Browsing by Subject "Pneumonia"
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Item Allergic Airway Disease in Mice Alters T and B Cell Responses during an Acute Respiratory Poxvirus Infection(Public Library of Science, 2013-04-19) Walline, Crystal C.; Sehra, Sarita; Fisher, Amanda J.; Guindon, Lynette M.; Kratzke, Ian M.; Montgomery, Jessica B.; Lipking, Kelsey P.; Glosson, Nicole L.; Benson, Heather L.; Sandusky, George E.; Wilkes, David S.; Brutkiewicz, Randy R.; Kaplan, Mark H.; Blum, Janice S.; Microbiology and Immunology, School of MedicinePulmonary viral infections can exacerbate or trigger the development of allergic airway diseases via multiple mechanisms depending upon the infectious agent. Respiratory vaccinia virus transmission is well established, yet the effects of allergic airway disease on the host response to intra-pulmonary vaccinia virus infection remain poorly defined. As shown here BALB/c mice with preexisting airway disease infected with vaccinia virus developed more severe pulmonary inflammation, higher lung virus titers and greater weight loss compared with mice inoculated with virus alone. This enhanced viremia was observed despite increased pulmonary recruitment of CD8(+) T effectors, greater IFNγ production in the lung, and high serum levels of anti-viral antibodies. Notably, flow cytometric analyses of lung CD8(+) T cells revealed a shift in the hierarchy of immunodominant viral epitopes in virus inoculated mice with allergic airway disease compared to mice treated with virus only. Pulmonary IL-10 production by T cells and antigen presenting cells was detected following virus inoculation of animals and increased dramatically in allergic mice exposed to virus. IL-10 modulation of host responses to this respiratory virus infection was greatly influenced by the localized pulmonary microenvironment. Thus, blocking IL-10 signaling in virus-infected mice with allergic airway disease enhanced pulmonary CD4(+) T cell production of IFNγ and increased serum anti-viral IgG1 levels. In contrast, pulmonary IFNγ and virus-specific IgG1 levels were reduced in vaccinia virus-treated mice with IL-10 receptor blockade. These observations demonstrate that pre-existing allergic lung disease alters the quality and magnitude of immune responses to respiratory poxviruses through an IL-10-dependent mechanism.Item Bcl6 Controls the Th2 Inflammatory Activity of Regulatory T Cells by Repressing Gata3 Function(Oxford University Press, 2012) Sawant, Deepali V.; Sehra, Sarita; Nguyen, Evelyn T.; Jadhav, Rohit; Englert, Kate; Shinnakasu, Ryo; Hangoc, Giao; Broxmeyer, Hal E.; Nakayama, Toshinori; Perumal, Narayanan B.; Kaplan, Mark H.; Dent, Alexander L.; Microbiology and Immunology, School of MedicineThe transcriptional repressor Bcl6 is a critical arbiter of Th cell fate, promoting the follicular Th lineage while repressing other Th cell lineages. Bcl6-deficient (Bcl6(-/-)) mice develop a spontaneous and severe Th2-type inflammatory disease, thus warranting assessment of Bcl6 in regulatory T cell (Treg) function. Bcl6(-/-) Tregs were competent at suppressing T cell proliferation in vitro and Th1-type colitogenic T cell responses in vivo. In contrast, Bcl6(-/-) Tregs strongly exacerbated lung inflammation in a model of allergic airway disease and promoted higher Th2 responses, including systemic upregulation of microRNA-21. Further, Bcl6(-/-) Tregs were selectively impaired at controlling Th2 responses, but not Th1 and Th17 responses, in mixed chimeras of Bcl6(-/-) bone marrow with Foxp3(-/-) bone marrow. Bcl6(-/-) Tregs displayed increased levels of the Th2 transcription factor Gata3 and other Th2 and Treg genes. Bcl6 potently repressed Gata3 transcriptional transactivation, providing a mechanism for the increased expression of Th2 genes by Bcl6(-/-) Tregs. Gata3 has a critical role in regulating Foxp3 expression and functional fitness of Tregs; however, the signal that regulates Gata3 and restricts its transactivation of Th2 cytokines in Tregs has remained unexplored. Our results identify Bcl6 as an essential transcription factor regulating Gata3 activity in Tregs. Thus, Bcl6 represents a crucial regulatory layer in the Treg functional program that is required for specific suppression of Gata3 and Th2 effector responses by Tregs.Item Bedside lung ultrasound for the diagnosis of pneumonia in children presenting to an emergency department in a resource-limited setting(BMC, 2023-01-09) Amatya, Yogendra; Russell, Frances M.; Rijal, Suraj; Adhikari, Sunil; Nti, Benjamin; House, Darlene R.; Emergency Medicine, School of MedicineBackground: Lung ultrasound (LUS) is an effective tool for diagnosing pneumonia; however, this has not been well studied in resource-limited settings where pneumonia is the leading cause of death in children under 5 years of age. Objective: The objective of this study was to evaluate the diagnostic accuracy of bedside LUS for diagnosis of pneumonia in children presenting to an emergency department (ED) in a resource-limited setting. Methods: This was a prospective cross-sectional study of children presenting to an ED with respiratory complaints conducted in Nepal. We included all children under 5 years of age with cough, fever, or difficulty breathing who received a chest radiograph. A bedside LUS was performed and interpreted by the treating clinician on all children prior to chest radiograph. The criterion standard was radiographic pneumonia, diagnosed by a panel of radiologists using the Chest Radiography in Epidemiological Studies methodology. The primary outcome was sensitivity and specificity of LUS for the diagnosis of pneumonia. All LUS images were later reviewed and interpreted by a blinded expert sonographer. Results: Three hundred and sixty-six children were enrolled in the study. The median age was 16.5 months (IQR 22) and 57.3% were male. Eighty-four patients (23%) were diagnosed with pneumonia by chest X-ray. Sensitivity, specificity, positive and negative likelihood ratios for clinician's LUS interpretation was 89.3% (95% CI 81-95), 86.1% (95%CI 82-90), 6.4, and 0.12 respectively. LUS demonstrated good diagnostic accuracy for pneumonia with an area under the curve of 0.88 (95% CI 0.83-0.92). Interrater agreement between clinician and expert ultrasound interpretation was excellent (k = 0.85). Conclusion: Bedside LUS when used by ED clinicians had good accuracy for diagnosis of pneumonia in children in a resource-limited setting.Item Clinical Prediction Models for Pneumonia in Children Presenting to an Emergency Department in a Resource-Limited Setting Using Lung Ultrasound Diagnosis as the Gold Standard(Springer Nature, 2025-03-28) House, Darlene R.; Amatya, Yogendra; Nti, Benjamin K.; Russell, Frances M.; Emergency Medicine, School of MedicineIntroduction: Clinical prediction rules for pediatric pneumonia often rely on radiographic pneumonia for diagnosis; however, lung ultrasound has higher diagnostic accuracy. Our objective was to derive a clinical prediction model for pneumonia in children under five using lung ultrasound as the criterion standard. Methods: This was a prospective study of children under five presenting to an emergency department (ED) with respiratory complaints in a resource-limited setting. Clinical findings, chest X-ray, and lung ultrasound results were recorded for each patient. Classification tree models were used to predict pneumonia using lung ultrasound as the criterion standard. Separate models were used without and with inclusion of chest X-ray results. Results: Of 386 patients enrolled, 125 patients (32.4%) had pneumonia on lung ultrasound. The mean age was 20.8 (SD 15.5) months. Using recursive feature selection, three variables provided the best prediction for pneumonia, namely, crepitations, retractions, and difficulty breathing, demonstrating a sensitivity of 74.2% and specificity of 38.5%. The algorithm including chest X-ray provided a sensitivity of 51.6% and specificity of 87.7%. Conclusions: Using lung ultrasound as the gold standard, no single clinical finding or combination of clinical findings provided enough accuracy to reliably diagnose pneumonia in children under five years.Item Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia(Oxford University Press, 2024-07-22) Madut, Deng B.; Chemaly, Roy F.; Dadwal, Sanjeet S.; Hill, Joshua A.; Lee, Yeon Joo; Haidar, Ghady; Luk, Alfred; Drelick, Alexander; Chin-Hong, Peter V.; Benamu, Esther; Khawaja, Fareed; Nanayakkara, Deepa; Papanicolaou, Genovefa A.; Butkus Small, Catherine; Fung, Monica; Barron, Michelle; Davis, Thomas; McClain, Micah T.; Maziarz, Eileen K.; Bedoya, Armando D.; Gilstrap, Daniel L.; Todd, Jamie L.; Barkauskas, Christina E.; Heldman, Madeleine R.; Bigelow, Robert; Leimberger, Jeffrey D.; Tsalik, Ephraim L.; Wolf, Olivia; Mughar, Mona; Lau, Constance; Noll, Nicholas; Hollemon, Desiree; Duttagupta, Radha; Lupu, Daniel S.; Bercovici, Sivan; Perkins, Bradley A.; Blauwkamp, Timothy A.; Fowler, Vance G., Jr.; Holland, Thomas L.; Bergin, Stephen P.; Pathology and Laboratory Medicine, School of MedicineBackground: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit. Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events. Results: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%). Conclusions: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.Item A cohort-study of patients suspected for MERS-CoV in a referral hospital in Saudi Arabia(Elsevier, 2017) Al-Tawfiq, Jaffar A.; Alfaraj, Sarah H.; Altuwaijri, Talal A.; Memish, Ziad A.; Department of Medicine, IU School of MedicineItem Community-Onset Bacterial Coinfection in Children Critically Ill With Severe Acute Respiratory Syndrome Coronavirus 2 Infection(Oxford University Press, 2023-03-06) Moffitt, Kristin L.; Nakamura, Mari M.; Young, Cameron C.; Newhams, Margaret M.; Halasa, Natasha B.; Reed, J. Nelson; Fitzgerald, Julie C.; Spinella, Philip C.; Soma, Vijaya L.; Walker, Tracie C.; Loftis, Laura L.; Maddux, Aline B.; Kong, Michele; Rowan, Courtney M.; Hobbs, Charlotte V.; Schuster, Jennifer E.; Riggs, Becky J.; McLaughlin, Gwenn E.; Michelson, Kelly N.; Hall, Mark W.; Babbitt, Christopher J.; Cvijanovich, Natalie Z.; Zinter, Matt S.; Maamari, Mia; Schwarz, Adam J.; Singh, Aalok R.; Flori, Heidi R.; Gertz, Shira J.; Staat, Mary A.; Giuliano, John S., Jr.; Hymes, Saul R.; Clouser, Katharine N.; McGuire, John; Carroll, Christopher L.; Thomas, Neal J.; Levy, Emily R.; Randolph, Adrienne G.; Pediatrics, School of MedicineBackground: Community-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce. Methods: We evaluated children and adolescents aged <19 years admitted to a pediatric intensive care or high-acuity unit for COVID-19 between March and December 2020. Based on qualifying microbiology results from the first 3 days of admission, we adjudicated whether patients had community-onset bacterial coinfection. We compared demographic and clinical characteristics of those who did and did not (1) receive antibiotics and (2) have bacterial coinfection early in admission. Using Poisson regression models, we assessed factors associated with these outcomes. Results: Of the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01-1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05-1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36-2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15-4.62]) was associated with bacterial coinfection. Conclusions: Community-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.Item Diagnosing Dyspneic Older Adult Emergency Department Patients Pilot Study: Diagnoses and Potential Role of Antimicrobial Peptides(Wiley, 2021) Hunold, Katherine M.; Schwaderer, Andrew L.; Exline, Matthew; Hebert, Courtney; Lampert, Brent C.; Southerland, Lauren T.; Stephens, Julie A.; Bischof, Jason J.; Caterino, Jeffrey M.; Pediatrics, School of MedicineStudy Objectives: Pneumonia, chronic obstructive pulmonary disease (COPD), and heart failure (HF) exacerbations can present similarly in the older adult in the Emergency Department (ED), leading to sub-optimal treatment from over- and under-diagnosis. There may be a role for antimicrobial peptides (AMPs) in improving the accurate diagnosis of pneumonia in these patients. Methods: This pilot was a prospective, observational cohort study of older adults (aged ≥65 years of age) who presented to the ED with dyspnea or elevated respiratory rate. To identify biomarkers of pneumonia, serum levels of white blood cell count, procalcitonin (PCT), and antimicrobial peptides (human beta defensin 1 and 2 [HBD-1, -2], human neutrophil peptides 1–3 [HNP1–3] and cathelididin [LL-37]) were compared between those with and without pneumonia. Criterion standard reviewers retrospectively determined the diagnoses present in the ED. Results: Three hundred ninety-one patients were screened, 140 were eligible, and 79 were enrolled. Based on criterion standard review, pneumonia was present in 10 (12.7%), COPD in 9 (11.4%) and HF in 31 (39.2%) with a co-diagnosis rate of 10.1% by criterion standard review. Comparatively, emergency medicine attending physicians diagnosed pneumonia in 16 (20.3%), COPD in 12 (15.2%), and HF in 30 (38.0%) with co-diagnosis rate of 15.2%. Emergency physicians agreed with criterion standard diagnoses in 90% of pneumonia, 75% of COPD and 65% of HF diagnoses. Differences in leukocyte count (p<0.01) and two novel AMPs (DEFA5 (p=0.08) and DEFB2 (p=0.09)) showed promise for diagnosing pneumonia. Conclusions: Emergency physicians continue to have poor diagnostic accuracy in dyspneic older adult patients. Serum AMP levels are one potential tool to improve diagnostic accuracy and outcomes for this important population and require further study.Item Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures(American Physiological Society, 2015-07-15) Schweitzer, Kelly S.; Chen, Steven X.; Law, Sarah; Van Demark, Mary; Poirier, Christophe; Justice, Matthew J.; Hubbard, Walter C.; Kim, Elena S.; Lai, Xianyin; Wang, Mu; Kranz, William D.; Carroll, Clinton J.; Ray, Bruce D.; Bittman, Robert; Goodpaster, John V.; Petrache, Irina; Department of Biochemistry & Molecular Biology, IU School of MedicineThe increased use of inhaled nicotine via e-cigarettes has unknown risks to lung health. Having previously shown that cigarette smoke (CS) extract disrupts the lung microvasculature barrier function by endothelial cell activation and cytoskeletal rearrangement, we investigated the contribution of nicotine in CS or e-cigarettes (e-Cig) to lung endothelial injury. Primary lung microvascular endothelial cells were exposed to nicotine, e-Cig solution, or condensed e-Cig vapor (1-20 mM nicotine) or to nicotine-free CS extract or e-Cig solutions. Compared with nicotine-containing extract, nicotine free-CS extract (10-20%) caused significantly less endothelial permeability as measured with electric cell-substrate impedance sensing. Nicotine exposures triggered dose-dependent loss of endothelial barrier in cultured cell monolayers and rapidly increased lung inflammation and oxidative stress in mice. The endothelial barrier disruptive effects were associated with increased intracellular ceramides, p38 MAPK activation, and myosin light chain (MLC) phosphorylation, and was critically mediated by Rho-activated kinase via inhibition of MLC-phosphatase unit MYPT1. Although nicotine at sufficient concentrations to cause endothelial barrier loss did not trigger cell necrosis, it markedly inhibited cell proliferation. Augmentation of sphingosine-1-phosphate (S1P) signaling via S1P1 improved both endothelial cell proliferation and barrier function during nicotine exposures. Nicotine-independent effects of e-Cig solutions were noted, which may be attributable to acrolein, detected along with propylene glycol, glycerol, and nicotine by NMR, mass spectrometry, and gas chromatography, in both e-Cig solutions and vapor. These results suggest that soluble components of e-Cig, including nicotine, cause dose-dependent loss of lung endothelial barrier function, which is associated with oxidative stress and brisk inflammation.Item ERG functionally overlaps with other Ets proteins in promoting TH9 cell expression of Il9 during allergic lung inflammation(American Association of Immunologists, 2023) Kharwadkar, Rakshin; Ulrich, Benjamin J.; Chu, Michelle; Koh, Byunghee; Hufford, Matthew M.; Fu, Yongyao; Birdsey, Graeme M.; Porse, Bo T.; Randi, Anna M.; Kaplan, Mark H.; Biochemistry and Molecular Biology, School of MedicineCD4+ TH cells develop into subsets that are specialized in the secretion of particular cytokines to mediate restricted types of inflammation and immune responses. Among the subsets that promote development of allergic inflammatory responses, IL-9-producing TH9 cells are regulated by a number of transcription factors. We have previously shown that the E26 transformation-specific (Ets) family members PU.1 and Ets translocation variant 5 (ETV5) function in parallel to regulate IL-9. In this study we identified a third member of the Ets family of transcription factors, Ets-related gene (ERG), that mediates IL-9 production in TH9 cells in the absence of PU.1 and ETV5. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9 promoter region is restricted to the TH9 lineage and is sustained during murine TH9 polarization. Knockdown or knockout of ERG during murine or human TH9 polarization in vitro led to a decrease in IL-9 production in TH9 cells. Deletion of ERG in vivo had modest effects on IL-9 production in vitro or in vivo. However, in the absence of PU.1 and ETV5, ERG was required for residual IL-9 production in vitro and for IL-9 production by lung-derived CD4 T cells in a mouse model of chronic allergic airway disease. Thus, ERG contributes to IL-9 regulation in TH9 cells.