Outcome of lung transplant recipients infected with SARS-CoV-2/Omicron/B.1.1.529: a Nationwide German study.

PURPOSE: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is currently the major threat for immunocompromised individuals. The course of COVID-19 in lung transplant recipients in the Omicron era remains unknown. The aim of the study was to assess outcome and associated factors in lung transplant recipients in a German-wide multicenter approach. METHODS: All affected individuals from January 1st to March 20th, 2022 from 8 German centers during the Omicron wave were collected. Baseline characteristics and antiviral measures were associated with outcome. RESULTS: Of 218 patients with PCR-proven SARS-CoV-2 infection 166 patients (76%) received any early (< 7 days) antiviral therapy median 2 (interquartile range 1-4) days after symptom onset. Most patients received sotrovimab (57%), followed by remdesivir (21%) and molnupiravir (21%). An early combination therapy was applied in 45 patients (21%). Thirty-four patients (16%) developed a severe or critical disease severity according to the WHO scale. In total, 14 patients (6.4%) died subsequently associated with COVID-19. Neither vaccination and antibody status, nor applied treatments were associated with outcome. Only age and glomerular filtration rate < 30 ml/min/1.73m2 were independent risk factors for a severe or critical COVID-19. CONCLUSION: COVID-19 due to Omicron remains an important threat for lung transplant recipients. In particular, elderly patients and patients with impaired kidney function are at risk for worse outcome. Prophylaxis and therapy in highly immunocompromised individuals need further improvement.

Cardiopulmonary response to high-altitude mountaineering in lung transplant recipients-The Jebel Toubkal experience.

OBJECTIVES: Only a small proportion of lung transplant recipients achieve a physical status comparable to healthy individuals in the long term. It is reasonable to hypothesize that the necessary cardiopulmonary adaptation required for strenuous physical exercise may be impaired. Exposure to high altitude provides an optimal platform to study the physiological cardiopulmonary adaptation in lung transplant recipients under aerobic conditions. To gain a deeper understanding, 14 healthy lung transplant recipients and healthcare professionals climbed the highest peak in North Africa (Mount Jebel Toubkal; 4167 m) in September 2019. METHODS: Monitoring included daily assessment of vital signs, repeated transthoracic echocardiography, pulmonary function tests, and capillary blood sampling throughout the expedition. RESULTS: Eleven out of fourteen lung transplant recipients reached the summit. All recipients showed a stable lung function and vital parameters and physiological adaptation of blood gases. Similar results were found in healthy controls. Lung transplant recipients showed worse results in the 6-minute walk test at low and high altitude compared to controls (day 1: 662 m vs. 725 m, p < 0.001, day 5: 656 m vs. 700 m, p = 0.033) and a lack of contractile adaptation of right ventricular function with increasing altitude as measured by tricuspid plane systolic excursion on echocardiography (day 2: 22 mm vs. 24 mm, p = 0.202, day 5: 23 mm vs. 26 mm, p = 0.035). CONCLUSIONS: Strenuous exercise in healthy lung transplant recipients is safe. However, the poorer cardiopulmonary performance in the 6-minute walk test and the lack of right ventricular cardiac adaptation may indicate underlying autonomic dysregulation.

Cognitive Function After Lung Transplantation.

Cognitive functioning after transplantation, which could influence medication compliance and independence, has not been well studied. This study investigated cognitive impairment after lung transplantation. Patients undergoing bilateral transplant between March 2013 and October 2015 underwent comprehensive neuropsychological assessment at 60.1 ± 44.1 months post-transplantation: verbal memory (Auditory-Verbal Learning Test, digit span forward), visual memory (Corsi Block-Tapping Test forward, Benton Visual Retention Test), concentration/speed of processing/attention (D2 Test of Attention, Trail Making Test (TMT) A, Grooved Pegboard), and executive functioning (TMT B, Stroop Color-Word Test, semantic and phonematic verbal fluency, digit span backward, Corsi Block-Tapping Test backward). Mean scores were compared with a normative dataset using a one-sample t-test. A cognitive domain was judged impaired if the score on two or more domain-specific tests was greater than one standard deviation below the normative dataset age range mean. Of 124 lung transplant recipients (51% male, 54.3 ± 9.0 years), 70% showed cognitive impairment in one or more domains. Executive function was most often impaired (78% of recipients not within the age range) followed by verbal memory impairment (72% not within the age range). Cognitive function reductions were largely independent of age, gender, education, immunosuppressive medications, and time since transplantation. The findings show that cognitive impairment is common after lung transplantation and should be subject to rehabilitation and psychological resilience strategies.

A randomized trial of everolimus-based quadruple therapy vs standard triple therapy early after lung transplantation.

Calcineurin inhibitor (CNI) therapy after lung transplantation increases risk of kidney failure. Early everolimus-based quadruple low CNI immunosuppression may improve renal function without compromising efficacy or safety. A prospective, randomized, open-label, 12-month multicenter trial was conducted at 8 German sites. Patients 3-18 months after lung transplantation were randomized (1:1), stratified by baseline estimated glomerular filtration rate (eGFR). In the quadruple low CNI regimen, patients received everolimus (target trough level 3-5 ng/mL) with reduced CNI (tacrolimus 3-5 ng/mL or cyclosporine 25-75 ng/mL) and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. Of the 180 patients screened, 130 were randomized: 67 in the quadruple low CNI group and 63 in the standard triple CNI group. The primary endpoint (eGFR after 12 months) demonstrated superiority of the quadruple low CNI regimen: 64.5 mL/min vs 54.6 mL/min for the standard triple group (least squares mean, analysis of covariance; P < .001). Key efficacy parameters (biopsy-proven acute rejection, chronic lung allograft dysfunction, and death) and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe. Clinical trials registry: ClinicalTrials.gov NCT01404325.

Expression pattern of co-inhibitory molecules on CMV-specific T-cells in lung transplant patients.

OBJECTIVES: Cytomegalovirus infection (CMVi) occurs frequently in transplant patients. Co-inhibitory molecules on CMV-specific T-cells (TCMV) in patients after lung transplantation were investigated. METHODS: 59 lung transplant patients were stratified according to anti-CMV serostatus at time of transplantation. The co-inhibitors Programmed-Death-Receptor-1 (PD1) and B-and-T-Lymphocyte-Attenuator (BTLA) were detected on TCMV by flow cytometry (FACS). RESULTS: TCMV were detectable in CMV sero-positive patients (R+) and in CMV sero-negative patients with a lung graft of a CMV sero-positive donor (D+/R-); in both cases, the frequency of TCMV was higher than in healthy controls (HC). PD-1 on TCMV was increased in D+/R+ and D+/R- patients as compared to HC. BTLA was significantly enhanced on TCMV of D+/R- patients vs. HC. R+ patients with CMV reactivation in the past had an increased fraction of BTLA+ TCMV. CONCLUSION: In conclusion, the expression pattern of co-inhibitory molecules on TCMV is altered in patients after lung transplantation.

Levels of angiopoietins 1 and 2 in induced sputum supernatant in patients with COPD.

Pathological features of chronic obstructive pulmonary disease (COPD) include lung vascular remodeling and angiogenesis. Angiopoietin-1 (Ang-1), is an essential mediator of angiogenesis by establishing vascular integrity, whereas angiopoietin-2 (Ang-2) acts as its natural inhibitor. We determined the levels of angiopoietins in sputum supernatants of patients with COPD and investigated their possible association with mediators and cells involved in the inflammatory and remodeling process. Fifty-nine patients with COPD, 25 healthy smokers and 20 healthy non-smokers were studied. All subjects underwent lung function tests, sputum induction for cell count identification and Ang-1, Ang-2, VEGF, TGF-ß1, MMP-2, LTB4, IL-8, albumin measurement in sputum supernatants. Airway vascular permeability (AVP) index was also assessed. Ang-2 levels were significantly higher in patients with COPD compared to healthy smokers and healthy non-smokers [median, interquartile ranges pg/ml, 267 (147-367) vs. 112 (67-171) and 98 (95-107), respectively; p<0.001]. Regression analysis showed a significant association between Ang-2 levels and AVP index, VEGF, IL-8 and MMP-2 levels in COPD, the strongest being with VEGF. Our results indicate that induced sputum Ang-2 levels are higher in COPD compared to healthy smokers and healthy non-smokers. Moreover, Ang-2 is associated with AVP, IL-8, MMP-2, and VEGF, indicating a possible role for Ang-2 in the pathogenesis of the disease.

Lung Transplantation for Adult Respiratory Distress Syndrome after SARS-CoV-2 Infection.

Background The majority of patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection present mild symptoms. However, some patients develop severe acute respiratory distress syndrome (ARDS) and subsequent irreversible lung damage despite extracorporeal membrane oxygenation, leaving lung transplantation the ultimate therapeutically option. Case Description Here, we report a case of lung transplantation in a 31-year-old male recipient suffering from post-coronavirus disease 2019 respiratory failure with irreversible ARDS after prolonged extracorporeal membrane oxygenation therapy. Conclusion Patient selection criteria are elucidated. One relevant mechanism for susceptibility to SARS-CoV-2 in the respiratory system, the acid sphingomyelinase/ceramide system might be altered during infection with SARS-CoV-2.

Five-year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients: Follow-up of the 4EVERLUNG Study.

BACKGROUND: Everolimus-based quadruple low calcineurin inhibitor (CNI) maintenance immunosuppression has been shown to be effective in preserving short-term renal function without compromising efficacy or safety after lung transplantation; however, long-term benefit remains unknown. METHODS: An investigator-initiated 5-y follow-up analysis of the 4EVERLUNG study (NCT01404325), comparing everolimus-based quadruple low CNI with standard triple regimen, was performed. Patients who remained on the randomized drug regimen until the end of the 5-y observation were analyzed as the per protocol (PP) population. Patients in whom the assigned regimen was switched were analyzed as the intention-to-treat (ITT) population. RESULTS: In total, 123 patients (95%) from the core study were analyzed. During the observation period in 11 patients (19%) of the standard triple regimen and in 30 patients (46%) of the quadruple low CNI regimen, the assigned immunosuppressive regimen was switched ( P = 0.002). Estimated glomerular filtration rate at 5-y follow-up did not differ between the groups in both the ITT (56 [48-73] versus 58 [48-69] mL/min; P =0.951) and PP (59 [50-73] versus 59 [48-69] mL/min; P = 0.946) populations. Thromboembolic events occurred more frequently in the quadruple low CNI regimen (ITT: 11% versus 24%, P = 0.048; PP: 11% versus 22%, P = 0.162). There was a trend for a higher chronic lung allograft dysfunction-free survival for the quadruple low CNI regimen in the PP population ( P = 0.082). No difference in the graft survival was found. CONCLUSIONS: Initiation of an early everolimus-based quadruple low CNI regimen may have no long-term benefit on renal function. The immunosuppressive efficacy and safety profile seems comparable with the standard triple regimen.

Increased levels of osteopontin in sputum supernatant in severe refractory asthma.

BACKGROUND: Osteopontin (OPN) is a glycoprotein that has been associated with inflammation and fibrosis. Severe refractory asthma (SRA) is characterised by an intense inflammatory and remodelling process. The aim of this study was to investigate the levels of OPN in sputum supernatants of patients with SRA, to compare them with milder forms of the disease and to investigate their possible association with mediators and cells involved in the inflammatory and remodelling process. METHODS: 33 patients with SRA, 29 with moderate asthma, 21 with steroid-naïve asthma and 20 healthy subjects were studied. All subjects underwent lung function tests, bronchial hyper-responsiveness assessment and sputum induction for cell count identification and measurement of OPN, vascular endothelial growth factor, transforming growth factor beta1 (TGF-beta1), cysteinyl leukotrienes, interleukin 13 (IL-13), eosinophilic cationic protein (ECP) and IL-8 in sputum supernatants. RESULTS: Median (IQR) OPN levels (pg/ml) were significantly higher in patients with SRA than in those with moderate asthma, steroid-naive asthma and healthy control subjects (1840 (1125-11000) vs 130 (100-210) vs 100 (67-130) vs 50 (42-70), respectively, p<0.001). Regression analysis showed a significant association between log OPN and sputum eosinophils, cysteinyl leukotrienes, IL-13, TGF-beta1 and ECP. TGF-beta1 represented the strongest association with OPN. The above associations were not observed in milder forms of the disease or in healthy subjects. CONCLUSIONS: The results indicate that OPN levels are higher in SRA than in less severe forms of the disease. Moreover, OPN is associated with mediators involved in both the inflammatory and remodelling process such as TGF-beta1, IL-13 and cysteinyl leukotrienes only in SRA.

Impact of normothermic ex vivo lung perfusion on early post-transplantation cytomegalovirus infection.

BACKGROUND: The low acceptance rates in lung transplantation underline the importance to use every potential transplantable organ. With the use of normothermic ex vivo lung perfusion (EVLP) there is a potential to use more donor lungs for transplantation. Aim of this study was to evaluate if EVLP has an effect on cytomegalovirus (CMV) infection after lung transplantation. METHODS: Between May 2016 and October 2018, 57 lung transplants were performed. Out of these 21 extended criteria lungs were evaluated by EVLP and 16 transplanted. In a retrospective study, results of EVLP treated lungs were compared with lungs after cold storage preservation (CSP). Donor/recipient CMV IgG status and seroconversion rate was examined. RESULTS: Donors were CMV IgG+ in EVLP 69% and CSP 61% (n.s.). Best pO2 on procurement at FiO2 1.0 was in EVLP 278±76 versus CSP 413±96 mmHg (P≤0.05). Recipients were CMV IgG+ in EVLP 38% and CSP 63% (P<0.07). CMV seroconversion: EVLP 12%, CSP 20% (P<0.05), in the CSP group in 5% recipients with more than 1,000 copies/mL were diagnosed by PCR and treated for CMV infection. Procalcitonin (PCT) levels from day 1 to day 5 were significantly lower for CSP group (P<0.05). 30-day mortality was 12% for EVLP recipients. CONCLUSIONS: Normothermic EVLP did not influence CMV infection rate, however early PCT levels were higher in EVLP group. Short-term results were comparable to standard lung transplantation.

Exhaled nitric oxide and exhaled breath condensate pH in severe refractory asthma.

BACKGROUND: Distinct inflammatory cellular phenotypes of severe refractory asthma (SRA) have been reported. Fractional exhaled nitric oxide (FeNO) primarily is related to eosinophilic inflammation. Exhaled breath condensate (EBC) pH has been suggested as a noninvasive tool in the assessment of patients with asthma. We sought to determine whether FeNO and EBC pH could identify the presence and type of the underlying cellular inflammation in patients with SRA. METHODS: Twenty-nine patients with SRA, 27 patients with moderate asthma, and 17 healthy subjects underwent FeNO measurement, EBC collection for pH measurement, and sputum induction for cell count identification. RESULTS: FeNO was significantly higher and pH significantly lower in patients with SRA than in the other groups. In SRA, FeNO levels of > 19 parts per billion were associated with a sensitivity of 0.78 and a specificity of 0.73 for sputum eosinophilia, whereas FeNO levels of < 19 parts per billion were associated with a sensitivity of 0.63 and a specificity of 0.9 for sputum neutrophilia irrespective of the presence of eosinophils. The pH failed to predict the cellular profile in SRA, but a cutoff value of < 7.37 could predict sputum eosinophilia in moderate asthma. CONCLUSIONS: In patients with SRA, different FeNO threshold values can identify those with predominant eosinophilia as well as those with neutrophilia. FeNO levels were reduced in patients with predominant neutrophilia regardless of the concomitant presence of eosinophilia. Although pH could not identify the cellular profile in SRA, it seemed to be a better index for predicting eosinophilia in moderate asthma.

Noninvasive evaluation of airway inflammation in asthmatic patients who smoke: implications for application in clinical practice.

BACKGROUND: Despite the limited pathological data in asthmatic patients who smoke, it is thought that cigarette smoking may modify airway inflammation. OBJECTIVES: To summarize the major clinical studies that have used samples obtained by noninvasive techniques, such as blood, urine, exhaled breath condensate (EBC), fractional exhaled nitric oxide (FeNO), and induced sputum, for the evaluation of airway inflammation and the response to treatment in asthmatic patients who smoke and to evaluate which biomarkers have been adequately validated to be used in routine clinical practice. DATA SOURCES: In this review, we collected the available literature that addressed this topic. We searched the MEDLINE database using a combination of the following keywords: smoking or asthma or inflammation or mechanisms or exhaled nitric oxide or induced sputum or EBC. STUDY SELECTION: We selected the articles that most adequately addressed this topic for inclusion in this review. RESULTS: Smoking significantly influences FeNO and negatively affects its concentration, although FeNO can distinguish steroid-naive asthmatic smokers from nonasthmatic smokers. Sputum neutrophilia is the predominant finding in induced sputum in asthmatic patients who smoke but inflammatory mediators derived either from neutrophils or from a T(H)1 response can also be measured in the supernatants. EBC gives the opportunity to evaluate neutrophil-derived cytokines, airway acidification, and plausible protective mechanisms in smoking asthma. CONCLUSIONS: Despite the encouraging updated results, the introduction of noninvasive techniques in daily clinical practice requires the reworking of some methodologic pitfalls and the identification of a reliable biomarker that is reproducible, possesses normal values, and provides information for the underlying inflammatory process and the response to treatment.