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• W1607336048 abstract "Human cytomegalovirus (HCMV) causes significant morbidity in lung transplant recipients (LTRs). The clinical effects of HCMV replication are determined partly by a type 1 T-helper cell (Th1) response. Because the chemokine interferon-inducible protein of 10 kilodaltons (IP-10, CXCL-10) induces a Th1 response, we investigated whether HCMV triggers IP-10 in LTRs. The IP-10 concentration and HCMV DNA load were determined in 107 plasma and 46 bronchoalveolar lavage fluid (BALF) samples from 36 LTRs. Initial HCMV detection posttransplantation was significantly associated with increased plasma IP-10, regardless of whether the patients showed HCMV DNAemia (p = 0.001) or HCMV replication only in the allograft (p < 0.0001). In subsequent episodes of HCMV detection, plasma IP-10 increased regardless of whether HCMV was detected in blood (p = 0.0078) or only in BALF (p < 0.0001) and decreased after successful antiviral therapy (p = 0.0005). Furthermore, levels of HCMV DNA and IP-10 correlated statistically (p = 0.0033). Increased IP-10 levels in HCMV-positive BALF samples were significantly associated with severe airflow obstruction, as indicated by a decrease in forced expiratory volume in one second (FEV1). Our data indicate that HCMV replication in LTRs evokes a plasma IP-10 response and that, when an IP-10 response is observed in BALF, it is associated with inflammatory airway obstruction in the allograft. Human cytomegalovirus (HCMV) causes significant morbidity in lung transplant recipients (LTRs). The clinical effects of HCMV replication are determined partly by a type 1 T-helper cell (Th1) response. Because the chemokine interferon-inducible protein of 10 kilodaltons (IP-10, CXCL-10) induces a Th1 response, we investigated whether HCMV triggers IP-10 in LTRs. The IP-10 concentration and HCMV DNA load were determined in 107 plasma and 46 bronchoalveolar lavage fluid (BALF) samples from 36 LTRs. Initial HCMV detection posttransplantation was significantly associated with increased plasma IP-10, regardless of whether the patients showed HCMV DNAemia (p = 0.001) or HCMV replication only in the allograft (p < 0.0001). In subsequent episodes of HCMV detection, plasma IP-10 increased regardless of whether HCMV was detected in blood (p = 0.0078) or only in BALF (p < 0.0001) and decreased after successful antiviral therapy (p = 0.0005). Furthermore, levels of HCMV DNA and IP-10 correlated statistically (p = 0.0033). Increased IP-10 levels in HCMV-positive BALF samples were significantly associated with severe airflow obstruction, as indicated by a decrease in forced expiratory volume in one second (FEV1). Our data indicate that HCMV replication in LTRs evokes a plasma IP-10 response and that, when an IP-10 response is observed in BALF, it is associated with inflammatory airway obstruction in the allograft. Human cytomegalovirus (HCMV) causes significant mortality and morbidity in lung transplant recipients (LTRs) (1Shah PD McDyer JF Viral infections in lung transplant recipients.Semin Respir Crit Care Med. 2010; 31: 243-254Crossref PubMed Scopus (34) Google Scholar, 2Humar A Snydman D Cytomegalovirus in solid organ transplant recipients.Am J Transplant. 2009; 9: S78-S86Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 3Zamora MR Cytomegalovirus and lung transplantation.Am J Transplant. 2004; 4: 1219-1226Crossref PubMed Scopus (118) Google Scholar). In addition to direct clinical effects of HCMV replication after lung transplantation (LuTX), such as HCMV syndrome and tissue-invasive HCMV disease, there is evidence that HCMV also mediates inflammatory processes that have been associated with long-term sequelae of LuTX (4Streblow DN Orloff SL Nelson JA Acceleration of allograft failure by cytomegalovirus.Curr Opin Immunol. 2007; 19: 577-582Crossref PubMed Scopus (105) Google Scholar, 5Westall GP Michaelides A Williams TJ Snell GI Kotsimbos TC Bronchiolitis obliterans syndrome and early human cytomegalovirus DNAaemia dynamics after lung transplantation.Transplantation. 2003; 75: 2064-2068Crossref PubMed Scopus (68) Google Scholar, 6Snyder LD Finlen-Copeland CA Turbyfill WJ Howell D Willner DA Palmer SM Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in lung transplantation.Am J Respir Crit Care Med. 2010; 181: 1391-1396Crossref PubMed Scopus (112) Google Scholar, 7Humar A Michaels M American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.Am J Transplant. 2006; 6: 262-274Crossref PubMed Scopus (379) Google Scholar, 8Ljungman P Griffiths P Paya C Definitions of cytomegalovirus infection and disease in transplant recipients.Clin Infect Dis. 2002; 34: 1094-1097Crossref PubMed Scopus (1032) Google Scholar). These include acute cellular rejection and bronchiolitis obliterans syndrome (BOS), which manifest clinically as progressive graft dysfunction (9Martinu T Chen DF Palmer SM Acute rejection and humoral sensitization in lung transplant recipients.Proc Am Thorac Soc. 2009; 6: 54-65Crossref PubMed Scopus (121) Google Scholar,10Belperio JA Weigt SS Fishbein MC Lynch IIIrd, JP Chronic lung allograft rejection: Mechanisms and therapy.Proc Am Thorac Soc. 2009; 6: 108-121Crossref PubMed Scopus (169) Google Scholar). To date, the mechanisms of HCMV pathogenesis after LuTX are not entirely understood. Previous studies have indicated that the HCMV serostatus of the donor and the recipient, individual viral kinetics, and the treatment regimen have a major impact on the clinical outcome of the infection (2Humar A Snydman D Cytomegalovirus in solid organ transplant recipients.Am J Transplant. 2009; 9: S78-S86Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar,11Emery VC Sabin CA Cope AV Gor D Hassan-Walker AF Griffiths PD Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation.Lancet. 2000; 355: 2032-2036Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar,12Kerschner H Jaksch P Karigl G Popow-Kraupp T Klepetko W Puchhammer-Stockl E Cytomegalovirus DNA load patterns developing after lung transplantation are significantly correlated with long-term patient survival.Transplantation. 2009; 87: 1720-1726Crossref PubMed Scopus (26) Google Scholar). Furthermore, the immune response of the host has been identified as decisive factor for development of HCMV disease (13Crough T Khanna R Immunobiology of human cytomegalovirus: From bench to bedside.Clin Microbiol Rev. 2009; 22: 76-98Crossref PubMed Scopus (467) Google Scholar). While the prominent role of HCMV-specific CD4+ T-helper cells with a type 1 cytokine profile (Th1 cells) has been verified in several studies, the role of chemokines associated with the Th1 response in HCMV infection is less clear (14Gamadia LE Remmerswaal EB Weel JF Bemelman F van Lier RA Ten Berge IJ Primary immune responses to human CMV: A critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease.Blood. 2003; 101: 2686-2692Crossref PubMed Scopus (355) Google Scholar, 15Shlobin OA West EE Lechtzin N et al.Persistent cytomegalovirus-specific memory responses in the lung allograft and blood following primary infection in lung transplant recipients.J Immunol. 2006; 176: 2625-2634Crossref PubMed Scopus (56) Google Scholar, 16Gerna G Lilleri D Fornara C et al.Monitoring of human cytomegalovirus-specific CD4 and CD8 T cell immunity in patients receiving solid organ transplantation.Am J Transplant. 2006; 6: 2356-2364Crossref PubMed Scopus (136) Google Scholar). Chemokines are small chemotactic cytokines that modulate inflammatory processes and regulate migration of leucocytes and cell–cell signaling in the immune system. Four subfamilies, based on the number and arrangement of conserved cysteines have been described (CXC, which is subdivided into non-ELR and ELR [Glu-Leu-Arg motif], CC, C and CX3C) (17Baggiolini M. Chemokines and leukocyte traffic.Nature. 1998; 392: 565-568Crossref PubMed Scopus (2395) Google Scholar,18Loetscher M Gerber B Loetscher P et al.Chemokine receptor specific for IP10 and mig: Structure, function, and expression in activated T-lymphocytes.J Exp Med. 1996; 184: 963-969Crossref PubMed Scopus (1059) Google Scholar). A restricted subset of non-ELR CXC inflammatory chemokines act as high-affinity ligands for the CXCR3 receptor found predominantly on activated Th1 cells and chemoattract effector T cells to the site of the infection, thereby inducing and shaping a Th1-polarized adaptive immune response (19Agostini C Facco M Siviero M et al.CXC chemokines IP-10 and mig expression and direct migration of pulmonary CD8+/CXCR3+ T cells in the lungs of patients with HIV infection and T cell alveolitis.Am J Respir Crit Care Med. 2000; 162: 1466-1473Crossref PubMed Scopus (93) Google Scholar, 20Hokeness KL Deweerd ES Munks MW Lewis CA Gladue RP Salazar-Mather TP CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection.J Virol. 2007; 81: 1241-1250Crossref PubMed Scopus (76) Google Scholar, 21Romagnani S. Regulation of the T cell response.Clin Exp Allergy. 2006; 36: 1357-1366Crossref PubMed Scopus (312) Google Scholar, 22Qin S Rottman JB Myers P et al.The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.J Clin Invest. 1998; 101: 746-754Crossref PubMed Scopus (1194) Google Scholar). Interferon-inducible protein of 10 kilodaltons (IP-10), or CXC ligand 10 (CXCL-10), is one of these CXCR3-binding chemokines that exerts a stimulating effect on the directional migration of activated and memory Th1 cells and promotes the production of Th1 cytokines (23Dufour JH Dziejman M Liu MT Leung JH Lane TE Luster AD IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking.J Immunol. 2002; 168: 3195-3204Crossref PubMed Scopus (863) Google Scholar). An association between specific viral airway infections and IP-10 production has been shown previously. In vitro studies have indicated that infections with influenza virus, human rhinovirus (HRV) and human respiratory syncytial virus (HRSV) are associated with IP-10 expression, mainly in bronchoalveolar epithelial cells and macrophages (24Oshansky CM Barber JP Crabtree J Tripp RA Respiratory syncytial virus F and G proteins induce interleukin 1alpha, CC, and CXC chemokine responses by normal human bronchoepithelial cells.J Infect Dis. 2010; 201: 1201-1207Crossref PubMed Scopus (48) Google Scholar, 25Neumann B Emmanuilidis K Stadler M Holzmann B Distinct functions of interferon-gamma for chemokine expression in models of acute lung inflammation.Immunology. 1998; 95: 512-521Crossref PubMed Scopus (40) Google Scholar, 26Sauty A Dziejman M Taha RA et al.The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells.J Immunol. 1999; 162: 3549-3558Crossref PubMed Google Scholar, 27Chan MC Cheung CY Chui WH et al.Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells.Respir Res. 2005; 6: 135Crossref PubMed Scopus (419) Google Scholar, 28Miller AL Bowlin TL Lukacs NW Respiratory syncytial virus-induced chemokine production: Linking viral replication to chemokine production in vitro and in vivo.J Infect Dis. 2004; 189: 1419-1430Crossref PubMed Scopus (158) Google Scholar, 29Wark PA Bucchieri F Johnston SL et al.IFN-gamma-induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations.J Allergy Clin Immunol. 2007; 120: 586-593Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 30Spurrell JC Wiehler S Zaheer RS Sanders SP Proud D Human airway epithelial cells produce IP-10 (CXCL10) in vitro and in vivo upon rhinovirus infection.Am J Physiol Lung Cell Mol Physiol. 2005; 289: L85-L95Crossref PubMed Scopus (233) Google Scholar). Recently, it was demonstrated that the plasma IP-10 level can also be used as biomarker for predicting inflammatory airway obstruction after HRV infection, which results in exacerbations of asthma bronchiale and chronic obstructive pulmonary disease (COPD, 29Wark PA Bucchieri F Johnston SL et al.IFN-gamma-induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations.J Allergy Clin Immunol. 2007; 120: 586-593Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar,31Quint JK Donaldson GC Goldring JJ Baghai-Ravary R Hurst JR Wedzicha JA Serum IP-10 as a biomarker of human rhinovirus infection at exacerbation of COPD.Chest. 2010; 137: 812-822Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). In transplantation, and in particular in LuTX, IP-10 has been shown to be involved in acute cellular rejection and in the development of obliterative bronchiolitis, where it triggers an influx of alloreactive CXCR3-positive T cells into the airways (32Agostini C Calabrese F Rea F et al.CXCR3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection.Am J Pathol. 2001; 158: 1703-1711Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Compared to asymptomatic LTRs, IP-10 levels are apparently increased in bronchoalveolar lavage fluid (BALF) or serum from LTRs who suffer from primary graft dysfunction, acute allograft rejection or BOS (33Belperio JA Keane MP Burdick MD et al.Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome.J Immunol. 2002; 169: 1037-1049Crossref PubMed Scopus (195) Google Scholar,34Hoffman SA Wang L Shah CV et al.Plasma cytokines and chemokines in primary graft dysfunction post-lung transplantation.Am J Transplant. 2009; 9: 389-396Crossref PubMed Scopus (84) Google Scholar). For HCMV, which infects cells of the lung allograft and plays a significant role in LuTX, there are still no data that reveal an association between HCMV replication in LTRs and IP-10 production. However, in vitro experiments show that monocytes massively upregulate IP-10 mRNA upon stimulation with HCMV (35Chan G Bivins-Smith ER Smith MS Smith PM Yurochko AD Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage.J Immunol. 2008; 181: 698-711Crossref PubMed Scopus (151) Google Scholar). We therefore investigated in the present study whether HCMV replication, as indicated by presence of HCMV DNA in blood or the lung allograft of LTRs during the posttransplant follow-up, was associated with an increase in IP-10 levels, which might have further implications for the transplant. We show that, in LTRs, HCMV triggers a plasma IP-10 response, irrespective of the compartment where the virus replicates, and that an increase in the IP-10 level in BALF due to HCMV is associated with inflammatory airway obstruction. In this retrospective study, 36 patients were included who received a lung transplant at the Medical University of Vienna between May 2002 and August 2008. 26 LTRs were selected as study patients if their virological records revealed at least one episode of HCMV replication with viral DNA levels exceeding 1000 copies/mL in BALF and/or plasma during the posttransplant period. Ten patients without any episode of HCMV replication during the follow-up served as control group. Clinical characteristics of study patients are presented in Table 1. All patients received immunosuppression with prednisolone, mycophenolate and cyclosporine or tacrolimus as well as HCMV prophylaxis. Prophylaxis consisted of hyperimmune globulin (10 mg/kg per dose every 12 hours) at days 1, 7, 14 and 21 after LuTX, ganciclovir administered intravenously for 3 weeks, and valganciclovir administered orally (450–900 mg, twice daily, depending on the patient’s weight and renal function) (Table 1). This study was conducted in accordance with the guidelines of the local ethics committee.Table 1:Clinical characteristics of study patientsPatient # IDSex (male/ female)Age (years)Primary diseaseType of LuTX (single/ double)Date of LuTX (month/ year)HCMV serostatus (donor/ recipient)Time point(s) (of) (day post LuTX)Compartment of first HCMV DNA detection (BALF only/plasma ± BALF)Quantitative PCR at first HCMV DNA detection (copies/mL)Histological grading of biopsy sample obtained at first HCMV DNA detection1Evaluated according to the 1996 International Society for Heart and Lung Transplantation working formulation: A0 = no acute rejection; A1 = minimal acute rejection; A2 = mild acute rejection; B0 = no airway inflammation; B1 = minimal airway inflammation; B2 = mild airway inflammation.Time point(s) of further episodes of HCMV detection within follow-up (day post LuTX)Onset of BOS (day post LuTX)Follow-up (days post LuTX)End of HCMV prophylaxisBaseline sample was obtainedFEV1 baseline was determinedFirst HCMV DNA detectionPlasmaBALFAcute rejectionAirway inflammationPlasma ± BALFBALF only#1m58COPDDouble01/2006D+R+10591113, 191220BALF only<10002400A0B1None409–440#2f60COPDSingle03/2006D+R+110110350, 425443BALF only<10001100A1B1None569, 684498684#3f56COPDDouble07/2006D−R+100100124, 158200BALF only<10001662A2B1–2235None–1198#4m53COPDDouble07/2006D+R+663366, 94122BALF only<1000140 000A0B0–1376192–1231#5f27CFDouble06/2005D+R−135501849, 877973BALF only<10002030A0B2NoneNone11581225#6m65COPDDouble06/2005D+R+7737115, 140168BALF only<10003170A0B0NoneNone7111617#7f19CFDouble05/2002D?R+98105No FEV1 data Available189BALF only<10005830A0–1B0–1None399–2459#8f64COPDSingle06/2007D+R+115101101, 115161BALF only<10002320A2B0–1NoneNone–892#9f45COPDDouble06/2006D+R+8383112, 143181BALF only<10006990A0B0–1259None–1147#10f63COPDDouble09/2003D?R+12736190, 212225BALF only<100061 500A0B0NoneNone–273#11f57COPDDouble07/2007D−R+63112133, 146175BALF only<100028 400A0B0–1None369–406#12m30CFDouble07/2007D?R+848484, 119189BALF only<100020 200A1B1None371–421#13m46COPDDouble04/2008D+R+10011256, 112177BALF only<10001840A0B1–2NoneNone–370#14f60COPDDouble05/2008D+R+963796, 156178BALF only<100020 500A0B0–1None369–369#15f57COPDDouble03/2008D−R+9235107, 139171BALF only<100065 700A0B1–2None275–580#16m53FibrosisSingle08/2006D+R+9557–141Plasma ± BALF16 400<1000A0B0–1NoneNone–1130#17m48COPDDouble05/2007D+R+9292–165Plasma ± BALF1680No BALFNo bronchoscopyNoneNone–933#18m58A1ADDouble08/2007D−R+7526–133Plasma ± BALF8050No BALFNo bronchoscopyNone364–819#19f48COPDSingle02/2006D+R+113251–310Plasma ± BALF3820No BALFNo bronchoscopy576, 764None4211396#20f50COPDDouble12/2007D−R+894141, 89147Plasma ± BALF4800119 000A0B0–1NoneNone339670#21m58COPDDouble06/2007D+R+9090–188Plasma ± BALF15 800No BALFNo bronchoscopyNone213569912#22m61COPDDouble07/2007D+R−36284–159Plasma ± BALF92 600No BALFNo bronchoscopyNone457–889#23m54COPDDouble09/2005D+R−364319–394Plasma ± BALF6380No BALFNo bronchoscopy880503, 649, 758581880#24m41CFDouble08/2008D+R−Permanent therapy30–157Plasma ± BALF7690No BALFNo bronchoscopyPersistent viremiaPersistent detection–245#25f59COPDDouble08/2007D?R+417777, 99137Plasma ± BALF29301410A0B1–2189, 264None–830#26m65FibrosisDouble05/2004D+R+10835No FEV1 data Available1863Plasma ± BALF63401840A0B1NoneNone–1875LuTX = lung transplantation; HCMV = human cytomegalovirus; COPD = chronic obstructive pulmonary disease; CF = cystic fibrosis; A1AD = alpha 1-antitrypsin deficiency; D = donor; R = recipient; BALF = bronchoalveolar lavage fluid; PCR = polymerase chain reaction; BOS = bronchiolitis obliterans syndrome.1 Evaluated according to the 1996 International Society for Heart and Lung Transplantation working formulation: A0 = no acute rejection; A1 = minimal acute rejection; A2 = mild acute rejection; B0 = no airway inflammation; B1 = minimal airway inflammation; B2 = mild airway inflammation. Open table in a new tab LuTX = lung transplantation; HCMV = human cytomegalovirus; COPD = chronic obstructive pulmonary disease; CF = cystic fibrosis; A1AD = alpha 1-antitrypsin deficiency; D = donor; R = recipient; BALF = bronchoalveolar lavage fluid; PCR = polymerase chain reaction; BOS = bronchiolitis obliterans syndrome. All samples investigated in this study were obtained in the course of the patients’ clinical routine follow-up posttransplantation, which included weekly collection of plasma samples for two months after LuTX, and thereafter, monthly, as well as bronchoscopies, with sampling of BALF at weeks 1, 2, 4, 8, 12, 24 and 52 after LuTX, with additional procedures performed if infection or rejection was suspected clinically. When plasma HCMV loads exceeded 1000 copies/mL during follow-up, preemptive valganciclovir therapy was initiated. For the study, the following specific samples from the follow-up were selected: (a)Baseline samples: From each patient, a pair of plasma and BALF samples, obtained on the same day in the posttransplant follow-up, was selected and defined as baseline based on the following criteria: (1) Clinical information obtained by retrospective chart review indicated no clinical signs of rejection, inflammation or infection on the day the samples were obtained, and the patients had received no antimicrobial therapy except valganciclovir and amphotericin B prophylaxis. (2) C-reactive protein, leucocyte and lymphocyte numbers were in normal range. (3) Histological investigation of a lung biopsy specimen obtained on the same day from all patients showed no evidence of rejection, infection, inflammation, T cell infiltration or viral inclusion bodies in the tissue, and immunohistochemistry and in situ hybridization gave negative results for HCMV and Epstein–Barr virus infection. (4) In the analysis of the baseline BALF sample, the bacterial count of the resident ororpharyngeal flora was lower than 107/mL, Candida albicans was detected at a concentration of no more than 100 colony forming units/mL, and acid-resistant rods and mycobacteria were undetectable by polymerase chain reaction (PCR) and culture. Furthermore, the BALF sample was negative for Toxoplasma gondii, Pneumocystis carinii (both by PCR) and Aspergillus fumigatus (culture), and the absence of respiratory viruses (adenovirus, HRSV, influenza A and B viruses, parainfluenza 1, 2 and 3 viruses) was verified by antigen enzyme-linked immunosorbent assay (ELISA). (5) HCMV was undetectable in plasma by PCR and in BALF by PCR and shell vial culture. The time point at which the baseline sample was obtained from each patient is shown in Table 1.(b)Samples at initial HCMV detection: From each of the 26 study patients, a plasma sample was tested that was taken on the day during the posttransplant follow-up when the HCMV DNA level in plasma and/or BALF first exceeded 1000 copies/mL. In 11 LTRs, this first emergence of HCMV DNA was detected in plasma, while in 15 LTRs, HCMV was first detected at levels higher than 1000 copies/mL only in BALF (Table 1). From these 15 patients, and from 3 LTRs in whom HCMV was initially detected in plasma and BALF, HCMV-positive BALF samples were investigated.(c)Samples from later episodes of HCMV detection and posttreatment samples: In addition, 23 plasma samples were analyzed that were obtained during further episodes of HCMV detection with a viral load exceeding 1000 copies/mL in plasma and/or BALF, including 8 episodes of HCMV detection in plasma and 15 episodes of HCMV replication only in BALF (Table 1). Twelve additional posttreatment plasma samples were included, which were the first HCMV-DNA-negative samples taken after oral valganciclovir treatment of either the initial episode or a later episode of HCMV replication. Quantitative assessment of the HCMV DNA load in plasma and BALF samples was performed by PCR using a Cobas Amplicor HCMV Monitor-Test Kit on a COBAS Amplicor Analyzer (Roche Molecular Systems, Branchburg). In addition, HCMV was detected in BALF by shell vial method and by immunofluorescence staining of immediate-early antigen in infected cells. Lung biopsy specimens were analyzed for presence of HCMV by immunohistochemistry. Gancyclovir resistance testing was performed as described previously (36Puchhammer-Stöckl E Görzer I Zoufaly A et al.Emergence of multiple cytomegalovirus strains in blood and lung of lung transplant recipients.Transplantation. 2006; 81: 187-194Crossref PubMed Scopus (66) Google Scholar). IP-10 levels in plasma and BALF were determined using a commercially available ELISA (BD OPTEIA Human IP-10 ELISA Set, Becton Dickinson Biosciences, San Diego, CA, USA). The lower limit of detection was 7.5 picograms (pg) per mL. All samples were stored at −20°C. Each plasma sample was tested undiluted, as well as in 10- and 20-fold dilutions. BALF samples were tested in serial dilutions of twofold steps from 1:2 to 1:64. As shown previously, the relationship between IP-10 concentration measurements in diluted and undiluted samples was not linear, but piecewise linear, with the degree of divergence increasing with increasing concentration (37Reiberger T Aberle JH Kundi M et al.IP-10 correlates with hepatitis C viral load, hepatic inflammation and fibrosis and predicts hepatitis C virus relapse or non-response in HIV-HCV coinfection.Antivir Ther. 2008; 13: 969-976Crossref PubMed Google Scholar). Therefore, the cutoff points for the pieces of linearity in plasma and BALF samples were determined, and the concentration in undiluted samples with higher IP-10 levels was estimated from the reverse function. The forced expiratory volume in one second (FEV1) was determined in 16 LTRs in whom HCMV DNA was detected in the BALF during the initial episode of viral replication posttransplant (Table 1). The FEV1 value at initial HCMV detection was compared to the arithmetically averaged mean of two FEV1 values determined at immediately preceding regular visits to the outpatient clinic when HCMV was undetectable and signs of infection, acute rejection or BOS were absent (FEV1 baseline) (Table 1). Within-patient comparison of IP-10 levels was performed using paired nonparametric t-tests (Wilcoxon matched pairs test). Groups of patients were compared by Mann–Whitney U test. Spearman’s rank test was used to estimate the association between HCMV DNA and IP-10 levels. For all statistical tests, a p-value of <0.05 was considered statistically significant. GraphPad Prism version 5.0 software was used for statistical analysis. First, we investigated whether initial detection of HCMV replication after LuTX was associated with a rise in plasma IP-10 levels. Therefore, we measured the IP-10 level in baseline plasma samples that had been obtained from each of the 26 LTRs included in the study at a time point when neither HCMV nor any other infection, inflammation or rejection was detectable (see Materials and Methods) and compared it to the IP-10 level in a plasma sample obtained later during the posttransplant follow-up, at the point when HCMV DNA was first detected. The samples were divided into two groups for analysis, according to the compartment where HCMV was first detected. In 11 of the LTRs, HCMV was first detected in the blood (Table 1). Analysis of samples from these 11 individuals, shown in Figure 1(A), revealed a significantly higher IP-10 concentration in HCMV-DNA-positive plasma samples than in the patients’ baseline plasma samples (Figure 1A, p = 0.001). In 15 LTRs, HCMV could initially be detected only in BALF. For each patient, the plasma IP-10 level on the day when HCMV was first detected in the BALF specimen was compared to the baseline level, as presented in Figure 1(B). Although the virus was not detected in the blood, the plasma IP-10 levels were also significantly increased compared to baseline when HCMV emerged in the BALF only (Figure 1B, p < 0.0001). Finally, we investigated whether the extent of the plasma IP-10 increase was associated with the compartment where HCMV replication was detected. The levels of plasma IP-10 in patients with HCMV DNA in their plasma were compared to those in patients with HCMV DNA in their BALF only, as shown in Figure 1(C). The HCMV-associated plasma IP-10 level was significantly lower in patients in whom HCMV was detected only in BALF than in those in whom the virus was detected in plasma (Figure 1C, p = 0.0059). Next, we addressed the question whether further episodes of HCMV detection that occurred after the initial detection of the virus during follow-up were also associated with an increase in plasma IP-10 levels. For this purpose, we tested 23 additional plasma samples obtained from 16 LTRs during further episodes of detectable HCMV DNA replication. In 8 episodes, HCMV DNA was detected in blood, and in 15, only in BALF (Table 1). During these episodes of HCMV detection, an increase in plasma IP-10 levels compared to the baseline was detected, regardless of whether viral DNA was found in plasma (Figure 2A, p = 0.0078) or in BALF only (Figure 2B, p < 0.0001). However, as shown in Figure 2(C), significantly higher levels of plasma IP-10 were found in patients with HCMV DNAemia (p = 0.0103) than in those with HCMV in BALF only. We further analyzed whether the plasma HCMV DNA load and the plasma IP-10 level correlated statistically in HCMV-positive plasma samples. As shown in Figure 3(A), a significant correlation was found between plasma HCMV-DNA load and plasma IP-10 concentration in the 19 HCMV-positive plasma samples investigated in this study (p = 0.0033, Spearman R = 0.6386). To compare the kinetics of viral load and IP-10 levels, HCMV DNA and IP-10 concentrations were measured in multiple plasma samples from one LTR (patient #24, Table 1) during the course of primary HCMV infection. As shown in Figure 3(B), in this patient, kinetics of the plasma IP-10 level paralleled those of the plasma HCMV DNA load during the entire follow-up," @default.
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• W1607336048 date "2011-03-01" @default.
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• W1607336048 title "Human Cytomegalovirus Infection in Lung Transplant Recipients Triggers a CXCL-10 Response" @default.
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