key: cord-0010327-2x0unh5v
authors: Reid, Gail E.; Lynch, Joseph P.; Weigt, Samuel; Sayah, David; Belperio, John A.; Grim, Shellee A.; Clark, Nina M.
title: Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes
date: 2016-08-03
journal: Semin Respir Crit Care Med
DOI: 10.1055/s-0036-1584793
sha: 26efe2480c96d93ed23f8adf49ace5671c55d6d1
doc_id: 10327
cord_uid: 2x0unh5v

Among immunocompromised individuals, members of the human Herpesviridae family are frequently encountered pathogens. Cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein–Barr virus, and human herpesvirus-6, -7, and -8 all establish latency after infection and can reactivate during periods of immunosuppression, leading to both direct and indirect adverse effects on the host including severe organ dysfunction as well as allograft rejection and loss after transplantation. While not all herpesviruses are primary respiratory pathogens, many of their manifestations include involvement of the respiratory tract. This article discusses the individual viruses, their epidemiology, and clinical manifestations as well as recommended treatment and preventive strategies.

Because of the frequency with which CMV is encountered after transplantation, its wide-ranging effects, and its impact on morbidity and mortality, it is one of the most significant infections that can occur in transplant recipients. After primary infection occurs, CMV establishes persistent latency in various cells including monocytes, dendritic cells, megakaryocytes, and progenitor myeloid cells in bone marrow, leading to the lifelong potential for reactivation. 5 Primary infection in immunocompetent hosts typically occurs with no symptoms or a mononucleosis-type illness, 6 but can be much more severe in immunocompromised persons. 7 CMV-seronegative SOT recipients may develop primary CMV infection from the donor organ, from blood transfusions or via contact with infected body fluids including saliva, semen, and breast milk. 8 Reactivation of latent infection may also occur after transplant, as can coinfection by a donor's CMV strain. 9 Organ transplant recipients who are CMV-seropositive before transplantation often develop less severe manifestations of infection compared with those who develop primary infection after transplantation. 10 CMV infection, characterized by the presence of viremia, should be viewed separately from "CMV disease"; the latter refers to CMV infection accompanied by signs and symptoms such as fever, leukopenia, or organ dysfunction. 11 If antiviral prophylaxis is not administered, CMV infection occurs within the first 3 months of transplant in SOT recipients who are seropositive or those who receive an organ from a seropositive donor, 10,12-14 as this is generally the period of greatest immunosuppression. Infection may be asymptomatic or associated with the disease. However, because CMV prophylaxis is commonly used after solid organ transplantation if the donor or recipient is seropositive, lateonset infection may occur after prophylaxis is discontinued, and has been identified in 17 to 37% of CMV D þ /RÀ recipients. 15-18 Late-onset infection usually occurs in the first year after transplant, 15,19-21 but can sometimes occur much later. 22 The late-onset disease is associated with mortality and graft loss. 19, 23 Clinical Manifestations CMV infection after transplant can lead to asymptomatic infection or life-threatening disease. Some patients develop what is termed "CMV syndrome," a nonspecific presentation characterized by fever and myelosuppression in association with CMV viremia. 11 CMV also causes tissue-invasive disease, including the most common manifestation in SOT recipients, enteritis. 14,24 This is characterized by symptoms, such as abdominal pain, nausea, and diarrhea with endoscopically identified gastrointestinal (GI) lesions and identification of CMV in a GI tissue specimen. 11 In addition, CMV pneumonitis can be a particularly severe disease with a high mortality, and it most commonly occurs in allogeneic HCT recipients and lung transplant recipients. 25 Pancreatitis, retinitis, nephritis, hepatitis, and encephalitis are additional manifestations of CMV infection that may occur in immunocompromised hosts. 26 The transplanted allograft may become infected, 27 possibly due to dysregulation of the immune response in the graft and/or the fact that the graft can be a reservoir for the virus. 27 CMV infection has been associated with increased mortality in transplant recipients, 13,19,22,28-30 both due to direct tissue damage as well as immunomodulatory effects. 8 CMV interacts with the host immune system in a complex manner. It can induce inflammatory cytokines and upregulate major histocompatibility complex antigens and proinflammatory adhesion molecules, and this may enhance immunogenicity of the organ. 7,27,31 This is a potential mechanism for the acute and chronic rejection and long-term graft dysfunction associated with CMV infection. 10,19,31-41 Bronchiolitis obliterans syndrome (BOS), a form of chronic rejection in lung transplant recipients, has been associated with CMV infection, 7 and CMV viremia in the first 6 months after lung transplant has been linked to a significantly higher risk of BOS. 42 The detection of CMV nucleic acids in bronchoalveolar lavage (BAL) fluid has also been identified as a risk for BOS by some, 43 but not all investigators. 44 CMV disease has also been associated with cardiac allograft vasculopathy in heart transplant recipients. 45 The virus can elicit inflammatory responses that damage cardiac allograft endothelial cells in animal models and result in thickening of the intima, 46 a process that can be prevented by the administration of ganciclovir. 31 Furthermore, cytokines and growth factors triggered by episodes of acute rejection can activate the expression of CMV, potentially leading to amplification of both processes. 31,32 Finally, the augmented immunosuppression used when treating rejection may lead to CMV reactivation and disease. 14, 47 CMV also appears to impair immune responses of the host, as it is an independent risk factor for secondary bacterial and fungal infections and EBV-related posttransplant lymphoproliferative disorder (PTLD). 14,48-51 CMV has also been associated with recurrent liver disease due to hepatitis C in liver transplant recipients, 52 new-onset diabetes mellitus after transplantation 53 and hepatic artery thrombosis after liver transplantation. 54

The most frequently used method for diagnosing CMV infection is quantitative nucleic acid testing (QNAT) via polymerase chain reaction (PCR) assays. 55, 56 QNAT can be used to rapidly detect infection, monitor response to antiviral therapy, assess severity of infection and the likelihood of tissue invasive disease, since higher viral loads correlate with risk of tissue-invasive disease. 57, 58 Due to differences in quantitative methods between laboratories, there are no established viremia thresholds above which it is agreed treatment should be initiated. 8, 59 However, a World Health Organization CMV international standard has been developed to calibrate assays for consistent viral load reporting. 59 Identifying a rapidly increasing viral load is more helpful in predicting disease than any single value, 58 and changes in viral loads of < 0.5 log 10 copies/mL are not considered significant variations. 60 PCR assays for CMV viremia may be less sensitive in patients with localized tissue-invasive disease such as enteritis; in one review of studies reporting transplant recipients with GI disease due to ganciclovir-susceptible CMV, viremia was detected in only 44 to 75% of the cases. 61 Therefore, CMV disease cannot be excluded by negative QNAT, and endoscopy and biopsy may be required to establish the diagnosis in patients with compatible clinical syndromes. In fact, the gold standard of diagnosis of tissue-invasive CMV disease is biopsy, with the appearance of "owl's eye" viral inclusion bodies, viral antigen staining by immunohistochemical methods and/ or the detection of viral nucleic acids in specimens confirming the diagnosis. 27 Tissue culture can be useful if positive, but is slower and less sensitive than molecular assays. 62 Identifying CMV in BAL fluid in lung transplant recipients may be a sign of asymptomatic viral replication rather than indicative of tissue-invasive disease, but quantitative assays may be more specific for diagnosing disease. [63] [64] [65] [66] The pp65 antigenemia test detects viral antigen in peripheral white blood cells. Higher levels of blood pp65 antigenemia have been correlated with disease. 67 However, the test is labor and time intensive, does not perform well in patients with neutropenia, and is less sensitive than QNAT at lower viral load ranges. 8, 57, 58, 68, 69 Therefore, most centers use QNAT for diagnosis of CMV infection. 70 Testing for antibody responses to CMV is not recommended for diagnosing transplant-related CMV infection as it takes time for antibodies to develop after infection, and antibody responses may be impaired in immunocompromised individuals. 26,27,71 Furthermore, CMV IgM assays are known to lack specificity, with frequent false-positive reactions. 72 

The most important predictor of developing CMV infection or disease in solid organ transplantation is the CMV serostatus of the donor-recipient pair; the highest risk of developing CMV disease occurs when a CMV-seronegative recipient receives an organ from a seropositive donor (CMV D þ /R À ). 10,73,74 CMV IgG testing is performed routinely on organ donors and recipients before transplant to stratify the risk of the recipient and inform the prophylaxis strategy. Approximately 20% of solid organ transplantation procedures performed in the United States occur in high-risk serodiscordant pairs. 75 For HCT recipients, CMV-seropositive recipients of grafts from seronegative donors have been noted to be at higher risk from CMV disease and death compared with recipients of grafts from seropositive donors, presumably because the latter type of recipient receives CMV-specific donor CD4þ and CD8þ T cells which can help contain infection. 76, 77 However, the results of studies of CMV-related outcomes in CMV-mismatched donor-recipient HCT pairs are inconsistent. 78 Other risk factors for CMV infection in HCT recipients include umbilical cord blood transplantation, receipt of T cell-depleted stem cells, graft-versus-host disease (GVHD), total body irradiation, and fludarabine-containing chemotherapy regimens. 79 CMV-seronegative transplant recipients receiving allografts from seronegative donors are at the lowest risk for CMV disease after transplantation and they should receive leukoreduced and/or CMV-seronegative blood products. 27, 80 The level of host immunosuppression is an important risk factor for CMV infection. Transplant recipients who receive antilymphocyte antibodies, such as thymoglobulin or alemtuzumab, or those receiving high-dose corticosteroids for treatment of rejection are at an increased risk of CMV infection and disease. 24, 47, 57, 81 Comorbidities can also enhance risk as can the type of organ transplanted, with lung and small intestine allograft recipients at highest risk among SOT recipients, perhaps due to the amount of lymphoid tissue in the organs and the intensity of immunosuppression. 27 Finally, certain host genetic factors have also been shown to confer variable risks for CMV infection. [82] [83] [84] Polymorphisms in genes of the innate immune system, including those for Toll-like receptors and mannose-binding lectin 83, 85, 86 have been shown to affect the risk for CMV in organ transplant recipients. Deficiencies in CMV-specific Tlymphocyte responses 87 and hypogammaglobulinemia after transplantation 88 have also been identified as risk factors for CMV disease.

The standard of care for treatment of CMV infection and disease is intravenous (IV) ganciclovir or its oral prodrug, valganciclovir. 27 The mechanism of action for ganciclovir and valganciclovir, like that of the other drugs approved for CMV treatment, foscarnet and cidofovir, is through inhibition of viral DNA polymerase activity. 89 Treatment dosing for IV ganciclovir is 5 mg/kg twice daily with a duration of 2 to 4 weeks, but longer therapy may be required, depending on the decline in viremia and resolution of symptoms. 90 Valganciclovir is dosed 900 mg orally twice daily and both ganciclovir and valganciclovir should be dose-adjusted for renal impairment. The equivalence of IV ganciclovir and oral valganciclovir for the treatment of mild-to-moderate CMV infection and disease in SOT recipients has been demonstrated in a multicenter, randomized trial comparing the two therapies in 321 SOT recipients. 90 Valganciclovir demonstrated a rate of viral clearance at 21 days similar to that of IV ganciclovir with comparable side effects. Also, there were no differences in long-term outcomes at 1 year of followup. 91 Of note, patients were excluded if they had a lifethreatening CMV disease and median initial viral loads were relatively low, < 20,000 copies/mL. In this study, most patients in each arm of the trial were viremic for longer than 21 days, demonstrating that treatment of CMV infection may need to be prolonged. Treatment should last at least 2 weeks and continue until viremia has resolved. 27,80 Low pretreatment CMV viral loads have been correlated with more rapid disease resolution with antiviral treatment. 55 Intravenous ganciclovir is recommended over valganciclovir for patients with impaired GI absorption, those with questionable compliance, or those with life-threatening disease. 27,80 Oral ganciclovir can prevent CMV disease, but neither it nor acyclovir is recommended for the treatment of CMV. 27, 80 Because of their toxicities, particularly nephrotoxicity, foscarnet and cidofovir are reserved for failure or intolerance of ganciclovir or valganciclovir. Reduction of immunosuppression should be considered in patients with moderate-tosevere CMV disease. 27, 80 CMV recurs in 25 to 30% of SOT recipients after treatment, and relapse is associated with longer time to viral clearance. 91-93 The best predictor of relapse of CMV is detectable CMV viremia at the time antiviral therapy is discontinued, 91 so treatment should be continued with weekly monitoring until viremia is resolved. 27, 80 The benefit of intravenous immune globulin (IVIG) or CMV immune globulin as adjuncts to antiviral therapy has not been established, but could be considered, particularly in cases of CMV pneumonitis or other severe disease due to CMV. 27,80,94 A 1 to 3 month course of secondary prophylaxis is often administered to SOT recipients after therapy is complete, but close monitoring of symptoms and viral loads is an acceptable alternative. 27, 80, 93 Ganciclovir-resistant CMV is uncommon, but is more likely to occur among lung transplant recipients and CMV D þ /RÀ transplant recipients with an incidence of 5 to 10%, 95-98 and in those who have received prolonged low doses of antiviral prophylaxis. 96 Resistance typically occurs as a result of a mutation in the viral UL97 kinase gene, which is required to phosphorylate ganciclovir and make it active. 97 Resistance is less commonly due to mutation in the UL54 CMV DNA polymerase gene, which incorporates ganciclovir triphosphate into the DNA resulting in termination of viral replication. 97 Foscarnet remains active against UL97 mutants, and cidofovir may also be a viable treatment option as neither requires phosphorylation by UL97 for activity. 8,27,97 Certain mutations in UL97 may not result in clinical resistance to ganciclovir, and low-level ganciclovir resistance can sometimes be overcome with increased doses of ganciclovir, up to 10 mg/kg twice daily. 27, 80 Mutations in UL54 are less common, but typically result in cross-resistance to foscarnet, cidofovir, and ganciclovir. 8,27,97 Ganciclovir resistance should be suspected if there is not a significant decline in the level of CMV viremia after 2 weeks of appropriate treatment, particularly in patients who have received prolonged antiviral prophylaxis or treatment. 27,80 Genotypic testing can confirm the presence of mutations that may confer clinical resistance. 97 Foscarnet, either alone or in combination with ganciclovir, can be effective in the treatment of ganciclovir-resistant CMV. 15,99 Foscarnet is very active against CMV, but is considered a second-line agent due to its nephrotoxicity. Cidofovir is another treatment option but is also nephrotoxic. An important adjunctive maneuver in treating CMV is reducing the level of immunosuppression. 27,80,100 Switching to a mammalian (or mechanistic) target of rapamycin [mTOR] inhibitor such as sirolimus (rapamycin) or everolimus may be helpful, as lower rates of CMV infection have been noted with these agents. 101 CMV immunoglobulin or IVIG may also be considered as they could bolster host defenses. 27, 80 Ganciclovir-resistant CMV infections have been associated with high rates of treatment toxicity, relapsed CMV infection, and mortality, 98 and there is a clear need for novel, nontoxic anti-CMV agents, particularly ones with activity against resistant strains. Medications currently being investigated for treatment of CMV include maribavir, leflunomide, cyclopropavir, synguanol, letermovir (AIC246), and artesunate. 8,102-108 In addition, brincidofovir is a lipid conjugate derivative prodrug of cidofovir with broad activity against double-stranded DNA viruses, including CMV, and it has been used in small series to successfully treat refractory or resis-tant CMV infections. 109, 110 It has enhanced potency compared with cidofovir and no nephrotoxicity or myelosuppressive effects. 111 Cytotoxic T-cells active against CMV can be engineered and have been employed to help overcome CMV infection in immunocompromised hosts, although this type of therapy remains under development and is not yet widely available. 112, 113 Prevention If CMV prophylaxis is not administered to SOT recipients at risk, CMV infection and disease may occur within the first 3 to 4 months after transplant. 114, 115 Antiviral therapy to prevent CMV is therefore recommended for CMV D þ /RÀ and CMV Rþ SOT recipients. 28,80 Prophylaxis can prevent CMV disease 10,12,20,28,116 and in some studies, protects against rejection, graft dysfunction, and graft loss. 10, 36, 45, 117 In addition, a study of over 61,000 adult recipients of deceased donor kidney allografts demonstrated that CMV prophylaxis of D þ /RÀ renal transplant recipients was associated with a significant decrease in cardiovascular deaths, particularly in those recipients ! 40 years of age. 118 The two strategies generally employed for CMV prevention are universal prophylaxis and preemptive treatment. 114 The former involves administering antiviral medication to all persons at risk (e.g., CMV D þ /RÀ and R þ), whereas the latter involves CMV testing at regular intervals (e.g., weekly) and starting antiviral therapy only when CMV is detected. Universal prophylaxis has the advantage of protecting against other herpesviruses, and it has been associated with a decreased risk for opportunistic processes such as PTLD, infection by Pneumocystis jiroveci, aspergillosis, and bacterial infections in SOT recipients. 10,49,119,120 Preemptive therapy avoids the use of potentially toxic and costly medications, and may also allow exposure to CMV so that immunity develops and limits the later development of CMV disease. 27, 80, 114 However, preemptive therapy is logistically difficult and the monitoring expensive, and this approach may not detect CMV infection before the onset of disease, particularly in CMV D þ /RÀ SOT recipients. Most SOT programs internationally and in the United States favor universal prophylaxis 70, 100 although studies vary in outcome differences between the two options. Two meta-analyses have shown reduced CMV disease and allograft rejection with both strategies, 4,116 with universal prophylaxis associated with fewer opportunistic infections and lower mortality in one study 4 but similar mortality in the other. 116 A more recent meta-analysis of 20 studies involving 2,744 SOT recipients showed a similar risk of CMV syndrome with the two approaches, but a higher risk of late-onset CMV for prophylaxis compared with preemptive therapy and no difference in graft loss, acute rejection, other opportunistic infections, or mortality. 121 The Swiss Transplant Cohort Study of over 1,200 SOT recipients demonstrated similar rates of CMV disease with prophylaxis and preemptive strategies but improved graft survival with prophylaxis. 122 The available randomized trials that compare universal prophylaxis and preemptive therapy have also shown similar efficacy for CMV disease prevention, 36,123-125 but improved allograft survival with universal prophylaxis in some studies. 36,124 Antiviral resistance has been encountered with each strategy. 27,95,126-128 Current CMV guidelines for SOT recipients recommend universal prophylaxis for D þ /RÀ SOT recipients and either prophylaxis or preemptive therapy for Rþ recipients. 27,80 CMV D À /RÀ SOT recipients do not require CMV prophylaxis. 27,80 Among HCT recipients, valganciclovir was not proven superior in preventing CMV disease, other infectious complications or death when compared with preemptive therapy in a randomized, double-blind trial, and more patients receiving valganciclovir required hematopoietic growth factors. 129 Valganciclovir 900 mg/day, oral ganciclovir 3 g/day, or IV ganciclovir 5 mg/kg/day are recommended for CMV prophylaxis in solid organ transplantation 27,80 based on randomized clinical trials. 12,16,18 In addition, valacyclovir 8 g/day may also be used for renal transplant recipients only. 10,27,80 Valganciclovir is most commonly used, including in liver and lung transplant recipients, 70,100 despite not being U.S. Food and Drug Administration -approved for prophylaxis in those populations. At some centers, IVIG is used in combination with antiviral therapy for thoracic transplant recipients, though data are sparse. 27,80,130-132 Use of low-dose valganciclovir prophylaxis (450 mg daily) is not recommended as it has been associated with breakthrough CMV infection and may also be associated with ganciclovir-resistant CMV infection. 133 CMV can occur in up to 80% of CMV-seropositive HCT recipients after allogeneic HCT but most HCT centers use preemptive therapy after HCT due to the myelosuppressive effects of ganciclovir and valganciclovir. 79 Newer agents have been studied for use in CMV prophylaxis. Maribavir at a dose of 100 mg orally twice daily was ineffective compared with oral ganciclovir for CMV prophylaxis in liver transplant recipients. 134 Similarly, maribavir was no more effective than placebo in preventing CMV disease in allogeneic HCT recipients. 135 However, letermovir, which has a novel mechanism of action against CMV, reduced the incidence of CMV infection in allogeneic HCT recipients compared with placebo and was well-tolerated. 136 Brincidofovir, an agent with a prolonged half-life, also appears to be a promising agent for CMV prophylaxis. A randomized trial of brincidofovir versus placebo in allogeneic HCT recipients has shown efficacy of brincidofovir in preventing CMV viremia and disease when dosed only twice weekly. 137 The results of a recently completed multicenter phase 3 trial in HCT recipients examining the efficacy of brincidofovir for CMV prevention have yet to be published. a The duration of antiviral prophylaxis for SOT recipients varies by transplant center and by organ and generally ranges from 3 to 6 months. 27,70,80,100 As noted above, a concern is the development of late-onset CMV after prophylaxis is discontinued. 16,18,21 Extended prophylaxis of 200 versus 100 days of valganciclovir in 316 CMV D þ /RÀ renal transplant recip-ients showed a significantly lower incidence of CMV disease at 12 months among those receiving 200 days of prophylaxis (16.1 vs. 36.8%, p < 0.0001) and a higher risk of opportunistic infections with 100 days of prophylaxis (27 vs. 13%, p ¼ 0.001) 14 and is recommended for these patients. 27, 80 Twelve versus 3 months of valganciclovir in lung transplant recipients significantly reduced the rate of CMV disease from 32 to 4% (p < 0.001) and CMV infection from 64 to 10% (p < 0.001) 18 and is recommended particularly for CMV D þ /RÀ lung transplant recipients but may also be used in Rþ lung transplant recipients. 27,80 Some have suggested even longer courses of prophylaxis in CMV D þ /RÀ lung transplant recipients. 138 However, the toxicities and costs of prolonged prophylaxis need to be considered. Although supportive data are limited, a hybrid approach to prophylaxis is an option, particularly for patients at high risk of late CMV disease or those on augmented immunosuppression. 80, 139 This approach involves a period of prophylactic antiviral therapy followed by a period of monitoring for CMV viremia. Unfortunately, the sensitivity of monitoring for CMV infection after prophylaxis discontinuation, and its specificity in predicting disease are low. 140, 141 Assays to measure CMV-specific immunity are under study. 73, 142, 143 The QuantiFERON-CMV assay, Cellestis, Valencia, CA) is an enzyme-linked immunosorbent assaybased measurement of interferon-gamma secretion in response to CMV peptides and is the only commercially available test for assessing CMV-specific immunity. Additional study is needed to determine its utility and the test sensitivity is low in patients with lymphopenia, but the assay has been able to predict disease and may help with stratifying patient risks for CMV and guiding prophylaxis or preemptive treatment. 73, 80, 142, 144 Finally, while none is available for clinical use, CMV vaccines are in development, with some in phase II clinical trials [145] [146] [147] [148] and an ongoing phase III DNA vaccine trial. 149 

Epidemiology and Prevalence EBV, also known as HHV-4, is a double-stranded DNA gamma herpesvirus that infects more than 90% of adults worldwide, usually causing asymptomatic infection in immunocompetent individuals. [150] [151] [152] [153] Primary EBV infection has been shown to occur with a bimodal distribution. 151, 152, 154, 155 The first peak is between 2 and 4 years of age with a higher incidence among children in day care settings. 151 The second peak occurs in adolescence and may be associated with higher socioeconomic groups that may have avoided early infection. 151, 152, 154, 155 Regardless, the primary route of infection is close salivary contact, although the virus has been detected in male and female genital secretions suggesting that sexual transmission may occur. 150, 156 The manifestations of EBV infection in immunocompromised hosts such as SOT or HCT recipients are wide-ranging, from asymptomatic infection to infectious mononucleosis to malignancy. 150, 157, 158 As discussed further below, EBV is also associated with certain malignancies occurring in immunocompetent individuals. 150 Given EBV's widespread prevalence and potentially devastating consequences in immunocompromised hosts, it is an important consideration in transplant medicine. After primary infection occurs, EBV establishes lifelong latency primarily in B lymphocytes (memory B cells), and to a lesser extent in T lymphocytes, and natural killer (NK) cells. 150, 158 The virus is shed in the saliva, hence its spread through close oral contact. EBV may replicate in squamous epithelial cells but not in the absence of B lymphocytes. 150 EBV also has the ability to transform B lymphocytes, and is associated with lymphomas, including Burkitt, Hodgkin, and immunoblastic lymphomas, as well as nonlymphoid malignancies including nasopharyngeal and gastric carcinomas. 150, [159] [160] [161] [162] Among SOT and HCT recipients, PTLD is the most concerning EBV manifestation as it may lead to high-grade monoclonal lymphoma. 158 EBV can exploit normal B lymphocyte biology through complex immunomodulatory effects of EBV proteins, leading to the malignant proliferation of cells. For example, Epstein-Barr nuclear antigen-1 protein binds to viral DNA, allowing the EBV genome to be maintained in the B cell, and additional EBV proteins can function as oncogenes, blocking differentiation and facilitating lymphocyte proliferation. 150, 159, 163 The importance of viral and cellular micro-RNAs in promoting EBV oncogenesis has also been recently noted. 159, 164 The immune response to EBV infection is mediated by NK cells and cytotoxic CD4 and CD8 T lymphocytes. 150, 165 With anti-T cell immunosuppression after transplant, EBV-infected B lymphocytes can proliferate with impunity. The polyclonal proliferation may transform to monoclonal proliferation that develops into a lymphoma. 150, 159, 166 In SOT recipients, the source of the EBV is usually reactivation from the recipient, [167] [168] [169] although PTLD that occurs early posttransplant is more likely to be of donor origin. 170 In HCT, the source of EBV is usually from the donor. 171, 172 Among SOT recipients, the highest rate of PTLD is in the first year after transplant, although more recent data suggest that this rate may be decreasing and that the onset of PTLD is getting later post-SOT. 158, 173, 174 Recent data among HCT recipients show a median time to development of PTLD ranging from 2 to 6 months post-HCT. 171, 174, 175 Clinical Manifestations Initial infection in young children is usually asymptomatic, while acute infection in immunocompetent young adults more often presents as a mononucleosis syndrome, with fever, generalized malaise, lymphadenopathy, sore throat, myalgia, and GI symptoms. 176 In immunocompromised individuals, EBV infection may be asymptomatic or the disease spectrum can range from a mononucleosis syndrome to lymphoid interstitial pneumonitis to PTLD. 158 PTLD is a heterogeneous spectrum of lymphocyte proliferation disorders comprising more than 20% of malignancies after transplant. 158, 177 Although EBV can cause a polymorphic lymphoid hyperplasia, an aggressive monomorphic lymphoma with gene rearrangements may occur. 178 Most PTLD lesions are of B cell origin and are EBV-positive; EBV-negative PTLD more often occurs years after transplant. 179 While potentially any organ can be affected by PTLD, pulmonary or intrathoracic PTLD is common, particularly among lung transplant recipients who develop PTLD early after transplant. 180 Nonmalignant pulmonary manifestations of EBV primary infection or reactivation are uncommon, but may occur in immunocompromised patients, and asymptomatic pneumonia is seen in 5 to 10% of patients with mononucleosis. 181 Rapidly progressive pneumonia and BOS have been described after SOT in association with EBV infection. 182 In addition, some have reported EBV reactivation in pleural fluid and suggested a role for EBV in the development of idiopathic pleural effusions, particularly in immunosuppressed patients. 183 , 184 An additional respiratory tract condition associated with EBV infection in SOT recipients is laryngeal smooth muscle tumors. 185, 186 Diagnosis In immunocompetent patients, EBV infection is typically diagnosed by detection of anti-EBV antibodies but, as with CMV diagnosis, antibody tests are unreliable for diagnosis of primary EBV infection or PTLD in immunocompromised individuals due to impairment in humoral responses to infection. 158 However, EBV serologic testing is useful in stratifying a transplant recipient's risk of EBV infection and PTLD, as discussed further below. QNAT is often used to quantify EBV viral loads in the blood and assist in diagnosing EBV infection and PTLD, although the variation in QNAT assays used by different centers and lack of a universally recognized cutoff to assess the clinical significance can make test results difficult to interpret. 179 EBV QNAT assays are sensitive for detecting infection, but have limited specificity in terms of predicting PTLD. 187 In addition, as mentioned above, not all PTLD is EBV-related. BAL fluid with EBV detected has been reported as a more sensitive marker for identifying PTLD in pediatric lung and heart-lung transplant recipients than peripheral blood EBV PCR. 188 Radiographic imaging of EBV pneumonia resembles that of other viruses on computed tomography. Findings include reticular opacities, small nodules, or consolidation of one or more lobes. 181 In cases of PTLD involving the thoracic region, plain radiographs or computed tomography (CT) images typically show single or multiple lung nodules or masses, infiltrates, adenopathy, or pleural effusion (►Fig. 1). 189 Positron emission tomography combined with CT may be more sensitive than CT alone in identifying PTLD. 190 Excisional biopsy can provide a reliable diagnosis if imaging has indicated a suspicious lesion, particularly in the setting of sustained EBV viremia.

Several factors increase the likelihood of developing PTLD or reactivation of EBV. The impaired T cell function associated with the use of antirejection medications after transplantation or with HIV infection increases risk, and the degree of immunosuppression has significant impact on the magnitude of risk. 158, 166, 191 Other risk factors include the transplant recipient age, with children at higher risk than adults, EBV serostatus, and type of organ transplanted. 158, 192 The incidence of PTLD is highest in haploidentical HCT, heart-lung and multivisceral transplantation (up to 20%), followed by liver (4.5%), heart and lung (2.5%), pancreas (2%), kidney (1-1.5%), and matched HCT (0.5-1%). 172 Receipt of antithymocyte globulin (ATG) and other T cell depleting therapies increase risk 192, 193 as well as an HLA mismatch in HCT recipients. 194 

There are no large controlled trials to guide the management of severe EBV manifestations. 158 For PTLD, the most dire manifestation of EBV infection posttransplant, the primary treatment is a reduction in immunosuppression, which carries the risk of graft dysfunction or loss 195 and incomplete tumor response. 196 Therefore, surgical resection, local radiation, and pharmacologic therapy are other modalities that may be required. 158, 197, 198 The role of antiviral therapy is unclear as there is limited evidence supporting its use, particularly in the absence of other therapeutic maneuvers. 158 Most EBV-infected cells within PTLD lesions are not undergoing lytic EBV DNA replication, the target for antiviral activity. 199 When antiviral treatment is used, ganciclovir is preferred to acyclovir given the former's superior in vitro activity against EBV. 158, 200, 201 Among patients with CD20þ PTLD, the use of rituximab, a monoclonal antibody that targets CD20, has been shown to achieve high rates of remission and improved 3-and 5-year survival rates. [202] [203] [204] [205] Treatment is generally well-tolerated, but the addition of chemotherapy may be required to prevent relapse, depending on specific risk factors. 158 Finally, adoptive transfer of EBV-specific cytotoxic T cells has been tried to both treat and prevent PTLD. [206] [207] [208] [209] The results are most promising for preemptive therapy, 206 but this process is complex and few centers have the ability to perform this type of adoptive immunotherapy.

There have been several reports of regression of PTLD after changing immunosuppression to an antiproliferative agent such as sirolimus, [210] [211] [212] [213] although data are limited as to the relative benefits of reduction of immunosuppression compared with using sirolimus to exploit its potential antitumor activity. 211, 213 Supporting the use of sirolimus are reports of mTOR inhibitors preventing replication of EBV in cell lines via inhibition of cell cycle progression and interleukin (IL)-10 production, an important stimulator of EBV-related tumors. 214 For smooth muscle tumors, surgical resection is an option if there are limited numbers of tumors. However, when there are multiple tumors, surgical resection may be insufficient. In addition, these tumors are usually refractory to chemotherapy, particularly in individuals with AIDS, and mTOR inhibitors might be useful in such cases. 185 Prevention Prophylactic use of antiviral therapy is not recommended for prevention of EBV reactivation or PTLD given the limited data supporting this practice. 158, 215, 216 In a very small study, Höcker et al prospectively compared ganciclovir or valganciclovir prophylaxis (N ¼ 20) to no prophylaxis (N ¼ 8) in EBVseronegative pediatric renal transplant recipients with EBVseropositive donors. 217 EBV primary infection occurred in 45% of antiviral recipients compared with 100% of controls (p < 0.0001). However, additional data are needed to fully assess the efficacy of this approach. IVIG, including CMV immune globulin, has also been studied as a prophylactic agent for PTLD, but the data are inconclusive for this approach as well. 215, [218] [219] [220] On the other hand, preemptive antiviral therapy may reduce the risk of PTLD, particularly in children. 179, 217, [221] [222] [223] [224] Hierro et al demonstrated that among 47 pediatric liver transplant recipients with detectable EBV DNA, an undetectable EBV viral load was achieved among almost half of patients with valganciclovir alone, largely without reduction in immunosuppression, and no new PTLD cases were seen. 223 In a similar population, Venturi et al reported partial or complete response to 30 days of ganciclovir in 64% of cases with an inverse correlation between QNAT viral load and ganciclovir serum concentration. 224 Among HCT recipients, rituximab has been used preemptively when high levels of EBV are detected by QNAT, and found to prevent approximately 90% of EBVassociated PTLD. 209 However, there is no definitive threshold of EBV viremia identified at which preemptive therapy is optimal. Patients at an increased risk for EBV reactivation and PTLD (e.g., seronegative SOT recipients of organs from seropositive donors and those receiving T cell depleting therapies such as ATG) should be closely monitored for clinical signs and symptoms of PTLD. 158 Herpes Simplex Viruses 1 and 2

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are common infections worldwide. In the United States, the seroprevalences of HSV-1 and HSV-2 are 58 and 17%, respectively. 225 Transmission of these viruses is by direct contact with infected skin or infected secretions. Transmission can occur during periods of subclinical viral shedding, when symptoms are absent. 226 

Among immunocompetent adults, both HSV-1 and HSV-2 cause a variety of infections that involve mucocutaneous surfaces. Syndromes overlap, but HSV-1 typically causes orolabial herpes, while HSV-2 causes anogenital disease. 227 Both syndromes are characterized by painful, ulcerating vesicles of the skin and mucous membranes of the affected region. After primary infection, HSV-1 and HSV-2 establish latent infection of sensory ganglion neurons. 228 Reactivation of latent virus leads to recurrent mucocutaneous disease. 229, 230 Severe HSV-1 or HSV-2 disease is uncommon in immunocompetent adults. However, important neurologic syndromes, including Bell palsy, meningitis, and encephalitis can occur and are associated with significant morbidity and mortality. 231 Immunocompromised patients with HSV disease most commonly develop one of the mucocutaneous syndromes described above. Most infections in immunocompromised patients represent reactivation, and recurrences are often more frequent, more extensive, and of longer duration than in immunocompetent patients. 232 The immunocompromised host is also at risk for both local extension of disease (e.g., HSV esophagitis) and disseminated infection. Although HSV is not considered a respiratory virus, the oropharyngeal HSV disease can extend to the lower respiratory tract, either by contiguous spread or by aspiration. 233 The lower respiratory tract disease can present as tracheobronchitis or pneumonia and manifest as fever, cough, dyspnea, bronchospasm, and/or chest pain. [233] [234] [235] Tracheobronchitis may be complicated by airway ulceration and hemorrhage. The most common radiographic findings reported with HSV pneumonia include bilateral symmetric ground glass attenuation, although consolidation has also been described. 236 Disseminated HSV infection with involvement of noncontiguous visceral organs is associated with very high mortality, especially with HSV hepatitis. 237 HSV hepatitis commonly presents with fever, transaminitis, hyperbilirubinemia, thrombocytopenia, and abdominal pain. 237 HSV viremia is associated with visceral involvement and increased mortality. Among a series of intensive care unit patients, HSV viremia had a high incidence of pneumonia (38%), hepatitis (15%), and death within 20 days (27%). 238 

Mucocutaneous HSV lesions, including esophageal or tracheobronchial ulcerations viewed endoscopically, are often diagnosed based on their characteristic appearance. Scrapings or biopsies of lesions can be tested for HSV by viral culture or direct immunofluorescence assays (DFA), though a combined approach may have the highest diagnostic yield. 230 Sampling early vesicular lesions is optimal; such lesions should be unroofed and scraped for culture or DFA. PCR-based identification of viral genomic material is both more sensitive and rapid than viral culture, and can be performed on blood or cerebrospinal fluid; CSF testing for HSV DNA is the gold standard for suspected herpes encephalitis. 239, 240 HSV pneumonia is difficult to diagnose due to the lack of specificity of symptoms, radiological features, and detection of HSV in the airway. 233 Historically, the diagnosis was often based upon autopsy findings. 233 HSV can be detected in clinical respiratory specimens by viral culture or PCR-based techniques, but the isolation of HSV from BAL fluid does not necessarily indicate true disease. Asymptomatic HSV-1 viral shedding in the lower respiratory tract is relatively common, especially in critically ill and immunocompromised patients. 241 It is suggested that a higher HSV viral load in BAL fluid is associated with a worse outcome and with pneumonitis, 241 but a causative association has not been proven. 233 Bronchoscopy does allow direct observation for signs of tracheobronchitis, but bronchoscopic examination can also be normal. 233 Overall, HSV is considered to be an uncommon cause of pneumonia, even in immunocompromised patients. In one series of 63 immunocompromised patients diagnosed with pneumonia, HSV was determined to be the leading cause in 2 patients (3%). 242

For severe HSV infections or when absorption of oral medications may be impaired, intravenous acyclovir should be used for treatment. 243, 244 Oral valacyclovir, a prodrug of acyclovir, and famciclovir, a prodrug of penciclovir, exhibit superior oral bioavailability and can be used to treat limited HSV disease with simpler dosing regimens as compared with oral acyclovir. 243,245 Acyclovir resistance is uncommon, but can be encountered among immunocompromised patients, and may occur in the setting of multiple courses of acyclovir for recurrent disease. 246, 247 Such strains are also famciclovir/ penciclovir resistant, but can be treated with foscarnet or cidofovir. 243, 245 Topical cidofovir has been used successfully to treat acyclovir-resistant mucocutaneous HSV infection in immunocompromised persons, thus avoiding the nephrotoxicity of systemic therapy. 248 Prevention Chronic suppressive therapy should be considered in patients with a history of HSV infection, particularly if episodes are recurrent. 247 In addition, HSV-seropositive transplant recipients are given antiviral medication to suppress HSV around the time of transplant (typically for 1 month) even if they have not had symptomatic episodes in the past. 247 Oral acyclovir or valacyclovir can be used, but most SOT recipients are administered valganciclovir for prophylaxis against CMV, and since this drug is also active against HSV, additional suppressive therapy directed at HSV is unnecessary. 247 Immunosuppressed HSV-seronegative persons should be made aware of the risks of acquiring HSV infection and should avoid contact with persons who have active HSV lesions, although, as noted above, infection can also be acquired from asymptomatic persons. 247 Daily antiviral therapy taken by an HSVinfected person is effective at preventing transmission to uninfected partners 249 and is an option for serodiscordant couples.

Varicella-zoster virus (VZV) is one of the most common opportunistic infections among hematopoietic stem cell transplant (HSCT) 250, 251 and SOT recipients. [252] [253] [254] [255] Primary varicella infection causes chickenpox, a febrile illness accompanied by a diffuse cutaneous vesicular exanthem. 256, 257 The course is usually selflimited, but immunocompromised hosts can rarely develop severe pneumonia, encephalitis, or visceral disease. 256, 258 Following resolution of the initial infection, VZV establishes latency within sensory ganglia. 257, 259 Reactivation of latent VZV may occur in individuals with impaired immunity and gives rise to stereotypical dermatomal vesicular skin lesions, termed herpes zoster (HZ) or "shingles." 250, 257, 259 Widespread cutaneous dissemination and visceral involvement can also occur in immunocompromised patients, but respiratory involvement is uncommon. 250, 260, 261 

Primary VZV infection in adults is unusual as more than 90% of adults in the United States are seropositive. 251,257,258 HZ occurs in more than 1 million patients annually and the lifetime attack rate is 10 to 30%. 257, 259 The incidence of HZ increases with age, rising to 10 cases per 1,000 patient-years by age 75. 257, 259 Patients with impaired cell-mediated immunity are at particularly high risk of HZ. 250, 257, 259 The incidence of HZ (per 1,000 person-years) was 29.4 among HIV-infected individuals compared with 2.0 cases among HIV-seronegative controls. 262 Data from the Veterans Affairs health care system cited an incidence rate among 1,107 SOT recipients of 22.2 per 1,000 patient-years. 252 The risk of VZV infection reflects the intensity of immunosuppression and VZV serological status. Among SOT recipients, incidence rates are as follows: renal 3 to 10% 252, 254, 263, 264 ; liver 5.7 to 12% 263, 265, 266 ; heart 6 to 16.8% 252, 263, 267 ; and lung 12.5 to 20.2%. 255, 263, 268 The highest rates of VZV infections have been reported among HSCT recipients (23-67%). 250, 251, 269 In one study of HSCT recipients, the incidence of HZ was 175 cases per 1,000 personyears, with cumulative incidence rates at 27% at 1 year; 36% at 2 years; and 44% at 3 years. 251 

With primary VZV infection, pneumonia is a rare but potentially serious complication, with an estimated incidence of 2.3 in 400 cases. 270 In contrast to HSV, involvement of the lungs occurs via the bloodstream rather than by local extension. 271 Typically, VZV pneumonia presents within 7 days of the onset of rash, but respiratory symptoms may precede rash. 272, 273 Among immunocompromised hosts, pneumonia is more common and may be more severe. 274, 275 Symptoms of VZV pneumonia include cough and dyspnea, and in severe cases hypoxemia, fulminant respiratory failure and death can occur. Classic chest radiographic manifestations of VZV pneumonia include diffuse interstitial nodular opacities that are often more severe than expected for the degree of clinical symptoms. 272, 275 The majority of HZ infections are limited to vesicular cutaneous lesions in a single dermatome, even in immunocompromised patients. 251, 257, 265 Dissemination with the involvement of noncontiguous dermatomes occurs in up to 10% of HSCT recipients. 251 However, visceral involvement, including respiratory tract involvement, and fatalities are rare (< 2%). 250, 255, 261 Rarely, immunocompromised patients may present with visceral involvement in the absence of cutaneous lesions of HZ. 276 

The diagnosis of primary VZV or HZ is often established clinically, but laboratory studies may be confirmatory. 251, 257 Direct detection methods, such as DFA, are more rapid and more sensitive than viral culture. 257 VZV may also be detected by PCR in blood or tissue. 257 PCR testing of serum or blood may be helpful in the immunocompromised patient who has visceral disease before the appearance of cutaneous lesions. 276 

Acyclovir (oral or IV), valacyclovir, or famciclovir are the preferred agents for VZV infections. 250, 251, 259, 277 Ganciclovir and valganciclovir display excellent in vitro activity against VZV and can be used. 253 Acyclovir resistance may occur, 278 particularly with prolonged use. 256 Foscarnet may be effective as salvage therapy for acyclovir-resistant VZV, 279,280 but resistance to foscarnet may also develop. 281

Prophylaxis with acyclovir or valacyclovir is effective in high risk immunosuppressed patients. 253, [282] [283] [284] [285] In one study of 263 cases of SOT recipients treated with oral valacyclovir for 1 year posttransplant, no cases of VZV infections were observed. 253 A live attenuated VZV vaccine (Oka strain; Zostavax Merck & Co., Inc., Kenilworth, NJ) has been shown to reduce the frequency and severity of VZV infections and postherpetic neuralgia in elderly adults and at-risk populations. [286] [287] [288] This vaccine was designed to stimulate waning immunity in the elderly and is distinct from the varicella vaccine (Varivax Merck & Co., Inc., Kenilworth, NJ) used to immunize seronegative persons, as the latter contains 10 to 12-fold less virus. 282, 289, 290 However, live viruses are generally contraindicated in immunosuppressed individuals. 288, 291, 292 Therefore, society guidelines recommend vaccination for varicella or herpes zoster before transplant, 291, 292 as long as there is at least 4 weeks between administration of a live vaccine and the initiation of highly immunosuppressive therapy. 291 Human Herpesvirus-6 Epidemiology and Prevalence HHV-6, first isolated in 1986 from the peripheral blood mononuclear cells (PBMCs) of six adults with lymphoproliferative disorders, 293 is classified in the β-herpesvirus subfamily, genus Roseolovirus, and is closely related to CMV. 294 HHV-6 exhibits tropism for CD4 lymphocytes, endothelial cells, and the central nervous system. 294 HHV-6 is a ubiquitous virus that infects > 80% of children by 3 years of age, [295] [296] [297] [298] and > 90% adults are seropositive. 299,300 Two subtypes (A and B) exist; HHV-6B accounts for > 98% of HHV-6 infections in the United States, Japan, and Western countries, 294,301 whereas HHV-6A predominates in sub-Saharan Africa. 302 HHV-6A is more neurotropic than HHV-6B. 294 HHV-6 is the only HHV known to integrate into the germline. 303 The complete HHV-6 genome may integrate into the telomeres of host cell chromosomes and be vertically transmitted. 303 This condition, chromosomally integrated HHV-6, is present in approximately 1% of the populations of the United States and United Kingdom and results in very high viral loads (exceeding 5.5 log 10 copies/mL) which are typically asymptomatic. 303, 304 This condition must be discerned from HHV-6 primary infection or reactivation which may result in the manifestations described below.

In 1988, Yamanishi et al implicated HHV-6 as the cause of roseola (exanthema subitum) or sixth disease in children. 305 In 1989, HHV-6 was isolated from PBMCs from 100% (26/26) of infants with roseola during the first 3 days of fever; the rate of viral isolation fell to 17% by day 5 to 7 and 0 by day 8. 306 Subsequent studies demonstrated that primary infection with HHV-6 was a common cause of acute febrile illness (with or without skin rash) in infants and young children. [307] [308] [309] [310] In a prospective study of 243 acutely ill children < 2 years old who presented to an emergency department (ED), HHV-6 viremia was detected in 34 (14%). 310 Symptoms of HHV-6 infection included: malaise (82%); fever > 40°C (65%); inflamed tympanic membranes (62%); nasal congestion (57%); rash (18%); seizure (3%). The typical rash of roseola was present in only three children. Only 2 were hospitalized and all 34 recovered, usually after an average of 4 days of fever. 310 In 1994, Hall et al studied 1,653 infants and young children (< age 3 years) who presented to an ED with acute febrile illnesses. 309 Overall, 160 (9.7%) had a primary HHV-6 infection, as documented by viremia and seroconversion; 21 (13%) were hospitalized and 21 (13%) had seizures. 309 Often the seizures appeared late and were prolonged or recurrent. Conversely, no primary HHV-6 infections were found among 582 infants and young children with acute nonfebrile illnesses or among 352 controls without acute illness. 309 In another cohort of 81 children < 2 years old with primary HHV-6 infections, the following symptoms were present: fever (57%); fussiness (69%); rhinorrhea (65%); diarrhea (26%); rash (31%); roseola (23%); and seizures (0%). 297 A study in the United States followed 227 children born to HIVseropositive mothers. 311 The cumulative infection rates of HHV-6 DNAemia at 6 and 12 months of age were 28 and 78% in HIV-negative children compared with 11 and 33%, respectively, among HIV-infected children (p < 0.001). 311 There was an association between high CD4 counts and HHV-6 infection, consistent with the tropism of this virus for CD4 lymphocytes. Among HIV-infected children, HHV-6 infection was associated with progression of HIV disease (p < 0.05). 311 HHV-6 is endemic in sub-Saharan Africa in healthy young children. 302, 312 In a study of 371 asymptomatic infants in Zambia, serum HHV-6 DNAemia was present in 15% at 6 months and 19% by 18 months. 302 Two studies from Zambia detected HHV-6 DNA in the blood of 5 to 30% of HIV-negative children admitted to the hospital with febrile illnesses. 302, 313 A prospective study of 303 pediatric inpatients aged between 3 weeks and 2 years in Zambia detected HHV-6 DNAemia in 20.8%. 312 Data regarding the importance of HHV-6 as a cause of community-acquired pneumonia (CAP) or acute respiratory infections in children are scant, as this pathogen is rarely looked for. However, in a study from rural China, Zhou et al obtained induced sputum from 354 hospitalized infants and children with acute respiratory infections (273 had CAP; 81, non-CAP). 308 HHV-6 was detected in 50.9% of children with CAP and 42% among 81 with non-CAP. These various studies suggest that HHV-6 is a common cause of acute febrile illness with or without rash in children, and the course is usually benign and self-limited over several days. 294 Pneumonia and seizures can occur, but are uncommon in immunocompetent hosts.

Primary HHV-6 infections are rare in older children or adults. 294, 301, 309 However, even among immunocompetent subjects, rare cases of hepatitis, infectious mononucleosislike syndrome, gastroenteritis, colitis, and neurological complications (seizures, encephalitis, chronic psychiatric disorders) may occur. 294, 314, 315 Further, several studies suggest a link between chronic HHV-6 infection and multiple sclerosis. [316] [317] [318] Fatal myocarditis, although rare, has been described. 319 Detection of HHV-6 in explanted hearts of children with idiopathic cardiomyopathy 320 suggests a possible pathogenic link, given the tropism of HHV-6 for endothelial cells. 321 Additionally, maternal HHV-6 infection during pregnancy may lead to fetal infection and fetal death. 294, 314 Reactivation of HHV-6 in Immunocompromised Hosts Like other herpes viruses, HHV-6 establishes lifelong latency in the host and may reactivate under conditions of impaired immunity. 294 Most severe HHV-6 infections occur in markedly immunocompromised children or adults 294 including HCT 322-325 or SOT recipients [326] [327] [328] [329] ; or those with congenital or acquired immunodeficiency disorders, 296, 330 HIV, 312,331 or lymphomas or hematological malignancies receiving chemotherapy. 293, 324, 332 Among HCT recipients, asymptomatic HHV-6 DNAemia is common (30-60%), 300,325,333,334 but the vast majority of infections are self-limited and do not require treatment. 314 In one study, 82 allogeneic HCT recipients had weekly blood tests for HHV-6 PCR; HHV-6 viremia was detected in 46 (56%) at a median of 23 days. 335 In another study of 315 allogeneic HCT recipients, blood was drawn twice weekly for 3 months for HHV-6 PCR; viremia was detected in 111 (35%) at a median of 20 days post-HCT. 333 In a recent study, plasma assays for HHV-6 DNA were performed in 106 pediatric allogeneic HCT recipients; HHV-6 viremia was detected in 48% at a mean of 20 days post-HCT and the onset of viremia coincided with the appearance of lymphocytes and monocytes in the peripheral blood. 334 Among SOT recipients, HHV-6 has been isolated in > 20% of subjects when serial samples are obtained, 299 295, 342, 347, 348 Encephalitis may result in dementia, memory loss, loss of consciousness, seizures, and even death. 295 Magnetic resonance imaging scans may show signal abnormalities in the limbic system, 295 but are often normal. 349, 350 Among organ transplant recipients, HHV-6 infections have been associated with increased mortality. 333, 342, 343 Among liver transplant recipients, HHV-6 may precipitate graft dysfunction or hepatitis, 327, 345, 351 and may increase the risk of fungal infections and mortality. 300, 328 However, severe hepatic failure has been rare. 352 Among renal transplant recipients, HHV-6 viremia is common (> 26%) and is usually asymptomatic 336 but fatal infections have been described. 353 Clinically significant HHV-6 infections rarely complicate heart transplantation, 354 but HHV-6 pericarditis 355 and encephalitis 356 have been reported. In a series of 30 lung or heart-lung transplant recipients, serial clinical specimens (blood, BAL fluid, tissue) were tested for HHV-6 PCR; HHV-6 was detected in 20 (66%) at a median of 18 days posttransplant. 337 Although no clinical disease was linked to HHV-6 infection, mortality was higher in HHV-6-infected patients (7/20 expired) compared with uninfected patients (0/10 expired). Additionally, eight of nine viral or fungal infections were associated with HHV-6. Another series of 26 lung transplant recipients detected no cases of HHV-6 infections in peripheral blood. 357 Costa et al examined 87 transbronchial biopsies from 30 lung transplant recipients by QNAT; HHV-6 DNA was detected in 6.9%, but did not correlate with allograft rejection and the clinical significance was not clear. 358 In another series, 22 lung or heart-lung transplant recipients were followed for 1 year posttransplant; HHV-6 antigenemia was detected in 20 (91%) in blood or BAL. 359 Only two had clinically significant disease (pneumonitis in one; encephalitis in one). 359 Neurohr et al followed 87 consecutive lung transplant recipients for a mean of 3.3 years; HHV-6 was detected in 20 (23%) and was associated with an increased risk of BOS. 338 However, in a subsequent study, Manuel et al followed 93 lung transplant recipients for 3 years, and measured HHV-6 PCR in all BAL specimens. 339 HHV-6 was detected in 20.4% of patients, but was not associated with acute lung allograft rejection or BOS. In summary, HHV-6 is isolated in blood or BAL in > 20% of lung transplant recipients but the clinical significance remains unclear. One case of HHV-6 colitis was reported in a lung transplant recipient. 346 HHV-6 may infect HIV-positive patients, but is often clinically silent. 360, 361 In a study of 32 HIV-infected males, HHV-6 was detected more frequently (100% detection) in subjects with CD4 counts > 400 compared with 58% with CD4 counts < 400 (58% detection, p < 0.06), consistent with the tropism of HHV-6 for CD4 lymphocytes. 360 Falasca et al evaluated the detection rate and viral load of HHV-6 in gastric, duodenal, and colon biopsies from HIV-positive (n ¼ 26) and HIV-negative (n ¼ 27) subjects. 331 HHV-6 DNA was detected in 88% of HIV-infected individuals compared with 63% of HIV-negative subjects. In a study of 50 HIVinfected children (aged 3-13 years), HHV-6 was detected in oral mucosal cells in 9 (18%). 362 In HIV-infected patients, endogenous reactivation of HHV-6 may occur. 302, 312 Primary HHV-6 infection in children with HIV has been associated with progression of HIV disease. 311

Identification of HHV-6 DNA in blood mononuclear cells, serum, or tissue and seroconversion have been the traditional methods to diagnose HHV-6 infection, 294, 297 but QNAT detection of HHV-6 DNA in biological samples by real-time PCR is the most convenient and most often used method currently. 300 Still, the clinical significance of HHV-6 DNAemia is not clear, as most subjects are asymptomatic and do not require treatment. 294 No threshold has been formally recognized to identify infection requiring treatment. 294 The decision to treat should be based on clinical features, viral load, and host features, including severity of immunosuppression.

The prognosis of HHV-6 infections is usually excellent; most cases spontaneously resolve without sequelae. The vast majority of patients infected with HHV-6 do not require treatment. However, treatment may be required for selected complications in immunocompetent patients, such as encephalitis, pneumonia, disseminated or lifethreatening disease, or for clinically significant disease in immunocompromised hosts. 294, 326 When patients are on immunosuppressive drugs, cessation or minimization of immunosuppression is a key to a favorable outcome. 294 The role of specific antiviral agents is controversial. Randomized therapeutic trials have not been done. However, ganciclovir, valganciclovir, foscarnet, and cidofovir all display in vitro activity against HHV-6, and favorable responses have been cited in anecdotal cases and small series. 294, 300, [363] [364] [365] Acyclovir is less active and should not be used. 294 The role of routine surveillance tests for HHV-6 is controversial. In one study of HCT recipients, high-level HHV-6 infection was associated with increased incidence of CMV infection, acute GVHD, and mortality. 333 By contrast, in another cohort of HHV-6 infected HCT recipients, early survival (3 and 6 months) was similar in patients receiving viral therapy or no treatment. 335 Adoptive immunotherapy (transfer of HHV-6 specific T cells) may be an option in the future. 366 Human Herpesvirus-7 Epidemiology and Prevalence HHV-7, another lymphotropic virus that was first identified in 1990, 367 belongs to the β herpesvirus family and has close homology with HHV-6. 368 HHV-7 is a ubiquitous virus that is acquired early in life (usually during the first 5 years), 369 presumably via contact with oropharyngeal secretions. 370 Like HHV-6, it infects more than 90% of the human population. 371, 372 In a prospective study, 496 children < 3 years old seen in the ED or clinic were evaluated for primary infections with HHV-6 and HHV-7; three cohorts were studied: (1) 250 children with fever, signs of sepsis, or seizures, (2) 65 healthy children for seen for "well visits," and (3) 161 children with chronic medical illness. 373 In the first cohort, 29/250 (11.6%) had a primary HHV-6 infection and 8 (3.2%) had a primary HHV-7 infection. Seizures occurred in 75% with HHV-7 compared with 17% with HHV-6 (p < 0.04). Median age was 23 months in subjects with HHV-7 compared with 9 months for HHV-6. No cases of HHV-7 infections were seen in the other two cohorts.

Importantly, the clinical spectrum of HHV-7 has not been well defined. HHV-7 may cause diseases similar to HHV-6, 374 including a roseola-like illness, 375 acute febrile respiratory disease, 373, 374 and seizures in young children. 372, 373 Rare manifestations include encephalitis and Guillain-Barre syndrome. 376, 377 Like HHV-6, HHV-7 establishes latency in lymphocytes for the life of the host. Reactivation of HHV-7 may occur among immunocompromised hosts, but clinically important infections are much less common than with HHV-6. 329,378 A recent study of 105 HCT recipients detected HHV-6 in 60.0% and HHV-7 in 8.6%, with peak detection approximately 21 days posttransplant. 325 Diagnosis HHV-7 PCR diagnostic assays are primarily used for research purposes as there is no common clinical scenario warranting HHV-7 diagnostic testing. 379 Given the rarity of HHV-7, and limited data regarding clinical importance and management, we will not further discuss this agent.

Human Herpesvirus-8 HHV-8, first discovered by Chang et al in 1994, 380 is closely related to EBV and is in the family of gamma herpesviruses. 381 HHV-8 is also termed Kaposi sarcoma-associated herpesvirus (KSHV). The importance of HHV-8 (KSHV) is its oncogenic properties. HHV-8 is the causative agent for at least three malignancies: (1) Kaposi sarcoma (KS), a lymphatic endothelial cell malignancy, 326, 381, 382 (2) multicentric Castleman disease (MCD), 381, 383, 384 and (3) primary effusion lymphoma (PEL). 381, [385] [386] [387] [388] In addition to these three "hallmark" malignancies, rare cases of hemophagocytic lymphohistiocytosis 381, 382, [389] [390] [391] [392] have been associated with HHV-8. The pathogenesis of these malignancies likely results from viral and cellular angiogenic and inflammatory factors. 381 HHV-8 can stimulate cell proliferation and inhibit apoptosis of tumor cells in KS, MCD, and PEL. 388 Epidemiology HHV-8 in endemic in sub-Saharan Africa, 393-400 with seroprevalence rates of 50 to 70%. 313, [393] [394] [395] 397, 398, 401 In Uganda, the seroprevalence of HHV-8 increases with age as follows: 1.5 to 2 years old, 16%; 10 to 13 years old, 32%; 14 to 19 years old, 37%; adult > 50 years old, 49%. 402 In sub-Saharan Africa, factors that increase seropositivity for HHV-8 include HIV infection and malaria parasitemia. 403 Seropositivity rates vary considerably among different regions/countries and are as follows: Europe 6 to 30%, with highest prevalence in Mediterranean countries 404 ; Southeast Asia 4.9 to 15.5% 404 ; the Caribbean 4.4% 404 ; Latin America 3 to 16% 405,406 ; and United States 1.5 to 6%. 388, 404, 407 High rates of KS and HHV-8 seroprevalence are also found among Amerindians from Brazil and Ecuador. 405 Several distinct subtypes of HHV-8 have been described, with some subtypes preferentially found in specific geographic regions (e.g., Africa, Asian Pacific, United States, Europe, Middle East, etc.). 393 HHV-8 may be transmitted by close contacts (e.g., saliva, bodily fluids) 382,408-410 or by sexual transmission. 410, 411 Transmission via blood transfusion 412 and organ transplantation 413, 414 has been described.

Primary infections with HHV-8 in immunocompetent subjects are mild and self-limited within a few days. 326 Children may develop fever and rash 400 ; in adults, fever, diarrhea, and lymphadenopathy may occur. 326, 415 Like other herpesviruses, following resolution of the primary infection, the virus persists in a latent state in lymphoid cells. 326 In immunocompetent individuals, pathogen-specific CD8 T cells control HHV-8 replication, preventing progression to neoplastic disease. 415 HHV-8 may reactivate in individuals with severe impairment in immune defense, 416 particularly those infected by HIV, 388, 417 SOT recipients, 329, 382, 395, 418, 419 and other congenital and acquired immunodeficiency syndromes. 420 Globally, HIV infection is associated with an increased prevalence of HHV-8 seropositivity compared with HIV-negative persons (odds ratio [OR] ¼ 1.99, 95% confidence interval [CI] ¼ 1.70-2.34). 417 The association is strongest among HIV-positive men who have sex with men (OR ¼ 3.95, 95% CI ¼ 2.92-5.35) and those with hemophilia (OR ¼ 3.11, 95% CI ¼ 1.19-8.11). 417 Additionally, HHV-8 is endemic in sub-Saharan Africa in both HIV-negative and HIV-positive individuals. 410 Diagnosis Serology has limited utility in the diagnosis of acute HHV-8 infection and there is no standard serological test for clinical use. 388 HHV-8 DNA can be quantified in plasma and PBMCs via PCR. HHV-8 viremia is invariably present with PEL and MCD, 421 and is associated with the clinical stage of KS. 422 Immunohistochemistry can identify HHV-8 proteins in tissue and is often used adjunctively in the diagnosis of KS, MCD, and PEL. 419

As noted above, HHV-8 has been associated with several distinct clinical manifestations, including KS, MCD, and PEL, and the clinical features of each are discussed separately below.

The disease most often associated with HHV-8 infection is KS, an angioproliferative cancer of endothelial cells. 420 Histopathological features of KS include spindle-shaped cells, inflammatory infiltration, and angioproliferation with extravasating erythrocytes. 423 Endothelial cell markers (CD31, CD34, factor VIII) and lymphatic endothelial markers may be present. 423 HHV-8 latency-associated nuclear antigen (LANA) is present in spindle cells in KS. 423 KS is classified as one of four epidemiologic forms: (1) Classic KS which primarily affects elderly Eastern European Jewish or Mediterranean men, (2) endemic KS which occurs in sub-Saharan Africa, 393, 398, 424 (3) epidemic KS is seen in HIV-infected subjects with AIDS, 396, 409 and (4) iatrogenic KS from immunosuppressive therapy. 381 KS has a variable clinical course ranging from very indolent cutaneous forms to a rapidly progressive multiorgan or disseminated disease. The clinical manifestations vary depending upon the immune status of the patient and organs involved. 389, 425 In the following sections, clinical features, among the four epidemiological forms will be discussed.

Classic KS primarily affects elderly Eastern European Jewish or Mediterranean men (male/female ratio: 10-15/1), typically presenting with indolent and chronic cutaneous plaques and nodules. 388 The KS skin lesions are characterized by purplish discoloration, usually first appearing on the extremities. 419 Classical KS in immunocompetent patients is usually chronic, persistent over many years and is not life threatening. 425 Disseminated disease is uncommon. 388 For localized forms, surgical resection, radiotherapy, or intralesional injections may be adequate as therapy.

The African endemic form of KS, is found in HIV-negative or HIV-positive individuals (children or adults) in countries of East and Central Africa. 393,394,398 KS is the most common cancer in sub-Saharan Africa. 404, 424 Among an estimated 66,200 cases of KS worldwide, 58,800 are believed to have occurred in sub-Saharan Africa. 426 The incidence of endemic KS in Africa is more common in males and adults > 35 year old. 398 Endemic KS in Africa is more aggressive than classic KS in Europe and Mediterranean Countries. 404 Typical cutaneous lesions are purplish/reddish in color, often affecting the lower extremities, and may infiltrate and destroy subcutaneous tissue and even bone. 427 In African children and adults with endemic KS, oral manifestations (soft palate, gingiva) are common. 428, 429 Multicentric involvement of GI tract, lungs or bronchi, spleen, liver, and lymph nodes may occur. 427 Males typically have a greater systemic tumor burden 429 and widely disseminated disease is usually fatal within 3 years. 427

Epidemic KS may complicate HIV infection in all areas of the world, 430 with the highest incidence in Africa. 381, 396 During the pre-antiretroviral therapy (ART) era, KS was the most common malignancy among HIV-infected persons (incidence 1,500-2,500 cases per 100,000 personyears). 431, 432 The use of ART has resulted in a significant decline in incidence to < 500 cases/per 100,000 personyears in developed, resource rich nations. 431, 432 By comparison, the incidence of KS in the general population is approximately 1:100,000 person-years. 404 The incidence of KS in HIV-positive individuals is approximately 1:20, with even higher rates (up to 30%) among HIV-infected men who have sex with men. 404, 409, 411, 430 The radiographic features of pulmonary KS are varied; multiple pulmonary nodules, tumorous masses, bronchovascular bundle thickening, and pleural effusions are the most common findings on chest CT scans. 433 Endobronchial KS may present as red or purple nodules or lesions at airway bifurcations 434 ; because of the risk of bleeding, endobronchial biopsy is not recommended. Immune reconstitution inflammatory syndrome-associated KS flares have been reported in pulmonary KS. 435 Musculoskeletal involvement with HIVassociated KS has rarely been described. 436 HHV-8 infection enhances HIV replication. HIV-infected men who are seropositive to HHV-8 have impaired proliferative responses to HHV-8. 437 Following ART in HIV-infected individuals with KS, cytotoxic lymphocyte responses to HHV-8 increase. 388 

Organ transplant recipients are at an increased risk of developing KS, 326,438,439 but the incidence varies considerably among different geographic regions. Among adult SOT recipients in the United States, Southeast Asia, and Northern Europe, the cumulative incidence of KS is approximately 0.5% compared with 6 to 28% incidence in regions of the Middle East and some Mediterranean regions. 326 symptoms, and anemia, has also been linked with HHV-8 in some, but not all cases. 440 MCD associated with HHV-8 is the plasma cell variant. 384, 388 MCD is driven by hypersecretion of IL-6, a cytokine that promotes B cell growth and angiogenesis. 381 As with KS, the majority of HHV-8-infected cells in MCD are latently infected, 381 but a subset expresses lytic genes. 381, 441 Exacerbations of MCD correlate with increased HHV-8 viral load and increased IL-6 and IL-10 levels, underscoring the importance of viral replication and cellular cytokines in the pathogenesis of this disease. [441] [442] [443] Tumor cells in HIV-positive individuals with MCD are plasmablasts that are scattered in the mantle zone of follicles, express B cell antigens, and are usually MUM1 (þ), CD138 (À), and CD138 (þ). 444 The HHV-8-infected cells may form small confluent clusters, sometimes coalesced into "microlymphomas" or large sheets of cells thought to represent frank lymphoma. 444 Importantly, these plasma cells harbor latent and lytic HHV-8. 444 MCD most commonly affects HIV-infected patients (> 90% males). 440, 443, [445] [446] [447] but may also occur in HIV-negative immunosuppressed persons, especially SOT recipients. [448] [449] [450] Among HIV-positive subjects, > 99% of cases of MCD are associated with HHV-8, as are > 50% of MCD among HIVnegative subjects. 440, 443, 444, 451 Cardinal features of MCD in HIV-infected patients include fever, constitutional symptoms, lymphadenopathy, splenomegaly, cytopenias, polyclonal hypergammaglobulinemia, and elevated inflammatory markers (e.g., C-reactive protein [CRP] and IL-6). 444 

PEL, a rare form of large B-cell lymphoma first described by Knowles et al in 1989, 454 is caused by HHV-8 and is associated with serous effusions (pleural, peritoneal, ascites) in the absence of lymphadenopathy or organomegaly. 455 Extracavitary or solid variants of PEL have been described, 387, 401, 456 but are rare. Most cases of PEL (50-80%) are coinfected with EBV. 388, 455 PEL cells most likely represent postgerminal center B cells with a plasma cell phenotype. 381, 457 In 1995, Cesarman et al identified HHV-8 DNA in all patients with PEL, 385 underscoring the critical role of HHV-8 in the pathogenesis of this malignancy. 381 The tumor cells of PEL are large, with abundant basophilic cytoplasm, irregular nuclear contours, and prominent nucleoli with plasmablastic, immunoblastic, or anaplastic differentiation. 401, 458 Immunohistochemical stains typically are negative for pan-B cell markers such as CD19, CD20, CD79a, and PAX-5, but the lymphoma cells express plasma cell markers including CD138, VS38c, and MUM1. 387, 388, 456 The tumor cells often express CD30, CD38, CD71, and epithelial membrane antigen. 456 Detecting HHV-8 in the tumor cells by in situ hybridization, PCR, or by immunohistochemistry against LANA is essential to diagnose PEL. 387, 401, 458 Most cases of PEL occur in HIV-infected patients, 387, 388, 443, 455, 459 but a few cases have been reported after SOT. [460] [461] [462] [463] PEL represents approximately 1-4% of AIDS-related lymphomas and 0.3% of all aggressive lymphomas in HIVnegative subjects. 388, 464 Cases of PEL have also been reported in older immunocompetent patients from geographic areas where HHV-8 is endemic, such as sub-Saharan Africa and the Mediterranean region. 465 PEL usually presents as a malignant pleural, peritoneal, and/ or pericardial effusion without a detectable solid mass. 455 Rare cases present as tumor masses and are considered to represent an extracavitary or a solid variant of PEL. 387, 401, 456 Unusual sites of involvement include skin, 466 GI tract, 387,401 lung, central nervous system, and lymph nodes. 401

The course of KS is more aggressive in persons with AIDS, compared with HIV-negative persons. 388, 467, 468 In HIV-infected persons with KS, oral mucosa and craniofacial regions are affected in 30% at initial presentation, 404, 467 and visceral involvement (e.g., GI tract, 469 liver, spleen, lymph nodes) is common. 388 Lung involvement occurs in 15 to 30% of HIVinfected persons, 468 and may be associated with hemoptysis which is sometimes fatal. 404 Even in the post-ART era, pulmonary KS has been associated with a worse prognosis. In a single center study of 305 cases of KS in HIV-infected patients from 1996 to 2004, 5-year survival rates were 49% (median survival 1.6 years) in subjects with pulmonary involvement compared with 82% survival among those without pulmonary involvement. 468 Survival rates for HIV-infected patients with KS are worse compared with HIV-negative subjects, but survival rates have improved in HIV-infected subjects in the post-ART era. 397 In the pre-ART era, staging systems were developed to predict prognosis in HIV-infected patients with KS. 470 In a cohort of 211 HIV-infected patients with KS, Italian investigators cited 3-year survival rates of > 80% among "good risk" subjects compared with 34% survival among "poor risk" patients. 470 The use of ART has markedly reduced the incidence of KS in HIV-infected subjects in resource-rich countries, 471 but reductions have not yet been achieved in sub-Saharan Africa. 404 Treatment of KS depends upon the immune state of the patient and the extent and severity of organ involvement. All patients with AIDS-associated KS should receive ART. 388 Among HIV-negative individuals on immunosuppressive therapy, a reduction in immunosuppression should be performed when feasible. 326, 425 For limited, localized disease, intralesional or topical chemotherapy, laser, cryotherapy, radiation therapy, or surgical resection may be adequate. 388, 404 Multiagent chemotherapy is reserved for patients with severe symptoms, visceral involvement, or multiorgan disease, but relapses are common and toxicities may be significant. 404, 419, 425 Optimal treatment is controversial, as no randomized controlled trial data are available. Clinical responses have been cited with a variety of agents, alone or in combination, including doxorubicin, vinca-alkaloids, etoposide, gemcitabine, interferon-α 2, taxanes, and radiation therapy. 326, 388, 419, 425, 472 In SOT recipients, a switch from calcineurin inhibitor therapy to sirolimus may also be useful based on the latter's known antiproliferative properties 326 ; changing cyclosporine to sirolimus was associated with regression of KS in all of 15 renal transplant recipients undergoing this this modification, with no episodes of acute rejection. 438 Ganciclovir, valganciclovir, foscarnet, and cidofovir have in vitro activity against HHV-8. 388 Novel strategies incorporating antiangiogenic factors, immunomodulatory agents, cytokines, and virus-activated cytotoxic therapy are being developed. 384, 404, 416, 470 Ganciclovir or valganciclovir as prophylactic antiviral therapy may reduce reactivation in high risk individuals. 473

Treatment of MCD is controversial, as randomized trials are lacking. Surgery and antiviral therapies including ART, 474 interferon-α, and chemotherapy have proved largely ineffective. 443, 445, 451 In one randomized trial, 79 HIV-negative and HHV-8-negative subjects with MCD were treated with the anti-IL-6 antibody siltuximab (n ¼ 53) or placebo (n ¼ 26); favorable responses were observed with siltuximab in 34% compared with 0% in the placebo group. 475 In several studies, prolonged remissions were achieved with the anti-CD20 monoclonal antibody rituximab, at the expense of B cell depletion and flares of KS. 445, 447, 451, 476, 477 Bower et al reported 49 HIV-positive patients with newly diagnosed MCD who were treated with rituximab with (n ¼ 14) or without (n ¼ 35) etoposide. 478 Survival rates were 94% at 2 years and 90% at 5 years compared with 42 and 33%, respectively, in 12 patients treated before the introduction of rituximab (p < 0.001). Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed relapse of MCD. All were successfully retreated and were alive in remission. The 2-and 5-year progression-free survival rates for all 49 patients treated with rituximab-based therapy were 85 and 61% respectively. In summary, HIV-associated MCD is a remitting-relapsing disease, but the outlook has improved dramatically in recent years with the introduction of rituximab-based therapy. 478 Rituximab also reduced by 11-fold the risk of developing lymphoma in HIV-positive patients with MCD. 476 

The prognosis for PEL is poor, with a median survival of less than 6 months. 443, 456, 459 Given the rarity of PEL, optimal therapy has not been elucidated. Anecdotal successes have been cited with chemotherapy and/or antiviral agents, but are rarely durable. 386, 388, 419, 460 Responses to intracavitary cidofovir have been cited in case reports. 479, 480 Sirolimus inhibits growth of PEL in vitro and in animal models 481 

CMV: Prevention, Diagnosis and Therapy

Interrelationships among quantity of human cytomegalovirus (HCMV) DNA in blood, donor-recipient serostatus, and administration of methylprednisolone as risk factors for HCMV disease following liver transplantation

Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation

An international multicenter performance analysis of cytomegalovirus load tests

CMV Working Group of the Complications of HIV Disease RAC, AIDS Clinical Trials Group. Comparison of quantitative and qualitative PCR assays for cytomegalovirus DNA in plasma

CMV PCR as a diagnostic tool for CMV gastrointestinal disease after solid organ transplantation

Multicenter comparison of the digene hybrid capture CMV DNA assay (version 2.0), the pp65 antigenemia assay, and cell culture for detection of cytomegalovirus viremia

The diagnosis of CMV pneumonitis in lung and heart/lung transplant patients by PCR compared with traditional laboratory criteria

Clinical utility of cytomegalovirus viral load in bronchoalveolar lavage in lung transplant recipients

Quantitative cultures of the cell fraction and supernatant of bronchoalveolar lavage fluid for the diagnosis of cytomegalovirus pneumonitis in lung transplant recipients

Human cytomegalovirus load in plasma and bronchoalveolar lavage fluid: a longitudinal study of lung transplant recipients

Monitoring of human cytomegalovirus, HHV-6 and HHV-7 infection in kidney transplant recipients by molecular methods to predict HCMV disease after transplantation: a prospective study

Cytomegalovirus load in whole blood is more reliable for predicting and assessing CMV disease than pp65 antigenaemia

Comparison of real-time PCR and pp65 antigen assays for monitoring the development of Cytomegalovirus disease in recipients of solid organ and bone marrow transplants

A survey of CMV prevention strategies after liver transplantation

Clinical utility of cytomegalovirus (CMV) serology testing in high-risk CMV Dþ/R-transplant recipients

Screening of blood donors for human cytomegalovirus (HCMV) IgG antibody with an enzyme immunoassay using recombinant antigens

Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study

Prophylactic therapy with valgancyclovir in high-risk (cytomegalovirus Dþ/R-) liver transplant recipients: a single-center experience

Cytomegalovirus serostatus pairing and deceased donor kidney transplant outcomes in adult recipients with antiviral prophylaxis

Donor serostatus has an impact on cytomegalovirus-specific immunity, cytomegaloviral disease incidence, and survival in seropositive hematopoietic cell transplant recipients

Impact of donor CMV status on viral infection and reconstitution of multifunction CMVspecific T cells in CMV-positive transplant recipients

Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation

Cytomegalovirus diseases after hematopoietic stem cell transplantation: a minireview

Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation

OKT3 treatment for allograft rejection is a risk factor for cytomegalovirus disease in liver transplantation

The R753Q polymorphism abrogates toll-like receptor 2 signaling in response to human cytomegalovirus

Influence of mannose-binding lectin gene polymorphisms on the invasiveness of cytomegalovirus disease after solid organ transplantation

Homozygosity for the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirus disease after liver transplantation

The influence of innate immunity gene receptors polymorphisms in renal transplant infections

Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation

Comparison of cytomegalovirus (CMV) enzyme-linked immunosorbent spot and CMV quantiferon gamma interferon-releasing assays in assessing risk of CMV infection in kidney transplant recipients

Hypogammaglobulinemia in lung transplant recipients

letermovir) against herpesviruses and other human pathogenic viruses

Brincidofovir (CMX001) for the treatment of serious or life-threatening double-stranded DNA virus infections in patients receiving liver transplant as part of multiorgan transplantation. Paper presented at: World Transplant Congress

Brincidofovir (CMX001) experience in renal transplant patients for treatment of refractory CMV infection. Paper presented at: World Transplant Congress

First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses

Induction of antiviral cytotoxic T cells by plasmacytoid dendritic cells for adoptive immunotherapy of posttransplant diseases

Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant

Prophylaxis versus preemptive therapy for cytomegalovirus disease in high-risk liver transplant recipients

Prospective study on CMV-reactivations under preemptive strategy in CMV-seropositive adult liver transplant recipients

Preventing post-organ transplantation cytomegalovirus disease with ganciclovir: a meta-analysis comparing prophylactic and preemptive therapies

Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report

Reduced rate of cardiovascular death after cytomegalovirus prophylaxis in renal transplant recipients

Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients

The clinical impact of ganciclovir prophylaxis on the occurrence of bacteremia in orthotopic liver transplant recipients

A direct and indirect comparison meta-analysis on the efficacy of cytomegalovirus preventive strategies in solid organ transplant

Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients

Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients

Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation

Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial

High incidence of anticytomegalovirus drug resistance among DþR-kidney transplant recipients receiving preemptive therapy

The impact of ganciclovir-resistant cytomegalovirus infection after lung transplantation

High incidence of ganciclovir-resistant cytomegalovirus infection among lung transplant recipients receiving preemptive therapy

Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial

Use of combination cytomegalovirus immune globulin plus ganciclovir for prophylaxis in CMV-seronegative liver transplant recipients of a CMVseropositive donor organ: a multicenter, open-label study

Cytomegalovirus immune globulin prophylaxis in liver transplantation. A randomized, double-blind, placebo-controlled trial

Following universal prophylaxis with intravenous ganciclovir and cytomegalovirus immune globulin, valganciclovir is safe and effective for prevention of CMV infection following lung transplantation

Increased risk of breakthrough infection among cytomegalovirus donor-positive/recipient-negative kidney transplant recipients receiving lower-dose valganciclovir prophylaxis

Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial

Maribavir 1263-300 Clinical Study Group. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial

AIC246 Study Team. Letermovir for cytomegalovirus prophylaxis in hematopoieticcell transplantation

CMX001-201 Clinical Study Group. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation

Cytomegalovirus disease and infection in lung transplant recipients in the setting of planned indefinite valganciclovir prophylaxis

Prophylaxis followed by preemptive therapy versus preemptive therapy for prevention of human cytomegalovirus disease in pediatric patients undergoing liver transplantation

Clinical utility of cytomegalovirus viral load testing for predicting CMV disease in Dþ/Rsolid organ transplant recipients

Clinical utility of molecular surveillance for cytomegalovirus after antiviral prophylaxis in high-risk solid organ transplant recipients

Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients

Linking CMV serostatus to episodes of CMV reactivation following lung transplantation by measuring CMV-specific CD8þ T-cell immunity

Prospective analysis of human cytomegalovirus DNAemia and specific CD8þ T cell responses in lung transplant recipients

Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial

A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, doubleblind, placebo-controlled, phase 2 trial

Cytomegalovirus vaccine: phase II clinical trial results

Detection and pharmacokinetics of a cytomegalovirus (CMV) DNA plasmid in human plasma during a clinical trial of an intramuscular CMV vaccine in hematopoietic stem cell transplant recipients

A study to evaluate a therapeutic vaccine, ASP0113, in cytomegalovirus (CMV)-seropositive recipients undergoing allogeneic, hematopoietic cell transplant (HCT) (HELIOS)

Biology and disease associations of Epstein-Barr virus

EB virus antibody at different ages

Development and persistence of immunity to Epstein-Barr virus in man

Age-specific prevalence of Epstein-Barr virus infection among individuals aged 6-19 years in the United States and factors affecting its acquisition

Immunofluorescence, interference, and complement fixation technics in the detection of the herpes-type virus in Burkitt tumor cell lines

Prevalence of antibodies to EB virus and other herpesviruses

A study of risk factors for acquisition of Epstein-Barr virus and its subtypes

Canadian PTLD Workshop Group -1999. Epstein-Barr virus infection in transplant recipients: Summary of a workshop on surveillance, prevention and treatment

AST Infectious Diseases Community of Practice. Epstein-Barr virus and posttransplant Seminars in Respiratory

lymphoproliferative disorder in solid organ transplantation

The pathogenesis of Epstein-Barr virus persistent infection

Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt's lymphoma from Ugandan prospective study

Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma

Characteristics of Hodgkin's lymphoma after infectious mononucleosis

Epstein-Barr virus infection

The role of microRNAs in Epstein-Barr virus latency and lytic reactivation

DNA viral infections complicating lung transplantation

Epstein-Barr virus-related posttransplant lymphoproliferative disorders: pathogenetic insights for targeted therapy

Southwest Oncology Group. Tumor origin and CD20 expression in posttransplant lymphoproliferative disorder occurring in solid organ transplant recipients: implications for immune-based therapy

Quantitative Epstein-Barr virus (EBV) serology in lung transplant recipients with primary EBV infection and/or posttransplant lymphoproliferative disease

Donor or recipient origin of posttransplant lymphoproliferative disorders following solid organ transplantation

Posttransplant lymphoproliferative disorders: determination of donor/recipient origin in a large cohort of kidney recipients

EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases

How I treat posttransplant lymphoproliferative disorders

Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas

Is there a difference in post-transplant lymphoproliferative disorder in adults after solid organ and haematologic stem cell transplantation? Experience in 41 patients

Epstein-Barr virus-related posttransplantation lymphoproliferative disorder after unmanipulated human leukocyte antigen haploidentical hematopoietic stem cell transplantation: incidence, risk factors, treatment, and clinical outcomes

Epstein-Barr virus

Posttransplantation lymphoproliferative disorder in lung transplant recipients: a 15-year single institution experience

Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology

Epstein-Barr virus infection and posttransplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder after lung transplantation: a review of 35 cases

Imaging of pulmonary viral pneumonia

Epstein-Barr virusassociated pneumonia and bronchiolitis obliterans syndrome in a lung transplant recipient

A possible role for Epstein-Barr virus in the pathogenesis of pleural effusion

Epstein-Barr virus-positive pleural effusion: Clinical features, cytomorphologic characteristics, and flow cytometric immunophenotyping

Epstein-Barr virus-associated pulmonary smooth muscle tumor after lung transplantation

Epstein-barr virus-associated smooth muscle tumor of the larynx: report of a rare case mimicking leiomyosarcoma

EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial

Screening for PTLD in lung and heart-lung transplant recipients by measuring EBV DNA load in bronchoalveolar lavage fluid using real time PCR

Epstein-Barr virusassociated pneumonia in patients with post-transplant lymphoproliferative disease after hematopoietic stem cell transplantation

18)F-fluorodeoxyglucose positron emission tomography/computed tomography in diagnosis of post-transplant lymphoproliferative disorder

Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients

Lymphomas after solid organ transplantation: a collaborative transplant study report

Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients

The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation

Experience with 274 cardiac transplant recipients with posttransplant lymphoproliferative Seminars in Respiratory

Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder

Posttransplant lymphoproliferative disorders: from epidemiology to pathogenesis-driven treatment

Pneumonia caused by herpesviruses in recipients of hematopoietic cell transplants

Increased Ignull B lymphocytes in the peripheral blood of pediatric solid organ transplant recipients with elevated Epstein-Barr viral loads

Evaluation of antiviral activity against human herpesvirus 8 (HHV-8) and Epstein-Barr virus (EBV) by a quantitative real-time PCR assay

Suppression of EBV release from irradiated B lymphoblastoid cell-lines: superior activity of ganciclovir compared with acyclovir

Post-transplant lymphoproliferative diseases in Asian solid organ transplant recipients: late onset and favorable response to treatment

Treatment of PTLD with rituximab or chemotherapy

CD20 expression predicts survival in paediatric post-transplant lymphoproliferative disease (PTLD) following solid organ transplantation

Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial

Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBVþ lymphomas after allogeneic hematopoietic cell transplantation

Reconstitution of the latent T-lymphocyte response to Epstein-Barr virus is coincident with long-term recovery from posttransplant lymphoma after adoptive immunotherapy

Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases

Sirolimus-induced remission of posttransplantation lymphoproliferative disorder

Inhibition of mTOR by sirolimus induces remission of post-transplant lymphoproliferative disorders

Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies

Outcome of rapamycin therapy for post-transplant-lymphoproliferative disorder after kidney transplantation: case series

Epstein-Barr virus, rapamycin, and host immune responses

Effect of cytomegalovirus prophylaxis with immunoglobulin or with antiviral drugs on post-transplant non-Hodgkin lymphoma: a multicentre retrospective analysis

Reactivation of viruses in solid organ transplant patients receiving cytomegalovirus prophylaxis

Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation

Effect of cytomegalovirus immunoglobulin on the incidence of lymphoproliferative disease after lung transplantation: single-center experience with 1157 patients

CMV-IVIG for prevention of Epstein Barr virus disease and posttransplant lymphoproliferative disease in pediatric liver transplant recipients

A randomized trial of ganciclovir versus ganciclovir plus immune globulin for prophylaxis against Epstein-Barr virus related posttransplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder in pediatric heart transplant recipients

Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients

Efficacy and safety of valganciclovir in liver-transplanted children infected with Epstein-Barr virus

Impact of valganciclovir on Epstein-Barr virus polymerase chain reaction in pediatric liver transplantation: preliminary report

Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States

Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection

Infection with herpes-simplex viruses 1 and 2

Infections with herpes simplex viruses

Natural history of genital herpes simplex virus type 1 infection

Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type

Viral encephalitis

Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: transmission by donated organ and the effect of OKT3 antibodies

Vandenbroucke-Grauls CM. Herpes simplex virus type 1 and respiratory disease in critically-ill patients: Real pathogen or innocent bystander?

Herpes simplex virus infection in heart-lung transplant recipients

Clinical relevance of and risk factors for HSV-related tracheobronchitis or pneumonia: results of an outbreak investigation

Herpes-Simplex-Virus 1 pneumonia in the immunocompromised host: high-resolution CT patterns in correlation to outcome and follow-up

Herpes simplex virus hepatitis after solid organ transplantation in adults

Clinical relevance of herpes simplex virus viremia in Intensive Care Unit patients

Diagnosis of genital herpes by real time PCR in routine clinical practice

Diagnosis of herpesvirus infections of the central nervous system

Herpes simplex virus load in bronchoalveolar lavage fluid is related to poor outcome in critically ill patients

Occurrence of HSV-1-induced pneumonitis in patients under standard immunosuppressive therapy for rheumatic, vasculitic, and connective tissue disease

Management of herpes virus infections following transplantation

Controlled clinical trial of intravenous acyclovir in heart-transplant patients with mucocutaneous herpes simplex infections

Viral infections affecting the skin in organ transplant recipients: epidemiology and current management strategies

Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up

AST Infectious Diseases Community of Practice. Herpes simplex virus in solid organ transplantation

Successful clearance of cutaneous acyclovir-resistant, foscarnet-refractory herpes virus lesions with topical cidofovir in an allogeneic hematopoietic stem cell transplant patient

Valacyclovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes

The epidemiology of herpes zoster in 226 children with acute lymphoblastic leukemia

High incidence of herpes zoster in nonmyeloablative hematopoietic stem cell transplantation

Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients

Herpesvirus infections in solid organ transplant patients at high risk of primary cytomegalovirus disease

Varicella zoster infection in renal transplant recipients: prevalence, complications and outcome

Incidence and clinical characteristics of herpes zoster after lung transplantation

Resistance testing of clinical varicella-zoster virus strains

Clinical practice. Herpes zoster

Vaccination of solid-organ transplantation candidates

Advances in the understanding of the pathogenesis and epidemiology of herpes zoster

Varicella-zoster virus infections in immunocompromised patients -a single centre 6-years analysis

Fatal visceral varicellazoster virus infection without skin involvement in a child with acute lymphoblastic leukemia

Herpes zoster and human immunodeficiency virus infection

Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era

Varicella zoster virus-associated disease in adult kidney transplant recipients: incidence and risk-factor analysis

Herpes zoster infection after liver transplantation: a case-control study

Herpes zoster after liver transplantation: incidence, risk factors, and complications

Infectious complications after heart transplantation in Chinese recipients

Herpes zoster after lung transplantation: incidence, timing, and outcome

Incidence, risk factors and outcome of varicella-zoster virus infection in children after haematopoietic stem cell transplantation

The epidemiology of varicella and its complications

Varicella pneumonitis: immunodiagnosis with a monoclonal antibody

Varicella pneumonia in adults

Respiratory manifestations of chicken pox; special consideration of the features of primary varicella pneumonia

Varicella pneumonia in patients with HIV/AIDS

Lung function tests and risk factors for pneumonia in adults with chickenpox

Molecular diagnosis of visceral herpes zoster

Recommendations for the management of herpes zoster

Compartmentalization of acyclovir-resistant varicella zoster virus: implications for sampling in molecular diagnostics

Foscarnet salvage therapy for acyclovir-resistant varicella zoster: report of a novel thymidine kinase mutation and review of the literature

Intravitreal foscarnet for the treatment of acyclovir-resistant acute retinal necrosis caused by varicella zoster virus

Single amino acid change in DNA polymerase is associated with foscarnet resistance in a varicella-zoster virus strain recovered from a patient with AIDS

AST Infectious Diseases Community of Practice. Varicella zoster virus in solid organ transplantation

Onset and complications of varicella zoster reactivation in the autologous hematopoietic cell transplant population

Longterm acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation-a randomized double-blind placebo-controlled study

One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicellazoster virus disease after drug discontinuation

Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults

Zoster vaccine (Zostavax): a review of its use in preventing herpes zoster and postherpetic neuralgia in older adults

Reisinger EC. Immunization in the adult immunocompromised host

Update on immunizations in solid organ transplant recipients: what clinicians need to know

Strategies for herpes zoster vaccination of immunocompromised patients

Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host

AST Infectious Diseases Community of Practice. Vaccination in solid organ transplantation

Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders

Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: what we do and do not know

Update on human herpesvirus 6 biology, clinical features, and therapy

A population-based study of primary human herpesvirus 6 infection

Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection

A prospective survey of human herpesvirus-6 primary infection in solid organ transplant recipients

Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review

Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A

Predominant human herpesvirus 6 variant A infant infections in an HIV-1 endemic region of Sub-Saharan Africa

Chromosomally integrated human herpesvirus 6: questions and answers

The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors

Identification of human herpesvirus-6 as a causal agent for exanthem subitum

Viremia and neutralizing antibody response in infants with exanthem subitum

Clinical features of infants with primary human herpesvirus 6 infection (exanthem subitum, roseola infantum)

Prevalence of herpes and respiratory viruses in induced sputum among hospitalized children with non typical bacterial community-acquired pneumonia

Human herpesvirus-6 infection in children. A prospective study of complications and reactivation

Primary human herpesvirus 6 infection in young children

Primary infection of human herpesvirus 6 in children with vertical infection of human immunodeficiency virus type 1

Prevalence and risk factors for betaherpesvirus DNAemia in children >3 weeks and <2 years of age admitted to a large referral hospital in sub-Saharan Africa

Infection with AIDSrelated herpesviruses in human immunodeficiency virus-negative infants and endemic childhood Kaposi's sarcoma in Africa

Detection of HHV-6 in over a thousand samples: new types of infection revealed by an analysis of positive results

Herpesvirus Respiratory Infections in Immunocompromised Patients Reid et al. 625

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited

Fatal human herpesvirus 6-associated encephalitis in two boys with underlying POLG mitochondrial disorders

Review part 2: Human herpesvirus-6 in central nervous system diseases

Evidence linking HHV-6 with multiple sclerosis: an update

Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter

Fatal acute myocarditis in an infant with human herpesvirus 6 infection

Human herpes virus 6 in archival cardiac tissues from children with idiopathic dilated cardiomyopathy or congenital heart disease

Human herpesvirus-6 modulates RANTES production in primary human endothelial cell cultures

Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation

Human herpesvirus 6 is an important pathogen in infectious lung disease after allogeneic bone marrow transplantation

Infectious pulmonary complications after stem cell transplantation or chemotherapy: diagnostic yield of bronchoalveolar lavage

Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation

Human herpesviruses 6, 7 and 8 in solid organ transplant recipients

Clinical impact of human herpesvirus 6 infection after liver transplantation

Human herpesvirus-6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome

Human herpesvirus 6, 7 and 8 in solid organ transplantation

Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency

Detection and quantification of EBV, HHV-6 and CMV DNA in the gastrointestinal tract of HIVpositive patients

Acute febrile myelodysplasia and pneumonitis due to human herpesvirus 6 after accelerated chemotherapy

HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation

Reactivation of human herpes virus-6 after pediatric stem cell transplantation: risk factors, onset, clinical symptoms and association with severity of acute graft-versus-host disease

Human herpesvirus 6 infection after hematopoietic cell transplantation: is routine surveillance necessary?

Human herpesvirus-6 DNAemia is a sign of impending primary CMV infection in CMV sero-discordant renal transplantations

Human herpesvirus-6 infection after lung and heart-lung transplantation: a prospective longitudinal study

Munich Lung Transplant Group. Human herpesvirus 6 in bronchalveolar lavage fluid after lung transplantation: a risk factor for bronchiolitis obliterans syndrome?

Lack of association between beta-herpesvirus infection and bronchiolitis obliterans syndrome in lung transplant recipients in the era of antiviral prophylaxis

Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies

Human herpesvirus 6-related pure red cell aplasia, secondary graft failure, and clinical severe immune suppression after allogeneic hematopoietic cell transplantation successfully treated with foscarnet

Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation

Early human herpesvirus type 6 reactivation after allogeneic stem cell transplantation: a large-scale clinical study

Human herpesvirus 6B infection of the large intestine of patients with diarrhea

Human herpesvirus 6 infection of the gastroduodenal mucosa

Case report: human herpesvirus 6 reactivation associated with colitis in a lung transplant recipient

Plasma HHV-6 viral loadguided preemptive therapy against HHV-6 encephalopathy after allogeneic stem cell transplantation: a prospective evaluation

Correlations of HHV-6 viral load and plasma IL-6 concentration with HHV-6 encephalitis in allogeneic stem cell transplant recipients

Cord-blood hematopoietic stem cell transplant confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis

Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation

High intrahepatic HHV-6 virus loads but neither CMV nor EBV are associated with decreased graft survival after diagnosis of graft hepatitis

The long-term outcomes of patients transplanted due to acute liver failure with hepatic human herpesvirus-6 infection

Fatal human herpesvirus-6 infection after renal transplantation

Detection of human herpesviruses 6 and 7 in heart transplant recipients by a multiplex polymerase chain reaction method

Pericarditis associated with human herpesvirus-6 reactivation in a patient after unrelated cord blood transplant

Encephalitis owing to human herpesvirus-6 after cardiac transplant

beta-Herpesvirus (human cytomegalovirus and human herpesvirus 6) reactivation in at-risk lung transplant recipients and in human immunodeficiency virus-infected patients

Quantitative detection of HHV-6 and HHV-7 in transbronchial biopsies from lung transplant recipients

Lautenschlager I. Human herpesvirus-6 and -7 after lung and heart-lung transplantation

Human herpesvirus 6 DNA in blood cells of human immunodeficiency virus-infected men: correlation of high levels with high CD4 cell counts

Prospective study of human herpesvirus 6, human herpesvirus 7, and cytomegalovirus infections in human immunodeficiency virus-positive patients

Current status of herpesvirus identification in the oral cavity of HIV-infected children

Antiviral agents active against human herpesviruses HHV-6, HHV-7 and HHV-8

Beta-herpesvirus challenges in the transplant recipient

Preemptive therapy of human herpesvirus-6 encephalitis with foscarnet sodium for high-risk patients after hematopoietic SCT

Immunotherapeutic strategies to prevent and treat human herpesvirus 6 reactivation after allogeneic stem cell transplantation

Isolation of a new herpesvirus from human CD4þ T cells

Human herpesvirus 7 is a Tlymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus

The natural history and laboratory diagnosis of human herpesviruses-6 and -7 infections in the immunocompetent

Human herpesvirus-6 and -7 in transplantation

Prevalence of antibody to human herpesvirus 7 by age

Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain and Ireland

Primary human herpesvirus 7 infection: a comparison of human herpesvirus 7 and human herpesvirus 6 infections in children

Human herpesviruses 6 and 7: identification of newly recognized viral pathogens and their association with human disease

Human herpesvirus 7: another causal agent for roseola (exanthem subitum)

FEBSTAT study team. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study

Delayed primary HHV-7 infection and neurologic disease

VICTOR study group. An assessment of herpesvirus co-infections in patients with CMV disease: correlation with clinical and virologic outcomes

Differentiation and quantitation of human herpesviruses 6A, 6B and 7 by real-time PCR

Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma

Kaposi Sarcoma-associated Herpesvirus: mechanisms of oncogenesis

A review of human herpesvirus 8, the Kaposi's sarcoma-associated herpesvirus, in the pediatric population

FHDH-ANRS CO4. Trends in survival after cancer diagnosis among HIV-infected individuals between 1992 and 2009. Results from the FHDH-ANRS CO4 cohort

Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)-an update

Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDSrelated body-cavity-based lymphomas

Extracavitary/solid variant of primary effusion lymphoma presenting as a gastric mass

HIV/ AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease

Fatal outcome of multiple clinical presentations of human herpesvirus 8-related disease after solid organ transplantation

Fatal HHV-8-associated hemophagocytic syndrome in an HIV-negative immunocompetent patient with plasmablastic variant of multicentric Castleman disease (plasmablastic microlymphoma)

Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8

The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman's disease

Herpesvirus Respiratory Infections in Immunocompromised Patients Reid et al. 627

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited

Human herpesvirus type 8 variants circulating in Europe, Africa and North America in classic, endemic and epidemic Kaposi's sarcoma lesions during pre-AIDS and AIDS era

Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: a nested case-control study

Children with Kaposi sarcoma in two southern African hospitals: clinical presentation, management, and outcome

The spectrum of human immunodeficiency virus-associated cancers in a South African black population: results from a case-control study

Kaposi's sarcoma at the University Teaching Hospital, Lusaka, Zambia in the antiretroviral therapy era

Risk factors for Kaposi's sarcoma: a case-control study of HIV-seronegative people in Uganda

Human herpesvirus 8 seropositivity among sexually active adults in Uganda

Primary gamma-herpesviral infection in Zambian children

Extracavitary/solid variant of primary effusion lymphoma

Human herpesvirus 8 infection in children and adults in a population-based study in rural Uganda

Risk factors for seropositivity to Kaposi sarcoma-associated herpesvirus among children in Uganda

Kaposi' s sarcoma in HIVpositive patients: the state of art in the HAART-era

Epidemiology and clinical characteristics of classic Kaposi's sarcoma, seroprevalence, and variants of human herpesvirus 8 in South America: a critical review of an old disease

Geographic variation in the prevalence of Kaposi sarcoma-associated herpesvirus and risk factors for transmission

Human herpesvirus 8 epidemiology: what we do and do not know

Mother-to-child transmission of human herpesvirus-8 in South Africa

HIV infection and human herpesvirus-8 oral shedding among men who have sex with men

Shedding of human herpesvirus 8 in oral and genital secretions from HIV-1-seropositive and -seronegative Kenyan women

Risk factors for human herpesvirus 8 infection among adults in the United States and evidence for sexual transmission

Transmission of human herpesvirus 8 by blood transfusion

Molecular evidence of organ-related transmission of Kaposi sarcoma-associated herpesvirus or human herpesvirus-8 in transplant patients

Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors

Primary human herpesvirus 8 infection generates a broadly specific CD8(þ) T-cell response to viral lytic cycle proteins

Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment

HIV and human herpesvirus 8 coinfection across the globe: Systematic review and meta-analysis

Human herpes virus type 8-associated Kaposi sarcoma in a pediatric liver transplant recipient

Human herpes virus 8 in solid organ transplantation

Kaposi sarcoma of childhood: inborn or acquired immunodeficiency to oncogenic HHV-8

Human herpesvirus 8 DNA quantification in matched plasma and PBMCs samples of patients with HHV8-related lymphoproliferative diseases

Viral load of human herpesvirus 8 in peripheral blood of human immunodeficiency virus-infected patients with Kaposi's sarcoma

Immunohistochemistry in Kaposi's sarcoma

AIDS-associated Kaposi's sarcoma is linked to advanced disease and high mortality in a primary care HIV programme in South Africa

Treatments for classic Kaposi sarcoma: a systematic review of the literature

Kaposi's sarcoma, a South African perspective: Demographic and pathological features

AIDS-related Kaposi's sarcoma: epidemiological, diagnostic, treatment and control aspects in sub-Saharan Africa

HIV-associated Kaposi sarcoma in African children

Oral Kaposi's sarcoma in Tanzania: presentation, immunopathology and human herpesvirus-8 association

Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma

International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults

Cancer burden in the HIVinfected population in the United States

Intrathoracic Kaposi's sarcoma. CT findings

Diagnosis of pulmonary Kaposi's sarcoma with fiberoptic bronchoscopy and endobronchial biopsy. A report of five cases

Recrudescent Kaposi's sarcoma after initiation of HAART: a manifestation of immune reconstitution syndrome

Kaposi sarcoma of the musculoskeletal system: a review of 66 patients

Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma

Sirolimus for Kaposi's sarcoma in renal-transplant recipients

Post renal transplantation Kaposi's sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy

The aetiology and management of Castleman disease at 50 years: translating pathophysiology to patient care

High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

High-level human herpesvirus-8 viremia and multicentric Castleman's disease following initiation of highly active antiretroviral therapy

Kaposi's sarcoma-associated herpesvirus: the role of lytic replication in targeted therapy

KSHV-associated multicentric Castleman disease: A tangle of different entities requiring multitarget treatment strategies

HIV-associated multicentric Castleman's disease

Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB Trial

Multicentric Castleman's disease in HIV infection: a systematic review of the literature

Post renal transplant Castleman's disease resolved after graft nephrectomy: a case report

Concomitant and fatal HHV-8þ multicentric Castleman's disease and Kaposi's sarcoma in the same lymph node of an HIV-liver transplant patient

Post-liver transplantation multicentric Castleman disease treated with valganciclovir and weaning of immunosuppression

Treatment of multicentric Castleman's disease in HIV-1 infected and uninfected patients: a systematic review

High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease

An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease

Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus

Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus

KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma

Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma has a plasma cell gene expression profile

Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis

Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a singleinstitution study

Human herpesvirus-8 (HHV-8)-associated primary effusion lymphoma in two renal transplant recipients receiving rapamycin

Primary effusion lymphoma after heart transplantation: a new entity associated with human herpesvirus-8

Primary-effusion lymphoma and Kaposi's sarcoma in a cardiac-transplant recipient

Individuals from North America, Australasia, and Africa are infected with four different genotypes of human herpesvirus 8

Epidemiology of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8

HHV-8-positive body-cavity-based lymphoma: a novel lymphoma entity

Extracavitary primary effusion lymphoma presenting as a cutaneous tumor: a case report and literature review

HIV -associated and non -HIV associated types of Kaposi's sarcoma in an African population in Tanzania. Status of immune suppression and HHV-8 seroprevalence

Pulmonary Kaposi sarcoma in the era of highly active antiretroviral therapy

Gastrointestinal malignancy in patients with AIDS

AIDS Clinical Trial Group Staging System in the Haart Era-the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive from Antiretrovirals. AIDS-related Kaposi's Sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era-the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Seminars in Respiratory and Critical Care Medicine

Patients Naive From Antiretrovirals

Impact of antiretroviral therapy on the incidence of Kaposi's sarcoma in resource-rich and resource-limited settings

Kaposi's sarcoma in children: an open randomised trial of vincristine, oral etoposide and a combination of vincristine and bleomycin

Human herpesvirus 8-associated neoplasms: the roles of viral replication and antiviral treatment

Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy

Siltuximab for multicentric Castleman's disease: a randomised, doubleblind, placebo-controlled trial

Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease

Brief communication: rituximab in HIV-associated multicentric Castleman disease

Clinical features and outcome in HIV-associated multicentric Castleman's disease

A nonchemotherapy treatment of a primary effusion lymphoma: durable remission after intracavitary cidofovir in HIV negative PEL refractory to chemotherapy

Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir

Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling

Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas