Early extracorporeal photopheresis treatment is associated with better survival in patients with chronic or recurrent acute lung allograft dysfunction.

BACKGROUND: Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non-responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment. METHODS: We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed-up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment. RESULTS: Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD-RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months). CONCLUSION: In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long-term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long-term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re-transplantation.

Antibody and T-cell response to bivalent booster SARS-CoV-2 vaccines in people with compromised immune function (COVERALL-3).

BACKGROUND: Bivalent mRNA vaccines, designed to combat emerging SARS-CoV-2 variants, incorporate ancestral strains and a new variant. Our study assessed the immune response in previously vaccinated individuals of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) following bivalent mRNA vaccination. METHODS: Eligible SHCS and STCS participants received approved bivalent mRNA SARS-CoV-2 vaccines (mRNA-1273.214 or BA.1-adapted BNT162b2) within clinical routine. Blood samples were collected at baseline, 4 weeks, 8 weeks, and 6 months post vaccination. We analyzed the proportion of participants with anti-spike protein antibody response ≥1642 units/ml (indicating protection against SARS-CoV-2 infection), and in a subsample T-cell response (including mean concentrations), stratifying results by cohorts and population characteristics. RESULTS: In SHCS participants, baseline anti-spike antibody concentrations ≥1642 were observed in 87% (96/112), reaching nearly 100% at follow-ups. Among STCS participants, 58% (35/60) had baseline antibodies ≥1642, increasing to 80% at 6 months. Except for lung transplant recipients, all participants showed a five-fold increase in geometric mean antibody concentrations at 4 weeks and a reduction by half at 6 months. At baseline, T-cell responses were positive in 96% (26/27) of SHCS participants and 36% (16/45) of STCS participants (moderate increase to 53% at 6 months). Few participants reported SARS-CoV-2 infections, side-effects, or serious adverse events. CONCLUSIONS: Bivalent mRNA vaccination elicited a robust humoral response in individuals with HIV or solid organ transplants, with delayed responses in lung transplant recipients. Despite a waning effect, antibody levels remained high at 6 months and adverse events were rare.

mTOR inhibitors after lung transplantation: a real-life experience.

Background: The mammalian target of rapamycin (mTOR) inhibitors in combination with calcineurin inhibitors (CNIs), antimetabolites and corticosteroids for immunosuppression after lung transplantation (TPL) have gained importance in patients with chronic kidney disease (CKD). The goal of this study was to characterize lung transplant recipients (LTR) treated with mTOR inhibitors, with a special focus on kidney function. Methods: LTR transplanted at the University Hospital Zurich between December 1992 and April 2022 were analyzed. Demographics, estimated glomerular filtration rate (eGFR) before and after mTOR initiation, TPL circumstances, immunosuppressive regimens, and allograft function were recorded. We used linear regression to calculate the Mitch curves and a linear mixed-effects model to compare the eGFR. Results: Of all LTR, 70/593 (12%) received mTOR inhibitors. Intolerance or adverse events of antimetabolites were the most common indications for mTOR inhibitor introduction. Discontinuation in 34/70 (49%) was often related to planned or urgent surgery to prevent impaired wound healing. The majority of patients had a preserved baseline eGFR at mTOR inhibitor introduction with CKD Kidney Disease Improving Global Outcomes (KDIGO) stage G1 or 2. The mean annual eGFR decline changed significantly from -16.19 mL/min/1.73 m2/year [95% confidence interval (CI): -22.27 to -10.11] 12 months before to -6.16 mL/min/1.73 m2/year (95% CI: -13.37 to 1.05) 12 months after mTOR initiation (P=0.009) showing better outcomes with earlier mTOR inhibitor initiation after lung TPL. Conclusions: This retrospective study suggests stabilization of kidney function after mTOR inhibitor initiation in LTR documented by a slower eGFR decline after mTOR inhibitor introduction with better outcomes early after lung TPL. Intolerance or adverse events of antimetabolites are important indications for the introduction of mTOR inhibitors. A relatively high discontinuation rate (49%) can be explained by planned discontinuation of mTOR inhibitors prior to surgery to avoid impaired wound healing.

Direct Oral Anticoagulation in Lung Transplant Recipients.

OBJECTIVES: Presently, the management of direct oral anticoagulants lacks specific guidelines for patients before and after transplant, particularly for lung transplant recipients. We aimed to consolidate the existing literature on direct oral anticoagulants and explore their implications in lung transplant recipients. MATERIALS AND METHODS: We conducted a comprehensive search in PubMed and Google Scholar databases for studies published between January 2000 and December 2022, using specific search terms. We only included studies involving lung transplant recipients and focusing on direct oral anticoagulants. RESULTS: Five relevant publications were identified, providing varied insights. None of the studies specifically addressed bleeding complications associated with direct oral anticoagulants in lung transplant recipients. Limited details were available on the type of solid-organ transplant or the specific direct oral anticoagulant used in these studies. CONCLUSIONS: Varied bleeding complications associated with direct oral anticoagulants in lung transplant recipients were reported, but studies lacked specificity on transplant type and direct oral anticoagulant variations. Notably, the incidence of venous thrombotic embolism in lung transplant recipients was comparatively higher than in other solid-organ transplant recipients, potentially linked to factors such as corticosteroid therapy, calcineurin inhibitors, and cytomegalovirus infections. Our synthesis on findings of use of direct oral anticoagulant in lung transplant recipients emphasized challenges of managing these medications in urgent transplant situations. Recommendations from experts suggested caution in initiation of direct oral anticoagulants posttransplant until stability in renal and hepatic function is achieved. The limited evidence on safety of direct oral anticoagulants in lung transplant recipients underscores the need for further research and guidance in this specific patient population.

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.

Multimodal Remote Home Monitoring of Lung Transplant Recipients during COVID-19 Vaccinations: Usability Pilot Study of the COVIDA Desk Incorporating Wearable Devices.

Background and Objectives: Remote patient monitoring (RPM) of vital signs and symptoms for lung transplant recipients (LTRs) has become increasingly relevant in many situations. Nevertheless, RPM research integrating multisensory home monitoring in LTRs is scarce. We developed a novel multisensory home monitoring device and tested it in the context of COVID-19 vaccinations. We hypothesize that multisensory RPM and smartphone-based questionnaire feedback on signs and symptoms will be well accepted among LTRs. To assess the usability and acceptability of a remote monitoring system consisting of wearable devices, including home spirometry and a smartphone-based questionnaire application for symptom and vital sign monitoring using wearable devices, during the first and second SARS-CoV-2 vaccination. Materials and Methods: Observational usability pilot study for six weeks of home monitoring with the COVIDA Desk for LTRs. During the first week after the vaccination, intensive monitoring was performed by recording data on physical activity, spirometry, temperature, pulse oximetry and self-reported symptoms, signs and additional measurements. During the subsequent days, the number of monitoring assessments was reduced. LTRs reported on their perceptions of the usability of the monitoring device through a purpose-designed questionnaire. Results: Ten LTRs planning to receive the first COVID-19 vaccinations were recruited. For the intensive monitoring study phase, LTRs recorded symptoms, signs and additional measurements. The most frequent adverse events reported were local pain, fatigue, sleep disturbance and headache. The duration of these symptoms was 5-8 days post-vaccination. Adherence to the main monitoring devices was high. LTRs rated usability as high. The majority were willing to continue monitoring. Conclusions: The COVIDA Desk showed favorable technical performance and was well accepted by the LTRs during the vaccination phase of the pandemic. The feasibility of the RPM system deployment was proven by the rapid recruitment uptake, technical performance (i.e., low number of errors), favorable user experience questionnaires and detailed individual user feedback.

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.

Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis.

BACKGROUND: The novel triple CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) improves lung function, body mass index (BMI), sinus clearance, and quality of life in patients with cystic fibrosis. Whether treatment with ELX/TEZ/IVA is associated with improved glucose tolerance is unknown. METHODS: This cohort study included adults with CF and at least one copy of F508del.. Study assessments before treatment and at least 3 months after ELX/TEZ/IVA initiation included an oral glucose tolerance test (OGTT) with glucose and insulin measurements, BMI, lung function test, and sweat chloride levels. We used an analysis of response profiles to calculate changes in outcomes. RESULTS: 33 patients (27.8 ± 6.3 years; 73% male; 64% F508del homozygous) were included. After a median of 184 [IQR, 107 - 278] days following treatment initiation 16 (48.5%) patients improved their glucose tolerance category, while 13 (39.4%) remained unchanged and 4 (12.1%) deteriorated. Overall, 60, 90 and 120 min OGTT glycemia decreased significantly from 11.9 ± 2.7 mmol/l to 10.6 ± 2.8 mmol/l (p = 0.012), 10.4 ± 3.0 mmol/l to 8.4 ± 3.6 mmol/l (p = 0.002) and 7.3 ± 3.1 mmol/l to 5.7 ± 3.0 mmol/l (p = 0.012). HbA1c levels also improved significantly, from 5.50±0.24% to 5.39±0.25% (p = 0.039). CONCLUSION: In adult patients with CF and at least one copy of F508del, treatment with the triple CFTR modulator was associated with possible improvement of glucose tolerance without increases of insulin secretion. Early initiation of treatment as assessed through long-term prospective trials is mandatory to demonstrate if decreased glucose control is preventable or even reversible.

Influence of mycophenolate mofetil dosage and plasma levels on the occurrence of chronic lung allograft dysfunction in lung transplants: a retrospective cohort analysis.

INTRODUCTION: Development of chronic lung allograft dysfunction is a limiting factor for post-lung transplant survival. We evaluated whether the dose of the immunosuppressant mycophenolate mofetil or plasma concentrations of the active metabolite mycophenolic acid affect the development of chronic lung allograft dysfunction. METHODS: In this retrospective cohort study we recruited 71 patients with a lung transplant between 2010 and 2014 which survived the first year after transplantation up to 1 July 2021. An event-time-analytical Cox proportional-hazards regression model with time-varying-covariates (18,431 measurements for MPA, mycophenolate mofetil dosage, lymphocytes) was used to predict chronic lung allograft dysfunction, with adjustment for sociodemographic factors and lung function at baseline. RESULTS: 37 patients did not develop chronic lung allograft dysfunction (age 41.3 ± 15.6 years, baseline FEV1 95.5 ± 19.1% predicted) and 34 patients developed chronic lung allograft dysfunction (age 50.9 ± 13.3 years, baseline FEV1 102.2 ± 25.4% predicted). Mean mycophenolic acid did not differ significantly between the groups (2.8 ± 1.7 and 3.0 ± 2.3 mg/l; p = 0.724). In the first 4 post-transplant years the death rate was 25%. A total of 50% of the patients died by the ninth post-transplant year. There was a dose-effect relationship between mycophenolate mofetil dosage, mycophenolic acid (r2 = 0.02, p <0.001), as well as lymphocyte levels (r2 = -0.007, p <0.001), but only the traditional risk factor age predicted chronic lung allograft dysfunction. Continuously measured mycophenolic acid did not predict chronic lung allograft dysfunction (hazard ratio 0.98, 95% confidence interval 0.90-1.06, p = 0.64 over a period of 382.97 patient-years). CONCLUSION: Mycophenolate mofetil dosage and mycophenolic acid were not associated with chronic lung allograft dysfunction development. Thus, the mycophenolate mofetil dose or mycophenolic acid plasma concentration are not a primary factor related to organ rejection, but chronic lung allograft dysfunction may be influenced by other components of immunosuppression or other factors.

Transbronchial Cryobiopsy Compared to Forceps Biopsy for Diagnosis of Acute Cellular Rejection in Lung Transplants: Analysis of 63 Consecutive Procedures.

BACKGROUND: Acute cellular rejection (ACR) is a complication after lung transplantation (LTx). The diagnosis of ACR is based on histologic findings using transbronchial forceps biopsy (FB). However, its diagnostic accuracy is limited because of the small biopsy size and crush artifacts. Transbronchial cryobiopsy (CB) provides a larger tissue size compared with FB. METHODS: FB and CB were obtained consecutively during the same bronchoscopy (February 2020-April 2021). All biopsies were scored according to the ISHLT criteria by three pathologists. Interobserver agreement was scored by the kappa index. We assessed the severity of bleeding and the presence of pneumothorax. RESULTS: In total, 35 lung transplant recipients were included, and 126 CBs and 315 FBs were performed in 63 consecutive bronchoscopies. ACR (A1-A3, minimal-moderate) was detected in 18 cases (28.6%) by CB, whereas ACR was detected in 3 cases (4.8%) by FB. Moderate and severe bleeding complicated FB and CB procedures in 23 cases (36.5%) and 1 case (1.6%), respectively. Pneumothorax occurred in 6.3% of patients. The interobserver agreement was comparable for both CB and FB. CONCLUSIONS: CB provided an improved diagnostic yield for ACR diagnosis, leading to reclassification and changes in treatment strategies in 28.6% of cases. Prospective studies should better define the role of CB after LTx.

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 messagesTwo 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.

Combined Pulmonary Fibrosis and Emphysema (CPFE) Clinical Features and Management.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is an underrecognized syndrome characterized by chronic, progressive disease with a dismal prognosis. Frequent co-morbidities with a higher incidence than in idiopathic pulmonary fibrosis or emphysema alone are pulmonary hypertension (WHO group 3) in 47-90% of the patients and lung cancer in 46.8% of the patients. OBJECTIVE: Review current evidence and knowledge concerning diagnosis, risk factors, disease evolution and treatment options of CPFE. METHODS: We searched studies reporting CPFE in original papers, observational studies, case reports, and meta-analyses published between 1990 and August 2020, in the PubMed, Embase, Cochrane Library, Wiley Online Library databases and Google Scholar using the search terms [CPFE], [pulmonary fibrosis] OR [IPF] AND [emphysema]. Bibliographies of retrieved articles were searched as well. Further inclusion criteria were publications in English, French, German and Italian, with reference to humans. In vitro data and animal data were not considered unless they were mentioned in studies reporting predominantly human data. RESULTS: Between May 1, 1990, and September 1, 2020, we found 16 studies on CPFE from the online sources and bibliographies. A total of 890 patients are described in the literature. Although male/female ratio was not reported in all studies, the large majority of patients were male (at least 78%), most of them were current or former heavy smokers. CONCLUSION: CPFE is a syndrome presenting with dyspnea on exertion followed by disruptive cough and recurrent exacerbations. The disease may progress rapidly, be aggravated by pulmonary hypertension WHO group 3 and is associated with an increased risk of lung cancer. Smoking and male sex are important risk factors. There is a need for more research on CPFE especially relating to etiology, influence of genetics, treatment and prevention options. Antifibrotic therapy might be an interesting treatment option for these patients.

[Vaping-Associated Pulmonary Illness]. / Vaping-assoziierte Lungenerkrankung «VAPI¼.

Vaping-Associated Pulmonary Illness Abstract. Electronic cigarettes are hand-held devices used to vaporize liquids by heating and thus allowing inhalation of aerosols. Recently, cases of patients have been published which presented with a syndrome associated with e-cigarette consumption, also known as vaping. The syndrome designated 'vaping-associated pulmonary illness' (VAPI) features either isolated respiratory, or combined respiratory gastro-intestinal or constitutional symptoms. VAPI can be rapidly progressive and lead to severe respiratory failure requiring intensive care treatment. Despite the as yet very incomplete understanding of the causative agents and pathogenesis we review the current knowledge of the clinical, pathological and radiological aspects in VAPI and summarise the current therapeutic strategies.