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Running Out of Air: Chronic Lung Allograft Dysfunction due to Respiratory Viral Infections

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Corey Hussain
The Ohio State University
Columbus, OH, USA

Chronic lung allograft dysfunction (CLAD) is nomenclature that consists of a syndrome of progressive loss of function and graft loss that was originally described in heart-lung transplant recipients in 1984 [1]. It is an irreversible cause of long term allograft failure and death affecting up to 45% to 75% of patients within five years after a lung transplant [2]. It is recognized as consisting of two distinct phenotypes, blronchiolitis obliterans syndrome (BOS) and restrictive CLAD (R-CLAD). A considerable number of risk factors have been associated with CLAD. These have historically included alloimmune rejection events; acute allograft injury as well as non-immune evens like gastroesophageal reflux and air pollution [3]. The greater the degree of HLA mismatch between the recipient and the donor, the higher is the risk of chronic rejection. More aggressive and effective immunosuppressant therapy has managed to decrease the incidence of acute allograft rejection but the rates of CLAD have continued unabated [4]. This implies that other factors in addition to the autoimmune mechanism are to blame for the development of CLAD.

An important non-immune risk factor for development of CLAD is the role of respiratory infections. Cytomegalovirus (CMV), respiratory viruses, bacteria and fungi that can routinely colonize or infect the respiratory tract have been implicated in causing CLAD [3]. Bridges et al. in 1998 described graft failure after adenoviral infections in lung or heart-lung transplant patients [5]. A year prior CMV pneumonitis was described as a significant risk factor for the development of BOS [6]. CMV pneumonitis in particular is linked with an increased production of an inflammatory cytokine CXCL 10 which has been directly linked with decreasing FEV1. Increased production of other cytokines such as CCL 2 and CCL 5 during CMV pneumonia, also predict the development of BOS and mortality in patients with a lung transplant [7].

Kumar et al. showed that symptomatic or asymptomatic community acquired respiratory viral infections were significantly associated with BOS compared to patient with a negative multiplex viral PCR test. The most common virus isolated was rhinovirus. Interestingly, community acquired viral infections did not have an impact on acute rejection [8]. Magnusson et al. followed up 3 years later with a retrospective cohort study demonstrating patients who had a respiratory viral pathogen isolated from BAL's within a year of their transplant had significantly faster development of BOS compared with patients who did not [9]. There have been older studies with conflicting data that show no impact of respiratory viral infections on allograft dysfunction, but these studies utilized older methods of isolating viral pathogens and only evaluated a limited scope of viruses [10]. They were also limited by small samples sizes. Recently, a more comprehensive retrospective analysis showed a significant and independent temporal link between symptomatic respiratory viral infections and the development of CLAD [11].

Historically there are data that both supports and negates the risk of respiratory viral infections and the risk of developing CLAD. The evidence however, is increasingly pointing to the former. This highlights an urgent need to prevent lung transplant recipients from being exposed to community acquired viral infections. Influenza, which is an important pathogen linked to CLAD, can be immunized against safely and effectively in the transplant population [12]. Effective immunization of health care workers and family members taking care of these patients adds another important layer of infection control. Other factors can assist in preventing nosocomial outbreaks of respiratory viral infections as well. These include effective hand hygiene as well as routinely admitting lung transplant recipients into mandatory masking and positive airway pressure rooms. Preventing contact with health care workers with a respiratory illness by re-assigning them to other non-immunocompromised patients can be an effective strategy as well.

Currently we have effective anti-influenza therapy and ribavirin that is sometimes used to treat symptomatic patients with respiratory syncytial virus (RSV), parainfluenza virus and human metapneumovirus. But there are no effective therapies for a number of other common respiratory viruses. As more studies continue to demonstrate a definitive link between community respiratory viruses as a risk factor for CLAD, there should be more momentum to discover effective and less toxic treatments of these other viral infections as well. Until then, infection control and prevention remain our best strategies in preventing this vulnerable population to succumbing to acute respiratory viral infections and the late sequelae that follows. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


  1. Burke CM, Theodore J, Dawkins KD, et al. Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest. 1984;86(6):824-829. doi:10.1378/chest.86.6.824.
  2. Burton CM, Iversen M, Mortensen J, et al. Post-transplant Baseline FEV1 and the Development of Bronchiolitis Obliterans Syndrome: An Important Confounder? J Hear Lung Transplant. 2007;26(11):1127-1134. doi:10.1016/j.healun.2007.07.041.
  3. Weigt SS, Wallace WD, Derhovanessian A, et al. Chronic allograft rejection: epidemiology, diagnosis, pathogenesis, and treatment. Semin Respir Crit Care Med. 2010;31(2):189-207. doi:10.1055/s-0030-1249116.
  4. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-first Official Adult Heart Transplant Report-2014; Focus Theme: Retransplantation. J Hear Lung Transplant. 2014;33(10):996-1008. doi:10.1016/j.healun.2014.08.003.
  5. Bridges ND, Spray TL, Collins MH, Bowles NE, Towbin JA. Adenovirus infection in the lung results in graft failure after lung transplantation. J Thorac Cardiovasc Surg. 1998;116(4):617-623. doi:10.1016/S0022-5223(98)70168-0.
  6. Kroshus TJ, Kshettry VR, Savik K, John R, Hertz MI, Bolman RM. Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg. 1997;114(2):195-202. doi:10.1016/S0022-5223(97)70144-2.
  7. Weigt SS, Derhovanessian A, Liao E, et al. CXCR3 chemokine ligands during respiratory viral infections predict lung allograft dysfunction. Am J Transplant. 2012;12(2):477-484. doi:10.1111/j.1600-6143.2011.03859.x.
  8. Kumar D, Husain S, Chen MH, et al. A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients. Transplantation. 2010;89(8):1028-1033. doi:10.1097/TP.0b013e3181d05a71.
  9. Magnusson J, Westin J, Andersson LM, Brittain-Long R, Riise GC. The Impact of Viral Respiratory Tract Infections on Long-Term Morbidity and Mortality Following Lung Transplantation: A Retrospective Cohort Study Using a Multiplex PCR Panel. Transplantation. 2013;95(2):383-388. doi:10.1097/TP.0b013e318271d7f0.
  10. Milstone AP, Brumble LM, Barnes J, et al. A single-season prospective study of respiratory viral infections in lung transplant recipients. Eur Respir J. 2006;28(1):131-137. doi:10.1183/09031936.06.00105505.
  11. Fisher CE, Preiksaitis CM, Lease ED, et al. Symptomatic Respiratory Virus Infection and Chronic Lung Allograft Dysfunction. Clin Infect Dis. 2015;62:313-319. doi:10.1093/cid/civ871.
  12. Kumar D, Blumberg EA, Danziger-Isakov L, et al. Influenza vaccination in the organ transplant recipient: review and summary recommendations. Am J Transplant. 2011;11(10):2020-2030. doi:10.1111/j.1600-6143.2011.03753.x.

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