Pseudomonas aeruginosa infection correlates with high MFI donor-specific antibody development following lung transplantation with consequential graft loss and shortened CLAD-free survival.

BACKGROUND: Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. METHODS: A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. RESULTS: High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. CONCLUSIONS: P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis.

DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function.

BACKGROUND: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. METHODS: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. FINDINGS: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. INTERPRETATION: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04382053.

[The start of the Hungarian lung transplantation program and the first results]. / A magyar tüdotranszplantációs program indulása és elso eredményei.

The first lung transplantation in Hungary was performed on 12th of December, 2015. It was a joint effort of the National Institute of Oncology and the Semmelweis University. Hereby we summarise the results and experiences from the first three years. Until August, 2018, 55 lung transplantations were performed in Hungary. This was a retrospective analysis. All patients were listed according to the recommendation of the Lung Transplantation Committee. All implanted lungs have been procured from brain dead donors. Postoperative treatment and rehabilitation of the patients were continued at the Semmelweis University. Between 12. 12. 2015 and 31. 07. 2018, our team performed 76 organ retrievals: out of 45 Hungarian offers, 23 came from Eurotransplant countries and 8 outside of the Eurotransplant region. From these donations, 54 double and 1 single side transplantations were successfully performed. The surgical approach was single side thoracotomy (n = 1), bilateral thoracotomy (n = 1) and in the majority of the cases clamshell incision (n = 53). For the intraoperative veno-arterial extracorporeal membrane oxygenation support was used. The extracorporeal membrane oxygenation support had to be prolonged in 3 patients into the early postoperative period, two other recipients were bridged to transplant with extracorporeal membrane oxygenation. In the same time period, one combined lung-kidney transplantation was also performed. The distribution of recipients according to the underlying disease was: chronic obstructive pulmonary disease (n = 28); idiopathic pulmonary fibrosis (n = 8); cystic fibrosis (n = 12); primary pulmonary hypertension (n = 2); hystiocytosis-X (n = 1); bronchiectasis (n = 2); lymphangioleiomyomatosis (n = 1); and re-transplantation following bronchiolitis obliterans syndrome (n = 1), respectively. The mean age of recipients was 47.5 ± 15.18 years. The youngest recipient was 13 years old. We unfortunately lost 12 patients on our waiting list. The mean intensive care unit stay was 24.6 ± 18.18 days. Two patients were lost in the early postoperative phase. Tracheostomy was necessary in 13 cases due to the need of prolonged ventilation. 1-year survival of the recipients was 82.96% (until 31. 07. 2018). When looking at the first three years of the program, the case numbers elevated quickly throughout the years which is rather unique when compared to other centres in their starting period. Perioperative mortality and morbidity is comparable with high-volume lung transplantation centres. In the future we would like to increase the number of patients on the waiting list, thus increasing the total number of transplantations performed, and we are also planning to implement the use of the ex vivo lung perfusion system (EVLP) in our program. Orv Hetil. 2018; 159(46): 1859-1868.

[Robot-assisted thoracic surgery. Our first experiences]. / Robotasszisztált mutétek helye a mellkassebészetben. Saját tapasztalatok.

Our goal was to examine the postoperative indicators after the first 300 thoracic robotic cases in the National Institute of Oncology. We retrospectively analyzed the clinicopathological and postoperative indicators of the first 300 patients. We also compared the first 30 cases performed by one surgeon to his 30 VATS (video-assisted thoracic surgery) and open cases. The average hospital stay was 5.2 days, the chest tube was removed on the second day. Conversion, need for reoperation and morbidity was low (1.8%, 2% and 10.6%, respectively). The change in operating time slows down after 20 cases. The hospital stay and complications were slightly favorable with RATS (robotic-assisted thoracic surgery) than with VATS. The intensive care stay, however, was significantly shorter while the amount of removed lymph nodes was significantly higher in RATS procedures. As a conclusion, RATS is a safe technique in thoracic surgery. Moreover, more lymph nodes are removed with RATS which can lead to better staging.

Lung Transplant Rehabilitation-A Review.

BACKGROUND: Both lung transplant recipients and candidates are characterised by reduced training capacity and low average quality of life (QoL). This review investigates the impact of training on exercise ability and QoL in patients before and after lung transplant. METHODS: Searches were conducted from the beginning to 7 March 2022 using the terms "exercise," "rehabilitation," "lung transplant," "exercise ability," "survival," "quality of life" and "telerehabilitation" in six databases, including Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, CINAHL, Nursing and Allied Health, and Scopus. The inclusion criteria were studies evaluating the effects of an exercise training programme concurrent with lung transplantation as well as patients and candidates (>18 years old) through any lung diseases. The term "lung transplant rehabilitation" was used to refer to all carefully thought-out physical activities with the ultimate or intermediate objective of improving or maintaining physical health. RESULTS: Out of 1422 articles, 10 clinical- and 3 telerehabilitation studies, candidates (n = 420) and recipients (n = 116) were related to the criteria and included in this review. The main outcome significantly improved in all studies. The 6-min walk distance, maximum exercise capacity, peak oxygen uptake, or endurance for constant load rate cycling improved measuring physical activity [aerobic exercises, breathing training, and aerobic and inspiratory muscle training sessions (IMT)]. Overall scores for dyspnoea improved after exercise training. Furthermore, health-related quality of life (HRQOL) also improved after aerobic exercise training, which was performed unsupervised or accompanied by breathing sessions. Aerobic training alone rather than combined with inspiratory muscle- (IMT) or breathing training enhanced exercise capacity. CONCLUSION: In conclusion, rehabilitation programmes seem to be beneficial to patients both preceding and following lung transplantation. More studies are required to determine the best training settings in terms of time scale, frequency, and work intensity in terms of improving exercise ability, dyspnoea, and HRQOL.

[COVID-19 and melanoma: a single center retrospective cohort study from Hungary]. / Covid-19 és a melanóma: egy év tapasztalatai az Országos Onkológiai Intézetben.

COVID-19 pandemic affected the diagnosis and management of many diseases, including the most vulnerable group of patients with cancer. In this retrospective survey we evaluated the course of disease of patients treated for melanoma, who got infected with COVID-19 virus between March 2020 and April 2021. 382 patients had been treated for advanced melanoma in our center in this time period. 24 of them had been infected with coronavirus. Six of them suffered in stage III melanoma, the remaining 18 patients had stage IV disease. 14, 5 and 4 of the infected patients had been administered with checkpoint inhibitor, targeted therapy and chemotherapy, respectively. Seven (29%) patients died in COVID-19 infection, in a median of 12 days. None of our patients who had been vaccinated at least one time, had severe symptoms. As a conclusion, the mortality of COVID-19 infection was significantly higher among our melanoma patients compared to the age-standardized mortality rate in Hungary.

Súlyos Covid-19-fertozés disszeminált melanómás betegnél, immunterápiát követoen.

The COVID-19 pandemic has created significant barriers to the treatment of cancer patients requiring regular hospitalisation, as coronavirus infection significantly increases the risk of serious and even fatal complications. In our case report, a middle-aged patient with advanced melanoma has developed immune-mediated pancreatitis after more than a year of pembrolizumab treatment. After changing the therapy, the patient was diagnosed with coronavirus infection, which led to nearly a month of hospitalisation and rehabilitation, thus suspending active oncotherapeutical treatment. Thanks to professional medical care, our patient successfully recovered from the severe COVID-19 pneumonia caused by the infection, even in the absence of a coronavirus vaccine. After recovery, he received two Pfizer- BioNTech vaccines in August and September 2021, and a follow-up CT scan showed almost complete remission. Given the patient's lack of complaints and the absence of tumours other than two residual pulmonary nodules, he was observed afterwards. Our patient was in a serious condition before the vaccines were introduced, but has recovered thanks to professional medical care.

Peripheral blood and bronchoalveolar leukocyte profile in lung transplant recipients and their changes according to immunosuppressive regimen: A single-center experience.

BACKGROUND: After lung transplantation (LuTX), lower respiratory tract infections (LRTI) and acute cellular rejection (ACR) are associated with changes in peripheral blood and bronchoalveolar lavage fluid mononuclear cell profile (PBMC and BALIC). PBMC is also influenced by immunosuppressive regimen and its changes with postoperative time. First-year PBMC and BALIC changes were evaluated in this study with rabbit anti-thymocyte globulin (ATG) and alemtuzumab (AL) induction therapy. METHODS: In total, 64 LuTX recipients were included, 53 of them received AL and 11 ATG as induction therapy. PBMC and BALIC were examined routinely and in cases suspicious of infection and/or rejection. A PBMC- and BALIC-based algorithm for infection and rejection prediction was also tested. RESULTS: In the AL group, peripheral blood lymphocyte and basophil cell numbers were significantly reduced, while the neutrophil cell number elevation during LRTI was significantly higher compared to the control. Early postoperative measurements showed a lower BALIC lymphocyte count. The algorithm had 17% sensitivity and 94% specificity for ACR in all patients and 33% sensitivity and 95% specificity for ACR with coexisting LRTI. CONCLUSION: BALIC is not significantly influenced by the immunosuppressive regimen. PBMC- and BALIC-based algorithm may improve the differential diagnosis of ACR.

The effectiveness of pulmonary rehabilitation in connection with lung transplantation in Hungary.

BACKGROUND: The role of pre- and post-lung transplant rehabilitation is to maintain or improve exercise tolerance, lung mechanics, peripheral and respiratory muscle function. Our aim was to measure the effectiveness of pre- and post-transplant rehabilitation in terms of the changes of functional and quality of life markers. METHODS: Sixty-three patients (40 COPD FEV1: 21±5%pred, 18 IPF TLC: 42±13%pred, 4 bronchiectasis FEV1: 28±4%pred and 1 alveolitis fibrotisans TLC: 31%pred) participated in a pre- and 14 took part in a post-transplant rehabilitation program (more than 2 months after lung transplantation (LTx), primary diagnoses: 9 COPD, 4 IPF). The rehabilitation program consisted of chest-wall stretching, controlled breathing techniques and personalized exercise of 20-30 minutes by cycling and treadmill 2-3 times per day for 4 weeks. Seven functional and quality of life markers, like lung function, chest wall expansion (CWE), 6-minute walking distance (6MWD), modified Medical Research Council Dyspnea Scale (mMRC), COPD Assessment Test (CAT), breath holding time (BHT) and hand grip strength (HGS) were measured at the onset and the end of the rehabilitation program. The safety profile of the rehabilitation program was followed-up. RESULTS: Pre-transplant pulmonary rehabilitation resulted in significant improvement in CWE (3.24±1.49 vs. 4.48±1.62 cm), CAT IQR {19 [13-25] vs. 15 [11-21]}, 6MWD (315±118 vs. 375±114 m), P<0.05. FEV1, FVC, mMRC, BHT and HGS did not change significantly. Post-transplant rehabilitation resulted in significant improvement in CWE (3.7±2.1 vs. 6.2±1.8 cm), CAT IQR {17 [11-23] vs. 10 [6-14], BHT (22±14 vs. 35±16 s), FEV1 (73±8 vs. 86±9%pred) and FVC (70±12 vs. 85±14%pred), P<0.05. The 6MWD, mMRC and HGS did not change significantly. No cardiovascular or other side effects were detected during the rehabilitation program. CONCLUSIONS: Our results underline the importance of perioperative pulmonary rehabilitation in the complex treatment of lung transplant patients in Hungary, as well. There was a limitation because no control group was evaluated without rehabilitation.

Different Trends in Excess Mortality in a Central European Country Compared to Main European Regions in the Year of the COVID-19 Pandemic (2020): a Hungarian Analysis.

Objective: This study examined cumulative excess mortality in European countries in the year of the Covid-19 pandemic and characterized the dynamics of the pandemic in different countries, focusing on Hungary and the Central and Eastern European region. Methods: Age-standardized cumulative excess mortality was calculated based on weekly mortality data from the EUROSTAT database, and was compared between 2020 and the 2016-2019 reference period in European countries. Results: Cumulate weekly excess mortality in Hungary was in the negative range until week 44. By week 52, it reached 9,998 excess deaths, corresponding to 7.73% cumulative excess mortality vs. 2016-2019 (p-value = 0.030 vs. 2016-2019). In Q1, only Spain and Italy reported excess mortality compared to the reference period. Significant increases in excess mortality were detected between weeks 13 and 26 in Spain, United Kingdom, Belgium, Netherland and Sweden. Romania and Portugal showed the largest increases in age-standardized cumulative excess mortality in the Q3. The majority of Central and Eastern European countries experienced an outstandingly high impact of the pandemic in Q4 in terms of excess deaths. Hungary ranked 11th in cumulative excess mortality based on the latest available data of from the EUROSTAT database. Conclusion: Hungary experienced a mortality deficit in the first half of 2020 compared to previous years, which was followed by an increase in mortality during the second wave of the COVID-19 pandemic, reaching 7.7% cumulative excess mortality by the end of 2020. The excess was lower than in neighboring countries with similar dynamics of the pandemic.

[Successful extracorporeal membrane oxygenation (ECMO) treatment in Legionella pneumonia]. / Sikeres extracorporalis membránoxigenizációs (ECMO-) kezelés Legionella-pneumoniában.

The mortality of severe ARDS is almost 60%. Ventilation-associated lung-injury can be avoided by low-pressure, low-volume ventilation. Potential use of ECMO in case of refractory hypoxemia beside modern ventilatory therapy can be considered. Increasing numbers of respiratory ECMO runs are seen worldwide, though the efficacy remains controversial. The authors present the first successful venovenous-ECMO treatment in severe ARDS in our Institute. We report the case of a 67-year-old male who was admitted with community-acquired pneumonia caused by Legionella. Despite empirical and later targeted antibiotic therapy, severe ARDS with sepsis evolved. Neither ventilation nor prone position resulted in permanent improvement in oxygenation. The patient was referred to our Institute for extracorporeal life support (ECLS) therapy. On admission, blood gas showed severe hypoxemia with mild hypercapnia (PaO2/FiO2: 60, pCO2: 53 mmHg at PEEP: 14 mmHg, PIP: 45 mmHg). X-ray showed bilateral patchy infiltrates while cardiac impairment (EF: 45%) and dilated right ventricle were seen on echocardiography. Elevated pulmonary artery pressure (mPAP: 41 mmHg) was measured. After implantation of femoral-jugular VV ECMO, oxygen saturation was appropriate with lung protective ventilation (FiO2: 0.5, TV: 3-4 ml/kg). Improving lung function enabled us to stop ECMO after 8 days and further 5 days later the patient was weaned off ventilation. After 21 days of intensive care we discharged him to the referral hospital. By reporting this case we emphasise the potential role of respiratory ECMO. Consideration should be given to increase the contingent of this modality in the Hungarian intensive care in accordance with international practice. Orv Hetil. 2019; 160(6): 235-240.

[Experiences with venovenous extracorporeal membrane oxygenation (ECMO) support for thoracic surgery in Hungary. Retrospective clinical study]. / Venovenosus extrakorporális membránoxigenizációval (ECMO) végzett mellkassebészeti mutétek tapasztalatai Magyarországon. Retrospektív klinikai tanulmány.

Introduction: Most modern thoracic operations are performed with single-lung ventilation balancing between convenient surgical approach and adequate gas exchange. The technical limitations include difficult airways or insufficient parenchyma for the intraoperative single-lung ventilation. Earlier, cardiopulmonary bypass was the only solution, however, today the extracorporeal membrane oxygenation is in the forefront. Aim: We retrospectively analysed our elective operations by use of venovenous ECMO to assess the indication, safety, perioperative morbidity and mortality. Patients and method: 12 patients were operated using venovenous (VV-) ECMO between 28 April 2014 and 30 April 2018 in the National Institute of Oncology. The main clinicopathological characteristics, data regarding the operation, the use of ECMO and survival were collected. Results: The mean age was 45 years, 2 patients had benign and 10 had malignant diseases. Extreme tracheal stricture was the indication for ECMO in 3 cases, while 4 patients had previous lung resection and lacked enough parenchyma for single-lung ventilation. 5 patients had both airway and parenchymal insufficiency. The average time of apnoea was 142 minutes without interruption in any of the cases. We did not experience any ECMO-related complication. We had no intraoperative death and 30-day mortality was 8.33%. Conclusion: In case of technical inoperability, when there is no airway or insufficient parenchyma for gas exchange, but pulmonary vascular bed is enough and there is no need for great-vessel resection, VV-ECMO can safely replace the complete gas exchange without further risk of bleeding. The use of VV-ECMO did not increase the perioperative morbidity and mortality. Previously inoperable patients can be operated with VV-ECMO. Orv Hetil. 2019; 160(42): 1655-1662.

Lung Transplant Patients on Kilimanjaro.

BACKGROUND: After its initial difficulties were overcome, lung transplantation became an accepted and effective treatment for end-stage lung disease. Patients can take part in almost all kinds of sports after lung transplantation, including high-altitude mountaineering, which is an extreme sport even for healthy individuals. Several articles have been published about high-altitude tolerance of transplanted patients. However, this was the first high-altitude expedition that included only lung transplant patients. METHODS: The Vienna lung transplantation team organized an expedition in 2017 to conquer the peak of Mount Kilimanjaro, which consisted of 10 lung transplanted patients and 24 accompanying medical personnel. The participants were tested before and several times during the hike to evaluate their general and cardiopulmonary status, the severity of altitude sickness, and radio-morphologic changes. The results of the lung transplanted patients were compared to the results of their healthy companions. RESULTS: The group started at 2360 meters and reached the 5895-meter-high summit of Mount Kilimanjaro after 6 days on June 18, 2017. Eight transplant patients and 24 escorting medical personnel reached the peak. This means that the success rate was 94%, which is significantly higher than the reported 85% for this route. The 2 transplant patients who did not make the summit turned back on the first and second day because they lacked the necessary fitness for the trip. We did not see a significant difference in the results regarding cardiopulmonary status or the severity of altitude sickness, although we observed mildly higher blood pressure and altitude sickness score results in the lung transplant group. CONCLUSION: Based on our experiences, we can state that a stable patient after lung transplantation who attains the necessary physical fitness can achieve similar or even better physical results than an average healthy individual.

First 3 Years of the Hungarian Lung Transplantation Program.

In this article we summarize the results of the first 3 years after launching the Hungarian Lung Transplantation Program. PATIENTS AND METHODS: The first lung transplant in Hungary was carried out on December 12, 2015, with the collaboration of the National Institute of Oncology and the Semmelweis University. Up to December 31, 2018, a total of 62 lung transplants were performed. Data were analyzed retrospectively. Patients were listed for lung transplant after the indication was established by the National Lung Transplantation Committee. Donor lungs were procured from brain-dead donors only. RESULTS: Within this period our team was involved in 87 lung procurements, 61 of which resulted in bilateral lung transplant and 1 in single-sided transplant. The operative approach was unilateral thoracotomy (n = 1), bilateral thoracotomy (n = 1), or clamshell incision (n = 60) with venoarterial extracorporeal membrane oxygenation support. The underlying disease of the recipients was obstructive lung disease (n = 30), lung fibrosis (n = 11), cystic fibrosis (n = 18), primary pulmonary hypertension (n = 2), histiocytosis-X syndrome (n = 1), bronchiectasis (n = 2), lymphangioleiomyomatosis (n = 1), and retransplant because of bronchiolitis obliterans syndrome (n = 1). The youngest patient was 13 years of age, while the oldest was 65 years. Three patients died in the early postoperative phase. One-year survival was 80%. DISCUSSION: The number of cases rises steadily in the Hungarian Lung Transplantation Program, which is exceptional compared with the start of other centrums. The incidence of complications and mortality is comparable with those of other experienced centers around the world. Our future goal is to broaden our waiting list, thus increasing the number of lung transplants carried out.

Donation After Cardiac Death, a Possibility to Expand the Donor Pool: Review and the Hungarian Experience.

INTRODUCTION: Lung transplantation is the only successful treatment option for patients experiencing end-stage lung disease. Results have improved significantly in the last decade; however, the number one limiting factor is still the shortage of donor lungs. Due to the discrepancy between available donor lungs and patients awaiting lung transplantation, many centers have reintroduced donation after cardiac death (DCD). According to their results, DCD and donation after brain death (DBD) are comparable in terms of survival and graft function. Currently in Hungary, donation is only allowed from DBD donors; however, due to the Eurotransplant agreement, non-heart-beating donation (NHBD) organs can be transplanted into Hungarian patients, and in some cases Hungarian transplant teams can also take part in NHBDs within the Eurotransplant region. The Hungarian experience. A Hungarian patient received a lung from a 15-year-old uncontrolled DCD in Vienna. The donor was reanimated for 54 minutes and after lung procurement the lungs were put on ex vivo lung perfusion and later successfully implanted into the Hungarian recipient. The recovery was very successful and the patient is still alive. The Hungarian Lung Transplantation Team was involved in a controlled Maastricht III donation in 2017. A 49-year-old female donor was reported from Ghent, Belgium. A multiorgan donation was carried out with 15 minutes of warm ischemic time in the case of the lungs. CONCLUSION: DCD is an effective, safe, and available method to increase the donor pool. In the case of controlled donations, the necessary protocols have already been prepared. Although DBD is working very successfully in Hungary, infrastructural developments, education of professionals, and social preparations are all needed to implement a DCD protocol in Hungary.