Publications by authors named "Robin Vos"

168 Publications

The Deteriorating Patient: Therapies Including Lung Transplantation.

Semin Respir Crit Care Med 2021 Aug 14;42(4):623-638. Epub 2021 Jul 14.

Department of Respiratory Diseases, AZ Nikolaas, Sint-Niklaas, Belgium.

In this review paper, we discuss the characteristics that define severe bronchiectasis and which may lead to deterioration of noncystic fibrosis bronchiectasis. These characteristics were used to establish the current severity scores: bronchiectasis severity index (BSI), FACED, and E-FACED (exacerbation frequency, forced expiratory volume in 1 second, age, colonization, extension and dyspnea score). They can be used to predict mortality, exacerbation rate, hospital admission, and quality of life. Furthermore, there are different treatable traits that contribute to severe bronchiectasis and clinical deterioration. When present, they can be a target of the treatment to stabilize bronchiectasis.One of the first steps in treatment management of bronchiectasis is evaluation of compliance to already prescribed therapy. Several factors can contribute to treatment adherence, but to date no real interventions have been published to ameliorate this phenomenon. In the second step, treatment in deteriorating patients with bronchiectasis should be guided by the predominant symptoms, for example, cough, sputum, difficulty expectoration, exacerbation rate, or physical impairment. In the third step, we evaluate treatable traits that could influence disease severity in the deteriorating patient. Finally, in patients who are difficult to treat despite maximum medical treatment, eligibility for surgery (when disease is localized), should be considered. In case of end-stage disease, the evaluation for lung transplantation should be performed. Noninvasive ventilation can serve as a bridge to lung transplantation in patients with respiratory failure.
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http://dx.doi.org/10.1055/s-0041-1730946DOI Listing
August 2021

Lung transplantation for acute respiratory distress syndrome: A multicenter experience.

Am J Transplant 2021 Jul 13. Epub 2021 Jul 13.

Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.

Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We reviewed posttransplant outcome of ARDS patients from three high-volume European transplant centers. Demographics and clinical data were collected and analyzed. Viral infection was the main reason for ARDS (n = 7/13, 53.8%). All patients were admitted to ICU and required mechanical ventilation, 11/13 were supported with ECMO at the time of listing. They were granted a median LAS of 76 (IQR 50-85) and waited for a median of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation was 33 days (IQR 17-52.5), median length of ICU and hospital stay were 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with a median duration of 2 days (IQR 2-7). 30-day mortality was 7.7%, 1 and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Given the lack of alternative treatment options, the herein presented results support the concept of offering live-saving LTx to carefully selected ARDS patients.
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http://dx.doi.org/10.1111/ajt.16759DOI Listing
July 2021

Interalveolar Pores Increase in Aging and Severe Airway Obstruction.

Am J Respir Crit Care Med 2021 Jul 9. Epub 2021 Jul 9.

Katholieke Universiteit Leuven and Universitair Ziekenhuis Gasthuisberg, Lung Transplant Unit, Leuven, Belgium;

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http://dx.doi.org/10.1164/rccm.202102-0530LEDOI Listing
July 2021

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis.

Front Immunol 2021 25;12:661761. Epub 2021 May 25.

Department of Chronic Diseases and Metabolism, Katholieke Universiteit, Leuven, Belgium.

Background: Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD).

Materials And Methods: CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.

Results: qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).

Conclusions: Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.
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http://dx.doi.org/10.3389/fimmu.2021.661761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187127PMC
May 2021

High-Intensity Training for 6 Months Safely, but Only Temporarily, Improves Exercise Capacity in Selected Solid Organ Transplant Recipients.

Transplant Proc 2021 May 25. Epub 2021 May 25.

Department of Microbiology, Immunology, and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium; Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Background: Organ transplantation is a life-saving intervention that improves quality of life of patients with irreversible organ failure. Although exercise training immediately after transplantation has been suggested to be beneficial, such interventions remain rare in stable transplant recipients, whereas effects of high-intensity training (HIT) are even less frequently investigated. Moreover, sustainability of such interventions has not yet been reported. We investigated the effects of a 6-month, cycling-based HIT program on physical performance in long-term stable solid organ transplant (SOT) recipients, with follow-up evaluation after 6 months.

Methods: Forty-two adult, stable, and selected SOT recipients participated in a 6-month individualized home- and group-based HIT program. Exercise capacity (VOmax), maximal power (Wmax), and body mass index were measured before, at the end, and 6 months after completion of the intervention.

Results: The study comprised 12 heart, 7 lung, 8 liver, and 15 kidney recipients (mean age, 41.4 ± 11.1 years; median time posttransplant, 3.4 [1.7-8.0] years). For 6 months, VOmax increased in the heart, lung, and kidney groups, Wmax increased in the heart group, and body mass index decreased in the liver group. Six months after the HIT program, the achieved gain in exercise capacity had disappeared in all groups.

Conclusion: Despite voluntary participation selection bias, our observations indicate that HIT is safe and may result in a beneficial effect on physical performance in selected, stable SOT recipients. However, there was no sustained beneficial effect once training stopped. Larger scale and longer term studies are still required to investigate longevity of improvement and overall beneficial effects on clinical outcomes.
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http://dx.doi.org/10.1016/j.transproceed.2021.03.040DOI Listing
May 2021

Selection Criteria for Lung Transplantation: Controversies and New Developments.

Semin Respir Crit Care Med 2021 Jun 24;42(3):329-345. Epub 2021 May 24.

Division of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.

Lung transplantation is an accepted therapeutic option for end-stage lung diseases. The imbalance between limited availability and vast need of donor organs necessitates careful selection of recipient candidates, ensuring the best possible utilization of the scarce resource of organs. Nonetheless, possible lung transplant candidates who could experience a meaningful improvement in survival and quality of life should not be excluded solely based on the complexity of their case. In this review, controversial issues or difficult limitations for lung transplantation, and new developments in recipient selection criteria, are discussed, which may help broaden recipient eligibility for lung transplantation without compromising long-term outcomes.
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http://dx.doi.org/10.1055/s-0041-1728756DOI Listing
June 2021

Antifungal Prophylaxis After Lung Transplantation: Where are We Now?

Transplantation 2021 Feb 22. Epub 2021 Feb 22.

1Faculty of Medicine, KU Leuven; Leuven, Belgium 2Dept. of Respiratory Diseases, University Hospitals Leuven; Leuven, Belgium 3Dept. of Microbiology, Immunology and Transplantation, KU Leuven; Leuven, Belgium and Dept. of Laboratory Medicine and National Reference Center for Mycosis, University Hospitals Leuven, Leuven, Belgium 4Dept. of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium and Dept. Pharmacy, University Hospitals Leuven, Leuven, Belgium. 5Dept. CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven; Leuven, Belgium.

Background: Lung transplantation is an important treatment option for various end-stage lung diseases. However, survival remains limited due to graft rejection and infections. Despite that fungal infections are frequent and carry a bad prognosis, there is currently no consensus on efficacy, optimal drug, route or duration of antifungal prophylaxis. This narrative review summarizes current strategies for antifungal prophylaxis after lung transplantation.

Methods: English-language articles in Embase, Pubmed, UptoDate and bibliographies were used to assess efficacy and safety of available antifungal agents for prophylaxis in adult lung transplant recipients.

Results: Overall, there are limited high quality data. Universal prophylaxis is more widely used and may be preferable over targeted prophylaxis. Both formulations of inhaled amphotericin B and systemic azoles are effective at reducing fungal infection rates, yet with their own specific advantages and disadvantages. The benefit of combination regimens has yet to be proven. Considering the post-transplant timing of onset of fungal infections, postoperative prophylaxis during the first postoperative months seems indicated for most patients.

Conclusions: Based on existing literature, universal antifungal prophylaxis with inhaled amphotericin B and/or systemic voriconazole for at least 3 to 6 months after lung transplantation may be advisable, with a slight preference for amphotericin B because of its better safety profile.Supplemental Visual Abstract; http://links.lww.com/TP/C166.
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http://dx.doi.org/10.1097/TP.0000000000003717DOI Listing
February 2021

Concomitant use of isavuconazole and CYP3A4/5 inducers: Where pharmacogenetics meets pharmacokinetics.

Mycoses 2021 May 8. Epub 2021 May 8.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

Background: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. Isavuconazole is metabolised by CYP3A4 and CYP3A5, and it has been shown that the CYP3A inducer rifampin reduces isavuconazole exposure. By extrapolation, the concomitant use of isavuconazole with moderate and strong CYP450 inducers is contraindicated, although it is known that some CYP450 inducers are less potent in comparison with rifampin.

Objectives: We aim to document exposure to isavuconazole in patients concomitantly treated with a CYP450 inducer that is less potent compared to rifampin. Moreover, although it is well known that CYP3A enzymes are important for the metabolism of isavuconazole, this induction effect has never been studied in combination with the patient's CYP3A genotype.

Patients: We report three patients treated with both isavuconazole and a CYP3A inducer that is less potent compared to rifampin (rifabutin or phenobarbital), in whom we determined isavuconazole concentrations.

Results: These cases suggest that the CYP3A4/5 genotype is an important determinant for isavuconazole exposure and that it might also influence the CYP450 induction interaction.

Conclusions: CYP3A inducers that are less potent compared to rifampin, may be combined with isavuconazole in patients with loss of CYP3A5 activity (CYP3A5*3/*3). Therapeutic drug monitoring is recommended during this combination. However, low-isavuconazole exposure was observed in the extensive metaboliser with CYP3A4*1/*1 and CYP3A5*1/*3 alleles.
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http://dx.doi.org/10.1111/myc.13300DOI Listing
May 2021

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

Semin Thromb Hemost 2021 Jun 23;47(4):362-371. Epub 2021 Apr 23.

Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.

Background:  Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis.

Methods:  Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism.

Results:  Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported.

Conclusion:  In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.
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http://dx.doi.org/10.1055/s-0041-1727284DOI Listing
June 2021

Once daily tacrolimus conversion in lung transplantation: A prospective study on safety and medication adherence.

J Heart Lung Transplant 2021 Jun 27;40(6):467-477. Epub 2021 Feb 27.

Department of Respiratory Diseases, Lung Transplantation Group, UZ Leuven, Campus Gasthuisberg, Leuven, Belgium; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium.

Background: Lung transplantation (LTx) requires a calcineurin inhibitor-based immunosuppressive regimen. A once daily (QD) tacrolimus regimen was developed to increase medication adherence. However, data concerning its safety and efficacy in LTx are lacking.

Methods: In this prospective study, stable LTx patients were consecutively converted from twice daily (BID) tacrolimus to QD tacrolimus on a 1 mg:1 mg basis. Trough level (C), renal function, cholesterol, fasting glucose, potassium and lung function were monitored six months before and up to one year after conversion. Adherence and its barriers were assessed by self-reported questionnaires (Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) and Identification of Medication Adherence Barriers questionnaire (IMAB)) and blood-based assays (mean C and coefficient of variation (CV)).

Results: We included 372 patients, in whom we observed a decrease in tacrolimus C of 18.5% (p < 0.0001) post-conversion, requiring subsequent daily dose adaptations in both cystic fibrosis (CF) (n = 72) and non-CF patients (n = 300). We observed a small decrease in eGFR one year post-conversion (p = 0.024). No significant changes in blood creatinine, potassium, fasting glucose, cholesterol or rate of lung function decline were observed. In a subgroup of 166 patients, significantly fewer patients missed doses (8.4% vs. 19.3%, p = 0.016) or had irregular intake post-conversion (19.3% vs. 32.5%, p = 0.019). Mean C and CV, as well as the total number of barriers, also decreased significantly post-conversion.

Conclusions: In LTx, conversion from BID to QD tacrolimus (1 mg:1 mg) requires close monitoring of tacrolimus C. QD tacrolimus after transplantation is safe with respect to renal function, metabolic parameters and allograft function and improves LTx recipient adherence.
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http://dx.doi.org/10.1016/j.healun.2021.02.017DOI Listing
June 2021

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

EBioMedicine 2021 Apr 19;66:103288. Epub 2021 Mar 19.

Department of Cardiovascular Sciences and Clinical Department of Laboratory Medicine, KU Leuven, Belgium.

Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19.

Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated.

Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care.

Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study.

Funding: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2021.103288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979145PMC
April 2021

ERS International Congress 2020: highlights from the Thoracic Surgery and Transplantation Assembly.

ERJ Open Res 2021 Jan 15;7(1). Epub 2021 Mar 15.

Dept of Pulmonary Medicine, Division of lung Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands.

The Thoracic Surgery and Lung Transplantation Assembly of the European Respiratory Society is delighted to present the highlights from the 2020 Virtual International Congress. We have selected four sessions that discussed recent advances in a wide range of topics. From the use of robotic surgery in thoracic surgery and extracorporeal life support as a bridge to lung transplantation, to lung transplantation in the era of new drugs. The sessions are summarised by early career members in close collaboration with the assembly leadership. We aim to give the reader an update on the highlights of the conference in the fields of thoracic surgery and lung transplantation.
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http://dx.doi.org/10.1183/23120541.00743-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957292PMC
January 2021

Bracing for the Next Wave on the Long Haul: Lung Transplantation for Post-COVID-19 Respiratory Failure.

Transplantation 2021 06;105(6):1173-1175

Department CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1097/TP.0000000000003707DOI Listing
June 2021

Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2-azithromycin trial.

Trials 2021 Feb 9;22(1):126. Epub 2021 Feb 9.

Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven, Leuven, Belgium.

Background: The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19.

Methods: DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician's discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days.

Discussion: The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context.

Trial Registration: EU Clinical trials register EudraCT Nb 2020-001614-38 . Registered on 22 April 2020.
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http://dx.doi.org/10.1186/s13063-021-05033-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871018PMC
February 2021

A novel experimental porcine model to assess the impact of differential pulmonary blood flow on ischemia-reperfusion injury after unilateral lung transplantation.

Intensive Care Med Exp 2021 Feb 5;9(1). Epub 2021 Feb 5.

Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.

Background: Primary graft dysfunction (PGD) remains a major obstacle after lung transplantation. Ischemia-reperfusion injury is a known contributor to the development of PGD following lung transplantation. We developed a novel approach to assess the impact of increased pulmonary blood flow in a large porcine single-left lung transplantation model.

Materials: Twelve porcine left lung transplants were divided in two groups (n = 6, in low- (LF) and high-flow (HF) group). Donor lungs were stored for 24 h on ice, followed by left lung transplantation. In the HF group, recipient animals were observed for 6 h after reperfusion with partially clamping right pulmonary artery to achieve a higher flow (target flow 40-60% of total cardiac output) to the transplanted lung compared to the LF group, where the right pulmonary artery was not clamped.

Results: Survival at 6 h was 100% in both groups. Histological, functional and biological assessment did not significantly differ between both groups during the first 6 h of reperfusion. injury was also present in the right native lung and showed signs compatible with the pathophysiological hallmarks of ischemia-reperfusion injury.

Conclusions: Partial clamping native pulmonary artery in large animal lung transplantation setting to study the impact of low versus high pulmonary flow on the development of ischemia reperfusion is feasible. In our study, differential blood flow had no effect on IRI. However, our findings might impact future studies with extracorporeal devices and represent a specific intra-operative problem during bilateral sequential single-lung transplantation.
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http://dx.doi.org/10.1186/s40635-021-00371-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862464PMC
February 2021

COVID-19 vaccination in our transplant recipients: The time is now.

J Heart Lung Transplant 2021 03 2;40(3):169-171. Epub 2021 Jan 2.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.

We are entering 2021 with an expanding and effective COVID-19 vaccine armamentarium. Recent interim results from COVID-19 vaccine trials, including more than 80,000 participants worldwide, demonstrate remarkable efficacy and low rate of serious adverse events. Based on experience with other vaccines in transplant recipients and knowing the risk of severe COVID-19 in this population, we believe that COVID-19 vaccines provide potential benefit with minimal risk. We strongly support and encourage COVID-19 vaccination of our transplant recipients.
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http://dx.doi.org/10.1016/j.healun.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834006PMC
March 2021

Commentary: "Cont"used though still used donor lungs for transplantation.

J Thorac Cardiovasc Surg 2020 Dec 5. Epub 2020 Dec 5.

Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.jtcvs.2020.12.001DOI Listing
December 2020

Rationale for azithromycin in COVID-19: an overview of existing evidence.

BMJ Open Respir Res 2021 01;8(1)

Respiratory Diseases, KU Leuven University Hospitals, Leuven, Flanders, Belgium.

Azithromycin has rapidly been adopted as a repurposed drug for the treatment of COVID-19, despite the lack of high-quality evidence. In this review, we critically appraise the current pharmacological, preclinical and clinical data of azithromycin for treating COVID-19. Interest in azithromycin has been fuelled by favourable treatment outcomes in other viral pneumonias, a documented antiviral effect on SARS-CoV-2 in vitro and uncontrolled case series early in the pandemic. Its antiviral effects presumably result from interfering with receptor mediated binding, viral lysosomal escape, intracellular cell-signalling pathways and enhancing type I and III interferon expression. Its immunomodulatory effects may mitigate excessive inflammation and benefit tissue repair. Currently, in vivo reports on azithromycin in COVID-19 are conflicting and do not endorse its widespread use outside of clinical trials. They are, however, mostly retrospective and therefore inherently biased. The effect size of azithromycin may depend on when it is started. Also, extended follow-up is needed to assess benefits in the recovery phase. Safety data warrant monitoring of drug-drug interactions and subsequent cardiac adverse events, especially with hydroxychloroquine. More prospective data of large randomised controlled studies are expected and much-needed. Uniform reporting of results should be strongly encouraged to facilitate data pooling with the many ongoing initiatives.
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http://dx.doi.org/10.1136/bmjresp-2020-000806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811960PMC
January 2021

Distinct Airway Involvement in Subtypes of End-Stage Fibrotic Pulmonary Sarcoidosis.

Chest 2021 Jan 10. Epub 2021 Jan 10.

BREATHE, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.

Background: Sarcoidosis is a systemic granulomatous disease that in most patients affects the lung. Pulmonary fibrotic sarcoidosis is clinically, radiologically, and pathologically a heterogeneous condition. Although substantial indirect evidence suggests small airways involvement, direct evidence currently is lacking.

Research Question: What is the role of the (small) airways in fibrotic sarcoidosis?

Study Design And Methods: Airway morphologic features were investigated in seven explant lungs with end-stage fibrotic sarcoidosis using a combination of CT scanning (large airways), micro-CT scanning (small airways), and histologic examination and compared with seven unused donor lungs as controls with specific attention focused on different radiologically defined sarcoidosis subtypes.

Results: Patients with central bronchial distortion (n = 3), diffuse bronchiectasis (n = 3), and usual interstitial pneumonia pattern (n = 1) were identified based on CT scan, showing a decrease and narrowing of large airways, a similar airway number and increased airway diameter of more distal airways, or an increase in airway number and airway diameter, respectively, compared with control participants. The number of terminal bronchioles per milliliter and the total number of terminal bronchioles were decreased in all forms of fibrotic sarcoidosis. Interestingly, the number of terminal bronchioles was correlated inversely with the degree of fibrosis. Furthermore, we identified granulomatous remodeling as a cause of small airways loss using serial micro-CT scanning and histologic examination.

Interpretation: The large airways are involved differentially in subtypes of sarcoidosis, but the terminal bronchioles universally are lost. This suggests that small airways loss forms an important aspect in the pathophysiologic features of fibrotic pulmonary sarcoidosis.
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http://dx.doi.org/10.1016/j.chest.2021.01.003DOI Listing
January 2021

Seroprevalence of Antibodies against Diphtheria, Tetanus and Pertussis in Adult At-Risk Patients.

Vaccines (Basel) 2021 Jan 4;9(1). Epub 2021 Jan 4.

Department of Public Health and Primary Care, Leuven University Vaccinology Center, KU Leuven, Kapucijnenvoer 35, P.O. Box 7001, 3000 Leuven, Belgium.

Patients with chronic diseases are at increased risk of complications following infection. It remains, however, unknown to what extend they are protected against vaccine-preventable diseases. We assessed seroprevalence of antibodies against diphtheria, tetanus and pertussis to evaluate whether current vaccination programs in Belgium are adequate. Antibody titers were assessed with a bead-based multiplex assay in serum of 1052 adults with chronic diseases. We included patients with diabetes mellitus type 1 (DM1) ( = 172), DM2 ( = 77), chronic kidney disease ( = 130), chronic obstructive pulmonary disease (COPD) ( = 170), heart failure ( = 77), HIV ( = 196) and solid organ transplant (SOT) recipients ( = 230). Factors associated with seroprevalence were analysed with multiple logistic regression. We found seroprotective titers in 29% for diphtheria (≥0.1 IU/mL), in 83% for tetanus (≥0.1 IU/mL) and 22% had antibodies against pertussis (≥5 IU/mL). Seroprotection rates were higher ( < 0.001) when vaccinated within the last ten years. Furthermore, diphtheria seroprotection decreased with age ( < 0.001). Tetanus seroprotection was less reached in women ( < 0.001) and older age groups ( < 0.001). For pertussis, women had more often a titer suggestive of a recent infection or vaccination (≥100 IU/mL, < 0.01). We conclude that except for tetanus, the vast majority of at-risk patients remains susceptible to vaccine-preventable diseases such as diphtheria and pertussis.
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http://dx.doi.org/10.3390/vaccines9010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824683PMC
January 2021

Immunogenicity And Safety Of The Nine-Valent Human Papillomavirus Vaccine In Solid Organ Transplant Recipients And Hiv-Infected Adults.

Clin Infect Dis 2020 Dec 29. Epub 2020 Dec 29.

Leuven University Vaccinology Centre, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.

Background: The burden of human papillomavirus (HPV) in HIV-infected persons and solid organ transplant (SOT) recipients is high. Clinical trials on HPV vaccines in HIV-infected persons and particularly in SOT recipients have been sparse to date, included low numbers of participants and none of them assessed the nine-valent HPV (9vHPV). We investigated the immunogenicity with respect to HPV types 6/11/16/18/31/33/45/52/58 and the safety of the 9vHPV vaccine in HIV-infected persons and recipients of a kidney, lung or heart transplant.

Methods: This is a phase III investigator-initiated study in 100 HIV-infected persons (age: 18-45 years) and 171 SOT recipients (age: 18-55 years). The 9vHPV vaccine was administered at day 1, month 2 and month 6. Primary outcome was seroconversion rates to the 9vHPV types at month 7. Secondary outcomes were geometric mean titers (GMTs) and frequency of adverse events (AEs).

Results: All HIV-infected participants seroconverted for all HPV types, but seroconversion ranged from 46% for HPV45 to 72% for HPV58 in SOT recipients. GMTs ranged from 180 to 2985 mMU/ml in HIV-positive participants and from 17 to 170 mMU/ml in SOT recipients, depending on the HPV type. Injection-site AEs occurred in 62% of participants but were mostly mild or moderate in intensity. None of the reported serious adverse events were deemed vaccine-related. No patients died during the study.

Conclusion: Immunogenicity of the 9vHPV vaccine is high in HIV-infected persons but suboptimal in SOT recipients. The vaccine is safe and well tolerated in both groups.
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http://dx.doi.org/10.1093/cid/ciaa1897DOI Listing
December 2020

Successful double-lung transplantation from a donor previously infected with SARS-CoV-2.

Lancet Respir Med 2021 03 1;9(3):315-318. Epub 2020 Dec 1.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Lung Transplant Unit, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/S2213-2600(20)30524-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831530PMC
March 2021

Flow-controlled ventilation during EVLP improves oxygenation and preserves alveolar recruitment.

Intensive Care Med Exp 2020 Nov 25;8(1):70. Epub 2020 Nov 25.

Unit of Anesthesiology and Algology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.

Background: Ex vivo lung perfusion (EVLP) is a widespread accepted platform for preservation and evaluation of donor lungs prior to lung transplantation (LTx). Standard lungs are ventilated using volume-controlled ventilation (VCV). We investigated the effects of flow-controlled ventilation (FCV) in a large animal EVLP model. Fourteen porcine lungs were mounted on EVLP after a warm ischemic interval of 2 h and randomized in two groups (n = 7/group). In VCV, 7 grafts were conventionally ventilated and in FCV, 7 grafts were ventilated by flow-controlled ventilation. EVLP physiologic parameters (compliance, pulmonary vascular resistance and oxygenation) were recorded hourly. After 6 h of EVLP, broncho-alveolar lavage (BAL) was performed and biopsies for wet-to-dry weight (W/D) ratio and histology were taken. The left lung was inflated, frozen in liquid nitrogen vapors and scanned with computed tomography (CT) to assess regional distribution of Hounsfield units (HU).

Results: All lungs endured 6 h of EVLP. Oxygenation was better in FCV compared to VCV (p = 0.01) and the decrease in lung compliance was less in FCV (p = 0.03). W/D ratio, pathology and BAL samples did not differ between both groups (p = 0.16, p = 0.55 and p = 0.62). Overall, CT densities tended to be less pronounced in FCV (p = 0.05). Distribution of CT densities revealed a higher proportion of well-aerated lung parts in FCV compared to VCV (p = 0.01).

Conclusions: FCV in pulmonary grafts mounted on EVLP is feasible and leads to improved oxygenation and alveolar recruitment. This ventilation strategy might prolong EVLP over time, with less risk for volutrauma and atelectrauma.
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http://dx.doi.org/10.1186/s40635-020-00360-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686942PMC
November 2020

Peripheral Blood Eosinophilia Is Associated with Poor Outcome Post-Lung Transplantation.

Cells 2020 11 20;9(11). Epub 2020 Nov 20.

Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium.

Eosinophils play a role in many chronic lung diseases. In lung transplantation (LTx), increased eosinophils in bronchoalveolar lavage (BAL) was associated with worse outcomes. However, the effect of peripheral blood eosinophilia after LTx has not been investigated thoroughly. A retrospective study was performed including all LTx patients between 2011-2016. Chronic lung allograft dysfunction (CLAD)-free and graft survival were compared between patients with high and low blood eosinophils using an 8% threshold ever during follow-up. A total of 102 patients (27.1%) had high blood eosinophils (≥8%) (45 before CLAD and 17 after, 40 had no CLAD) and 274 (72.9%) had low eosinophils (<8%). Patients with high blood eosinophils demonstrated worse graft survival ( = 0.0001) and CLAD-free survival ( = 0.003) compared to low eosinophils. Patients with both high blood and high BAL (≥2%) eosinophils ever during follow-up had the worst outcomes. Within the high blood eosinophil group, 23.5% had RAS compared to 3% in the group with low eosinophils ( < 0.0001). After multivariate analysis, the association between high blood eosinophils and graft and CLAD-free survival remained significant ( = 0.036, = 0.013) independent of high BAL eosinophils and infection at peak blood eosinophilia, among others. LTx recipients with ever ≥8% blood eosinophils demonstrate inferior graft and CLAD-free survival, specifically RAS, which requires further prospective research.
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http://dx.doi.org/10.3390/cells9112516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699939PMC
November 2020

Free Airway C4d after Lung Transplantation - A Quantitative Analysis of Bronchoalveolar Lavage Fluid.

Transpl Immunol 2021 02 17;64:101352. Epub 2020 Nov 17.

Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Laboratory of Respiratory Diseases & Thoracic Surgery (BREATHE), UZ/KU Leuven, Leuven, Belgium. Electronic address:

In recent years, the utility of vascular complement factor 4d (C4d) deposition as diagnostic tool for antibody mediated rejection (AMR) after lung transplantation, has become a controversial issue. We aimed to pinpoint the problematic nature of C4d as biomarker with a simple experiment. We quantified C4d in broncho-alveolar lavage (BAL) of lung transplant patients with diverse post-transplant complications in 3 different settings of clinically clear cases of: 1/ chronic lung allograft dysfunction (CLAD); 2/ acute complications acute rejection (AR), lymphocytic bronchiolitis (LB), antibody-mediated rejection (AMR) and respiratory infection (INF); 3/ patients with parallel C4d immunostaining and Anti-HLA. All groups were compared to BAL of stable patients. C4d was measured via standard ELISA. C4d was increased in CLAD, predominantly in RAS (p = 0.0026) but not in BOS (p = 0.89). C4d was increased in all acute events, AR (p = 0.0025), LB (p < 0.0001), AMR (p = 0.0034), infections (p < 0.0001). In patients with parallel C4d immunostaining and serum HLA antibodies, C4d was increased in C4d-/HLA- (p = 0.0011); C4d-/HLA+ (p = 0.013); HLA+/C4d + (p = 0.0081). A correlation of systemic C-reactive protein (CRP) with C4d was found in all patients (r = 0.49; p < 0.0001). We hypothesize that free C4d in BAL may only be representative of a general immune response in the transplanted lung.
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http://dx.doi.org/10.1016/j.trim.2020.101352DOI Listing
February 2021

Hemoptysis after Lung Transplantation Caused by Bronchial Arterial Neovascularization: Angiographic Analysis and Successful Embolization.

J Vasc Interv Radiol 2021 01 31;32(1):56-60. Epub 2020 Oct 31.

Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium; Department of Respiratory Diseases, Lung Transplantation Unit, University Hospitals Leuven, Leuven, Belgium. Electronic address:

This report discusses 3 bilateral lung transplant recipients (2 female, 1 male) who presented with late hemoptysis (10 y, 18 y, and 19 y after transplantation). All patients had a history of pulmonary infections, bronchiectasis, and/or Aspergillus infection. Arteriography, through catherization of the common femoral artery, demonstrated spontaneous bronchial and systemic neovascularization arising from the thyrocervical trunk, internal thoracic artery, intercostal arteries, and dorsal scapular artery. Embolization was performed with microspheres, polyvinyl alcohol microparticles, and/or glue and effectively terminated hemoptysis. One patient died 10 d later as a result of fungal infection, and the 2 others remained in stable condition (18- and 26-mo postembolization follow-up available).
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http://dx.doi.org/10.1016/j.jvir.2020.07.030DOI Listing
January 2021