Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response.

BACKGROUND: Months after infection with severe acute respiratory syndrome coronavirus 2, at least 10% of patients still experience complaints. Long-COVID (coronavirus disease 2019) is a heterogeneous disease, and clustering efforts revealed multiple phenotypes on a clinical level. However, the molecular pathways underlying long-COVID phenotypes are still poorly understood. OBJECTIVES: We sought to cluster patients according to their blood transcriptomes and uncover the pathways underlying their disease. METHODS: Blood was collected from 77 patients with long-COVID from the Precision Medicine for more Oxygen (P4O2) COVID-19 study. Unsupervised hierarchical clustering was performed on the whole blood transcriptome. These clusters were analyzed for differences in clinical features, pulmonary function tests, and gene ontology term enrichment. RESULTS: Clustering revealed 2 distinct clusters on a transcriptome level. Compared with cluster 2 (n = 65), patients in cluster 1 (n = 12) showed a higher rate of preexisting cardiovascular disease (58% vs 22%), higher prevalence of gastrointestinal symptoms (58% vs 29%), shorter hospital duration during severe acute respiratory syndrome coronavirus 2 infection (median, 3 vs 8 days), lower FEV1/forced vital capacity (72% vs 81%), and lower diffusion capacity of the lung for carbon monoxide (68% vs 85% predicted). Gene ontology term enrichment analysis revealed upregulation of genes involved in the antiviral innate immune response in cluster 1, whereas genes involved with the adaptive immune response were upregulated in cluster 2. CONCLUSIONS: This study provides a start in uncovering the pathophysiological mechanisms underlying long-COVID. Further research is required to unravel why the immune response is different in these clusters, and to identify potential therapeutic targets to create an optimized treatment or monitoring strategy for the individual long-COVID patient.

The alveolar fibroproliferative response in moderate to severe COVID-19-related acute respiratory distress syndrome and 1-yr follow-up.

COVID-19-related acute respiratory distress syndrome (ARDS) can lead to long-term pulmonary fibrotic lesions. Alveolar fibroproliferative response (FPR) is a key factor in the development of pulmonary fibrosis. N-terminal peptide of procollagen III (NT-PCP-III) is a validated biomarker for activated FPR in ARDS. This study aimed to assess the association between dynamic changes in alveolar FPR and long-term outcomes, as well as mortality in COVID-19 ARDS patients. We conducted a prospective cohort study of 154 COVID-19 ARDS patients. We collected bronchoalveolar lavage (BAL) and blood samples for measurement of 17 pulmonary fibrosis biomarkers, including NT-PCP-III. We assessed pulmonary function and chest computed tomography (CT) at 3 and 12 mo after hospital discharge. We performed joint modeling to assess the association between longitudinal changes in biomarker levels and mortality at day 90 after starting mechanical ventilation. 154 patients with 284 BAL samples were analyzed. Of all patients, 40% survived to day 90, of whom 54 completed the follow-up procedure. A longitudinal increase in NT-PCP-III was associated with increased mortality (HR 2.89, 95% CI: 2.55-3.28; P < 0.001). Forced vital capacity and diffusion for carbon monoxide were impaired at 3 mo but improved significantly at one year after hospital discharge (P = 0.03 and P = 0.004, respectively). There was no strong evidence linking alveolar FPR during hospitalization and signs of pulmonary fibrosis in pulmonary function or chest CT images during 1-yr follow-up. In COVID-19 ARDS patients, alveolar FPR during hospitalization was associated with higher mortality but not with the presence of long-term fibrotic lung sequelae within survivors.NEW & NOTEWORTHY This is the first prospective study on the longitudinal alveolar fibroproliferative response in COVID-19 ARDS and its relationship with mortality and long-term follow-up. We used the largest cohort of COVID-19 ARDS patients who had consecutive bronchoalveolar lavages and measured 17 pulmonary fibroproliferative biomarkers. We found that a higher fibroproliferative response during admission was associated with increased mortality, but not correlated with long-term fibrotic lung sequelae in survivors.

Optimisation of detecting chronic thromboembolic pulmonary hypertension in acute pulmonary embolism survivors: the InShape IV study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is often diagnosed late in acute pulmonary embolism (PE) survivors: more efficient testing to expedite diagnosis may considerably improve patient outcomes. The InShape II algorithm safely rules out CTEPH (failure rate 0.29%) while requiring echocardiography in only 19% of patients but may be improved by adding detailed reading of the computed tomography pulmonary angiography (CTPA) diagnosing the index PE. METHODS: Twelve new algorithms, incorporating the CTEPH prediction score, ECG reading, NT-proBNP levels and dedicated CTPA reading were evaluated in the international InShape II (n=341) and part of the German FOCUS cohort (n=171). Evaluation criteria included failure rate, defined as the incidence of confirmed CTEPH in PE patients in whom echocardiography was deemed unnecessary by the algorithm, and the overall net reclassification index (NRI) compared to the InShape II algorithm. RESULTS: The algorithm starting with CTPA reading of the index PE for 6 signs of CTEPH, followed by the ECG/NTproBNP assessment and echocardiography resulted in the most beneficial change compared to InShape II with a need for echocardiography in 20% (+5%), a failure rate of 0%, and an NRI of +3.5, reflecting improved performance over the InShape II algorithm. In the FOCUS cohort, this approach lowered echocardiography need to 24% (-6%) and missed no CTEPH cases, with an NRI of +6.0. CONCLUSION: Dedicated CTPA reading of the index PE improved the performance of the InShape II algorithm and may improve the selection of PE survivors who require echocardiography to rule out CTEPH.

The Incidence of Pulmonary Embolism in Hospitalized Non-ICU Patients with COVID-19 during the First Wave: A Multicenter Retrospective Cohort Study in the Netherlands.

INTRODUCTION: During the first COVID-19 outbreak in 2020 in the Netherlands, the incidence of pulmonary embolism (PE) appeared to be high in COVID-19 patients admitted to the intensive care unit (ICU). This study was performed to evaluate the incidence of PE during hospital stay in COVID-19 patients not admitted to the ICU. METHODS: Data were retrospectively collected from 8 hospitals in the Netherlands. Patients admitted between February 27, 2020, and July 31, 2020, were included. Data extracted comprised clinical characteristics, medication use, first onset of COVID-19-related symptoms, admission date due to COVID-19, and date of PE diagnosis. Only polymerase chain reaction (PCR)-positive patients were included. All PEs were diagnosed with computed tomography pulmonary angiography (CTPA). RESULTS: Data from 1,852 patients who were admitted to the hospital ward were collected. Forty patients (2.2%) were diagnosed with PE within 28 days following hospital admission. The median time to PE since admission was 4.5 days (IQR 0.0-9.0). In all 40 patients, PE was diagnosed within the first 2 weeks after hospital admission and for 22 (55%) patients within 2 weeks after onset of symptoms. Patient characteristics, pre-existing comorbidities, anticoagulant use, and laboratory parameters at admission were not related to the development of PE. CONCLUSION: In this retrospective multicenter cohort study of 1,852 COVID-19 patients only admitted to the non-ICU wards, the incidence of CTPA-confirmed PE was 2.2% during the first 4 weeks after onset of symptoms and occurred exclusively within 2 weeks after hospital admission.

Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality.

INTRODUCTION: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) show limited systemic hyperinflammation, but immunomodulatory treatments are effective. Little is known about the inflammatory response in the lungs and if this could be targeted using high-dose steroids (HDS). We aimed to characterise the alveolar immune response in patients with COVID-19-related ARDS, to determine its association with mortality, and to explore the association between HDS treatment and the alveolar immune response. METHODS: In this observational cohort study, a comprehensive panel of 63 biomarkers was measured in repeated bronchoalveolar lavage (BAL) fluid and plasma samples of patients with COVID-19 ARDS. Differences in alveolar-plasma concentrations were determined to characterise the alveolar inflammatory response. Joint modelling was performed to assess the longitudinal changes in alveolar biomarker concentrations, and the association between changes in alveolar biomarker concentrations and mortality. Changes in alveolar biomarker concentrations were compared between HDS-treated and matched untreated patients. RESULTS: 284 BAL fluid and paired plasma samples of 154 patients with COVID-19 were analysed. 13 biomarkers indicative of innate immune activation showed alveolar rather than systemic inflammation. A longitudinal increase in the alveolar concentration of several innate immune markers, including CC motif ligand (CCL)20 and CXC motif ligand (CXCL)1, was associated with increased mortality. Treatment with HDS was associated with a subsequent decrease in alveolar CCL20 and CXCL1 levels. CONCLUSIONS: Patients with COVID-19-related ARDS showed an alveolar inflammatory state related to the innate host response, which was associated with a higher mortality. HDS treatment was associated with decreasing alveolar concentrations of CCL20 and CXCL1.

Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19.

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome.

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

A modified perfusion protocol for pulmonary endarterectomy in a patient with a hematologic malignancy treated with a tyrosine kinase inhibitor.

Tyrosine kinase inhibitors (TKI) are known to be highly effective in the treatment of various cancers with kinase-domain mutations such as chronic myelogenous leukemia. However, they have important side effects such as increased vascular permeability and pulmonary hypertension. In patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest, these side effects may exacerbate postoperative complications such as reperfusion edema and persistent pulmonary hypertension. We report on a simple modification of the perfusion strategy to increase intravascular oncotic pressure by retrograde autologous priming and the addition of packed cells and albumin in a patient treated with a TKI.

Enrichment of CCR6+ CD8+ T cells and CCL20 in the lungs of mechanically ventilated patients with COVID-19.

Despite high levels of CXCR3 ligands in mechanically ventilated COVID-19 patients, BALF CD8 T cells were not enriched in CXCR3+ cells but rather CCR6+ , likely due to high CCL20 levels in BALF, and had very high PD-1 expression. In mechanically ventilated, but not ward, patients Th-1 immunity is impaired. ​.

Home monitoring of lung function, symptoms and quality of life after admission with COVID-19 infection: The HOMECOMIN' study.

BACKGROUND AND OBJECTIVE: To develop targeted and efficient follow-up programmes for patients hospitalized with coronavirus disease 2019 (COVID-19), structured and detailed insights in recovery trajectory are required. We aimed to gain detailed insights in long-term recovery after COVID-19 infection, using an online home monitoring programme including home spirometry. Moreover, we evaluated patient experiences with the home monitoring programme. METHODS: In this prospective multicentre study, we included adults hospitalized due to COVID-19 with radiological abnormalities. For 6 months after discharge, patients collected weekly home spirometry and pulse oximetry measurements, and reported visual analogue scales on cough, dyspnoea and fatigue. Patients completed the fatigue assessment scale (FAS), global rating of change (GRC), EuroQol-5D-5L (EQ-5D-5L) and online tool for the assessment of burden of COVID-19 (ABCoV tool). Mixed models were used to analyse the results. RESULTS: A total of 133 patients were included in this study (70.1% male, mean age 60 years [SD 10.54]). Patients had a mean baseline forced vital capacity of 3.25 L (95% CI: 2.99-3.44 L), which increased linearly in 6 months with 19.1% (Δ0.62 L, p < 0.005). Patients reported substantial fatigue with no improvement over time. Nevertheless, health status improved significantly. After 6 months, patients scored their general well-being almost similar as before COVID-19. Overall, patients considered home spirometry useful and not burdensome. CONCLUSION: Six months after hospital admission for COVID-19, patients' lung function and quality of life were still improving, although fatigue persisted. Home monitoring enables detailed follow-up for patients with COVID-19 at low burden for patients and for the healthcare system.

Prescribing errors in post - COVID-19 patients: prevalence, severity, and risk factors in patients visiting a post - COVID-19 outpatient clinic.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has challenged healthcare globally. An acute increase in the number of hospitalized patients has necessitated a rigorous reorganization of hospital care, thereby creating circumstances that previously have been identified as facilitating prescribing errors (PEs), e.g. a demanding work environment, a high turnover of doctors, and prescribing beyond expertise. Hospitalized COVID-19 patients may be at risk of PEs, potentially resulting in patient harm. We determined the prevalence, severity, and risk factors for PEs in post-COVID-19 patients, hospitalized during the first wave of COVID-19 in the Netherlands, 3 months after discharge. METHODS: This prospective observational cohort study recruited patients who visited a post-COVID-19 outpatient clinic of an academic hospital in the Netherlands, 3 months after COVID-19 hospitalization, between June 1 and October 1 2020. All patients with appointments were eligible for inclusion. The prevalence and severity of PEs were assessed in a multidisciplinary consensus meeting. Odds ratios (ORs) were calculated by univariate and multivariate analysis to identify independent risk factors for PEs. RESULTS: Ninety-eight patients were included, of whom 92% had ≥1 PE and 8% experienced medication-related harm requiring an immediate change in medication therapy to prevent detoriation. Overall, 68% of all identified PEs were made during or after the COVID-19 related hospitalization. Multivariate analyses identified ICU admission (OR 6.08, 95% CI 2.16-17.09) and a medical history of COPD / asthma (OR 5.36, 95% CI 1.34-21.5) as independent risk factors for PEs. CONCLUSIONS: PEs occurred frequently during the SARS-CoV-2 pandemic. Patients admitted to an ICU during COVID-19 hospitalization or who had a medical history of COPD / asthma were at risk of PEs. These risk factors can be used to identify high-risk patients and to implement targeted interventions. Awareness of prescribing safely is crucial to prevent harm in this new patient population.

Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19.

BACKGROUND: Knowledge of the pathophysiology of COVID-19 is almost exclusively derived from studies that examined the immune response in blood. We here aimed to analyse the pulmonary immune response during severe COVID-19 and to compare this with blood responses. METHODS: This was an observational study in patients with COVID-19 admitted to the intensive care unit (ICU). Mononuclear cells were purified from bronchoalveolar lavage fluid (BALF) and blood, and analysed by spectral flow cytometry; inflammatory mediators were measured in BALF and plasma. FINDINGS: Paired blood and BALF samples were obtained from 17 patients, four of whom died in the ICU. Macrophages and T cells were the most abundant cells in BALF, with a high percentage of T cells expressing the ƴδ T cell receptor. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells (87·3% and 83·8%, respectively), and these cells expressed higher levels of the exhaustion marker programmad death-1 than in peripheral blood. Prolonged ICU stay (>14 days) was associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. INTERPRETATION: The bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood. Fully elucidating COVID-19 pathophysiology will require investigation of the pulmonary immune response.

Divergent SARS-CoV-2-specific T- and B-cell responses in severe but not mild COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding the immune response that provides specific immunity but may also lead to immunopathology is crucial for the design of potential preventive and therapeutic strategies. Here, we characterized and quantified SARS-CoV-2-specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T-cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. Furthermore, in these critically ill patients, a massive influx of circulating T cells into the lungs was observed, overwhelming the local T-cell compartment, and indicative of vascular leakage. The observed disparate T- and B-cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients.

Evolution of CT findings after anticoagulant treatment for acute pulmonary embolism in patients with and without an ultimate diagnosis of chronic thromboembolic pulmonary hypertension.

INTRODUCTION: The pulmonary arterial morphology of patients with pulmonary embolism (PE) is diverse and it is unclear how the different vascular lesions evolve after initiation of anticoagulant treatment. A better understanding of the evolution of computed tomography pulmonary angiography (CTPA) findings after the start of anticoagulant treatment may help to better identify those PE patients prone to develop chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the evolution of various thromboembolic lesions on CTPA over time after the initiation of adequate anticoagulant treatment in individual acute PE patients with and without an ultimate diagnosis of CTEPH. METHODS: We analysed CTPA at diagnosis of acute PE (baseline) and at follow-up in 41 patients with CTEPH and 124 patients without an ultimate diagnosis of CTEPH, all receiving anticoagulant treatment. Central and segmental pulmonary arteries were scored by expert chest radiologists as normal or affected. Lesions were further subclassified as 1) central thrombus, 2) total thrombotic occlusion, 3) mural thrombus, 4) web or 5) tapered pulmonary artery. RESULTS: Central thrombi resolved after anticoagulant treatment, while mural thrombi and total thrombotic occlusions either resolved or evolved into webs or tapered pulmonary arteries. Only patients with an ultimate diagnosis of CTEPH exhibited webs and tapered pulmonary arteries on the baseline scan. Moreover, such lesions always persisted after follow-up. CONCLUSIONS: Webs and tapered pulmonary arteries at the time of PE diagnosis strongly indicate a state of chronic PE and should raise awareness for possible CTEPH, particularly in patients with persistent dyspnoea after anticoagulant treatment for acute PE.

Chronic thromboembolic pulmonary hypertension anno 2021.

PURPOSE OF REVIEW: In the past decades, the diagnostic and therapeutic management of chronic thromboembolic pulmonary hypertension (CTEPH) has been revolutionized. RECENT FINDINGS: Advances in epidemiological knowledge and follow-up studies of pulmonary embolism patients have provided more insight in the incidence and prevalence. Improved diagnostic imaging techniques allow accurate assessment of the location and extend of the thromboembolic burden in the pulmonary artery tree, which is important for the determination of the optimal treatment strategy. Next to the pulmonary endarterectomy, the newly introduced technique percutaneous pulmonary balloon angioplasty and/or P(A)H-targeted medical therapy has been shown to be beneficial in selected patients with CTEPH and might also be of importance in patients with chronic thromboembolic pulmonary vascular disease. SUMMARY: In this era of a comprehensive approach to CTEPH with different treatment modalities, a multidisciplinary approach guides management decisions leading to optimal treatment and follow-up of patients with CTEPH.

COVID-19: Histopathological correlates of imaging patterns on chest computed tomography.

BACKGROUND AND OBJECTIVE: Patients with coronavirus disease 2019 (COVID-19) pneumonia present with typical findings on chest computed tomography (CT), but the underlying histopathological patterns are unknown. Through direct regional correlation of imaging findings to histopathological patterns, this study aimed to explain typical COVID-19 CT patterns at tissue level. METHODS: Eight autopsy cases were prospectively selected of patients with PCR-proven COVID-19 pneumonia with varying clinical manifestations and causes of death. All had been subjected to chest CT imaging 24-72 h prior to death. Twenty-seven lung areas with typical COVID-19 patterns and two radiologically unaffected pulmonary areas were correlated to histopathological findings in the same lung regions. RESULTS: Two dominant radiological patterns were observed: ground-glass opacity (GGO) (n = 11) and consolidation (n = 16). In seven of 11 sampled areas of GGO, diffuse alveolar damage (DAD) was observed. In four areas of GGO, the histological pattern was vascular damage and thrombosis, with (n = 2) or without DAD (n = 2). DAD was also observed in five of 16 samples derived from areas of radiological consolidation. Seven areas of consolidation were based on a combination of DAD, vascular damage and thrombosis. In four areas of consolidation, bronchopneumonia was found. Unexpectedly, in samples from radiologically unaffected lung parenchyma, evidence was found of vascular damage and thrombosis. CONCLUSION: In COVID-19, radiological findings of GGO and consolidation are mostly explained by DAD or a combination of DAD and vascular damage plus thrombosis. However, the different typical CT patterns in COVID-19 are not related to specific histopathological patterns. Microvascular damage and thrombosis are even encountered in the radiologically normal lung.

Cyclophosphamide for interstitial lung disease-associated acute respiratory failure: mortality, clinical response and radiological characteristics.

BACKGROUND: Treatment for interstitial lung disease (ILD) patients with acute respiratory failure (ARF) is challenging, and literature to guide such treatment is scarce. The reported in-hospital mortality rates of ILD patients with ARF are high (62-66%). Cyclophosphamide is considered a second-line treatment in steroid-refractory ILD-associated ARF. The first aim of this study was to evaluate the in-hospital mortality in patients with ILD-associated ARF treated with cyclophosphamide. The second aim was to compare computed tomographic (CT) patterns and physiological and ventilator parameters between survivors and non-survivors. METHODS: Retrospective analysis of patients with ILD-associated ARF treated with cyclophosphamide between February 2016 and October 2017. Patients were categorized into three subgroups: connective tissue disease (CTD)-associated ILD, other ILD or vasculitis. In-hospital mortality was evaluated in the whole cohort and in these subgroups. Clinical response was determined using physiological and ventilator parameters: Sequential Organ Failure Assessment Score (SOFA), PaO2/FiO2 (P/F) ratio and dynamic compliance (Cdyn) before and after cyclophosphamide treatment. The following CT features were quantified: ground-glass opacification (GGO) proportion, reticulation proportion, overall extent of parenchymal disease and fibrosis coarseness score. RESULTS: Fifteen patients were included. The overall in-hospital mortality rate was 40%. In-hospital mortality rates for CTD-associated ILD, other ILD and vasculitis were 20, 57, and 33%, respectively. The GGO proportion (71% vs 45%) was higher in non-survivors. There were no significant differences in the SOFA score, P/F ratio or Cdyn between survivors and non-survivors. However, in survivors the P/F ratio increased from 129 to 220 mmHg and Cdyn from 75 to 92 mL/cmH2O 3 days after cyclophosphamide treatment. In non-survivors the P/F ratio hardly changed (113-114 mmHg) and Cdyn even decreased (27-20 mL/cmH2O). CONCLUSION: In this study, we found a mortality rate of 40% in patients treated with cyclophosphamide for ILD-associated ARF. Connective tissue disease-associated ILD and vasculitis were associated with a lower risk of death. In non-survivors, the CT GGO proportion was significantly higher. The P/F ratio and Cdyn in survivors increased after 3 days of cyclophosphamide treatment.

Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD.

Persistent exercise intolerance after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

AIM: Haemodynamic normalisation is the ultimate goal of pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). However, whether normalisation of haemodynamics translates into normalisation of exercise capacity is unknown. The incidence, determinants and clinical implications of exercise intolerance after PEA are unknown. We performed a prospective analysis to determine the incidence of exercise intolerance after PEA, assess the relationship between exercise capacity and (resting) haemodynamics and search for preoperative predictors of exercise intolerance after PEA. METHODS: According to clinical protocol all patients underwent cardiopulmonary exercise testing (CPET), right heart catheterisation and cardiac magnetic resonance (CMR) imaging before and 6 months after PEA. Exercise intolerance was defined as a peak oxygen consumption (V'O2 ) <80% predicted. CPET parameters were judged to determine the cause of exercise limitation. Relationships were analysed between exercise intolerance and resting haemodynamics and CMR-derived right ventricular function. Potential preoperative predictors of exercise intolerance were analysed using logistic regression analysis. RESULTS: 68 patients were included in the final analysis. 45 (66%) patients had exercise intolerance 6 months after PEA; in 20 patients this was primarily caused by a cardiovascular limitation. The incidence of residual pulmonary hypertension was significantly higher in patients with persistent exercise intolerance (p=0.001). However, 27 out of 45 patients with persistent exercise intolerance had no residual pulmonary hypertension. In the multivariate analysis, preoperative transfer factor of the lung for carbon monoxide (T LCO) was the only predictor of exercise intolerance after PEA. CONCLUSIONS: The majority of CTEPH patients have exercise intolerance after PEA, often despite normalisation of resting haemodynamics. Not all exercise intolerance after PEA is explained by the presence of residual pulmonary hypertension, and lower preoperative T LCO was a strong predictor of exercise intolerance 6 months after PEA.

The quantitative assessment of interstitial lung disease with positron emission tomography scanning in systemic sclerosis patients.

OBJECTIVES: The reversibility of interstitial lung disease (ILD) in SSc is difficult to assess by current diagnostic modalities and there is clinical need for imaging techniques that allow for treatment stratification and monitoring. 18F-Fluorodeoxyglucose (FDG) PET/CT scanning may be of interest for this purpose by detection of metabolic activity in lung tissue. This study aimed to investigate the potential role of 18F-FDG PET/CT scanning for the quantitative assessment of SSc-related active ILD. METHODS: 18F-FDG PET/CT scans and high resolution CT scans of eight SSc patients, including five with ILD, were analysed. For comparison, reference groups were included: eight SLE patients and four primary Sjögren's syndrome (pSS) patients, all without ILD. A total of 22 regions of interest were drawn in each patient at apical, medial and dorsobasal lung levels. 18F-FDG uptake was measured as mean standardized uptake value (SUVmean) in each region of interest. Subsequently, basal/apical (B/A) and medial/apical (M/A) ratios were calculated at patient level (B/A-p and M/A-p) and at tissue level (B/A-t and M/A-t). RESULTS: SUVmean values in dorsobasal ROIs and B/A-p ratios were increased in SSc with ILD compared with SSc without ILD (P = 0.04 and P = 0.07, respectively), SLE (P = 0.003 and P = 0.002, respectively) and pSS (P = 0.03 and P = 0.02, respectively). Increased uptake in the dorsobasal lungs and increased B/A-t ratios corresponded to both ground glass and reticulation on high resolution CT. CONCLUSION: Semi-quantitative assessment of 18F-FDG PET/CT is able to distinguish ILD from non-affected lung tissue in SSc, suggesting that it may be used as a new biomarker for SSc-ILD disease activity.