Pulmonary infections prime the development of subsequent ICU-acquired pneumonia in septic shock

Sepsis is an infection-related life-threatening condition characterized by an initial overwhelming pro-inflammatory response followed by a complex immunosuppressive response [1]. Septic shock, its most severe presentation, remains associated with a crude 40% mortality rate, as well as with numerous short-term and long-term complications. Thanks to early recognition of the disorder as well as prompt institution of antimicrobial treatment and advanced life support, most septic shock patients nowadays survive the early phase of resuscitation but then become highly susceptible to intensive care unit (ICU)-acquired infections (ICU-AI) which account for a major cause of death in this setting [2, 3]. Prevention and management of complications in patients recovering from the primary insult now appear as cornerstone therapeutic challenges to improve the overall prognosis of septic shock.

ICU-acquired pneumonia accounts for the majority of ICU-AI in critically ill patients and is associated with increased mortality and other relevant poor outcomes such as prolonged ventilation and prolonged length of stay in the ICU and in the hospital. Classical risk factors for ICU-acquired pneumonia rely on patients’ characteristics including underlying immune and non-immune comorbid conditions, clinical severity and requirements for invasive ventilatory support [4]. Hence, endotracheal intubation and duration of mechanical ventilation are major determinants of so-called ventilator-associated pneumonia. Furthermore, a new paradigm of post-aggressive immunosuppression has emerged in critically ill patients [5]. Accordingly, sepsis-induced immune dysfunctions of most circulating immune cells have been associated with increased susceptibility to secondary infections in previously immunocompetent patients. Such explorations have been conducted in circulating blood cells for obvious accessibility reasons. The impact of multiple sequential insults within target organs on the subsequent risk of infectious complications remains unclear.

We hypothesize that a primary pulmonary infection may contribute to alterations in lung defense and thereby may favor the development of ICU-acquired pneumonia. The aim of this study is to investigate the determinants and the prognosis of ICU-acquired pneumonia in patients with septic shock, with a particular emphasis on linking primary and secondary infectious insults.

We herein reported that ICU-acquired pneumonia account for the majority of secondary infections in patients who survived the early days of septic shock. After adjustment with potential confounders, including the exposition to invasive mechanical ventilation, a primary pulmonary infection was independently associated with the development of further ICU-acquired pneumonia. This suggests that a primary pulmonary insult may impair lung defense mechanisms toward secondary infections.

Recent cohorts of sepsis and septic shock patients have reported that ICU-acquired infections remain frequent and dreaded complications, with incidence ranging from 13.5 to 23% [2, 11]. Incidence of nosocomial infections is higher in critical care setting than in general hospital wards given the complex interactions between underlying diseases, the severity of acute illness and the multiplicity and the maintenance of invasive devices [12, 13]. We reported here a slightly higher incidence ICU-AI of 31%, with a majority of nosocomial pneumonia, probably linked to the underlying characteristics of our cohort. Although ICU-AI are clearly associated with a higher risk of death in critically ill patients, whether they directly contribute to mortality or only account for a surrogate marker of frailty remains questionable. Moreover, the burden of antimicrobial resistance is increasing, due to extensive antimicrobial use and protracted hospital length of stay, and raises new therapeutic challenges. Hence, early identification of ICU-AI and infection control measures are of major concern in preventing ICU-AI and decreasing the spread of antimicrobial resistance.

Although the development of ICU-AI is commonly associated with an increased risk of death, multiple additional factors are likely to contribute to mortality in critically ill patients including underlying comorbid conditions, accumulation of organ failures, infectious and non-infectious complications. This may frequently result in therapeutic limitations that may prevent appropriate diagnostic work-up and treatment. Sophisticated statistical models taking into account such confounders allow addressing the specific attributable mortality of nosocomial infections, defined as the percentage of death that would not have occurred without infection. Thus, recent studies retrieved little impact of ICU-acquired infections, and more specifically of ventilator-associated pneumonia, on ICU mortality [2, 14, 15]. Using a multivariate cause-specific hazard model, we observed that both pulmonary ICU-AI and non-pulmonary ICU-AI were not significantly associated with a higher risk of ICU mortality.

The major result of this study lies in the link between primary and secondary sources of infection. Specifically, we found that the pulmonary source of the primary infection was a risk factor for further ICU-acquired pneumonia, independent from prior requirement and duration of invasive mechanical ventilation. This result suggests regional disparities induced by different sources of infection that rely on the compartmentalization of immune responses. Primary pulmonary or non-pulmonary insults may differentially impact on lung defense and modulate the further susceptibility to superimposed infectious insults. The regimen and duration of prior antibiotics may also impact on the type of pathogens involved in ventilator-associated pneumonia and their eventual susceptibility to antimicrobials [16]. We also found that male patients had an increased risk of developing pulmonary ICU-AI. We could hardly find a definite explanation, but it is likely that sexual hormones play a role in the regulation of the immune system and may therefore impact on the eventual susceptibility to and outcome of sepsis [17].

It is now well documented that both pulmonary and non-pulmonary sepsis may induce various quantitative and functional changes in most immune cells [18], which have been associated with an increased susceptibility to secondary infections [19‐22]. Furthermore, experimental studies have highlighted that different body compartments may not behave similarly following an infectious insult. For instance, alveolar macrophages do not produce interferon-β after LPS stimulation when compared to peritoneal macrophages [23]. Therefore, assuming a regional compartmentalization of immune response, several mechanisms could participate to explain the susceptibility of the lung to a second infectious hit after septic shock of pulmonary origin. A recent study reported acquired tolerogenic properties of pulmonary dendritic cells, an important subset of antigen-presenting cells, following severe primary pulmonary infection with an increased susceptibility to secondary infections [24]. Besides sepsis-induced immunosuppression, various ICU interventions such as mechanical ventilation or systemic therapeutics such as antimicrobials, corticosteroids and transfusions may contribute to alter lung susceptibility to secondary infections. Since mechanical ventilation is a well-known risk factor for ventilator-associated pneumonia [9], pulmonary alterations due to mechanical ventilation may participate to lung susceptibility to secondary infections. In experimental models, ventilated injured lungs develop direct damage in both epithelial and endothelial cells [25]. Another interesting line of approach is the relation between microbiota and antimicrobial treatment. A recent experimental study provides data suggesting that both intestinal and upper airway microbiota promote the innate response to pulmonary infections by enhancing pathogens clearance [26]. One could hypothesize that a previous episode of pneumonia could modify the bacterial composition of respiratory microbiota and therefore promote susceptibility to secondary infections.

As already reported in a previous study involving part of the present cohort, we observed that the underlying immune status did not confer a higher susceptibility toward ICU-acquired infections [27]. Although this observation may contradict a common belief, several explanations can be proposed. All septic shock patients were exposed to invasive procedures and breakthrough of natural barriers to infections. Most non-immunocompromised patients exhibited non-immune comorbidities also likely to impair local and/or systemic anti-infectious defense mechanisms. Finally, sepsis-induced dysfunctions can promote profound immunosuppression smoothing away the immune capacities between immunocompromised and non-immunocompromised patients.

This study has several limitations. First, this was a retrospective study, performed in a single center with a particular case mix of patients and a high prevalence of immune comorbidities. Such a study can only identify association but not causality links between variables. Second, we were able to collect only ICU-acquired infections, but we did not address the incidence of further hospital-acquired infections following ICU discharge. Third, the study did not include a control group of patients with primary pneumonia but no septic shock, which may allow understanding the respective roles of pulmonary insults and shock on the further susceptibility to pulmonary ICU-AI. In addition, some potential confounders such as prior pulmonary lesions and prior antimicrobial exposure may also impact on the risk of pulmonary ICU-AI. Fourth, we focused on the first episode of ICU-acquired infection, whereas one third of those patients exhibited additional infection episodes throughout the ICU stay.

A prior episode of pulmonary infection in patients with septic shock may represent a major risk factor for secondary ICU-acquired pneumonia. A better understanding of pathophysiological mechanisms of post-septic alterations in lung defense could contribute to better stratify the risk of secondary pneumonia, and therefore identify patients likely to benefit from innovative preventive or therapeutic approaches.