Differences in Mortality Among Patients With Asthma and COPD Hospitalized With COVID-19.

BACKGROUND: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19). OBJECTIVE: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease. METHODS: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021. Airway disease diagnoses were defined using International Classification of Diseases, 10th Revision codes. Mortality and sequential organ failure assessment (SOFA) scores were compared among groups. Logistic regression analysis was used to identify and adjust for confounding clinical features associated with mortality. RESULTS: The median SOFA score in patients without airway disease was 0.32 and mortality was 11%. In comparison, asthma patients had lower SOFA scores (median 0.15; P < .01) and decreased mortality, even after adjusting for age, diabetes, and other confounders (odds ratio 0.65; P = .01). Patients with COPD had higher SOFA scores (median 0.86; P < .01) and increased adjusted odds of mortality (odds ratio 1.40; P < .01). Blood eosinophil count of 200 cells/µL or greater, a marker of type 2 inflammation, was associated with lower mortality across all groups. Importantly, patients with asthma showed improved outcomes even after adjusting for eosinophilia, indicating that noneosinophilic asthma was associated with protection as well. CONCLUSIONS: COVID-19 severity was increased in patients with COPD and decreased in those with asthma, eosinophilia, and noneosinophilic asthma, independent of clinical confounders. These findings suggest that COVID-19 severity may be influenced by intrinsic immunological factors in patients with airway diseases, such as type 2 inflammation.

Impact of Prophylactic Antibacterials on Coagulation Profiles and Bleeding in Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often receive antibacterial prophylaxis. Antibacterial agents can cause elevations in the prothrombin time and international normalized ratio (INR). The impact of prophylactic antibacterials on the coagulation profiles and bleeding risk in patients with AML/MDS is unknown. We evaluated patients with AML or MDS who were being admitted to the hospital. The cohort was divided into two groups of patients: (1) those receiving and (2) those not receiving prophylactic antibacterials, at the time of admission. We conducted a retrospective cohort study of adult patients with AML/MDS admitted to Yale-New Haven Hospital between 2015-2019. The study was approved by the Yale Institutional Review Board. Inclusion criteria included patients >18 years old with a diagnosis of AML or MDS admitted to the hospital. We identified 150 individual patient encounters with active AML/MDS admitted to Yale-New Haven of which 32 occurred while on and 118 while off antibacterial prophylaxis. Median duration of pre-admission antibacterial exposure was 2 (range: 0.07-24) months. Patients on antibacterial prophylaxis had higher INR (median 1.14 vs. 1.03, p = 0.0002), and higher partial thromboplastin time prolongation (median 26.5 vs. 24.3, p < 0.0014), than patients without antibacterial prophylaxis. Patients without antibacterial prophylaxis had higher rates of bleeding using the ISTH-defined criteria (24.6% vs. 6.3%, p = 0.043), including higher rates of ISTH major (2 vs. 0) and clinically relevant bleeding (9 vs. 0). Patients with AML/MDS on antibacterial prophylaxis were more likely to have an abnormal coagulation profile when compared with their counterparts not on prophylaxis. Conversely, rates of bleeding were higher in patients not on prophylaxis. These data suggest that prophylactic antibacterials do not increase bleeding risk in patients with AML/MDS.

Nonutility of procalcitonin for diagnosing bacterial pneumonia in patients with severe COVID-19.

Background: Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. Methods: We retrospectively identified 185 patients hospitalized with severe COVID-19 who underwent lower respiratory culture; 85 had evidence of bacterial superinfection. Receiver operating characteristic curve and area under the curve (AUC) analyses were performed to assess the utility of procalcitonin for diagnosing superinfection. Results: This approach demonstrated that procalcitonin measured at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). The AUC not affected by exposure to antibiotics, treatment with immunomodulatory agents, or timing of procalcitonin measurement. Conclusion: Static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

IFN-γ Is Protective in Cytokine Release Syndrome-associated Extrapulmonary Acute Lung Injury.

The mechanisms by which excessive systemic activation of adaptive T lymphocytes, as in cytokine release syndrome (CRS), leads to innate immune cell-mediated acute lung injury (ALI) or acute respiratory distress syndrome, often in the absence of any infection, remains unknown. Here, we investigated the roles of IFN-γ and IL-17A, key T-cell cytokines significantly elevated in patients with CRS, in the immunopathogenesis of CRS-induced extrapulmonary ALI. CRS was induced in wild-type (WT), IL-17A- and IFN-γ knockout (KO) human leukocyte antigen-DR3 transgenic mice with 10 µg of the superantigen, staphylococcal enterotoxin B, given intraperitoneally. Several ALI parameters, including gene expression profiling in the lungs, were studied 4, 24, or 48 hours later. Systemic T-cell activation with staphylococcal enterotoxin B resulted in robust upregulation of several chemokines, S100A8/A9, matrix metalloproteases, and other molecules implicated in tissue damage, granulocyte as well as agranulocyte adhesion, and diapedesis in the lungs as early as 4 hours, which was accompanied by subsequent neutrophil/eosinophil lung infiltration and severe ALI in IFN-γ KO mice. These pathways were significantly underexpressed in IL-17A KO mice, which manifested mildest ALI and intermediate in WT mice. Neutralization of IFN-γ worsened ALI in WT and IL-17A KO mice, whereas neutralizing IL-17A did not mitigate lung injury in IFN-γ KO mice, suggesting a dominant protective role for IFN-γ in ALI and that IL-17A is dispensable. Ruxolitinib, a Janus kinase inhibitor, increased ALI severity in WT mice. Thus, our study identified novel mechanisms of ALI in CRS and its differential modulation by IFN-γ and IL-17A.

Complications Associated with Continuous RRT.

Continuous renal replacement therapy (CRRT) is a form of renal replacement therapy that is used in modern intensive care units (ICUs) to help manage acute kidney injury (AKI), end stage kidney disease (ESKD), poisonings, and some electrolyte disorders. CRRT has transformed the care of patients in the ICU over the past several decades. In this setting, it is important to recognize CRRT-associated complications but also up-to-date management of these complications. Some of these complications are minor, but others may be more significant and even life-threatening. Some CRRT complications may be related to dialysis factors and others to specific patient factors. Our overarching goal in this article is to review and discuss the most significant CRRT-related complications at the different stage of management of CRRT. With the advent of newer solutions, there have been newer complications as well.

Prevalence and treatment of postobstructive pneumonia among older adults with advanced cancer.

Among 124 older adults with advanced cancer who were hospitalized with pneumonia, 7.3% met criteria for postobstructive pneumonia. There were no differences in antibiotic duration, antibiotic spectrum, 30-day and 90-day readmissions, or mortality between those with and without postobstructive pneumonia. Bacteria were identified in 5 patients with postobstructive pneumonia.

A dual role for CRTH2 in acute lung injury.

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid onset respiratory failure following acute lung injury (ALI). Its increased incidence due to COVID-19 and high mortality rate (∻40%) make the study of ARDS pathogenesis a crucial research priority. CRTH2 is a G protein-coupled receptor with established roles in type 2 immunity and well-characterized inhibitors. Prior studies have shown it also promotes neutrophilic inflammation, indicating that CRTH2 inhibition may be a potential therapeutic strategy for ARDS. To test this hypothesis, we first examined the expression pattern of CRTH2 on murine neutrophils. We found it is expressed on neutrophils, but only after extravasation into the lung. Next, we showed that extravasated lung neutrophils generate inflammatory responses upon stimulation with the CRTH2-specific agonist DK-PGD2, as demonstrated by reactive oxygen species (ROS) production. This response was abrogated in CRTH2 KO neutrophils. Inhibition of CRTH2 with fevipiprant suppressed baseline ROS production, indicating an autocrine PGD2-CRTH2 signaling loop. We then evaluated the role of CRTH2 in vivo using a murine model of LPS-induced ALI. Despite the pro-inflammatory effects of CRTH2 on neutrophils in vitro, we observed worsening of lung injury in CRTH2-deficient mice in terms of neutrophilic inflammation, vascular leak, and survival. Bulk RNAseq of lung tissue indicated an impairment in type 2 immune signaling; qPCR and ELISA confirmed downregulation of the key type 2 effector cytokine, IL-4. Thus, CRTH2 appears to play a dual role in ALI, directly promoting neutrophil effector responses, but indirectly suppressing lung injury and neutrophilic inflammation through type 2 immunity. These findings reveal a novel protective function for CRTH2 during lung injury and argue against the use of CRTH2 inhibitors in ARDS.

Nonutility of procalcitonin for diagnosing bacterial pneumonia in COVID-19.

Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. To do so, we identified 185 patients with severe COVID-19 who underwent lower respiratory culture; 85 had superinfection. Receiver operating characteristic curve analysis showed that procalcitonin at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). We conclude that static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

Understanding the Host in the Management of Pneumonia. An Official American Thoracic Society Workshop Report.

Pneumonia causes a significant burden of disease worldwide. Although all populations are at risk of pneumonia, those at extremes of age and those with immunosuppressive disorders, underlying respiratory disease, and critical illness are particularly vulnerable. Although clinical practice guidelines addressing the management and treatment of pneumonia exist, few of the supporting studies focus on the crucial contributions of the host in pneumonia pathogenesis and recovery. Such essential considerations include the host risk factors that lead to susceptibility to lung infections; biomarkers reflecting the host response and the means to pursue host-directed pneumonia therapy; systemic effects of pneumonia on the host; and long-term health outcomes after pneumonia. To address these gaps, the Pneumonia Working Group of the Assembly on Pulmonary Infection and Tuberculosis led a workshop held at the American Thoracic Society meeting in May 2018 with overarching objectives to foster attention, stimulate research, and promote funding for short-term and long-term investigations into the host contributions to pneumonia. The workshop involved participants from various disciplines with expertise in lung infection, pneumonia, sepsis, immunocompromised patients, translational biology, data science, genomics, systems biology, and clinical trials. This workshop report summarizes the presentations and discussions and important recommendations for future clinical pneumonia studies. These recommendations include establishing consensus disease and outcome definitions, improved phenotyping, development of clinical study networks, standardized data and biospecimen collection and protocols, and development of innovative trial designs.

Determinants of Outcomes of Acute Kidney Injury: Clinical Predictors and Beyond.

Acute kidney injury (AKI) is a common clinical syndrome characterized by rapid impairment of kidney function. The incidence of AKI and its severe form AKI requiring dialysis (AKI-D) has been increasing over the years. AKI etiology may be multifactorial and is substantially associated with increased morbidity and mortality. The outcome of AKI-D can vary from partial or complete recovery to transitioning to chronic kidney disease, end stage kidney disease, or even death. Predicting outcomes of patients with AKI is crucial as it may allow clinicians to guide policy regarding adequate management of this problem and offer the best long-term options to their patients in advance. In this manuscript, we will review the current evidence regarding the determinants of AKI outcomes, focusing on AKI-D.

A 62-Year-Old Woman With Lung Cancer, Ulcerating Rash, and Rapidly Progressive Hypoxemia.

CASE PRESENTATION: A 62-year-old nonsmoking woman with no medical history initially presented with a 3-month history of rash. A painful, erythematous exanthem had progressed from her forehead, cheeks, and upper chest to her eyes (heliotrope rash) and hands, primarily involving the extensor surface finger joints with prominent digital ulceration.

Quantification of bronchoalveolar neutrophil extracellular traps and phagocytosis in murine pneumonia.

The past two decades have witnessed a resurgence in neutrophil research, inspired in part by the discovery of neutrophil extracellular traps (NETs) and their myriad roles in health and disease. Within the lung, dysregulation of neutrophils and NETosis have been linked to an array of diseases including pneumonia, cystic fibrosis, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and severe asthma. However, our understanding of pathologic neutrophil responses in the lung remains incomplete. Two methodologic issues have contributed to this gap: first, an emphasis on studying neutrophils from blood rather than the lung and second, the technical difficulties of interrogating neutrophil responses in mice, which has largely restricted basic murine research to specialized laboratories. To address these limitations, we have developed a suite of techniques for studying neutrophil effector functions specifically in the mouse lung. These include ex vivo assays for phagocytosis and NETosis using bronchoalveolar neutrophils and in situ evaluation of NETosis in a murine model of pneumonia. Throughout, we have prioritized technical ease and robust, quantitative readouts. We hope these assays will help to standardize research on lung neutrophils and improve accessibility to this burgeoning field.

Severe respiratory viral infection induces procalcitonin in the absence of bacterial pneumonia.

INTRODUCTION: Procalcitonin expression is thought to be stimulated by bacteria and suppressed by viruses via interferon signalling. Consequently, during respiratory viral illness, clinicians often interpret elevated procalcitonin as evidence of bacterial coinfection, prompting antibiotic administration. We sought to evaluate the validity of this practice and the underlying assumption that viral infection inhibits procalcitonin synthesis. METHODS: We conducted a retrospective cohort study of patients hospitalised with pure viral infection (n=2075) versus bacterial coinfection (n=179). The ability of procalcitonin to distinguish these groups was assessed. In addition, procalcitonin and interferon gene expression were evaluated in murine and cellular models of influenza infection. RESULTS: Patients with bacterial coinfection had higher procalcitonin than those with pure viral infection, but also more severe disease and higher mortality (p<0.001). After matching for severity, the specificity of procalcitonin for bacterial coinfection dropped substantially, from 72% to 61%. In fact, receiver operating characteristic curve analysis showed that procalcitonin was a better indicator of multiple indices of severity (eg, organ failures and mortality) than of coinfection. Accordingly, patients with severe viral infection had elevated procalcitonin. In murine and cellular models of influenza infection, procalcitonin was also elevated despite bacteriologic sterility and correlated with markers of severity. Interferon signalling did not abrogate procalcitonin synthesis. DISCUSSION: These studies reveal that procalcitonin rises during pure viral infection in proportion to disease severity and is not suppressed by interferon signalling, in contrast to prior models of procalcitonin regulation. Applied clinically, our data suggest that procalcitonin represents a better indicator of disease severity than bacterial coinfection during viral respiratory infection.

Fluorescent stem peptide mimics: In situ probes for peptidoglycan crosslinking.

Understanding the mechanisms of bacterial cell wall synthesis is essential for microbiology and medicine alike. A key step in this process is peptidoglycan crosslinking, which confers mechanical strength to the cell wall and represents a target for numerous classes of antibiotics. However, the biology of crosslinking remains poorly understood due to a lack of tools for studying the reaction in vivo. Recently, we developed a class of synthetic probes called fluorescent stem peptide mimics (FSPMs) that meet this need, allowing quantification and localization of crosslinking activity in live bacteria. We have utilized FSPMs to describe novel aspects of peptidoglycan synthesis in the human pathogen, Staphylococcus aureus. To enable wider use of our methodology, we provide detailed protocols herein for the synthesis of FSPMs, labeling of live bacteria, and evaluation of crosslinking by flow cytometry and super-resolution microscopy. We believe that FSPMs, together with complementary biosynthetic probes and traditional bacteriologic methods, will help to advance our understanding of peptidoglycan biology and accelerate the search for new antibiotics.

Measurement of Chitinase Activity in Biological Samples.

Chitinases are the enzymes that cleave chitin. Even in the absence of chitin, mammalians have significant amounts of chitinases present in the body including at baseline. The precise role of chitinase is not known, however it was believed to play important role in digestion and host defense against chitin-containing food and pathogens, respectively. Recent work, including ours, has shown an important role of chitinase and chitinase-like proteins in host immunity and allergic diseases. Importantly, chitinase activities serve as important biomarkers of disease severity in a wide-range of diseases including type 2 inflammatory diseases such as asthma and pulmonary fibrosis. Similarly, patients with genetic disorders like Gaucher disease have significantly elevated chitinase levels, which not only correlate with disease severity but also serve as a reliable biomarker for therapeutic effectiveness. The protocol outlined here describes a simple, quick, and straightforward way to measure chitinase activity in BAL or serum samples of mice and can be widely adapted to human subjects and other model organisms due to the highly conserved nature of the enzymes.