSV-seropositive SCT recipients and in some autologous patients with high risk for mucositis (Centers for Disease Control (CDC), 2000). It is particularly important to consider drug absorption early after transplant and in patients who have been vomiting or have diarrhoea, as breakthroughs can then occur (Gluckman et al, 1983; Wade et al, 1984b; Engelhard et al, 1988). In these patients intravenous acyclovir should be considered. The duration of antiviral prophylaxis should be adjusted for each individual but should be continued throughout the aplastic phase. A longer duration of prophylaxis should be considered in patients with graft-versus-host disease (GVHD) or a history of frequent reactivations before transplantation (CDC, 2000). It is important to realise that HSV reactivations frequently occur quickly after prophylaxis is stopped and might require therapy (Saral et al, 1981; Hann et al, 1983; Wade et al, 1984a,b). Long-term prophylaxis studies with acyclovir have been performed and in those studies the frequency of reactivations has been lower after stopping prophylaxis, but long-term prophylaxis is rarely indicated as reactivations occurring after the aplastic phase usually are mild (Ljungman et al, 1986; Shepp et al, 1987). Valacyclovir, the prodrug of acyclovir, can presumably be used in place of acyclovir as prophylaxis. No controlled study has been performed in transplant patients, however. Valacyclovir gives similar acyclovir serum levels to i.v. acyclovir in neutropenic patients (Höglund et al, 2001). Established HSV disease can be treated either orally or intravenously. The most commonly used drug is acyclovir, which should be given intravenously in patients with disseminated HSV or suspected central nervous system (CNS) disease therapy. The most frequently used agents for HSV prophylaxis and therapy all require the viral enzyme thymidine kinase for activation. Virus resistance, usually caused by a mutant lacking this enzyme, can develop. Although acyclovir has now been in extensive use for almost 20 years, there has been only a moderate increase in the detection rate of acyclovir-resistant strains (Wade et al, 1983; Englund et al, 1990; Reusser et al, 1996). In a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation (BMT), 25% of the centres reported patients with proven or suspected acyclovir-resistant HSV infections (Reusser et al, 1996). However, recently, acyclovir-resistant HSV seems to have become more common, particularly in unrelated and human leucocyte antigen (HLA)-mismatched family transplant recipients and in patients with GVHD (Darville et al, 1998; Chakrabarti et al, 2000; Chen et al, 2000). The recommended drug for acyclovir-resistant HSV has been foscarnet (Safrin et al, 1990; Verdonck et al, 1993; Naik et al, 1995). Recently, two reports have described several patients with mutants resistant to both acyclovir and foscarnet (Chakrabarti et al, 2000; Chen et al, 2000). Currently, the only available antiviral drug available for treatment of double resistant HSV is cidofovir. However, although HSV strains have been sensitive in vitro, the clinical response in high-risk allogeneic SCT patients treated with cidofovir has been variable (Chakrabarti et al, 2000; Chen et al, 2000). A primary VZV infection (varicella) is a very severe complication in SCT patients. Owing to the epidemiological pattern of infection, the risk is highest in children. Varicella vaccine has been shown to be safe in children with acute leukaemia, but no controlled trial in SCT recipients has been published and its use is not recommended earlier than 24 months after transplantation (Ljungman, 1999; CDC, 2000). Varicella-zoster immune globulin is the recommended prophylactic measure in seronegative SCT recipients after a close or household exposure to varicella if it can be given within 4 d of exposure (CDC, 2000). Another option could be antiviral chemo-prophylaxis with acyclovir or valacyclovir, but there is no published data regarding the efficacy of this strategy. The risk of herpes zoster is highest between 3 and 6 months after transplantation. Thus, the duration of antiviral prophylaxis must be long enough to prevent reactivated VZV disease. Two randomized, controlled studies have been performed comparing 6 months of prophylactic acyclovir with placebo (Ljungman et al, 1986; Selby et al, 1989). In addition, a non-controlled study of acyclovir or ganciclovir prophylaxis was recently published (Steer et al, 2000). All three studies showed that acyclovir was effective in reducing the risk for herpes zoster during the 6 months of therapy, but at 12 months after transplantation there was no longer any difference. An unpublished study by Bowden and co-workers from the Seattle group indicated that the rebound in VZV disease does not occur if the prophylaxis is prolonged to 12 months (R. Bowden, personal communication). Valacyclovir has not been studied for VZV prophylaxis, but the rate of VZV disease was reduced in a study when valacyclovir was compared to acyclovir as CMV prophylaxis (Ljungman et al, 1998a). Some centres, however, do use valacyclovir as long-term prophylaxis against VZV (CDC, 2000). The recommended therapy for a primary varicella or disseminated herpes zoster is intravenous acyclovir 10 mg/kg (or 500 mg/m2) three times daily. For localized dermatomal herpes zoster, oral acyclovir 800 mg given five times daily was compared with i.v. acyclovir in a small randomized study in allogeneic SCT patients and the outcome was comparable (Ljungman et al, 1989b). Fancyclovir 500 mg given three times daily was compared with acyclovir 800 mg five times daily in SCT, solid organ transplant and oncology patients, and the results indicated similar efficacy (Tyring et al, 2001). No controlled study has been performed with valacyclovir given for treatment of a herpes zoster in SCT patients. VZV resistance to acyclovir is rare but has been reported after SCT (Reusser et al, 1996). Patients who are CMV seronegative before transplantation should if possible be transplanted from a CMV-seronegative donor (Bowden et al, 1991a). This is often not possible as only a limited number of donors are available and the time to find a donor is frequently critical. If a CMV-seronegative donor is found, the risk for CMV transmission is mainly through blood products. Two options exist for reducing this risk of CMV transmission; to use blood products from CMV-seronegative donors or to use leucocyte-depleted blood products. These two options were tested in a randomized trial and shown to be comparable (Bowden et al, 1995). However, whether it is enough in high-risk patients to rely on filtration for CMV-seronegative patients receiving grafts from CMV-seronegative donors remains controversial. If a CMV-seropositive donor has to be used, the risk for transmission to the recipient has been reported to be between 20% and approximately 40% (own unpublished results) (Miller et al, 1986; Ruutu et al, 1997). The use of CMV-seronegative blood products does not have a significant impact on the risk for a CMV-seronegative recipient receiving a graft from a CMV-seropositive donor (Bowden et al, 1986). Immune globulin is also not effective (Bowden et al, 1991b; Ruutu et al, 1997). No data exists regarding the possible effectiveness of antiviral prophylaxis against a primary infection in seronegative patients receiving a SCT from CMV-seropositive donors. Patients who are CMV seropositive before transplantation have approximately a 75% risk of reactivation of CMV and, if no preventive measures are taken, approximately a 20–30% risk of developing CMV disease. As the prognosis of therapy of established CMV disease is still poor, preventive measures are very important. These can be divided into prevention of a recurrence/reactivation of CMV (prophylaxis) or prevention of development of disease when reactivation has occurred (pre-emptive therapy). Prophylactic strategies. Several randomized trials of prophylactic i.v. immune globulin have been performed giving diverging results. Bass et al (1993) summarized these trials in a meta-analysis showing a slight but significant reduction in CMV disease and pneumonia. Due to the high cost of high dose i.v. immune globulin and its modest effect, immune globulin has been replaced in most transplant centres by prophylactic strategies with antiviral agents. Despite the fact that acyclovir and valacyclovir have only modest effects in vitro and in vivo on CMV replication, two large studies of acyclovir prophylaxis (500 mg/m2 three times daily during the aplastic phase followed by 800 mg orally four times daily) have shown a reduction of CMV infection and an improvement in survival (Meyers et al, 1988; Prentice et al, 1994, 1997). The survival benefit of these studies was not only mediated through a reduction in CMV disease, and breakthroughs of CMV disease were not infrequent. Valacyclovir was shown in a large randomized prospective trial to significantly reduce the risk for CMV viraemia above what was achieved with a high dose of acyclovir (Ljungman et al, 2002). There was no survival advantage and no reduction in the risk for CMV disease. Therefore, if either acyclovir or valacyclovir is to be used as CMV prophylaxis after allogeneic SCT, a strategy of pre-emptive therapy must also be used. As illustrated by a randomized trial (Ljungman et al, 2002), valacyclovir can reduce the need for pre-emptive therapy to approximately 50% and thereby, presumably, the risks for side-effects caused by the more toxic agents (ganciclovir and/or foscarnet). It was reported in acquired immunodeficiency syndrome (AIDS) patients that a high dosage of valacyclovir was associated with thrombotic microangiopathy (TMA). This was not seen in the study in SCT patients in whom the dose was carefully adjusted to renal function (Ljungman et al, 2002). Intravenous ganciclovir is effective for prevention of CMV disease. Two randomized, double-blind placebo-controlled trials have been performed with slightly different regimens (Goodrich et al, 1993a; Winston et al, 1993). Ganciclovir reduced the incidence of CMV infection in both studies and the incidence of CMV disease was significantly reduced in one study. Mortality rates did not differ between the ganciclovir and placebo groups in either study. There are two possible reasons for the lack of survival benefit. First, these studies were performed before the widespread use of growth factors such as granulocyte colony-stimulating factor (G-CSF) and ganciclovir-induced neutropenia was a problem in both studies. Second, ganciclovir prophylaxis has been associated with delayed immune reconstitution to CMV and thereby the development of late CMV disease (Li et al, 1994). Oral ganciclovir has been investigated only in a small prophylactic study in 21 recipients showing a poor tolerability and a high rate of CMV infection (Boeckh et al, 1998). A larger randomized study is ongoing. Valganciclovir is the prodrug of ganciclovir and is also currently being evaluated in SCT patients. Foscarnet has been used in three small trials and, although it inhibits CMV replication effectively and its major side-effect, renal toxicity, can be reduced with careful monitoring and hydration, no data on survival has been presented (Ringden et al, 1989; Reusser et al, 1992; Bacigalupo et al, 1994). The risk for CMV disease after autologous SCT is generally low. However, certain patient groups can have an increased risk, as illustrated by Holmberg et al (1999) who showed a high risk in CD34 cell-depleted patients. In addition, the prognosis of pneumonia in particular is poor (Ljungman et al, 1994). No controlled trial of prophylactic measures against CMV has been performed in autologous SCT recipients. It could be logical, however, to try to prevent primary infections in autologous SCT recipients, for example with the use of leucocyte-depleted or CMV-negative blood products. Boeckh et al (1995) in a retrospective analysis showed that high-dose acyclovir did not influence the risk for CMV disease. Goodrich et al (1991) showed that pre-emptive therapy based on the shell vial assay could reduce the risk for CMV disease and improve survival. Since then, pre-emptive therapy based on early detection of CMV has become the most commonly used strategy for prevention of CMV disease after allogeneic SCT (Ljungman et al, 1993a; Avery et al, 2000). The advantage is that only the patients at the highest risk will need treatment, which would reduce the risk of side-effects and, potentially, the cost. The disadvantage is that some patients will develop CMV disease before the indicator technique used becomes positive; the risk varies with the category of patients and the sensitivity of the indicator test. In the study by Goodrich et al (1991) using rapid isolation, the risk for CMV disease developing before or concomitantly with positive rapid isolation was 12%. Einsele et al (1995) showed, in a randomized trial, that the use of a polymerase chain reaction (PCR)-based diagnostic technique reduced the incidence of CMV disease and the risk for CMV-associated mortality compared with rapid isolation. Boeckh et al (1996) showed in a randomized study that antigenaemia-based pre-emptive therapy could be used with similar efficacy in preventing CMV disease to ganciclovir prophylaxis. This study illustrates the strengths and weaknesses of the two strategies well. Ganciclovir prophylaxis was more effective in preventing CMV disease during the time it was given (the first 100 d after SCT), while the risk for late CMV disease, ganciclovir-associated neutropenia and invasive fungal disease were higher in the ganciclovir prophylaxis group, equalizing the risk for CMV disease and survival at 180 d after transplantation. Furthermore, Boeckh et al (1999) showed that the results of the pre-emptive therapy strategy could be improved during the first 100 d by using a more sensitive antigenaemia assay. Today, several different techniques are available for the early detection of CMV disease, which can be used for monitoring CMV infection and used as indicator tests for initiating pre-emptive antiviral therapy. These include quantitative PCR (Gor et al, 1998), detection of mRNA (Gerna et al, 2000) and the hybrid capture assay (Hebart et al, 2001). These techniques have not yet been evaluated in comparison with the previously available techniques, but such studies are ongoing. Either ganciclovir or foscarnet can be used for pre-emptive therapy. Ganciclovir has been used in most published studies. In one small study, there was no difference between foscarnet and ganciclovir (Moretti et al, 1998). A larger randomized trial by the EBMT found no difference in efficacy, while there was less neutropenia in the foscarnet arm but no difference in renal toxicity (Reusser et al, 2002). Other options include the combination of ganciclovir and foscarnet that has been used with high efficacy in patients with a high-level antigenaemia without additional toxicity (Bacigalupo et al, 1996). Cidofovir (1–5 mg/kg per week) might be an effective alternative as second-line pre-emptive therapy, resulting in a 66% success rate when instituted after failure of either ganciclovir or foscarnet (Ljungman et al, 2001a). A recent small prospective study of pre-emptive cidofovir (5 mg/kg per week for 2 weeks followed by 5 mg/kg every 2 weeks) showed a difference in effectiveness when used in patients who had undergone non-myeloablative conditioning (7/10 patients) compared with those (0/7) who had received standard myeloablative conditioning (Platzbecker et al, 2001). However, cidofovir is associated with significant renal toxicity and controlled prospective studies are necessary. The duration of pre-emptive therapy has varied greatly in different published studies. The two most commonly used variations have been from the first positive indicator test and continued until d 100 after transplantation, resulting in a duration of 6–8 weeks in most patients and therapy until the indicator test becomes negative, usually resulting in 2–4 weeks duration of therapy (Einsele et al, 1995; Reusser et al, 2002). The drawback with shorter courses of therapy is that treatment might have to be restarted, but the advantages are lower cost, less risk of side-effects and potentially better reconstitution of the specific immune response to CMV. Treatment of established disease. The results of therapy in established CMV disease are still poor. Survival in CMV pneumonia remains at approximately 50% when the combination of ganciclovir and immune globulin is used (Emanuel et al, 1988; Reed et al, 1988; Schmidt et al, 1988; Ljungman et al, 1992). The combination is perceived as the 'gold standard' despite the fact that no randomized trial has been performed. Machado et al (2000) have recently published the results of an uncontrolled study of 139 allogeneic SCT patients showing that the advantage of adding immune globulin is limited with no improvement in survival over ganciclovir therapy given alone. For patients with CMV disease other than pneumonia, the addition of immune globulin does not seem to be beneficial (Ljungman et al, 1998b). The combination of ganciclovir and foscarnet is suggested to offer a clinical benefit in the treatment of CMV disease without a significant increase in toxicity (Bacigalupo et al, 1996). In a non-randomized trial including 33 patients, intravenous ganciclovir combined with foscarnet improved survival compared with mono therapy (Bacigalupo et al, 1996). Recently, a retrospective survey reported that cidofovir could salvage nine of 16 patients with CMV pneumonia failing therapy with ganciclovir, foscarnet or the combination (Ljungman et al, 2001a). Resistance. Resistance to ganciclovir is usually mediated through mutations in the UL97 gene. It has been more commonly reported in AIDS and in solid-organ transplant recipients than in stem cell transplant patients. It has been proposed that prolonged exposure to ganciclovir, a high viral load in the presence of suboptimal concentrations of antiviral drugs, and heavy immunosuppression, predisposes for the emergence of resistant strains (Emery & Griffiths, 2000; Limaye et al, 2000). Other therapeutic alternatives are then foscarnet or cidofovir. However, only increasing antigenaemia early after initiation of antiviral therapy is usually not a sign of antiviral resistance (Nichols et al, 2001a). Other strategies. Despite that fact that major advances have been reached in CMV management, several problems still exist including the increased incidence of CMV disease with a delayed onset. The lack of specific immunity to CMV, both regarding cytotoxic T-cell (CTL) response and helper T-cell response to CMV has been associated with a high risk for CMV disease. A series of landmark studies has shown that specific CTL can be cloned in vitro, safely be given to the patient, and their activity can be detectable during follow-up (Reusser et al, 1991; Riddell et al, 1992; Walter et al, 1995). A phase II study has recently been completed but has not been published. Preliminary data indicate that the risk for CMV infection and disease was low and side-effects were rare (S. Riddell, personal communication). Recently, new techniques such as the use of peptide pulsed dendritic cells and the tetramer technology have been developed that might allow an easier selection of CMV-specific T-cells, and several laboratories are presently testing these strategies in early phase clinical trials (Cwynarski et al, 2001; Kleihauer et al, 2001; Peggs et al, 2001; Szmania et al, 2001). Although EBV is frequent in the general population with a majority of adults being infected, little or nothing is known about its importance after allogeneic and autologous SCT respectively. Indeed, a few published studies have indicated that it is not important as a direct cause of viral disease, although case reports of meningo-encephalitis (Dellemijn et al, 1995) and hairy leucoplakia have been published (Epstein et al, 1993). Instead, the most important clinical manifestation of EBV infection is the post-transplant lymphoproliferative disease. This usually monoclonal disease occurs in < 1% of the patients after allogeneic SCT. However, the frequency can be much higher in mismatched and unrelated transplants particularly if the grafts are T-cell depleted (Shapiro et al, 1988). Studies in solid organ transplant recipients have reported that a high EBV viral load is predictive for post-transplant lymphproliferative disease (PTLD) (Stevens et al, 2001). Similar studies have been performed and reported in abstract form for SCT recipients but the results have been variable, presumably due to selection of patients with various degrees of risk for development of PTLD. The primary first-line therapy for EBV-associated PTLD is to reduce the immunosuppressive therapy. This is frequently not possible, for example after T cell-depleted SCT. Several antiviral drugs including acyclovir, ganciclovir, foscarnet and cidofovir have antiviral effects against EBV. However, no study has been performed to study these antiviral agents' efficacy against EBV in SCT recipients. There are data from solid organ transplant recipients indicating a reduction of EBV shedding during antiviral therapy, but rapid rebounds when the antiviral therapy was withdrawn. Instead, most interest over the last few years has been directed towards other therapeutic modalities such as therapy with specific or non-specific T-cells and with monoclonal antibodies. The group at St. Jude's has used cloned EBV-specific donor T-cells (Rooney et al, 1995) and the group at Memorial Sloan Kettering unspecific donor lymphocyte infusions (Papadopoulos et al, 1994). Both strategies were shown to be effective with regression of the tumour masses, but the use of unspecific donor lymphocyte infusions was associated with an increased risk for severe acute GVHD. The strategy of EBV-specific T-cell infusions has also been used prophylactically to prevent EBV lymphoproliferative disorders after SCT (Rooney et al, 1995). EBV cytotoxic T-lymphocytes (CTL) can also reduce the EBV viral load (Gustafsson et al, 2000). The monoclonal antibody directed against the B-cell antigen CD20 (retuximab) has also been used to treat PTLD after both solid organ and SCT. Milpied et al (2000) reported results from 26 solid organ and 6 SCT patients. Four of the latter were treated for suspected PTLD with high EBV viral load. Sixty-five per cent of the solid organ transplant patients and five out of six SCT patients responded. Kuehnle et al (2000) reported successful treatment with anti-CD20 of three patients with proven EBV-lymphomas. Recently, Haddad et al (2001) reported promising results with the use of anti-interleukin 6 for therapy of PTLD. HHV-6 exists in two subtypes that differ from each other in 4–8% of the DNA. Subtype B is the cause of exanthem subitum in childhood and is the most common cause of admission to hospital in infants below 1 year of age. It has also been linked to febrile seizures in childhood. It is unclear what, if any, disease is caused by the primary infection of subtype A. As this infection is very common early in life, the rate of seropositivity in adults is very high (> 95%). HHV-6 has been associated with interstitial pneumonia, encephalitis, hepatitis and bone marrow suppression after SCT. There is no published study on the use of antiviral prophylaxis against HHV-6. Wang et al (1996) showed in an epidemiological study that patients who received high-dose acyclovir had lower HHV-6 DNA levels and were less likely to suffer from a delayed marrow engraftment. In vitro studies show that both ganciclovir and foscarnet should be effective against HHV-6. Both ganciclovir and foscarnet have been reported to be effective against HHV-6 meningo-encephalitis after SCT (Wang et al, 1999). Respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza viruses, and influenza A and B are widespread in the community with major seasonal variations. Despite the fact that these viruses are so common, it is only during recent years that their role as pathogens in immunocompromised patients has started to be appreciated. An important aspect to consider regarding infections with respiratory viruses is that these infections can easily be spread nosocomially through immune-competent staff and patient relatives. The infections can be spread through the air by droplets but are more commonly spread through the hands of staff. Thus, infection control measures are important in the control of respiratory infections. RSV pneumonia has been associated with high mortality. Harrington et al (1992) described an outbreak at the Fred Hutchinson Cancer Research Center in which 31 cases of RSV infections were documented and the overall mortality was 45%. The mortality in the 18 patients who developed pneumonia was 78%. Whimbey et al (1996) presented 33 patients with an overall mortality of 37%. In a recent prospective survey by the EBMT, the overall mortality in patients with a RSV lower respiratory tract infection was 30% and the RSV-associated mortality was 17%. The outcome is worse after allogeneic than after autologous transplantation. The most important risk factor for lower respiratory tract disease was lymphocytopenia. In other studies, RSV infections occurring before marrow engraftment have been associated with a poor outcome (Whimbey et al, 1996). No study has been performed regarding prevention of infection with RSV in SCT recipients and no controlled study has been performed with pre-emptive therapy to prevent lower respiratory tract disease after detection of an upper respiratory tract infection. In a small phase I study of the RSV monoclonal antibody palivizumab, three patients were treated for an upper respiratory tract infection and none developed lower respiratory tract disease (Boeckh et al, 2001). Another pre-emptive therapy option would be ribavirin. No controlled study has been published and results of non-controlled studies are inconclusive. Ghosh et al (2000) treated 14 patients with the combination of ribavirin and high-dose i.v. immune globulin and 4 out of 14 patients developed pneumonia. In a recent prospective survey, no regimen was superior to any other or to no therapy (Ljungman et al, 2001b), strongly supporting the necessity for controlled studies. One such study comparing aerosolized ribavirin with placebo is ongoing. Only uncontrolled phase II studies of treatment of RSV disease have been performed. In the series of Harrington et al (1992), 13 patients with pneumonia were treated with aerosolized ribavirin and four patients survived. Whimbey et al (1995) combined aerosolized ribavirin with a high titre of anti-RSV immune globulin and showed that those patients treated with the combination before respiratory failure developed had a mortality rate of 31%. However, patients who had therapy instituted when ventilatory support was necessary had a mortality rate of 100%. DeVincenzo et al (2000) reported 11 children treated with ahigh-titre anti-RSV immune globulin, in 10 children in combination with ribavirin. Ten out of 11 children survived (91%). On the other hand, McCarthy et al (1999) reported 26 patients with RSV infections and no apparent effect on outcome with ribavirin therapy. As aerosolized ribavirin is cumbersome and potentially teratogenic, care should be taken so that staff and visitors are not exposed to aerosolized ribavirin. Therefore, other delivery options have been investigated. Lewinsohn et al (1996) studied intravenous ribavirin in 10 patients in a phase I study but the results were poor. Recently, Ljungman et al (2001b) reported in a prospective but non-controlled study similar outcomes with ribavirin given intravenously and as aerosol. Controlled studies are needed to assess the best therapeutic option for RSV lower respiratory tract infections. Parainfluenza viruses can produce severe and fatal infections after SCT, although the mortality seems to be lower than for RSV (Ljungman et al, 1989a; Wendt et al, 1992; Nichols et al, 2001b). The usefulness of antiviral therapy is still to be determined. The presently available antiviral agent is ribavirin. Wendt et al (1992) and Nichols et al (2001b) failed to find any effect of ribavirin therapy, while Lewis et al (1996) reported five patients treated with aerosolized ribavirin; three were treated before respiratory failure developed and all survived, while the two patients who required ventilator support both died. Influenza can also cause morbidity and significant mortality after SCT (Ljungman et al, 1993b, 2001b; Whimbey et al, 1994). Whimbey et al (1994) reported a mortality of 17% and Ljungman et al (2001b) reported an overall mortality of 23% and influenza-related mortality of 15%. There was no difference in the risk for a fatal outcome in patients undergoing autologous or allogeneic transplantation. Fatal cases of influenza can occur both early and late after transplantation and preventive measures are therefore indicated. The primary mode for prevention of influenza is vaccination. The main problem is the poor responses to vaccination if given early after transplantation. Vaccination was shown to be ineffective in eliciting a protective antibody response if given earlier than 6 months after allogeneic andautologous SCT (Engelhard et al, 1993). Influenza vaccination is recommended both by the EBMT and the CDC, and should be given to all transplant patients from 6 months after transplantation and yearly while the patients areimmunosuppressed (Ljungman, 1999; CDC, 2000). Pauksen et al (2000) performed a randomized trial, finding a slight but significant advantage with the addition of granulocyte–macrophge CSF over vaccination. Consideration should also be given to vaccinating health care professionals who take care of transplant patients, and family members of the transplant patients. The possibilities for prevention with antiviral agents include amantadine/rimantadine and the new neuramidase inhibitors. Amantadine/rimantadine has been effective in the elderly, but the rate of resistance development is rapid and, although anecdotal reports exist, it is not possible from these case reports to assess its usefulness. No controlled study has been performed regarding either prevention or therapy of influenza in SCT patients. However, the CDC recommends amantadine or rimantadine as prophylaxis during community outbreaks to patients < 6 months after a SCT (CDC, 2000). Amantadine, rimantadine, ribavirin (Hayden et al, 1996) and the neuramidase inhibitors (zanamivir and oseltamivir) could theoretically be used for therapy of severe influenza infections, but there is currently no data to support either agent. Adenoviruses are DNA viruses and commonly cause infections in immune-competent individuals, particularly young children. Adenoviruses exist in more than 50 separate serotypes and can be a cause of very severe disseminated infections in SCT recipients. Shields et al (1985) showed a frequency of adenovirus infections of 5%. Approximately one third (1·7%) had severe infections and the total mortality was 0·4%. Flomenberg et al (1994) documented an adenovirus infection frequency of 20·8% and adenovirus disease in one third of these patients. Acute GVHD and use of mismatched or unrelated donors have been associated with a higher risk of development of adenovirus disease. The most severe disease manifestations are pneumonia, encephalitis and fulminant hepatitis, but haemorrhagic cystitis and gastroenteritis are more common. Currently there is no established effective prophylaxis or therapy for adenovirus infections in SCT recipients. Anecdotal cases have reported the use of i.v. immune globulin (Flomenberg et al, 1994). Ribavirin has been used in case reports with varying outcomes (Cassano, 1991; Liles et al, 1993; Hromas et al, 1994; Kapelushnik et al, 1995; Mann et al, 1998; Chakrabarti et al, 1999; Baldwin et al, 2000; Miyamura et al, 2000). La Rosa et al (2001) showed no appreciable impact of ribavirin therapy in 12 patients, of whom only two survived. Bordigoni et al (2001) treated 13 patients with definite (three), probable (five) disease, or asymptomatic infection with ribavirin. Only three of these 13 patients survived. Cidofovir might have an effect against adenovirus infections but no controlled studies have been performed in SCT recipients. Legrand et al (2001) recently reported seven children treated with cidofovir for adenovirus gastrointestinal disease. Five patients resolved the adenovirus infection, one patient died of progressive adenovirus disease and one patient died of aspergillosis. The Infectious Diseases Working Party of the EBMT has performed a retrospective study of 45 patients given cidofovir therapy for adenovirus infections with a success rate of 69% (Ljungman et al, 2001c). As adenovirus disease is associated with severe immune incompetence, the use of adenovirus-specific CTL has been proposed and adenovirus-specific CTL have been produced in vitro (Regn et al, 2001). Papovaviruses are a group of DNA-viruses with two members – JC-virus and BK-virus – that can be pathogenic in SCT patients. JC-virus is the agent causing progressive multifocal leucoencephalopathy (PML) and BK-virus has been implicated in haemorrhagic cystitis and nephropathy in transplant recipients. However, several other viruses such as adenovirus and CMV have been shown to cause haemorrhagic cystitis and, furthermore, many patients excrete BK-virus in urine without any signs of haemorrhagic cystitis, making interpretations of preventive and therapeutic measures difficult. Case reports of successful cidofovir treatment for PML in AIDS patients but not in transplant patients have been published. The situation for BK-virus is similar. No controlled study has been published. One case report of cidofovir showing a reduction in the urine viral load of BK-virus and improvement of haemorrhagic cystitis has been published (Held et al, 2000). HBV infections are common in many countries and therefore patients or their donors might be HBV antibody or antigen positive pre transplant. In patients who are HBsAg positive before transplantation, there does not seem to be an obvious increased risk for severe liver complications after transplantation (Reed et al, 1991; Locasciulli et al, 1995a), and long-term survival is similar in HBV-positive and -negative patients (Lau et al, 1997a). Patients who are anti-hepatitis B surface antigen (HBs) positive at the time of transplant can become HBsAg and HBV-DNA positive during a long-term follow-up because of loss of specific antibodies to HBV. However, true long-term data does not exist in assessing, for example, the risk for hepatocellular carcinoma in SCT patients positive for HBsAg. The use of an HBV antigen-positive marrow donor for a seronegative recipient should be avoided but, if that is not possible, different strategies could be considered, although none have been tested in a controlled clinical trial. The risk of transfer of HBV is high and hepatitis is likely to develop (Lau et al, 2000). A pre-transplant vaccination of the patient would be logical as Locasciulli et al (1995a) showed that patients who are antibody positive to HBV before transplant were less likely to develop severe liver complications. Thus, if the patient's clinical status allows a delay of the transplant, vaccination could be considered. HBV-specific immune globulin can be given to the patient before transplantation and was used in some patients in the study by Locasciulli et al (1995a). No data exist on antiviral prophylaxis (famciclovir or lamivudine) in patients receiving a graft from a HBsAg-positive donor. There are two antiviral agents with efficacy against HBV that could be used for prevention of severe HBV in seropositive SCT patients – famciclovir and lamivudine. As famciclovir is also effective against HSV and VZV, its use could be considered with the aim of both preventing HSV reactivations and potentially reducing the risk of HBV-associated complications. In one study of eight HBV-positive patients compared with 24 historical controls, famciclovir reduced the risk for post-transplant hepatitis (Lau et al, 1998a). Another antiviral agent, lamivudine, with more potent anti-HBV activity, has also been used in SCT patients to prevent reactivation (Picardi et al, 1998; Uchida et al, 2000; Endo et al, 2001). Additional studies are needed to assess the usefulness of these agents to prevent HBV-associated complications in SCT recipients. Another very interesting possibility, showing the effect of donor immunity in control of viral infections in the recipient, is that the use of anti-HBc-positive donors have been reported, resulting in clearance of HBV in HBsAg-positive recipients (Ilan et al, 1993; Lau et al, 1997b, 1998b). Hepatitis C virus is the major agent causing parenteral non-A, non-B hepatitis. It is mainly spread through blood transfusions and plasma-derived products, although other ways of transmission occur. If the marrow donor is HCV RNA positive the risk for transmission to the patient is very high, although the resulting hepatitis is mild (Shuhart et al, 1994). Several studies have looked at the risk of severe liver complications such as veno-occlusive disease (VOD) in patients who are HCV RNA positive before transplantation. Locasciulli et al (1995b) showed no impact of HCV status. However, patients with HCV and abnormal liver function tests were reported to have an increased risk for VOD (Locasciulli et al, 1999; Strasser et al, 1999a). HCV-infected patients surviving more than 20 years after allogeneic SCT have a very high risk of developing liver cirrhosis (Strasser et al, 1999b). The only available agent that could be given to patients who are HCV positive before SCT is ribavirin. In a small pilot study in four patients, oral ribavirin could be given through the aplastic phase without severe side-effects and three of these patients became HCV negative during long-term follow-up (Ljungman et al, 1996). As the risk for cirrhosis is high in long-term survivors, therapy with interferon, with or without ribavirin, could be indicated. Two small series have been published, both showing that the therapy is feasible without severe side-effects, and can result in HCV-RNA negativity and reduction of the inflammatory score in liver biopsies (Ljungman et al, 1995; Giardini et al, 1997). Whether this therapy will change the long-term outcome and thereby reduce the risk for late complications is presently unknown. The use of an HCV-positive donor should be avoided if alternatives exist. Interferon-α with the addition of ribavirin is the treatment of choice in immune-competent individuals and, if there is time, therapy of the intended donor could be attempted. One case report has been published in which a HCV-RNA donor was treated for 6 months and RNA negativity was obtained (Vance et al, 1996). No transmission to the recipient occurred after transplantation and engraftment was prompt. In summary, viral infections have been major obstacles to successful SCT. During recent decades, several antiviral agents have been developed that have been used against a variety of viruses. However, with the exception of antiviral strategies used against HSV, VZV and CMV, existing data is from non-controlled studies and case reports. Therefore, a challenge for the future is the design, realization and publication of large randomized, controlled trials so that more can be learned about how best to prevent and treat viral infections in SCT recipients.