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Interstitial lung disease (ILD) is characterized by chronic inflammation and scarring of the lungs, of which idiopathic pulmonary fibrosis (IPF) is the most devastating pathologic form. Idiopathic pulmonary fibrosis pathogenesis leads to loss of lung function and eventual death in 50% of patients, making it the leading cause of ILD-associated mortality worldwide. Persistent and subclinical microbial infections are implicated in the acute exacerbation of chronic lung diseases. However, while epidemiological studies have highlighted pollutants, gastric aspirate, and microbial infections as major causes for the progression and exacerbation of IPF, the role of persistent microbial infections in the pathogenesis of IPF remains unclear. In this review, we have focused on the role of persistent microbial infections, including viral, bacterial, and fungal infections, and their mechanisms of action in the pathogenesis of IPF. In particular, the mechanisms and pathogenesis of the Gram-negative bacteria Non-typeable Haemophilus influenzae (NTHi) in ILDs are discussed, along with growing evidence of its role in IPF, given its unique ability to establish persistent intracellular infections by leveraging its non-capsulated nature to evade host defenses. While antibiotic treatments are presumably beneficial to target the extracellular, interstitial, and systemic burden of pathogens, their effects are significantly reduced in combating pathogens that reside in the intracellular compartments. The review also includes recent clinical trials, which center on combinatorial treatments involving antimicrobials and immunosuppressants, along with antifibrotic drugs that help mitigate disease progression in IPF patients. Finally, future directions focus on mRNA-based therapeutics, given their demonstrated effectiveness across a wide range of clinical applications and feasibility in targeting intracellular pathogens.

The global population is aging at an unprecedented rate, resulting in a growing and vulnerable elderly population in need of efficient comprehensive healthcare services that include long-term care and skilled nursing facilities. In this context, severe aspiration pneumonia, a condition that carries substantial morbidity, mortality, and financial burden, especially among elderly patients requiring admission to the intensive care unit, has attracted greater concern. Aspiration pneumonia is defined as a pulmonary infection related to aspiration or dysphagia in etiology. Prior episodes of coughing on food or liquid intake, a history of relevant underlying conditions, abnormalities on videofluoroscopy or water swallowing, and gravity-dependent shadow distribution on chest imaging are among the clues that suggest aspiration. Patients with aspiration pneumonia tend to be elderly, frail, and suffering from more comorbidities than those without this condition. Here, we comprehensively address the epidemiology, clinical characteristics, diagnosis, treatment, prevention, and prognosis of severe aspiration community-acquired pneumonia in the elderly to optimize care of this high-risk demographic, enhance outcomes, and minimize the healthcare costs associated with this illness. Emphasizing preventive measures and effective management strategies is vital in ensuring the well-being of our aging population.

Capnocytophaga canimorsus is a gram-negative bacterium commonly found in the saliva of dogs and cats. Despite the frequency of animal bites, infection with Capnocytophaga species is rare, and severe infections are usually associated with underlying risk factors, such as alcohol use disorder, asplenia, or immunosuppression. We describe a case of a man who presented with a purpuric rash, lower extremity edema, and acute renal failure and was found to have tricuspid valve endocarditis and infection-associated glomerulonephritis due to C. canimorsus. Despite treatment with cefepime, the vegetation increased in size and valvular function worsened. He was readmitted with an inferior wall myocardial infarction, heart failure, and pulmonary embolism. He underwent an urgent tricuspid valve replacement with a bioprosthetic valve. A 16S ribosomal RNA amplicon sequencing performed on the resected valve tissue verified involvement of C. canimorsus. Post-operatively, he had several episodes of gastrointestinal hemorrhage requiring multiple endoscopic interventions and arterial embolization. The recurrent gastrointestinal hemorrhage combined with his severe functional decline ultimately led to his death. This patient had an uncommon presentation with leukocytoclastic vasculitis and infection-associated glomerulonephritis, which revealed an underlying diagnosis of infective endocarditis due to C. canimorsus, a rare gram-negative bacterial etiology of infective endocarditis.

Abstract Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Background: Severe community-acquired pneumonia (sCAP) is the most frequent admission for acute respiratory failure in intensive care medicine. Observational studies have found a correlation between patients who were admitted with CAP and the development of cardiovascular events. The risk of acute myocardial damage in patients with CAP is particularly high within the first 30 days of hospitalization. Research design and methods: Multicenter prospective cohort analysis conducted in consecutive patients admitted to an ICU with microbiologically confirmed diagnoses of sCAP. The aim was to determine any structural cardiac damage detected by advanced imagining techniques (cardiac MRI) and cardiac biomarkers in patients with sCAP. The patients were stratified, according to their etiology, into pneumococcal or not-pneumococcal sCAP. The primary outcome was cardiac damage at day 5 and 7 of clinical presentation. Results: A total of 23 patients were consecutively and prospectively enrolled for two winter periods. No significant differences were observed between the median troponin when comparing the pneumococcal vs. non-pneumococcal. The incidence of myocardial damage was numerically higher in the pneumococcal subgroup (70% vs. 50%, p = 0.61) on day 5 and on day 7 (53% vs. 40%, p = 0.81) but did not achieve significance. Confirming a correlation between the biomarkers of cell damage and the biomarkers of myocardial damage, only a positive and significant correlation was observed between h-FABP and DNA on day 1 (r = 0.74; p < 0.01) and day 3 (r = 0.83; p < 0.010). Twenty cardiac MRIs were performed on the 23 patients (87%). No presence of fibrosis was observed in any of the studies carried out within the first 15 days of admission. Conclusions: No significant myocardial damage was found in patients with sCAP independent of the bacterial etiology in accordance with biomarker alterations (Troponin and/or h-FABP) or cardiac MRI. Using cardiac MRI, we could not find any presence of myocardial fibrosis within the first 15 days of admission.

Background: Corticosteroids (CSs), specifically dexamethasone (DEX), are the treatment of choice for severe acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia (CARDS). However, data from both ARDS and relatively small CARDS clinical trials have suggested improved outcomes with methylprednisolone (MP) versus DEX. The objective of this retrospective cohort study was to compare the safety and effectiveness of MP and DEX in critically ill CARDS patients. Methods: The study cohort included CARDS patients admitted to a tertiary referral intensive care unit (ICU) between April and September 2020 who received at least 5 days of CSs for CARDS. Results: The cohort was notable for a high severity of illness (overall, 88.5% of patients required mechanical ventilation and 16% required vasopressors on admission). The DEX group ( n = 62) was significantly older with a higher illness severity [Sequential Organ Failure Assessment (SOFA) 6 (4.75–8) versus 4.5 (3–7), p = 0.008], while the MP group ( n = 51) received significantly more loading doses [19 (37.3%) versus 4 (6.5%), p

Abstract Background Some unanswered questions persist regarding the effectiveness of corticosteroids for severe coronavirus disease 2019 (COVID-19) patients. We aimed to assess the clinical effect of corticosteroids on intensive care unit (ICU) mortality among mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients. Methods This was a retrospective study of prospectively collected data conducted in 70 ICUs (68 Spanish, one Andorran, one Irish), including mechanically ventilated COVID-19-associated ARDS patients admitted between February 6 and September 20, 2020. Individuals who received corticosteroids for refractory shock were excluded. Patients exposed to corticosteroids at admission were matched with patients without corticosteroids through propensity score matching. Primary outcome was all-cause ICU mortality. Secondary outcomes were to compare in-hospital mortality, ventilator-free days at 28 days, respiratory superinfection and length of stay between patients with corticosteroids and those without corticosteroids. We performed survival analysis accounting for competing risks and subgroup sensitivity analysis. Results We included 1835 mechanically ventilated COVID-19-associated ARDS, of whom 1117 (60.9%) received corticosteroids. After propensity score matching, ICU mortality did not differ between patients treated with corticosteroids and untreated patients (33.8% vs. 30.9%; p = 0.28). In survival analysis, corticosteroid treatment at ICU admission was associated with short-term survival benefit (HR 0.53; 95% CI 0.39–0.72), although beyond the 17th day of admission, this effect switched and there was an increased ICU mortality (long-term HR 1.68; 95% CI 1.16–2.45). The sensitivity analysis reinforced the results. Subgroups of age

Abstract Background Lack of training is currently the most common barrier to implementation of point-of-care ultrasound (POCUS) use in clinical practice, and in-person POCUS continuing medical education (CME) courses have been paramount in improving this training gap. Due to travel restrictions and physical distancing requirements during the COVID-19 pandemic, most in-person POCUS training courses were cancelled. Though tele-ultrasound technology has existed for several years, use of tele-ultrasound technology to deliver hands-on training during a POCUS CME course has not been previously described. Methods We conducted a retrospective observational study comparing educational outcomes, course evaluations, and learner and faculty feedback from in-person versus tele-ultrasound POCUS courses. The same POCUS educational curriculum was delivered to learners by the two course formats. Data from the most recent pre-pandemic in-person course were compared to tele-ultrasound courses during the COVID-19 pandemic. Results Pre- and post-course knowledge test scores of learners from the in-person (n = 88) and tele-ultrasound course (n = 52) were compared. Though mean pre-course knowledge test scores were higher among learners of the tele-ultrasound versus in-person course (78% vs. 71%; p = 0.001), there was no significant difference in the post-course test scores between learners of the two course formats (89% vs. 87%; p = 0.069). Both learners and faculty rated the tele-ultrasound course highly (4.6–5.0 on a 5-point scale) for effectiveness of virtual lectures, tele-ultrasound hands-on scanning sessions, and course administration. Faculty generally expressed less satisfaction with their ability to engage with learners, troubleshoot image acquisition, and provide feedback during the tele-ultrasound course but felt learners completed the tele-ultrasound course with a better basic POCUS skillset. Conclusions Compared to a traditional in-person course, tele-ultrasound POCUS CME courses appeared to be as effective for improving POCUS knowledge post-course and fulfilling learning objectives. Our findings can serve as a roadmap for educators seeking guidance on development of a tele-ultrasound POCUS training course whose demand will likely persist beyond the COVID-19 pandemic.

An amendment to this paper has been published and can be accessed via the original article.

Metformin may potentially reverse various age-related conditions; however, it is unclear whether metformin can also mitigate or delay the deterioration of immunological resilience that occurs in the context of infections that are commonly observed in older persons. We examined whether metformin promotes the preservation of immunological resilience in an acute S. pneumoniae (SPN) infection challenge in young adult mice. Mice were fed metformin (MET-alone) or standard chow (controls-alone) for 10 weeks prior to receiving intratracheal inoculation of SPN. A subset of each diet group received pneumococcal conjugate vaccine at week 6 (MET + PCV and control + PCV). Compared to controls-alone, MET-alone had significantly less infection-associated morbidity and attenuated inflammatory responses during acute SPN infection. Metformin lowered the expression of genes in the lungs related to inflammation as well as shorter lifespan in humans. This was accompanied by significantly lower levels of pro-inflammatory cytokines (e.g., IL6). MET + PCV vs. control + PCV manifested enhanced SPN anticapsular IgM and IgG levels. The levels of SPN IgM production negatively correlated with expression levels of genes linked to intestinal epithelial structure among MET + PCV vs. control + PCV groups. Correspondingly, the gut microbial composition of metformin-fed mice had a significantly higher abundance in the Verrucomicrobia, Akkermansia muciniphila, a species previously associated with beneficial effects on intestinal integrity and longevity. Together, these findings indicate metformin’s immunoprotective potential to protect against infection-associated declines in immunologic resilience.

Background: Severe community-acquired pneumococcal pneumonia is commonly associated with bacteraemia. Although it is assumed that the bacteraemia solely derives from pneumococci entering the blood from the lungs it is unknown if other organs are important in the pathogenesis of bacteraemia. Using three models, we tested the relevance of the spleen in pneumonia-associated bacteraemia. Methods: We used human spleens perfused ex vivo to explore permissiveness to bacterial replication, a non-human primate model to check for splenic involvement during pneumonia and a mouse pneumonia-bacteraemia model to demonstrate that splenic involvement correlates with invasive disease. Findings: Here we present evidence that the spleen is the reservoir of bacteraemia during pneumonia. We found that in the human spleen infected with pneumococci, clusters with increasing number of bacteria were detectable within macrophages. These clusters also were detected in non-human primates. When intranasally infected mice were treated with a non-therapeutic dose of azithromycin, which had no effect on pneumonia but concentrated inside splenic macrophages, bacteria were absent from the spleen and blood and importantly mice had no signs of disease. Interpretation: We conclude that the bacterial load in the spleen, and not lung, correlates with the occurrence of bacteraemia. This supports the hypothesis that the spleen, and not the lungs, is the major source of bacteria during systemic infection associated with pneumococcal pneumonia; a finding that provides a mechanistic basis for using combination therapies including macrolides in the treatment of severe community-acquired pneumococcal pneumonia. Funding: Oxford University, Wolfson Foundation, MRC, NIH, NIHR, and MRC and BBSRC studentships supported the work.

Background The relationship between early oseltamivir treatment (within 48 h of symptom onset) and mortality in patients admitted to intensive care units (ICUs) with severe influenza is disputed. This study aimed to investigate the association between early oseltamivir treatment and ICU mortality in critically ill patients with influenza pneumonia. Methods This was an observational study of patients with influenza pneumonia admitted to 184 ICUs in Spain during 2009–2018. The primary outcome was to evaluate the association between early oseltamivir treatment and ICU mortality compared with later treatment. Secondary outcomes were to compare the duration of mechanical ventilation and ICU length of stay between the early and later oseltamivir treatment groups. To reduce biases related to observational studies, propensity score matching and a competing risk analysis were performed. Results During the study period, 2124 patients met the inclusion criteria. All patients had influenza pneumonia and received oseltamivir before ICU admission. Of these, 529 (24.9%) received early oseltamivir treatment. In the multivariate analysis, early treatment was associated with reduced ICU mortality (OR 0.69, 95% CI 0.51–0.95). After propensity score matching, early oseltamivir treatment was associated with improved survival rates in the Cox regression (hazard ratio 0.77, 95% CI 0.61–0.99) and competing risk (subdistribution hazard ratio 0.67, 95% CI 0.53–0.85) analyses. The ICU length of stay and duration of mechanical ventilation were shorter in patients receiving early treatment. Conclusions Early oseltamivir treatment is associated with improved survival rates in critically ill patients with influenza pneumonia, and may decrease ICU length of stay and mechanical ventilation duration.

Abstract Background Empirical antibiotic coverage for atypical pathogens in community-acquired pneumonia (CAP) has long been debated, mainly because of a lack of epidemiological data. We aimed to assess both testing for atypical pathogens and their prevalence in hospitalized patients with CAP worldwide, especially in relation with disease severity. Methods A secondary analysis of the GLIMP database, an international, multicentre, point-prevalence study of adult patients admitted for CAP in 222 hospitals across 6 continents in 2015, was performed. The study evaluated frequency of testing for atypical pathogens, including L. pneumophila, M. pneumoniae, C. pneumoniae, and their prevalence. Risk factors for testing and prevalence for atypical pathogens were assessed through univariate analysis. Results Among 3702 CAP patients 1250 (33.8%) underwent at least one test for atypical pathogens. Testing varies greatly among countries and its frequency was higher in Europe than elsewhere (46.0% vs. 12.7%, respectively, p

Chronic obstructive pulmonary disease (COPD) is a frequent comorbid condition associated with increased morbidity and mortality. Pneumonia is the most common infectious disease condition. The purpose of this review is to evaluate the impact of pneumonia in patients with COPD. We will evaluate the epidemiology and factors associated with pneumonia. We are discussing the clinical characteristics of COPD that may favor the development of infections conditions such as pneumonia. Over the last 10 years, there is an increased evidence that COPD patients treated with inhaled corticosteroids are at increased risk to develp pneumonia. We will review the avaialbe information as well as the possible mechanism for this events. We also discuss the impact of influenza and pneumococcal vaccination in the prevention of pneumonia in COPD patients.

Abstract Background Limited data are available regarding fit and healthy patients with pneumonia at different ages. We evaluated the association of age with clinical presentation, serotype and outcomes among healthy and well-functioning patients hospitalized for bacteremic pneumococcal community–acquired pneumonia. Methods We performed a prospective cohort study of consecutive healthy and well-functioning patients hospitalized for this type of pneumonia. Patients were stratified into younger (18 to 64 years) and older (≥65 years) groups. Results During the study period, 399 consecutive patients were hospitalized with bacteremic pneumococcal pneumonia. We included 203 (50.8%) patients who were healthy and well-functioning patients, of whom 71 (35%) were classified as older. No differences were found in antibiotic treatment, treatment failure rate, antibiotic resistance, or serotype, except for serotype 7F that was less common in older patients. In the adjusted multivariate analysis, the older patients had higher 30-day mortality (OR 6.83; 95% CI 1.22–38.22; P = 0.028), but were less likely to be admitted to the ICU (OR 0.14; 95% CI 0.05–0.39; P

Point-of-care lung ultrasound (LUS) is an attractive alternative to chest X-ray (CXR), but its diagnostic accuracy compared to CXR has not been well studied in coronavirus disease 2019 (COVID-19) patients. We conducted a prospective observational study to assess the correlation between LUS and CXR findings in COVID-19 patients. Ninety-six patients with a clinical diagnosis of COVID-19 underwent an LUS exam and CXR upon presentation. Physicians blinded to the CXR findings performed all LUS exams. Detection of pulmonary infiltrates by CXR versus LUS was compared between patients categorized as suspected or confirmed COVID-19 based on reverse transcriptase-polymerase chain reaction. Sensitivities and correlation by Kappa statistic were calculated between LUS and CXR. LUS detected pulmonary infiltrates more often than CXR in both suspected and confirmed COVID-19 subjects. The most common LUS abnormalities were discrete B-lines, confluent B-lines, and small subpleural consolidations. Most important, LUS detected unilateral or bilateral pulmonary infiltrates in 55% of subjects with a normal CXR. Substantial agreement was demonstrated between LUS and CXR for normal, unilateral or bilateral findings (Κ = 0.48 (95% CI 0.34 to 0.63)). In patients with suspected or confirmed COVID-19, LUS detected pulmonary infiltrates more often than CXR, including more than half of the patients with a normal CXR.

This study aimed to describe real-life microbiological testing of adults hospitalised with community-acquired pneumonia (CAP) and to assess concordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) and 2011 European Respiratory Society (ERS) CAP guidelines. This was a cohort study based on the Global Initiative for Methicillin-resistant Staphylococcus aureus Pneumonia (GLIMP) database, which contains point-prevalence data on adults hospitalised with CAP across 54 countries during 2015. In total, 3702 patients were included. Testing was performed in 3217 patients, and included blood culture (71.1%), sputum culture (61.8%), Legionella urinary antigen test (30.1%), pneumococcal urinary antigen test (30.0%), viral testing (14.9%), acute-phase serology (8.8%), bronchoalveolar lavage culture (8.4%) and pleural fluid culture (3.2%). A pathogen was detected in 1173 (36.5%) patients. Testing attitudes varied significantly according to geography and disease severity. Testing was concordant with IDSA/ATS and ERS guidelines in 16.7% and 23.9% of patients, respectively. IDSA/ATS concordance was higher in Europe than in North America (21.5% versus 9.8%; p

Background: Obstructive sleep apnea (OSA) is an important cause of morbidity in the elderly population. Limited data are available regarding the healthcare utilization and predisposing conditions related to OSA in the elderly. Our aim was to evaluate the healthcare utilization and the conditions associated with new and chronic diagnosis of OSA in a large cohort of elderly patients in the Veterans Health Administration (VHA). Materials and Methods: This retrospective cohort study used inpatient and outpatient VHA data to identify the individuals diagnosed with OSA using ICD-9 codes during the fiscal years 2003-2005. Primary outcomes were emergency department (ED) visits and hospitalizations. Multivariable logistic regression analysis was performed to identify the demographic and clinical characteristics associated with new and chronic diagnosis of OSA. Results: Of 1,867,876 elderly veterans having 2 years of care, 82,178 (4.4%) were diagnosed with OSA. Individuals with OSA were younger and more likely to have chronic diseases than those without OSA. Individuals with chronic OSA were more likely to have diagnoses of congestive heart failure (CHF), pulmonary circulation disorders, COPD, and obesity and less likely to have diagnoses of hypertension, osteoarthritis, and stroke than individuals with newly diagnosed OSA. The proportion of patients with new OSA diagnosis who required at least one ED visit was higher than the proportion of chronic OSA and no OSA patients (37%, 32%, and 15%, respectively; P-value

OBJECTIVES/SPECIFIC AIMS: The aims of this study are (1) to develop and characterize a novel nonhuman primate model of pneumococcal pneumonia that mimics human disease; and (2) determine whether Streptococcus pneumoniae can: (a) translocate to the heart, (b) cause adverse cardiac events, (c) induce cardiomyocyte death, and (d) lead to scar formation during severe pneumonia in baboons. METHODS/STUDY POPULATION: Six adult baboons (Papio cynocephalus) were surgically tethered to a monitoring system to continuously assess their heart rate, temperature, and electrocardiogram (ECG). A baseline transthoracic echocardiogram, 12-lead ECG, serum troponin-I levels, brain natriuretic peptide, and heart-type fatty acid binding protein (HFABP) levels were obtained before infection and at the end of the experiment to determine cardiovascular damage during pneumococcal pneumonia. Animals were challenged with 108 colony-forming units of S. pneumoniae in the right middle lobe using flexible bronchoscopy. Three baboons were rescued with ampicillin therapy (80 mg/kg/d) after the development of pneumonia. Cardiac damage was confirmed by examination of tissue sections using immunohistochemistry as well as electron and fluorescence microscopy. Western-blots and tissue staining were used to determine the presence of necroptosis (RIP3 and pMLKL) and apoptosis (Caspase-3) in the cardiac tissue. Cytokine and chemokine levels in the heart tissue were determined using Luminex technology. RESULTS/ANTICIPATED RESULTS: Four males (57%) and three (43%) females were challenged. The median age of all baboons was 11 (IQR, 10-19) years old, which corresponds to a middle-aged human. Infected baboons consistently developed severe pneumonia. All animals developed systemic inflammatory response syndrome with tachycardia, tachypnea, fever, and leukocytosis. Infection was characterized by initial leukocytosis followed by severe leukopenia on day 3 postinoculation. Non-specific ischemic alterations by ECG (ST segment and T-wave flattering) and in the premortem echocardiogram were observed. The median (IQR) levels of troponin I and HFABP at the end of the experiment were 3550 ng/mL (1717–5383) and 916.9 ng/mL (520.8–1323), respectively. Severe cardiomyopathy was observed using TEM and H&E stains in animals with severe pneumonia. Necroptosis was detected in cardiomyocytes of infected animals by the presence of pMLKL and RIP3 in cardiac tissues. Signs of cardiac remodeling indicated by disorganized collagen deposition was present in rescued animals but not in the other animals. DISCUSSION/SIGNIFICANCE OF IMPACT: We confirmed that baboons experience cardiac injury during severe pneumococcal pneumonia that is characterized by myocardial invasion, activation of necroptosis, and tissue remodeling in animals rescued by antimicrobial therapy. Cardiac damage by invading pneumococci may explain why adverse cardiac events that occur during and after pneumococcal pneumonia in adult human patients.

RATIONALE:Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and infectious death in adults worldwide. A non-human primate model is needed to study the molecular mechanisms that underlie the development of severe pneumonia, identify diagnostic tools, explore potential therapeutic targets, and test clinical interventions during pneumococcal pneumonia. OBJECTIVE:To develop a non-human primate model of pneumococcal pneumonia. METHODS:Seven adult baboons (Papio cynocephalus) were surgically tethered to a continuous monitoring system that recorded heart rate, temperature, and electrocardiography. Animals were inoculated with 109 colony-forming units of S. pneumoniae using bronchoscopy. Three baboons were rescued with intravenous ampicillin therapy. Pneumonia was diagnosed using lung ultrasonography and ex vivo confirmation by histopathology and immunodetection of pneumococcal capsule. Organ failure, using serum biomarkers and quantification of bacteremia, was assessed daily. RESULTS:Challenged animals developed signs and symptoms of pneumonia 4 days after infection. Infection was characterized by the presence of cough, tachypnea, dyspnea, tachycardia and fever. All animals developed leukocytosis and bacteremia 24 hours after infection. A severe inflammatory reaction was detected by elevation of serum cytokines, including Interleukin (IL)1Ra, IL-6, and IL-8, after infection. Lung ultrasonography precisely detected the lobes with pneumonia that were later confirmed by pathological analysis. Lung pathology positively correlated with disease severity. Antimicrobial therapy rapidly reversed symptomology and reduced serum cytokines. CONCLUSIONS:We have developed a novel animal model for severe pneumococcal pneumonia that mimics the clinical presentation, inflammatory response, and infection kinetics seen in humans. This is a novel model to test vaccines and treatments, measure biomarkers to diagnose pneumonia, and predict outcomes.

Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1β was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD.