Prevalence of Human Herpesvirus-6 Chromosomal Integration (CIHHV-6) in Italian Solid Organ and Allogeneic Stem Cell Transplant Patients
2009; Elsevier BV; Volume: 9; Issue: 7 Linguagem: Inglês
10.1111/j.1600-6143.2009.02685.x
ISSN1600-6143
AutoresLeonardo Potenza, Patrizia Barozzi, Michele Masetti, Monica Pecorari, Pablo Diego Bresciani, Agnès Gautheret‐Dejean, Giovanni Riva, Daniela Vallerini, Sara Tagliazucchi, Mauro Codeluppi, Fabrizio Di Benedetto, Giorgio Enrico Gerunda, Franco Narni, Giuseppe Torelli, Mario Luppi,
Tópico(s)Polyomavirus and related diseases
ResumoThe unique phenomenon of human herpesvirus-6 (HHV-6) chromosomal integration (CIHHV-6) may account for clinical drawbacks in transplant setting, being misinterpreted as active infection and leading to unnecessary and potentially harmful treatments. We have investigated the prevalence of CIHHV-6 in 205 consecutive solid organ (SO) and allogeneic stem cell transplant (alloSCT) Italian patients. Fifty-two (38.5%) of 135 solid organ transplant (SOT) and 16 (22.8%) of 70 alloSCT patients resulted positive for plasma HHV-6 DNA by real-time polymerase chain reaction. Seven SOT and three alloSCT patients presented HHV-6-related diseases, requiring antivirals. Two further patients (0.9%) were identified, presenting high HHV-6 loads. The quantification of HHV-6 on hair follicles disclosed the integrated state, allowing the discontinuation of antivirals. Before starting specific treatments, CIHHV-6 should be excluded in transplant patients with HHV-6 viremia by the comparison of HHV-6 loads on different fluids and tissues. Pretransplantation screening of donors and recipients may further prevent the misdiagnosis of CIHHV-6. The unique phenomenon of human herpesvirus-6 (HHV-6) chromosomal integration (CIHHV-6) may account for clinical drawbacks in transplant setting, being misinterpreted as active infection and leading to unnecessary and potentially harmful treatments. We have investigated the prevalence of CIHHV-6 in 205 consecutive solid organ (SO) and allogeneic stem cell transplant (alloSCT) Italian patients. Fifty-two (38.5%) of 135 solid organ transplant (SOT) and 16 (22.8%) of 70 alloSCT patients resulted positive for plasma HHV-6 DNA by real-time polymerase chain reaction. Seven SOT and three alloSCT patients presented HHV-6-related diseases, requiring antivirals. Two further patients (0.9%) were identified, presenting high HHV-6 loads. The quantification of HHV-6 on hair follicles disclosed the integrated state, allowing the discontinuation of antivirals. Before starting specific treatments, CIHHV-6 should be excluded in transplant patients with HHV-6 viremia by the comparison of HHV-6 loads on different fluids and tissues. Pretransplantation screening of donors and recipients may further prevent the misdiagnosis of CIHHV-6. Human herpesvirus-6 (HHV-6) is an ubiquitous β- herpesvirus existing in two variants, namely variant A and B (1Zerr DM Meier AS Selke SS Frenkel LM Huang ML Wald A A population-based study of primary human herpesvirus 6 infection..N Engl J Med. 2005; 352: 768-776Crossref PubMed Scopus (336) Google Scholar). It is the causative agent of the sixth disease of the childhood and infects, virtually, all children within the first few years of life (1Zerr DM Meier AS Selke SS Frenkel LM Huang ML Wald A A population-based study of primary human herpesvirus 6 infection..N Engl J Med. 2005; 352: 768-776Crossref PubMed Scopus (336) Google Scholar). Like other herpesviruses, after the primary infection, HHV-6 establishes latency, from which it may reactivate and cause illnesses in immunosuppressive states (2Clark DA Griffiths PD Human herpesvirus-6: Relevance of infection in the immunocompromised host..Br J Haematol. 2003; 120: 384-395Crossref PubMed Scopus (56) Google Scholar,3Zerr DM Corey L Kim HW Huang M-L Nguy L Boeckh M Clinical outcome of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation..Clin Infect Dis. 2005; 40: 932-940Crossref PubMed Scopus (256) Google Scholar). Approximately 60% of solid organ transplant (SOT) and 40% of allogeneic stem cell transplant (alloSCT) patients experience HHV-6 reactivation, mainly of variant B, with variant A accounting for 2–3% of the events (2Clark DA Griffiths PD Human herpesvirus-6: Relevance of infection in the immunocompromised host..Br J Haematol. 2003; 120: 384-395Crossref PubMed Scopus (56) Google Scholar,3Zerr DM Corey L Kim HW Huang M-L Nguy L Boeckh M Clinical outcome of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation..Clin Infect Dis. 2005; 40: 932-940Crossref PubMed Scopus (256) Google Scholar). Primary infection may also occur in the small fraction of seronegative patients undergoing transplantation, usually as a result of the transmission of the virus from the donor through the infected organ (2Clark DA Griffiths PD Human herpesvirus-6: Relevance of infection in the immunocompromised host..Br J Haematol. 2003; 120: 384-395Crossref PubMed Scopus (56) Google Scholar, 3Zerr DM Corey L Kim HW Huang M-L Nguy L Boeckh M Clinical outcome of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation..Clin Infect Dis. 2005; 40: 932-940Crossref PubMed Scopus (256) Google Scholar, 4Potenza L Luppi M Barozzi P et al.HHV-6A in syncytial giant-cell hepatitis..N Engl J Med. 2008; 40: 31-40Google Scholar). Fever, bone marrow suppression, encephalitis, pneumonitis and hepatitis have been reported as direct sequelae of HHV-6 active infection, while graft versus host disease, delayed platelet engraftment and susceptibility to opportunistic agents have been appreciated to a greater extent as indirect sequelae (2Clark DA Griffiths PD Human herpesvirus-6: Relevance of infection in the immunocompromised host..Br J Haematol. 2003; 120: 384-395Crossref PubMed Scopus (56) Google Scholar, 3Zerr DM Corey L Kim HW Huang M-L Nguy L Boeckh M Clinical outcome of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation..Clin Infect Dis. 2005; 40: 932-940Crossref PubMed Scopus (256) Google Scholar, 4Potenza L Luppi M Barozzi P et al.HHV-6A in syncytial giant-cell hepatitis..N Engl J Med. 2008; 40: 31-40Google Scholar, 5Rogers J Rohal S Carrigan D et al.Human herpesvirus-6 infection in liver transplant recipients: Role in pathogenesis of fungal infections, neurologic complications and outcome..Transplantation. 2000; 69: 2566-2573Crossref PubMed Scopus (112) Google Scholar). A lesser-recognized form of HHV-6 latency is the integration of the viral genome in a host chromosome (CIHHV-6) (6Luppi M Marasca R Barozzi P et al.Three cases of human herpesvirus-6 latent infection: Integration of viral genome in peripheral blood mononuclear cell DNA..J Med Virol. 1993; 40: 44-52Crossref PubMed Scopus (148) Google Scholar). This phenomenon features a high viral copy number either in whole blood (>6 log10 HHV-6 copies/mL) or sera (>3.5 log10 copies/mL) or other body sites (>4 log10 copies/hair follicle or/mL of cerebrospinal fluid), as a consequence of inheritance of viral sequences through the germ line and their retainance in every nucleated cell (7Ward KN Leong HN Nacheva EP et al.Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles..J Clin Microbiol. 2006; 44: 1571-1574Crossref PubMed Scopus (168) Google Scholar). The prevalence of CIHHV-6 has been resulted 0.21% in healthy subjects from Japan and ranging from 0.8% to 3% in the general population from United Kingdom, while it is 1.5% in children treated for acute leukemias in the Czech Republic (8Leong HN Tuke PW Tedder RS et al.The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors..J Med Virol. 2007; 79: 45-51Crossref PubMed Scopus (161) Google Scholar, 9Tanaka-Taya K Sashihara J Kurahashi H et al.Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV- 6 DNA..J Med Virol. 2004; 73: 465-473Crossref PubMed Scopus (171) Google Scholar, 10Hubacek P Muzikova K Hrdlickova A et al.Prevalence of HHV-6 integrated chromosomally among children treated for acute lymphoblastic or myeloid leukemia in the Czech Republic..J Med Virol. 2009; 81: 258-263Crossref PubMed Scopus (41) Google Scholar). Although the integrated viral genome may be transcriptionally active, to date, no replication has been reported either in vitro or in vivo(11Clark DA Tsao EHF Leong HN Ward KN Nacheva EP Griffiths PD Reply to Boutolleau et al and Luppi et al..J Infect Dis. 2006; 194: 1021-1023Crossref Scopus (12) Google Scholar). CIHHV-6 is commonly considered neither affecting the host health status nor requiring clinical intervention (11Clark DA Tsao EHF Leong HN Ward KN Nacheva EP Griffiths PD Reply to Boutolleau et al and Luppi et al..J Infect Dis. 2006; 194: 1021-1023Crossref Scopus (12) Google Scholar), but its clinical significance remains largely unknown. Only one case of CIHHV-6 and concurring encephalomyelitis, subsequently relieved by antivirals, has so far been reported in an immunocompetent subject (12Troy SB Blackburn BG Yeom K Caulfied AK Bhangoo MS Montoya JG Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpes virus 6 and clinical response to treatment with foscarnet plus ganciclovir..Clin Infect Dis. 2008; 47: e93-e96Crossref PubMed Scopus (46) Google Scholar). Essentially, CIHHV-6 may confound the laboratory diagnosis of HHV-6 active infection prompting possibly unnecessary and harmful antiviral treatment, as recently published (13Clark DA Nacheva EP Leong HN et al.Transmission of integrated human herpesvirus 6 through stem cell transplantation: Implications for laboratory diagnosis.J Infect Dis. 2006; 193: 912-916Crossref PubMed Scopus (136) Google Scholar,14Hubacek P Maalouf J Zajickova M et al.Failure of multiple antivirals to affect high HHV-6 DNAaemia resulting from viral chromosomal integration in case of severe aplastic anemia..Haematologica. 2007; 92: e98-e100Crossref PubMed Scopus (35) Google Scholar). Here, we report the prevalence of CIHHV-6 in a cohort of SOT and alloSCT patients from a single Italian center and discuss issues related to the clinical manifestations and the management of the patients carrying CIHHV-6. Three hundred and forty-three SOT and 78 alloSCT consecutive patients from the Liver and Multivisceral Transplant Center and the Section of Hematology of the University Hospital of Modena were evaluated for the study from April 2000 to April 2008. The clinical characteristics of the patients are reported in Table 1.Table 1Clinical characteristics of the patientsSCT PatientsPts numberMedian age (years)Disease (%)Donor sibling/unrelatedStem cell sourceATG in induction immunosupression (%)GVHD acute/ chronicGVHD grading II-III/IVHHV-6 screening (%)7845ALL 14 (18)63/15BM 921 (27)19/1817/170 (90)AML 22 (28)PB 67MDS 5 (6)BM + PB 1MPD 12 (15)CB 1Lymphoma 13 (17)MM 11 (14)Solid tumor 1 (2)SOT patientsPts numberMedian age (years)Type of transplant (%)Induction immunosuppressive regimen (%)Maintenance immunosuppressive regimen (%)Rejection acute/ chronicRejection treatmentHHV-6 screening (%)34357Liver 303 (88)ATG 3 (0.8)CyA 77 (23)152/15PDN 128135 (39)Liver-kidney 15 (4.5)CyA 77 (23)FK 255 (74)OKT3 21Liver-heart 1 (0.2)PDN 1 (0.2)Sirolimus 11 (3)CyA 7Liver-small bowel 3 (0.8)MMF 4 (1)FK 11small bowel 21 (6.5)FK 258 (75)Pts = patients; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; MPD = myeloproliferative disorder; MM = multiple myeloma; BM = bone marrow; PB = peripheral blood; CB = cord blood; ATG = antithymocyte globulin; GVHD = graft versus host disease; HHV-6 = human herpes virus six; CyA = cyclosporine A; PDN = prednisone; MMF = mycophenolate mofetil; FK = tacrolimus; OKT3 = antiCD3 antibody. Open table in a new tab Pts = patients; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; MPD = myeloproliferative disorder; MM = multiple myeloma; BM = bone marrow; PB = peripheral blood; CB = cord blood; ATG = antithymocyte globulin; GVHD = graft versus host disease; HHV-6 = human herpes virus six; CyA = cyclosporine A; PDN = prednisone; MMF = mycophenolate mofetil; FK = tacrolimus; OKT3 = antiCD3 antibody. Plasma samples, ficoll-separated peripheral blood mononuclear cells, whole peripheral and bone marrow blood, bronchoalveolar lavage fluid, cerebrospinal fluid and tissue specimens, namely bone marrow trephine biopsy, gastric and cutaneous biopsies and hair follicles were collected and screened for HHV-6 active infection in the presence of clinical manifestations for which a viral etiology was suspected, either in the early posttransplant period or during the outpatient controls as a part of a routine virologic screening. On the same occasions, cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) were investigated by quantitative real-time polymerase chain reaction (qrt-PCR) on plasma and whole blood, and CMV also by pp65 antigenemia assay on pheripheral blood polymorphonuclear cells, as described (4Potenza L Luppi M Barozzi P et al.HHV-6A in syncytial giant-cell hepatitis..N Engl J Med. 2008; 40: 31-40Google Scholar). SOT recipients at high risk for CMV infections, because CMV seronegative and receiving a CMV seropositive graft, underwent antiviral prophylaxis with oral valganciclovir 450 mg bis in die (b.i.d.) until the third month posttransplantation. Until 1 year posttransplantation, all the other SOT patients received oral acyclovir, at a dose of 400 mg b.i.d., while SCT patients received acyclovir at a dose of 500 mg/m2 ter in die (t.i.d.) endovenously during the first 30 day posttransplantation, then orally. The median follow-up was 35.7 ± 29 months. The study was approved by the local Ethical Committee. Each patient gave the informed consent for the study. CMV, EBV and HHV-6 viral loads have been quantified by commercially available kits (Nanogen Advanced Diagnostics, Turin, Italy), able to detect a minimal quantity of 10 genome Equivalent of each virus per reaction, as previously reported (4Potenza L Luppi M Barozzi P et al.HHV-6A in syncytial giant-cell hepatitis..N Engl J Med. 2008; 40: 31-40Google Scholar). Cases suspected to carry CIHHV-6 were confirmed by an independent laboratory with a different quantitative PCR method as previously reported (15Gautheret-Dejean A Manichanch C Thien-Ah-Koon F et al.Development of a real-time polymerase chain reaction assay for the diagnosis of human herpesvirus-6 infection and application to bone marrow transplant patients..J Virol Methods. 2002; 100: 27-35Crossref PubMed Scopus (135) Google Scholar). HHV-6 variant characterization was performed by restriction analysis of the HHV-6 PCR product and also by a highly sensitive primer-specific PCR assay, as described (4Potenza L Luppi M Barozzi P et al.HHV-6A in syncytial giant-cell hepatitis..N Engl J Med. 2008; 40: 31-40Google Scholar). The HHV-6 variant specific PCR has demonstrated a sensitivity threshold of about 10 copies/well for HHV-6 variant A and 1 copy/well for HHV-6 variant B and the assay may detect and identify one variant in the presence of more than 1000 times higher concentrations of the other variant in virus mixtures (16Boutolleau D Duros C Bonnafocus C et al.Identification of human herpesvirus 6 variants A and B by primer-specific real-time PCR may help to revisit their respective role in pathology..J Clin Virol. 2006; 35: 257-263Crossref PubMed Scopus (87) Google Scholar). HHV-6, CMV and EBV associated diseases have been defined as reported (Ref. 1Zerr DM Meier AS Selke SS Frenkel LM Huang ML Wald A A population-based study of primary human herpesvirus 6 infection..N Engl J Med. 2005; 352: 768-776Crossref PubMed Scopus (336) Google Scholar, 2Clark DA Griffiths PD Human herpesvirus-6: Relevance of infection in the immunocompromised host..Br J Haematol. 2003; 120: 384-395Crossref PubMed Scopus (56) Google Scholar, 3Zerr DM Corey L Kim HW Huang M-L Nguy L Boeckh M Clinical outcome of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation..Clin Infect Dis. 2005; 40: 932-940Crossref PubMed Scopus (256) Google Scholar, Supporting Information). Biopsy specimens from patients were studied with hematoxylin and eosin staining for routine histologic studies. Immunohistochemical analyses with standard immunoperoxidase-staining procedures were performed with the use of the mouse monoclonal antibodies, as previously described (4Potenza L Luppi M Barozzi P et al.HHV-6A in syncytial giant-cell hepatitis..N Engl J Med. 2008; 40: 31-40Google Scholar). During the entire follow-up period, 292 episodes of HHV-6 viremia (218 in SOT and 74 in SCT setting, respectively), were recorded (Figure 1A). Total numbers of patients screened for HHV-6 DNA either on body fluids and tissue specimens, were 135 out of 343 (39%) SOT and 70 out of 78 (90%) alloSCT (1014 samples analyzed; median of 4.9 sample/patient). Fifty-two (39%) out 135 SOT and 16 (23%) out of 70 alloSCT patients presented at least one positive sample for HHV-6. Seven (13.4%) out of 52 SOT and 3 (18%) out of 16 alloSCT patients presented symptoms and signs consistent with HHV-6-related diseases, namely thrombocytopenia 2, fever 2, fever and lymphadenopaties 1, neutropenia and thrombocytopenia 4, syncytial giant cell hepatitis 1 (Figure 1B). This latter patient has been previously reported (4Potenza L Luppi M Barozzi P et al.HHV-6A in syncytial giant-cell hepatitis..N Engl J Med. 2008; 40: 31-40Google Scholar). The patients with HHV-6-related diseases presented HHV-6 loads included between 20 and 1000 HHV-6 genome copies (gc)/mL of plasma (Figure 1A). Nineteen (36.5%) out of 52 SOT and 4 (25%) out of 16 SCT patients with HHV-6 viremia presented CMV coinfection. Patients with concomitant HHV-6 and CMV viremia presented neither higher values of CMV antigenemia nor worse clinical course than patients with CMV alone. The percentage of HHV-6 coinfection, either in SOT or SCT patients with CMV viremia and their clinical outcome are consistent with those recently reported by Humar et al. in SOT patients alone and are in agreement with the raised possibility that coinfections may only reflect a more intense immunosuppressive states, without a clear clinical significance (17Humar A Asberg A Kumar D et al.An assessment of herpesvirus co-infections in patients with CMV disease: Correlation with clinical and virologic outcomes..Am J Transplant. 2009; 9: 374-381Crossref PubMed Scopus (62) Google Scholar). Two (0.9%) out of 205 patients, one alloSCT and one SOT patient, respectively, demonstrated HHV-6 loads consistent with CIHHV-6. Their clinical outcome has been reported in detail, below. Seven hundred and forty-one episodes of CMV viremia (493 in SOT and 248 in SCT setting, respectively) were registered (Figure 1A). All but five patients were treated with antivirals on a preemptive basis, the remaining five cases presented CMV diseases. Eight hundred and sixty-five episodes of Epstein-Barr virus viremia (631 in SOT and 234 in SCT setting, respectively) were also detected (Figure 1A). Eleven out of 70 alloSCT patients with EBV viremia were treated with preemptive rituximab, according to studies suggesting that early treatment may avoid progression to posttransplant lymphproliferative disorders (PTLDs) and thus improve the outcome of EBV associated diseases (18Weinstock DM Ambrossi GG Brennan C Kiehn TE Jakubowski A Preemptive diagnosis and treatment of Epstein-Barr virus associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: An approach in development..Bone Marrow Transplant. 2006; 37: 539-546Crossref PubMed Scopus (91) Google Scholar). All the 11 patients had complete resolution of their elevated viremia without further complications. Four out of 135 SOT patients developed PTLDs, of which two resulted EBV positive and two EBV negative on immunohistochemical and molecular studies. All four cases were treated with rituximab alone and only two patients responded. A 60-year-old Caucasian man underwent a peripheral blood stem cell transplant from a human leukocyte antigen-matched, unrelated donor because of high-risk myelodysplastic syndrome. Immunsuppressive regimen consisted of antithymocyte globulin (10 mg/kg days from −4 to −2), methotrexate (10 mg/m2 day +3 and +6), cyclosporine from day −1 (blood trough level 200–400 ng/mL). On day +21 the patient presented maculopapular, somewhere confluent, erythematous exanthema involving the trunk and the limbs and his peripheral white blood cell count demonstrated a delayed recovery, being leukocytes 340/mm3. HHV-6 DNA was disclosed on plasma [6478 gc/mL] (Figure 2A). Bone marrow HHV-6 DNAemia also resulted extremely elevated (374 682 gc/mL) (Figure 2B). Foscarnet was started at 60 mg/kg t.i.d. and a skin biopsy was performed (Figure 2A). The histologic examination revealed cutaneous grade II acute graft versus host disease (GVHD), and corticosteroids (2 mg/kg) were added. From day +43, acute GVHD improved, but HHV-6 was still detectable at high loads (Figure 2A). Steroids were tapered at 0.20 mg/kg and foscarnet continued. On day +58, nonetheless the HHV-6 loads persisted unmodified, either on plasma or bone marrow blood, foscarnet was reduced at the maintenance dosage (90 mg/day, 5 day/week) (Figure 2A). On day +97, HHV-6 persisted detectable at high level either on plasma or bone marrow blood, but the patient resulted asymptomatic and foscarnet was finally discontinued. On day +110, he complained severe gastric pain, dyspepsia and the skin rash reappeared. HHV-6 loads increased on plasma, while remained unmutated on bone marrow blood (Figure 1A). Gastric and skin biopsies demonstrated GVHD grade II to III. HHV-6 load was 138046 gc/105 cells, on gastric tissue, but immunohistochemical analysis failed to demonstrate HHV-6 productive infection of the gastric cells. Before restarting antiviral therapy, the quantification of HHV-6 on the patient's hair follicles was performed and resulted 5318242 gc/106 cells. The viral variant was typed as variant A. The patient was considered to carry CIHHV-6 and the antiviral treatment judged unnecessary. Currently, at day +259, bone marrow HHV-6 DNAemia persists at high level, while HHV-6, on plasma, has been reduced to 96 gc/mL, as a consequence of the improvement in peripheral blood chimerism from 3.5log10 copies/mL in plasma or CSF, and >6log10 copies/mL in whole peripheral or bone marrow blood) at about one copy per cell are highly suggestive of CIHHV-6 rather than active infection (6Luppi M Marasca R Barozzi P et al.Three cases of human herpesvirus-6 latent infection: Integration of viral genome in peripheral blood mononuclear cell DNA..J Med Virol. 1993; 40: 44-52Crossref PubMed Scopus (148) Google Scholar, 7Ward KN Leong HN Nacheva EP et al.Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles..J Clin Microbiol. 2006; 44: 1571-1574Crossref PubMed Scopus (168) Google Scholar, 8Leong HN Tuke PW Tedder RS et al.The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors..J Med Virol. 2007; 79: 45-51Crossref PubMed Scopus (161) Google Scholar, 9Tanaka-Taya K Sashihara J Kurahashi H et al.Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV- 6 DNA..J Med Virol. 2004; 73: 465-473Crossref PubMed Scopus (171) Google Scholar). The determination of viral variant is useless for this scope, as either variant A or variant B have been found integrated. Viral isolation and the antigenemia test are still time consuming and not always reliable. The search for HHV-6 DNA in hair follicles, nails or tissue specimens should be performed to confirm the occurrence of CIHHV-6. These latter tests and a proper clinical evaluation may preclude unnecessary and potentially harmful treatments. Nonetheless, also considering the report by Troy et al. (12Troy SB Blackburn BG Yeom K Caulfied AK Bhangoo MS Montoya JG Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpes virus 6 and clinical response to treatment with foscarnet plus ganciclovir..Clin Infect Dis. 2008; 47: e93-e96Crossref PubMed Scopus (46) Google Scholar), the antiviral treatment may not be completely dismissed, also in the case of CIHHV-6, if the clinical symptoms are suggestive of HHV-6-related diseases and all other possible causative agents have been excluded. Larger studies urge to be performed, to understand the clinical implications of the phenomenon of CIHHV-6. Finally, a wider pretransplantation screening, including also HHV-6 quantification, of organ donors and recipients, could prevent misinterpretation of CIHH-6 in the recipients after transplantation and, if applied in a prospective study from a specific geographical area, may help to definitively estimate the prevalence of CIHHV-6 phenomenon in transplant patients in a given country. This study was supported by the Italian Ministry for Education, Universities and Research (MIUR), Rome, Italy (G.T.); the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy (M.L.); the European Commission's FP6 Life-Science-Health Programme (INCA project; LSHC-CT-2005–018704) (M.L.); the Associazione Italiana Lotta alle Leucemie, Linfoma e Mieloma (AIL)-Sezione 'Luciano Pavarotti'-Modena-ONLUS (L.P.); and the Programma di ricerca Regione-Università 2007–2009 (G.T). We are indebted with Professor Antonio Daniele Pinna and Dr Stefania Cocchi for the follow-up of the patients, with Professor Claudio Cermelli and Dr Fabio Rumpianesi for technical advices. Additional Supporting Information may be found in the online version of this article: Download .doc (.02 MB) Help with doc files
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