Community-acquired pneumonia (CAP) is a leading cause of hospitalization and death globally, with various pathogens, including bacteria and viruses, contributing to its etiology. The COVID-19 pandemic highlighted the significant role of respiratory viruses in CAP. Obesity, diabetes, hypertension, and cardiovascular disease are established risk factors for severe outcomes in COVID-19 and other CAP etiologies. Individuals with obesity often present with impaired ventilatory capacity (obesity hypoventilation syndrome), physical inactivity, dyslipidemia, and diabetes, all linked to insulin resistance, chronic inflammation, and low adiponectin levels. This chronic inflammation negatively impacts the immune system, increasing susceptibility to severe infections due to impaired immune responses. Exaggerated cytokine responses can also lead to immunopathology, a phenomenon observed in COVID-19. While COVID-19 CAP appears to have more severe outcomes than other etiologies, direct comparisons of obesity, physical capacity, metabolic dysregulation, and inflammatory responses between CAP types were lacking. This study aimed to compare body composition, physical capacity, glucometabolic, and inflammatory profiles in patients with COVID-19 CAP, influenza CAP, and bacterial CAP.

The literature extensively documents the risk factors associated with severe outcomes in CAP, irrespective of the causative agent. Obesity consistently emerges as a significant risk factor, increasing the likelihood of intensive care unit admission and mechanical ventilation. The underlying mechanisms often involve obesity hypoventilation syndrome, reduced ventilatory drive and capacity, along with dyslipidemia, diabetes, and cardiovascular comorbidities. These conditions are frequently characterized by insulin resistance, chronic low-grade inflammation, and reduced adiponectin levels, which collectively contribute to impaired immune responses and increased susceptibility to infections. Studies on COVID-19 have further revealed abnormal cytokine levels, suggesting a dysregulated inflammatory response as a key driver of disease severity. However, there was limited research directly comparing the clinical presentation, metabolic features, and inflammatory responses among different CAP etiologies before this study.

This prospective cohort study enrolled 164 Danish patients hospitalized with CAP (SARS-CoV-2, influenza A, or bacterial) between January 8, 2019, and May 26, 2020. Inclusion criteria included age ≥18 years, a new pulmonary infiltrate on chest X-ray/CT, and at least one symptom (fever, cough, pleuritic chest pain, dyspnea, or focal chest signs). Patients without pathogen detection were excluded. Data collection included demographic characteristics, comorbidities (assessed using CURB-65 and Charlson Comorbidity Index), symptoms, and medical history. Blood samples were collected within 48 hours of admission for complete blood count, C-reactive protein (CRP), coagulation factors, procalcitonin, kidney/liver function tests, diabetes biomarkers, and lipid profiles. Cytokine analysis (IL-5, IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12p70, TNF-α, IL-18, and adiponectin) was performed using multiplex assays. Body composition (fat mass [FM], fat-free mass [FFM]) was assessed using bioelectrical impedance analysis. Physical capacity was evaluated using questionnaires (International Physical Activity Questionnaire Short Form [IPAQ]), handgrip strength, Barthel Index, EQ-5D-5L, FRAIL scale, and Nutritional Risk Screening-2002. Known, undiagnosed diabetes, prediabetes, and hyperglycemia were defined according to established criteria. Statistical analysis included ANOVA, Kruskal-Wallis test, and Chi-squared tests, with appropriate post-hoc tests. The study adhered to ethical guidelines and obtained informed consent from all participants.

The study included 40 COVID-19 CAP patients, 25 influenza CAP patients, and 99 bacterial CAP patients. Demographic and comorbidity profiles were generally similar across groups, although patients with COVID-19 had fewer comorbidities. A high prevalence of pre-diabetes (51.3%), known diabetes (15.2%), undiagnosed diabetes (6.1%), hyperglycemia (81%), and low HDL-cholesterol (60%) was observed across all CAP etiologies. Body weight, BMI, FFM, FM, and FM percentage were comparable across groups, with a high prevalence of abdominal obesity (73%). Physical capacity (handgrip strength, physical activity levels) was similar among the groups. However, COVID-19 patients demonstrated significantly higher levels of IFN-γ, IL-4, IL-5, and IL-6 compared to influenza patients, and higher IFN-γ and IL-10 compared to bacterial CAP patients. Other inflammatory markers (IL-1β, TNF-α, IL-8, IL-18, IL-12p70, and CRP) showed no significant differences between groups. COVID-19 patients showed a tendency toward higher ICU admission rates and mortality compared to patients with influenza and bacterial CAP, although the length of hospital stay was similar across all groups.

This study found remarkable similarities in the metabolic profiles, body composition, and physical capacity of patients with CAP, regardless of the etiology (COVID-19, influenza, or bacteria). The high prevalence of obesity, pre-diabetes, and dyslipidemia across groups indicates a common unhealthy metabolic phenotype among hospitalized CAP patients. The finding that COVID-19 patients, despite having less abdominal obesity, exhibited a significantly heightened inflammatory response compared to other CAP groups suggests that metabolic factors alone may not fully explain the observed differences in disease severity. The increased levels of IFN-γ, IL-4, IL-5, IL-6, and IL-10 in COVID-19 may indicate a more robust or dysregulated adaptive immune response compared to other etiologies. This study provides valuable insights into the pathophysiology of CAP, emphasizing the complex interplay between metabolic factors, immune responses, and disease severity.

This study demonstrates that despite similar metabolic profiles and body composition, COVID-19 patients exhibited a more pronounced inflammatory response compared to patients with influenza or bacterial CAP. These findings highlight the importance of considering the unique immunological aspects of COVID-19, beyond metabolic factors, to fully understand its impact and inform therapeutic strategies. Future research should investigate the long-term effects of COVID-19 on metabolic health and explore targeted interventions aimed at modulating the inflammatory response in severe CAP.

This study's limitations include the use of self-reported data for some variables, which could introduce bias. The study's single-center design might limit generalizability. The relatively small sample size of the influenza group could affect statistical power. The temporal differences in patient recruitment across groups also require consideration. Finally, the study focused on acute-phase responses; further research is needed to investigate long-term metabolic and immunological outcomes.