COVID-Related Chronic Allograft Dysfunction in Lung Transplant Recipients: Long-Term Follow-up Results from Infections Occurring in the Pre-vaccination Era

Introduction: We report on characteristics and lung function outcomes among lung transplant recipients (LTRs) after COVID-19 with infections occurring in the first year of the coronavirus pandemic prior to introduction of the vaccines. Methods: This was a retrospective study of 18 LTRs who tested positive for SARS-CoV-2 between 1 February 2020 and 1 March 2021. The mean age was 49.9 (22–68) years; 12 patients (67%) were male. Two patients died due to severe COVID-19. Results: During the study period, there were 18 lung transplant recipients with a community-acquired SARS-CoV-2 infection. In this cohort, seven had mild, nine had moderate, and two had severe COVID-19. All patients with mild and moderate COVID-19 survived, but the two patients with severe COVID-19 died in the intensive care unit while intubated and on mechanical ventilation. Most patients with moderate COVID-19 showed a permanent lung function decrease that did not improve after 12 months. Conclusion: A majority of LTRs in the current cohort did not experience an alteration in the trajectory of FEV1 evolution after developing SARS-CoV-2 infection. However, in the patients with moderate COVID-19, most patients had a decline in the FEV1 that was present after 1 month after recovery and did not improve or even deteriorated further after 12 months. In LTRs, COVID-19 can have long-lasting effects on pulmonary function. Treatment strategies that influence this trajectory are needed

COVID-19-Associated Lung Fibrosis: Two Pathways and Two Phenotypes, Lung Transplantation, and Antifibrotics

COVID-19 can be associated with lung fibrosis. Although lung fibrosis after COVID-19 is a relatively rare finding, the mere fact that globally a very large number of patients have had COVID-19 leads to a significant burden of disease. However, patients with COVID-19-associated lung fibrosis have different clinical and radiological features. The aim of this review is to define the different phenotypes of COVID-19-associated lung fibrosis, based on the medical literature. We found that two phenotypes have emerged. One phenotype is COVID-19-related acute respiratory distress syndrome (CARDS); the other phenotype is post-COVID-19 pulmonary fibrosis (PCPF). Both phenotypes have different risk factors, clinical, and radiological features, and differ in their pathophysiological mechanisms and prognoses. A long-term follow-up of patients with pulmonary complications after COVID-19 is warranted, even in patients with only discrete fibrosis. Further studies are needed to determine the optimal treatment because currently the literature is scarce, and evidence is only based on small case series or case reports

Frailty as a Prognostic Indicator in Lung Transplantation: A Comprehensive Analysis

Frailty is a complex pathobiological process characterized by diminished physiological reserve and increased vulnerability to stressors, which has been associated with unfavorable outcomes before and after lung transplantation. Methods: We undertook an extensive narrative review, encompassing a thorough exploration of original papers, observational studies, case reports, and meta-analyses published between 1990 and July 2023, in various databases, including PubMed, Embase, Cochrane Library, Wiley Online Library databases, and Google Scholar. The search terms [frailty] AND [lung transplant] were utilized. Additionally, the reference lists of retrieved articles were examined. Inclusion criteria comprised studies written in English and involving human subjects. The identified studies were categorized into pre-transplant and post-transplant populations, and the measurement tools used to assess frailty were analyzed, along with the clinical implications reported in the studies. Results: From 1 January 1990 to 1 July 2023, a total of 10 studies on frailty and lung transplantation were identified through online sources and bibliographic searches, involving a total of 2759 patients. Among these studies, six focused on the pre-transplant population, while four examined the post-transplant population. The Fried Frailty Phenotype (FFP) and the Short Physical Performance Battery (SPPB) were the most employed tools for measuring frailty. A table presents additional frailty assessment instruments and the clinical implications described in the studies. Conclusions: Frailty is prevalent both in patients with end-stage respiratory diseases awaiting lung transplantation and in postoperative lung transplant recipients. Most transplant centers recognize the value of assessing frailty in the evaluation of potential candidates for lung transplantation. Frailty has been shown to impact mortality on the waitlist and in the post-transplant period. However, the most effective methods for measuring frailty in lung transplant candidates and recipients have yet to be determined. Strategies to reverse frailty are available and show promising results on outcomes

Practical approach to early postoperative management of lung transplant recipients

Meticulous attention to detail during the early postoperative period after lung transplantation is crucial for the overall success of the procedure. It starts in the intensive care unit with the initiation of immunosuppression, implementation of anti-infective strategies and stabilisation of respiratory function. The subsequent days and weeks on the regular ward focus on titration of immunosuppressive drugs, vigilant fluid management, early mobilisation and initiation of physiotherapy. In parallel, the lung transplant recipients are actively taught about self-monitoring and self-management strategies to allow for a smooth transition to outpatient follow-up care. This article intends to communicate the practical aspects and principles of the patient management used at the authors' centre on a daily basis by a multi-disciplinary transplant team, having at its core both a transplant pulmonologist and a thoracic surgeon. It focuses on the first month after lung transplantation, but does not cover surgical techniques, rare complications or long-term management issues of lung transplant recipients. The target audience of this practical guide are advanced trainees of pulmonology, thoracic surgery, intensive care, anaesthesiology and other clinicians involved in the early postoperative care of lung transplant recipients either in the intensive care unit or on the peripheral ward

COVID-19-related end stage lung disease: two distinct phenotypes

In COVID-19 related end stage lung disease, there are two distinct phenotypes. The first phenotype is the COVID-19 related acute respiratory distress syndrome (CARDS) showing a classical histopathological pattern of fibrotic diffuse alveolar damage (DAD). The second phenotype is the post-COVID pulmonary fibrosis (PCPF), in which the diagnosis is based on the combined clinical, radiological and (if available) pathological information. Both phenotypes have different clinical features, risk factors, biomarkers and pathophysiology. The exact prognosis in these two phenotypes as well as optimal treatment needs further studies. Key messages Two different phenotypes exist for COVID-19 related pulmonary fibrosis. The CARDS phenotype has a worse prognosis compared to the PCPF phenotype, which requires longer-term follow-up and evolves without ARDS picture. The best treatment options for the two different phenotypes, such as anti-fibrotic drugs or lung transplantation, still needs to be defined in future studies

Adaptive Immunosuppression in Lung Transplant Recipients Applying Complementary Biomarkers: The Zurich Protocol

Achieving adequate immunosuppression for lung transplant recipients in the first year after lung transplantation is a key challenge. Prophylaxis of allograft rejection must be balanced with the adverse events associated with immunosuppressive drugs, for example infection, renal failure, and diabetes. A triple immunosuppressive combination is standard, including a steroid, a calcineurin inhibitor, and an antiproliferative compound beginning with the highest levels of immunosuppression and a subsequent tapering of the dose, usually guided by therapeutic drug monitoring and considering clinical results, bronchoscopy sampling results, and additional biomarkers such as serum viral replication or donor-specific antibodies. Balancing the net immunosuppression level required to prevent rejection without overly increasing the risk of infection and other complications during the tapering phase is not well standardized and requires repeated assessments for dose-adjustments. In our adaptive immunosuppression approach, we additionally consider results from the white blood cell counts, in particular lymphocytes and eosinophils, as biomarkers for monitoring the level of immunosuppression and additionally use them as therapeutic targets to fine-tune the immunosuppressive strategy over time. The concept and its rationale are outlined, and areas of future research mentioned

Recipient Comorbidities for Prediction of Primary Graft Dysfunction, Chronic Allograft Dysfunction and Survival After Lung Transplantation

Since candidates with comorbidities are increasingly referred for lung transplantation, knowledge about comorbidities and their cumulative effect on outcomes is scarce. We retrospectively collected pretransplant comorbidities of all 513 adult recipients transplanted at our center between 1992–2019. Multiple logistic- and Cox regression models, adjusted for donor-, pre- and peri-operative variables, were used to detect independent risk factors for primary graft dysfunction grade-3 at 72 h (PGD3-T72), onset of chronic allograft dysfunction grade-3 (CLAD-3) and survival. An increasing comorbidity burden measured by Charleston-Deyo-Index was a multivariable risk for survival and PGD3-T72, but not for CLAD-3. Among comorbidities, congestive right heart failure or a mean pulmonary artery pressure >25 mmHg were independent risk factors for PGD3-T72 and survival, and a borderline risk for CLAD-3. Left heart failure, chronic atrial fibrillation, arterial hypertension, moderate liver disease, peptic ulcer disease, gastroesophageal reflux, diabetes with end organ damage, moderate to severe renal disease, osteoporosis, and diverticulosis were also independent risk factors for survival. For PGD3-T72, a BMI>30 kg/m2 was an additional independent risk. Epilepsy and a smoking history of the recipient of >20packyears are additional independent risk factors for CLAD-3. The comorbidity profile should therefore be closely considered for further clinical decision making in candidate selection

Mammalian Target of Rapamycin Inhibitors and Kidney Function After Thoracic Transplantation: A Systematic Review and Recommendations for Management of Lung Transplant Recipients

Background: Chronic kidney disease (CKD) after lung transplantation is common and limits the survival of transplant recipients. The calcineurin inhibitors (CNI), cyclosporine A, and tacrolimus being the cornerstone of immunosuppression are key mediators of nephrotoxicity. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used in combination with reduced CNI dosage after lung transplantation. Methods: This systematic review examined the efficacy and safety of mTOR inhibitors after lung transplantation and explored their effect on kidney function. Results: mTOR inhibitors are often introduced to preserve kidney function. Several clinical trials have demonstrated improved kidney function and efficacy of mTOR inhibitors. The potential for kidney function improvement and preservation increases with early initiation of mTOR inhibitors and low target levels for both mTOR inhibitors and CNI. No defined stage of CKD for mTOR inhibitor initiation exists, nor does severe CKD preclude the improvement of kidney function under mTOR inhibitors. Baseline proteinuria may negatively predict the preservation and improvement of kidney function. Discontinuation rates of mTOR inhibitors due to adverse effects increase with higher target levels. Conclusions: More evidence is needed to define the optimal immunosuppressive regimen incorporating mTOR inhibitors after lung transplantation. Not only the indication criteria for the introduction of mTOR inhibitors are needed, but also the best timing, target levels, and possibly discontinuation criteria must be defined more clearly. Current evidence supports the notion of nephroprotective potential under certain conditions

Impact of SARS-CoV-2-Related Hygiene Measures on Community-Acquired Respiratory Virus Infections in Lung Transplant Recipients in Switzerland

Background and Objectives: Community-acquired respiratory virus (CARV) infections pose a serious risk for lung transplant recipients (LTR) as they are prone to severe complications. When the COVID-19 pandemic hit Switzerland in 2020, the government implemented hygiene measures for the general population. We investigated the impact of these measures on the transmission of CARV in lung transplant recipients in Switzerland. Materials and Methods: In this multicenter, retrospective study of lung transplant recipients, we investigated two time periods: the year before the COVID-19 pandemic (1 March 2019–29 February 2020) and the first year of the pandemic (1 March 2020–28 February 2021). Data were mainly collected from the Swiss Transplant Cohort Study (STCS) database. Descriptive statistics were used to analyze the results. Results: Data from 221 Swiss lung transplant cohort patients were evaluated. In the year before the COVID-19 pandemic, 157 infections were diagnosed compared to 71 infections in the first year of the pandemic (decline of 54%, p < 0.001). Influenza virus infections alone showed a remarkable decrease from 17 infections before COVID-19 to 2 infections after the beginning of the pandemic. No significant difference was found in testing behavior; 803 vs. 925 tests were obtained by two of the three centers during the respective periods. Conclusions: We observed a significant decline in CARV infections in the Swiss lung transplant cohort during the first year of the COVID-19 pandemic. These results suggest a relevant impact of hygiene measures when implemented in the population due to the COVID-19 pandemic on the incidence of CARV infections

Impact of extended sinus surgery on allograft infection, allograft function and overall survival in cystic fibrosis lung transplant recipients

BACKGROUND Studies investigating the impact of sinus surgery for cystic fibrosis (CF) patients performed early after lung transplantation (Ltx) are scarce. Recent studies evaluating frequency of respiratory infections and graft outcomes are not available. OBJECTIVES/HYPOTHESIS To determine whether there is a difference in allograft infection, allograft function and overall survival among CF lung transplant recipients with and without concomitant sinus surgery. STUDY DESIGN Retrospective single-center study. METHODS We examined 71 CF patients who underwent Ltx between 2009 and 2019 at our center. Fifty-nine patients had sinus surgery before or/and after transplantation and twelve did not undergo sinus surgery. We assessed the survival, the diagnosis of chronic allograft dysfunction (CLAD) and all elevated (> 5 mg/l) c-reactive protein episodes during the observed period. The infectious events of the upper and lower airways were categorized in mild infections (5-15 mg/l CRP) and severe infections (> 15 mg/l CRP). RESULTS There was no difference in the long-time overall survival (p = 0.87) and no benefit in the short-term survival at 4 year post-transplant (p = 0.29) in both groups. There was no difference in both groups concerning CLAD diagnosis (p = 0.92). The incidence of severe upper and lower airway infections (CRP > 15 mg/l) was significantly decreased in the sinus surgery group (p = 0.015), whereas in mild infections there was a trend to decreased infections in the sinus surgery group (p = 0.056). CONCLUSIONS CF patients undergoing Ltx benefit from extended endoscopic sinus surgery (eESS) in terms of frequency of severe infectious events of the upper and lower airways. There was no difference in overall survival and frequency of CLAD in the two groups