infections in patients with hematological malignancies an - Nature

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Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT P Ljungman, R de la Camara, C Cordonnier, H Einsele, D Engelhard, P Reusser, J Styczynski and K Ward, for the European Conference on Infections in Leukemia1 Department of Hematology, Karolinska University Hospital/Huddinge, Stockholm, Sweden

These recommendations were prepared by the European Conference on Infections in Leukaemia following a predefined methodology. Literature searches were made to identify studies pertinent to management of CMV, HHV-6, -7 and -8 infections. For CMV, 76 studies were reviewed: 72 published and 4 presented as abstracts. Twenty-nine of these studies were prospective randomized trials. For the other herpesviruses, HHV-6, -7 and -8, no randomized controlled trial has been performed, although data from some studies with other primary endpoints have been used to assess the management of HHV-6 infection. Works presented only as abstracts were used to a very limited extent. The quality of evidence and level of recommendation were graded according to the Center for Disease Control (CDC) criteria. Bone Marrow Transplantation (2008) 42, 227–240; doi:10.1038/bmt.2008.162; published online 30 June 2008 Keywords: CMV; HHV-6; HHV-7; HHV-8; SCT; antiviral drugs

tional or using historical controls, so that drawing firm conclusions was challenging. For CMV, 76 studies were reviewed: 72 published and 4 presented as abstracts. Twentynine of these studies were prospective randomized trials. Larger, properly controlled studies carried more weight in the deliberations, although no formal meta-analyses were performed. For the other herpesviruses, HHV-6, -7 and -8, no randomized controlled trial has been performed, although data from some studies with other primary endpoints have been used to assess the management of HHV-6 infection. In addition, other sources were also drawn on while considering the recommendations, for example, diagnostic procedures. Preliminary sets of recommendations were prepared by a writing committee of eight members. The quality of evidence and level of recommendation were graded according to the Center for Disease Control (CDC) criteria (Table 1). The recommendations were then presented at a consensus conference with 53 experts representing 25 countries (24 European countries and Australia). If necessary, voting was performed on the proposals. The recommendations were then revised according to the discussions and again presented at the conference for final acceptance.

Introduction The recommendations of the European Conference on Infections in Leukaemia are based on a review of the English-language literature following a predefined methodology.1 Briefly, literature searches were made to identify studies pertinent to management of CMV, HHV-6, -7 and -8 infections. Works presented only as abstracts were used to a very limited extent. Unfortunately, many of the published studies were not properly controlled, being either observa-

Correspondence: Dr P Ljungman, Department of Hematology, Karolinska University Hospital/Huddinge, Stockholm S-14186, Sweden. E-mail: [email protected] 1 A Joint Project of the European Organization for Research and Treatment of Cancer Infectious Diseases Group, European Bone Marrow Transplantation Infectious Diseases Working Party, European Leukemia Net Supportive Care Working Group and International Immunocompromised Host Society. Received 28 December 2007; revised 14 April 2008; accepted 23 April 2008; published online 30 June 2008

CMV CMV can cause multi-organ disease both early and late after SCT2–4 and remains one of the most important complications after allogeneic transplant. Seropositivity for CMV remains a risk factor for TRM in T-cell-depleted and unrelated transplant patients despite major advances in early diagnosis and management.5–8 Its relevance in other patient populations is less well known. Historically, the incidence of CMV disease in non-transplant cancer patients was very low, as shown in a large autopsy study done at the MD Anderson Cancer Center reporting a frequency of CMV pneumonitis of 0.4%.9 However, a recent publication from the same center found that CMV disease was diagnosed in 2.9% of 2136 patients.10 A striking frequency was seen in patients with CLL (9%), especially those autopsied most recently (16%). Furthermore, in nontransplant patients, those with lymphoid hematological malignancies (CLL, lymphoma and ALL) and myeloma

Recommendations for herpesvirus management P Ljungman et al

228 Table 1 Evidence-based system used to determine strength of recommendations Strength of recommendations149 A Strong evidence for efficacy and substantial clinical benefit B Strong or moderate evidence for efficacy but only limited clinical benefit C Insufficient evidence for efficacy; or efficacy does not outweigh possible adverse consequences (for example, drug toxicity or interactions) or cost of chemoprophylaxis or alternative approaches D Moderate evidence against efficacy or of adverse outcome E Strong evidence against efficacy or of adverse outcome

Strongly recommended Generally recommended Optional

Generally not recommended Never recommended

Quality of evidence supporting recommendation149 I Evidence from at least one well-executed randomized trial II Evidence from at least one well-designed clinical trial without randomization; cohort or casecontrolled analytic studies (preferably from more than one center; multiple time-series studies; or dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities based on clinical experience, descriptive studies or reports from expert committees

have a higher frequency of positive CMV antigenemia (13.6%) than those with myeloid hematological malignancies (3.9%; Po0.001).11 Thus, CMV is an increasingly important pathogen in some populations of non-transplant patients, particularly in seropositive patients having received potent immunosuppressive therapies, such as fludarabine or alemtuzumab.

Definitions The following definitions are used in the paper: Primary CMV infection: CMV detected in a previously CMV-seronegative patient. Recurrent CMV infection: CMV detected in a CMVseropositive patient. Symptomatic CMV infection: patients developing symptoms (fever with or without BM suppression) and carrying detectable CMV virions, Ags or nucleic acid but with no sign of CMV endorgan disease. CMV disease: CMV detected by a test with appropriate sensitivity and specificity in an organ in a biopsy or in samples from other invasive procedures (broncho-alveolar lavage (BAL), CSF) together with symptoms and/or signs from the affected organ. For CMV retinitis, typical findings by ophthalmologic examination are sufficient. More detailed definitions of CMV disease have been published elsewhere.12 Prophylaxis: antiviral agents administered to a patient to prevent either primary CMV or recurrent infection. Pre-emptive therapy: antiviral agents administered for an asymptomatic CMV infection detected by a screening assay. Bone Marrow Transplantation

Techniques for the diagnosis of CMV infection Several techniques exist allowing rapid diagnosis of CMV with high sensitivity. Serologic determination of either IgG or IgM has no place in the diagnosis of CMV infection or disease but is useful to determine risk of subsequent CMV infection. It has been shown in allo-SCT recipients that detection of CMV in blood has a strong prognostic impact on subsequent development of CMV disease.13 Currently, the most used tests for diagnosis of CMV infection are detection of Ag (pp65; antigenemia assay), DNA or mRNA. All these techniques have been prospectively evaluated and perform similarly. However, as these tests vary from laboratory to laboratory, each hematology center should establish a good collaboration with their diagnostic laboratory to determine how test results should be interpreted in clinical practice. As regards the detection of CMV DNA by PCR, the specimen varies, but nowadays, either whole blood or plasma is most commonly used. Moreover, the quantification of viral load by quantitative PCR can give important prognostic information and this technique is now widely available.14–18 Other techniques for detecting DNA, such as the hybrid capture assay, have also been evaluated.19 Detection of mRNA by nucleic acid sequence-based amplification is also a sensitive and rapid technique and in randomized trials, has been shown to be as effective as pp65 antigenemia or detection of DNA by PCR.20,21 The CMV antigenemia assay or techniques detecting CMV DNA or RNA are recommended for diagnosis of CMV infection in peripheral blood (AI). Use of a quantitative assay gives additional information valuable for patient management (BII).

Diagnosis of CMV disease The diagnosis of CMV disease must be based on symptoms consistent with CMV disease together with detection of CMV in the appropriate specimen from the concerned tissue.12 There are several techniques that can be used for detection of CMV in tissue specimens but PCR is not usually recommended for this purpose as the positive predictive value is too low, especially when CMV is present in the blood. Quantitative PCR on BAL fluid has been used to improve the predictive value for diagnosis of CMV pneumonia, but more work is needed.22 However, symptoms of organ involvement together with CMV detection only in blood, regardless of the method, are not enough for the diagnosis of CMV disease, as many other infectious agents can give similar symptoms and signs and coinfections are common; the exception is CMV retinitis (see above). CMV gastrointestinal disease is particularly difficult to diagnose with certainty, as CMV is frequently present together with gut GVHD. The recommended definition of CMV gastrointestinal disease is the combination of clinical symptoms, findings of macroscopic mucosal lesions on endoscopy and demonstration of CMV by culture, histopathologic testing, immunohistochemistry or in situ hybridization in a biopsy specimen. PCR on biopsy material is insufficient for the diagnosis of CMV gastrointestinal disease.


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The diagnosis of CMV disease must be based on symptoms and signs consistent with CMV disease together with detection of CMV by an appropriate method applied to a specimen from the involved tissue (AII). Symptoms of organ involvement together with CMV detection in blood are not enough for diagnosis of CMV disease. There are several possible techniques that can be used for detection of CMV in tissue specimens and each transplant center should collaborate closely with a good diagnostic virology and histopathological laboratory (AII). PCR is usually not appropriate for documentation of CMV disease in tissue specimens, as the positive predictive value is too low (BIII).

Prevention of primary CMV infection With proper management, CMV-seronegative patients have low risk for contracting CMV infection. To reduce the risk of CMV transmission, blood products from CMVseronegative donors or leukocyte-depleted blood products should be used.23–25 It is not settled which strategy is preferable26,27 and no controlled study has investigated whether there is any extra benefit from the use of both seronegative and filtered blood products. In many centers, and even in entire countries, leukocyte filtration of blood products is mandatory. Leukocyte filtration should be performed at the blood bank and the established quality standard of o5 106 residual leukocytes/unit followed.26,27 Immune globulin has a minor effect in the prevention of primary infection and has therefore been replaced by other more effective strategies. Allogeneic SCT patients. CMV serological status should be assessed as early as possible when a candidate is considered for allo-SCT, so that a donor with the most appropriate CMV status can be selected. For instance, it has been clearly shown that CMV-seronegative patients with CMV-seronegative stem-cell donors have a lower risk for post transplant complications both from CMV and from the effects of CMV-associated immunosuppression with its concomitant increased risks for bacterial and fungal infections. In a seropositive patient, the choice of the proper donor is controversial. It was reported that seropositive patients undergoing unrelated, non-T-celldepleted SCT had an improved survival if they received a graft from a seropositive donor.28,29 Others studies have failed to confirm this finding.8,30 SCT patients should be tested before SCT for CMV Abs (AI). Stem cell transplant donors should be tested for CMV Abs (AI). If a patient is found to be seronegative, a CMVseronegative donor should be used if possible (AI) CMV-seronegative allo-SCT patients with CMV-seronegative donors (AI) should receive leukocyte-depleted or CMV-seronegative blood products only. If leukocyte-depleted blood products are used, the products should contain o5 106 residual leukocytes/ unit (AII). Immune globulin for prevention of CMV infection or disease is not recommended (EII).

If a patient is CMV-seropositive, a graft from a CMVseropositive unrelated or mismatched donor should be considered (BII). Patients with hematological malignancies including autoSCT recipients. The non-allogeneic patient groups at maximum risk of developing CMV-associated complications are those receiving T-cell suppressive therapy with purine analogues or alemtuzumab31–35 and auto-SCT patients.36–38 The baseline CMV serological status has an important impact on the incidence of CMV infection in non-transplant cancer patients as well. CMV-seronegative non-transplant patients had an antigenemia rate of 2.5% compared with 14.3% in seropositive patients.11 Patients with a CMV infection developing close to a planned allo-SCT have a very high risk of death after transplantation.39 Owing to the increasing use of alemtuzumab and other highly immunosuppressive therapies, the number of patients that will develop pre-transplant CMV disease will probably increase. The prevention of CMV disease in non-transplant patients is therefore very important for SCT candidates. As this need is unknown for the majority of patients at diagnosis, preventive strategies against CMV disease should be applied to all patients at risk. Patients who might receive alemtuzumab or in whom allo-SCT can be envisaged should be tested for CMV Abs (BII). All patients with CMV disease before SCT should be considered as very high-risk patients for CMV disease after SCT. If possible, the transplant should be delayed to allow appropriate length of treatment before SCT (BIII). In patients with CMV disease before SCT, use of secondary anti-CMV prophylaxis during SCT could be considered (BIII). Such patients should be closely monitored during the SCT procedure and a low threshold for pre-emptive treatment must be used (CIII). CMV-seronegative patients receiving T-cell suppressive therapy should receive leukocyte-depleted or CMVseronegative blood products only (BIII). CMV-seronegative auto-SCT patients should receive leukocyte-depleted or CMV-seronegative blood products only (BIII). Immune globulin for prevention of CMV infection or disease is not recommended (EIII).

Prevention of CMV disease The different preventive strategies for CMV disease include the use of antiviral agents, such as chemoprophylaxis, preemptive therapy or treatment of symptomatic CMV infection. The currently available antiviral agents for prevention of CMV infection and disease are acyclovir, valacyclovir, ganciclovir, valganciclovir, foscarnet and cidofovir. Detection of CMV infection and pre-emptive antiviral therapy Allo-SCT patients. Monitoring by a sensitive technique allows early intervention in most cases before the development of CMV disease. The most used techniques are Bone Marrow Transplantation


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antigenemia and quantitative PCR. Results from several studies indicate that the risk of development of CMV disease can be assessed by determination of the viral load, which in turn reflects the extent of viral replication and the specific immune response. Viral load can also be used to assess the response to antiviral therapy.16,18,40–42 One advantage of pre-emptive therapy is that a lower proportion of patients will need antiviral therapy as not all patients at risk for CMV will develop active infection.

The alternate drugs, ganciclovir or foscarnet, can be considered for second-line pre-emptive therapy (AI). Cidofovir can be considered for second-line pre-emptive therapy (3–5 mg/kg) but careful monitoring of renal function is required (BII). Valganciclovir might be used in place of i.v. agents especially in low-risk patients (provisional BII). The combination of ganciclovir and foscarnet might be considered for second-line pre-emptive therapy (CII).

All allo-SCT patients, regardless of whether they receive CMV prophylaxis, should be monitored for CMV in peripheral blood at least weekly using either CMV antigenemia assay or a technique for the detection of either CMV DNA or RNA (AI). The duration of monitoring should be at least 100 days (BIII). Longer monitoring is recommended in patients with acute or chronic GVHD, in those having experienced CMV infection after SCT earlier and in those having undergone mismatched or unrelated donor transplantation (BII).

Patients treated with alemtuzumab. CMV is the most common opportunistic infection in patients with CLL treated with alemtuzumab and has been reported in 10– 25% patients.61 The rate of CMV detection after alemtuzumab therapy ranged between 6 and 100% depending on whether surveillance was done, the frequency of surveillance and on the characteristics of the patients.31,32,62 In recently published studies, the incidence of symptomatic CMV infection ranged from 4 to 29%31 and was usually lower in previously untreated compared with treated patients. The risk for CMV infection peaks after 3–6 weeks of alemtuzumab therapy at around the same time as the nadir of severe lymphopenia and neutrophil or shortly thereafter.31 The most frequent symptoms is fever sometimes associated with myelosuppression,31,32,63 but CMV disease may occur in some patients, although the frequency is not known. A CMV management strategy should be adopted in patients receiving alemtuzumab. Such a strategy could be either monitoring for CMV or antiviral prophylaxis. The management of recurrent CMV infection is complicated because the relationship between the risk of CMV disease and CMV viral load, such as rate of rise or number of copies/ml of plasma or persistently positive serial test results, is not known. There is no conclusion whether alemtuzumab should be stopped when CMV is detected. Some authors recommend this action,61,62,64,65 others do not mention which action should be taken66–68 and the remaining do not recommend interruption of alemtuzumab in asymptomatic patients.31,32,69,70

Ganciclovir is the most used drug for pre-emptive therapy. Valganciclovir is the prodrug of ganciclovir, and it has been shown in two randomized pharmacokinetic studies that equal or even higher drug exposure can be achieved by valganciclovir compared with i.v. ganciclovir,43,44 although efficacy and safety are similar.44 A recent interim analysis of a randomized study suggests similar efficacy and toxicity of valganciclovir as of ganciclovir.45 Use of valganciclovir has also been analyzed in uncontrolled studies.46–48 Although foscarnet is as effective as ganciclovir,49 it is usually used as a second-line drug. Cidofovir (3–5 mg/kg per week) is another second-line agent, and although the weekly dosing regimen is attractive, it is associated with renal toxicity.50–52 The combination of ganciclovir and foscarnet has also been used but with increased toxicity and no improved efficacy.53,54 Case reports with varying results have been published on treatment with leflunomide or artesunate in patients failing other antiviral therapy.55–59 The duration of therapy should be a minimum of 2 weeks depending on whether CMV is detected at the end of the course. Resistance is quite rare in SCT patients and increasing antigenemia or CMV DNA early after initiation of antiviral therapy is usually not a sign of antiviral resistance and therefore does not necessitate change of therapy.41,60 If CMV is still detected after 2 weeks of therapy, maintenance therapy can be given.49 Repeated courses of pre-emptive therapy or a prolonged duration of initial preemptive therapy might be needed, in particular, in patients who have undergone an unrelated or mismatched transplantation. Pre-emptive antiviral therapy based on the detection of CMV Ag or nucleic acid is effective for prevention of CMV disease in allo-SCT patients (AI). Either i.v. ganciclovir or foscarnet can be used for firstline pre-emptive therapy (AI). The choice depends on the risk of toxicity and which antiviral drugs have been used earlier (BIII). Bone Marrow Transplantation

A CMV management strategy must be put in place for patients receiving alemtuzumab (BIII). Monitoring and antiviral treatment of patients tested positive for CMV and showing symptoms compatible with a CMV infection is one management option in patients receiving alemtuzumab (BII). In these patients, regular monitoring with antigenemia or PCR is recommended during the period of maximum immunosuppression (that is, during treatment and until 2 months after the end) (BII). Treating asymptomatic patients is not obligatory but careful clinical observation of patients with documented CMV infection is necessary (BII). Withholding alemtuzumab is not considered necessary, unless symptoms persist (BIII). Other patients. The frequency of CMV infection in auto-SCT patients is similar to that observed after alloSCT with the exception of patients receiving CD34-selected grafts.38 However, the number of patients who actually


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require treatment or develop CMV disease is quite small. Routine surveillance is unnecessary in patients undergoing auto-SCT because of the low likelihood of CMV disease.11,71,72 There are, however, subgroups who have a higher risk for acquiring CMV disease, including those receiving CD34-selected grafts and prior treatment with fludarabine or cladribine.38 Leukemia patients with a lesser degree of immunosuppression do not need a specified prophylactic strategy but CMV disease must be in the differential diagnosis if symptoms compatible with CMV develop.10 High-risk auto-SCT patients might potentially benefit from monitoring and the use of pre-emptive therapy (CII). Routine monitoring and pre-emptive therapy are not considered necessary in other hematology patients (DIII). CMV disease should be considered in patients receiving T-cell suppressive therapy and in CMV-seronegative patients who receive stimulated granulocyte transfusions from unscreened donors, if they develop symptoms compatible with CMV (unexplained fever, drop in blood counts, lung infiltrates or gastrointestinal symptoms) (BII).

Antiviral prophylaxis Antiviral chemoprophylaxis is an alternative to pre-emptive therapy and can be used for all patients or subgroups of patients, that is, patients at high risk for CMV disease. Several different antiviral drugs can be used, but immune globulin is not indicated as CMV prophylaxis either against infection or disease, as more efficacious and cost-effective alternatives exist.73 Allo-SCT recipients. In randomized studies, high doses of either acyclovir or valacyclovir was shown to reduce the risk of CMV infection but not CMV disease.74,75 One study also reported improved survival, although the mechanism for this improvement is not clear.74 Valacyclovir prophylaxis can reduce the need for pre-emptive therapy, but monitoring for CMV and use of pre-emptive therapy is absolutely essential if acyclovir/valacyclovir prophylaxis is to be used.75 Intravenous ganciclovir prophylaxis was tested in randomized trials76–79 and was shown to reduce the risk of CMV disease compared with placebo, but did not improve survival as it was associated with neutropenia and secondary bacterial and fungal infections. There was no difference in the risk of CMV disease or the chance of survival between ganciclovir and valacyclovir prophylaxis, or between ganciclovir prophylaxis and ganciclovir given as pre-emptive therapy. No study with valganciclovir given as prophylaxis has been reported in SCT recipients and therefore no recommendation can be given. Foscarnet prophylaxis has only been used in uncontrolled trials. Intravenous ganciclovir prophylaxis is an effective strategy for the prevention of CMV disease and could be used in subgroups of allo-SCT patients at high risk for CMV disease (BI).

Acyclovir or valacyclovir can be used as prophylaxis against CMV in allo-SCT patients (BI). However, their use must be combined with monitoring and the use of pre-emptive therapy (AI). Immune globulin has no role as prophylaxis against CMV infection (EII). Patients receiving alemtuzumab. Preliminary data are available from a randomized study in 40 patients with heterogeneous diseases comparing valacyclovir and valganciclovir as prophylaxis against CMV treated with alemtuzumab alone or in combination.80 The study was stopped early, as the stopping rules for early termination were met. Symptomatic CMV infection was observed in none of the 20 patients in the valganciclovir group, compared with 7 in the valacyclovir group (P ¼ 0.004). Myelosuppression related to valganciclovir could not be analyzed given the heterogeneity of regimens. Valganciclovir prophylaxis is effective and reduces the risk of symptomatic CMV infection in patients receiving alemtuzumab (BII). However, the side-effect profile is still unclear as is the risk/benefit compared with the strategy of treating when a symptomatic CMV infection develops (CII). Other patients. Routine antiviral prophylaxis is not recommended (DIII)

Treatment of symptomatic infections Patients with CMV detected in blood and those showing symptoms compatible with CMV (fever with or without BM suppression), but without signs of CMV endorgan disease, should be carefully assessed. Patients with suspected CMV organ involvement should undergo appropriate diagnostic procedures. Although no randomized controlled trial has been performed in this situation, it is logical to assume that intervention in patients at highest risk for progression to CMV endorgan disease, that is, alloSCT patients and patients receiving alemtuzumab, should benefit from antiviral therapy. For other patients, the risks and benefits should be considered before a decision is made regarding antiviral therapy. The choice of antiviral agent will depend on the individual patient, the risk for progression to CMV disease and the risk for side effects of the chosen drug. Allo-SCT patients (AI) and patients receiving alemtuzumab (AII) should be given antiviral therapy. The benefit in other patient groups is lower but antiviral therapy could be considered (CIII). Patients with suspected organ involvement of CMV should undergo appropriate diagnostic procedures (BIII). The choice of antiviral agent will depend on the individual patient, the risk for progression to CMV disease and the risk for side effects of the chosen drug. *

In allo-SCT patients, i.v. ganciclovir or foscarnet are first-line agents (BII). Bone Marrow Transplantation


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In other patients, such as patients receiving alemtuzumab, valganciclovir may be considered in addition to ganciclovir and foscarnet (BIII).

Treatment of CMV disease Allo-SCT patients. Development of CMV disease should be regarded as a failure of the preventive strategies described above. Such disease can develop any time after SCT from the early neutropenic phase up to several years after transplantation.2 Even today, CMV pneumonia, in particularly, is still associated with high mortality.2,81 CMV retinitis is more common as a late rather than an early manifestation of CMV disease and patients developing visual disturbances should be assessed by an ophthalmologist.82,83 The established therapy for CMV pneumonia is a combination of i.v. ganciclovir and high dose i.v. immune globulin.84–87 Whether the administration of immune globulin improves outcome is still controversial.81,88 No data indicate any advantage of the so-called CMV hyperimmune globulin over standard immune globulin. There are also no data to support the administration of immune globulin for the treatment of manifestations of CMV disease, other than pneumonia, including CMV gastroenteritis.89 There is no standard duration recommended but a commonly used schedule for therapy is 21–28 days of induction therapy followed by maintenance for 4 weeks. In a randomized study, 2 weeks of ganciclovir was found to be too less to effectively treat CMV gastrointestinal disease.90 Either cidofovir or the combination of i.v. ganciclovir and foscarnet, each given in full dosage, may be used as second-line therapy for CMV disease. Other patients. CMV disease is rare in auto-SCT patients but is associated with a similar morbidity and mortality as that after allo-SCT.37,38 Deaths due to CMV pneumonitis and CMV hepatitis have been reported in patients who received alemtuzumab but seem to be rare. From the limited data available, there seems to be no value in giving i.v. immune globulin in addition to antiviral therapy in either auto-SCT patients or other patients with hematological diseases. Treatment of CMV pneumonia *

* *

*

Antiviral therapy with ganciclovir is recommended (AII). Foscarnet might be used in place of ganciclovir (AIII). The addition of immune globulin to antiviral therapy should be considered (CII). Cidofovir or the combination of foscarnet and ganciclovir can be used as second-line therapy (BII).

*

Cidofovir or the combination of i.v. ganciclovir and foscarnet can be used as second-line therapy for CMV disease (BII).

Antiviral resistance Resistance to antiviral drugs is infrequent in SCT patients60,91 and usually does not emerge until after several weeks of antiviral therapy. Rising CMV antigenemia or DNA levels, or progress of CMV disease symptoms, might indicate clinical or viral resistance. Clinical resistance depends on host factors, whereas viral resistance is due to mutations in the viral genome. In most situations where CMV can still be detected despite adequate antiviral therapy, the cause is clinical resistance. Certainly, it has been shown that a rise in the viral load during the first week of such a treatment is not an indication of viral resistance.60 The presence of antiviral resistance can be determined by either phenotypic or genotypic assay. DNA sequencing can be used to screen for the most commonly seen mutations in ganciclovir-resistant strains of CMV. Testing for foscarnet, cidofovir and the less common ganciclovir-resistant mutants is, however, more difficult, as the viral mutations are less well defined. Development of double and triple resistant strains is rare but does occur. Where possible, resistance testing should be performed to allow selection of the correct second-line antiviral therapy (BIII). If the turn-around time for resistance testing is prolonged, then a change of treatment for a patient with rising viral load or worsening disease in the face of adequate treatment should precede receipt of the test result (BII).

Adoptive immunoprophylaxis It is well recognized that patients lacking a specific immune response to CMV are at an increased risk for developing CMV disease.2,3,92–94 Monitoring of CD8 and/or CD4 CMV-specific T cells can be applied using different techniques, including detection by tetramers or measurement of peptide-specific lymphocyte responses. However, none are standardized for routine use. Several groups have studied the usefulness of adoptive transfer of T cells95–97 or vaccination with CMV-primed DC.98 These technologies seem not to be associated with significant toxicity but their effectiveness needs to be further assessed in controlled trials. Immunological monitoring after SCT might yield important information for patient management, although no standard test exists (CII). Immunological interventions by infusion of CMVspecific lymphocytes or DC vaccination are interesting options and should undergo controlled prospective clinical trials (CII).

Treatment of other types of CMV disease *

For other types of CMV disease and in other patient groups, either i.v. ganciclovir or foscarnet administration without the addition of immune globulin is recommended (BII).

Bone Marrow Transplantation

HHV-6 HHV-6 is a recognized pathogen in allo-SCT recipients despite the considerable problems in the interpretation of


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available data. There are two closely related, yet molecularly and biologically distinct, variants of HHV-6, namely A and B (HHV-6A/B). Although HHV-6B is now established as the cause of exanthem subitum (roseola infantum),99 no disease has yet been causally linked to HHV-6A. HHV-6B primary infection usually occurs in the first 2 years of life and the virus thereafter persists with the potential for recurrent infection and disease. HHV-6 reactivates early after SCT and is found in the blood in about half of all allo-SCT recipients, making it difficult to make disease associations. HHV-6B is identified much more frequently than variant A, which accounts for only 2– 3% of cases.100–104 As regards HHV-6 disease, HHV-6 encephalitis after SCT is the most significant clinical manifestation.105,106 HHV-6 can infect hematological progenitor cells in vitro, thereby reducing colony formation,107– 109 and HHV-6 infection has been associated with delayed engraftment after SCT.103,110,111 No disease has been associated with HHV-6 in patients with hematological malignancies who have not undergone SCT. HHV-6A and B differ from other human herpesviruses because of the unique ability of their genomes to integrate in a persistent latent state into the chromosomes and to be transmitted from parent to child in the germ line.112–116 The incidence of HHV-6 chromosomal integration (CI) runs at about 2% in the population of the United Kingdom.116,117 Although there is no evidence to date of active virus replication, the occasional patient with such an integration is easily identifiable, as every leukocyte contains viral sequences and, thus, there are characteristically persistently high levels of HHV-6 DNA in both whole blood and serum.118,119 Diagnostic pitfalls result from the phenomenon of viral CI.118–120 If the donor has HHV-6 CI, there will be an asymptomatic elevation of HHV-6 DNA load after SCT to characteristically and strikingly high levels that will correlate with leukocyte engraftment,118,121 but such high levels do not respond to antiviral therapy.122 On the other hand, if the recipient has HHV-6 CI, the reverse will occur, that is, high levels before SCT will disappear, although low level HHV-6 DNA will persist in blood, presumably due to the release of chromosomal DNA from the recipient’s nonhematopoietic cells.123

Definitions The following definitions are used in this paper: Primary infection: detection of HHV-6 or specific Abs to HHV-6 in a previously HHV-6-seronegative individual. Recurrent HHV-6 infection: HHV-6 detected in a previously HHV-6-seropositive patient. HHV-6 CI: characteristically high, persistent HHV-6 DNA levels in whole blood equivalent to at least 1 copy/ leukocyte, and in serum or plasma equivalent to at least 1 copy/lysed leukocyte. HHV-6 disease: HHV-6 detected by a test with appropriate sensitivity and specificity (see Diagnosis of HHV-6 disease) in the affected organ in a biopsy or in samples from other invasive procedure (BAL, CSF) together with symptoms and/or signs from the affected organ. Note: in suspected cases of primary or recurrent HHV-6 infection and HHV-6 disease, the phenomenon

of HHV-6 CI should be borne in mind as an alternative cause.

Diagnosis of HHV-6 infection Antibody tests. Diagnosis of primary HHV-6 infection in young children is based on Ab detection using indirect immunofluorescence124,125 but such tests are difficult to interpret in older children and adults. Serology has no role in the diagnosis of HHV-6 infection in allo-SCT recipients and there is no test that distinguishes between Abs to HHV-6A and B. Antigenemia tests. Such tests have been used for the diagnosis of HHV-6 infection in blood,126 but there is limited experience as their use has not been widespread. DNA tests on peripheral blood. The gold standard is virus isolation in cord blood but this is a specialized technique that is labor intensive and not available to most diagnostic laboratories. Instead, the norm is to use PCR to detect viral DNA. The type of sample investigated varies between laboratories but the most common are whole blood and plasma. In view of the differing natural histories of variants A and B (see above), it is recommended to use a quantitative PCR that distinguishes between the two. If HHV-6 CI is suspected, it can most easily be established by checking donor and recipient samples obtained prior to transplant for the characteristic high levels of HHV-6 DNA using quantitative PCR. Quantitative PCR for HHV-6A and B DNA is recommended for diagnosis of HHV-6 infection in peripheral blood or CSF (BII). HHV-6 CI should be excluded (BIII).

Diagnosis of HHV-6 disease HHV-6 encephalitis. HHV-6 encephalitis after SCT is a relatively rare event with approximately 40 cases described in the literature.127,128 In over three-fourth of all the reported cases, the patient had received a mismatched related or unrelated SCT, and only one publication reports a case occurring in an auto-SCT recipient. In addition, longitudinal observational studies have established a correlation between HHV-6 detection in peripheral blood and CNS disease.103 Patients characteristically present with depressed consciousness, convulsions, confusion and disorientation often with short-term memory loss.127,128 Few patients have focal findings on neurological examination. Apart from HHV-6 DNA in CSF, other findings may be normal; elevated CSF protein levels are found in about two-thirds of patients and about half have CSF pleocytosis. Computed tomography of the brain is often normal. Abnormalities are more usual in magnetic resonance imaging of the brain; these include multiple non-enhancing, low attenuation lesions in the gray matter, sometimes involving the temporal lobes (especially the medial temporal). Electroencephalography studies are usually diffusely abnormal but sometimes involve the temporal region. Before the diagnosis of HHV-6 encephalitis is finally accepted, other infectious agents should be excluded by Bone Marrow Transplantation


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culture, microscopy or nucleic acid test; malignant disease (based on computed tomography or magnetic resonance imaging, and microscopy and immune staining of CSF). HHV-6 CI should likewise be excluded.

Foscarnet or ganciclovir are recommended as first-line therapies for HHV-6 encephalitis after SCT (BII). Cidofovir is recommended as a second-line therapy (CIII).

HHV-6 BM suppression. Diagnosis requires evidence of failed engraftment, especially of platelets, in the absence of any other cause together with the detection of HHV-6 DNA in blood. Exclusion of HHV-6 CI is required.

HHV-7

Other possible organ disease. Symptoms and signs from the organ in question together with HHV-6 detection in blood are not enough for the diagnosis of disease, as many other infectious agents may be responsible. Tests on tissue are required to establish evidence of HHV-6 replication and consequent pathology. Possible techniques include in situ hybridization and immunohistochemistry, but these are not generally available. PCR for HHV-6 DNA is not recommended on tissue samples. The diagnosis of HHV-6 encephalitis after SCT must be based on features consistent with HHV-6 disease, namely CNS symptoms and signs, together with abnormal magnetic resonance imaging or diffuse electroencephalography changes and detection of HHV-6 DNA in CSF (BII). The diagnosis of HHV-6 BM suppression after SCT must be based on delayed engraftment together with HHV-6 DNA in blood and the exclusion of other possible causes (BII). HHV-6 CI should be excluded (BIII). As regards other suspected organ diseases, it is recommended to test for HHV-6 infection in the relevant tissue—there are several possible techniques, although these are not generally available (CIII). PCR on tissue is not recommended for documentation of HHV-6 disease, as the positive predictive value is too low (DIII).

Antiviral treatment Antiviral prophylaxis against HHV-6. Foscarnet, ganciclovir and cidofovir have been shown to inhibit HHV-6 replication in vitro. Data from two small non-randomized studies of SCT recipients suggest that prophylactic ganciclovir can prevent recurrent HHV-6 infection.129,130 However, given the low risk of HHV-6 disease and the toxicity of the available antiviral drugs, such a policy cannot be recommended. Anti-HHV-6 chemoprophylaxis is not recommended to prevent HHV-6 disease after SCT or in other patients (EIII). Treatment of HHV-6 encephalitis. Most patients reported with HHV-6 encephalitis after SCT received either foscarnet or ganciclovir;127,128 however, although one series demonstrated virological response to these drugs,131 a high morbidity and mortality remained. Despite the lack of controlled trials, the International Herpes Management Forum recommends foscarnet or ganciclovir, either alone or in combination, for the treatment of HHV-6 CNS disease.132 Bone Marrow Transplantation

HHV-7 is closely related to HHV-6 and primary infection has a similar natural history in young children occasionally causing exanthem subitum,133,134 and more rarely status epilepticus with fever.135 However, in contrast to HHV-6, there is no evidence of CI. There is no suggestion of disease in patients with hematological malignancies, such as leukemia, and very little information regarding SCT recipients is available. HHV-7 detection after SCT is relatively infrequent,111,136 and there are only a handful of cases in which HHV-7 has been associated with CNS disease.137–140 In view of the limited data, no recommendations can be made regarding HHV-7 as a potential pathogen in leukemia patients or after SCT.

Kaposi’s sarcoma-associated herpesvirus or HHV-8 Kaposi’s sarcoma-associated herpesvirus (KSHV) is also known as HHV-8. It is the cause of Kaposi’s sarcoma (KS) but has also been associated with primary effusion lymphoma and multicentric Castleman’s disease. Transmission of the virus is sexual in homosexual and bisexual men but non-sexual, probably via saliva, in areas of high endemicity. KSHV may be transmitted by blood transfusion141 and by solid organ transplantation.142 KS is very rare after SCT,143,144 as are descriptions of an association with non-malignant clinical manifestations, especially BM failure.145–147 Part of the explanation for the low incidence may lie in the worldwide variation in the prevalence of KSHV; thus, the prevalence of KSHV infection is very high (450%) in older children and adults in Africa and parts of the Amazon basin; intermediate (5–20%) in the Mediterranean, Middle-Eastern countries and the Caribbean; and low (o5%) in North America, North Europe and Asia (o5%).

Diagnosis of KSHV infection There are currently no generally accepted diagnostic techniques. Ab tests. These are useful for screening donor and recipient in at-risk populations, but, wherever available, are of variable sensitivity and specificity.148 DNA tests on peripheral blood. Methods exist to detect KSHV DNA by quantitative PCR using whole blood, plasma or serum but there are so few studies that recommendations cannot be made. Ab testing pre-SCT to identify patients at risk of KS is not recommended (DIII).


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Diagnosis of KSHV disease KS can be clinically defined on the basis of characteristic skin lesions or histopathologically defined by immunostaining of tissue from a malignant tumor arising elsewhere in the body. In cases where KS is suspected and the site of malignancy is not accessible for biopsy, KSHV detection in blood may be helpful, although a negative result does not exclude the diagnosis. Although the diagnosis of KS is usually clinically or histopathologically defined, detection of KSHV DNA in blood may assist with diagnosis where the site of malignancy is not accessible for biopsy (BIII). Knowledge of risk factors and local seroprevalence should be kept in mind (BIII).

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