Obesity is associated with a better prognosis in patients with community-acquired pneumonia (the so-called obesity survival paradox), but conflicting results have been found.

To investigate the relationship between all-cause mortality and body mass index in patients with community-acquired pneumonia.

This retrospective study included patients with community-acquired pneumonia hospitalized in the First Hospital of Qinhuangdao from June 2013 to November 2018. The patients were grouped as underweight (< 18.5 kg/m²), normal weight (18.5-23.9 kg/m²), and overweight/obesity (≥ 24 kg/m²). The primary outcome was all-cause hospital mortality.

Among 2327 patients, 297 (12.8%) were underweight, 1013 (43.5%) normal weight, and 1017 (43.7%) overweight/obesity. The all-cause hospital mortality was 4.6% (106/2327). Mortality was lowest in the overweight/obesity group and highest in the underweight group (2.8%, vs 5.0%, vs 9.1%, P < 0.001). All-cause mortality of overweight/obesity patients was lower than normal-weight patients [odds ratio (OR) = 0.535, 95% confidence interval (CI) = 0.334-0.855, P = 0.009], while the all-cause mortality of underweight patients was higher than that of normal-weight patients (OR = 1.886, 95%CI: 1.161-3.066, P = 0.010). Multivariable analysis showed that abnormal neutrophil counts (OR = 2.38, 95%CI: 1.55-3.65, P < 0.001), abnormal albumin levels (OR = 0.20, 95%CI: 0.06-0.72, P = 0.014), high-risk Confusion-Urea-Respiration-Blood pressure-65 score (OR = 2.89, 95%CI: 1.48-5.64, P = 0.002), and intensive care unit admission (OR = 3.11, 95%CI: 1.77-5.49, P < 0.001) were independently associated with mortality.

All-cause mortality of normal-weight patients was higher than overweight/ obesity patients, lower than that of underweight patients. Neutrophil counts, albumin levels, Confusion-Urea-Respiration-Blood pressure-65 score, and intensive care unit admission were independently associated with mortality in patients with community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a lower respiratory tract infection due to one or more pathogens acquired outside of a hospital setting[1]. This contrasts with pneumonia acquired within the hospital setting, including nosocomial pneumonia and ventilator-associated pneumonia[1]. The incidence of CAP ranges from 10.6 to 44.8 cases per 1000 person-years and increases with age[2]. CAP risk factors include age, smoking, chronic comorbidities (such as diabetes mellitus and chronic lung, renal, heart, or liver disease), orodental/periodontal disease, treatment with proton pump inhibitors, prescription opioids, and high alcohol consumption[3-5]. Pathogens that cause CAP include respiratory viruses, Streptococcus pneumoniae (S. pneumoniae), Mycoplasma pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella species, Staphylococcus aureus, and Gram-negative rods[6,7]. Complications of pneumonia include parapneumonic effusion, empyema, lung abscess, sepsis, and cardiac complications, such as heart failure, cardiac arrhythmias, and acute coronary syndromes[8,9]. Lower respiratory tract infections are among the top 4 causes of death, and the most common infectious cause of death, worldwide[10]. The mortality rate is highly variable, ranging from < 1% to > 30%, depending on comorbidities and findings at presentation[11-13].

The prognostic factors for CAP include sex, cognitive symptoms, high urea levels, high respiratory rate, low blood pressure, age ≥ 65 years, comorbidities (cancer, chronic liver disease, heart failure, cerebrovascular disease, and chronic renal disease), and low or higher body temperature[14,15]. Obesity is associated with increased morbidity and mortality, including increased risk of cardiovascular events and increased risk of certain cancers[16-18].

Nevertheless, several studies have shown that the mortality of obese individuals is reduced in various diseases, a phenomenon that is referred to as the “obesity survival paradox”[19]. Lacroix et al[20] found a negative correlation between body mass index (BMI) and pneumonia mortality in an observational study of 2600 middle-aged American men. In a cohort study of 110000 Japanese adults, BMI (≥ 25 kg/m²) had a protective effect on pneumonia mortality [odds ratio (OR) = 0.7, 95% confidence interval (CI): 0.5-0.8][21]. Thus, in some diseases, obesity has emerged as a protective factor that could improve prognosis and reduce mortality[22-24]. Nevertheless, conflicting results are found in the literature[25,26]. In pneumonia caused by severe acute respiratory syndrome coronavirus 2, obesity is associated with worse outcomes[27], but the present study investigated “classical” CAP, not coronavirus disease 2019.

This study aimed to investigate the relationship between BMI and all-cause mortality of CAP and to examine the mechanism of overweight/obesity as a protective factor in CAP prognosis. The results could help our understanding and management of CAP.

Although obesity is associated with increased mortality due to multiple causes[16-18], it is associated with a better prognosis in patients with CAP (the so-called obesity survival paradox)[19-24]. However, conflicting results have been found[25,26], especially regarding the categories of patients at risk of higher mortality. Therefore, this study aimed to investigate the relationship between all-cause mortality and BMI in patients with CAP. The results strongly suggested that overweight/obesity patients accounted for the largest proportion of CURB-65 low-risk patients with CAP. The all-cause mortality of overweight/obesity patients was lower than that of normal-weight patients and NEUT counts, ALB levels, CURB-65 score, and ICU admission were independently associated with mortality in patients with CAP.

This study showed that abnormal NEUT counts were independently associated with a poor prognosis of CAP, which is already well-known[31-34]. Hypoalbuminemia is a well-known marker of adverse prognosis in a number of conditions and can be the result of various underlying conditions such as sepsis, cirrhosis, nephrotic syndrome, protein-losing enteropathy, malnutrition, and frailty[35]. Hypoalbuminemia is also associated with a poor prognosis in hospitalized patients[35,36] and in those with CAP[37,38]. The CURB-65 score is a well-known scoring system for the prognosis of pneumonia in the ICU setting[39,40]. It is based on confusion, uremia, respiratory rate, blood pressure, and age, and it can be used to guide management[41]. Finally, of course, ICU admission indicates a severe condition with a higher likelihood of a poor outcome[42-44].

As a general rule, obesity is associated with a higher risk of surgical-site infections, nosocomial infections, periodontitis, skin infections, and acute pancreatitis[45,46]. In overweight patients, there are recognized changes that include hypoxia, oxidative stress, and insulin resistance. Immune cells adapt to an altered tissue microenvironment by adapting their metabolism, eventually leading to an immune response imbalance, chemotaxis damage, and immune cell differentiation[47]. The relationship between obesity and chronic respiratory diseases, including obstructive sleep apnea and obesity hypopnea syndrome, has also been well described[48]. Obese patients show lung function changes, including decreased lung volume, reduced respiratory compliance, reduced gas exchange, impaired respiratory muscle function, and increased airway resistance[49]. Given that these clinical manifestations collectively indicate an increased risk of infection with bacterial and viral pathogens and drive potential changes in lung function, it is logical to theorize that obese patients would be at increased risk for both the development of pneumonia and for much worse clinical outcomes. It can be intuitively assumed that obese patients are more likely to exhibit adverse clinical outcomes and an increased mortality secondary to pneumonia.

Nevertheless, the risk of developing CAP in obese individuals is lower than in the general population[3,46]. BMI and the prognosis of pneumonia have recently emerged as a subject of increased and intense study[19-26]. The present study confirms that overweight/obesity patients actually have lower all-cause mortality. This is consistent with the fact that the inflammatory indices of overweight/obesity patients were lower than those of underweight patients, and the majority of overweight/obesity patients were at low CURB-65 risk. Similarly, overweight/obesity patients do not have a higher ICU occupancy rate. On the contrary, underweight patients are more likely to be admitted to the ICU.

Previous studies on the relationship between obesity, pneumonia, and mortality have yielded intriguing observations. For example, an early study by Lacroix et al[20] showed a negative correlation between BMI and pneumonia-associated mortality in an observational study of 2600 middle-aged American men. In a prospective study of 110 thousand Japanese adults, it was also found that BMI ≥ 25 kg/m² promoted a protective effect in the context of pneumonia-associated mortality[21], and the trend between BMI and CAP mortality showed a significant inverse relationship (P < 0.001). Braun et al[50] found that in 763 patients, the 64 obese patients (BMI > 30 kg/m²) had a significantly lower 6-year all-cause mortality compared with normal-weight patients (BMI 18.5-25 kg/m²). Other studies also report similar results[22-24], supporting the present study. Nevertheless, some points still remain to be clarified. Indeed, Kornum et al[25] showed that males were at a higher risk of hospitalization than females, which was not observed in the present study. In addition, the relationship between obesity and clinical outcomes appears to be different between children and adults[26], but the present study did not include children.

Some hypotheses can be formulated to try to explain these results. One of the protective factors involved in the better prognosis of CAP in obesity might be an increase in the relative number and frequency of circulating M1 macrophages in overweight patients. Indeed, in an animal model, the content of macrophages in adipose tissue was positively correlated with adipocyte volume and the extent of obesity[51]. Under the regulation of chemokines, inflammatory factors, and free fatty acids in adipose tissue of obese people, IKKS, which is the activator of NF-κB in macrophages, activates the signal pathway via phosphorylation of p65, which stimulates a greater number of macrophages to display the M1 sub-type[52]. The increased number of M1 macrophages form a coronal aggregate that expands around the necrotic adipocytes to form similar foam cells, opening lysosomes and autophagic pathways, allowing macrophages to absorb and degrade the ectopic accumulation of lipid[53]. M1 macrophages can also reduce the acute inflammatory response by increasing PPAR-γ activation, autophagy, and lipid oxidation[54]. There is also hyperleptinemia in obese patients, which is involved in innate and acquired immunity and increases the activity of macrophages, chemotaxis of neutrophils, cytotoxicity of natural killer cells, and the production of T and B cells[55]. This activation of all immune cells could promote bacterial clearance. In an animal model reported in 2007, Hsu et al[56] found that ob/ob mice had a leptin deficiency. Using wild-type mice as controls, both the ob/ob and wild-type strains were infected with S. pneumoniae. It was found that the ob/ob mice had higher mortality and lower lung bacterial clearance rate, which was related to an impaired phagocytic function of the alveolar macrophages, decreased pulmonary neutrophil counts, and a decrease in bioactive proinflammatory cytokines. Exogenous leptin increased the survival rate and lung bacterial clearance rate of ob/ob mice.

A systematic analysis of 13 randomized controlled trials (n = 1954) of glucocorticoids for adult CAP showed that glucocorticoids significantly reduced mortality [risks ratio (RR): 0.58, 95%CI: 0.40-0.4] and significantly lowered the early clinical failure rate in adults with severe CAP (RR: 0.32, 95%CI: 0.15-0.7)[57]. Glucocorticoids shorten the clinical cure time, hospital stay, and ICU stay time and reduce the incidence of pneumonia-associated complications. Glucocorticoids play a key role in anti-viral functions, the immune response, and display anti-inflammatory properties and promote other physiological functions, such that the symptoms of pulmonary parenchyma edema can be relieved in the early stages of inflammation. In the recovery period, glucocorticoids can effectively inhibit the proliferation of capillaries, downregulate collagen, inhibit the proliferation of granulation tissue and scar formation in the lung, and avoid pulmonary fibrosis. In addition, glucocorticoids can combine with lipopolysaccharide, which is the main component of Gram-negative bacterial endotoxins, so that it can effectively reduce the damage caused by endotoxins and relieve the corresponding symptoms. At the same time, it can also improve the microcirculation of patients, effectively avoiding platelet aggregation and thus preventing the formation of thromboses. Studies have shown that glucocorticoids in obese people are higher than in the general population[58,59]. The endogen glucocorticoid axis might be another hypothesis for the results observed in the present study.

In the current study, BMI could not be included in the multivariable analysis because it was the variable that was covariant with the largest number of other variables included in the models. Indeed, being underweight is associated with hypoalbuminemia and an inflammatory condition and with a poor prognosis in a variety of conditions[60-62]. Hence, the independent contribution of BMI to CAP mortality could be assessed, as it is an easy-to-determine factor that could be considered in patient management.

This study has limitations. The patients were all from a single hospital. Therefore, when considering the relatively high incidence of CAP, the sample size was relatively small. In addition, it included only hospitalized patients and did not include patients with mild pneumonia and those who returned home with antibiotics. Finally, due to the study’s retrospective nature, only all-cause mortality could be examined, and CAP-specific mortality should be investigated in the future. Additional studies are still necessary to examine the prognostic factors of CAP.

The inflammatory index and the severity of pneumonia in overweight/obesity patients with CAP were lower than in the normal-weight group, and the all-cause mortality was lower. NEUT counts, ALB levels, CURB-65 score, and ICU admission were independently associated with mortality in patients with CAP.

The authors would like to thank all study participants who were enrolled in this study.