CARVs, CLAD, and CMV: A Call for Heightened Awareness in Lung Transplant Recipients

Community-acquired respiratory viruses (CARVs) are of significant interest in lung transplant recipients (LuTRs) not only because of the short-term illness and the often severe course attributed to intense immunosuppression but also because CARVs naturally trigger inflammatory responses in the allogenic setting of the lung transplant, which may accelerate progression to chronic lung allograft disease (CLAD).^1-3 Notably, the variety of different CARVs seems to have a different propensity in this regard. We congratulate Permpalung et al⁴ for their focus on human metapneumovirus (HMPV) and human parainfluenza virus (HPIV) infections in LuTRs. In their single-center retrospective study (2010–2019), the authors identified 31 HMPV-infected and 53 HPIV-infected LuTRs, of whom one-third developed CLAD within 1 y postinfection irrespective of ribavirin use and mycophenolate discontinuation. Despite the limited sample size and the retrospective nature, this study stresses the associated unmet clinical need of these CARVs.³

Nevertheless, we believe that the following aspects may benefit from a stronger emphasis. First, modern molecular diagnostics have dramatically improved the detection of CARVs in real time, including for HPIV types, HMPVs, and also human respiratory syncytial viruses A and B (HRSV) not addressed by these authors. Comprehensive multiplex CARV testing is important for clinical cases as defined³ and offers prospective surveillance or screening below the clinical radar to uncover pathophysiological aspects regarding cytopathic damage, innate inflammatory, and adaptive alloimmune responses. This may be key to identify initiating insults and subsequent mechanisms, to then develop and tailor antiviral, anti-inflammatory, and antirejection interventions that counter CLAD progression and extent lung allograft survival. Second, HMPV, HPIV, and HRSV may affect 5% to 15% of LuTR but are remarkable for targeting the lower respiratory tract and hence the actual lung allograft. The virological factors, the role of virus- and variant-specific neutralizing antibodies, and of cytomegalovirus as classic non-CARV replicating locally in the lower respiratory tract as a copathogen and promoter of CLAD need to be also assessed as intervention target.¹ Indeed, while Permpalung et al describe a relatively mild clinical presentation at onset, we note that this study also confirms the alarming tropism of these CARVs for the lower respiratory tract in >50% of cases.⁴ In this complex viral and immunological setting, reducing immunosuppression is often considered but may ignite an unspecific cascade of innate and adaptive “non-self” responses associated with acute and protracted loss of actual lung function. Indeed, forced expiratory volume in 1s percentage decline of ≥10% from baseline at 90 d after CARV infection was a potential predictor for CLAD progression in this study.⁴ In our earlier prospective study,¹ the functional evaluation at 3 mo was indeed predictive of CLAD after CARV infections and readily adoptable in clinical practice.¹ Given the lack of therapeutic options, such studies^1,2,4 also provide a rationale to develop novel treatments and prevention measures, including risk-adapted preemptive therapies for CARVs and for local cytomegalovirus replication in LuTRs, to mitigate CLAD progression.⁴ The current severe acute respiratory syndrome coronavirus 2 pandemic has resulted in a paradigmatic reevaluation of CARV infections, the modalities of transmission, pathophysiology, prevention, and treatment in all patient groups, including in transplant patients as described.⁵

Therefore, the contribution by Permpalung et al is most important for not scotomizing CARVs, such as HMPV, HPIV, HRSV, and influenza viruses, for which a tsunami wave must be feared as they return after low seasonal circulation and waning specific immunity during the past 2 seasons of the severe acute respiratory syndrome coronavirus 2 pandemic and for which we need to prepare.