Management of herpes virus infections following transplantation

A Report from the British Society for Antimicrobial Chemotherapy Working Party* on Antiviral Therapy

Introduction

Herpesvirus infections lead to significant morbidity and mortality in transplant recipients.1 Cytomegalovirus (CMV) is the most important virus in this respect, and prevention of CMV disease has been the subject of a large number of clinical trials. In addition, herpes simplex virus (HSV) and varicella zoster virus (VZV) can lead to severe disease. With regard to Epstein–Barr virus (EBV), post-transplant lymphoproliferative disease (PTLD) is increasingly recognized as a major complication. By contrast, disease association with human herpes virus 6 (HHV-6) and human herpes virus 7 (HHV-7) infections following transplantation requires clarification, as does the natural history of these infections. There is little information available on human herpes virus 8 (HHV-8) infection in the transplant scenario.

An increasing number of antiviral agents are available for treatment and prevention of these infections, including acyclovir and its prodrug, valaciclovir; ganciclovir and its prodrug, valganciclovir; foscarnet; famciclovir; adefovir; and cidofovir. In addition, interferons and immunoglobulin preparations have been utilized. These agents can be used in one or more of the following ways.

(i) Prophylaxis: antiviral therapy given from time of transplant, either universally or according to specific risk factors such as recipient/donor serostatus.
(ii) Pre-emptive therapy: targeted therapy to those at particularly high risk of developing disease, based on laboratory results with high predictive value.
(iii) Treatment: initiation of therapy following onset of symptoms. The success of this strategy is highly dependent on the disease in question.

These strategies, undertaken with some of the drugs above, have been subjected to controlled clinical trials. Nevertheless, many transplant units utilize protocols that have not been subject to trials. The purpose of this report is to summarize results from randomized, controlled trials, make general recommendations based on these results and identify areas requiring further research. We have categorized these recommendations according to three levels, 1, 2 or 3, with Category 1 representing the strongest level of evidence. These are described in Table IGo. All of our recommendations are discussed within the text, and are also summarized in Table IIGo.


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Table I. Categories of recommendation
 

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Table II. Summary of recommendations
 
Bone marrow transplantation—general aspects

Bone marrow transplantation (BMT) is now used to treat a wide range of haematological malignancies and also some non-malignant conditions. Conditioning with chemotherapy or chemoradiotherapy is used to eradicate the diseased marrow which is then replaced with donor marrow either of autologous or allogeneic origin. The conditioning also results in ablation of the recipient's humoral and cellular immunity, which only recover slowly as the host is repopulated with donor cells. Thus, after an initial leucopenia, newly derived neutrophils, as well as platelets and erythrocytes, are able to carry out their most important respective functions. However, the functional activity of the newly generated T- and B-lymphocytes is depressed for months to years after transplant, presumably because recapitulation of immune ontogeny must occur. Immunodeficiency is moderate after autologous BMT since there is no need for immunosuppressive therapy. In contrast, immunosuppressive therapy is an absolute requirement after allogeneic transplant to prevent acute graft-versus-host disease (GVHD). Those receiving BMT from a volunteer unrelated donor (VUD) rather than from a sibling are at higher risk of chronic GVHD and therapeutic immunosuppression may need to be continued for years. It is therefore not surprising that immunodeficiency is profound and that virus infections are a major complication after allogeneic but not autologous transplants. A recently introduced alternative technique involving the transplantation of peripheral blood stem cells seems likely to give accelerated haemopoietic recovery and hence reduce the period of immunocompromise relative to BMT. Therefore, as experience is gained with this new technique, guidelines for antiviral prophylaxis and treatment will certainly require amendment. HSV, CMV and VZV are the most important clinically and disease shows a characteristic temporal pattern but fortunately considerable progress has been made in the prevention of morbidity and mortality caused by these herpes viruses. Nevertheless, several problems remain including symptomatic breakthrough of virus infection in the absence of drug-resistant virus (e.g. in patients with severe GVHD receiving intensive chemotherapy), the occurrence of late-onset disease and the rare occurrence of drug-resistant virus, usually as a result of prolonged antiviral therapy.

Solid organ transplantation—general aspects

The timing of herpes virus infections following solid organ transplantation is similar to that described for BMT. The risk of CMV infection in this group of patients is directly related to recipient/donor CMV serostatus and the receipt of poorly matched organs.

Interestingly, manifestations of CMV disease are highly dependent on the transplanted organ. CMV-seropositive lung and heart–lung recipients are at particular risk of obliterative bronchiolitis, whereas liver transplant recipients suffer from CMV hepatitis. The risk of CMV infection and disease is proportional to the amount of immunosuppression given, and immunosuppressive protocols vary according to organ transplant type, and differ between units for any given organ type. Therefore, a new strategy may not be accurately assessed in the context of another unit's experience. During the evolution of organ transplantation, there has been a trend toward the administration of more conservative immunosuppressive protocols, a phenomenon which partially explains the declining incidence of serious opportunistic infection. For instance, many units no longer use anti-lymphocyte preparations for the treatment or prophylaxis of graft rejection. The use of new immunosuppressive agents (for example, mycophenolate mofetil and rapamycin) may influence the incidence of both rejection and opportunistic infection, including CMV.

Therefore, organ-specific, unit-specific and immunosuppression-specific factors must be considered in the evaluation of putative prophylactic strategies.

Cytomegalovirus

An important determinant of CMV disease risk in transplant recipients is the recipient/donor serostatus. Seropositivity infers the presence of latent viral infection. In bone marrow transplantation, recipient CMV seropositivity represents the highest risk, whereas donor seropositivity, whatever the recipient status, is more important for solid organ recipients. CMV active infection is defined by the detection of virus in any bodily compartment following transplantation, and can be undertaken by virus culture, antigen detection or, increasingly, molecular detection. Serological diagnosis (seroconversion, increase in antibody titre or specific IgM detection) has no role to play in the immunocompromised host, other than determining pre-transplant serostatus. Infection is defined as recurrent if the virus reactivates in a recipient who was infected before transplant (CMV seropositive), or primary if he or she was previously uninfected (CMV seronegative). In solid organ and BMT recipients, seropositive recipients of seropositive organs can experience re-infection as well as reactivation of their pre-existing virus. CMV disease (or symptomatic infection) is defined by organ-specific or systemic symptoms in the presence of CMV at the relevant site (or blood in the case of CMV syndrome), in the absence of another recognized cause.

Management of CMV disease: BMT patients

Data regarding CMV infection, disease and use of antiviral agents after autologous BMT are limited. However, although the incidence of CMV active infection is similar to that in allogeneic BMT, the incidence of CMV disease is substantially lower2 and the natural history of CMV infection appears similar to that in solid organ transplants. The following comments are therefore limited to allogeneic BMT patients.

CMV infections remain the most important viral cause of morbidity and mortality after allogeneic BMT despite the availability of the antiviral agents ganciclovir and foscarnet, both of which are effective at suppressing virus replication in vivo. CMV is a common cause of non-bacterial pneumonia,3 a less frequent cause of gastrointestinal ulcers ranging from oesophagus to colon4,5 and a very rare cause of retinitis.6 The period of highest risk of CMV disease is between 1 and 3 months after transplant; CMV active infection occurs at a mean of day 40 and may be followed by CMV pneumonitis about 15 days later.7 CMV-seropositive recipients, regardless of their donor's antibody status, are at high risk of reactivated CMV infection whereas CMV-seronegative individuals who receive marrow from a CMV-seropositive donor are at a lower risk of primary infection, suggesting that the donor marrow is of limited importance in the transmission of CMV. The risk of disease is, of course, entirely dependent on the risk of CMV active infection, and viraemia in particular has a high positive predictive value for subsequent disease.7 Secondary factors include severe GVHD,8 a transplant using T-cell depleted stem cells9 or from a VUD,10 and delayed reconstitution of the CMV-specific cytotoxic T-cell response.11

Treatment

Untreated CMV pneumonitis has a mortality of at least 80%. Therapy with ganciclovir or foscarnet alone proved ineffective and it was not until ganciclovir was combined with iv immunoglobulin that a slight improvement in outcome was noted with mortality rates of 30–70% being reported12 from uncontrolled studies. On this rather tenuous basis ganciclovir plus immunoglobulin has become the recommended treatment for CMV pneumonitis. Both normal immunoglobulin or immunoglobulin selected for a particularly high titre of CMV antibody (CMVIg) have been used in various doses, but a retrospective survey gave no evidence that the one preparation was superior to the other.12 It is possible that these preparations act to modulate the possible immunopathogenic mechanisms underlying CMV pneumonitis. As regards the treatment of CMV gastrointestinal disease, a randomized, placebo-controlled trial of ganciclovir showed no effect as compared with supportive care.13 In practice, either ganciclovir or foscarnet is used for CMV disease, although there is little supporting evidence.

Recommendation.
Ganciclovir plus normal immunoglobulin should be used for treatment of CMV pneumonitis (Category 3).

Prophylaxis

Various strategies have been assessed. First, the use of CMV-seronegative blood products,14,15 can prevent CMV infection in CMV-seronegative recipients who receive marrow from a seronegative donor. CMV is latent within white blood cells and thus platelets and red blood cells depleted of leucocytes can be used as an alternative preventative policy.16 Indeed, leucocyte depletion has now become routine practice for all blood within the UK.

Unfortunately, these policies can only reduce the amount of CMV infection in seronegative individuals who receive marrow from a seropositive donor.14,15 Indeed, the best strategy for the prevention of CMV disease under these circumstances is unknown but nevertheless many bone marrow transplant centres use ganciclovir according to one of the strategies described below.

The second preventive strategy is the use of normal iv immunoglobulin or CMVIg but there is no general agreement as to whether this is effective against CMV disease in either CMV-seronegative or -seropositive recipients. The main benefit is probably non-specific and due to a reduction in both GVHD and bacterial infection.17,18

Prophylactic high-dose acyclovir is only partially effective in preventing CMV disease after allogeneic BMT; the probability of CMV active infection is somewhat reduced and onset of viraemia delayed.19 Nevertheless, a recent report has demonstrated improved 1 year survival using iv acyclovir followed by 6 months' oral acyclovir.20 At this time early very sensitive detection and pre-emptive therapy of CMV infection were not widely used. Thus, the results of this study were questioned regarding nonstandardized use of ganciclovir at different centres.21 In the event the use of high-dose acyclovir was not widely adopted,22 perhaps because the difference in survival could not clearly be attributed to a reduction in CMV-associated mortality. Of interest, any potential survival benefit of acyclovir, at least when administered between transplantation and engraftment, is lost in the context of pre-emptive ganciclovir therapy or ganciclovir prophylaxis from time of engraftment.23 Early data from a phase I/II trial of iv penciclovir/oral famciclovir as CMV prophylaxis in BMT suggests some antiviral activity24 and further data are awaited with interest. However, should oral acyclovir prophylaxis for CMV be contemplated, the prodrug valaciclovir has been shown in a randomized trial to be more effective.25

Ganciclovir prophylaxis studies have utilized dosages of 5–6 mg/kg/day with a frequency of three times weekly to daily for 3–4 months, in CMV-seropositive patients. In the three early studies26,27,28 that evaluated ganciclovir prophylaxis, a historical control group was used for comparison of rates of CMV disease. The results were in each case similar, showing a decrease in the incidence of CMV infection but no improvement in overall survival. Subsequently, two double-blind placebo-controlled trials29,30 clearly demonstrated that prophylaxis is very effective at reducing the incidence and severity of CMV disease in these patients but confirmed that there was no improvement in overall survival. Moreover, prolonged use of ganciclovir caused neutropenia29,30 and hence bacterial infection;30 the risk of both these complications was higher than in the studies using pre-emptive therapy.31,32 The use of prophylactic ganciclovir also has the added disadvantage that many patients will be exposed to the toxic side effects of ganciclovir although they will never develop either CMV active infection or CMV disease.33 Thus, prophylaxis should perhaps be reserved for those at the highest risk of CMV disease, e.g. VUD BMT patients. Finally, patients given prophylactic or early ganciclovir therapy are not able fully to reconstitute the immune response to CMV and are thus at risk of late CMV disease after therapy has been discontinued.30,32

Unfortunately none of the trials described below was designed to take account of possible differences in response between sibling and VUD BMT patients. Such differences are important in view of the increased risk of chronic GVHD and infections, especially CMV, in the latter group.10

Recommendations.
CMV-seronegative blood or leucodepleted blood should be used for CMV-seronegative allogeneic BMT patients regardless of donor marrow CMV serostatus and also for autologous transplants (Category 1).

Prophylactic high-dose acyclovir improves survival following allogeneic BMT (Category 2), although this may be rendered unnecessary in the context of pre-emptive or prophylactic ganciclovir (Category 3).

Prophylactic ganciclovir reduces CMV infection and disease following allogeneic BMT in CMV-seropositive patients although overall survival is not improved (Category 1). Consider as an alternative to CMV antigen-guided therapy (see pre-emptive therapy below) for patients at especially high risk of CMV disease, e.g. CMV-seropositive patients receiving grafts from unrelated or HLA-mismatched donors.

Pre-emptive therapy

Pre-emptive therapy requires at least weekly screening for CMV infection for at least 100 days post-transplant. In the initial proof-of-concept studies in BMT, pre-emptive ganciclovir was initiated following detection of CMV using short-term cultures (detection of early antigen fluorescent focus; DEAFF) in blood, urine, pharynx washings or broncho-alveolar lavage, continuing for 3–4 months after transplantation. Two large studies using this principle31,32 showed a significant reduction in CMV morbidity and mortality, but the policy failed in some cases because CMV disease coincided with the first detection of CMV infection. Moreover, prolonged ganciclovir therapy caused neutropenia at a median of 35 days' treatment.32 One of the two studies32 demonstrated an improvement in survival, whereas there was no change in outcome in the other;31 the explanation probably lying in differences such as the total ganciclovir dose and the exact mix of patients in the studies.

In view of the continuing difficulty in controlling CMV disease, especially following VUD,3336 recent studies have aimed at identifying better the subgroup of patients at the highest risk of CMV disease and using short courses of ganciclovir treatment (CMV infection-guided treatment) as opposed to prolonged ganciclovir therapy, prophylactic or pre-emptive, in order to reduce toxicity; this has been made possible by the development of novel, more sensitive methods for CMV screening of blood, such as antigenaemia and polymerase chain reaction (PCR).3739

As regards PCR, Einsele et al.40 compared CMV infection-guided treatment in a prospective study based on PCR for CMV DNA or on short-term culture (DEAFF). As expected, DEAFF failed to detect CMV before disease in some patients, but the incidence of CMV disease and associated mortality was reduced when ganciclovir treatment was based on PCR positivity. In both groups, therapy was continued until clinical signs disappeared and PCR negativity was documented. This policy was found to be safe since no patient developed CMV disease after cessation of the drug and it also gave a reduction in the duration and side effects of ganciclovir therapy, especially in the PCR arm of the study.

Other investigators have chosen to use the CMV antigenaemia test as an early indication of CMV infection. Boeckh et al.41 conducted a double-blind study in which BMT patients were randomized at engraftment to receive placebo (CMV infection-guided treatment group) or ganciclovir (prophylaxis group). If CMV antigenaemia was detected, study drug (i.e. placebo or ganciclovir) was discontinued and open-label ganciclovir treatment given for 3 weeks or until 6 days after the CMV antigenaemia test became negative, whichever occurred later, and resumed only if antigenaemia recurred. The CMV active infection-guided treatment group experienced more CMV disease before day 100 post-BMT than the prophylaxis group. However, ganciclovir prophylaxis was associated with more early invasive fungal infections and more late-onset CMV disease (after cessation of ganciclovir at day 100 post-stem cell transplantation) resulting in similar survival rates.

Recommendations.
Pre-emptive therapy with ganciclovir, guided by rapid culture, reduces CMV active infection and disease after allogeneic BMT (Category 1). This has now been superseded by CMV active infection-guided treatment based on antigenaemia or PCR for CMV DNA and resulting in shorter courses of ganciclovir (Category 2). With both strategies overall survival may not be improved.

All patients at risk of CMV disease by virtue of CMV seropositivity in either donor or recipient should be monitored at least weekly with either the antigenaemia assay or PCR. Monitoring should be for at least 100 days. Longer monitoring is recommended in patients who have received an unrelated or HLA-mismatched transplant, or more for those to whom at least one course of pre-emptive therapy has been administered. Implementation of CMV active infection-guided treatment is highly dependent on the availability of local clinical virology laboratories providing the relevant assays.

Management of CMV disease: liver and renal transplantation

Recently published clinical trials suggest that symptomatic CMV infection (CMV disease) in liver and renal transplantation may be preventable. However, efforts taken to prevent CMV disease should be commensurate with the magnitude of the clinical problem. Suggested strategies for CMV prevention should be subjected to careful cost–benefit analysis and the results or interpretation of such analyses may differ between transplant units. For example, a strategy might be deemed appropriate for liver recipients in one transplant centre, but may be inappropriate for renal recipients at another centre.

Treatment

No controlled studies of treatment of CMV disease in liver or renal transplant recipients have been undertaken. Nevertheless, it is common practice to treat established disease with ganciclovir, with or without immunoglobulin

Recommendations.
CMV disease should be treated with ganciclovir with (for pneumonitis) or without normal immunoglobulin (Category 3).

Prophylaxis

Interferons, human immunoglobulin preparations, acyclovir and ganciclovir have been subjected to randomized, controlled (not necessarily with placebo) studies of prophylaxis.

Early studies with interferons (in renal transplantation) demonstrated mixed results,4244 depending on the type and dosage of interferon used. In general, CMV active infection could be delayed and decreased by using interferons, but this was not reflected by a decrease in the incidence of CMV disease.

Studies with human immunoglobulin preparations have also shown mixed results,4552 primarily because of the heterogeneity of these studies. Trials have compared iv immunoglobulin with no prophylaxis,45,48,50,51 with iv albumin as placebo46,47 or with ganciclovir.52 Protocols for administration of immunoglobulin vary between these studies, as does the benefit observed for the treated groups. Thus, some clinical studies have demonstrated superiority to no prophylaxis45,47,48,50 but others have shown no benefit compared with no prophylaxis, placebo or ganciclovir.46,51,52 The advantage of expensive CMV-specific hyperimmune globulin over normal immunoglobulin appears marginal.49 It must be remembered that immunoglobulins are derived from pooled human donations, with associated risks.

Randomized studies evaluating acyclovir prophylaxis5357 suggest that, compared with no prophylaxis, high-dose treatment may reduce the incidence of CMV disease in liver and renal transplant recipients.53,55 A single study also suggested superiority over ganciclovir in recipients with primary CMV exposure.56 However, the incidence of disease observed for recipients with primary CMV exposure remains high despite high-dose acyclovir prophylaxis, and some studies suggest absence of benefit for this at-risk group.57 Proponents of high-dose acyclovir prophylaxis need to re-evaluate their policy in the context of emerging data that suggest superiority of protocols comprising or at least including ganciclovir. One such study in paediatric liver transplantation suggested no benefit of acyclovir added to ganciclovir, compared with ganciclovir prophylaxis alone.54

By contrast, recent data from a placebo-controlled valaciclovir prophylaxis study in renal transplantation suggest significant benefit in reduction of CMV disease in recipients with primary CMV exposure.58

Regarding ganciclovir prophylaxis,5968 trials have compared iv ganciclovir with high-dose oral acyclovir62 or with no prophylaxis or placebo.59,66,67 The most outstanding results were achieved in the former study,62 in which ganciclovir or acyclovir was given for 100 days following liver transplantation. Of 124 patients who received ganciclovir, only one patient developed CMV disease. The incidence of CMV disease observed for the acyclovir group was 10%. This landmark study convincingly demonstrates that symptomatic CMV infection is a preventable disease within this patient group, and that ganciclovir is superior to high-dose acyclovir. However, the study may be most remarkable for the absence of treatment-related morbidity despite the need for prolonged iv access in the ganciclovir treatment group, and is also notable for the observed patient compliance with protocol. Irrespective of apparent safety and patient compliance, and despite remarkable efficacy, few transplant units would adopt this protocol. Most would find the costs associated with the administration of this protocol prohibitive, and compliance outside of the context of a carefully conducted clinical trial might be hard to achieve. Importantly, these findings have subsequently been reproduced using oral ganciclovir, also in liver transplant recipients, in a placebo-controlled study.64 Finally, oral ganciclovir has been shown to be more effective than high-dose oral acyclovir prophylaxis against CMV active infection and disease in renal transplant recipients.65

Thus, prolonged administration of ganciclovir can reduce the incidence of CMV disease, but costs associated with the drug and with its administration may militate against the implementation of these protocols. Alternative strategies include short-term iv administration of ganciclovir, either during the first 2 weeks post-transplant with subsequent prolonged administration of high-dose oral acyclovir60,61,63,68 or during post-transplant weeks 3 and 4 without subsequent acyclovir.59,66,67

These studies suggest that (i) short-term iv ganciclovir may achieve a small reduction in the incidence of CMV infection,59 even in recipients with primary CMV exposure,67 and may diminish the severity and delay the onset of symptoms,66 and (ii) sequential iv ganciclovir then oral acyclovir is superior to placebo68 or to oral acyclovir alone.69,70,72 Protocols including ganciclovir are therefore clearly superior to those reliant on high-dose oral acyclovir alone, and maximal efficacy is observed when the period of ganciclovir administration is prolonged (of at least 3 months' duration).

Recommendation.
Ganciclovir (iv or oral) or acyclovir, given for at least 3 months following transplantation, reduces the incidence of symptomatic CMV infection (CMV disease), and its use should be considered for recipients other than seronegative recipients of organs from seronegative donors (Category 1). Ganciclovir provides greater protection than acyclovir (Category 2).

Pre-emptive therapy

Pre-emptive therapy strategies based on the need for anti-lymphocyte preparations following transplantation, have utilized both human immunoglobulin preparations (either CMV-specific or unselected) and ganciclovir.69,7173 In general, these studies have shown a reduction in the incidence and severity of CMV disease. The only randomized study of pre-emptive treatment based on positive viral cultures,70 showed that a short course of iv ganciclovir in this setting was significantly better at preventing CMV disease than was oral acyclovir administered for 6 months from the time of transplantation. Pre-emptive ganciclovir has not been compared with ganciclovir prophylaxis.

Recommendation.
Pre-emptive administration of ganciclovir can reduce the incidence of symptomatic CMV infection (Category 1).

Management of CMV disease: thoracic transplants

CMV infection remains an important cause of morbidity and mortality in thoracic transplant recipients despite the advent of effective antiviral therapy. Although the spectrum of disease in heart and lung transplant recipients is generally similar to that in other solid organ transplant recipients, CMV disease is more frequent, and often more severe, in lung transplant recipients.

Treatment

Following early reports of its effectiveness on CMV disease in immunocompromised patients, ganciclovir has become established as the treatment of choice for symptomatic CMV infection and CMV disease in thoracic transplant recipients, although no placebo-controlled trials have been published in this patient group.

Recommendation.
CMV disease in thoracic transplant recipients should be treated with ganciclovir with (for pneumonitis) or without normal immunoglobulin (Category 3).

Prophylaxis

Most of the studies on prevention have been in heart transplant recipients, with fewer in lung transplant recipients. However, although there is now an extensive literature, which has been comprehensively reviewed recently,7476 there are only two placebo-controlled trials, both conducted in heart transplant recipients.77,78

These studies of ganciclovir prophylaxis in heart transplantation both found reductions in the incidence of CMV disease, but reached different conclusions about the effect on primary and reactivated active infection. Merigan et al. 77 reported a multi-centre prospective study of 4 weeks high-dose (14 days 5 mg/kg bd followed by 6 mg/kg/day 5 days/week) ganciclovir in which there was a significant reduction in CMV disease in CMV-seropositive transplant recipients. By contrast, Macdonald et al.78 reported a study using ganciclovir 5 mg/kg three times weekly, for 6 weeks in which there was a significant reduction in CMV disease in seronegative recipients of organs from seropositive donors, but no reduction in CMV disease in CMV-seropositive recipients. The different findings between the two studies may be due to differences in dose and duration of ganciclovir prophylaxis; other differences in study design, particularly in immunosuppressive regimes, may also be relevant. A randomized study of high-dose ganciclovir for 14 days against CMV immunoglobulin in CMV-seropositive heart transplant recipients treated with OKT3 as anti-rejection therapy demonstrated a significant reduction of CMV disease in the ganciclovir arm.79

The only study in lung transplant recipients that has so far been published in full80 compared ganciclovir prophylaxis with acyclovir prophylaxis for 90 days post-transplant. Although cases of CMV disease and obliterative bronchiolitis were reduced in the ganciclovir group during early follow-up, this difference was lost by 2 years of follow-up, suggesting that ganciclovir prophylaxis may delay onset of disease, as observed in the BMT population.

Recommendation.
Ganciclovir prophylaxis should be used for heart and lung transplant recipients who are CMV seropositive, or who are recipients of seropositive organs (Category 1).

Pre-emptive therapy

More recently there has been increasing interest in developing pre-emptive approaches, based on the application of newer diagnostic methods, particularly the CMV antigenaemia assay and PCR. At present however, there are no placebo-controlled studies of pre-emptive therapy; indeed given that prophylaxis is now established practice it seems unlikely that such studies will be possible. The only study of pre-emptive therapy that has been published in full so far81 was not placebo controlled; instead a historical control group was used to assess the antigenaemia assay as the basis of pre-emptive therapy in heart and lung transplant recipients.

The results suggested that pre-emptive therapy was associated with a significant reduction in the incidence of CMV disease, combined with a reduction in prophylactic usage of ganciclovir, although no decrease in mortality was observed. However, as the authors explained, further work is necessary to confirm this finding and refine the approach. Such studies are likely to include evaluations of the role of quantitative CMV PCR, which has greater potential clinical value than the CMV antigenaemia assay.82

Recommendations.
. Ganciclovir pre-emptive therapy based on the CMV viraemia assay should be considered where rapid techniques are locally available (Category 2).

Future strategies for control of CMV disease in transplantation

Although widespread use of ganciclovir has markedly reduced the extent of CMV disease and mortality after allogeneic BMT, problems remain, especially in those patients receiving T-cell depleted8385 or VUD transplants.86,87 This is due, at least in part, to the increased susceptibility of these patients to ganciclovir-induced neutropenia because of inherent problems with graft failure. Ganciclovir-related neutropenia is a much greater problem after BMT than after solid organ transplant (frequency 41% versus 10%, respectively), and risk factors have been defined recently as early liver dysfunction, elevated serum creatine and low marrow cellularity.88 Foscarnet should therefore be considered as an alternative to ganciclovir for CMV prophylaxis in BMT patients with such risk factors;89 preliminary results from a randomized multi-centre study comparing foscarnet and ganciclovir for early treatment of CMV infection in BMT patients demonstrate equal efficacy of both drugs.90 Finally, combined foscarnet and ganciclovir therapy91 as opposed to ganciclovir alone may be more effective in patients with high levels of cytomegaloviraemia, e.g. VUD BMT patients.

With regard to thoracic transplantation, CMV disease remains a major problem, especially in lung transplant recipients. Fewer controlled studies have been published for this patient group, and we encourage more work in this area. By contrast, many feel that CMV disease in liver and renal recipients is now a preventable disease. However, the cost and logistic problems associated with administration of prolonged ganciclovir prophylaxis may be prohibitive. Implementation of these protocols should consider the potential problems of cost (for both iv and oral administration) and patient compliance (particularly with prolonged iv administration). For large units, the prolonged outpatient administration of iv prophylaxis has enormous resource implications, which may be prohibitive. The safety of prolonged iv access for immunosuppressed patients should be confirmed.

Pre-emptive strategies for solid organ recipients are attractive, but the results of published successes may be difficult to extrapolate to other units. Immunosuppressive protocols and laboratory diagnostic tests (and skills) vary from unit to unit, as will the predictive power (for the subsequent development of disease) of positive laboratory results. Implementation of pre-emptive strategies requires reliable protocols with frequent patient review, rapid laboratory turn-around and immediate response to positive results. Units may struggle with these logistic problems. Units should examine their own experience, and attempt to identify patients at high risk for the subsequent development of serious infection. Such patients might receive prophylaxis or pre-emptive therapy. When symptomatic infection presents despite such a strategy, a minority of patients (in the liver and renal setting) experience disease, and most respond briskly to a reduction in immunosuppression and therapy with iv ganciclovir with or without human immunoglobulin.

There is a role for health economic approaches to identify the most cost-beneficial anti-CMV strategy in different patient groups.

The final eradication of CMV disease in high-risk transplant recipients will depend on new formulations of existing drugs, such as valaciclovir or valganciclovir, or different drugs, such as the phosphonomethylether compounds,92 e.g. cidofovir (HPMPC), GW1263 or antisense compounds such as GEM 132. Encouraging data have been presented from early studies on immunotherapy, in the form of adoptive transfer of CMV-specific CD8+ cytotoxic T-cell clones.93,94 Another possibility is the boosting of donor and/or recipient immunity using inactivated CMV subunit vaccines, e.g. that devised by Gonczol et al.95

Herpes simplex virus

Management of herpes simplex disease: BMT patients

Symptomatic HSV infections occur in the first weeks after BMT (Table IGo) during the period of leucopenia, when mucosal damage is maximal as a consequence of the radiotherapy and chemotherapy used for conditioning.96 Oral ulceration, often painful and necrotic and lasting for several weeks, is the most common clinical manifestation and results from reactivation of long-standing latent infection in the trigeminal ganglion. Peri-oral lesions often spread into the mouth and may give rise to oesophagitis and pneumonia by direct spread from the oral cavity: HSV pneumonitis occurred in 2% of BMT recipients before effective antiviral therapy was introduced.97 Only rarely does infection become disseminated to produce HSV hepatitis. Persons previously infected with HSV in the sacral ganglia are also at risk of reactivation to produce genital ulceration. Mucocutaneous recurrences of HSV occurring later after BMT, even though there may still be some cellular immunodeficiency, are usually less severe.

Treatment
Both oral98 and iv99 acyclovir is very effective in reducing the duration of viral shedding and time to healing of mucocutaneous lesions in BMT recipients. There are no placebo-controlled trials of iv acyclovir in HSV infections of visceral organs but there is a good deal of anecdotal evidence of benefit. Oral acyclovir is likely to be useful in patients with oral, oesophageal or genital lesions but for severe localized or disseminated disease in BMT patients, iv acyclovir is more suitable.

Intravenous penciclovir has been tested in an open trial and seems effective for mucocutaneous HSV in immunosuppressed patients, although only one of the patients was a BMT patient.100

Acyclovir-resistant HSV has been isolated from BMT patients.101 Most such isolates have altered or deficient thymidine kinase enzymes and foscarnet is preferable to vidarabine for treatment of such acyclovir-resistant strains in patients with AIDS102,103 but no randomized studies have been performed in transplant recipients. Both topical104 and iv105 cidofovir have been shown anecdotally to be effective in the treatment of mucocutaneous HSV in BMT patients, but the only controlled trial so far demonstrated efficacy of topical cidofovir in patients with AIDS.106

Recommendations.
. Intravenous acyclovir (250 mg/m2 or 5 mg/kg q 8h) should be used for treatment of severe localized HSV in allogeneic BMT patients (Category 2). For less severe mucocutaneous disease, oral acyclovir (400 mg five times daily) is recommended (Category 2). Intravenous acyclovir is recommended for visceral or disseminated HSV infection (Category 3).

Prophylaxis
Pre-transplant screening of recipients' blood by ELISA for IgG antibody to HSV should be undertaken, since seronegative patients are not at risk of HSV infection and do not need prophylaxis, whereas seropositive individuals have a 70–80% risk of asymptomatic virus reactivation and disease.96 Several studies have demonstrated that iv acyclovir (250 mg/m2 or 5 mg/kg),107110 given one to three times daily for about 1 month post-transplantation, completely prevents symptomatic HSV reactivation during the period of administration to seropositive BMT recipients. Oral acyclovir (200 mg or 400 mg four or five times daily)111,112 is almost as effective, providing that patients are compliant and that there is no severe gastrointestinal damage, limiting absorption of the drug. Data from Seattle showed that acyclovir prophylaxis reduced and delayed the extent of HSV infection to less than 25% of that of seropositive patients in the first 100 days.96 Once prophylaxis ends, HSV reactivation frequently recurs promptly, although not necessarily associated with symptoms.

Intravenous ganciclovir, while being given as prophylaxis against CMV in BMT recipients, was effective at suppressing oral HSV excretion.29,30 Acyclovir prophylaxis against CMV disease has also been effective at suppressing HSV. Giving iv acyclovir (500 mg/m2 tds for those with normal renal function) from days –5 to +30 followed by high-dose oral acyclovir (800 mg qds) until 6 months after BMT significantly reduced the probability of HSV disease during that period.20

Recommendations.
Acyclovir prophylaxis (iv or oral) is recommended from the start of conditioning for a period of 4 weeks for HSV-seropositive recipients who are not receiving prophylactic ganciclovir (Category 1). Patients who are receiving ganciclovir prophylaxis against CMV disease are also protected against HSV reactivation (Category 1). Acyclovir should be stopped as ganciclovir commences.

Management of herpes simplex disease: solid organ transplant patients including thoracic transplantation

The timing of HSV reactivation after solid organ transplantation is similar to that after BMT but HSV disease is generally less problematic. Although the rate of reactivation may approach 50% within the first month posttransplant, the morbidity associated with such infections is small and treatment of disease is generally effective.

Treatment

Intravenous acyclovir has been used very effectively for the treatment of mucocutaneous HSV infections after renal, heart and liver transplantation.113,114 There are no specific trials of oral acyclovir, famciclovir or valaciclovir therapy for mucocutaneous HSV in solid organ transplant recipients but anecdotal evidence of efficacy exists for all three drugs. In addition, the benefits of topical acyclovir versus placebo in renal transplant patients suggests that oral therapy will also be efficacious.

Recommendations.
For mucocutaneous HSV disease in renal transplant patients oral acyclovir, famciclovir or valaciclovir is recommended (Category 3). For more severe disease in renal transplants and for all forms of disease in other solid organ transplant recipients iv acyclovir is recommended (Category 3)

Prophylaxis

Oral acyclovir prophylaxis is of proven efficacy in renal transplantation.115118 However, prophylaxis against HSV may also be provided for high-risk solid organ transplant patients as part of the ganciclovir regimen used for CMV prophylaxis. Oral acyclovir (800 mg qds for those with normal renal function), given for 12 weeks, reduced the development of mucocutaneous HSV disease in seropositive recipients from 36% to 7% (P = 0.012).55 Similarly, in liver transplant both iv ganciclovir and high-dose acyclovir provided protection against HSV excretion and completely prevented symptomatic mucocutaneous infections62 and, in another study of liver transplant recipients oral ganciclovir reduced symptomatic HSV infections from 23.5% to 3.5% (although the patients were not stratified by HSV seropositivity).64

Oral valaciclovir, 2 g qds, administered for 90 days post-renal transplantation (to CMV-seronegative recipients of a CMV-seropositive allograft) in order to reduce the incidence of CMV disease was highly effective at diminishing HSV disease (by 67%).58

Recommendations.
If acyclovir or ganciclovir are used for CMV prophylaxis this will obviate the need for additional prophylaxis directed at HSV (Category 3). Oral acyclovir is recommended for all HSV-seropositive patients not receiving CMV prophylaxis (Category 1).

Varicella-zoster virus

Management of VZV disease: BMT patients

Primary infection with VZV causes chickenpox whereas reactivation of latent virus causes shingles (herpes zoster). Chickenpox has a high mortality in immunocompromised patients but is fortunately rare in BMT recipients. Before the use of passive vaccination and acyclovir prophylaxis varicella occurred in 25% of children during the first 6 months after BMT.119

Herpes zoster, on the other hand, is frequently seen as a relatively late complication after BMT, occurring within the first 2–10 months (mean 5 months) after BMT (Table IGo). Before the use of prophylaxis, about one-third of both autologous and allogeneic adult BMT patients experienced either localized or disseminated herpes zoster within the first year.120,121 Skin and visceral dissemination (which causes pneumonitis, hepatitis and, rarely, encephalitis and which is especially high after allogeneic BMT) occur in 25% and 15%, respectively, of cases of herpes zoster in such patients: the mortality of this form of disease approaches 30%. Cutaneous dissemination of herpes zoster usually precedes visceral dissemination. Contralateral hemiparesis is also a recognized complication of ophthalmic herpes zoster.122

Subclinical viraemia and clinical episodes of herpes zoster provide in vivo re-exposure to VZV antigens and help the recovery of virus-specific cytotoxic T-cell function.123 A recent study of varicella vaccine has shown that BMT recipients immunized with an inactivated varicella vaccine showed early reconstitution of immunity.124

Treatment
Chickenpox in a BMT patient should be treated as a matter of utmost urgency. There are no studies of oral antivirals in this context but iv acyclovir at a dose of 10 mg/kg tds for at least 7 days has been shown to be highly effective in children with malignancy.125,126 Treatment of herpes zoster after BMT with acyclovir (500 mg/m2 or 10 mg/kg tds for at least 7 days) has been shown to be effective at preventing the dissemination of the disease, both initial cutaneous dissemination and also visceral dissemination in those who already have cutaneous dissemination.127,128 There was no significant effect on local healing or pain, perhaps because treatment was started after several days of rash in some patients.

In the rare case of herpes zoster where the virus is resistant to acyclovir, foscarnet has been shown to be effective.129

There are no randomized trials addressing the issue, but it is likely that valaciclovir or famciclovir would have antiviral effects in this patient group.

Recommendations.
Intravenous acyclovir is the treatment of choice for VZV infection, occurring within the 9–12 months following BMT and later if the patient is still receiving immunosuppressive therapy for GVHD (Category 1). Later VZV infections can be treated with oral acyclovir (Category 3).

Prophylaxis
Any BMT patient who has been in contact with either chickenpox or herpes zoster should be tested for antibody to VZV at that time regardless of a previous history of chickenpox or of pre-existing antibody. Those few individuals found to be seronegative should be given human varicella-zoster immunoglobulin (VZIG) as prophylaxis within 7 days of the first contact.130

Prolonged prophylaxis with acyclovir has been shown to prevent herpes zoster in two placebo-controlled trials: iv acyclovir (250 mg/m2 tds, starting 5 days before the transplant) for 5 weeks and followed by long-term (6 months) oral acyclovir (400 mg tds) prevented herpes zoster in allogeneic BMT patients,108 and similar results were obtained with higher doses of acyclovir, given primarily to prevent CMV disease.19 Herpes zoster was prevented during the period of prophylaxis but once the acyclovir was stopped, herpes zoster frequently occurred. A study by Selby et al.118 showed no overall reduction in herpes zoster in allogeneic BMT recipients given acyclovir for 6 months, although reactivation was suppressed during the period of prophylaxis itself. Furthermore, given the ease with which reactivation of VZV can generally be treated, the use of long-term prophylaxis specifically against VZV seems unwarranted.

Three doses of varicella vaccine 1, 2 and 3 months after BMT dramatically reduced disease severity in those patients who developed herpes zoster and this provides the first evidence of the benefits of active immunization to boost the VZV immunity post-transplantation.124

Recommendations.
No specific prophylactic antiviral is recommended for VZV infection in BMT (Category 3).

Management of VZV disease: solid organ transplant patients including thoracic transplantation

Chickenpox in young children undergoing solid organ transplantation is often severe with a high risk of dissemination.131,132 Reactivation of VZV is less common following solid organ transplantation.

Treatment

The high efficacy of parenteral acyclovir (10 mg/kg) has been shown in immunosuppressed children with chickenpox.126

There are no placebo-controlled clinical trials but anecdotal reports suggest that oral acyclovir, famciclovir and valaciclovir are effective therapy for herpes zoster in many solid organ transplant recipients.

Recommendations.
Intravenous acyclovir is recommended for varicella in solid organ transplant recipients of all ages (Category 2). For herpes zoster either iv or oral acyclovir, iv penciclovir, oral famciclovir or oral valaciclovir may be used (Category 3).

Prophylaxis

In liver transplant recipients given either iv ganciclovir or iv followed by high-dose oral acyclovir until day 100, there were no cases of VZV infection.62 High-dose oral acyclovir (800 mg four times daily) given for 24 weeks after liver transplantation, as one arm of a trial comparing this with ganciclovir pre-emptive therapy for CMV disease, also prevented herpes zoster in the small number of patients studied, although there was only one case in the group given pre-emptive ganciclovir.70

Another strategy is to administer VZV vaccine to VZV seronegative candidates for transplantation. Such a policy has been shown to reduce the risk of VZV infection following solid organ transplantation in children.133,134

Recommendations.
No antiviral prophylaxis specifically directed at VZV infection is recommended (Category 3). Vaccination of seronegative children before transplant with live attenuated vaccine can reduce the risk of post-transplant primary VZV infection (Category 3).

Epstein–Barr virus

EBV infects B-cells where it persists for life in the latent state. Such infected B-cells have the potential to proliferate indefinitely but this tendency is normally controlled by virus-specific cytotoxic T-lymphocytes. In severely immunosuppressed patients, however, the EBV-infected B-cells proliferate,135 causing a continuum of PTLDs from polyclonal (plasmacytic hyperplasia) to monoclonal (polymorphic B-cell hyperplasia and polymorphic B-cell lymphomas) to frankly malignant (immunoblastic lymphoma).136

PTLDs in allogeneic BMT recipients are usually of donor origin developing within 3 to 6 months after transplant, and are already disseminated at presentation following an aggressive course which is not susceptible to conventional therapy and has a high fatality rate.137139 Overall the incidence of PTLD is very low except in those patients who received T-cell-depleted stem cells from unrelated or mismatched donors in whom the incidence is between 16–24%;137,138 the method of depletion is important in that the risk is low if reagents that also remove B-cells are used140,141 whereas the use of certain T-cell-specific monoclonal antibodies carries a very high risk.138 In the context of T-cell depletion it is interesting to note that PTLDs develop at about 3–6 months after transplant during which interval cytotoxic T-cells are at undetectable levels in the peripheral blood of BMT recipients.142

Papadopoulos et al.143 reasoned that if EBV-specific T-cells were given to BMT patients with PTLD then the lesions would regress. Unseparated leucocytes from EBV-seropositive donors were infused into five patients and in each case the PTLD regressed completely but this success was marred because there were fatal pulmonary complications in two patients and the survivors suffered severe GVHD. Thus, there is a need for EBV-specific leucocyte populations devoid of alloreactive T-cells. Rooney and co-workers144 have pioneered the use of EBV-specific donor-derived T-cell lines for treatment of PTLD and so far this approach looks promising.

Following solid organ transplantation, primary exposure to EBV (from donor) is also associated with an increased risk for the development of PTLD, so PTLD is more commonly observed in paediatric transplantation. Risk also appears to be related to the total dose and duration of immunosuppression. The use of anti-lymphocyte preparations such as anti-lymphocyte globulin and OKT3 is strongly associated with the development of lymphoma. Therefore, risk for the development of PTLD could be diminished by the use of EBV-seronegative organ donors (not a realistic option in the context of other logistic constraints in liver and renal transplantation), and by the more cautious use of immunosuppression in patients with primary EBV exposure. The incidence of PTLD is low, and studies that specifically examine strategies for the prevention of EBV-related post-transplant syndromes, including PTLD, have not been undertaken.

Most clinicians agree that immunosuppression should be reduced or completely withdrawn.145 Complete withdrawal of immunosuppression may be more easily achieved for the renal, than for the liver recipient. Withdrawal of immunosuppression may be complicated by graft failure. Renal graft failure re-establishes a need for dialysis. Liver graft failure is more likely to result in recipient death. Response of PTLD to reduction of immunosuppression suggests recovery of EBV-specific T-cell control.

Antivirals have also been recommended for treatment of EBV-associated disease following organ transplantation. Immunosuppression increases viral shedding from the oropharynx, an effect inhibited by treatment with acyclovir, ganciclovir and interferon. The transforming activity of patient blood, however, remains unaffected by antiviral therapy, an observation which suggests no concomitant reduction in the levels of EBV infection of circulating B-cells. B-cells contain EBV in a latent non-lytic form, and in this setting EBV should not be susceptible to currently available antiviral therapy. Linear (non-episomal) forms of EBV have, however, been detected in EBV-associated lymphomas, and antivirals have been recommended for treatment. A role for antivirals in treatment and prophylaxis remains unproven, and Shapiro reports six patients who developed PTLD while receiving prophylactic acyclovir.146

It is possible that EBV viraemia post-transplant may predict PTLD, and this may allow studies of antiviral intervention.147

Recommendations.

EBV-associated PTLD should be managed by a reduction in immunosuppressive therapy, if possible (Category 3). There is no evidence that antiviral therapy is beneficial in the treatment of PTLD (Category 3).

Other herpes viruses

Finally, the role of the most newly discovered human herpes viruses, HHV-6, HHV-7 and HHV-8, also known as Kaposi's sarcoma-associated herpes virus148150 in the causation of disease in transplant recipients, has yet to be fully evaluated. Evidence is accumulating that HHV-6 may be associated with pneumonitis, encephalitis and self-limiting symptoms following bone marrow and solid organ transplantation.151155 In such cases ganciclovir or foscarnet may be considered for treatment on the basis of the in vitro sensitivity of HHV-6,156 although no randomized trials have been reported. HHV-6 and HHV-7 infection may also impact on the severity of CMV disease.157,158 Transplantation-associated Kaposi's sarcoma (KS) occurs following BMT159,160 and in up to 5% of renal transplant recipients.161166 HHV-8 reactivation has also been demonstrated serologically in such patients.167 The natural history of HHV-8 infection in transplantation requires greater clarification before antiviral strategies can be considered. Preliminary data indicate that reduction of immunosuppression may lead to regression of KS lesions,168,169 as noted for EBV-related PTLD.

Conclusions

Despite significant recent advances in therapy, herpes virus infections continue to pose serious problems for BMT recipients. Suitable antiviral drugs are available for the prophylaxis and/or treatment of HSV, VZV and CMV infections but, at least in BMT, these are not always effective in vivo because of the profound immunosuppression experienced and to a lesser extent because of the emergence of viral drug resistance after prolonged therapy. Treatment of CMV infection, in particular, remains difficult but proper assessment of the risk of CMV disease for individual patients provides a basis on which to undertake prophylactic strategies based on firm data. Finally, turning to the other herpes virus infections, immunotherapy shows promise for control of PTLD and much is still to be learned concerning the clinical significance of HHV-6, -7 and -8 infections.

Notes

*Corresponding author. Deenan Pillay, Public Health Laboratory Service (PHLS), Antiviral Susceptibility Reference Unit, Division of Immunity and Infection, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Tel: +44-121-414-6957; Fax: +44-121-414-3096; E-mail: D.Pillay{at}bham.ac.uk

Working Party Members. Deenan Pillay (Chair), PHLS Antiviral Susceptibility Reference Unit, Birmingham; David Mutimer, The Queen Elizabeth Hospital, Birmingham; Saket Singhal (co-opted), The Queen Elizabeth Hospital, Birmingham; Andrew Turner, Newcastle Public Health Laboratory, Newcastle-upon-Tyne; Katherine Ward, Royal Free and University College London Medical School, London; and Martin Wood, Birmingham Heartlands Hospital, Birmingham, UK.

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