Autopsy-Based Pulmonary and Vascular Pathology: Pulmonary Endotheliitis and Multi-Organ Involvement in COVID-19 Associated Deaths.

BACKGROUND: Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO-VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology. METHODS: Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22-89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ2 and Mann-Whitney U tests. RESULTS: Severe pulmonary endotheliitis (p = 0.031, p = 0.029) and multi-organ involvement (p = 0.026, p = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either. CONCLUSIONS: Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO-VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome.

Coagulation and Fibrinolysis in Obstructive Sleep Apnoea.

Obstructive sleep apnoea (OSA) is a common disease which is characterised by repetitive collapse of the upper airways during sleep resulting in chronic intermittent hypoxaemia and frequent microarousals, consequently leading to sympathetic overflow, enhanced oxidative stress, systemic inflammation, and metabolic disturbances. OSA is associated with increased risk for cardiovascular morbidity and mortality, and accelerated coagulation, platelet activation, and impaired fibrinolysis serve the link between OSA and cardiovascular disease. In this article we briefly describe physiological coagulation and fibrinolysis focusing on processes which could be altered in OSA. Then, we discuss how OSA-associated disturbances, such as hypoxaemia, sympathetic system activation, and systemic inflammation, affect these processes. Finally, we critically review the literature on OSA-related changes in markers of coagulation and fibrinolysis, discuss potential reasons for discrepancies, and comment on the clinical implications and future research needs.

Night-to-night variability of respiratory events in obstructive sleep apnoea: a systematic review and meta-analysis.

BACKGROUND: It is current practice to use a single diagnostic sleep study in the diagnostic workup of obstructive sleep apnoea (OSA). However, a relevant night-to-night variability (NtNV) of respiratory events has been reported. METHODS: We evaluated the NtNV of respiratory events in adults with suspected or already diagnosed OSA who underwent more than one diagnostic sleep study. Data sources were PubMed, Cochrane and Embase up to 23 January 2019. Random-effects models were used for evidence synthesis. For moderator analysis, mixed-effects regression analysis was performed. The study was registered with PROSPERO (CRD42019135277). RESULTS: Of 2143 identified papers, 24 studies, comprising 3250 participants, were included. The mean Apnoea-Hypopnoea Index (AHI) difference between the first and second night was -1.70/hour (95% CI -3.61 to 0.02). REM time differences (first to second night) were significantly positive associated with differences in mean AHI (ß coefficient 0.262 (95% CI 0.096 to 0.428). On average, 41% (95% CI 27% to 57%) of all participants showed changes of respiratory events >10/hour from night to night. Furthermore, 49% (95% CI 32% to 65%) of participants changed OSA severity class (severity thresholds at 5/hour, 15/hour and 30/hour) at least once in sequential sleep studies. Depending on the diagnostic threshold (5/hour, 10/hour or 15/hour), on average 12% (95% CI 9% to 15%), 12% (95% CI 8% to 19%) and 10% (95% CI 8% to 13%) of patients would have been missed during the first night due to single night testing. CONCLUSION: While there was no significant difference between mean AHI in two sequential study nights on a group level, there was a remarkable intraindividual NtNV of respiratory events, leading to misdiagnosis and misclassification of patients with suspected OSA.

Obstructive sleep apnoea treatment and blood pressure: which phenotypes predict a response? A systematic review and meta-analysis.

The treatment for obstructive sleep apnoea (OSA) with continuous positive airway pressure (CPAP) or mandibular advancement devices (MADs) is associated with blood pressure (BP) reduction; however, the overall effect is modest. The aim of this systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the effect of such treatments on BP was to identify subgroups of patients who respond best to treatment.The article search was performed in three different databases with specific search terms and selection criteria. From 2289 articles, we included 68 RCTs that compared CPAP or MADs with either passive or active treatment. When all the studies were pooled together, CPAP and MADs were associated with a mean BP reduction of -2.09 (95% CI -2.78- -1.40) mmHg for systolic BP and -1.92 (95% CI -2.40- -1.43) mmHg for diastolic BP and -1.27 (95% CI -2.34- -0.20) mmHg for systolic BP and -1.11 (95% CI -1.82- -0.41) mmHg for diastolic BP, respectively. The subgroups of patients who showed a greater response were those aged <60 years (systolic BP -2.93 mmHg), with uncontrolled BP at baseline (systolic BP -4.14 mmHg) and with severe oxygen desaturations (minimum arterial oxygen saturation measured by pulse oximetry <77%) at baseline (24-h systolic BP -7.57 mmHg).Although this meta-analysis shows that the expected reduction of BP by CPAP/MADs is modest, it identifies specific characteristics that may predict a pronounced benefit from CPAP in terms of BP control. These findings should be interpreted with caution; however, they are particularly important in identifying potential phenotypes associated with BP reduction in patients treated for OSA.

Effect of Breathing Oxygen-Enriched Air on Exercise Performance in Patients with Chronic Obstructive Pulmonary Disease: Randomized, Placebo-Controlled, Cross-Over Trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) experience dyspnea and hypoxemia during exercise. OBJECTIVE: The aim of this study was to evaluate the effects of breathing oxygen-enriched air on exercise performance and associated physiological changes in patients with COPD. METHODS: In a randomized, placebo-controlled, single-blind, cross-over trial, 20 patients with COPD (11 women, age 65 ± 6 years, FEV1 64 ± 19% pred., resting SpO2 ≥90%) performed 4 cycle ergospirometries to exhaustion using an incremental exercise test (IET) and a constant work rate (at 75% maximal workload with air) exercise test (CWRET), each with ambient (FiO2 0.21) and oxygen-enriched (FiO2 0.5) air. The main outcomes were the change in maximal workload in the IET and the change in exercise duration in the CWRET with oxygen versus air. Electrocardiogram, pulmonary gas exchange, thoracic volumes by inductance plethysmography, arterial blood gases, and cerebral and quadriceps muscle tissue oxygenation (CTO and MTO) were additionally measured. RESULTS: In the IET, maximal workload increased from 96 ± 21 to 104 ± 28 W with oxygen. In the CWRET, exercise duration increased from 605 ± 274 to 963 ± 444 s with oxygen. At end-exercise with oxygen, CTO, MTO, PaO2, and PaCO2 were increased, while V'E/V'CO2 was reduced and thoracic volumes were similar. At the corresponding time to end of exercise with ambient air, oxygen decreased heart rate, respiratory rate, minute ventilation, and V'E/V'CO2, while oxygenation was increased. CONCLUSION: In COPD patients without resting hypoxemia, breathing oxygen-enriched air improves exercise performance. This relates to a higher arterial oxygen saturation promoting oxygen availability to muscle and cerebral tissue and an enhanced ventilatory efficiency. COPD patients may benefit from oxygen therapy during exercise training.

Long-Term Mechanical Ventilation: Recommendations of the Swiss Society of Pulmonology.

Long-term mechanical ventilation is a well-established treatment for chronic hypercapnic respiratory failure (CHRF). It is aimed at improving CHRF-related symptoms, health-related quality of life, survival, and decreasing hospital admissions. In Switzerland, long-term mechanical ventilation has been increasingly used since the 1980s in hospital and home care settings. Over the years, its application has considerably expanded with accumulating evidence of beneficial effects in a broad range of conditions associated with CHRF. Most frequent indications for long-term mechanical ventilation are chronic obstructive pulmonary disease, obesity hypoventilation syndrome, neuromuscular and chest wall diseases. In the current consensus document, the Special Interest Group of the Swiss Society of Pulmonology reviews the most recent scientific literature on long-term mechanical ventilation and provides recommendations adapted to the particular setting of the Swiss healthcare system with a focus on the practice of non-invasive and invasive home ventilation in adults.

Characteristics and risk profiles of patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension living permanently at >2500 m of high altitude in Ecuador.

Over 80 Mio people worldwide live >2500 m, including at least as many patients with pulmonary vascular disease (PVD), defined as pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH), as elsewhere (estimated 0.1‰). Whether PVD patients living at high altitude have altered disease characteristics due to hypobaric hypoxia is unknown. In a cross-sectional study conducted at the Hospital Carlos Andrade Marin in Quito, Ecuador, located at 2840 m, we included 36 outpatients with PAH or CTEPH visiting the clinic from January 2022 to July 2023. We collected data on diagnostic right heart catheterization, treatment, and risk factors, including NYHA functional class (FC), 6-min walk distance (6MWD), and NT-brain natriuretic peptide (BNP) at baseline and at last follow-up. Thirty-six PVD patients (83% women, 32 PAH, 4 CTEPH, mean ± SD age 44 ± 13 years, living altitude 2831 ± 58 m) were included and had the following baseline values: PaO2 8.2 ± 1.6 kPa, PaCO2 3.9 ± 0.5 kPa, SaO2 91 ± 3%, mean pulmonary artery pressure 53 ± 16 mmHg, pulmonary vascular resistance 16 ± 4 WU, 50% FC II, 50% FC III, 6MWD 472 ± 118 m, BNP 490 ± 823 ng/L. Patients were treated for 1628 ± 1186 days with sildenafil (100%), bosentan (33%), calcium channel blockers (33%), diuretics (69%), and oxygen (nocturnal 53%, daytime 11%). Values at last visit were: FC (II 75%, III 25%), 6MWD of 496 ± 108 m, BNP of 576 ± 5774 ng/L. Compared to European PVD registries, ambulatory PVD patients living >2500 m revealed similar blood gases and relatively low and stable risk factor profiles despite severe hemodynamic compromise, suggesting that favorable outcomes are achievable for altitude residents with PVD. Future studies should focus on long-term outcomes in PVD patients dwelling >2500 m.

ERBB2-amplified lobular breast carcinoma exhibits concomitant CDK12 co-amplification associated with poor prognostic features.

Most invasive lobular breast carcinomas (ILBCs) are luminal-type carcinomas with an HER2-negative phenotype (ERBB2 or HER2 un-amplified) and CDH1 mutations. Rare variants include ERBB2-amplified subtypes associated with an unfavorable prognosis and less response to anti-HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2-amplified ILBC and compared these characteristics with ERBB2-unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin-embedded formalin-fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast-specific markers was tested by immunohistochemistry (IHC). Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2-amplified ILBC had higher tumor stage (p < 0.0001), more frequent positive nodal status (p = 0.00022), more distant metastases (p = 0.012), and higher histological grade (p < 0.0001), and were more often hormone receptor negative (p < 0.001) and more often SOX10 positive (p = 0.005). ERBB2 short variant sequence mutations were more often detected in ERBB2-unamplified tumors (6/10, p = 0.027), whereas CDH1 mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2-positive ILBC (p = 0.0009). CDK12 gene amplification (≥6 copies) was detected in 7 of 10 ERBB2-amplified ILBC (p = 0.018). There were no CDK12 gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. ERBB2-amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2-unamplified ILBC. CDK12/ERBB2 co-amplification may explain the poor prognosis and therapy resistance of ERBB2-amplified ILBC.

ERS International Congress 2023: highlights from the Sleep Disordered Breathing Assembly.

The topic of sleep-related breathing disorders is always evolving, and during the European Respiratory Society (ERS) International Congress 2023 in Milan, Italy, the latest research and clinical topics in respiratory medicine were presented. The most interesting issues included new diagnostic tools, such as cardiovascular parameters and artificial intelligence, pathophysiological traits of sleep disordered breathing from routine polysomnography or polygraphy signals, and new biomarkers and the diagnostic approach in patients with excessive daytime sleepiness. This article summarises the most relevant studies and topics presented at the ERS International Congress 2023. Each section has been written by early career members of ERS Assembly 4.

Anti-IgLON5 Disease: A New Bulbar-Onset Motor Neuron Mimic Syndrome.

OBJECTIVE: To expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5-seropositive cases with bulbar motor neuron disease-like phenotype. METHODS: We characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients. RESULTS: Patients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy. CONCLUSION: IgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.

Apnoea-hypopnoea-index comparing the 2007 and 2012 American Academy of Sleep Medicine criteria in chronic obstructive pulmonary disease/obstructive sleep apnoea overlap syndrome.

BACKGROUND: In 2007 and 2012, the American Academy of Sleep Medicine (AASM) updated their scoring criteria for nocturnal respiratory events. We hypothesised that this could have led to changes in the apnoea-hypopnoea index (AHI) of patients with chronic obstructive pulmonary disease (COPD)/obstructive sleep apnoea (OSA) overlap syndrome. METHODS: In a retrospective study, polysomnographic (PSG) recordings of 34 patients with COPD/OSA overlap syndrome were independently analysed using the AASM criteria from 2007 (AASM2007) and 2012 (AASM2012). The primary outcome was the difference in AHI, the secondary outcomes were frequency of hypopnoeas, diagnosis of overlap syndrome and differences between the AASM 2007 recommended (AASM2007Rec) and altered (AASM2007Alt) classifications. Data are presented as mean (standard deviation) if normally distributed, and as median (interquartile range) if non-normally distributed. RESULTS: The PSGs of 34 elderly [aged 67 (7.0) years] and predominantly male (m:f, 31:3) patients with COPD [FEV1%pred 48.4% (19.6%)] were analysed. The AHI using AASM2007Rec criteria was 5.9 (2.0, 15.1) events/hour vs. 20.4 (11.5, 28.0) events/hour using the 2012 criteria (P<0.001); with the AASM2007Alt criteria, the AHI was 15.0 (9.3, 26.3) events/hour (P<0.001). Using the 2012 classification, the number of scored hypopnoeas increased by +48% compared to the AASM2007Rec criteria (P<0.001), 92% of these events were associated with arousal. Although statistically non-significant, using the AASM2007Alt classification, 12% of our cohort would not have been diagnosed with COPD/OSA overlap syndrome (P=0.114), this was also the case for 47% of the cohort when the AASM2007Rec classification was used (P<0.01). CONCLUSIONS: The use of the AASM2012 scoring rules results in a significantly higher AHI compared to the AASM2007 criteria in patients with COPD/OSA overlap syndrome, mostly due to an increased number of arousal-associated hypopnoeas. These observations are important for the definition of the COPD/OSA overlap syndrome.

Ultrasound assessment of upper airway dilator muscle contraction during transcutaneous electrical stimulation in patients with obstructive sleep apnoea.

BACKGROUND: Electrical current can be used to stimulate upper airway dilator muscles to treat obstructive sleep apnoea (OSA). Ultrasound devices are widely available and may be used to detect contraction of the upper airway dilator muscles assessing the functionality of electrical stimulation (ES) used for this treatment. METHODS: In a physiological sub-study of a randomised controlled trial, patients with OSA underwent ultrasound examination to assess contraction of the upper airway dilator muscles in response to transcutaneous ES. Ultrasound scans were scored according to the picture quality (poor = '0', acceptable = '1' and good = '2'). Tongue base thickness was assessed in mid-sagittal and coronal planes with (D2, A2) and without ES (D1, A1), while awake and seated. The primary outcome was to determine the increase in tongue thickness during ES in both views (D2 - D1 = ΔD), as well as any increase in the cross-sectional area (CSA) in the coronal view (A2 - A1 = ΔA). Data were presented as mean and standard deviation (SD). RESULTS: Fourteen patients [eight male, age 57.5 (9.8) years, body mass index (BMI) 29.5 (2.8) kg/m2] with OSA [Apnea-Hypopnea Index (AHI) 19.5 (10.6) × hour-1] were studied. Quality of the ultrasound scans was acceptable or good with 1.5 (0.5) points. In the mid-sagittal plane, ΔD was +0.17 (0.07) cm in midline and +0.21 (0.09) cm in the widest diameter, a percentual change of 12.2% (4%) and 12.8% (5.2%) (P<0.001, respectively). In the coronal plane, ΔD was +0.17 (0.04) cm, an increase of 12.3% (4.6%) (P<0.001, respectively), ΔA in the CSA increased by +18.9% (3.0%) with stimulation (P<0.001). There was a negative correlation between age and ΔA (r= -0.6, P=0.03), but no significant associations were found with gender, BMI, neck circumference, Epworth Sleepiness Scale (ESS), AHI, skin and subcutaneous tissue in the submental area. CONCLUSIONS: Ultrasound can visualise upper airway dilator muscle contraction during transcutaneous ES in awake patients with OSA. Contraction is best detected in the CSA of the tongue base in the coronal plane.

Accuracy of the Hospital Anxiety and Depression Scale for identifying depression in chronic obstructive pulmonary disease patients.

Psychological morbidity is common in chronic respiratory diseases. The diagnostic accuracy of the Hospital Anxiety and Depression Scale (HADS) and risk factors for comorbid depression in chronic obstructive pulmonary disease (COPD) are addressed. Consecutive COPD patients (GOLD stage I-IV, 40-75 years old) were enrolled in a multicentre, cross-sectional cohort study. Diagnosis of depression was ascertained through clinical records. Lung function, HADS score, 6-minute walking test (6-MWT), MRC dyspnoea score, and COPD Assessment Test (CAT) were evaluated. Two hundred fifty-nine COPD patients (mean age 62.5 years; 32% female; mean FEV1 48% predicted) were included. Patients diagnosed with depression (29/259; 11.2%) had significantly higher HADS-D and HADS-Total scores than nondepressed patients (median (quartiles) HADS-D 6 [4; 9] versus 4 [2; 7], median HADS-Total 14 [10; 20] versus 8 [5; 14]). Receiver-operating characteristic plots showed moderate accuracy for HADS-D, AUC 0.662 (95%CI 0.601-0.719), and HADS-Total, AUC 0.681 (95%CI 0.620-0.737), with optimal cut-off scores of >5 and >9, respectively. Sensitivity and specificity were 62.1% and 62.6% for HADS-D compared to 75.9% and 55.2% for HADS-Total. Age, comorbidities, sex, and lower airflow limitation predicted depression. The HADS exhibits low diagnostic accuracy for depression in COPD patients. Younger men with comorbidities are at increased risk for depression.