Pneumonia-Induced Inflammation, Resolution and Cardiovascular Disease: Causes, Consequences and Clinical Opportunities.

Pneumonia is inflammation in the lungs, which is usually caused by an infection. The symptoms of pneumonia can vary from mild to life-threatening, where severe illness is often observed in vulnerable populations like children, older adults, and those with preexisting health conditions. Vaccines have greatly reduced the burden of some of the most common causes of pneumonia, and the use of antimicrobials has greatly improved the survival to this infection. However, pneumonia survivors do not return to their preinfection health trajectories but instead experience an accelerated health decline with an increased risk of cardiovascular disease. The mechanisms of this association are not well understood, but a persistent dysregulated inflammatory response post-pneumonia appears to play a central role. It is proposed that the inflammatory response during pneumonia is left unregulated and exacerbates atherosclerotic vascular disease, which ultimately leads to adverse cardiac events such as myocardial infarction. For this reason, there is a need to better understand the inflammatory cross talk between the lungs and the heart during and after pneumonia to develop therapeutics that focus on preventing pneumonia-associated cardiovascular events. This review will provide an overview of the known mechanisms of inflammation triggered during pneumonia and their relevance to the increased cardiovascular risk that follows this infection. We will also discuss opportunities for new clinical approaches leveraging strategies to promote inflammatory resolution pathways as a novel therapeutic target to reduce the risk of cardiac events post-pneumonia.

A multiple comorbidities mouse lung infection model in ApoE­deficient mice.

Acute pneumonia is characterised by a period of intense inflammation. Inflammation is now considered to be a key step in atherosclerosis progression. In addition, pre-existing atherosclerotic inflammation is considered to play a role in pneumonia progression and risk. In the present study, a multiple comorbidities murine model was used to study respiratory and systemic inflammation that results from pneumonia in the setting of atherosclerosis. Firstly, a minimal infectious dose of Streptococcus pneumoniae (TIGR4 strain) to produce clinical pneumonia with a low mortality rate (20%) was established. C57Bl/6 ApoE -/- mice were fed a high-fat diet prior to administering intranasally 105 colony forming units of TIGR4 or phosphate-buffered saline (PBS). At days 2, 7 and 28 post inoculation (PI), the lungs of mice were imaged by magnetic resonance imaging (MRI) and positron emission tomography (PET). Mice were euthanised and investigated for changes in lung morphology and changes in systemic inflammation using ELISA, Luminex assay and real-time PCR. TIGR4-inoculated mice presented with varying degrees of lung infiltrate, pleural effusion and consolidation on MRI at all time points up to 28 days PI. Moreover, PET scans identified significantly higher FDG uptake in the lungs of TIGR4-inoculated mice up to 28 days PI. The majority (90%) TIGR4-inoculated mice developed pneumococcal-specific IgG antibody response at 28 days PI. Consistent with these observations, TIGR4-inoculated mice displayed significantly increased inflammatory gene expression [interleukin (IL)-1ß and IL-6] in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7 and 28 days PI respectively. The mouse model developed by the authors presents a discovery tool to understand the link between inflammation related to acute infection such as pneumonia and increased risk of cardiovascular disease observed in humans.

Guideline-Concordant Antibiotic Therapy for the Hospital Treatment of Community-Acquired Pneumonia and 1-Year All-Cause and Cardiovascular Mortality in Older Adult Patients Surviving to Discharge.

BACKGROUND: Selection of empiric antibiotic treatment for community-acquired pneumonia (CAP) that is concordant with clinical practice guidelines has been associated with improved short-term outcomes of this infection, but whether it is also associated with longer-term outcomes is unknown. RESEARCH QUESTION: Is guideline-concordance of the initial antibiotic treatment given to older adult patients hospitalized with CAP associated with the 1-year all-cause and cardiovascular mortality risk of those patients who survive hospitalization for this infection? STUDY DESIGN AND METHODS: A total of 1,909 older (> 65 years of age) patients were identified who survived hospitalization for CAP at The Ottawa Hospital (Ontario, Canada) between 2004 and 2015. Linking patients' information to hospital and provincial data sets, this study analyzed whether the selection of the initial antibiotic therapy for their CAP was concordant with current clinical practice guidelines, and whether guideline-concordance was associated with 1-year all-cause and cardiovascular mortality following their index CAP hospitalization. Adjustments were made for the patients' overall 1-year expected death risk; CAP severity; and history of previous pneumonia admissions, myocardial infarction, heart failure, or cerebrovascular disease. RESULTS: Selection of guideline-concordant antibiotic therapy was associated with a trend towards lower all-cause mortality at 1 year post-CAP (hazard ratio, 0.82; 95% CI, 0.65-1.04; P = .099). Furthermore, the use of guideline-concordant antibiotic therapy was associated with a significant almost 50% reduction in cardiovascular death risk 1 year following CAP admission (hazard ratio, 0.53; 95% CI, 0.34-0.80; P = .003). INTERPRETATION: Use of guideline-concordant antibiotic therapy for CAP treatment in older hospitalized patients is associated with a significant reduction in the risk of cardiovascular death at 1 year post-CAP. This finding further supports current clinical practice guideline recommendations for CAP treatment.

Cardiovascular changes after pneumonia in a dual disease mouse model.

Residual inflammation in cardiovascular organs is thought to be one of the catalysts for the increased risk of cardiovascular complications seen following pneumonia. To test this hypothesis, we investigated changes in plaque characteristics and inflammatory features in ApoE-/- mouse aorta and heart following pneumonia. Male ApoE-/- mice were fed a high fat diet for 8 weeks before intranasal inoculation with either Streptococcus pneumoniae serotype 4 (test group) or phosphate buffered saline (control group). Mice were sacrificed at 2-, 7- and 28-days post-challenge. Changes in plaque burden and characteristics in aortic root and thoracic aorta were characterized by Oil red O and Trichrome stains. Inflammatory changes were investigated by FDG-PET imaging and immunofluorescence staining. We found TIGR4-infected mice present with increased plaque presence in the aortic root and thoracic aorta at 2- and 28-days post-inoculation, respectively. Aortic wall remodelling was also more pronounced in mice challenged with pneumococci at 28 days post-inoculation. Aortic root plaques of infected mice had reduced collagen and smooth muscle cells, consistent with an unstable plaque phenotype. Pneumonia alters plaque burden, plaque characteristics, and aortic wall remodelling in ApoE-/- mice. These effects caused by Streptococcus pneumoniae TIGR4, may contribute to the increased risk of cardiovascular complications seen in survivors of this infection.

Anti-inflammatory effect of rosuvastatin in patients with HIV infection: An FDG-PET pilot study.

AIMS: This study aimed to evaluate markers of systemic as well as imaging markers of inflammation in the ascending aorta, bone marrow, and spleen measured by 18F-FDG PET/CT, in HIV+ patients at baseline and following therapy with rosuvastatin. METHODS AND RESULTS: Of the 35 HIV+ patients enrolled, 17 were randomized to treatment with 10 mg/day rosuvastatin and 18 to usual care for 6 months. An HIV- control cohort was selected for baseline comparison of serum inflammatory markers and monocyte markers of inflammation. 18F-FDG-PET/CT imaging of bone marrow, spleen, and thoracic aorta was performed in the HIV+ cohort at baseline and 6 months. While CD14++CD16- and CCR2 expressions were reduced, serum levels of IL-7, IL-8, and MCP-1 were elevated in the HIV+ population compared to the controls. There was a significant drop in FDG uptake in the bone marrow (TBRmax), spleen (SUVmax) and thoracic aortic (TBRmax) in the statin-treated group compared to the control group (bone marrow: - 10.3 ± 16.9% versus 5.0 ± 18.9%, p = .0262; spleen: - 9.8 ± 20.3% versus 11.3 ± 28.8%, p = .0497; thoracic aorta: - 19.1 ± 24.2% versus 4.3 ± 15.4%, p = .003). CONCLUSIONS: HIV+ patients had significantly markers of systemic inflammation including monocyte activation. Treatment with low-dose rosuvastatin in the HIV+ cohort significantly reduced bone marrow, spleen and thoracic aortic FDG uptake.

Persistent Lung Inflammation After Clinical Resolution of Community-Acquired Pneumonia as Measured by 18FDG-PET/CT Imaging.

BACKGROUND: Survivors of community-acquired pneumonia (CAP) are at increased risk of cardiovascular disease, cognitive and functional decline, and death, but the mechanisms remain unknown. RESEARCH QUESTION: Do CAP survivors have evidence of increased inflammatory activity in their lung parenchyma on 2-deoxy-2-[18F]fluoro-d-glucose (18FDG)-PET/CT imaging after clinical resolution of infection? STUDY DESIGN AND METHODS: We obtained 18FDG-PET/CT scans from 22 CAP survivors during their hospitalization with pneumonia (acute CAP) and 30 to 45 days after hospital discharge (post-CAP). In each set of scans, we assessed the lungs for foci of increased 18FDG uptake by visual interpretation and by total pulmonary glycolytic activity (tPGA), a background-corrected measure of total metabolic activity (as measured by 18FDG uptake). We also measured, post-CAP, the glycolytic activity of CAP survivor lung areas with volumes similar to the areas in 28 matched historical control subjects without pneumonia. RESULTS: Overall, 68% of CAP survivors (95% CI, 45%-85%) had distinct residual areas of increased 18FDG uptake in their post-CAP studies. tPGA decreased from 821.5 (SD, 1,140.2) in the acute CAP period to 80.0 (SD, 81.4) in the post-CAP period (P = .006). The tPGA post-CAP was significantly higher than that in lung areas of similar volume in control subjects (80.0 [SD, 81.4] vs -19.4 [SD, 5.9]; P < .001). INTERPRETATION: An important proportion of CAP survivors have persistent pulmonary foci of increased inflammatory activity beyond resolution of their infection. As inflammation contributes to cardiovascular disease, cognitive decline, functional waning, and mortality risk in the general population, this finding provides a plausible mechanism for the increased morbidity and mortality that have been observed post-CAP.

Accuracy of Administrative Database Algorithms for Hospitalized Pneumonia in Adults: a Systematic Review.

BACKGROUND: Administrative data algorithms (ADAs) to identify pneumonia cases are commonly used in the analysis of pneumonia burden, trends, etiology, processes of care, outcomes, health care utilization, cost, and response to preventative and therapeutic interventions. However, without a good understanding of the validity of ADAs for pneumonia case identification, an adequate appreciation of this literature is difficult. We systematically reviewed the quality and accuracy of published ADAs to identify adult hospitalized pneumonia cases. METHODS: We reviewed the Medline, EMBase, and Cochrane Central databases through May 2020. All studies describing ADAs for adult hospitalized pneumonia and at least one accuracy statistic were included. Investigators independently extracted information about the sampling frame, reference standard, ADA composition, and ADA accuracy. RESULTS: Thirteen studies involving 24 ADAs were analyzed. Compliance with a 38-item study-quality assessment tool ranged from 17 to 29 (median, 23; interquartile range [IQR], 20 to 25). Study setting, design, and ADA composition varied extensively. Inclusion criteria of most studies selected for high-risk populations and/or increased pneumonia likelihood. Reference standards with explicit criteria (clinical, laboratorial, and/or radiographic) were used in only 4 ADAs. Only 2 ADAs were validated (one internally and one externally). ADA positive predictive values ranged from 35.0 to 96.5% (median, 84.8%; IQR, 65.3 to 89.1%). However, these values are exaggerated for an unselected patient population because pneumonia prevalences in the study cohorts were very high (median, 66%; IQR, 46 to 86%). ADA sensitivities ranged from 31.3 to 97.8% (median, 65.1%; IQR 52.5-72.4). DISCUSSION: ADAs for identification of adult pneumonia hospitalizations are highly heterogeneous, poorly validated, and at risk for misclassification bias. Greater standardization in reporting ADA accuracy is required in studies using pneumonia ADA for case identification so that results can be properly interpreted.

Knowledge and Attitudes of Canadian Cardiac Surgeons Regarding Patients With Human Immunodeficiency Virus.

BACKGROUND: Current data on cardiac surgical practices for people living with human immunodeficiency virus (HIV) are lacking. We hypothesized that cardiac surgeons would consider people living with HIV as candidates for the full scope of cardiac surgery, including heart transplant for these patients. METHODS: We conducted a prospective survey of 155 cardiac surgeons across Canada to evaluate their current clinical perceptions regarding cardiac surgery in people living with HIV. Specifically, we evaluated their assessment of eligibility toward a wide scope of cardiac surgeries by using representative clinical scenarios. RESULTS: A total of 63 surgeon responses (40.6%) were completed. The majority of surgeons agreed that a 50-year-old man with HIV and no other comorbidities, who had been receiving combination antiretroviral therapy for 5 years with an undetectable viral load since starting therapy and a CD4 count greater than 350 cells/µL, would be a candidate for valve replacement (73%), valve repair surgery (74.6%), or coronary artery bypass graft surgery (79.4%). Few surgeons believed that this patient would be eligible for cardiac transplantation (7.9%) or could be a cardiac transplant donor (1.6%). There was clinical equipoise over the eligibility for ventricular assist device surgery. CONCLUSIONS: A majority of cardiac surgeons would perform coronary artery bypass graft surgery or valve surgery on patients with controlled HIV, but most consider HIV status as a prohibitive risk factor for cardiac transplantation. Although this may represent an opportunity for continuing medical education for cardiac surgeons, it also highlights the need for contemporary, high-quality evidence in this patient population.

Modelling the linkage between influenza infection and cardiovascular events via thrombosis.

There is a heavy burden associated with influenza including all-cause hospitalization as well as severe cardiovascular and cardiorespiratory events. Influenza associated cardiac events have been linked to multiple biological pathways in a human host. To study the contribution of influenza virus infection to cardiovascular thrombotic events, we develop a dynamic model which incorporates some key elements of the host immune response, inflammatory response, and blood coagulation. We formulate these biological systems and integrate them into a cohesive modelling framework to show how blood clotting may be connected to influenza virus infection. With blood clot formation inside an artery resulting from influenza virus infection as the primary outcome of this integrated model, we demonstrate how blood clot severity may depend on circulating prothrombin levels. We also utilize our model to leverage clinical data to inform the threshold level of the inflammatory cytokine TNFα which initiates tissue factor induction and subsequent blood clotting. Our model provides a tool to explore how individual biological components contribute to blood clotting events in the presence of influenza infection, to identify individuals at risk of clotting based on their circulating prothrombin levels, and to guide the development of future vaccines to optimally interact with the immune system.

Coronary artery calcium before and after hospitalization with pneumonia: The MESA study.

BACKGROUND: Epidemiological analyses demonstrate that pneumonia survivors have a higher risk of myocardial infarction than people with similar load of risk factors for atherosclerotic cardiovascular disease (ASCVD) but without pneumonia. This may be due to a higher baseline burden of ASCVD in patients with pneumonia that is not captured by the accounting of known ASCVD risk factors in epidemiological analyses or to unfavorable accelerating effects of pneumonia on atherosclerosis. METHODS: We analyzed data from the Multi-Ethnic Study of Atherosclerosis. We identified 54 participants that were hospitalized for pneumonia during study follow-up and that also had assessment of coronary artery calcium (CAC, an objective marker of coronary atherosclerotic burden) before and after this hospitalization. We matched them to 54 participants who were not hospitalized for pneumonia but that had CAC assessments at the same study visits as the pneumonia cases. We compared baseline CAC scores and their progression between groups. RESULTS: Baseline CAC scores were similar in both groups (median [IQR]; 6.3 [0-356.8] in pneumonia participants vs. 10.8 [0-178.3] in controls; p = 0.25). After a median of 4.8 years, the direction and magnitude of CAC score change, and the slope of CAC score progression between groups was also similar (median change [IQR], 21.8 [0 to 287.29] in participants with pneumonia versus 15.8 [0 to 140.94] in controls, p = 0.28; difference in slope, 7.7, 95% CI -9.0 to 24.6, p = 0.18). However, among participants with high baseline ASCVD risk (i.e. ACC/AHA 10-year risk estimate ≥7.5%), participants with pneumonia showed a larger increase in CAC scores (median change [IQR]; 159.10 [38.55-407.34] versus 48.72 [0.97-246.99] in controls; p = 0.02) and a trend towards a steeper slope of CAC score progression (difference in slope, 19.7, 95% CI -6.6 to 45.6, p = 0.07). CONCLUSION: Pneumonia may accelerate the progression of atherosclerosis in people with high baseline ASCVD risk.

Right Heart Function During and After Community-Acquired Pneumonia in Adults.

BACKGROUND: New-onset or worsening heart failure is the most common extra-pulmonary complication of community-acquired pneumonia (CAP) during the first 30 days after diagnosis. METHODS: We evaluated the changes in the right ventricular function amongst adult CAP survivors from the time of acute infection to its resolution. We performed comprehensive transthoracic echocardiographic examinations to assess right heart function during the acute illness and the convalescent period (4 to 6 weeks after hospital discharge). RESULTS: Twenty-six patients underwent acute measurements, of which convalescent measurements were completed in 19 subjects. There was no significant change in any of the right heart function parameters from the acute to convalescent stage of CAP. CONCLUSIONS: Our results suggest that right ventricular function does not meaningfully change in the transition from the acute to convalescent stage of CAP in non-critically ill adult CAP survivors.

Cardiovascular Complications and Short-term Mortality Risk in Community-Acquired Pneumonia.

BACKGROUND.: Previous reports suggest that community-acquired pneumonia (CAP) is associated with an enhanced risk of cardiovascular complications. However, a contemporary and comprehensive characterization of this association is lacking. METHODS.: In this multicenter study, 1182 patients hospitalized for CAP were prospectively followed for up to 30 days after their hospitalization for this infection. Study endpoints included myocardial infarction, new or worsening heart failure, atrial fibrillation, stroke, deep venous thrombosis, cardiovascular death, and total mortality. RESULTS.: Three hundred eighty (32.2%) patients experienced intrahospital cardiovascular events (CVEs) including 281 (23.8%) with heart failure, 109 (9.2%) with atrial fibrillation, 89 (8%) with myocardial infarction, 11 (0.9%) with ischemic stroke, and 1 (0.1%) with deep venous thrombosis; 28 patients (2.4%) died for cardiovascular causes. Multivariable Cox regression analysis showed that intrahospital Pneumonia Severity Index (PSI) class (hazard ratio [HR], 2.45, P = .027; HR, 4.23, P < .001; HR, 5.96, P < .001, for classes III, IV, and V vs II, respectively), age (HR, 1.02, P = .001), and preexisting heart failure (HR, 1.85, P < .001) independently predicted CVEs. One hundred three (8.7%) patients died by day 30 postadmission. Thirty-day mortality was significantly higher in patients who developed CVEs compared with those who did not (17.6% vs 4.5%, P < .001). Multivariable Cox regression analysis showed that intrahospital CVEs (HR, 5.49, P < .001) independently predicted 30-day mortality (after adjustment for age, PSI score, and preexisting comorbid conditions). CONCLUSIONS.: CVEs, mainly those confined to the heart, complicate the course of almost one-third of patients hospitalized for CAP. More importantly, the occurrence of CVEs is associated with a 5-fold increase in CAP-associated 30-day mortality.

Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults.

BACKGROUND: Pneumonia is associated with high risk of heart failure (HF) in the short term (30 days) postinfection. Whether this association persists beyond this period is unknown. METHODS: We studied 5,613 elderly (≥65 years) adults enrolled in the Cardiovascular Health Study between 1989 and 1994 at 4 US communities. Participants had no clinical diagnosis of HF at enrollment, and they were followed up through December 2010. Hospitalizations for pneumonia were identified using validated International Classification of Disease Ninth Revision codes. A centralized committee adjudicated new-onset HF events. Using Cox regression, we estimated adjusted hazard ratios (HRs) of new-onset HF at different time intervals after hospitalization for pneumonia. RESULTS: A total of 652 participants hospitalized for pneumonia during follow-up were still alive and free of clinical diagnosis of HF by day 30 posthospitalization. Relative to the time of their hospitalization, new-onset HF occurred in 22 cases between 31 and 90 days (HR 6.9, 95% CI 4.46-10.63, P < .001), 14 cases between 91 days and 6 months (HR 3.2, 95% CI 1.88-5.50, P < .001), 20 cases between 6 months and 1 year (HR 2.6, 95% CI 1.64-4.04, P < .001), 76 cases between 1 and 5 years (HR 1.7, 95% CI 1.30-2.12, P < .001), and 71 cases after 5 years (HR 2.0, 95% CI 1.56-2.58, P < .001). Results were robust to sensitivity analyses using stringent definitions of pneumonia and extreme assumptions for potential informative censoring. CONCLUSION: Hospitalization for pneumonia is associated with increased risk of new-onset HF in the intermediate and long term. Studies should characterize the mechanisms of this association in order to prevent HF in elderly pneumonia survivors.