Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant - a historical prospective study.

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2 /FiO2  ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized.

Ten-Year Survival in Patients with Idiopathic Pulmonary Fibrosis After Lung Transplantation.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal fibrosing lung disease with a median survival of approximately 3 years after diagnosis. The only medical option to improve survival in IPF is lung transplantation (LTX). The purpose of this study was to evaluate trajectory data of IPF patients listed for LTX and to investigate the survival after LTX. METHODS AND RESULTS: Data were retrospectively collected from September 1989 until July 2011 of all IPF patients registered for LTX in the Netherlands. Patients were included after revision of the diagnosis based on the criteria set by the ATS/ERS/JRS/ALAT. Trajectory data, clinical data at time of screening, and donor data were collected. In total, 98 IPF patients were listed for LTX. During the waiting list period, 30 % of the patients died. Mean pulmonary artery pressure, 6-min walking distance, and the use of supplemental oxygen were significant predictors of mortality on the waiting list. Fifty-two patients received LTX with a median overall survival after transplantation of 10 years. CONCLUSIONS: This study demonstrated a 10-year survival time after LTX in IPF. Furthermore, our study demonstrated a significantly better survival after bilateral LTX in IPF compared to single LTX although bilateral LTX patients were significantly younger.

The effect of COVID-19 on transplant function and development of CLAD in lung transplant patients: A multicenter experience.

BACKGROUND: Concerns have been raised on the impact of coronavirus disease (COVID-19) on lung transplant (LTx) patients. The aim of this study was to evaluate the transplant function pre- and post-COVID-19 in LTx patients. METHODS: Data were retrospectively collected from LTx patients with confirmed COVID-19 from all 3 Dutch transplant centers, between February 2020 and September 2021. Spirometry results were collected pre-COVID-19, 3- and 6-months post infection. RESULTS: Seventy-four LTx patients were included. Forty-two (57%) patients were admitted, 19 (26%) to the intensive care unit (ICU). The in-hospital mortality was 20%. Twelve out of 19 ICU patients died (63%), a further 3 died on general wards. Patients with available spirometry (78% at 3 months, 65% at 6 months) showed a significant decline in mean forced expiratory volume in 1 second (FEV1) (ΔFEV1 138 ± 39 ml, p = 0.001), and forced vital capacity (FVC) (ΔFVC 233 ±74 ml, p = 0.000) 3 months post infection. Lung function improved slightly from 3 to 6 months after COVID-19 (ΔFEV1 24 ± 38 ml; ΔFVC 100 ± 46 ml), but remained significantly lower than pre-COVID-19 values (ΔFEV1 86 ml ± 36 ml, p = 0.021; ΔFVC 117 ± 35 ml, p = 0.012). FEV1/FVC was > 0.70. CONCLUSIONS: In LTx patients COVID-19 results in high mortality in hospitalized patients. Lung function declined 3 months after infection and gradually improved at 6 months, but remained significantly lower compared to pre-COVID-19 values. The more significant decline in FVC than in FEV1 and FEV1/FVC > 70%, suggested a more restrictive pattern.

Vaccination and their importance for lung transplant recipients in a COVID-19 world.

INTRODUCTION: Lung transplant patients are immunocompromised because of the medication they receive to prevent rejection, and as a consequence are susceptible to (respiratory) infections. Adequate vaccination strategies, including COVID-19 vaccination, are therefore needed to minimize infection risks. AREAS COVERED: The international vaccination guidelines for lung transplant patients are reviewed, including the data on immunogenicity and effectivity of the vaccines. The impact on response to vaccination of the various categories of immunosuppressive drugs, used in the posttransplant period, on response to vaccination is described. A number of immunosuppressive and/or anti-inflammatory drugs also is used for controlling the immunopathology of severe COVID-19. Current available COVID-19 vaccines, both mRNA or adenovirus based are recommended for lung transplant patients. EXPERT OPINION: In order to improve survival and quality of life, infections of lung transplant patients should be prevented by vaccination. When possible, vaccination should start already during the pre-transplantation period when the patient is on the waiting list. Booster vaccinations should be given post-transplantation, but only when immunosuppression has been tapered. Vaccine design based on mRNA technology could allow the design of an array of vaccines against other respiratory viruses, offering a better protection for lung transplant patients.

Waiting List Dynamics and Lung Transplantation Outcomes After Introduction of the Lung Allocation Score in The Netherlands.

The Netherlands was the third country to adopt the lung allocation score (LAS) for national allocation of donor lungs in April 2014. Evaluations of the introduction of the LAS in the United States and Germany showed mainly beneficial effects, including increased survival after transplantation. METHODS: Data for transplant candidates from 2010 to 2019 were retrieved from the Dutch Transplant Foundation database. Diagnosis categories and outcomes were compared between the periods before and after the introduction of the LAS. Time-dependent Cox regression and Fine-Gray analyses were performed to compare the chance for transplantation before and after introduction of the LAS. RESULTS: The cohort comprised 1276 patients. After introduction of the LAS, the annual number of transplantations and waiting list mortality did not change. The proportion of patients on the waiting list and transplanted patients with pulmonary fibrosis increased (25%-37%, P < 0.001; 22%-39%, P < 0.001). The chance of transplantation increased significantly for patients with pulmonary fibrosis after introduction of the LAS (hazard ratio 1.9 [95% confidence interval 1.4-2.9]). Patients who died on the waiting list had an increased LAS compared to the time of placement on the waiting list, reflecting clinical deterioration. This was not the case in patients with chronic obstructive pulmonary disease (P < 0.001). Overall survival was similar after introduction of the LAS (5-y survival 68%, compared to 74% [P = 0.171]). CONCLUSIONS: After the introduction of the LAS in The Netherlands, an increased proportion of transplantations was performed for patients with pulmonary fibrosis. Overall survival after transplantation did not change.

Pneumococcal Conjugate Vaccination Followed by Pneumococcal Polysaccharide Vaccination in Lung Transplant Candidates and Recipients.

BACKGROUND: Pneumococcal conjugate vaccination as well as pneumococcal polysaccharide vaccination are recommended for lung transplant candidates and recipients, but the combination of these vaccines has not been extensively studied in these specific populations. METHODS: Lung transplant candidates and recipients were vaccinated with a 13-valent pneumococcal conjugate vaccine, followed 8 weeks later by a pneumococcal polysaccharide vaccine. Pneumococcal antibody levels against 13 pneumococcal serotypes were measured and followed up after 1 year in the transplant recipients. These values were compared with a historical control group vaccinated with the polysaccharide vaccine alone. RESULTS: Twenty-five lung transplant candidates and 23 lung transplant recipients were included. For the majority of serotypes, there was no significant increase in antibody levels after additional vaccination with the polysaccharide vaccine in both patient groups. When compared with the historical control group, the antibody response in lung transplant recipients 1 year after vaccination did not seem to have improved by vaccination with both vaccines instead of the polysaccharide vaccine alone. CONCLUSIONS: Serologic vaccination responses in lung transplant candidates and recipients were not improved by giving a 23-valent pneumococcal polysaccharide vaccine after a 13-valent pneumococcal conjugate vaccine. The benefit of this vaccination schedule in lung transplant recipients seems to differ from other immunocompromised populations. The optimal vaccination schedule for lung transplant candidates and recipients remains to be determined.

Lung Transplant Patients Show a Dissimilar Peripheral B-Cell Subset Ratio Compared With Healthy Controls.

OBJECTIVES: Lung transplant is a last treatment option for patients with end-stage pulmonary disease. Chronic lung allograft dysfunction, which generally manifests as bronchiolitis obliterans syndrome, is a major long-term survival limitation. Bronchiolitis obliterans syndrome is diagnosed when forced expiratory volume in 1 second declines > 20% in the absence of known causes. B cells can either contribute or restrain the development of bronchiolitis obliterans syndrome (eg, via induction of alloimmune antibodies, regulation of cellular immunity, and induction of tolerance). Here, we explored how peripheral B-cell subsets were altered in lung transplant recipients with bronchiolitis obliterans syndrome. MATERIALS AND METHODS: Fresh whole blood samples were analyzed from 42 lung transplant recipients, including 17 with bronchiolitis obliterans syndrome; samples from these groups were compared with 10 age-matched healthy control samples. B-cell subsets were analyzed using flow cytometry, and relative distributions of subsets were compared. Changes in forced expiratory volume in 1 second were also determined. RESULTS: Absolute B-cell count was significantly increased in transplant recipients with bronchiolitis obliterans syndrome. Transitional (CD24+CD38+) and naïve (CD27-IgD+) B cells were decreased in lung transplant patients, with transitional B cells almost absent in those with bronchiolitis obliterans syndrome. Double-negative (CD27-IgD-) memory B cells were significantly increased (P < .001). No differences were found for plasmablasts (CD38+CD24-) and switched (CD27+IgD-) and non-switched (CD27+IgD+) memory B cells. Correlation analyses showed positive correlations between lung function and naïve B cells in transplant recipients (P = .0245; r = -0.458). CONCLUSIONS: Peripheral B-cell count and subset distribution were altered in lung transplant recipients with and without bronchiolitis obliterans syndrome compared with healthy controls. Transitional and naïve B-cell decreases may be caused by differentiation toward double-negative B-cells, which were increased. The correlation between forced expiratory volume and naïve B cells during follow-up care may be clinically interesting to investigate.

An unusual presentation of a patient with severe hypogammaglobulinemia.

We present a patient who was diagnosed with severe hypogammaglobulinemia after her newborn child presented with two episodes of meningitis. The patient had no history or symptoms suggestive of immunodeficiency. Thus far, a cause for the immunodeficiency has not been found, even after extensive immunological evaluation.

Case report on a defective antibody response against pneumococcal serotype 9V in a patient with a single episode of pneumonia.

BACKGROUND: Patients with recurrent respiratory tract infections and an impaired response to pneumococcal polysaccharide vaccination are diagnosed with a specific antibody deficiency. In adult patients with pneumococcal pneumonia an impaired antibody response to the infecting pneumococcal serotype can sometimes be found. It is unknown whether these patients are unable to produce an adequate anti-polysaccharide antibody response to pneumococcal vaccination after recovery. CASE PRESENTATION: The authors describe a case of invasive pneumonia caused by Streptococcus pneumoniae serotype 9V in a previously healthy 35-year-old female. This patient did not produce serotype-specific antibodies against the infecting serotype during disease. After pneumococcal polysaccharide vaccination 3 months after recovery, she responded adequately to most other pneumococcal serotypes, but still had no response to the infecting serotype 9V. However, after 9 years (and prior to pneumococcal-conjugate vaccination) normal antibody levels against 9V were found. These antibody levels further increased after pneumococcal-conjugate vaccination. CONCLUSION: The authors believe that this case is the first description of a temporary deficient response to the infecting pneumococcal serotype in adults, while other reports with similar observations all involved children.

Immune status assessment in adult lung transplant candidates.

BACKGROUND: Lung transplant recipients have an increased susceptibility to a variety of infections due to immunosuppressive therapy. Current guidelines recommend pneumococcal and other vaccinations, prior to lung transplantation to protect against post-transplant infections, but measurement of the antibody response to vaccination is not advised. Immune status investigation in lung transplant candidates, including the response to pneumococcal polysaccharide vaccination, has not been described. METHODS: Immune status investigation, including measurement of immunoglobulins, complement and the response to 23-valent pneumococcal polysaccharide vaccination (23vPPV) was performed in 81 adult lung transplant candidates. RESULTS: Eighteen patients had low IgG levels and 32 patients had low IgG1 and/or IgG2 levels. After vaccination with 23vPPV the median antibody concentration of all serotypes increased significantly. Fifty-two patients had protective IgG-post-vaccination antibody levels to at least 10 serotypes. Twenty-nine patients had an impaired response to 23vPPV. CONCLUSIONS: In conclusion, a significant proportion of our cohort of lung transplant candidates had one or more abnormalities in the immune status. It is likely that these patients have an increased risk for infections after transplantation. Revaccination, including measurement of antibody response, and possibly antibody replacement therapy should be considered to minimize infection risk.

Long-term Clinical Outcome of Antibody Replacement Therapy in Humoral Immunodeficient Adults With Respiratory Tract Infections.

In severe humoral immunodeficiency the indication for antibody replacement therapy (ART) is clear, and supported by several large studies. However, for milder forms of humoral immunodeficiency, the indication for ART is less clear. This is a retrospective cohort study of 87 adults with recurrent respiratory tract infections who received ART. The patients had severe or mild humoral immunodeficiency, and were followed up for a median of 62months. Infection frequency, pharmacy-registered antibiotics use and hospital admissions significantly decreased under ART compared to the year prior to starting ART (median 5.50 (anamnestically)-0.82 (physician-confirmed) infections/year, p<0.001; median 4.00-2.05antibioticscourses/year, p<0.001; mean 0.75-0.44hospitaladmissions/year, p=0.009). These beneficial effects of ART were seen in both severe and mild immunodeficiency. Bronchiectasis was present in 27 patients when ART was started, but was not associated with clinical outcomes. An increase in hospital admissions under ART, observed in some patients, was significantly associated with pulmonary emphysema and current smoking. In conclusion, this study shows that ART is a long-term effective therapy in adults with recurrent respiratory tract infections with severe as well as with milder forms of humoral immunodeficiency.

Long-term Follow-up of Humoral Immune Status in Adult Lung Transplant Recipients.

BACKGROUND: Lung transplant recipients have an increased risk for infections in the posttransplant period due to immunosuppressive therapy. Protection against infections can be achieved through vaccination, but the optimal vaccination schedule in lung transplant recipients is unknown. Data on long-term immunological follow up and vaccination responses after lung transplantation are scarce. METHODS: Here we present long-term immunological follow up of a cohort of 55 lung transplant recipients. This includes detailed antibody responses after 23-valent pneumococcal polysaccharide vaccination (23vPPV). RESULTS: All patients were vaccinated with 23vPPV before transplantation. Median follow-up after transplantation was 6.6 years (379 patient-years). After transplantation, there is a significant decrease of all immunoglobulins, IgG subclasses and pneumococcal polysaccharide antibodies. After the first year posttransplantation, there is a gradual increase of all immunoglobulins and IgG subclasses, but values were always significantly lower than in the pretransplant period. After a median of 4.4 years posttransplantation, patients were revaccinated with 23vPPV. The pneumococcal polysaccharide antibody response was impaired in 87% of patients (ie, antibody titer above cutoff and twofold increase between pre and postvaccination values for <70% of serotypes). CONCLUSIONS: We found that impairment of humoral immunity was most outspoken in the first year after lung transplantation. Immunoglobulin levels remain decreased several years after transplantation and the response to pneumococcal polysaccharide vaccine was significantly lower posttransplantation compared to the pretransplantation response. However, most patients did show a partial response to vaccination. Based on our results, revaccination with pneumococcal vaccines after transplantation should be considered 1 year after transplantation.

Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction After Lung Transplantation.

CD59 is a complement regulatory protein that inhibits membrane attack complex formation. A soluble form of CD59 (sCD59) is present in various body fluids and is associated with cellular damage after acute myocardial infarction. Lung transplantation (LTx) is the final treatment for end-stage lung diseases, however overall survival is hampered by chronic lung allograft dysfunction development, which presents itself obstructively as the bronchiolitis obliterans syndrome (BOS). We hypothesized that, due to cellular damage and activation during chronic inflammation, sCD59 serum levels can be used as biomarker preceding BOS development. We analyzed sCD59 serum concentrations in 90 LTx patients, of whom 20 developed BOS. We observed that BOS patients exhibited higher sCD59 serum concentrations at the time of diagnosis compared to clinically matched non-BOS patients (p = 0.018). Furthermore, sCD59 titers were elevated at 6 months post-LTx (p = 0.0020), when patients had no BOS-related symptoms. Survival-analysis showed that LTx patients with sCD59 titers ≥400 pg/ml 6 months post-LTx have a significant (p < 0.0001) lower chance of BOS-free survival than patients with titers ≤400 pg/ml, 32% vs. 80% respectively, which was confirmed by multivariate analysis (hazard ratio 6.2, p < 0.0001). We propose that circulating sCD59 levels constitute a novel biomarker to identify patients at risk for BOS following LTx.

Profiling of peripheral blood mononuclear cells does not accurately predict the bronchiolitis obliterans syndrome after lung transplantation.

After lung transplantation (LTx), circulating mononuclear cell composition and their subsets may be predictive for the bronchiolitis obliterans syndrome (BOS). We investigated the cellular composition in patients developing BOS, or not, by analyzing peripheral blood taken at multiple time points after transplantation. PBMCs of 11 BOS and 39 non-BOS patients were analyzed by FACS for monocytes, dendritic cells, NK-, NKT-, B- and T cells as well as B- and T cell subsets. Analysis of blood samples taken monthly during the first year post-LTx showed that circulating NK, NKT and dendritic cell percentages were not indicative of BOS development, whereas increases in T cells, monocytes and lowered fractions of B cells were related to BOS development. B- and T cell subset analysis at month 5 post-LTx indicated that IgM+IgD- memory B cells and central memory CD8+ T cells were decreased, whereas NKT cells were increased in BOS patients compared to non-BOS patients. Prior to BOS diagnosis, the composition of specific mononuclear cells on a group level differs from patients remaining BOS free. However, given the overlap in percentages of cellular frequencies between the patient groups investigated, this analysis does not allow prediction or risk stratification for development of BOS in individual patients.

Antibody replacement therapy in primary antibody deficiencies and iatrogenic hypogammaglobulinemia.

Antibody replacement therapy has been used in the treatment of primary antibody deficiencies (PADs) for several decades, and an evidence-based guideline for its treatment is currently available. By contrast, the use of antibody replacement therapy in iatrogenic hypogammaglobulinemia (IHG), a condition that is associated with immunosuppressive medication, has hardly any evidence base and no guidelines. As IHG can be equally as severe as PAD and is much more prevalent, evidence-based guidelines are urgently needed. This review will focus on the differences and similarities between PAD and IHG and the use of antibody replacement therapy in both conditions. Suggestions for the development of evidence-based guidelines and future research are given.

Crossed wiring closure technique for bilateral transverse thoracosternotomy is associated with less sternal dehiscence after bilateral sequential lung transplantation.

OBJECTIVE: Bilateral transverse thoracosternotomy (clamshell incision) is a widely used approach in bilateral sequential lung transplantation, but the closure technique is associated with sternal dehiscence. This study compares the incidence of sternal dehiscence between the crossed and uncrossed closure techniques. METHODS: In 129 patients who underwent transplantation through a clamshell incision, the sternum was closed using either the crossed or the uncrossed method based on the surgeon's preference. The position of the sternal parts was evaluated on lateral chest radiographs and scored as normal, override, or separation. RESULTS: We observed sternal override in 38 patients and separations in 18 patients. The sternum was closed using the uncrossed method in 79 patients and the crossed method in 50 patients. There were significantly fewer overrides (n = 6, 12.0%) and separations (n = 6, 12.0%) of the sternal parts using the crossed closure technique compared with the uncrossed technique (32 overrides, 41.0%; and 12 separations, 15.1%; P < .001). Reconstructive surgery was only performed in patients with separation of the sternal parts (n = 10). CONCLUSIONS: Using the crossed closure technique for the sternum after bilateral sequential lung transplantation reduces the incidence of sternal dehiscence compared with the uncrossed closure technique and, therefore, reduces the necessity of reconstructive surgery.

[High mortality in patients with idiopathic pulmonary fibrosis on Dutch lung transplant waiting list]. / Hoge sterfte van patiënten met idiopathische pulmonale fibrose op Nederlandse longtransplantatiewachtlijst.

OBJECTIVE: To describe patients diagnosed with idiopathic pulmonary fibrosis (IPF) registered for lung transplantation and to evaluate the current referral guidelines for lung transplantation in the Netherlands. DESIGN: Retrospective study. METHOD: All patients diagnosed with interstitial lung disease and registered for lung transplantation from September 1989-June 2010 were included in this study. Patients who had been diagnosed with IPF according to the American Thoracic Society-European Respiratory Society criteria were included. Clinical data of these patients at the time of screening for lung transplantation and survival data were collected. RESULTS: In total, 289 patients with IPF were registered for lung transplantation. After a first waiting list. During the waiting period, 30 patients (33%) died, 7 were taken off the list due to newly developed comorbidity and excessive physical deterioration, 51 underwent transplantation and 2 were still on the waiting list at the time of study closure. At the time of screening, the mean FVC% predicted of these patients was 51% (SD: 19.0) and the mean diffusing capacity was 27% of predicted (SD: 9.3). CONCLUSION: One-third of the IPF patients on the waiting list died before donor lungs became available. The mean diffusing capacity of 27% of predicted at the time of screening was considerably lower than advised in the international guidelines for placement on the waiting list. This study, therefore, shows that the timing of screening IPF patients for lung transplantation can be improved in the Netherlands.

Pulmonary embolism and pulmonary infarction after lung transplantation.

Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a common occurrence in patients undergoing surgery and is a potentially fatal complication. Especially after lung transplantation, vascular complications can compromise the function of the allograft and limit survival. Typically, the risk of pulmonary infarction after PE in lung transplant recipients is high because the absence or poor development of the collateral bronchial circulation may predispose lung transplant recipients to pulmonary infarction. This article reports 2 cases of PE with associated pulmonary infarction after lung transplantation with significant morbidity.