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Rationale: Current guidelines recommend patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia receive empirical antibiotics for suspected bacterial superinfection on the basis of weak evidence. Rates of ventilator-associated pneumonia (VAP) in clinical trials of patients with SARS-CoV-2 pneumonia are unexpectedly low. Objectives: We conducted an observational single-center study to determine the prevalence and etiology of bacterial superinfection at the time of initial intubation and the incidence and etiology of subsequent bacterial VAP in patients with severe SARS-CoV-2 pneumonia. Methods: Bronchoscopic BAL fluid samples from all patients with SARS-CoV-2 pneumonia requiring mechanical ventilation were analyzed using quantitative cultures and a multiplex PCR panel. Actual antibiotic use was compared with guideline-recommended therapy. Measurements and Main Results: We analyzed 386 BAL samples from 179 patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. Bacterial superinfection within 48 hours of intubation was detected in 21% of patients. Seventy-two patients (44.4%) developed at least one VAP episode (VAP incidence rate = 45.2/1,000 ventilator days); 15 (20.8%) initial VAPs were caused by difficult-to-treat pathogens. The clinical criteria did not distinguish between patients with or without bacterial superinfection. BAL-based management was associated with significantly reduced antibiotic use compared with guideline recommendations. Conclusions: In patients with SARS-CoV-2 pneumonia requiring mechanical ventilation, bacterial superinfection at the time of intubation occurs in

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation. Analysis of bronchoalveolar lavage fluid samples from patients with SARS-CoV-2-induced respiratory failure suggests that SARS-CoV-2 infects alveolar macrophages to cause release of T cell chemoattractants, thereby inducing local inflammatory cytokine release and further T cell activation, ultimately resulting in a positive feedback loop that drives alveolar inflammation.

Rationale: The frequency of superinfection with Aspergillus among patients with severe COVID-19-related respiratory failure is unknown. The association of bronchoalveolar lavage (BAL) fluid markers, such as galactomannan, with the presence of Aspergillus infections is also unclear. Methods: Our cohort included all patients with COVID-19 admitted to the Northwestern Memorial Hospital ICU from March to November 2020 who were intubated and underwent a BAL;patients were identified as having COVID-19 by the presence of a flag in the electronic medical record. We evaluated BAL fluid data for fungal organisms and markers. Data analysis was performed in Excel and Prism, with non-parametric values compared by two-tailed Mann Whitney tests. Results: We identified 274 patients meeting study entry criteria. The median (interquartile range) age was 62 years (47-69), and 93 (34%) were female. 714 BALs were performed on these patients, and 457 galactomannan tests were sent from these BALs. Only six (2.2%) patients grew Aspergillus on BAL fluid culture;one patient never grew Aspergillus but given his significantly elevated BAL galactomannan of 7.81, was empirically treated. The median (IQR) optical density index of galactomannan for the BAL samples that grew Aspergillus was 6.69 (3.37-8.87) compared with 0.08 (0.06-0.13) for those that did not, p 0.5 as positive, with patients who grew Aspergillus on culture as gold standard, the test sensitivity was 91.7% and specificity was 94.6%;using the ATS recommended cutoff of >1.0 as positive, the sensitivity was 75.0% and specificity was 97.5%. The median (IQR) age of patients who grew Aspergillus was 71.5 years (64-80.5) (p=0.02 compared with the overall cohort). Only two were immunocompromised (diffuse large B-cell lymphoma and another was status post liver transplant). Of note, two patients who grew Aspergillus had visible mold or plaque seen during bronchoscopy;three had cavitary findings on imaging;three died. Conclusions: Aspergillus superinfection is uncommon among ventilated patients with COVID-19 but can occur in patients without typical immunocompromising risk factors. BAL fluid galactomannan levels are lower in patients without Aspergillus, and had reasonable specificity especially if cutoff of >1.0 was used. Future analysis should focus on additional factors that differentiate between these two groups.

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS) [1]. Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from other types of pneumonia [2]. We collected bronchoalveolar lavage fluid samples from 86 patients with SARS-CoV-2-induced respiratory failure and 252 patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling. We performed single cell RNA-Seq in 5 bronchoalveolar lavage fluid samples collected from patients with severe COVID-19 within 48 hours of intubation. In the majority of patients with SARS-CoV-2 infection at the onset of mechanical ventilation, the alveolar space is persistently enriched in alveolar macrophages and T cells without neutrophilia. Bulk and single cell transcriptomic profiling suggest SARS-CoV-2 infects alveolar macrophages that respond by recruiting T cells. These T cells release interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote T cell recruitment. Our results suggest SARS-CoV-2 causes a slowly unfolding, spatially-limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 transcripts and T cells form a positive feedback loop that drives progressive alveolar inflammation.This manuscript is accompanied by an online resource: https://www.nupulmonary.org/covid-19/One sentence summarySARS-CoV-2-infected alveolar macrophages form positive feedback loops with T cells in patients with severe COVID-19.

Aims HIV-infected persons may have elevated risks for heart failure, but factors associated with heart failure in the modern era of HIV therapy are insufficiently understood. Despite substantial disagreement between physician-adjudicated heart failure and heart failure diagnosis codes, few studies of HIV cohorts have evaluated adjudicated heart failure. We evaluated associations of HIV viremia, immunosuppression, and cardiovascular risk factors with physician-adjudicated heart failure. Methods and results We analyzed clinical characteristics associated with heart failure in a cohort of 5041 HIV-infected patients receiving care at an urban hospital system between 2000 and 2016. We also evaluated characteristics of HIV-infected patients who screened negative for heart failure, screened positive for possible heart failure but did not have heart failure after adjudication, and had adjudicated heart failure. HIV-infected patients with heart failure ( N = 216) were older and more likely to be black, hypertensive, and have diabetes than HIV-infected patients without heart failure; heart failure with reduced ejection fraction was more common than heart failure with preserved ejection fraction. In our primary analyses restricted to HIV-infected patients whose heart failure diagnoses did not precede their HIV diagnoses ( N = 149), peak HIV viral load ≥100,000 copies/mL (odds ratio (OR) 2.12, 1.28-3.52) and nadir CD4 T-cell count200 cells/mm

Background: Analyses of administrative data suggest that HIV+ persons have elevated risks for HF from HIV-related and traditional cardiovascular disease (CVD) risk factors. However, none of these studies adjudicated HF diagnoses, which is essential given poor agreement between administrative coding and physician adjudication. We sought to create a reproducible protocol for identifying and adjudicating HF in HIV+ persons and to compare characteristics between those with and without adjudicated HF. Methods: We screened for and adjudicated HF diagnoses in a cohort of 5,052 HIV+ persons receiving care at an academic center. Screening for possible HF included any of the following: 1) HF diagnosis code, 2) B-type natriuretic peptide (BNP) >100 pg/mL, or 3) intravenous diuretic use. Two physicians then independently reviewed all records. Definite HF was adjudicated if all of the following were present: HF symptoms, physician diagnosis, HF medication use, and objective evidence of myocardial dysfunction. Demographics and clinical characteristics were compared for HIV+ patients with screened+/adjudicated+ HF, screened+/adjudicated- HF, and those who screened- for HF. Results: There was >96% agreement in HF diagnoses between the two adjudicators (Kappa = 0.91). Race differed significantly across the three groups, with more black patients among those with adjudicated+ HF (Table 1). Patients with adjudicated+ HF were significantly more likely than patients who screened+/adjudicated- HF to have diabetes, hypertension, atrial arrhythmias, a diagnosis of myocardial infarction, and any smoking history (p Conclusions: There are significant clinical differences between HIV+ patients with and without adjudicated HF. These findings underscore the importance of adjudicating HF in future studies characterizing CVD for HIV+ persons.

Background: HIV+ persons appear to have elevated risks for HF. However, few studies have evaluated clinical characteristics of HF in HIV and none has adjudicated HF diagnoses. Thus, the extent to which traditional and HIV-specific risk factors contribute to HF in HIV remains unclear. We hypothesized

Background: HIV+ persons have elevated risks for various manifestations of cardiovascular disease (CVD), but no studies to our knowledge have evaluated AF and AFL for HIV+ persons and matched uninfected controls. Methods: Patients from an electronic cohort of 5,052 HIV+ patients and 10,121