Clinical characteristics and risk factors associated with mortality in patients with severe community-acquired pneumonia and type 2 diabetes mellitus

Community-acquired pneumonia (CAP) is a leading cause of infection among adults worldwide and is associated with high rates of hospitalization and hospital length of stay (LOS) [1]. The most common pathogens include human rhinovirus, influenza virus, Streptococcus pneumoniae, and Staphylococcus aureus [2]. According to the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) consensus guidelines, severe community-acquired pneumonia (SCAP) was defined as fulfilment of at least 1 major criterion (septic shock with need for vasopressors; respiratory failure requiring mechanical ventilation) or 3 minor criteria (respiratory rate ≥ 30 breaths/min; PaO₂/FiO₂ ratio ≤ 250; multilobar infiltrates; confusion/disorientation; blood urea nitrogen level ≥ 20 mg/dL; white blood cell count < 4000 cells/µL; platelet count < 100,000/µL; core temperature < 36 °C; hypotension requiring aggressive fluid resuscitation) [3]. The mortality related to SCAP has barely changed during the past decades and remains a major concern despite advances in vaccine strategies and rapid diagnostic tests, appropriate and adequate antibiotic coverage, and earlier ventilatory support [4]. Cavallazzi et al. conducted a prospective population-based cohort study including 7449 patients in the USA. They reported that 23% of CAP patients required intensive care, and their mortality rates were 27% at 30 days and 47% at one year [5].

Type 2 diabetes mellitus (T2DM) also places a huge burden on health care systems, with globally increased incidence and prevalence in recent years. It is estimated that 500 million people live with T2DM worldwide [6]. Most prior studies have revealed that individuals with diabetes are at increased risk of CAP and adverse outcomes after CAP, including short-term and long-term mortality rates [7‐9]. However, one retrospective study including 354 cases of pneumonia in Saudi Arabia also found that there was no significant difference in mortality between diabetic and nondiabetic CAP patients [10], which might be due partly to the heterogeneous study designs, sample sizes, and potential unadjusted confounding factors. Previous studies have also found that, compared with CAP patients without diabetes, those with diabetes were older and had more comorbidities, increased rates of development of pleural effusion, and mortality. However, there were no significant differences in etiology [11].

Considering that little is known about SCAP in T2DM patients, additional studies in different areas and patients are required to further investigate their clinical features and prognosis, which might be beneficial for treatment options. Moreover, considering the high prevalence of T2DM among people with SCAP, early evaluation, risk stratification and prediction of mortality might be crucial for improving prognosis. The CURB-65 score, including confusion, urea > 7 mmol/L, respiratory rate ≥ 30 breaths/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years, and pneumonia severity index (PSI), including age, nursing home residence, coexisting illnesses, physical examination findings, and laboratory and radiographic findings, are the two most widely used severity scores for pneumonia. However, their accuracy and applicability are decreased in T2DM patients [12]. Hence, there is an urgent need for novel, reliable and convenient predictive tools.

The present study was performed to explore the associations between T2DM and outcomes of SCAP, as well as the risk factors and a novel prediction model for hospital mortality in patients with SCAP and T2DM.

In our study population, there was a high burden of T2DM among SCAP patients. After minimizing the effects of common confounders, of particular concern is that the existence of T2DM, the increased diabetes-related complications, and the occurrence of DKA or HHS all had significant adverse impacts on the prognosis of SCAP patients. These seven easily obtained independent risk factors are important for the early recognition and risk evaluation of patients. Then, we established and validated a predictive nomogram for hospital mortality, which was verified to be superior to PSI in T2DM patients.

The results of the current study are partly concordant with past evidence indicating the association between diabetes and outcomes of CAP. Kornum et al. demonstrated that diabetic patients had greater adjusted 30-day (RR: 1.16, 95% CI: 1.07–1.27) and 90-day mortality (RR: 1.10, 95% CI: 1.02–1.18) following pneumonia than other patients in northern Denmark [8]. Martins et al. reported that CAP episodes in patients with DM had, on average, a 0.8-day longer hospital stay (P < 0.0001) and significantly higher hospital mortality (15.2% vs. 13.5%, P = 0.002) than patients without DM in Portugal [20]. However, López-de-Andrés found that T2DM was only related to higher CAP incidence rates but was not a risk factor for death during CAP (OR 0.92, 95% CI 0.91–0.94) in Spain [21]. One possible explanation might be that the methodology applied by researchers in previous studies was not uniform. More importantly, researchers speculated that patients with diabetes were more likely to be hospitalized with less severe CAP. In our study cohort comprising only patients with SCAP, T2DM was still found to be associated with longer ICU LOS and higher ICU and hospital mortality after matching. Hence, our results might add important evidence to previous information. We further found that SCAP patients with T2DM were less likely to exhibit some classical symptoms, such as fever, cough, dyspnea, and chest pain, than those without diabetes, which is consistent with prior reports [22]. Clinicians should take into account those atypical symptoms for the early diagnosis of SCAP.

The relationship between T2DM and the prognosis of SCAP might be mediated by several factors. First, evidence has been found that the reduction in diffusion capacity in pulmonary function abnormalities and microangiopathy due to impaired pulmonary microvasculature alveolar epithelial basal lamina in diabetes might be related to more severe CAP [23]. Then, it is plausible that impaired immunocompetence, disturbances in pulmonary host defense and dysregulated pulmonary inflammatory function play a major role in the poor prognosis of SCAP. For instance, excessive or chronic activation of the NLRP3 inflammasome, an important innate immune sensor and inflammation regulator, and subsequent interleukin release are implicated in the pathogenesis of diabetes and pneumococcal pneumonia [24]. However, these conclusions are not supported by strong scientific evidence. It has also been reported that the mechanism of association between pre-existing diabetes and a higher risk of death following CAP might not be due to an altered immune response but to worsening of pre-existing cardiovascular and kidney disease [25]. In addition, some other risk factors that negatively affect immune function and host defense mechanisms, such as obesity and other lifestyle factors, might be involved [26]. Although we have demonstrated a clear association between T2DM and mortality among SCAP patients after adjusting for confounders, more research about the pathophysiological mechanisms in SCAP patients with T2DM is warranted. In addition, the true association of T2DM and SCAP needs more verification after excluding other potential confounders, such as prior use of pneumococcal vaccine, treatments of T2DM, duration of symptoms prior to admission, and time to first dose of appropriate antibiotic therapy [27].

Cheng et al. established a risk score, including NLR ≥ 4, pulse ≥ 125/min, confusion, and glucose on admission ≥ 9 mmol/L, to predict in-hospital mortality among 1360 patients with T2DM and concomitant CAP (AUC: 0.858) [28]. In another recent study, Ma et al. included 531 patients and developed a similar nomogram consisting of age, pulse, urea and albumin for predicting in-hospital mortality of CAP in patients with T2DM (AUC: 0.814, 95% CI: 0.770–0.853) [29]. However, the present study still has some strengths. First, our study had a large sample size and focused solely on ICU settings and SCAP patients, which had significantly increased systemic complications and mortality during hospitalization. Then, we included more comprehensive independent risk factors, including comorbidities, indicators of shock and cardiac insufficiency, and inflammatory and acidosis indices. It should be noted that the increased serum glucose and HbA1c levels at admission might inevitably be affected by information that was difficult to capture or remained unmeasured. In addition, they were not significantly associated with the risk of death in CAP patients with diabetes, which was shown in previous studies and the current study [30, 31]. Therefore, we speculate that prehospital T2DM-related complications might be better suited than serum glucose or HbA1c levels to reflect the chronicity and severity of diabetes and could be used to predict mortality. Additionally, compared with the two above predictive tools, the current nomogram had a higher C index and greater net benefits in DCA in both the training cohort and testing cohort.

In SCAP patients with T2DM, the predictive values of comorbidities and decreased blood pressure or signs of shock at admission are in agreement with previous reports from general CAP patients. The increased NLR during SCAP represents the ratio of increased neutrophils reflecting aggravated inflammation and systemic inflammatory storms and decreased lymphocytes representing dysregulated and compromised immune responses. It could effectively overcome the drawbacks of absolute values that may be affected by factors such as dehydration and was independently associated with hospital and ICU mortality in patients with SCAP [32]. As another common inflammatory index, the association of increased CRP at admission or sequential evaluation after admission and poor outcome of SCAP has been widely identified and confirmed. [33, 34] Christ-Crain et al. concluded that BNP, a common marker of cardiac stress and heart failure, is still a powerful and independent predictor of death and treatment failure (AUC: 0.75) in CAP after the exclusion of patients with a history of heart failure and coronary or hypertensive heart disease. Furthermore, they found that, when used in conjunction with PSI, BNP significantly improved the risk prediction compared with PSI alone (AUC 0.78 vs. 0.71; P = 0.02) [35]. In this situation, we might attribute increased BNP to hypoxia, leading to pulmonary vasoconstriction, pulmonary hypertension and right heart overload [36]. Meanwhile, proinflammatory cytokines could also induce BNP secretion [37]. As expected, in line with prior studies about CAP, our investigation showed that blood lactate level remained a significant prognostic factor of mortality in multivariate analysis [38, 39]. We speculate that hypoxia, circulatory disorder and hypoperfusion, and organ failure might cause increased lactate.

Based on these results, more intensive and individualized surveillance should be considered, and efforts should be made to improve the management strategies for patients admitted with T2DM in the ICU due to its significant adverse impacts on the prognosis of SCAP. For SCAP patients with T2DM, a cost-effective, convenient and accurate tool may help identify patients at increased risk of death and curb poor outcomes. However, several questions remain unanswered. There is still a knowledge gap in the available literature concerning the features of chest computed tomography (CT) images of T2DM patients, the biological mechanisms underlying the associations between DKA or HHS and outcomes of SCAP, and the clinical characteristics of SCAP patients with T1DM. Additionally, definite recommendations on the optimal cutoff values of these risk factors used in prediction models are lacking. Therefore, our nomogram needs to be updated or recalibrated in further studies.

Our study is subject to several limitations. First, this was a retrospective, single-center study with routinely collected data in a limited number of patients. A small percentage of the potential study population had no available clinical data and therefore was not included. Meanwhile, some participants might have had undetected or undiagnosed T2DM on admission. These conditions could have led to bias or misclassification in our results. Although we divided patients into a training cohort and a testing cohort, the nomogram was derived from particular periods and places where data were collected. We did not have more external validation study data for our prediction model and therefore were unable to formally determine the robustness of the results. Second, the results might have been affected by some unadjusted confounders or other risk factors, such as interventions and antibiotic therapies. Third, we lacked dynamic clinical and laboratory data and failed to perform follow-up after discharge due to the scarcity of relevant information.

In summary, SCAP patients with T2DM have distinct clinical characteristics and higher mortality than nondiabetic patients. The subset of patients with increased numbers of diabetes-related complications and the development of DKA or HHS had a poor prognosis. Independent factors on admission for mortality in SCAP patients with T2DM were increased numbers of comorbidities and diabetes-related complications; elevated CRP, NLR, BNP and blood lactate; as well as decreased blood pressure. Our nomogram has good predictive performance for hospital mortality and might be generally applied after more external validations.