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Competing Interests: The authors have no funding or conflicts of interest to disclose.

Abstract: We present the case of a 65-year-old patient who was treated with high-dose benzylpenicillin for severe invasive pneumococcal pneumonia, complicated by acute renal failure managed with continuous venovenous hemofiltration. After cessation of continuous venovenous hemofiltration, the patient experienced multiple tonic-clonic seizures. Therapeutic drug monitoring revealed high total serum concentrations of benzylpenicillin, identifying it as the likely cause of the neurotoxicity. This case study presents the first documented total serum benzylpenicillin concentration associated with neurotoxicity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Objective: We aimed to investigate the impact of preceding seasonal influenza on the clinical characteristics of adult patients with invasive pneumococcal disease (IPD) in Japan., Methods: Data for 1722 adult patients with IPD were analyzed before (2017-2019) and during the COVID-19 pandemic (2020-2022)., Results: The seasonal influenza epidemic disappeared soon after the emergence of the pandemic. Compared with that before the pandemic (66.7%), we observed a lower bacteremic pneumonia proportion in patients with IPD during the pandemic (55.6%). The clinical presentations of IPD cases significantly differed between those with and without preceding influenza. The proportion of bacteremic pneumonia was higher in IPD patients with preceding influenza than in those without in both younger (44.9% vs 84.2%) and older adults (65.5% vs 87.0%) before the pandemic. The case fatality rate was significantly higher in IPD patients with preceding influenza (28.3%) than in those without (15.3%) in older adults before the pandemic (P = 0.020). Male and aging are high risk factors for death in older patients with IPD who had preceding influenza., Conclusion: Our study reveals that preceding seasonal influenza plays a role in the development of bacteremic pneumococcal pneumonia, increasing the risk of death in older adults., Competing Interests: Declaration of competing interest The authors have no competing interests relevant to this article to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

We report a case of a 62-year-old female presenting with shortness of breath, who was subsequently diagnosed with Austrian syndrome. The patient had a complicated clinical course, including invasive central nervous system pneumococcal disease, pneumococcal bacteremia, and mitral valve vegetation with possible leaflet perforation. Despite aggressive treatment, her condition continued to worsen. We will discuss the clinical features of this disease, approaches to diagnosis and treatment, and outcomes in light of this rare condition.

Purpose: To evaluate the impact of an optimal and reproducible cutoff value set according to a predefined lymphopenia scale as an early predictor of in-hospital mortality and other outcomes in patients hospitalized with pneumococcal pneumonia and positive urinary antigen at admission to the emergency department., Methods: An observational cohort study was conducted based on analysis of a prospective registry of consecutive immunocompetent adults hospitalized for pneumococcal pneumonia in two tertiary hospitals. Generalized additive models were constructed to assess the smooth relationship between in-hospital mortality and lymphopenia., Results: We included 1173 patients. Lymphopenia on admission was documented in 686 (58.4%). No significant differences were observed between groups regarding the presence of comorbidities. Overall, 299 (25.5%) patients were admitted to intensive care and 90 (7.6%) required invasive mechanical ventilation. Fifty-nine (5%) patients died, among them 23 (38.9%) in the first 72 h after admission. A lymphocyte count < 500/μL, documented in 282 (24%) patients, was the predefined cutoff point that best predicted in-hospital mortality. After adjustment, these patients had higher rates of intensive care admission (OR 2.9; 95% CI 1.9-4.3), invasive mechanical ventilation (OR 2.2; 95% CI 1.2-3.9), septic shock (OR 1.8; 95% CI 1.1-2.9), treatment failure (OR 2.1; 95% CI 1.2-3.5), and in-hospital mortality (OR 2.2; 95% 1.1-4.9). Severe lymphopenia outperformed PSI score in predicting early and 30-day mortality in patients classified in the higher-risk classes., Conclusion: Lymphocyte count < 500/μL could be used as a reproducible predictor of complicated clinical course in patients with an early diagnosis of pneumococcal pneumonia., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Streptococcus pneumoniae ( Sp ) frequently causes secondary pneumonia after influenza A virus (IAV) infection, leading to high morbidity and mortality worldwide. Concomitant pneumococcal and influenza vaccination improves protection against coinfection but does not always yield complete protection. Impaired innate and adaptive immune responses have been associated with attenuated bacterial clearance in influenza virus-infected hosts. In this study, we showed that preceding low-dose IAV infection caused persistent Sp infection and suppression of bacteria-specific T-helper type 17 (Th17) responses in mice. Prior Sp infection protected against subsequent IAV/ Sp coinfection by improving bacterial clearance and rescuing bacteria-specific Th17 responses in the lungs. Furthermore, blockade of IL-17A by anti-IL-17A antibodies abrogated the protective effect of Sp preinfection. Importantly, memory Th17 responses induced by Sp preinfection overcame viral-driven Th17 inhibition and provided cross-protection against different Sp serotypes following coinfection with IAV. These results indicate that bacteria-specific Th17 memory cells play a key role in providing protection against IAV/ Sp coinfection in a serotype-independent manner and suggest that a Th17-based vaccine would have excellent potential to mitigate disease caused by coinfection. IMPORTANCE Streptococcus pneumoniae ( Sp ) frequently causes secondary bacterial pneumonia after influenza A virus (IAV) infection, leading to increased morbidity and mortality worldwide. Current pneumococcal vaccines induce highly strain-specific antibody responses and provide limited protection against IAV/ Sp coinfection. Th17 responses are broadly protective against Sp single infection, but whether the Th17 response, which is dramatically impaired by IAV infection in naïve mice, might be effective in immunization-induced protection against pneumonia caused by coinfection is not known. In this study, we have revealed that Sp -specific memory Th17 cells rescue IAV-driven inhibition and provide cross-protection against subsequent lethal coinfection with IAV and different Sp serotypes. These results indicate that a Th17-based vaccine would have excellent potential to mitigate disease caused by IAV/ Sp coinfection., Competing Interests: The authors declare no conflict of interest.

Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.

Objective: To construct a prediction model for bacteraemia in patients with pneumococcal community-acquired pneumonia (P-CAP) based on variables easily obtained at hospital admission., Methods: This prospective observational multicentre derivation-validation study was conducted in patients hospitalised with P-CAP between 2000 and 2020. All cases were diagnosed based on positive urinary antigen tests in the emergency department and had blood cultures taken on admission. A risk score to predict bacteraemia was developed., Results: We included 1783 patients with P-CAP (1195 in the derivation and 588 in the validation cohort). A third (33.3%) of the patients had bacteraemia. In the multivariate analysis, the following were identified as independent factors associated with bacteraemia: no influenza vaccination the last year, no pneumococcal vaccination in the last 5 years, blood urea nitrogen (BUN) ≥30 mg/dL, sodium <130 mmol/L, lymphocyte count <800/µl, C-reactive protein ≥200 mg/L, respiratory failure, pleural effusion and no antibiotic treatment before admission. The score yielded good discrimination (AUC 0.732; 95% CI: 0.695-0.769) and calibration (Hosmer-Lemeshow p-value 0.801), with similar performance in the validation cohort (AUC 0.764; 95% CI:0.719-0.809)., Conclusions: We found nine predictive factors easily obtained on hospital admission that could help achieve early identification of bacteraemia. The prediction model provides a useful tool to guide diagnostic decisions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Background: Necrotizing pneumonia rarely occurs in children, but when it does it can be complicated by bronchopleural fistula, empyema, pneumothorax, sepsis, and acute respiratory distress syndrome (ARDS). Antimicrobial therapy is the cornerstone of its management; however, surgery is necessary in some cases. Ideally, surgical interventions are kept to a minimum, but this is not always possible if there is a mass effect from air and fluid in the pleural space, pulmonary necrosis leading to massive hemoptysis, uncontrolled sepsis, or difficulties with assisted ventilation. Case Presentation: Herein we present a patient with refractory pyopneumothorax and ARDS due to pneumococcal necrotizing pneumonia complicated by a bronchopleural fistula. The patient's clinical condition deteriorated despite antibiotics, surgical drainage, and assisted ventilation. Owing to pneumothorax with a high percentage of air leakage, bilateral diffuse collapse of the lungs, and insufficient oxygenation, surgical treatment was considered, but because of the patient's lack of tolerance for surgery due to hemodynamic reasons and the complications associated with surgery, medical treatment was determined to be more appropriate. Surfactant treatment was administered to the patient, resulting in significant clinical improvement. Conclusion: To the best of our knowledge, this is the first report of the use of surfactant to treat ARDS due to necrotizing pneumonia. Based on the presented case, we think surfactant can be considered as a salvage treatment for such patients.

Although Klebsiella pneumoniae pneumonia is an insidious threat among the elderly, the role of radiological features has not been elucidated. We aimed to evaluate thin-section chest computed tomography (CT) features and assess its associations with disease prognosis in elderly patients with acute K. pneumoniae pneumonia. We retrospectively included elderly patients, admitted for acute K. pneumoniae pneumonia, and investigated thin-section CT findings to determine whether bronchopneumonia or lobar pneumonia was present. The association between the radiological pattern of pneumonia and in-hospital mortality was analyzed. Eighty-six patients with acute K. pneumoniae pneumonia were included, and among them, the bronchopneumonia pattern was observed in 70 (81%) patients. Twenty-five (29%) patients died in hospital, and they had a greater incidence of lobar pneumonia pattern (40% in nonsurvivors vs 10% in survivors; P = .008), low albumin level (2.7 g/dL, range, 1.6-3.8 in nonsurvivors vs 3.0 g/dL, range, 1.7-4.2 in survivors; P = .026) and higher levels of aspartate aminotransferase (30 U/L, range, 11-186 in nonsurvivors vs 23 U/L, range, 11-102 in survivors, P = .017) and C-reactive protein (8.0 mg/dL, range, 0.9-26.5 in nonsurvivors vs 4.7 mg/dL, range, 0.0-24.0 in survivors; P = .047) on admission. Multivariate analysis showed that lobar pneumonia pattern was independently associated with increased in-hospital mortality (adjusted hazard ratio, 3.906; 95% CI, 1.513-10.079; P = .005). In elderly patients with acute K. pneumoniae pneumonia, the lobar pneumonia pattern may be less commonly observed, and this pattern could relate to poor prognosis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Pneumonia is commonly caused by Streptococcus pneumoniae (pneumococcus) and associated with subsequent cardiovascular complications and increased mortality. Potential short-term survival benefits conferred by acetylsalicylic acid (ASA) use in pneumonia remain controversial, and long-term outcomes have not been studied., Objectives: To evaluate the association between ASA use and survival for up to 1 year following bacteremic pneumococcal pneumonia., Methods: All bacteremic pneumococcal episodes in Iceland from 1975 to 2019 were reviewed. The study cohort consisted of individuals at least 18 years of age with symptoms and imaging results consistent with pneumonia. Differences in survival were assessed at 30 days, 90 days and 1 year using propensity score weighting (inverse probability weighting). Splitting and stratifying on survival at 7 days was done for the 30-day survival, because of nonproportionality., Results: In total, 815 bacteremic pneumococcal pneumonia episodes (median age 67 years, females 48%) were identified. Cox regression using propensity score weighting on the association of ASA with survival at 30 days showed an average hazard ratio (HR) of 0.60 (95% confidence interval [CI] 0.34-1.05). A significantly improved survival was observed within 7 days (HR = 0.42, 95% CI 0.19-0.92) but not during days 7-30 (HR = 1.08, 95% CI 0.46-2.55). ASA was associated with survival at 90 days (HR = 0.53, 95% CI 0.32-0.87) and 1 year (HR = 0.48, 95% CI 0.31-0.75)., Conclusion: Use of ASA upon admission for bacteremic pneumococcal pneumonia is associated with significantly reduced mortality for up to 1 year after diagnosis. ASA therapy in patients with pneumonia and other infectious syndromes warrants further study., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

A 61-year-old woman was transferred with a complaint of a fever and productive cough. She had tested positive for Mycobacterium avium and Nocardia cyriacigeorgica at least twice, and Streptococcus pneumonia (PISP) was isolated (3+) from her purulent sputum. As radiological findings, a lower lung field-dominant infiltration shadow and nodular shadow with cavity were recognized in the bilateral lung fields. We diagnosed her with pneumococcal pneumonia co-infection with M. avium and N. cyriacigeorgica. She was treated with MEPM for pneumococcal pneumonia, a standard regimen containing clarithromycin for pulmonary M. avium complex (MAC) disease, and sulfamethoxazole/trimethoprim for pulmonary nocardiosis. She improved with appropriate treatment.

Pneumonia is a leading cause of morbidity and mortality. While inflammation is a host protective response that ensures bacterial clearance, a finely regulated response is necessary to prevent bystander tissue damage. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a GC-induced protein with anti-inflammatory and proresolving bioactions, yet the therapeutical role of GILZ in infectious diseases remains unexplored. Herein, we investigate the role and effects of GILZ during acute lung injury (ALI) induced by LPS and Streptococcus pneumoniae infection. GILZ deficient mice (GILZ -/- ) presented more severe ALI, characterized by increased inflammation, decreased macrophage efferocytosis and pronounced lung damage. In contrast, pulmonary inflammation, and damage were attenuated in WT mice treated with TAT-GILZ fusion protein. During pneumococcal pneumonia, TAT-GILZ reduced neutrophilic inflammation and prevented the associated lung damage. There was also enhanced macrophage efferocytosis and bacterial clearance in TAT-GILZ-treated mice. Mechanistically, TAT-GILZ enhanced macrophage phagocytosis of pneumococcus, which was lower in GILZ -/- macrophages. Noteworthy, early treatment with TAT-GILZ rescued 30% of S. pneumoniae -infected mice from lethal pneumonia. Altogether, we present evidence that TAT-GILZ enhances host resilience and resistance to pneumococcal pneumonia by controlling pulmonary inflammation and bacterial loads leading to decreased lethality. Exploiting GILZ pathways holds promise for the treatment of severe respiratory infections.

Objective: To analyse differences in clinical presentation and outcome between bacteraemic pneumococcal community-acquired pneumonia (B-PCAP) and sSvere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pneumonia., Methods: This observational multi-centre study was conducted on patients hospitalized with B-PCAP between 2000 and 2020 and SARS-CoV-2 pneumonia in 2020. Thirty-day survival, predictors of mortality, and intensive care unit (ICU) admission were compared., Results: In total, 663 patients with B-PCAP and 1561 patients with SARS-CoV-2 pneumonia were included in this study. Patients with B-PCAP had more severe disease, a higher ICU admission rate and more complications. Patients with SARS-CoV-2 pneumonia had higher in-hospital mortality (10.8% vs 6.8%; P=0.004). Among patients admitted to the ICU, the need for invasive mechanical ventilation (69.7% vs 36.2%; P<0.001) and mortality were higher in patients with SARS-CoV-2 pneumonia. In patients with B-PCAP, the predictive model found associations between mortality and systemic complications (hyponatraemia, septic shock and neurological complications), lower respiratory reserve and tachypnoea; chest pain and purulent sputum were protective factors in these patients. In patients with SARS-CoV-2 pneumonia, mortality was associated with previous liver and cardiac disease, advanced age, altered mental status, tachypnoea, hypoxaemia, bilateral involvement, pleural effusion, septic shock, neutrophilia and high blood urea nitrogen; in contrast, ≥7 days of symptoms was a protective factor in these patients. In-hospital mortality occurred earlier in patients with B-PCAP., Conclusions: Although B-PCAP was associated with more severe disease and a higher ICU admission rate, the mortality rate was higher for SARS-CoV-2 pneumonia and deaths occurred later. New prognostic scales and more effective treatments are needed for patients with SARS-CoV-2 pneumonia., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To explore the negative predictive value (NPV) of C-reactive protein (CRP) at admission to exclude complicated disease manifestations of pneumococcal disease., Methods: A Dutch multicentre retrospective cohort study was conducted between 01-01-2012 and 30-06-2020. Adults with positive blood cultures for Streptococcus pneumoniae, whose CRP was measured at admission and whose infection focus was known, were included. Electronic medical and microbiological records were reviewed., Results: Of the 832 bacteraemic patients enrolled, 30% had complicated manifestations of pneumococcal disease; most frequent were pleural effusion (8.9%), pleural empyema (5.4%) and meningitis (7.5%). Compared to solitary pneumonia, patients with pleural effusion and empyema presented with higher CRP levels. Although low CRP levels did not exclude complicated disease in general, a CRP level < 114 mg/L at admission could reliably exclude empyema among adult pneumonia patients with an NPV of 93% and a specificity of 26%. However, in cases where pleural fluid was present, CRP levels were mostly > 114 mg/L, such that suspicion of empyema could only be ruled out in a minority of cases (10%)., Conclusions: Complicated manifestations are prevalent in adult pneumococcal bacteraemia. Low blood CRP levels can reliably exclude the development of pulmonary empyema. Practical value may be largest in settings without thoracic imaging at hand., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In 2013, the Dominican Republic introduced 13-valent pneumococcal conjugate vaccine (PCV13) using a 3-dose schedule (at 2, 4 and 12 months of age). We evaluated the impact of PCV13 on serotypes causing pneumococcal pneumonia with pleural effusion., Methods: Surveillance data after PCV13 introduction (July 2014 to June 2016) were compared with data before PCV13 introduction (July 2009 to June 2011). Cases were defined as radiologic evidence of pneumonia with pleural effusion in a child aged <15 years. Pneumococcus was detected in pleural fluid by either culture or polymerase chain reaction, and serotyping was performed. The Ministry of Health's PCV13 uptake data for 2014-2016 were obtained., Results: The prevalence of pneumococcus among cases was similar before and after PCV13 introduction (56.4% and 52.8%, respectively). The proportion of pneumococcal cases caused by vaccine serotypes was 86% for children <2 years old both before and PCV13 introduction. Compared with before PCV13, serotype 14 accounted for a smaller (28% vs 13%, respectively; P = .02) and serotype 1 for a larger (23% vs 37%; P = .09) proportion of pneumococcal cases after PCV13 introduction. National uptake for the first, second, and third PCV13 doses was 94%, 81%, and 28%, respectively, in 2014 and 75%, 61%, and 26% in 2015., Discussion: While the decrease in pneumococcal pneumonia with pleural effusion caused by serotype 14 may reflect an early effect of PCV13 implementation, other vaccine serotypes, including serotype 1, are not well controlled. Better PCV13 coverage for all 3 doses is needed., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Background: Studies have reported an increased risk for asthma following lower respiratory tract infections, but few studies have specifically assessed this risk in children diagnosed with pneumonia in infancy. Furthermore, it is not fully understood whether this association is indicative of a causal relationship or if certain children have a predisposition for both diseases., Research Question: Are children diagnosed with pneumonia in infancy at increased risk for asthma, and what is the role of familial confounding and pneumococcal conjugate vaccine immunization on the association?, Study Design and Methods: This study was a nationwide register-based cohort analysis of > 900,000 Swedish children to assess the association between pneumonia in infancy and prevalent asthma at 4 years. A secondary aim was to assess if the association has changed after the introduction of nationwide pneumococcal conjugate vaccine (PCV) immunization as this has led to a shift in pneumonia etiology. The study controlled for important confounders, including shared environmental and familial confounding, by using sibling analyses., Results: There was a strong association between pneumonia diagnosis in infancy and prevalent asthma at 4 years (adjusted OR, 3.38; 95% CI, 3.26-3.51), as well as in the full sibling analyses (adjusted OR, 2.81; 95% CI, 2.58-3.06). The risk for asthma following pneumonia diagnosis in infancy was slightly higher for those born in the PCV period compared with the pre-PCV period (adjusted OR, 3.80 [95% CI, 3.41-4.24] vs 3.28 [95% CI, 3.15-3.42]) when the proportion of viral pneumonia etiology was also higher (14.5% vs 10.7%, respectively) and the overall asthma prevalence was lower (5.3% vs 6.6%)., Interpretation: Children diagnosed with pneumonia in infancy have a highly increased risk for prevalent asthma at 4 years, which might have implications for future asthma preventive measures and needs to be considered when assessing the morbidity that can be attributed to pneumonia., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Resolution of the acute respiratory distress syndrome (ARDS) from pneumonia requires repair of the injured lung endothelium and alveolar epithelium, removal of neutrophils from the distal airspaces of the lung, and clearance of the pathogen. Previous studies have demonstrated the importance of specialized proresolving mediators (SPMs) in the regulation of host responses during inflammation. Although ARDS is commonly caused by Streptococcus pneumoniae , the role of lipoxin A4 (LXA4) and resolvin D1 (RvD1) in pneumococcal pneumonia is not well understood. In the present experimental study, we tested the hypothesis that endogenous SPMs play a role in the resolution of lung injury in a clinically relevant model of bacterial pneumonia. Blockade of formyl peptide receptor 2 (ALX/FPR2), the receptor for LXA4 and RvD1, with the peptide WRW4 resulted in more pulmonary edema, greater protein accumulation in the air spaces, and increased bacteria accumulation in the air spaces and the blood. Inhibition of this receptor was also associated with decreased levels of proinflammatory cytokines. Even in the presence of antibiotic treatment, WRW4 inhibited the resolution of lung injury. In summary, these experiments demonstrated two novel findings: LXA4 and RvD1 contribute to the resolution of lung injury due to pneumococcal pneumonia, and the mechanism of their benefit likely includes augmenting bacterial clearance and reducing pulmonary edema via the restoration of lung alveolar-capillary barrier permeability.

Community-acquired pneumonia is the most common type of pneumonia and remains a leading cause of morbidity and mortality worldwide. Although many different pathogens can contribute to pneumonia, Streptococcus pneumoniae is one of the common bacterial pathogens that underlie community-acquired pneumonia. RIPK3 (receptor-interacting protein kinase 3) is widely recognized as a key modulator of inflammation and cell death. To elucidate a potential role of RIPK3 in pneumonia, we examined plasma from healthy control subjects and patients positive for streptococcal pneumonia. In human studies, RIPK3 protein concentrations were significantly elevated and were identified as a potential plasma marker of pneumococcal pneumonia. To expand these findings, we used an in vivo murine model of pneumococcal pneumonia to demonstrate that RIPK3 deficiency leads to reduced bacterial clearance, severe pathological damage, and high mortality. Our results illustrated that RIPK3 forms a complex with RIPK1, MLKL (mixed-lineage kinase domain-like protein), and MCU (mitochondrial calcium uniporter) to induce mitochondrial calcium uptake and mitochondrial reactive oxygen species(mROS) production during S. pneumoniae infection. In macrophages, RIPK3 initiated necroptosis via the mROS-mediated mitochondrial permeability transition pore opening and NLRP3 inflammasome activation via the mROS-AKT pathway to protect against S. pneumoniae . In conclusion, our study demonstrated a mechanism by which RIPK3-initiated necroptosis is essential for host defense against S. pneumoniae .

The urinary antigen test (UAT) is a rapid diagnostic method for pneumococcal pneumonia, but the high false-negative rate of 30% may affect its reliability. To maximize the utility of UAT, it is necessary to investigate the patient factors affecting UAT results. However, there is no report elucidating the association between its utility and pre-existing lung abnormalities. We retrospectively reviewed 388 patients with pneumococcal pneumonia confirmed by blood and/or sputum culture tests. Finally, 94 of 388 patients who had the results of UAT and computed tomography scans were enrolled to evaluate the association between the utility of UAT and patient factors including pulmonary emphysema and fibrosis. The overall positive rate of UAT was 69.1%. The positive rates of UAT in the patients with emphysema were significantly lower than those in individuals without emphysema (33.3% and 77.6%, p < 0.001). Univariate logistic regression analysis showed that the presence of emphysema was associated with a low positive rate (odds ratio 6.944, 95% confidence interval 2.268-21.231). Multivariate logistic analysis showed that the presence of emphysema and lower levels of serum blood urea nitrogen (BUN) were significantly and independently associated with a low positive rate. The combination of emphysema and BUN can potentially stratify the positive rate of UAT in patients with pneumococcal pneumonia. Patients with pneumococcal pneumonia and emphysema have a lower positive rate of UAT. Additionally, the combination of emphysema and serum BUN value may be useful to evaluate the reliability of the negative results of pneumococcal UAT.

A 44-year-old previously well woman presented with features of respiratory sepsis including a productive cough and fevers, with a recent preceding influenza-like illness. She was diagnosed with community-acquired pneumonia on chest radiograph, influenza infection via nasopharyngeal swab and Streptococcus pneumoniae bloodstream infection with associated purulent pericarditis. She was managed with pericardial drainage and concurrent treatment with antibiotics and made an excellent recovery. This case highlights the complications of both influenza and S. pneumoniae infections, and the importance of prevention via vaccination., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

A 61-year-old man died suddenly after a brief history of shortness of breath and hemoptysis. At autopsy he had lobar pneumonia involving the right upper and left lower lobes of the lung. Significantly there was also a 30 × 20 mm (in cross-section) thyroglossal duct cyst compressing the upper airway. Death was attributed to respiratory failure due to the combined effects of lobar pneumonia (cultures positive for Streptococcus pneumoniae) and airway narrowing from a thyroglossal duct cyst. Although such cysts are usually found in childhood they may on occasion be diagnosed in adults. Despite being the most common congenital cyst in the neck cases associated with a lethal outcome are extremely rare.

Streptococcus pneumoniae is an opportunistic human pathogen that causes invasive diseases, including pneumonia, with greater health risks upon influenza A virus (IAV) co-infection. To facilitate pathogenesis studies in vivo, we developed an inducible CRISPR interference system that enables genome-wide fitness testing in one sequencing step (CRISPRi-seq). We applied CRISPRi-seq to assess bottlenecks and identify pneumococcal genes important in a murine pneumonia model. A critical bottleneck occurs at 48 h with few bacteria causing systemic infection. This bottleneck is not present during IAV superinfection, facilitating identification of pneumococcal pathogenesis-related genes. Top in vivo essential genes included purA, encoding adenylsuccinate synthetase, and the cps operon required for capsule production. Surprisingly, CRISPRi-seq indicated no fitness-related role for pneumolysin during superinfection. Interestingly, although metK (encoding S-adenosylmethionine synthetase) was essential in vitro, it was dispensable in vivo. This highlights advantages of CRISPRi-seq over transposon-based genetic screens, as all genes, including essential genes, can be tested for pathogenesis potential., Competing Interests: Declaration of Interests The authors declare no conflicting interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BACKGROUND Increased susceptibility to bacterial infections is a hallmark of multiple myeloma (MM). Invasive infections with Streptococcus pneumoniae may be the first manifestation of underlying MM. Clinicians treating patients with invasive S. pneumoniae infections may consider searching for underlying MM in the presence of certain diagnostic findings. CASE REPORT A previously healthy 60-year-old man was referred from his general physician because of fever, cough, and chills despite treatment with clarithromycin. The patient had experienced night sweats, weight loss, and recurrent episodes of fever and cough during the last 3 months. Examination was significant for left-sided pulmonary rales. A chest X-ray showed a retrocardiac consolidation of the left lower lobe. The patient was started on empirical antimicrobial therapy for community-acquired pneumonia. Subsequently, blood and sputum cultures were positive for S. pneumoniae. Given the history of night sweats and weight loss, the discrepancy between elevated total protein and low albumin levels, and the diagnosis of pneumococcal bacteremia, multiple myeloma (MM) was suspected and confirmed by immunofixation and bone marrow biopsy. CONCLUSIONS This case showed that clinicians should be vigilant for features of MM, which are encountered during history (e.g., weight loss, bone pain) or routine laboratory workup (e.g., unexplained anemia, renal failure, hypercalcemia, or a discrepancy between elevated total protein and low albumin levels) in elderly patients presenting with invasive pneumococcal disease.

Objetives: To assess the incidence, related factors, timing and duration of new- onset atrial fibrillation in a cohort of consecutive patients diagnosed with pneumococcal pneumonia., Methods: Observational study including all immunocompetent adults hospitalized for pneumococcal pneumonia. Patients were classified by time (atrial fibrillation recognized on emergency room arrival or developed during hospitalization) and duration (paroxysmal or persistent). Patients were followed-up for 6 months after discharge., Results: We included 1092 patients, of whom 109 (9.9%) had new-onset atrial fibrillation. An early event was documented in 87 (79.8%) cases. Arrhythmia was classified as paroxysmal in 78 patients. Older age, heavy drinking, respiratory rate ≥ 30/minute, leukopenia, severe inflammation and bacteremia were independent risk factors for developing new-onset atrial fibrillation on admission. Overall, 48 (4.4%) patients died during hospitalization, the rate being higher in those patients who developed new-onset arrhythmia (17.9% vs 2.9% p<0.001). Among patients with events recognized at admission, in-hospital mortality was higher in those with persistent arrhythmia (34.8% vs 6.3%, p = 0.002) and 6-month survival was better among those who developed paroxysmal event., Conclusions: The development of new-onset atrial fibrillation was associated with pneumonia severity, and higher in-hospital mortality. Bacteremia and severe systemic inflammation were factors associated with its development., (Copyright © 2020. Published by Elsevier Ltd.)

Background: In the context of the COVID-19 pandemic the risk of misdiagnosis of other causes of respiratory infection is likely. In this work we aim to describe the clinical characteristics, treatment and outcome of pneumococcal infection in COVID-19 patients., Patients and Methods: Every COVID-19 patient presenting with concomitant pneumococcal pneumonia during March 2020 in a tertiary teaching Hospital In Barcelona, Spain., Results: Five patients with PCR confirmed COVID19 or clinical and radiological suspicion were diagnosed of pneumococcal infection. In all cases chest X-ray were abnormal, with unilateral or bilateral infiltrates. Procalcitonin showed to be not sensitive enough to detect pneumococcal infection. Antibiotherapy was promptly started in all five cases with subsequent satisfactory evolution., Conclusion: International guidelines do not include the universal screening for bacterial co-infection. Radiological pattern of COVID-19 can be indistinguishable from that of pneumococcus pneumonia and frequency of co-infection is not well stablished, therefore clinicians should be aware of the possible SARS-CoV-2-pneumococcus association to avoid misdiagnosis and delay antibiotic therapy., (Copyright © 2020 Elsevier España, S.L.U. All rights reserved.)

Background: Streptococcus pneumoniae infection can result in bacteremia with devastating consequences including heart damage. Necroptosis is a proinflammatory form of cell death instigated by pore-forming toxins such as S. pneumoniae pneumolysin. Necroptosis-inhibiting drugs may lessen organ damage during invasive pneumococcal disease (IPD)., Methods: In vitro experiments were carried out with human and mouse cardiomyocytes. Long-term cardiac damage was assessed using high-resolution echocardiography in ampicillin-rescued mice 3 months after challenge with S. pneumoniae. Ponatinib, a necroptosis-inhibiting and Food and Drug Administration-approved drug for lymphocytic leukemia treatment, was administered intraperitoneally alongside ampicillin to test its therapeutic efficacy. Histology of heart sections included hematoxylin-eosin staining for overt damage, immunofluorescence for necroptosis, and Sirius red/fast green staining for collagen deposition., Results: Cardiomyocyte death and heart damage was due to pneumolysin-mediated necroptosis. IPD leads to long-term cardiac damage, as evidenced by de novo collagen deposition in mouse hearts and a decrease in fractional shortening. Adjunct necroptosis inhibition reduced the number of S. pneumoniae foci observed in hearts of acutely infected mice and serum levels of troponin I. Ponatinib reduced collagen deposition and protected heart function in convalescence., Conclusions: Acute and long-term cardiac damage incurred during IPD is due in part to cardiomyocyte necroptosis. Necroptosis inhibitors may be a viable adjunct therapy., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Streptococcus pneumoniae can cause disease in various human tissues and organs, including the ear, the brain, the blood, and the lung, and thus in highly diverse and dynamic environments. It is challenging to study how pneumococci control virulence factor expression, because cues of natural environments and the presence of an immune system are difficult to simulate in vitro. Here, we apply synthetic biology methods to reverse-engineer gene expression control in S. pneumoniae A selection platform is described that allows for straightforward identification of transcriptional regulatory elements out of combinatorial libraries. We present TetR- and LacI-regulated promoters that show expression ranges of four orders of magnitude. Based on these promoters, regulatory networks of higher complexity are assembled, such as logic AND gates and IMPLY gates. We demonstrate single-copy genome-integrated toggle switches that give rise to bimodal population distributions. The tools described here can be used to mimic complex expression patterns, such as the ones found for pneumococcal virulence factors. Indeed, we were able to rewire gene expression of the capsule operon, the main pneumococcal virulence factor, to be externally inducible (YES gate) or to act as an IMPLY gate (only expressed in absence of inducer). Importantly, we demonstrate that these synthetic gene-regulatory networks are functional in an influenza A virus superinfection murine model of pneumonia, paving the way for in vivo investigations of the importance of gene expression control on the pathogenicity of S. pneumoniae ., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: Reports on the effectiveness of pneumococcal conjugate vaccines (PCVs) on pediatric parapneumonic effusion are limited. We report the changes in cases and etiologies of pediatric parapneumonic effusion in a children's hospital before and after national PCV13 vaccination programs., Methods: We screened medical records of children 0-18 years admitted to the National Taiwan University Hospital with diagnoses of lobar pneumonia and parapneumonic effusion between 2008 and 2017. Patients with effusion analyses were included. Results of blood, pleural fluid, and respiratory specimens surveyed as standard care were analyzed., Results: Diagnostic testing revealed at least a pathogen in 85% of 202 children with lobar pneumonia and parapneumonic effusion. After national PCV13 immunization, pneumococcal empyema decreased by 72% among 2- to 5-year olds. Mycoplasma pneumoniae was the second most common etiology. There were marked differences in effusion characteristics, metabolic, and respiratory parameters between children infected with pneumococcus and M. pneumoniae., Conclusion: The effectiveness of the national PCV13 immunization programs on pneumococcal empyema was evident and remained substantial after 4 years in Taiwan. Continuous surveillance is important to monitor the emergence of other pathogens including non-PCV serotypes and M. pneumoniae., (Copyright © 2020. Published by Elsevier B.V.)

Background and Objectives: Streptococcus pneumoniae urinary antigen (u-Ag) testing has recently gained attention in the early diagnosis of severe and critical acute respiratory syndrome coronavirus-2/pneumococcal co-infection. The aim of this study is to assess the effectiveness of Streptococcus pneumoniae u-Ag testing in coronavirus disease 2019 (COVID-19) patients, in order to assess whether pneumococcal co-infection is associated with different mortality rate and hospital stay in these patients., Materials and Methods: Charts, protocols, mortality, and hospitalization data of a consecutive series of COVID-19 patients admitted to a tertiary hospital in northern Italy during COVID-19 outbreak were retrospectively reviewed. All patients underwent Streptococcus pneumoniae u-Ag testing to detect an underlying pneumococcal co-infection. Covid19+/u-Ag+ and Covid19+/u-Ag- patients were compared in terms of overall survival and length of hospital stay using chi-square test and survival analysis., Results: Out of 575 patients with documented pneumonia, 13% screened positive for the u-Ag test. All u-Ag+ patients underwent treatment with Ceftriaxone and Azithromycin or Levofloxacin. Lopinavir/Ritonavir or Darunavir/Cobicistat were added in 44 patients, and hydroxychloroquine and low-molecular-weight heparin (LMWH) in 47 and 33 patients, respectively. All u-Ag+ patients were hospitalized. Mortality was 15.4% and 25.9% in u-Ag+ and u-Ag- patients, respectively ( p = 0.09). Survival analysis showed a better prognosis, albeit not significant, in u-Ag+ patients. Median hospital stay did not differ among groups (10 vs. 9 days, p = 0.71)., Conclusions: The routine use of Streptococcus pneumoniae u-Ag testing helped to better target antibiotic therapy with a final trend of reduction in mortality of u-Ag+ COVID-19 patients having a concomitant pneumococcal infection. Randomized trials on larger cohorts are necessary in order to draw definitive conclusion.

The purpose of this review is to describe Streptococcus pneumoniae-associated hemolytic uremic syndrome (P-HUS) with emphasis on new insights into the pathophysiology and management over the past 10 years. Even though awareness of this clinico-pathological entity has increased, it likely remains under-recognized. Recent observations indicate that although neuraminidase activity and exposure of the T-antigen are necessary for development of P-HUS, they are not sufficient; activation of the alternate pathway of complement may also contribute. It is unclear, however, whether or not eculizumab and/or plasmapheresis are of value.

Necrotising pneumonia (NP) is a potentially severe complication of community-acquired pneumonia characterised by necrosis of consolidated lung tissue. A 7-year-old boy and a 6-year-old boy are presented, both of whom had a complicated influenza infection which evolved into severe NP caused by Streptococcus pneumoniae . Both needed intensive care for invasive respiratory support. Despite extensive pleural involvement in both cases, only one required thoracic surgery. Case 1 also developed anaemia, hyponatraemia and hypo-albuminaemia, resulting in generalised oedema. Despite the severe morbidity, both boys made a full recovery. The diagnosis of NP should always be considered in a child with pneumonia who remains unwell despite 72 hours of appropriate antibiotics, particularly if there is evidence of pleural disease. Although S. pneumoniae is the main agent for NP, the influenza virus may be a precipitating factor.

Background: Although people living with human immunodeficiency virus (PLWH) are at increased risk of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP), it is unclear whether this remains the case in the setting of early initiation of combination antiretroviral therapy (cART), at high CD4 cell counts. This is important, as pneumococcal vaccination coverage in PLWH is low in Europe and the United States, despite longstanding international recommendations., Methods: We identified all CAP and IPD cases between 2008 and 2017 in a cohort of PLWH in a Dutch HIV referral center. We calculated incidence rates stratified by CD4 count and cART status and conducted a case-control study to identify risk factors for CAP in PLWH receiving cART., Results: Incidence rates of IPD and CAP in PLWH were 111 and 1529 per 100 000 patient-years of follow-up (PYFU). Although IPD and CAP occurred more frequently in patients with CD4 counts <500 cells/μL (incidence rate ratio [IRR], 6.1 [95% confidence interval, 2.2-17] and IRR, 2.4 [95% confidence interval, 1.9-3.0]), the incidence rate in patients with CD4 counts >500 cells/μL remained higher compared with the general population (946 vs 188 per 100 000 PYFU). All IPD isolates were vaccine serotypes. Risk factors for CAP were older age, CD4 counts <500 cells/μL, smoking, drug use, and chronic obstructive pulmonary disease., Conclusions: The incidence of IPD and CAP among PLWH remains higher compared with the general population, even in those who are virally suppressed and have high CD4 counts. With all serotyped IPD isolates covered by pneumococcal vaccines, our study provides additional argumentation against the poor current adherence to international recommendations to vaccinate PLWH., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

The competence regulon of pneumococcus regulates both genetic transformation and virulence. However, competence induction during host infection has not been examined. By using the serotype 2 strain D39, we transcriptionally fused the firefly luciferase ( luc ) to competence-specific genes and spatiotemporally monitored the competence development in a mouse model of pneumonia-derived sepsis. In contrast to the universally reported short transient burst of competent state in vitro , the naturally developed competent state was prolonged and persistent during pneumonia-derived sepsis. The competent state began at approximately 20 h postinfection (hpi) and facilitated systemic invasion and sepsis development and progressed in different manners. In some mice, acute pneumonia quickly led to sepsis and death, accompanied by increasing intensity of the competence signal. In the remaining mice, pneumonia lasted longer, with the competence signal decreasing at first but increasing as the infection became septic. The concentration of pneumococcal inoculum (1 × 10 6 to 1 × 10 8 CFU/mouse) and postinfection lung bacterial burden did not appreciably impact the kinetics of competence induction. Exogenously provided competence stimulating peptide 1 (CSP1) failed to modulate the onset kinetics of competence development in vivo The competence shutoff regulator DprA was highly expressed during pneumonia-derived sepsis but failed to turn off the competent state in mice. Competent D39 bacteria propagated the competence signal through cell-to-cell contact rather than the classically described quorum-sensing mechanism. Finally, clinical pneumococcal strains of different serotypes were also able to develop natural competence during pneumonia-derived sepsis., (Copyright © 2020 American Society for Microbiology.)

Studies demonstrated that pneumonia can decrease vitamin A productions and vitamin A reduction/deficiency may promote asthma development. Our previous study showed that neonatal Streptococcus pneumoniae (S. pneumoniae) infection promoted asthma development. Whether neonatal S. pneumoniae pneumonia induced asthma was associated with vitamin A levels remains unclear. The aim of this study was to investigate the effects of neonatal S. pneumoniae pneumonia on vitamin A expressions, to explore the effects of vitamin A supplement after neonatal S. pneumoniae pneumonia on adulthood asthma development. Non-lethal S. pneumoniae pneumonia was established by intranasal inoculation of neonatal (1-week-old) female BALB/c mice with D39. S. pneumoniae pneumonia mice were supplemented with or without all-trans retinoic acid 24 hours after infection. Vitamin A concentrations in lung, serum and liver were measured post pneumonia until early adulthood. Four weeks after pneumonia, mice were sensitized and challenged with OVA to induce allergic airway disease (AAD). Twenty-four hours after the final challenge, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. We stated that serum vitamin A levels in neonatal S. pneumoniae pneumonia mice were lower than 0.7µmol/L from day 2-7 post infection, while pulmonary vitamin A productions were significantly lower than those in the control mice from day 7-28 post infection. Vitamin A supplement after neonatal S. pneumoniae pneumonia significantly promoted Foxp3 + Treg and Th1 productions, decreased Th2 and Th17 cells expressions, alleviated airway hyperresponsiveness (AHR) and inflammatory cells infiltration during AAD. Our data suggest that neonatal S. pneumoniae pneumonia induce serum vitamin A deficiency and long-time lung vitamin A reduction, vitamin A supplement after neonatal S. pneumoniae pneumonia inhibit the progression of asthma by altering CD4 + T cell subsets.

Multiorgan dysfunction syndrome is the most common cause of mortality in intensive care units. The lungs and kidneys are frequently affected, so up to 60% of patients require simultaneous respiratory support and renal replacement therapy. Extracorporeal CO 2 elimination systems have now been developed with the aim of reducing the incidence of acute lung injury. These systems can be combined with renal support therapies in patients with dysfunction of both organs. We present a case of respiratory septic shock with renal failure and respiratory distress syndrome, in which extracorporeal elimination of CO 2 therapy facilitated the use of protective ventilation, with a low tidal volume of 4ml/kg, plateau pressure below 30cmH 2 O, and PaCO 2 values of less than 60mmHg., (Copyright © 2019 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

Pneumonia is responsible for more deaths in the United States than any other infectious disease. Severe pneumonia is a common cause of acute respiratory failure and acute respiratory distress syndrome (ARDS). Despite the introduction of effective antibiotics and intensive supportive care in the 20th century, death rates from community-acquired pneumonia among patients in the intensive care unit remain as high as 35%. Beyond antimicrobial treatment, no targeted molecular therapies have yet proven effective, highlighting the need for additional research. Despite some limitations, small animal models of pneumonia and the mechanistic insights they produce are likely to continue to play an important role in generating new therapeutic targets. Here we describe the development of an innovative mouse model of pneumococcal pneumonia developed for enhanced clinical relevance. We first reviewed the literature of small animal models of bacterial pneumonia that incorporated antibiotics. We then did a series of experiments in mice in which we systematically varied the pneumococcal inoculum and the timing of antibiotics while measuring systemic and lung-specific end points, producing a range of models that mirrors the spectrum of pneumococcal lung disease in patients, from mild self-resolving infection to severe pneumonia refractory to antibiotics. A delay in antibiotic treatment resulted in ongoing inflammation and renal and hepatic dysfunction despite effective bacterial killing. The addition of fluid resuscitation to the model improved renal function but worsened the severity of lung injury based on direct measurements of pulmonary edema and lung compliance, analogous to patients with pneumonia and sepsis who develop ARDS following fluid administration.

Empyema necessitans is a rare complication of acute bacterial pneumonia, especially in children. It is a complication of empyema characterised by the extension of pus from the pleural cavity into the thoracic wall to form a mass of purulent fluid in the adjacent soft tissue. An inflammatory chest wall mass following pneumonia caused by Streptococcus pneumonia in a six-month-old infant is reported. The case emphasises that children presenting with persistent fever and a painful chest wall mass following pneumonia should be investigated immediately as there might be an urgent need for surgery.

Purulent pericarditis leading to constrictive pericarditis is a rare but serious complication following invasive pneumococcal infection. Early recognition of this complication is crucial to prevent mortality. Here, we report a previously healthy child who developed constrictive pericarditis due to purulent pericarditis following necrotising pneumococcal pneumonia, which is not common in this current antibiotic and pneumococcal vaccine era. The child was successfully treated with pericardiectomy.

Background: Most cases of complicated pneumonia in children are caused by pneumococcal infections. Thomsen-Friedenreich antigen (TA) is present on erythrocytes, platelets and glomeruli, and it can be activated during pneumococcal infection. The aim of this study was to investigate the predictive value of TA activation for pneumococcal infection and association with the severity of complicated pneumonia., Materials and Methods: Patients with lobar pneumonia were routinely tested for TA at the Department of Pediatrics, Mackay Memorial Hospital from January 2010 to December 2015. We retrospectively reviewed and analyzed their charts and data including age, sex, etiology of infection, chest tube insertion or video-assisted thoracoscopic surgery, length of hospital stay, TA activation, white blood cell count and level of C reactive protein., Results: A total of 142 children with lobar pneumonia were enrolled, including 35 with empyema, 31 with effusion, 11 with necrotizing pneumonia and four with lung abscess. Streptococcus pneumoniae was the most commonly identified pathogen. Twenty-two patients (15.4%) had activated TA, all of whom were infected with S. pneumoniae. TA activation had 100% specificity and 100% positive predictive value for pneumococcal infection. In the multivariate analysis in lobar pneumonia, TA activation (OR, 15.8; 95% CI, 3.0-83.5; p = 0.001), duration of fever before admission (OR, 1.2; 95% CI, 1.1-1.5; p = 0.013) and initial CRP level (OR, 1.1; 95% CI, 1.0-1.1; p = 0.004) were independent predictors of empyema., Conclusions: TA activation is a specific marker for pneumococcal pneumonia and might indicate higher risk for complicated pneumonia., (Copyright © 2017. Published by Elsevier B.V.)

It is now well recognized that cardiovascular events (CVE) occur quite commonly, both in the acute phase and in the long-term, in patients with community-acquired pneumonia (CAP). CVE have been noted in up to 30% of patients hospitalized with all-cause CAP. One systematic review and meta-analysis of hospitalized patients with all-cause CAP noted that the incidence rates for overall cardiac events were 17.7%, for incident heart failure were 14.1%, for acute coronary syndromes were 5.3% and for incident cardiac arrhythmias were 4.7%. In the case of pneumococcal CAP, almost 20% of patients studied had one or more of these cardiac events. Recent research has provided insights into the pathogenesis of the acute cardiac events occurring in pneumococcal infections. With respect to the former, key involvements of the major pneumococcal protein virulence factor, pneumolysin, are now well documented, whilst systemic platelet-driven neutrophil activation may also contribute. However, events involved in the pathogenesis of the long-term cardiovascular sequelae remain largely unexplored. Emerging evidence suggests that persistent antigenaemia may predispose to the development of a systemic pro-inflammatory/prothrombotic phenotype underpinning the risk of future cardiovascular events. The current manuscript briefly reviews the occurrence of cardiovascular events in patients with all-cause CAP, as well as in pneumococcal and influenza infections. It highlights the close interaction between influenza and pneumococcal pneumonia. It also includes a brief discussion of mechanisms of the acute cardiac events in CAP. However, the primary focus is on the prevalence, pathogenesis and prevention of the longer-term cardiac sequelae of severe pneumococcal disease, particularly in the context of persistent antigenaemia and associated inflammation., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)