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Shedding of hyaluronan (HA), the component of endothelial cell (EC) glycocalyx, has been associated with acute lung injury. HA degradation allows plasma proteins and fluid to penetrate across the vascular wall leading to lung edema formation and leukocyte recruitment. Here, we analyzed sHA levels and size in patients with community-acquired pneumonia (CAP) and acute respiratory distress syndrome (ARDS), correlated them to disease severity, and evaluated the impact of pneumolysin (PLY), the Streptococcus pneumoniae (S.p.) exotoxin, on HA shedding from human pulmonary microvascular EC (HPMVEC). sHA levels were elevated in CAP and ARDS and correlated with the CRB65 severity score and with markers of inflammation (interleukin-6), EC activation (E-selectin), and basement membrane destruction (collagen IV). Furthermore, sHA levels were associated with an increase in 28-day mortality. Small and large sHA fragments were detected in plasma of most severe CAP or ARDS patients, and the presence of large sHA fragments was accompanied by the elevated levels of circulating collagen IV. In vitro, PLY induced sHA release from HPMVEC. This effect was dependent on reactive oxygen species (ROS) production and was not associated with endothelial barrier dysfunction. Conversely, HA shedding was impaired following HPMVEC infection with a S.p. PLY-deficient mutant. Our study identifies association between the severity of CAP and ARDS and the levels and size of sHA in plasma. It links sHA levels with, inflammation, EC activation status and basement membrane disassembly in ARDS and provides insights into the mechanism of HA shedding during infection.

BackgroundPaediatric community-acquired pneumonia (CAP) is a leading cause of paediatric morbidity. However, particularly for outpatients with paediatric CAP, data on aetiology and management are scarce.MethodsThe prospective pedCAPNETZ study multicentrically enrols children and adolescents with outpatient-treated or hospitalised paediatric CAP in Germany. Blood and respiratory specimens were collected systematically, and comprehensive analyses of pathogen spectra were conducted. Follow-up evaluations were performed until day 90 after enrolment.ResultsBetween December 2014 and August 2020, we enrolled 486 children with paediatric CAP at eight study sites, 437 (89.9%) of whom had radiographic evidence of paediatric CAP. Median (interquartile range) age was 4.5 (1.6–6.6) years, and 345 (78.9%) children were hospitalised. The most prevalent symptoms at enrolment were cough (91.8%), fever (89.2%) and tachypnoea (62.0%). Outpatients were significantly older, displayed significantly lower C-reactive protein levels and were significantly more likely to be symptom-free at follow-up days 14 and 90. Pathogens were detected in 90.3% of all patients (one or more viral pathogens in 68.1%; one or more bacterial strains in 18.7%; combined bacterial/viral pathogens in 4.1%). Parainfluenza virus andMycoplasma pneumoniaewere significantly more frequent in outpatients. The proportion of patients with antibiotic therapy was comparably high in both groups (92.4% of outpatientsversus86.2% of hospitalised patients).ConclusionWe present first data on paediatric CAP with comprehensive analyses in outpatients and hospitalised cases and demonstrate high detection rates of viral pathogens in both groups. Particularly in young paediatric CAP patients with outpatient care, antibiotic therapy needs to be critically debated.

BackgroundImmune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro.MethodsIn our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters.ResultsWe observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort.ConclusionThe cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology.

Supplemental material, sj-pdf-1-tar-10.1177_17534666221148663 for Standardized airway wall thickness Pi10 from routine CT scans of COPD patients as imaging biomarker for disease severity, lung function decline, and mortality by Kathrin Kahnert, Rudolf A. Jörres, Hans-Ulrich Kauczor, Peter Alter, Franziska C. Trudzinski, Felix Herth, Bertram Jobst, Oliver Weinheimer, Sebastian Nauck, Pontus Mertsch, Diego Kauffmann-Guerrero, Jürgen Behr, Robert Bals, Henrik Watz, Klaus F. Rabe, Tobias Welte, Claus F. Vogelmeier and Jürgen Biederer in Therapeutic Advances in Respiratory Disease

Additional file 2: Table S2. Competing risk regression model for intracranial hemorrhage treating death without intracranial hemorrhage as a competing event and study site as a frailty term.

Additional file 1: Table S1. Linear mixed effect model for the prediction of the anti-Xa activity.

Supplemental material, sj-docx-2-tar-10.1177_17534666221148663 for Standardized airway wall thickness Pi10 from routine CT scans of COPD patients as imaging biomarker for disease severity, lung function decline, and mortality by Kathrin Kahnert, Rudolf A. Jörres, Hans-Ulrich Kauczor, Peter Alter, Franziska C. Trudzinski, Felix Herth, Bertram Jobst, Oliver Weinheimer, Sebastian Nauck, Pontus Mertsch, Diego Kauffmann-Guerrero, Jürgen Behr, Robert Bals, Henrik Watz, Klaus F. Rabe, Tobias Welte, Claus F. Vogelmeier and Jürgen Biederer in Therapeutic Advances in Respiratory Disease

Human alpha-1-antitrypsin (AAT) encoded by theSERPINA1gene, is an acute phase glycoprotein that regulates inflammatory responsesviaboth protease inhibitory and non-inhibitory activities. We previously reported that AAT controls ATP-induced IL-1β release from human mononuclear cells by stimulating the release of small bioactive molecules. In the current study, we aimed to elucidate the identity of these putative effectors released from human PBMCs in response to AAT, which may inhibit the LPS-induced release of IL-1β. We pre-incubated human PBMCs alone or with different preparations of AAT (4 mg/ml) for 30 min at 37°C, 5% CO2, and collected cell supernatants filtered through centrifugal filters (cutoff 3 kDa) to eliminate AAT and other high molecular weight substances. Supernatants passed through the filters were used to culture PBMCs isolated from the autologous or a heterologous donors with or without adding LPS (1 μg/ml) for 6 h. Unexpectedly, supernatants from PBMCs pre-incubated with AAT (Zemaira®), but not with other AAT preparations tested or with oxidized AAT (Zemaira®), lowered the LPS-induced release of IL-1β by about 25%–60% without affectingIL1BmRNA. The reversed-phase liquid chromatography coupled with mass spectrometry did not confirm the hypothesis that small pro-resolving lipid mediators released from PBMCs after exposure to AAT (Zemaira®) are responsible for lowering the LPS-induced IL-1β release. Distinctively from other AAT preparations, AAT (Zemaira®) and supernatants from PBMCs pre-treated with this protein contained high levels of total thiols. In line, mass spectrometry analysis revealed that AAT (Zemaira®) protein contains freer Cys232 than AAT (Prolastin®). Our data show that a free Cys232 in AAT is required for controlling LPS-induced IL-1β release from human PBMCs. Further studies characterizing AAT preparations used to treat patients with inherited AAT deficiency remains of clinical importance.

BackgroundDespite the availability of COVID-19 vaccinations, there remains a need to investigate treatments to reduce the risk or severity of potentially fatal complications of COVID-19, such as acute respiratory distress syndrome (ARDS). This study evaluated the efficacy and safety of the transient receptor potential channel C6 (TRPC6) inhibitor, BI 764198, in reducing the risk and/or severity of ARDS in patients hospitalised for COVID-19 and requiring non-invasive, supplemental oxygen support (oxygen by mask or nasal prongs, oxygen by non-invasive ventilation or high-flow nasal oxygen).MethodsMulticentre, double-blind, randomised phase II trial comparing once-daily oral BI 764198 (n=65) with placebo (n=64) for 28 days (+2-month follow-up). Primary endpoint: proportion of patients alive and free of mechanical ventilation at day 29. Secondary endpoints: proportion of patients alive and discharged without oxygen (day 29); occurrence of either in-hospital mortality, intensive care unit admission or mechanical ventilation (day 29); time to first response (clinical improvement/recovery); ventilator-free days (day 29); and mortality (days 15, 29, 60 and 90).ResultsNo difference was observed for the primary endpoint: BI 764198 (83.1%) versus placebo (87.5%) (estimated risk difference –5.39%; 95% CI –16.08 to 5.30; p=0.323). For secondary endpoints, a longer time to first response (rate ratio 0.67; 95% CI 0.46 to 0.99; p=0.045) and longer hospitalisation (+3.41 days; 95% CI 0.49 to 6.34; p=0.023) for BI 764198 versus placebo was observed; no other significant differences were observed. On-treatment adverse events were similar between trial arms and more fatal events were reported for BI 764198 (n=7) versus placebo (n=2). Treatment was stopped early based on an interim observation of a lack of efficacy and an imbalance of fatal events (Data Monitoring Committee recommendation).ConclusionsTRPC6 inhibition was not effective in reducing the risk and/or severity of ARDS in patients with COVID-19 requiring non-invasive, supplemental oxygen support.Trial registration numberNCT04604184.

Background Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. Methods In the original RCT, patients with septic shock of Results A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). Conclusions Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994).

Additional file1: Table S1. Linear mixed effect model for the prediction of norepinephrine doses. Table S2. Linear mixed effect model for the prediction of serum lactate levels. Table S3. Linear mixed effect model for the prediction of the norepinephrine dose.

Additional file 1. Supplementary Tables and Figures.

Additional file 1: Figure S1. Genotyping of MMP-2 KO, MMP-9 KO, and MMP-2/-9 double KO mice. Schematic overview of genotyping of MMP-2 KO and MMP-9 KO mice and genotyping of MMP-2 KO, MMP-9 KO, and MMP-2/-9 double KO mice by PCR. Table S1. Patient characteristics. Characteristics of ILD-patients and disease controls.

BackgroundChronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study.MethodsWe analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income.ResultsOverall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19–1.94), wheeze (OR 1.37, 95% CI 1.16–1.63) and dyspnoea (OR 1.83, 95% CI 1.53–2.20), but not lower FVC (β=0.02 L, 95% CI −0.02–0.06 L) or lower FEV1/FVC (β=0.04%, 95% CI −0.49–0.58%). Some findings differed by sex and gross national income.ConclusionAt a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.

Additional file 1: Additional table 1. Characteristics of the samples used for the study.

Additional file 2: Additional table 2. Characteristics of dogs in the study.

Additional file 3: Additional table 3. Results of RT-PCR tests of TADD-membranes and dog noses after testing sessions.

Additional file 1: Table S1. Results of the Random Forest and AdaBoost procedures for different sets of variables included. The table shows the variables in the rank order of importance according to the criterion of the mean decrease in accuracy (Random Forest) and the importance measure defined in the AdaBoost procedure. The overall classification error refers to 10-fold cross-validation in the case of AdaBoost and CHAID. SGRQ4 “I have attacks of wheezing”, SGRQ5 “How many attacks of chest trouble did you have during the last year?”, SGRQ8, “How would you describe your chest condition?”, SGRQ11 sub-item 5 “I have become frail or an invalid because of my chest”, SGRQ12 sub-item 1 “I take a long time to get washed or dressed”, SGRQ12 sub-item 3 “I walk slower than other people, or I stop for rests”, SGRQ12 sub-item 4 “Jobs such as housework take a long time, or I have to stop for rests”, SGRQ13 sub-item 1 “I cannot play sports or games”, SGRQ14 “How does your chest trouble affect you? Table S2. Technical details of the CT assessment. The acquisition protocol is given in the upper part and details on the scanner models in the lower part of the table. *Vendor-specific generic names for Siemens/GE/Philips. Table S3. Items from the “St. George’s Respiratory Questionnaire” (SGRQ) that turned out to be informative in the single decision trees. Table S4. Items from the COPD Assessment test (CAT). Table S5. Modified Medical Research Council (mMRC) scale. This self-rating questionnaire is used to measure the degree of disability that breathlessness poses on day-to-day activities on a scale from 0 to 4.

Bronchiectasis (BE) might be frequently present in COPD but masked by COPD symptoms. We studied the relationship of clinical signs of bronchiectasis to the presence and extent of its radiological signs in patients of different COPD severity. Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was used. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0: absence, 1: ≤50%, 2: >50% BE-involvement for each lobe). 1176 patients were included (61%male, age 67.3y), among them 38 (3.2%) with reported physicians' diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). CT scans were obtained in 429 patients. Within this group, any signs of bronchiectasis were found in 46.6% of patients, whereby ≤50% BE occurred in 18.6% in ≤2 lobes, in 10.0% in 3-4 lobes, in 15.9% in 5-6 lobes; >50% bronchiectasis in at least 1 lobe was observed in 2.1%. Scores ≥4 correlated with an elevated ratio FRC/RV. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. In COPD patients, clinical diagnosis and radiological signs of BE showed only weak correlations. Correlations became significant with increasing BE-severity implying radiological alterations in several lobes. This indicates the importance of reporting both presence and extent of bronchiectasis on CT. Further research is warranted to refine the criteria for CT scoring of bronchiectasis and to determine the relevance of radiologically but not clinically detectible bronchiectasis and their possible implications for therapy in COPD patients.

The COPD Assessment Test (CAT) is in widespread use for the evaluation of patients with chronic obstructive pulmonary disease (COPD). We assessed whether the CAT items carry additional information beyond the sum score regarding COPD characteristics including emphysema. Patients of GOLD grades 1 to 4 from the COPD cohort COSYCONET (German COPD and Systemic Consequences - Comorbidities Network) with complete CAT data were included (n = 2270), of whom 493 had chest CT evaluated for the presence of emphysema. Comorbidities and lung function were assessed following standardised procedures. Cross-sectional data analysis was based on multiple regression analysis of the single CAT items against a panel of comorbidities, lung function, or CT characteristics (qualitative score, 15th percentile of mean lung density), with age, BMI and gender as covariates. This was supported by exploratory factor analysis. Regarding the relationship to comorbidities and emphysema, there were marked differences between CAT items, especially items 1 and 2 versus 3 to 8. This grouping was basically confirmed by factor analysis. Items 4 and 5, and to a lower degree 1, 2 and 6, appeared to be informative regarding the presence of emphysema, whereas the total score was not or less informative. Regarding comorbidities, similar findings as for the total CAT score were obtained for the modified Medical Research Council scale (mMRC) which was also informative regarding emphysema. Our findings suggest that the usefulness of the CAT can be increased if evaluated on the basis of single items which may be indicating the presence of comorbidities and emphysema.

Rationale Alterations of acid-base metabolism are an important outcome predictor in acute exacerbations of COPD, whereas sufficient metabolic compensation and adequate renal function are associated with decreased mortality. In stable COPD there is, however, only limited information on the combined role of acid-base balance, blood gases, renal and respiratory function on exacerbation risk grading. Methods We used baseline data of the COPD cohort COSYCONET, applying linear and logistic regression analyses, the results of which were implemented into a comprehensive structural equation model. As most informative parameters it comprised the estimated glomerular filtration rate (eGFR), lung function defined via forced expiratory volume in 1 s (FEV1), intrathoracic gas volume (ITGV) and (diffusing capacity for carbon monoxide (DLCO), moreover arterial oxygen content (CaO2), partial pressure of oxygen (PaCO2), base exess (BE) and exacerbation risk according to GOLD criteria. All measures were adjusted for age, gender, body-mass index, the current smoking status and pack years. Results 1506 patients with stable COPD (GOLD grade 1–4; mean age 64.5 ± 8.1 y; mean FEV1 54 ± 18 %predicted, mean eGFR 82.3 ± 16.9 mL/min/1.73 m2) were included. BE was linked to eGFR, lung function and PaCO2 and played a role as indirect predictor of exacerbation risk via these measures; moreover, eGFR was directly linked to exacerbation risk. These associations remained significant after taking into account medication (diuretics, oral and inhaled corticosteroids), whereby corticosteroids had effects on exacerbation risk and lung function, diuretics on eGFR, BE and lung function. Conclusion Even in stable COPD acid-base metabolism plays a key integrative role in COPD risk assessment despite rather small deviations from normality. It partially mediates the effects of impairments in kidney function, which are also directly linked to exacerbation risk.

Table S4. Sociodemographic and clinical parameters of the study sample comparing patients who were not included due to missing follow-up assessment of QoL in comparison to the cohort included into the analyses. (DOCX 24 kb)

Table S2. Patients in high-risk subgroup categories (ITT population). (DOCX 13 kb)

Supplemental material, Reviewer_1_v.1 for Chronic progressive pulmonary paracoccidioidomycosis in a female immigrant from Venezuela by Moritz Kayser, Volker Rickerts, Nora Drick, Jasmin Gerkrath, Hans Kreipe, Bisharah Soudah, Tobias Welte and Hendrik Suhling in Therapeutic Advances in Respiratory Disease

Additional file 1. BMC Pulm Med pedCAPNETZ_Wetzke_Supplementary Material. In this file, two additional tables provide information on (1) current guidelines on antibiotic therapy with references and (2) PCR based screening for CAP associated pathogens

Figure S1. Early improvement (ITT population). a. Early improvement at Day 3 in patients with CAP, by risk factor (ITT population). b. Early improvement at Day 4 in patients with HAP (excluding VAP) by risk factor (ITT population). c. Early improvement in high-risk group patients by pathogen type (ITT population). aThe comparator treatment was ceftriaxone Âą linezolid in CAP patients and ceftazidime plus linezolid in HAP (excluding VAP) patients. bBetween treatment difference calculated as ceftobiprole minus comparator. cTwo-sided 95% confidence interval is based on a normal approximation to the difference of the two proportions. Early clinical improvement is defined as improved or cured at Day 3 in patients with CAP, and improved or cured at Day 4 in patients with HAP (excluding VAP). Early clinical improvements were evaluated by the investigator, based on an assessment of symptoms using standardised criteria. (PDF 681 kb)

Supplemental Figures. (PPTX 279 kb)

Table S4. Baseline characteristics for CAP and HAP all-patients group (ITT population). (DOCX 13 kb)

Figure S1. Mean difference in QoL scores for patients with one, two, three and more than three hospitalizations compared to patients who were not hospitalized during the follow-up. (EQ-5D VAS, EuroQol five-dimensional questionnaire, recorded as a visual analog scale; QoL, quality of life; SGRQ, St. Georgeâ s Respiratory Questionnaire; USCD-SOBQ, University of California San Diego Shortness of Breath Questionnaire; WHO-5, World Health Organization-5 Well-Being Index). (DOCX 110 kb)

Supplemental material, Author_response_to_reviewer_comments for Chronic progressive pulmonary paracoccidioidomycosis in a female immigrant from Venezuela by Moritz Kayser, Volker Rickerts, Nora Drick, Jasmin Gerkrath, Hans Kreipe, Bisharah Soudah, Tobias Welte and Hendrik Suhling in Therapeutic Advances in Respiratory Disease

Table S1. Baseline characteristics for the all-patients groups for CAP and HAP (CE population). (DOCX 22 kb)

Table S1. Quality of life scores at each follow-up visit and change in quality of life over the 3-year follow-up. Table S2. Quality of life scores at last follow-up and change in quality of life between baseline and last follow-up by change in lung function parameters within 1 year after baseline. Table S3. Quality of life scores at visit prior to hospitalisation and subsequent visit after hospitalisation in follow-up. (DOCX 40 kb)

Table S5. Clinical cure at TOC visit by high-risk factor and pathogen type (ITT population) (DOCX 14 kb)

Supplement Description. (DOCX 16 kb)

Figure S2. 30-day all-cause mortality (ITT population). a. 30-day all-cause mortality in patients with CAP, by risk factor (ITT population). b. 30-day all-cause mortality in patients with HAP (excluding VAP) by risk factor (ITT population). c. 30-day all-cause mortality in high-risk group patients by pathogen type (ITT population). aThe comparator treatment was ceftriaxone Âą linezolid in CAP patients and ceftazidime plus linezolid in HAP (excluding VAP) patients. bBetween treatment difference calculated as ceftobiprole minus comparator. cTwo-sided 95% confidence interval is based on a normal approximation to the difference of the two proportions. (PDF 667 kb)

Table S3. Baseline characteristics for high-risk patients with CAP and HAP (excluding VAP) (ITT population). (DOCX 13 kb)

Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown. Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury. Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence. Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues. Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

Table S1. Microbial spectrum and initial anti-infective therapy. Demonstrated are characteristics of the site of infection, infectious pathogen species, initial anti-infective regimen, and sensitivity of the pathogen to initial therapy for each patient. (DOCX 106 kb)

Background: Interferon lambdas (IFNLs) have important anti-viral/bacterial and immunomodulatory functions in the respiratory tract. How do IFNLs impact COPD and its exacerbations? Methods: Five hundred twenty eight patients were recruited in a prospective observational multicentre cohort (PROMISE) study. The genetic polymorphisms (rs8099917 and rs12979860) within the IFNL3/4 gene region and circulating levels of IFNL3 in COPD patients were determined and associated with disease activity and outcome during a median follow-up of 24 months. Results: The GG genotype significantly influenced severe exacerbation rate (42 vs. 23%; p = 0.032) and time to severe exacerbation (HR = 2.260; p = 0.012). Compared to the TT or TG genotypes, the GG genotype was associated with severe dyspnoea (modified medical research council score ≥ median 3; 22 vs 42%, p = 0.030). The CC genotype of the rs12979860 SNP was associated with a poorer prognosis (body mass index, airflow obstruction, dyspnea and exercise capacity index ≥ median 4; 46 vs. 36% TC vs. 20.5% TT; p = 0.031). Patients with stable COPD and at exacerbation had significantly lower circulating IFNL3 compared to healthy controls (p < 0.001 and p < 0.001, respectively). Circulating IFNL3 correlated to post-bronchodilator FEV1%predicted and the tissue maturation biomarker Pro-collagen 3. Conclusion: IFNL3/4 polymorphisms and circulating IFNL3 may be associated with disease activity and outcomes in COPD. Trial registration: Clinical Trial registration http://www.isrctn.com/ identifier ISRCTN99586989 on 16 April 2008.

Figure S1. Cumulative incidence of (A) and in-hospital mortality in (B) Pneumocystis pneumonia (PcP) at Hannover Medical School from 2000 to 2017. Figure S2. Receiver operating characteristic (ROC) curves for in-hospital mortality applied to the total sample. Figure S3. ROC curves for in-hospital mortality applied to subgroups regarding underlying etiology of immunosuppression and for the ICU cohort. Figure S4. ROC curves for in-hospital mortality with the LDH prediction model applied in three strata (years 2000–2005, 2005–2010, 2010–2017). Figure S5. Association between trimethoprim-sulfamethoxazole (TMP-SMX) dose and mortality (DOCX 21 kb)

Table S2. Possible determinants of immediate and sustained clinical response to plasma exchange. Compared are differences in clinical and biochemical characteristics for the subgroups immediate response/nonresponse and sustained response/nonresponse, respectively. (DOCX 23 kb)

Additional details on methods. (DOC 62 kb)

Ethics Committees. (DOCX 18 kb)

Comparison of baseline characteristics of patients with and without available QoL data (total enrolled patients n = 737). (DOCX 15 kb)

Analysis of lung density by CT (available for 379 patients). (f) n = 3 missings, (g) n = 89 missings, *panlobular emphysema, PLE; centrilobular emphysema, CLE. Table E2. Multivariate linear regression model with TLCO %pred. as dependent variable. AATD refers to the presence of AATD versus COPD. Figure S1. Patients with AATD revealed a reduced TLCO %pred at similar levels of ITGV %pred. (A, B) or BMI (B, D) for both female and male patients after adjustment for FEV1, sex, BMI, packyears, and age (AATD - dotted line, COPD - straight line). Table S3. Results (Odds Ratio [95% confidence interval] and p-value) of multivariable logistic regression analyses for different comorbidities as dependent variable. (DOCX 265 kb)