Disease burden and prognostic factors for clinical failure in elderly community acquired pneumonia patients

Lower respiratory tract infections (LRTIs) fell to 4th place of global causes of deaths worldwide in 2016, yet community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality for hospitalization in LRTIs patients, especially for patients aged ≥65 years [1‐3]. After initiation of empirical antibiotic therapy, patients with CAP can experience different clinical outcomes, clinical improvement, clinical failure (CF) and non-resolving pneumonia. CF is a matter of great concern in the management of CAP. The incidence of CF among hospitalized patients with CAP ranges from 6 to 24% [4‐8], and can reach up to 31% for patients with severe CAP [9]. CF leads to longer hospital stay and higher mortality [4, 5, 9], longer duration of intravenous antimicrobial therapy [5], higher need for admission to intensive care unit (ICU) and more appearance of complications [4, 5].

Studies demonstrated that CF was due to an inadequate host–pathogen response, the initial severity of the infection, the presence of comorbidities, the causative organism, and the antimicrobial therapy administered [4, 5, 9]. Of which, underlying comorbidity [10, 11], severity of illness [10, 12] and antimicrobial regimen [13, 14] were independent factors for mortality of elderly hospitalized CAP. CF and mortality are the most relevant outcomes in elderly patients with CAP, yet there is rare discussion in literatures about its incidence and etiology.

It is crucial to understand the etiology of failure so as to implement different strategies at both national and local levels to prevent adverse outcomes. Therefore, we designed a retrospective study for hospitalized elderly CAP patients in order to identify the disease burden of CF and to explore the independent prognostic factors that predict failure to respond.

This is the first retrospective multicenter study to assess the disease burden of clinical failure in hospitalized elderly patients with CAP in China. The major findings of our study were as follows: 1) CF contributes to a significantly prolonged length of stay (LOS) and increased median overall treatment costs; 2) Independent risk factors for CF were undertreatment, high CURB-65 score, lower PH, lower PaO₂/FiO₂, hyponatremia, HCAP, leukocytosis, plural effusion and CHF; 3) Male and patients with bronchiectasis were associated with lower CF rate.

In our study, we adopted the term of clinical failure to include all patients whose condition deteriorated [9, 17]. Although data from a prospective series of 1383 non-immunosuppressed hospitalized adults with CAP demonstrated that older age (> 65 years) was an independent factor associated with clinical failure [5], the incidence of clinical failure in elderly hospitalized CAP patients in our study was 13.1%, lower than that in previous studies [4, 5, 8, 9, 18, 19], mainly due to larger proportion of mild-to-moderate patients in our study.

The median overall treatment cost for one CAP episode was RMB 12,950.9 (mean ± SD RMB 24,564.7 ± 111,003.3). And they were nearly two-fold higher in CF patients, which was in accordance with previously published data [19]. Furthermore, we found median overall treatment cost in undertreated patients of CF group was significantly higher, which was mainly relative to extra examination and prolonged hospital stay. Patients experiencing CF required a significantly prolonged hospital stay compared with successfully treated patients (mean LOS 16.4 ± 17.0 versus 13.0 ± 8.2 days), which was similar to other studies from Switzerland [8], Netherlands [9] and Germany [19]. Prolonged hospital stay was associated with increased hospitalization costs. Our study demonstrated that CF patients, especially undertreated patients, were associated with significantly higher treatment costs. Thereby we postulate that any strategy to prevent discordant treatment and CF is of great interest in terms of medical cost savings.

Assessment in CF patients was more severe than CS patients, similar to outcome of recent studies [18, 19], and laboratory and imaging findings in our data also supported these information. Direct etiology of CF related to CAP was defined as causes with the pulmonary infection and the systemic inflammatory response; and medical complications, such as cardiac arrhythmia, acute myocardial infarction, or the deterioration of comorbidities, were resulted from CAP-related systemic inflammatory response [17]. From our data, acute cardiac events and other organ dysfunctions were more common in CF group than CS group, suggesting complications were causes leading to failure.

Although the CURB-65 score may underestimate severity and mortality in the lower scoring patients, especially the elderly [20], in our study, the CURB-65 score was identified to be an independent risk factor for CF. In previous literatures, more data showed PSI or APACHE II score was independent factor associated with failure [4, 5, 21, 22]. Patients aged over 65 years old had more underlying comorbidity and poor outcome [10, 11, 15, 23]; meanwhile, data in our study revealed patients in CF group also had more underlying comorbidity than successfully treated patients. Aliberti et al. had found that a history of cardiac disease and cardiac events was related with clinical failure in CAP patients [17]; physicians should pay more attention to prevent cardiac complications as well as further investigations for these patients. Data from our study demonstrated acute heart failure and arrhythmias were the most common cardiac events during hospitalization, and a history of congestive heart failure was responsible for clinical failure related to elderly CAP patients. Additionally, we also found a history of bronchiectasis was a protective factor for clinical failure. We considered that was associated with administration of anti-pseudomonal β-lactam. In our recently published report [15], data showed that Pseudomonas aeruginosa was the most common pathogen in elderly CAP patients, overuse of anti-pseudomonal β-lactam, to some extent, may lead to a certain concordant treatment.

Discordant treatment accounted for more than 70% in CF group, significantly higher than CS group, and both were higher than data from Roson et al. [5]. In the prospective observational analysis, discordant therapy in early failure only constituted 30.8% [5]. Discordant treatment, especially overtreatment, is a very serious problem in China for CAP patients [15, 24]. In our study, some patients transferred from other hospitals or received antimicrobial treatment; therefore, the so-called initial antimicrobial treatment was not the really true initial treatment regimen. Part of the patients may have experienced clinical failure before admission. Wherefore a broad-spectrum antimicrobial treatment was prescribed after admission, resulting in overtreatment. Additionally, undertreatment was given for some patients due to inadequate assessment of severity and misjudgment of the pathogen.

Standardized antimicrobial treatment and a positive attitude toward guidelines is an urgent matter for all pneumology specialists. In our study, discordant treatment (undertreatment) was identified to be an independent risk factor for clinical failure, in accordance with previous data [4, 5, 25].

In this study, the multivariable logistic analysis of independent risk factors to predict failure also concluded PH<7.3, PaO₂/FiO₂<200 mmHg, hyponatremia and plural effusion. These factors were easily acceptable for clinicians, because they are already known to be associated with a poor prognosis and higher score on the PSI [26] or CURXO [27] or SMART-COP [28]. Studies from Menendez et al. [4], Hoogewerf et al. [9] and Aliberti et al. [17] had the similar conclusion that above variables were associated with clinical failure. A prospective multicenter cohort study performed in 1424 hospitalized patients from 15 Spanish hospitals revealed that leucopenia was associated with an almost four-fold higher risk of treatment failure [4]. Kolling and coworkers found that leucocytes had a beneficial effect on antimicrobial activity and modulation of the pro-inflammatory cytokine response in CAP [29]. In contrast, leukocytosis (WBC > 10,000/mm³) was confirmed to be a prognostic factor for failure in our data. In one CAPNETZ study about the inflammatory markers, they found WBC levels were associated with increasing CRB-65 score, while CRB-65 score was associated with short–term and long-term mortality [30]. Our data had discovered CURB-65 was a prognostic factor for failure; therefore leukocytosis was easily acceptable as a predictor of failure. Previous studies about elderly CAP patients revealed that male sex was associated with higher mortality [31] and higher rate of re-hospitalization [31, 32]. Interestingly, multivariable analysis in this study showed that male was a protective factor for failure. We surmise there are maybe differences in both the biological response to infection and therapeutic patterns of health care on sex.

Our study has some limitations. The present study was a retrospective observational study, to some degree, there was bias on data which may affect certain analysis. Additionally, the rate of clinical failure is underestimated than that in the real world. Our previous study had showed that 42.3% of the elderly CAP patients had a documented history of pre-hospital medication ¹⁵, and quite a few patients admitted to hospital was due to failure of pre-hospital antimicrobial treatment.

This is the first attempt to explore the burden and prognostic factor for clinical failure of hospitalized elderly CAP patients in China. For country of aging society, it is important to recognize risk factors early, strengthen the awareness and concept of standardized treatment and reduce or avoid inappropriate treatment. Strategies for improved patient care should be implemented for specialists.