Mucins MUC5AC and MUC5B Are Variably Packaged in the Same and in Separate Secretory Granules.

Rationale: MUC5AC (mucin 5AC, oligomeric gel-forming) and MUC5B (mucin 5B, oligomeric gel-forming) are the predominant secreted polymeric mucins in mammalian airways. They contribute differently to the pathogenesis of various muco-obstructive and interstitial lung diseases, and their genes are separately regulated, but whether they are packaged together or in separate secretory granules is not known. Objectives: To determine the packaging of MUC5AC and MUC5B within individual secretory granules in mouse and human airways under varying conditions of inflammation and along the proximal-distal axis. Methods: Lung tissue was obtained from mice stimulated to upregulate mucin production by the cytokines IL-1ß and IL-13 or by porcine pancreatic elastase. Human lung tissue was obtained from donated normal lungs, biopsy samples of transplanted lungs, and explanted lungs from subjects with chronic obstructive pulmonary disease. MUC5AC and MUC5B were labeled with antibodies from different animal species or, in mice only, by transgenic chimeric mucin-fluorescent proteins and imaged using widefield deconvolution or Airyscan fluorescence microscopy. Measurements and Main Results: In both mouse and human airways, most secretory granules contained both mucins interdigitating within the granules. Smaller numbers of granules contained MUC5B alone, and even fewer contained MUC5AC alone. Conclusions: MUC5AC and MUC5B are variably stored both in the same and in separate secretory granules of both mice and humans. The high fraction of granules containing both mucins under a variety of conditions makes it unlikely that their secretion can be differentially controlled as a therapeutic strategy. This work also advances knowledge of the packaging of mucins within secretory granules to understand mechanisms of epithelial stress in the pathogenesis of chronic lung diseases.

Involvement of IL-26 in bronchiolitis obliterans syndrome but not in acute rejection after lung transplantation.

BACKGROUND:  The main long-term complication after lung transplantation is bronchiolitis obliterans syndrome (BOS), a deadly condition in which neutrophils may play a critical pathophysiological role. Recent studies show that the cytokine interleukin IL-26 can facilitate neutrophil recruitment in response to pro-inflammatory stimuli in the airways. In this pilot study, we characterized the local involvement of IL-26 during BOS and acute rejection (AR) in human patients. METHOD:  From a biobank containing bronchoalveolar lavage (BAL) samples from 148 lung transplant recipients (LTR), clinically-matched patient pairs were identified to minimize the influence of clinical confounders. We identified ten pairs (BOS/non-BOS) with BAL samples harvested on three occasions for our longitudinal investigation and 12 pairs of patients with and without AR. The pairs were matched for age, gender, preoperative diagnosis, type of and time after surgery. Extracellular IL-26 protein was quantified in cell-free BAL samples using an enzyme-linked immunosorbent assay. Intracellular IL-26 protein in BAL cells was determined using immunocytochemistry (ICC) and flow cytometry. RESULTS:  The median extracellular concentration of IL-26 protein was markedly increased in BAL samples from patients with BOS (p < 0.0001) but not in samples from patients with AR. Intracellular IL-26 protein was confirmed in alveolar macrophages and lymphocytes (through ICC and flow cytometry) among BAL cells obtained from BOS patients. CONCLUSIONS:  Local IL-26 seems to be involved in BOS but not AR, and macrophages as well as lymphocytes constitute cellular sources in this clinical setting. The enhancement of extracellular IL-26 protein in LTRs with BOS warrants further investigation of its potential as a target for diagnosing, monitoring, and treating BOS.

COVID-19 and kidney transplantation: the impact of remdesivir on renal function and outcome - a retrospective cohort study.

OBJECTIVES: The aim of the study was to evaluate the impact of remdesivir on overall mortality, ICU mortality, and renal functional outcome in hospitalized patients with COVID-19 who received kidney transplant. METHODS: We reviewed 165 patients with KTx hospitalized owing to COVID-19 between March 1, 2020, and May 31, 2021. A total of 38 patients with KTx received a 5-day RDV treatment, whereas 127 received standard of care (SOC). Overall and ICU mortality along with functional outcome were assessed. RESULTS: The 2 groups had similar baseline characteristics. RDV treatment was completed in all patients without any adverse effects attributable to RDV. In terms of overall mortality, there was no difference between the RDV and SOC groups (18% vs 23%, p >0.05), but the ICU mortality was significantly reduced in the RDV group (39% vs 83%, p <0.05). RDV seems to have no nephrotoxic effect on patients with KTx because there was no difference in the incidence of AKI between RDV and SOC groups (50% vs 43%, p >0.05), and the discharge eGFR values significantly improved in the RDV group compared with the admission values (57 ± 23 vs 44 ± 22, p <0.05). CONCLUSION: Five-day RDV treatment appears safe in KTx recipients, and without obvious nephrotoxic effects. Also, RDV may decrease ICU mortality attributed to COVID-19.

Inspiratory and end-expiratory effects of lung recruitment in the prone position on dorsal lung aeration - new physiological insights in a secondary analysis of a randomised controlled study in post-cardiac surgery patients.

Background: Cardiac surgery produces dorso-basal atelectasis and ventilation/perfusion mismatch, associated with infection and prolonged intensive care. A postoperative lung volume recruitment manoeuvre to decrease the degree of atelectasis is routine. In patients with severe respiratory failure, prone positioning and recruitment manoeuvres may increase survival, oxygenation, or both. We compared the effects of lung recruitment in prone vs supine positions on dorsal inspiratory and end-expiratory lung aeration. Methods: In a prospective RCT, 30 post-cardiac surgery patients were randomly allocated to recruitment manoeuvres in the prone (n=15) or supine position (n=15). The primary endpoints were late dorsal inspiratory volume (arbitrary units [a.u.]) and left/right dorsal end-expiratory lung volume change (a.u.), prone vs supine after extubation, measured using electrical impedance tomography. Secondary outcomes included left/right dorsal inspiratory volumes (a.u.) and left/right dorsal end-expiratory lung volume change (a.u.) after prone recruitment and extubation. Results: The last part of dorsal end-inspiratory volume after extubation was higher after prone (49.1 a.u.; 95% confidence interval [CI], 37.4-60.6) vs supine recruitment (24.2 a.u.; 95% CI, 18.4-29.6; P=0.024). Improvement in left dorsal end-expiratory lung volume after extubation was higher after prone (382 a.u.; 95% CI, 261-502) vs supine recruitment (-71 a.u., 95% CI, -140 to -2; n=15; P<0.001). After prone recruitment, left vs right predominant end-expiratory dorsal lung volume change disappeared after extubation. However, both left and right end-expiratory volumes were higher in the prone group, after extubation. Conclusions: Recruitment in the prone position improves dorsal inspiratory and end-expiratory lung volumes after cardiac surgery. Clinical trial registration: NCT03009331.

Long-term Extracorporeal Membrane Oxygenation Bridge to Lung Transplantation After COVID-19.

This report describes a patient with severe acute respiratory syndrome coronavirus 2 infection and irreversible lung destruction who underwent successful lung transplantation after 138 days of bridging with extracorporeal membrane oxygenation support. The case exemplifies that lung transplantation may be a possibility after very long-term coronavirus disease 2019 care, even if the patient is initially an unsuitable candidate.

Baseline characteristics and survival of patients of idiopathic pulmonary fibrosis: a longitudinal analysis of the Swedish IPF Registry.

BACKGROUND: Observational data under real-life conditions in idiopathic pulmonary fibrosis (IPF) is scarce. We explored anti-fibrotic treatment, disease severity and phenotypes in patients with IPF from the Swedish IPF Registry (SIPFR). METHODS: Patients enrolled between September 2014 and April 2020 and followed ≥ 6 months were investigated. Demographics, comorbidities, lung function, composite variables, six-minute walking test (6MWT), quality of life, and anti-fibrotic therapy were evaluated. Agreements between classification of mild physiological impairment (defined as gender-age-physiology (GAP) stage 1) with physiological and composite measures of severity was assessed using kappa values and their impact on mortality with hazard ratios. The factor analysis and the two-step cluster analysis were used to identify phenotypes. Univariate and multivariable survival analyses were performed between variables or groups. RESULTS: Among 662 patients with baseline data (median age 72.7 years, 74.0% males), 480 had a follow up ≥ 6 months with a 5 year survival rate of 48%. Lung function, 6MWT, age, and BMI were predictors of survival. Patients who received anti-fibrotic treatment ≥ 6 months had better survival compared to untreated patients [p = 0.007, HR (95% CI): 1.797 (1.173-2.753)] after adjustment of age, gender, BMI, smoking status, forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO). Patients with mild physiological impairment (GAP stage 1, composite physiological index (CPI) ≤ 45, DLCO ≥ 55%, FVC ≥ 75%, and total lung capacity (TLC) ≥ 65%, respectively) had better survival, after adjustment for age, gender, BMI and smoking status and treatment. Patients in cluster 1 had the worst survival and consisted mainly of male patients with moderate-severe disease and an increased prevalence of heart diseases at baseline; Cluster 2 was characterized by mild disease with more than 50% females and few comorbidities, and had the best survival; Cluster 3 were younger, with moderate-severe disease and had few comorbidities. CONCLUSION: Disease severity, phenotypes, and anti-fibrotic treatment are closely associated with the outcome in IPF, with treated patients surviving longer. Phenotypes may contribute to predicting outcomes of patients with IPF and suggest the patients' need for special management, whereas single or composite variables have some limitations as disease predictors.

[Lungtransplantation in Sweden - over 1 200 patients transplanted since 1990]. / Lungtransplantationer i Sverige ­ över 1 200 patienter sedan 1990.

Lung transplantation is an accepted treatment for end stage lung diseases and performed at two national centers in Sweden - Gothenburg and Lund. Since the start in 1990 over 1 200 patients have been transplanted.  The indications are severe progressive lung diseases with short expected survival or severe negative effects on daily life. There are several contraindications among which severe other organ disease, recent malignancy or psychiatric disease are most important.  The most common causes for lung transplantation are chronic obstructive pulmonary disease (COPD), interstitial pulmonary disease, cystic fibrosis and pulmonary hypertension.  Long term survival after 5 years is 63 %, and after 10 years 48 %, which is better than the results reported in the international registry (57 % and 36 % respectively).   Lung transplantation is today a therapy for end stage pulmonary diseases with acceptable survival results. It is likely that the number of patients will increase in the future.

Extended use of extra corporeal membrane oxygenation as bridge to lung transplantation in two patients.

BACKGROUND: We have previously reported our outcome after extra-corporeal membrane oxygenation as bridge-to-lung transplantation, which initially was considered controversial, but over time have gained acceptance and now is performed in most high-volume institutions. CASE PRESENTATION: We now report two "extreme" extra-corporeal membrane oxygenation (ECMO) bridge-to-lung transplantation cases, on ECMO > 200 days prior to lung transplantation. One patient survived long-term and the other one did not, and clinical cause and morbidity is outlined in this case-report. CONCLUSION: We believe these two cases highlight the medical, ethical and resource allocation difficulties involved with saving patients in very dire circumstances. We have shown that a patient can survive extremely long duration of ECMO bridge to lung transplantation, but selection remains crucial to achieve a reasonable cost-benefit.

Idiopathic Pulmonary Fibrosis: Best Practice in Monitoring and Managing a Relentless Fibrotic Disease.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease that is, by definition, progressive. Progression of IPF is reflected by a decline in lung function, worsening of dyspnea and exercise capacity, and deterioration in health-related quality of life. In the short term, the course of disease for an individual patient is impossible to predict. A period of relative stability in forced vital capacity (FVC) does not mean that FVC will remain stable in the near future. Frequent monitoring using multiple assessments, not limited to pulmonary function tests, is important to evaluate disease progression in individual patients and ensure that patients are offered appropriate care. Optimal management of IPF requires a multidimensional approach, including both pharmacological therapy to slow decline in lung function and supportive care to preserve patients' quality of life.

Outcomes and Long-term Survival After Pulmonary Retransplantation: A Single-Center Experience.

BACKGROUND: The median survival after lung retransplantation (ReLTx) reported to the International Society of Heart and Lung Transplantation is restricted to 2.5 years. We report the results after ReLTx from our center. METHODS: A retrospective data collection was performed for the 635 patients who underwent lung transplantation between 1991 and 2017 at our center. Recipient variables were compared between patients undergoing only primary lung transplantation (PLTx) and those undergoing PLTx and later ReLTx. Time to death was compared using the Kaplan-Meier method. The risk of ReLTx was analyzed in Cox regression models. Any interaction between type of transplantation, single/double, and PLTx/ReLTx was investigated. RESULTS: ReLTx was performed in 49 patients. Survival after ReLTx at 30 days and 1, 2, and 5 years was 90%, 76%, 71%, and 55%, respectively, and the corresponding survival after PLTx was 94%, 82%, 76%, and 61%, respectively. A hazard ratio of 1.73 for ReLTx was shown (95% confidence interval [CI], 1.14 to 2.63; P = .011). After adjustments for sex, age, diabetes, renal function, preoperative ventilator, and extracorporeal membrane oxygenation, the hazard ratio was 1.43 (95% CI, 0.90 to 2.26; P = .13). ReLTx was performed in 8 patients (16%) within the first year after PLTx. The 1-year survival for this group was 50% compared with 81% (P = .18) for patients who underwent ReLTx later than 1 year after the PLTx. One-year survival after double ReLTx was 60% (95% CI, 25% to 83%) compared with 79% (95% CI, 63% to 89%) for single ReLTx. CONCLUSIONS: ReLTx is a reasonable option for a selected group of patients. Ideally, a number of well-established risk factors are avoided and the ReLTx is performed more than 1 year after the PLTx.

Relationship between preoperative symptoms and improvement of quality of life in patients undergoing elective inguinal herniorrhaphy.

BACKGROUND: Improvement of quality of life (QoL) is the ultimate goal for inguinal hernia repair. Data on QoL before surgery are scarce, and it is not known whether postoperative improvement of QoL relates to preoperative symptoms. METHODS: Symptoms and self-reported QoL were evaluated and compared with matched control patients from a normal population in 309 male subjects before and 1 year after unilateral open inguinal hernia repair. RESULTS: Before operation, 91 % of patients noted a bulge, whereas 75% had symptoms, most commonly pain (64%); the other 25% were asymptomatic. Physical QoL scores (physical component score) were decreased in patients compared with matched controls (median [interquartile range] PCS 47 [38-53] vs 54 [48-57] P < .05), whereas mental scores (mental component score) were not affected (P = .401). PCS was less in patients with pain compared with those without pain (44 [35-50] vs 53 [48-56] P = .001). In patients without pain, no difference was found compared with control patients (P = .57). At 1 year after surgery, PCS was increased to 55 (53-57) in patients and was slightly greater than control patients (P < .05). The increase was greater in patients who reported preoperative pain (from 44 [35-50] to 55 [52-57] vs from 53 [48-56] to 56 [54-57], P < .00001). MCS did not change after inguinal herniorrhaphy. CONCLUSION: Preoperative affection as well as postoperative improvement in self-reported physical QoL seems to be strongly associated with preoperative inguinal pain. This finding underscores that occurrence of preoperative pain is an important symptom to evaluate before taking the decision to operate for inguinal hernia.

The impact of viral respiratory tract infections on long-term morbidity and mortality following lung transplantation: a retrospective cohort study using a multiplex PCR panel.

BACKGROUND: The major factor affecting morbidity and mortality after lung transplantation (LTX) is bronchiolitis obliterans syndrome. Earlier studies have suggested a connection between the presence of viral agents and morbidity in this patient group, but data are somewhat conflicting. The objective of this study was to investigate the development of bronchiolitis obliterans syndrome and graft loss after LTX in relation to the presence of respiratory viruses during the first year after LTX. METHOD: The study is a retrospective cohort study of 39 LTX recipients 11Y13 years after surgery. Patients were operated between January 1, 1998 and December 31, 2000 at Sahlgrenska University Hospital. The presence of virus in bronchoalveolar lavage (BAL) fluids from patients during the first year after surgery was analyzed retrospectively using a multiplex polymerase chain reaction test capable of detecting 15 respiratory agents. The time to BOS or graft loss was analyzed in relation to the positive findings in BAL during the first year after LTX. RESULTS: Patients with one or more viruses detected in BAL during the first year after transplantation demonstrated a significantly faster development of BOS (P=0.005) compared with patients with no virus detected. No significant difference in graft survival was found. CONCLUSION: Our results suggest that the long-term prognosis after LTX may be negatively affected by viral respiratory tract infections during the first year after LTX.