Clinical characteristics and treatment strategy of nocardiosis in lung transplant recipients: A single-center experience.

Objective: Nocardia are infrequent pathogens that disproportionately afflict organ transplant recipients. The present study aimed to summarize the clinical manifestations, diagnostic approaches, and treatment strategies of nocardiosis in lung transplant recipients. Methods: This retrospective study reviewed the clinical data of adult lung transplant recipients who were complicated with nocardiosis between January 2018 and December 2021 at the largest lung transplant center in South China. Results: The incidence of nocardiosis was 4.2% (13/316), including 9 cases of pulmonary nocardiosis and 4 disseminated nocardiosis (blood, pulmonary and intracranial). The accuracy in diagnosing nocardiosis was 77.8% by culture and 100% by metagenomic next-generation sequencing (mNGS). Nocardia farcinica was the most common causative pathogen. Trimethoprim-sulfamethoxazole-based combination therapy was administered initially, followed by a single antibiotic as the maintained therapy, lasting for 4-8 months. Conclusions: mNGS is more accurate than culture in diagnosing nocardiosis. Most patients responded well to the antibiotic therapy with combined antibiotics at the initial stage followed by a single antibiotic treatment.

Lung transplantation for anti-MDA5-positive dermatomyositis-associated rapid progressive interstitial lung disease: report of two cases and review of the literature.

Lung transplantation is an ultimate lifesaving treatment for many patients with end-stage lung disease, whereas whether it is an optional intervention for the anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis (DM)-associated rapid progressive interstitial lung disease (RP-ILD) remain controversial. We report two patients diagnosed with anti-MDA5-positive DM-associated RP-ILD, who were both bridging to lung transplant with extracorporeal membrane oxygenation (ECMO) after failing to respond to extensive immunosuppressants. The first patient received full rehabilitation, but the second patient died of DM flare at the early-stage post-lung transplantation. Most of the clinical information was parallel in these two patients except the anti-MDA5 antibody level, which gradually decreased and became negative in the first patient but always hovering in high titers in the second patient, although both of the two patients received standard immunosuppressive regimen for prevention of rejection after lung transplantation. A total of 11 patients with anti-MDA5-positive DM-associated RP-ILD who underwent lung transplantation from the literature were identified. Most patients (10/11, 90.1%) were successfully discharged and without DM flare during the follow-up period post-lung transplantation. Nine of them were followed up more than 1 year, and anti-MDA-5 antibody was reported to be negative in four patients, whereas the others were unavailable. Combined with the case series in the literature, our limited experience suggests that lung transplantation is a promising therapeutic option for end-stage patients with anti-MDA5-positive DM-associated RP-ILD, with ECMO as a bridge to lung transplantation, if necessary. However, clearance or a downtrend of anti-MDA5 antibody may be required pre-transplant to avoid DM flare and recurrent RP-ILD post-transplantation.

The Airway Microbiota Signatures of Infection and Rejection in Lung Transplant Recipients.

Infection and rejection are the two most common complications after lung transplantation (LT) and are associated with increased morbidity and mortality. We aimed to examine the association between the airway microbiota and infection and rejection in lung transplant recipients (LTRs). Here, we collected 181 sputum samples (event-free, n = 47; infection, n = 103; rejection, n = 31) from 59 LTRs, and performed 16S rRNA gene sequencing to analyze the airway microbiota. A significantly different airway microbiota was observed among event-free, infection and rejection recipients, including microbial diversity and community composition. Nineteen differential taxa were identified by linear discriminant analysis (LDA) effect size (LEfSe), with 6 bacterial genera, Actinomyces, Rothia, Abiotrophia, Neisseria, Prevotella, and Leptotrichia enriched in LTRs with rejection. Random forest analyses indicated that the combination of the 6 genera and procalcitonin (PCT) and T-lymphocyte levels showed area under the curve (AUC) values of 0.898, 0.919 and 0.895 to differentiate between event-free and infection recipients, event-free and rejection recipients, and infection and rejection recipients, respectively. In conclusion, our study compared the airway microbiota between LTRs with infection and acute rejection. The airway microbiota, especially combined with PCT and T-lymphocyte levels, showed satisfactory predictive efficiency in discriminating among clinically stable recipients and those with infection and acute rejection, suggesting that the airway microbiota can be a potential indicator to differentiate between infection and acute rejection after LT. IMPORTANCE Survival after LT is limited compared with other solid organ transplantations mainly due to infection- and rejection-related complications. Differentiating infection from rejection is one of the most important challenges to face after LT. Recently, the airway microbiota has been reported to be associated with either infection or rejection of LTRs. However, fewer studies have investigated the relationship between airway microbiota together with infection and rejection of LTRs. Here, we conducted an airway microbial study of LTRs and analyzed the airway microbiota together with infection, acute rejection, and clinically stable recipients. We found different airway microbiota between infection and acute rejection and identify several genera associated with each outcome and constructed a model that incorporates airway microbiota and clinical parameters to predict outcome. This study highlighted that the airway microbiota was a potential indicator to differentiate between infection and acute rejection after LT.

Metagenomic Next-Generation Sequencing for Diagnosing Infections in Lung Transplant Recipients: A Retrospective Study.

Background: Accurate identification of pathogens is essential for the diagnosis and control of infections. We aimed to compare the diagnostic performance of metagenomic next-generation sequencing (mNGS) and conventional detection methods (CDM) in lung transplant recipients (LTRs). Methods: We retrospectively analyzed 107 LTRs with suspected infection of pulmonary, blood, central nervous system or chest wall between March 2018 and November 2020. Bronchoalveolar lavage fluid and other body fluids were subject to pathogen detection by both mNGS and CDM. Results: Of the 163 specimens, 84 (51.5%) tested positive for both mNGS and culture, 19 (11.7%) of which were completely consistent, 44 (27.0%) were partially congruent, and 21 (12.9%) were discordant (kappa = .215; p = .001). Compared with CDM, mNGS detected a higher diversity of pathogens. Moreover, the turn-around time was significantly shorter for mNGS compared with culture (2.7 ± .4 vs. 5.5 ± 1.6 days, p < .001). As an auxiliary method, treatment strategies were adjusted according to mNGS findings in 31 cases (29.0%), including eight patients with non-infectious diseases, who were finally cured. Conclusion: mNGS can identify pathogens with a shorter turn-around time and therefore provide a more accurate and timely diagnostic information to ascertaining pulmonary infections. mNGS might have a role in differentiating infectious from non-infectious lung diseases in LTRs.

High-throughput next-generation sequencing for identifying pathogens during early-stage post-lung transplantation.

BACKGROUND: High-throughput next-generation sequencing (HT-NGS) has the potential to detect a large variety of pathogens; however, the application of HT-NGS in lung transplant (LTx) recipients remains limited. We aimed to evaluate the value of HT-NGS for pathogen detection and diagnosis of pulmonary infection during early-stage post-lung transplantation. METHODS: In this retrospective study, we enrolled 51 LTx recipients who underwent lung transplantation between January 2020 and December 2020. Bronchoalveolar lavage fluid (BALF) samples were collected for the detection of pathogens using both HT-NGS and conventional microbiological testing. The detection of pathogens and diagnostic performance of HT-NGS were compared with that of conventional methods. RESULTS: HT-NGS provided a higher positive rate of pathogen detection than conventional microbiological testing (88.24% vs. 76.47%). The most common bacteria detected via HT-NGS during early-stage post-lung transplantation were Enterococcus, Staphylococcus, Pseudomonas and Klebsiella, while all fungi were Candida and all viruses were Herpesvirus. Uncommon pathogens, including Strongyloides, Legionella, and Mycobacterium abscesses were identified by HT-NGS. The sensitivity of HT-NGS for diagnosing pulmonary infection was significantly higher than that of conventional microbiological testing (97.14% vs. 68.57%; P < 0.001). For three LTx recipients, treatment regimens were adjusted according to the results of HT-NGS, leading to a complete recovery. CONCLUSION: HT-NGS is a highly sensitive technique for pathogen detection, which may provide diagnostic advantages, especially in LTx recipients, contributing to the optimization of treatment regimens against pulmonary infection during early-stage post-lung transplantation.

Recommended prophylactic and management strategies for severe acute respiratory syndrome coronavirus 2 infection in transplant recipients.

Since December 2019, increasing attention has been paid to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in Wuhan, China. SARS-CoV-2 primarily invades the respiratory tract and lungs, leading to pneumonia and other systemic disorders. The effect of SARS-CoV-2 in transplant recipients has raised significant concerns, especially because there is a large population of transplant recipients in China. Based on the current epidemic situation, this study reviewed publications on this virus and coronavirus disease 2019 (COVID-19), analyzed common features of respiratory viral pneumonias, and presented the currently reported clinical characteristics of COVID-19 in transplant recipients to improve strategies regarding the diagnosis and treatment of COVID-19 in this special population.

Plasma myostatin levels are related to the extent of right ventricular dysfunction in exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To investigate the relationship between plasma myostatin levels and right ventricle (RV) dysfunction (RVD) in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: The study recruited 84 patients with AECOPD. Plasma myostatin was analyzed and tricuspid annular plane systolic excursion (TAPSE) < 16 mm was used as the main indicator for RVD. RESULTS: Plasma myostatin levels were significantly higher in 47 patients with RVD than 37 ones without (P < 0.005). Multivariate regression analysis revealed that myostatin levels correlated significantly with TAPSE values and RV myocardial performance index (p < 0.001) among the study patients. CONCLUSION: Plasma myostatin is a potential biomarker for improving diagnosis of RVD in AECOPD.

Higher Plasma Myostatin Levels in Cor Pulmonale Secondary to Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To analyze plasma myostatin levels and investigate their relationship with right ventricular (RV) function in patients with cor pulmonale secondary to chronic obstructive pulmonary disease (COPD). METHODS: The study recruited 81 patients with advanced COPD and 40 age-matched controls. The patients were divided into two groups: those with cor pulmonale and those without. Echocardiography was used to evaluate RV function and morphology, and the value of tricuspid annular plane systolic excursion (TAPSE) less than 16 mm was considered RV dysfunction. Plasma myostatin levels were analyzed by enzyme-linked immunosorbent assay, and B-type natriuretic peptide (BNP) levels were analyzed as a comparison of myostatin. RESULTS: The data detected cor pulmonale in 39/81 patients, with the mean value of TAPSE of 14.3 mm. Plasma myostatin levels (ng/mL) were significantly higher in patients with cor pulmonale (16.68 ± 2.95) than in those without (13.56 ± 3.09), and much higher than in controls (8.79±2.79), with each p<0.01. Significant differences were also found in plasma BNP levels among the three groups (p<0.05). Multivariate regression analysis suggested that myostatin levels were significantly correlated with the values of TAPSE and RV myocardium performance index among the COPD patients, and that BNP levels were significantly correlated only with systolic pulmonary arterial pressure, with each p<0.05. CONCLUSIONS: Plasma myostatin levels are increased in COPD patients who have cor pulmonale. Stronger correlations of plasma myostatin levels with echocardiographic indexes of the right heart suggest that myostatin might be superior to BNP in the early diagnosis of cor pulmonale in COPD.

Role of serum and induced sputum surfactant protein D in predicting the response to treatment in chronic obstructive pulmonary disease.

This study was designed to determine the expression of serum and sputum surfactant protein D (SP-D) in chronic obstructive pulmonary disease (COPD) and its association with treatment response. Sixty-five treatment-naive patients with COPD and 26 normal control subjects were recruited in the study. The concentrations of serum and sputum SP-D were measured, and the associations of SP-D with pulmonary function and the modified Medical Research Council dyspnea scale (mMRC) and the St. George's Respiratory Questionnaire (SGRQ) scores before and after three months of treatment with an inhaled corticosteroid and a long-acting ß2-agonist were analyzed. The concentrations of serum and sputum SP-D in the COPD group (45.46±37.78 and 173.23±186.93 ng/ml, respectively) were significantly higher than those of the normal control group (31.68±12.04 and 89.59±70.29 ng/ml, respectively). After three months of treatment, serum SP-D levels were reduced to 30.7±13.9 ng/ml and were significantly lower than the baseline levels (t=2.217, P=0.031). However, no significant reduction in sputum SP-D levels was observed following the treatment (P>0.05). A significant association between baseline sputum SP-D and change in SGRQ activity scores (r=-0.652, P=0.012) was observed; however no association was established with the changes in other clinical profiles following the treatment (P>0.05). This result suggested that an increased baseline sputum SP-D may be a weak predictive indicator of response to treatment with inhaled corticosteroids and long-acting ß2-agonists in patients with COPD.

Serum surfactant protein D: biomarker of chronic obstructive pulmonary disease.

BACKGROUND: Surfactant protein D (SP-D) is a lung-specific protein proposed to predict clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). However, the changes in serum SP-D during acute exacerbation (AECOPD) episodes and the relationship of serum SP-D with the overall severity of the disease in stable COPD (SCOPD) remain unclear. METHODS: Serum SP-D levels were analyzed in three groups, including AECOPD (n=40), SCOPD (n=71), and controls (n=60). In AECOPD group, serum SP-D levels were determined at 1, 5, 14, and 30 days post-exacerbation. In SCOPD group, BODE (body mass index, airflow obstruction, dyspnea, exercise capacity) index was evaluated for severity assessment. RESULTS: Serum SP-D levels were sequentially elevated from the controls to the SCOPD, and then to the AECOPD (p< 0.001). During an AECOPD episode, the raised serum SP-D levels subsided at day 5 (p> 0.05), fell markedly at day 14 (p< 0.001), and continued to decline at day 30 (p< 0.001). Among patients with SCOPD, serum SP-D levels correlated positively with the BODE index (p< 0.01). CONCLUSIONS: The longitudinal changes in serum SP-D levels during an AECOPD episode suggest that SP-D may be a potential systemic biomarker for COPD exacerbation. The correlation of serum SP-D levels with the BODE index suggests that circulating SP-Ds can reflect the overall severity of SCOPD.

Serum myostatin levels and skeletal muscle wasting in chronic obstructive pulmonary disease.

INTRODUCTION: It is well confirmed that myostatin is a negative regulator of skeletal muscle mass and implicated in several diseases involved in muscle wasting and cachexia. Skeletal muscle wasting is an important systemic manifestation of chronic obstructive pulmonary disease (COPD), while the expression of circulating myostatin in COPD remains unclear. The aim of this study was to investigate the expression of circulating myostatin and its relationship with skeletal muscle wasting in COPD. METHODS: Seventy-one patients with stable COPD and sixty age-matched, healthy control subjects participated in the study. Total skeletal muscle mass (SMM) were calculated according to a validated formula by using age and anthropometric measurements. Serum levels of myostatin, tumor necrosis factor (TNF)-α and interleukin-6 were determined by ELISA. RESULTS: Serum myostatin levels were significantly elevated in COPD patients when compared to controls [(11.85 ± 4.01) ng/ml vs. (7.46 ± 2.21) ng/ml, p < 0.01], while total SMM was significantly decreased in COPD patients when compared to controls [(20.81 ± 1.74) kg vs. (27.31 ± 2.18) kg for male, and (11.70 ± 0.56) kg vs. (19.89 ± 1.47) kg for female] (both p < 0.05). Regression correlation analysis on all COPD patients showed that serum myostatin levels weren't significantly correlated with SMM, but correlated with TNF-α levels (R(2) = 0.042, p = 0.048). However, when stratified for gender, serum myostatin levels were correlated inversely both with SMM (R(2) = 0.20, p = 0.000) and with BMI (R(2) = 0.084, p = 0.019) in subgroup of male patients. CONCLUSION: This study demonstrates that circulating myostatin levels are elevated in COPD and related to SMM in male patients, suggesting that myostatin contributes to skeletal muscle wasting in COPD.

Quadriceps strength assessed by magnetic stimulation of femoral nerve in patients with chronic obstructive pulmonary disease.

BACKGROUND: Skeletal muscle dysfunction is one of important systemic manifestations of chronic obstructive pulmonary disease (COPD) and is associated with mortality in patients with COPD, thus quantifying its strength is of great clinical interest and of particular value. Quadriceps maximal volitional contraction (MVC) is often used for the routine measurements of this muscle's strength; while twitch tension (TwQ) evoked by magnetic stimulation of the femoral nerve has been employed for measurement of quadriceps strength non-volitionally. We aimed to investigate the prevalence and severity of skeletal muscle dysfunction in COPD patients by measurement of quadriceps strength with volitional and non-volitional techniques, and to probe into some methodological issues. METHODS: We recruited 71 COPD patients and 60 control subjects. Quadriceps strength was measured with both maximality of TwQ and MVC force. The reproducibility for TwQ and MVC was investigated using within-occasion variability from three repeated maneuvers. RESULTS: Maximal TwQ was achieved in 121 participants at a mean of 90% of the stimulator's maximum output. The mean maximality of TwQ was decrease by about 44% - 47% in COPD patients as compared with controls (P < 0.05), so was MVC. There was a significant correlation between quadriceps TwQ and MVC, and the mean ratio of TwQ/MVC was 0.29 in controls and 0.33 in patients. The coefficient of variation showed that TwQ yielded lower within-occasion variability than MVC in both groups. CONCLUSIONS: Quadriceps strength is commonly and substantially impaired in patients with COPD, in terms of MVC as well as TwQ. The magnetic stimulation of the femoral nerve presents a higher reproducibility and is a better technique for measurement of quadriceps strength for the general population, especially for those who are too unwell to perform a full MVC; while it may not be applied to subjects who are over-weighted.

[Serum myostatin levels and malnutrition in patients with chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the prevalence and severity of malnutrition in patients with stable chronic obstructive pulmonary disease (COPD), analyze serum levels of myostatin, tumor necrosis factor alpha (TNFα) and C reactive protein (CRP), and investigate the relationship between serum myostatin and malnutrition in COPD. METHODS: Seventy-one patients with stable COPD and 60 age-matched healthy volunteers were recruited in this study. Pulmonary function was tested in all of the subjects and the severity of malnutrition was evaluated by a multiple-parameter malnutritional index (MNI). Based on the MNI scores, patients with COPD were divided into group I (MNI ≥ 5 score) and group II (MNI < 5 score), the former represents the patients with severe or very severe malnutrition while the latter represents the patients with mild or without malnutrition. Serum concentration of myostatin, TNFα and CRP were measured by enzyme-linked immunosorbent assay. RESULTS: The MNI score was significantly elevated in patients with COPD [(7.75 ± 3.86) score] compared with the controls [(1.13 ± 0.96) score; P < 0.001], and 55 patients (77%) in COPD group I showed MNI ≥ 5 (9.30 ± 3.01) score. Serum myostatin concentration was significantly elevated in COPD group I [(12.18 ± 4.76) µg/L] than in COPD group II [(9.73 ± 2.85) µg/L] and controls [(7.93 ± 2.35) µg/L], with each P < 0.001. Serum TNFα concentration was also significantly elevated in patients with COPD compared with the controls (P < 0.001). Pearson correlation analysis showed that serum myostatin levels were significantly correlated with MNI scores (r = 0.438, P = 0.000) and TNFα levels (r = 0.234, P = 0.041) in COPD group (combined group I and II) while MNI scores were correlated inversely with BMI in COPD group (r = -0.530, P = 0.000). After stratified with subgroups, the correlation between myostatin levels and MNI scores was more significant and the correlation coefficient was higher (r = 0.464, P = 0.000) in COPD group I patients. Moreover, myostatin levels were inversely correlated with BMI (r = -0.287, P = 0.034) and forced expiratory volume in one second of the predicted value (r = -0.264, P = 0.049) in COPD group I patients. CONCLUSIONS: Malnutrition commonly and substantially exists in patients with COPD; serum myostatin concentration is significantly elevated and is correlated with the severity of malnutrition in the patients. The elevation of serum myostatin may contribute to malnutrition in COPD patients.

[Investigation of the quadriceps strength in patients with chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the quadriceps strength in patients with stable chronic obstructive pulmonary disease (COPD), and the characteristics of quadriceps dysfunction in COPD patients. METHODS: All participants including 71 (male 54, female 17) patients with stable COPD and 60 (male 21, female 39) normal subjects underwent lung function tests, anthropometric measurements, quadriceps function assessments and physical activities evaluation. Quadriceps function was assessed by measurement of the maximal isometric volitional contraction (QMVC), endurance time and the maximal twitch tension. SPSS 12.0 was used to perform statistics. The results were presented as the (-x) +/- s for all variables that were normally distributed. Differences between the two groups (i.e., patients vs. controls) were analyzed using a two-tailed grouped t test. Differences between the groups within the COPD patients were analyzed using one-way ANOVA, and q-test was used to analyze the differences between them. Linear regression analysis was used to investigate the relationships between variables. RESULTS: The mean QMVC was (42 +/- 8) kg, endurance time was (81 +/- 27) s, the maximal twitch tension was (13.9 +/- 6.7) kg in normal men, while they were (23 +/- 6) kg, (51 +/- 18) s and (7.0 +/- 2.3) kg respectively in their COPD counterparts (t value was 5.89 - 10.73, all P < 0.01). The mean QMVC was (29 +/- 5) kg, endurance time was (83 +/- 32) s and the maximal twitch tension was (7.4 +/- 2.1) kg in normal female subjects, while they were (16 +/- 4) kg, (56 +/- 8) s and (4.2 +/- 0.9) kg respectively in female COPD patients (t value was 3.47 - 9.35, all P < 0.01). Correlation analysis showed that QMVC positively correlated with lung function variables, body mass index and mid-thigh muscle circumference in COPD patients (r value was 0.27 - 0.76, all P < 0.01). CONCLUSIONS: Our data showed that quadriceps dysfunction was common in COPD patients. QMVC was impaired to a greater extent than isometric endurance, and QMVC positively correlated with the severity of airflow obstruction. The maximal twitch tension induced by magnetic femoral nerve stimulation was an objective method to assess quadriceps strength.

Expressions of tumor necrosis factor-converting enzyme and ErbB3 in rats with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha (TNF-alpha) is found to take part in systemic inflammation, and ErbB3 plays an important role in mucin hypersecretion of COPD. Since TNF-alpha converting enzyme (TACE) is involved in the activation of both TNF-alpha and ErbB3, we established rat models of COPD to investigate the expressions of TACE, TNF-alpha and ErbB3 and to explore the correlations among TACE, TNF-alpha and ErbB3 respectively. METHODS: Thirty Wistar male rats were randomly divided into COPD group (group C, n = 10), saline solution parallel group (group P, n = 8), and normal control group (group N, n = 8). Group C was challenged with passive cigarette smoking and intratracheal instillation of lipopolysaccharide. Six weeks later pulmonary functions were tested, bronchoalveolar fluid and arterial blood gases were assayed, and histopathological evaluations were performed in turn. The expressions of TACE, TNF-alpha and ErbB3 in lungs of all rats were determined histochemically. RESULTS: The expressions of TACE, TNF-alpha and ErbB3 were significantly higher in group C than in group N (P < 0.01). The contents of TNF-alpha in serum (P < 0.01) and bronchoalveolar lavage fluid (BALF) (P < 0.01) were elevated more significantly in group C than in group N. A positive correlation existed between TACE and TNF-alpha (r = 0.784, P < 0.01) and between TACE and ErbB3 (r = 0.526, P < 0.01) respectively. CONCLUSIONS: TNF-alpha and ErbB3 are involved in the pathogenesis of COPD. TACE contributes to the progress of COPD indirectly through the function of TNF-alpha and ErbB3.