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VIRAL INFECTIONS IN LUNG TRANSPLANT RECIPIENTS piratory syncytial virus (RSV), ... ognized as common pathogens after solid organ transplantation.3-5 ..... Husain S, Singh N. Bronchiolitis obliterans and lung transplantation: evidence ...
Viral Infections in lung transplant recipients: devils or trolls?

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P. SOLIDORO 1, E. BALESTRO 2, M. BOFFINI 3

Lung transplantation is a therapeutic option for end stage lung diseases. One of the most important topics in transplant management is the role of viral infections in chronic lung allograft dysfunction (CLAD) and in particular in acute rejection (AR). This review arise from a recent study BY Brideaux et al. that offers the opportunity to investigate deeply the incidence, risk factors, symptomatology and clinical outcome of respiratory viral infections. Although most respiratory viral infections cause self-limited upper respiratory diseases, lung transplant recipients (LTRs) are particularly prone to develop complications. The absence of symptoms is a pivotal problem in managing these patients as it can depend on absence of active replication or on the effect of immunosuppressive regimen. In one word viruses can be just passengers or aggressive drivers in a facilitated environment, and the potential damage is completely different, as the management. PCR samplings give us an idea of the presence but not the certainty of the activity of viruses, and this is another common problem in reading data. In Herpes Virus infections this problem can be overtaken by studying biological samples and immune response, balancing the presence (PCR) and the activity (shell vial) of viruses with specific immune response (elispot). In fact viral presence doesn’t mean activity and activity doesn’t mean pathology in case of competent immune response. All these data can be matched in every single patient and

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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.

MINERVA MED 2014;105(Suppl. 2 to No. 3):15-21

Corresponding author: P. Solidoro, Unit of Pneumology, Cardiovascular Thoracic Department, A.O. Città della Salute e della Scienza, C.so Bramante 88, 10126 Turin, Italy. E-mail: [email protected].

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1Unit of Pneumology Cardiovascular Thoracic Department A.O. Città della Salute e della Scienza di Torino Turin, Italy 2Respiratory Disease Department University of Padua, Padua, Italy 3Cardiac Surgery Division Surgical Sciences Department University of Turin A.O. Città della Salute e della Scienza di Torino Torino, Italy

managed by a tailored approach, either monitoring or treating. Key words: Virus disease - Lung transplantation Diagnosis.

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ung transplantation is a therapeutic option for end-stage lung diseases.1 The main historical problem in followup of lung tranplanted patients is the complex balance between immunosuppression and infections. Viral infections are central in decision making process because of the frequency and consequences, sometimes dramatic on the point of view of survival. One of the most important topics in transplant management is the role of viral infections in chronic lung allograft disfunction (CLAD) and in particular in acute rejection (AR). In particular we can divide the virus infections in two great categories: commu-

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piratory syncytial virus (RSV), adenovirus, rhinoviruses and coronaviruses and the recently described human metapneumovirus. Lung transplant recipients are at particular risk for viral RTIs due to a number of factors. These include potent immunosuppression regimens, decreased cough reflex due to denervation of the transplanted lung, abnormal lymphatic drainage, impaired mucociliary clearance and direct exposure of the allograft to the environment.6, 7 It has been suggested that lung transplant recipients infected with community-acquired viral RTIs have a high rate of progression to severe viral pneumonitis.8  In addition to direct sequelae, accumulating data, primarily from retrospective studies, suggest that these viruses can have serious indirect effects. Specifically, they may trigger immunologically mediated lung injury resulting in the development of acute and chronic rejection, the main limitation to long-term survival. The proposed mechanisms of such injury likely relate to the upregulation of inflammatory cytokine production initiated by viral replication or a direct cytopathic effect on the respiratory epithelium.9  The investigation of the incidence of respiratory viral infections, the clinical presentation and their different clinical impact on acute rejection, lung function and incidence of bronchiolitis obliterans syndrome (BOS) is of extremely importance to study strategy and ensure a better outcome after LT. In addition, diagnostic tools such as highly sensitive molecular assays as Bridevaux et al. performed in this paper have been shown to increase the rate of diagnosis of respiratory pathogens and have not routinely been used since last years. In fact, in the decade following the first heart–lung transplantation in 1981, surveys of infectious complications only made occasional note of respiratory viral infections. Since the 1990s, studies focusing on respiratory viral infections have shown that they are a cause of significant morbidity and mortality in lung transplant recipients.10, 11 These studies have accurately defined the clinical presentation and more serious outcomes of respiratory viral infections in this population, but have some limitations due

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nity acquired respiratory viruses (CARV) and herpes viruses (HVV), having different diagnostic and therapeutic approaches because of respectively an acute and chronic behavior. In case of herpes viruses, prophylaxis allows the clinicians to reduce the immunobiologic controls but it prevents a physiological immune response. Other disadvantages are mainly related with costs and kidney and bone marrow side effects. Conversely, preemptive therapy needs strict control of herpes viruses reactivation without a univocal agreement about monitoring specimens and cutoff. This review arise from a recent study by Brideaux et al.2 This group studied incidence and outcomes of CARV respiratory viral infections in lung transplant recipients. In particular in a large number of patients who underwent lung transplantation were matched molecular viral diagnositics, transbronchial biopsies and functional tests to understand the real impact on AR, lung function impairment and survival.  This article offers the opportunity to investigate deeply the incidence, risk factors, symptomatology and clinical outcome of respiratory viral infections. The authors, by means of molecular assays and both scheduled and urgent visit have tried to collect as many infection as possible to avoid the under diagnosis that usually happens. Furthermore, they studied the possible association between viral infections and the occurrence of acute allograft rejection. Community-acquired viral respiratory tract infections (RTI) are common causes of acute respiratory illness in the general community and have been increasingly recognized as common pathogens after solid organ transplantation.3-5 Although most respiratory viral infections cause self-limited upper respiratory diseases, lung transplant recipients (LTRs) are particularly prone to develop complications. In this patient population, infection with these pathogens can occasionally result in severe pulmonary disease with significant morbidity and mortality. The most common community respiratory viruses include influenza A and B, parainfluenza serotypes 1, 2 and 3, res-

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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.

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literature confirming a causal relationship between respiratory viruses and respiratory symptoms, but cannot confirm a link between respiratory viruses and acute lung rejection. This result was mainly related, in the opinion of the authors, to the heterogeneity and limitations of available studies. On the contrary, some other authors found an association between CARV infection and pulmonary grafts with onset of acute rejection.17 In fact, a prospective study of the Toronto group enrolled 50 lung transplant recipients with symptoms of viral respiratory tract infection and, as a control group, 50 stable lung transplant recipients. In 66% of the patients with symptoms of respiratory tract infections, CARV were detected in nasopharyngeal and oropharyngeal swabs. In the control group, only rhinovirus was detected in 8% (4 patients). Three months after enrollment, episodes of acute rejection occurred in 16% and FEV1 decline of more than 20% in 18% of transplant recipients with a respiratory tract infection, while none experienced an acute rejection nor a decline in FEV1 more than 20% in the control group. The impact of rhinoviral infection in human lung transplants has been investigated with interesting results. In 48 consecutive patients (and 240 monitoring BAL) a high frequency of viral infections was detected (67%): particularly cytomegalovirus (CMV) and rhinovirus (76% and 24% respectively). Viral co-infections were found in 27% with frequent occurrence of CMV/rhinovirus (53%). Patients with rhinovirus and rhinovirus/CMV positive BALs showed a significant higher rejection index than patients with only CMV positive BALs. These  data demonstrated that CMV/rhinovirus is a frequent coinfection in lung transplant patients and that the synergic action of the two viruses could play a crucial role in the induction of acute rejection.18  However this association remains still debated as it is underlined by the authors who followed 50 ambulatory lung transplant patients during a single winter season, using viral antigens, viral cultures and PCR of nasal washes or bronchoalveolar lavages. They found that respiratory viral infection

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to their retrospective design. Also, most studies did not employ more recently available diagnostic techniques, such as PCR, to determine the presence of viral infection. Previous authors studied lung recipients with a broad panel of PCR tests for respiratory viruses.12 However, only patients who had undergone bronchoscopy with available respiratory viral cultures were studied. Thus, it was not possible to calculate the incidence of respiratory viral infections in that study population or compare infected with uninfected patients. Respiratory viruses were detected by PCR in 55% of 31 lung recipients who were thought to have respiratory viral infection by clinical criteria. Of the detected viruses, 53% were rhinoviruses and the remainder were paramyxoviruses, orthomyxoviruses or adenoviruses. The current work found the way to overcome most of the limitation of previous works in particular thanks to the design study. CARV and respiratory tract infections

Airway infections with CARV are common in lung transplant recipients. The incidence of CARV infection in lung transplant recipients with symptoms of airway tract infections can be up to 57%.13 The presentation of CARV infection varies from being asymptomatic to mild upper airway tract infections to severe pneumonia. The severity of the infections is also related to the type of virus. Adenovirus infections of the pulmonary graft can be associated with a high mortality rate.14 However, even rhinoviruses (thought to be less virulent) can cause lower respiratory tract infections and have been persistently detected in two lung transplant recipients with graft dysfunction as in the study by Kaiser et al.15 Bacterial and fungal super infections are a feared complication of CARV infections.

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Association between CARV and AR The same authors of the present study reviewed systematically 16 the published

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was not associated with subsequent graft dysfunction.19 Association between CARV and BOS

the risk was tripled. Moreover, these risks from CARV infections were distinct from the risk attributable to other risk factors, such as acute rejection. In addition, CARV infection was also a significant risk factor for more advanced stages of BOS and death. Identification of CARV infections as a unique BOS risk factor suggests that antiviral strategies aimed to prevent or treat viral infection may provide a strategy to modify the onset or progression of post-CARV BOS.22 Similar results have been found 23 in a cohort of sixty-four patients with a follow-up period from a minimum of 1 year to 3 years divided in two groups: 30 patients with BOS and 34 patients without BOS. Polymerase chain reaction for different community acquired respiratory virus CARV were applied and in the group without BOS, CMV was detected in BAL of about half of patients while 20% of recipients showed a positive BAL for rhinovirus. Other viruses were present with very low incidence. Patients showed upper and/or lower respiratory disorders. CMV/RV was frequently detected before AR with an average of 7.5 days. Recurrent/De novo CMV/RV infection was observed in 37% (8/22) of samples. By contrast, comparing with the group with different grade of BOS, almost 90% of BAL were positive for CMV detection and 30% for rhinovirus. Infection were associated with a significantly increased risk for BOS in univariate analysis where Infection Index was significantly increased in the groups with BOS compared to the group without BOS (mean value 37% vs. 28%; P=0.04). In a multivariate analysis patients with viral infections, in particular CMV, detected in BAL are three times more likely to develop BOS than those who experienced acute rejection suggesting that CMV is independently associated with an increased risk of BOS in respect to all other well known risk factors. The study supported the hypothesis that a non-immunological risk factors as recurrent viral infections with predominance of CMV, distinct from the risk attributable to acute rejection, have a crucial role in the pathogenesis of BOS. Bridevaux et al. gave us something more

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BOS has remained the most significant cause of graft failure and mortality after lung transplantation partly because the pathophysiologic mechanisms of disease are poorly defined and treatment options are limited. Many risk factors for BOS have been reported in literature and are described as probable risk factors and potential risk factors in need of further analysis. In respect of probable risk factors late or recurrent/refractory and/or high-grade acute rejection episodes are recognized as classical immunological risk factors. However, many patients with AR do not develop BOS, and some patients with BOS have never experienced AR. Several potential risk factors have been proposed although not yet widely accepted for conflicting data. In particular the impact of CMV and CARV on the development of BOS remains controversial. CMV is difficult to consider as a risk factor for two main reasons: the pattern of CMV has changed with the widespread use of prophylactic strategies directed against the virus and with varying definitions of infection, disease, and pneumonitis among institutions. Other studies documented a decreased risk of CMV in the development BOS, either decreased incidence or delay in onset, after the use of CMV prophylaxis. Previous studies have suggested that CARV infections are associated with the development of BOS. Initial, uncontrolled pediatric and adult retrospective case series postulated an association between CARV infections and subsequent BOS. Recently, two cohort analyses have also supported this link.20, 21 A recent retrospective cohort study demonstrated that CARV infections in the adult were associated with an increased risk of subsequent BOS and death. The authors, in fact estimated that a patient who developed a CARV infection after lung transplantation had twice the risk of developing BOS stage 1, and if the infection involved the lower respiratory tract,

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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.

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mean pathology in case of competent immune response. All these data can be matched in every single patient and managed by a tailored approach, either monitoring in case of a lower risk or treating (antiviral therapy) in case of higher risk.30-36 This tailored approach is much more difficult to manage with CARV because of the acute life threatening infection and the need to make a rapid decision. An important problem referred by the Authors is the incidence of lymphocytic bronchitis bronchiolitis (LBB). This is one of the most important risk factors for chronic rejection and BOS, and it seems to be frequently represented in trans bronchial biopsies (TBB) in CARV patients. LBB and AR are not necessarily directly correlated but both are risk factors for CLAD. It’s difficult to think that such a representative prevalence in TBB is not related to a long term dysfunction of graft allograft. In many study an aggressive approach to viral infections, in particular CMV infections, have reduces dramatically the percentage of LBB and AR and not only the number of lung pneumonia.37, 38 The absence of AR doesn’t mean the absence of a potential rejection related lung damage. Moreover, only some  of the patients screened have undergone functional tests and bronchoscopy with TBB. It’s difficult to believe in a statistical analysis if all the screened patients don’t undergo an invasive diagnostic procedure because are too ill or too healthy: we lose the extreme parts of the curve of patients with CARV, probably the most interesting ones to understand the functional and histologic behavior during CARV infections. In fact, a chronic slow infection without symptoms can be the cause of a LBB activating a HLA class 1 or 2 immune response, similar to the one activated by herpes viruses by alloimmune or autoimmune response,39-45 and, on the other side, viral histologic acute damage can be the first act of organizing pneumonia with obliterans bronchiolitis (BOOP) or without (OP).46 In conclusion so much is yet to under-

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in terms of a greater insight into the epidemiology of all respiratory viruses by the means of a complete extensive panel of molecular assays in a standardised manner. This approach allows the authors to detect all clinically significant viral infections. The current article provides fully and comprehensive analysis (112 patients evaluated on 903 visits) as compared to previous works. In fact the different study design gives the opportunity to cover all four season, in a prospective assessment and for a long period of observation and prolonged follow-up (over 3 year with further 2 year follow-up). In addition, the sensitivity of the assays used and the patients screened, even in the absence of symptoms, offer a unique opportunity to evaluate the incidence of asymptomatic viral infection. The authors, differently from previous report, investigated the recipients during three different admission: screening, emergency and routine visit. Furthermore, BAL samples for PCR investigation was used not only during routine visit but also in emergency. It is really difficult to imagine such an important deal of data in follow-up of lung transplant patients but some bias can be pointed out. In many cases CARV positivity at screening visits was asymptomatic. The absence of symptoms is a pivotal problem in managing these patients as it can depend on absence of active replication or on the effect of immunosuppressive regimen. In one word viruses can be just passengers or aggressive drivers in a facilitated environment, and the potential damage is completely different, as the management. PCR sampling give us an idea of the presence but not the certainty of the activity of viruses, and this is another common problem in reading data.24-29 In Herpes Virus infections this problem can be overtaken by studying biological samples and immune response balancing the presence (PCR) and the activity (shell vial) of viruses with specific immune response (elispot) of CMV, Epstein-Barr virus and other viruses. In fact viral presence doesn’t mean activity and activity doesn’t

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ment of infections after lung transplantation. Clin Infect Dis 2001;33:S58-S65.  8. Garantziotis S, Howell DN, McAdams HP, Davis RD, Henshaw NG, Palmer SM. Influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome. Chest 2001;119:1277-80.  9. Husain S, Singh N. Bronchiolitis obliterans and lung transplantation: evidence for an infectious etiology. Semin Respir Infect 2002;17:310-4. 10. Palmer SM, Henshaw NG, Howell DN, Miller SE, Davis RD, Tapson VE. Community respiratory viral infection in adult lung transplant recipients. Chest 1998;113:944-50. 11. Holt ND, Gould FK, Taylor CE, Harwood JF, Freeman R, Healy MD et al. Incidence and significance of noncytomegalovirus viral respiratory infection after adult lung transplantation. J Heart Lung Transplant 1997;16:416-9. 12. Garbino J, Gerbase MW, Wunderli W, Deffernez C, Thomas Y, Rochat T et al. Lower respiratory viral illnesses: improved diagnosis by molecular methods and clinical impact. Am J Respir Crit Care Med 2004;170:1197-203. 13. Gerna G, Vitulo P, Rovida F, Lilleri D, Pellegrini C, Oggionni T et al. Impact of human metapneumovirus and human cytomegalovirus versus other respiratory viruses on the lower respiratory tract infections of lung transplant recipients. J Med Virol 2006;78:408-16. 14. Ohori NP, Michaels MG, Jaffe R, Williams P, Yousem SA. Adenovirus pneumonia in lung transplant recipients. HumPathol 1995;26:1073-9. 15. Kaiser L, Aubert JD, Pache JC, Deffernez C, Rochat T, Garbino J et al. Chronic rhinoviral infection in lung transplant recipients. Am J Respir Crit Care Med 2006;174:1392-9. 16. Vu DL, Bridevaux PO, Aubert JD, Soccal PM, Kaiser L. Respiratory viruses in lung transplant recipients: a critical review and pooled analysis of clinical studies. Am J Transplant 2011;11:1071-8. 17. Kumar D, Erdman D, Keshavjee S, Peret T, Tellier R, Hadjiliadis D et al. Clinical impact of community-acquired respiratory viruses on bronchiolitis obliterans after lung transplant. Am J Transplant 2005;5:2031-6. 18. Lunardi F, Giacometti C, Marulli G. Impact of rhinoviral infection in human lung transplants. ATS International Conference 2007. 19. Milstone AP, Brumble LM, Barnes J, Estes W, Loyd JE, Pierson RN 3rd et al. A single-season prospective study of respiratory viral infections in lung transplant recipients. Eur Respir J 2006;28:131-7. 20. Bridges ND, Spray TL, Collins MH, Bowies NE, Towbin JA. Adenovirus infection in the lung results in graft failure after lung transplantation. J Thorac Cardiovasc Surg 1998;116:617-23. 21. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. JHeart Lung Transplant 2002;21:559-66. 22. Khalifah AP, Hachem RR, Chakinala MM, Schechtman KB, Patterson GA, Schuster DP et al. Respiratory Viral Infections Are a Distinct Risk for Bronchiolitis Obliterans Syndrome and Death. Am J Respir Crit Care Med 2004;170:181-7. 23. Balestro E, Loy M, Damin M. The impact of viral infections on the occurrence of bronchiolitis obliterans syndrome and its influence on BOS stage. ISHLT Meeting 2010 oral presentation. 24. Costa C, Bergallo M, Astegiano S, Terlizzi ME, Sidoti F, Solidoro P et al. Detection of Mimivirus in bronchoalveolar lavage of ventilated and nonventilated patients. Intervirology 2012;55:303-5.

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stand in viral infections in lung transplantation. First there is a great difference between an active role of respiratory viruses and a quiet presence or colonization of respiratory tract and in CARV we would  need to develop methods similar to the ones studied for herpes virus infections (specimen’s choice, immunospecific assays, viral loads and cultures) to understand a real and useful cut off to treat them. In fact a positivity in a screening doesn’t necessary mean an infection because of the delicate balance in the activity of immune system. Then a clear definition of LBB is necessary to share the active viral infection from the risk factor for chronic rejection as the therapeutic approach is the opposite: respectively reducing or increasing immunosuppression. Finally as different specimens have different impact on diagnosis it’s important to define the relationships between them (BAL, TBB, others). Only answering all these questions, step by step, we’ll be able to distinguish the different roles of viral infections, CARV and others, on lung transplantation programs’ outcomes and their consequences on lung graft. In few words distinguishing tragedies from dramas or comedies, recognizing devils from trolls. References

 1. Boffini M, Ranieri VM, Rinaldi M. Lung Transplantation: is it still an experimental procedure?  Curr Opin Crit Care;2010:16:53-61.  2. Bridevaux PO, Aubert JD, Soccal M, Mazza-Stalder J, Berrutto C, Rochat T et al. Incidence and outcomes of respiratory viral infections in lung transplant recipients: a prospective study. Thorax 2014;69:32-8.  3. Hodges TN, Torres FP, Marqueson J, Diercks M, Zamora MR. Community acquired respiratory viruses in lung transplant patients: incidence and outcomes. J Heart Lung Transplant 2001;20:169-70.  4. Billings JL, Hertz MI, Wendt CH. Community respiratory virus infections following lung transplantation. Transpl Infect Dis 2001;3:138-48.  5. Vilchez R, McCurry K, Dauber J, Iacono A, Keenan R, Griffith B et al. Influenza and parainfluenza respiratory viral infection requiring admission in adult lung transplant recipients. Transplantation 2002;73:1075-8.   6. Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1999;340:1081-91.   7. Speich R, van der Bij W. Epidemiology and manage-

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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.

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in Lung transplant Recipient: A Single-Center Experience. Transplantation Proceedings 2013;45:2736-40. 37. Solidoro P, Libertucci D, Delsedime L, Ruffini E, Bosco M, Costa C et al. Combined cytomegalovirus prophylaxis in lung transplantation: effects on acute rejection, lymphocytic bronchitis/bronchiolitis, and herpesvirus infections. Transplant Proc 2008;40:20134. 38. Solidoro P, Delsedime L, Bergallo M, Libertucci D, Ruffini E, Costa C et al. Combined prophylaxis decreases incidence of CMV-associated pneumonia after lung transplantation. Transplant Proc 2009;41:1347-8. 39. Gottlieb J, Schulz TF, Welte T, Fuehner T, Dierich M, Simon AR et al. Community acquired respiratory viral infections in lung transplant recipients: a single season cohort study. Transplantation 2009;87:1530-7. 40. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002;21:559-66. 41. Kumar D, Husain S, Chen MH, Moussa G, Himsworth D, Manuel O et al. A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients. Transplantation 2010;89:1028-33. 42. Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Pitt ML, Rainer SP et al. Association of minimal rejection in lung transplant recipients with obliterative bronchiolitis. Am J Respir Crit Care Med 2004;170:1022-6. 43. Uckay I, Gasche-Soccal PM, Kaiser L, Stern R, MazzaStalder J, Aubert JD et al. Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy. J Heart Lung Transplant 2010;29:299-305 44. Ng BJ, Glanville AR, Snell G, Musk M, Holmes M, Chambers DC et al. The impact of pandemic influenza A H1N1 2009 on Australian lung transplant recipients. Am J Transplant 2011;11:568-74. 45. Khalifah AP, Hachem RR, Chakinala MM, Schechtman KB, Patterson GA, Schuster DP et al. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med 2004;170:181-7. 46. Cordier JF. Organising pneumonia. Thorax 2000; 55:318-28.

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25. Costa C, Bergallo M, Astegiano S, Sidoti F, Terlizzi ME, Gambarino S et al. Detection of human rhinoviruses in the lower respiratory tract of lung transplant recipients. Arch Virol 2011;156:1439-43. 26. Costa C, Bucca C, Bergallo M, Solidoro P, Rolla G, Cavallo R. Unsuitability of exhaled breath condensate for the detection of herpesviruses DNA in the respiratory tract. J Virol Methods 2011;173:384-6. 27. Bergallo M, Costa C, Terlizzi ME, Astegiano S, Curtoni A, Solidoro P et al. Quantitative detection of the new polyomaviruses KI, WU and Merkel cell virus in transbronchial biopsies from lung transplant recipients. J Clin Pathol 2010;63:722-5. 28. Astegiano S, Bergallo M, Solidoro P, Terlizzi ME, libertucci D, Baldi S et al. Prevalence and clinical impact of polyomaviruses KI and WU in lung transplant recipients. Transplant Proc 2010;42:1275-8. 29. Gambarino S, Mantovani S, Astegiano S, Libertucci D, Solidoro P, Baldi S et al. Lower respiratory tract viral infections in hospitalized adult patients. Minerva Med 2009;100:349-55. 30. Costa C, Libertucci D, Solidoro P, Sinesi F, Bergallo M, Margio S et al. Rapid shell vial culture for the detection of respiratory viruses from bronchoalveolar lavage in immunocompromised patients. Panminerva Med 2007;49:1-6. 31. Costa C, Delsedime L, Solidoro P, Curtoni A, Bergallo M, Libertucci D et al. Herpesviruses detection by quantitative real-time polymerase chain reaction in bronchoalveolar lavage and transbronchial biopsy in lung transplant: viral infections and histopathological correlation. Transplant Proc 2010;42:1270-4. 32. Terlizzi ME, Astegiano S, Sidoti F, Gambarino S, Cavallo R, Costa C et al. Development of an Elispot assay for detection of CMV- specific immune response. Microbiologia Medica 2010;25:130. 33. Costa C, Saldan A, Sinesi F, Sidoti F, Balloco C, Simeone S et al. The lack of cytomegalovirus-specific cellular immune response may contribute to the onset of organ infection and disease in lung transplant recipients. Int J Immunopathol Pharmacol 2012;25:1003-9. 34. Costa C, Astegiano S, Terlizzi ME, Sidoti F, Curtoni A, Solidoro P et al. Evaluation and significance of cytomegalovirus-specific cellular immune response in lung transplant recipients. Transplant Proc 2011;43:1159-61.  35. Rittà M, Costa C, Sinesi F, Sidoti F, Di Nauta A, Mantovani S et al. Evaluation of Epstein-Barr virus-specific immunologic response in solid organ transplant recipients with an enzyme-linked ImmunoSpot assay. Transplant Proc 2013;45:2754-7. 36. Solidoro P, Costa C, Libertucci D, Sidoti F, Boffini M, Ricci D et al. Tailored Cytomegalovirus Management

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VIRAL INFECTIONS IN LUNG TRANSPLANT RECIPIENTS SOLIDORO

Vol. 105 - Suppl. 2 to No. 3

Received on May 21, 2014. Accepted for publication on May 27, 2014. Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

MINERVA MEDICA

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