Once in a blue moon: Primaquine-induced methemoglobinemia - A case report.

Methemoglobinemia is a rare blood disorder that should be suspected in patients with cyanosis and low oxygen saturation of around 85%, especially when both do not improve despite supplemental oxygen. We describe the case of a 67-year-old lung transplant patient who was treated with primaquine and clindamycin because of a positive Pneumocystis jirovecii polymerase chain reaction on bronchoalveolar lavage fluid. Soon thereafter the patient developed increasing shortness of breath, central cyanosis and hypoxia, with an oxygen saturation of 86% on pulse oximetry despite supplemental oxygen. Arterial blood gas analysis showed a peculiar dark brown color and a significantly increased methemoglobin percentage. A diagnosis of methemoglobinemia due to primaquine was made. As treatment option, we preferred ascorbic acid over methylene blue because of concerns of possibly eliciting a serotonin syndrome. Our patient recovered rapidly after initiation of appropriate treatment. A high index of suspicion is crucial since this condition is potentially fatal.

Real life experience with mTOR-inhibitors after lung transplantation.

Mammalian target of rapamycin inhibitors (mTORi) are increasingly used after lung transplantation as part of a calcineurin inhibitor sparing regimen, aiming to preserve renal function. The aim of our study was to determine whether immunosuppressive therapy using mTORi in lung transplant recipients (LTR) is feasible in practice, or limited by intolerance and adverse events. Data were retrospectively assessed for all LTR transplanted between July 1991 and January 2020. Patients ever receiving mTORi (monotherapy or in combination with calcineurin inhibitor) as treatment of physicians' choice were included. 149/1184 (13%) of the LTR ever received mTORi. Main reasons to start were renal insufficiency (67%) and malignancy (21%). In 52% of the patients, mTORi was stopped due to side effects or drug toxicity after a median time of 159 days. Apart from death, main reasons for discontinuation were infection (19%) and edema (14%). Early discontinuation (<90 days) was mainly due to edema or gastrointestinal intolerance. As mTORi was stopped due to adverse events or drug intolerance in 52% of LTR, cautious consideration of advantages and disadvantages when starting mTORi is recommended.

Endoscopic advanced imaging of the respiratory tract: exploring probe-based confocal laser endomicroscopy in emphysema.

: Probe-based confocal laser endomicroscopy (pCLE) was performed in 15 patients with emphysema and 15 healthy subjects to visualise small airways in a direct and dynamic way. Morphometry shows that the median cross-sectional area of the alveolar openings at the level of the alveolar ducts is significantly larger in emphysema (7.2×104 µm2) as compared with healthy subjects (5.2×104 µm2) (p=0.0002). Normalised autofluorescence intensity histograms show a decrease in median autofluorescence intensity (mAFI) in emphysema (p=0.001). mAFI correlates well with Tiffeneau index (r=0.66, p=0.007, 95% CI 0.21 to 0.88). Autofluorescence intensity in emphysema correlates with corresponding data of CT-based quantification. pCLE-based morphometry and autofluorescence intensity analysis in emphysema is able to detect regional changes inside the 'quiet zone'. TRIAL REGISTRATION NUMBER: Results, NCT01204970.

"White-Out" After Lung Transplantation: A Multicenter Cohort Description of Late Acute Graft Failure.

Graft failure represents a leading cause of mortality after organ transplantation. Acute late-onset graft failure has not been widely reported. The authors describe the demographics, CT imaging-pathology findings, and treatment of patients presenting with the latter. A retrospective review was performed of lung transplant recipients at two large-volume centers. Acute late-onset graft failure was defined as sudden onset of bilateral infiltrates with an oxygenation index <200 without identifiable cause or concurrent extrapulmonary organ failure. Laboratory, bronchoalveolar lavage (BAL), radiology, and histology results were assessed. Between 2005 and 2016, 21 patients were identified. Median survival was 19 (IQR 13-36) days post onset. Twelve patients (57%) required intensive care support at onset, 12 (57%) required mechanical ventilation, and 6 (29%) were placed on extracorporeal life support. Blood and BAL analysis revealed elevated neutrophilia, with CT demonstrating diffuse ground-glass opacities. Transbronchial biopsy samples revealed acute fibrinoid organizing pneumonia (AFOP), organizing pneumonia, and diffuse alveolar damage (DAD). Assessment of explanted lungs confirmed AFOP and DAD but also identified obliterative bronchiolitis. Patients surviving to discharge without redo transplantation (n = 2) subsequently developed restrictive allograft syndrome. This study describes acute late-onset graft failure in lung allograft recipients, without known cause, which is associated with a dismal prognosis.

Radiological Analysis of Unused Donor Lungs: A Tool to Improve Donor Acceptance for Transplantation?

Despite donor organ shortage, a large proportion of possible donor lungs are declined for transplantation. Criteria for accepting/declining lungs remain controversial because of the lack of adequate tools to aid in decision-making. We collected, air-inflated, and froze a large series of declined/unused donor lungs and subjected these lung specimens to CT examination. Affected target regions were scanned by using micro-CT. Lungs from 28 donors were collected. Two lungs were unused, six were declined for non-allograft-related reasons (collectively denominated nonallograft declines, n = 8), and 20 were declined because of allograft-related reasons. CT scanning demonstrated normal lung parenchyma in only four of eight nonallograft declines, while relatively normal parenchyma was found in 12 of 20 allograft-related declines. CT and micro-CT examinations confirmed the reason for decline in most lungs and revealed unexpected (unknown from clinical files or physical inspection) CT abnormalities in other lungs. CT-based measurements showed a higher mass and density in the lungs with CT alterations compared with lungs without CT abnormalities. CT could aid in the decision-making to accept or decline donor lungs which could lead to an increase in the quantity and quality of lung allografts.

The role of recipient derived interleukin-17A in a murine orthotopic lung transplant model of restrictive chronic lung allograft dysfunction.

The single most important cause of late mortality after lung transplantation is chronic lung allograft dysfunction (CLAD). However, the pathological development of CLAD was not as simple as previously presumed and subclassification phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD), have been introduced. We want to re-investigate how CLAD manifests in the murine orthotopic lung transplant model and investigate the role of interleukin 17A (IL-17A) within this model. Orthotopic LTx was performed in CB57BL/6, IL-17 WT and IL-17 KO mice. In a first experiment, CB57BL/6 mice receiving an isograft (CB57BL/6) or allograft (BALB/C) were compared. In a second experiment IL-17 WT and IL-17 KO mice (both CB57BL/6 background) received an allograft (BALB/C). Mice received daily immunosuppression with steroids and cyclosporine and were sacrificed 10weeks after transplantation for histopathological analysis by an experienced lung pathologist. After murine orthotopic lung transplantation, the allograft histopathologically presented features of human rCLAD (i.e. overt inflammation, pleural/parenchymal fibrosis and obliterative bronchiolitis). In the IL-17A KO group, less inflammation in the bronchovascular axis (p=0.03) was observed and a non-significant trend towards less bronchovascular fibrosis, pleural/septal inflammation and fibrosis, and parenchymal inflammation and fibrosis when compared to WT mice. The major mismatch orthotopic lung transplant model resembles features of human rCLAD. IL-17A mediated immunity is involved in the inflammatory component, but had little influence on the degree of fibrosis. Further mechanistic and therapeutic studies in this mouse model are needed to fully understand the mechanisms in rCLAD.

Parametric Response Mapping of Bronchiolitis Obliterans Syndrome Progression After Lung Transplantation.

Bronchiolitis obliterans syndrome (BOS) remains a major complication after lung transplantation. Air trapping and mosaic attenuation are typical radiological features of BOS; however, quantitative evaluation remains troublesome. We evaluated parametric response mapping (PRM, voxel-to-voxel comparison of inspiratory and expiratory computed tomography [CT] scans) in lung transplant recipients diagnosed with BOS (n = 20) and time-matched stable lung transplant recipients (n = 20). Serial PRM measurements were performed prediagnosis, at time of BOS diagnosis, and postdiagnosis (Tpre , T0 , and Tpost , respectively), or at a postoperatively matched time in stable patients. PRM results were correlated with pulmonary function and confirmed by microCT analysis of end-stage explanted lung tissue. Using PRM, we observed an increase in functional small airway disease (fSAD), from Tpre to T0 (p = 0.006) and a concurrent decrease in healthy parenchyma (p = 0.02) in the BOS group. This change in PRM continued to Tpost , which was significantly different compared to the stable patients (p = 0.0002). At BOS diagnosis, the increase in fSAD was strongly associated with a decrease in forced expiratory volume in 1 s (p = 0.011). Micro-CT confirmed the presence of airway obliteration in a sample of a BOS patient identified with 67% fSAD by PRM. We demonstrated the use of PRM as an adequate output to monitor BOS progression in lung transplant recipients.

Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial.

Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re-evaluated the long-term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention-to-treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD-free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long-term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long-term CLAD prevalence and improves CLAD-free survival, pulmonary function, and functional exercise capacity after LTx.