In the present study we showed different characteristics on admission as well as significant differences in mortality among hospitalized patients with CAP according to the presence of ARF and SS on admission. Three distinct groups of CAP patients have been identified: those with neither ARF nor SS (4% mortality), those with only ARF (9% mortality), and those with both ARF and SS on admission (26% mortality). After adjustment, ARF alone on admission has an OR for mortality of 1.84 and the association of ARF and SS increases the OR for mortality up to 6.55. Furthermore, the evaluation of the presence of multilobar infiltrate on CXR on admission can help in better stratifying CAP patients according to their risk of death.
A lack of data exists about the prevalence of ARF in a general population of CAP patients admitted to the hospital. Furthermore, the characteristics of the patients enrolled in previous studies are very different from each other, as well as definitions of ARF [3, 13–15]. Although all these factors make it difficult to compare the results, the prevalence of ARF reported in previous literature ranges between 16 to 73%, mostly in line with the 56% of prevalence detected in our study. SS represents a common complication in CAP patients, involving up to 34% of patients, and it seems to be acquired during the first days of hospitalization [16, 17]. The prevalence of SS rises up to 67% in patients with ARF who are admitted to the ICU for different diseases . Our data are in line with previous experiences showing the presence of SS on admission in 20% of hospitalized patients with CAP.
We identified three different groups of patients with CAP based on the absence of both ARF and SS, the presence of ARF alone, and the presence of both ARF and SS. In view of the differences between patients belonging to these three groups in terms of both baseline characteristics and mortality, we could speculate that three distinct clinical phenotypes of CAP patients exist. Furthermore, we have shown that the evaluation of the presence of multilobar involvement on admission on CXR can help in stratifying patients according to in-hospital mortality. A recent meta-analysis by Mannu and coworkers showed that multilobar involvement is an independent risk factor for mortality . We observed the highest in-hospital mortality among CAP patients with ARF, severe sepsis and multilobar infiltrates. Furthermore, we were able to unmask an effect of gas exchange (PaO2/FiO2 ratio) on in-hospital mortality only in this group of patients. Multilobar involvement is a well-known reflection of the severity of the CAP and could indicate either a direct involvement of the microbial challenge or an indirect involvement in the context of acute respiratory distress syndrome (ARDS). Based on our results, it could be suggested that in patients with both severe sepsis and ARF due to a multilobar CAP, the lung should be considered as the starting point of a systemic inflammatory response such as for ARDS and not just as an organ affected by a single infectious process.
The findings of the present study could lead to some speculations from both a clinical and a research point of view. Clinically, it is widely accepted that an early and correct identification of patients at risk of death is a crucial step in the management of CAP patients and several indices to predict mortality have been developed . Although these scores have been validated in the scientific literature over the last 20 years, it seems they have serious difficulties to be implemented in daily clinical practice and that they are inconsistent with clinical judgment in a significant percentage of patients in low risk classes [21–23]. Furthermore, it has been recently shown that the CURB-65, the most simple tool suggested by international guidelines to decide hospitalization for CAP patients, suffers of a lack a formal assessment of hypoxemia, a major drawback in light of the importance of assessing oxygenation immediately on arrival at the ER [24, 25]. Furthermore, no score in the decision to hospitalize patients in the ICU has been widely accepted in clinical practice [26, 27]. Some authors have suggested a more pathophysiological and simple approach in the assessment of severity of CAP based on evaluation of the presence of ARF and SS . The three-group classification of CAP patients we proposed could be useful in this sense and may help to build up a new algorithm for the site-of-care decision .
A meta-analysis of the data from our three study sites showed no heterogeneity in the risks associated with ARF and ARF/SS, validating that these are consistent, robust phenotypes. The presence of these three groups that clearly differ in characteristics and outcomes makes it necessary to search for different underlying biological and molecular processes. Previous data have shown a different genotype association for septic shock and hypoxemic ARF in CAP patients . The identification of these three clinically different phenotypes would be an important guide in the interpretation of the large amount of information that will possibly come from the “-omics” world in next few years. The explanation at a basic level of these clinical findings could finally allow the development of new and interesting therapeutic measurements, especially in CAP patients with SS.
Our study has some limitations. We were not able to collect data concerning the response to fluid challenge in case of initial hypotension. Thus, patients with septic shock are included in the severe sepsis definition, although a higher mortality should be expected in these patients. Time to first antibiotic dose and treatment of ARF and SS during hospitalization were not evaluated in our study. However, recent data suggest that time to first antibiotic dose should be interpreted as marker of optimal care in CAP patients rather than a predictor of outcomes . Furthermore, all three centers have standard operating procedure for CAP patients and ARF and SS are managed according to international guidelines.
Our study was strengthened by the evaluation of three large cohorts of consecutive, prospectively enrolled patients in three different regions in Europe in very large and robust data collections. The second main strength is that we described a population, easy to identify with clinical and laboratory variable collected at the emergency room, having a high probability to die, which is a target population to implement intensive treatment. This concept fits perfectly with the idea of CAP as a medical emergency .