Three Decades Single Center Experience of Airway Complications After Lung Transplantation.

Post lung transplantation airway complications like necrosis, stenosis, malacia and dehiscence cause significant morbidity, and are most likely caused by post-operative hypo perfusion of the anastomosis. Treatment can be challenging, and airway stent placement can be necessary in severe cases. Risk factors for development of airway complications vary between studies. In this single center retrospective cohort study, all lung transplant recipients between November 1990 and September 2020 were analyzed and clinically relevant airway complications of the anastomosis or distal airways were identified and scored according to the ISHLT grading system. We studied potential risk factors for development of airway complications and evaluated the impact on survival. The treatment modalities were described. In 651 patients with 1,191 airway anastomoses, 63 patients developed 76 clinically relevant airway complications of the airway anastomoses or distal airways leading to an incidence of 6.4% of all anastomoses, mainly consisting of airway stenosis (67%). Development of airway complications significantly affects median survival in post lung transplant patients compared to patients without airway complication (101 months versus 136 months, p = 0.044). No significant risk factors for development of airway complication could be identified. Previously described risk factors could not be confirmed. Airway stents were required in 55% of the affected patients. Median survival is impaired by airway complications after lung transplantation. In our cohort, no significant risk factors for the development of airway complications could be identified.

Diagnostic performance of FDG-PET/CT of post-transplant lymphoproliferative disorder and factors affecting diagnostic yield.

PURPOSE: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, requiring a timely and accurate diagnosis. In this study, we evaluated the diagnostic performance of FDG-PET/CT in patients with suspected PTLD and examined if lactate dehydrogenase (LDH) levels, Epstein-Barr virus (EBV) load, or timing of FDG-PET/CT relate to detection performance of FDG-PET/CT. METHODS: This retrospective study included 91 consecutive patients with clinical suspicion of PTLD and a total of 97 FDG-PET/CT scans within an 8-year period. Pathology reports and a 2-year follow-up were used as the reference standard. Diagnostic performance of FDG-PET/CT for detection of PTLD as well as logistic regression analysis for factors expected to affect diagnostic yield were assessed. RESULTS: The diagnosis of PTLD was established in 34 patients (35%). Fifty-seven FDG-PET/CT scans (59%) were true negative, 29 (30%) were true positive, 6 (6%) false positive, and 5 (5%) false negative. Sensitivity of FDG-PET/CT for the detection of PTLD was 85%, specificity 90%, positive predictive value 83%, and negative predictive value 92%, with good inter-observer variability (k = 0.78). Of the parameters hypothesized to be associated with a true positive FDG-PET/CT result for the diagnosis of PTLD, only LDH was statistically significant (OR 1.03, p = 0.04). CONCLUSION: FDG-PET/CT has a good diagnostic performance in patients suspected of PTLD, with a good inter-observer agreement. Only LDH levels seemed to influence the detection performance of FDG-PET/CT. EBV-DNA load and timing of FDG-PET/CT after transplantation did not affect FDG-PET/CT diagnostic yield.

Patient-reported health outcomes in long-term lung transplantation survivors: A prospective cohort study.

During the last three decades lung transplantation (LTx) has become a proven modality for increasing both survival and health-related quality of life (HRQoL) in patients with various end-stage lung diseases. Most previous studies have reported improved HRQoL shortly after LTx. With regard to long-term effects on HRQoL, however, the evidence is less solid. This prospective cohort study was started with 828 patients who were on the waiting list for LTx. Then, in a longitudinal follow-up, 370 post-LTx patients were evaluated annually for up to 15 years. For all wait-listed and follow-up patients, the following four HRQoL instruments were administered: State-Trait Anxiety Inventory, Zung Self-rating Depression Scale, Nottingham Health Profile, and a visual analogue scale. Cross-sectional and generalized estimating equation (GEE) analysis for repeated measures were performed to assess changes in HRQoL during follow-up. After LTx, patients showed improvement in all HRQoL domains except pain, which remained steady throughout the long-term follow-up. The level of anxiety and depressive symptoms decreased significantly and remained constant. In conclusion, this study showed that HRQoL improves after LTx and tends to remain relatively constant for the entire life span.

A Multicenter Study on Long-Term Outcomes After Lung Transplantation Comparing Donation After Circulatory Death and Donation After Brain Death.

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool.

Development of a Hyperactive Primary Hemostatic System During Off-Pump Lung Transplantation Resulting From an Unbalance Between von Willebrand Factor and Its Cleaving Protease ADAMTS13.

An unbalance between the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 is a risk factor for thrombosis. Here, we assessed levels and functionality of VWF and ADAMTS13 in patients undergoing off-pump lung transplantation. We analyzed plasma of 10 patients and distinguished lung transplantation-specific effects from those generally accompanying open-chest surgeries by comparing results with 11 patients undergoing off-pump coronary bypass graft (CABG) surgery. Forty healthy volunteers were included for reference values. VWF antigen levels as well as the VWF ristocetin cofactor activity/VWF antigen ratio increased during lung transplantation and after CABG surgery. An increase in VWF propeptide levels was paralleled by a decrease in ADAMTS13 activity. This was more pronounced during lung transplantation. Similarly, the capacity of plasma to support platelet aggregation under shear flow conditions in vitro was more increased during lung transplantation. The proportion of high molecular weight VWF multimers was elevated in both groups without evidence for ultra-large VWF. VWF's collagen binding activity remained unchanged. In conclusion, a hyperactive primary hemostatic system develops during lung transplantation resulting both from a pronounced (functional) increase of the VWF molecule and decrease of ADAMTS13. This may increase the risk of platelet thrombosis within the allograft.

Former smoking is a risk factor for chronic kidney disease after lung transplantation.

Chronic kidney disease (CKD) is a common complication after lung transplantation (LTx). Smoking is a risk factor for many diseases, including CKD. Smoking cessation for >6 months is required for LTx enlistment. However, the impact of smoking history on CKD development after LTx remains unclear. We investigated the effect of former smoking on CKD and mortality after LTx. CKD was based on glomerular filtration rate (GFR) ((125) I-iothalamate measurements). GFR was measured before and repeatedly after LTx. One hundred thirty-four patients never smoked and 192 patients previously smoked for a median of 17.5 pack years. At 5 years after LTx, overall cumulative incidences of CKD-III, CKD-IV and death were 68.5%, 16.3% and 34.6%, respectively. Compared to never smokers, former smokers had a higher risk for CKD-III (hazard ratio [HR] 95% confidence interval [95%CI]= 1.69 [1.27-2.24]) and IV (HR = 1.90 [1.11-3.27]), but not for mortality (HR = 0.99 [0.71-1.38]). Adjustment for potential confounders did not change results. Thus, despite cessation, smoking history remained a risk factor for CKD in LTx recipients. Considering the increasing acceptance for LTx of older recipients with lower baseline renal function and an extensive smoking history, our data suggest that the problem of post-LTx CKD may increase in the future.

Limiting factors of exercise performance 1 year after lung transplantation.

BACKGROUND: After lung transplantation (LTx) exercise capacity frequently remains limited, despite significantly improved pulmonary function. The aim of this study was to evaluate maximal exercise capacity and peripheral muscle force before and 1 year after LTx, and to determine whether peripheral muscle force and lactate threshold (LT) limit exercise capacity 1 year after LTx. METHODS: Twenty-five subjects (mean age 43 years, 8 women and 17 men, 4 single-lung transplantations) were included in the study. Measurements included maximal exercise capacity, lactate threshold (symptom-limited bicycle ergometer test) and muscle force test (hand-held dynamometer) were performed before and 1 year after LTx. RESULTS: Before LTx, all patients showed severe exercise intolerance (mean +/- SD): work capacity (W(peak)), 11.6 +/- 18 W; peak oxygen uptake (Vo(2)), 8.6 +/- 3.6 ml/min/kg. After LTx, exercise capacity improved significantly: W(peak), 69 +/- 27 W (p < 0.001); peak Vo(2), 15.7 +/- 4.3 ml/min/kg (p < 0.001). Ventilatory factors did not appear to limit exercise capacity. Quadriceps muscle force pre- vs post-LTx was: 248 +/- 73 N vs 281 +/- 68 N (p < 0.05). Post-LTx, a significant correlation was found between LT and exercise capacity (r = 0.76, p < 0.001), between muscle force and exercise capacity (r = 0.41, p < 0.05) and between the LT and muscle force (r = 0.53, p < 0.01). CONCLUSIONS: The occurrence of an early and pathologic LT and peripheral muscle weakness contributes to the limitation of exercise capacity and reflects a peripheral deficit post-LTx.

[Improved exercise tolerance can be achieved in chronic obstructive pulmonary disease (COPD) by means of non-pharmacological treatment]. / Betere inspanningstolerantie bij COPD door niet-medicamenteuze behandeling.

A 67-year-old man with severe COPD and a 56-year-old woman with very severe COPD were dyspnoeic during even mild exercise, so that they could no longer take care of themselves properly. The man followed a rehabilitation programme aimed at restoration of his physical condition and self-confidence and optimisation of his nutritional status. The woman was subjected to surgery to reduce her lung volume. Both were subsequently able to live independently. During the past decade, considerable attention has been given to the non-pharmacological treatment of patients with COPD. Together with optimal pharmacotherapy, COPD can be effectively treated by rehabilitation, lung volume reduction surgery and lung transplantation. Clinically relevant improvements can be achieved in both exercise capacity and quality of life. The clinical condition, lung function and radiological findings guide the choice of treatment in each individual.

Cost-effectiveness of lung transplantation in relation to type of end-stage pulmonary disease.

The purpose of this study was to explore the relationship between diagnosis and the cost-effectiveness and cost-utility of lung transplantation. A microsimulation model was used, based on empirical data from the Dutch lung transplantation program, collected between 1991 and 1999. We assessed life-years, quality-adjusted life-years, and costs with and without transplantation for the diagnostic categories alfa-1 antitrypsin deficiency, COPD/emphysema, bronchiectasis, primary and secondary pulmonary hypertension, cystic fibrosis, and pulmonary fibrosis. Alfa-1 antitrypsin deficiency and bronchiectasis had the highest survival gain. Secondary pulmonary hypertension and pulmonary fibrosis had the lowest survival gain and the lowest gain of quality-adjusted life-years. As compared with COPD/emphysema, alfa-1 antitrypsin deficiency, bronchiectasis, and CF had 25%, 40% and 19% more favorable cost-effectiveness ratios, respectively. Cost-utility ratios varied less, with values of -7%, -14% and -11% for alfa-1 antitrypsin deficiency, bronchiectasis, and primary pulmonary hypertension, respectively, compared with COPD. In conclusion, our model suggests that there is considerable variation in cost-effectiveness and, to a lesser degree, in cost-utility between the different diagnostic categories. These variations are the result of differences in survival and in quality of life with and without lung transplantation.

Epoprostenol therapy for primary pulmonary hypertension after rejection of a single donor lung.

Before prostacyclins became available, lung or heart/lung transplantation was the only effective treatment for patients with primary pulmonary hypertension (PPH) who deteriorated under supportive medical treatment. Unfortunately, acute and chronic rejections occur in a large number of cases, limiting the average survival to 4.5 yrs. A female patient, age 35 yrs, was diagnosed with PPH and underwent single lung transplantation. Despite aggressive immunosuppressive therapy, the patient had several episodes of acute rejection. Eventually, chronic rejection with bronchiolitis obliterans developed. After 5 yrs, the donor lung was no longer functional. The patient was in New York Heart Association (NYHA) class 4, had a 6-min walking distance of 50 m and a resting arterial oxygen tension (Pa,O2) of 9.8 kPa (74 mmHg) when using 3 L x min(-1) of oxygen. Epoprostenol treatment was started and the patient showed remarkable improvement. After 17 months the patient was NYHA class 2, walked 503 m in 6 min and had a resting Pa,O2 of 10.9 kPa (82 mmHg) without supplemental oxygen. In this patient, treatment with epoprostenol was effective after rejection of a single donor lung transplanted for primary pulmonary hypertension.

Size matching in lung transplantation using predicted total lung capacity.

Height is used in allocation of donor lungs as an indirect estimate of thoracic size. Total lung capacity (TLC), determined by both height and sex, could be a more accurate functional estimation of thoracic size. Size-matching criteria based on height versus predicted TLC was retrospectively evaluated, and, furthermore, whether a TLC mismatch was related to clinical and functional complications. The ratio of donor and recipient height, as well as the ratio of predicted TLC in donors and recipients, were calculated in 80 patients after bilateral lung transplantation. Complications evaluated included persistent atelectasis, persistent pneumothorax and increased number of days in intensive care, occurrence of bronchiolitis obliterans syndrome and limitation of exercise capacity. Median height donor/recipient ratio was 1.01 (0.93-1.12). Median predicted TLC donor/recipient ratio was 1.01 (with a clearly broader range 0.72-1.41). Neither sex mismatch nor TLC mismatch were related to clinical or functional complications. Allocation of donor lungs based upon height alone leads to a substantial mismatch in total lung capacity caused by sex mismatch. The absence of complications suggests that a greater height donor/recipient discrepancy can be accepted for allocation than previously assumed.

Simulated waiting list prioritization for equitable allocation of donor lungs.

BACKGROUND: In lung transplantation (LTx), allocation of donor lungs is usually based on blood group, height and waiting time. Long waiting times favor patients with a slowly progressive end-stage lung disease and make the current allocation system the subject of discussion. In an attempt to equalize the chances for transplantation for every patient, irrespective of diagnosis, we investigated the effect of diagnosis-dependent prioritization on the waiting list, using a simulation model. METHODS: For the main disease categories on the waiting list, the relative risks of dying while on the waiting list were calculated using empirical data from the Dutch LTx program gathered over a period of 10 years. In a microsimulation model of the Dutch LTx program based on data from the actual situation, patients with diagnoses associated with a statistically significant increased risk of death while on the waiting list were prioritized by multiplying the time on the waiting list by the relative risk. RESULTS: Relative risks of death on the waiting list were increased significantly in patients with cystic fibrosis, primary pulmonary hypertension and pulmonary fibrosis. Prioritization resulted in an increased chance of transplantation for the prioritized diagnoses and a decreased chance for the non-prioritized diagnoses. The distribution of diagnoses after LTx was almost equal to the distribution of diagnoses on the waiting list. CONCLUSION: The simulated method of prioritization on the waiting list is a step forward to a more equitable allocation of donor lungs. Moreover, this method is clinically feasible, as long as the waiting list is updated frequently.

Long-term survival despite early loss of graft function after single lung transplantation for pulmonary fibrosis.

We report a patient who received a single, left lung transplantation for idiopathic pulmonary fibrosis. The effect of the graft on pulmonary improvement was only temporary, because the patient developed obliterative bronchiolitis (OB), resulting in complete destruction of the graft. The patient, however, remains alive 6 years after OB was diagnosed, apparently as a consequence of native lung improvement with triple-immunosuppressive medicine. This case is of interest for several reasons: first, it shows that pulmonary fibrosis may respond to intensive immunosuppressive therapy; second, it demonstrates that ventilation scintigraphy is useful in addition to pulmonary function tests in estimating the actual function of the graft after single lung transplantation; and third, it appears that the gradation of bronchiolitis obliterans syndrome (BOS) after single lung transplantation may overestimate the true function of the transplant.

Extracorporeal membrane oxygenation before induction of anesthesia in critically ill thoracic transplant patients.

Cardiorespiratory failure just before surgery in critically ill thoracic transplant patients can have catastrophic consequences. We judged the cardiorespiratory condition in three of 160 thoracic transplant procedures performed in our center too unstable for a safe induction of anesthesia. In these 3 patients, extracorporeal membrane oxygenation support was installed before induction of anesthesia to maintain an adequate cardiorespiratory state. This strategy was successful for all 3 patients, and long-term survival was achieved with a good quality of life. Guidelines for indications to follow this strategy are discussed.

Expression dynamics of human cytomegalovirus immune evasion genes US3, US6, and US11 in the blood of lung transplant recipients.

Delayed elimination of human cytomegalovirus (HCMV)-infected cells by the host immune system may contribute to viral dissemination and pathogenesis of HCMV infection. The mRNA expression dynamics of HCMV-encoded immune evasion genes US3, US6, and US11 expressed after active HCMV infection were analyzed in blood samples of lung transplant recipients by means of quantitative nucleic acid sequence-based amplification. The results were compared with the expression dynamics of IE1 mRNA and pp67 late mRNA, levels of pp65 antigenemia, and antiviral treatment. During acute infection, high levels of US3 and US6 RNA were detected before antigenemia, which were detected simultaneously with IE1 RNA. US11 RNA was detected simultaneously with antigenemia but before late pp67 RNA. These data suggest an active role of viral immune evasion during HCMV infection in vivo. Interestingly, immune evasion RNA remained detectable after clinical recovery, often independently of IE1 RNA expression, indicating persistent viral activity, which may have implications for long-term control of HCMV.

Management of cytomegalovirus infection and disease after solid-organ transplantation.

Cytomegalovirus (CMV) continues to be a cause of substantial morbidity and death after solid-organ transplantation. There are 3 major consequences of CMV infection: CMV disease, including a wide range of clinical illnesses; superinfection with opportunistic pathogens; and injury to the transplanted organ, possibly enhancing chronic rejection. This article discusses the considerable progress that has been made in elucidating risk factors for CMV disease, in the rapid detection of CMV in clinical specimens, and in the use of antiviral chemotherapy and immunoglobulin to prevent and treat CMV disease after solid-organ transplantation.