Culture positivity may correlate with long-term mortality in critically ill patients

The long-term outcome is currently an emerging research niche in critical care medicine due to increasing awareness of sequelae after the critical illness [1, 2]. However, early determinants for long-term outcome in critically ill patients remains largely unexplored. Growing studies, particularly microbiome-associated studies, have shown the prolonged microbial-associated impact in critically ill patients [3‐5]. A number of studies have investigated the association between culture positivity and mortality in critically ill patients; however, discordant evidence were found, and the discrepancy mainly result from the distinct follow-up duration among these studies [6‐9]. Li et al., analysing seven studies involving 22,655 patients, recently reported that culture positivity was not associated with short-term mortality; however, the hospital-day and ventilator-day were longer in culture-positive patients than those in culture-negative patients, implicating a potential long-term impact of the microbial factor in critically ill patients [10]. We hence aimed to explore the association between culture positivity during admission and long-term mortality in critically ill patients. In the present study, we linked the critical care database at Taichung Veteran General Hospital (TCVGH) with the death registration data of the Taiwanese National Health Insurance Research Database (NHIRD) to address the association of microbial factors, including pathogen and culture sites, and long-term mortality in critically ill patients.

The long-term outcome is an emerging research niche in critical care medicine, and identifying early determinants for long-term mortality is an unmet need. In the present study, we linked two databases to address the association between culture positivity and long-term mortality in critically ill patients. We found that culture positivity in the blood, respiratory tract and urinary tract were independently associated with long-term mortality after the adjustment of a number of covariates. We also identified long-term mortality relevant predictors, and these findings should be crucial for risk stratification that may in turn to ensure implementation of preventive strategies in patients who survived from critical illness.

Long-term outcome in critically ill patients is currently an emerging research niche due to increased awareness of sequelae among patients who survived from critical illness [1, 20]. Moitra et al. reported that the 1-year mortality among 34,696 ICU survivors in Medicare claim was 26.6% [21], and the finding was similar to our data that 1-year mortality among ICU survivors was approximately 26.5% (857/3228). In addition to recognising the crucial role of long-term outcomes in critically ill patients, a number of studies, including our previous study, have identified the early determinant for the long-term outcome [17, 22]. Our recently published studies also revealed that an early positive fluid balance status was associated with high long-term mortality in critically ill cancer patients [17]. In the present study, we further discovered that culture positivity was associated with long-term mortality after adjustment of covariates including early fluid status in critically ill patients. These early predictors for long-term mortality provide clinical evidence for risk stratification that should ensue early implementation of nutritional, physical, and psychological support after critical illness [23].

The association between culture positivity and outcomes, particularly long-term outcomes, in critically ill patients remains inconclusive. A number of studies have explored the short-term impact of culture positivity in critically ill patients [6, 7]. Phua et al. conducted a single-centre study in Singapore to compare the outcome between 415 culture-negative and 586 culture-positive patients with severe sepsis during 2004–2009 [6]. They found lower hospital mortality in the culture-negative group than those in the culture-positive group (35.9% vs. 44.0%, p = 0.01) in the univariable analysis, but culture positivity was no longer associated with mortality after adjusting covariates [6]. Kim et al. recently used the 2014–2018 septic shock registry at a Korean tertiary referral centre to explore the association between culture positivity and 90-day mortality among 1718 patients with septic shock, mainly result from biliary tract infection and pneumonia and found similar 90-day mortality in culture-positive and culture-negative patients (32.2% vs. 32.7%, p = 0.83) [7]. Few studies have explored the association between culture positivity and long-term outcome in critically ill patients.

In line with our finding, Francisco et al., conducting a single hospital study in Portugal involving 1013 patients admitted with severe infection during 2008–2009, reported the 5-year mortality was 37%, and culture-positive was independent predictors (aOR 1.48; 95% CI 1.07–2.06) for 5-year mortality [24]. Similarly, Nannan Panday et al., investigating 2659 septic patients admitted to 34 hospitals in the Netherlands during 2014–2016, found that 42.6% of them was culture-positive and culture positivity was associated with high 90-day mortality (relative risk 1.41, 95% CI 1.15–1.71) [9]. To address the distinct association of culture positivity with the short-term and long-term outcome, we conducted further analysis of predictors for 30-day mortality of the enrolled 4,610 critically ill patients in the present study (Additional file 1: Table S2). Compared with data in the present study addressing long-term mortality (Table 3), the high comorbidity, disease severity and management had a similar association with 30-day mortality, whereas culture positivity was unrelated with the 30-day mortality. Therefore, culture positivity tends to be associated with long-term outcome, instead of short-term outcome. These evidence highlight the previously less recognised impact on long-term mortality of culture positivity in critically ill patients.

The damaged microbiome with low diversity may be a plausible biological basis of the prolonged impact of culture positivity in critically ill patients [3, 25]. The altered microbiome has being increasingly recognised not only to be merely a disrupted mucosal barrier but also to affect immune function through regulating the expansion of pathogenic bacteria and modulating the immune response in critically ill patients [3, 26]. The altered microbiome in critically ill patients may be attributed to not only the infectious disease as well as antibiotics but also critical ill relevant medications, including proton pump inhibitors, vasopressors, opioids, and analgesics [27]. Notably, the impact of disruption of the gut microbiome has been found to be long-lasting, and it may take longer than 6 months for recovery [5, 28]. Furthermore, accumulating evidence have shown the cross-talk between the microbiome and immune response, particularly CD4 T cell [29, 30]. Recently, Fay et al. demonstrated that the gut microbiome may affect the immunophenotype and survival from sepsis in the mouse sepsis model with cecal ligation and puncture (CLP) [29]. In brief, Fay et al. identified distinct microbiome between genetically identical age- and gender-matched mice from Jackson Laboratory (Jax) and Charles River Laboratory (CR) and distinct 7-day mortality after CLP (90% in Jax vs. 53% in CR). In septic CR mice, an altered immunophenotype with high IFN − γ + CD4 + T cells and effector/central memory CD4 + T cells in the spleen, Peyer’s patches, and mesenteric lymph nodes were found. After the cohouse for 3 weeks, the differences in immunophenotype and microbiome no longer existed, and the post-CLP mortality of cohoused Jax mice improved, implicating the microbiome tends to affect immunophenotype and mortality in sepsis [29]. Xu et al. conducted a prospective cohort study with 98 critically ill neurological patients and 84 matched healthy subjects found that increased intestinal Enterobacteriales and Enterobacteriaceae within the first week were associated with high 180-day mortality [31]. The aforementioned animal and clinical evidence highlight that early alternation of the gut microbiome has a prolonged immunological impact and may affect the long-term outcome in critically ill patients.

In the present study, we found similar trends among the three major types of pathogen pathogens (Fig. 2). The mortality association was also similar in distinct culture sites (Fig. 3), although the strength of association in skin soft tissue and abdomen did not reach statistical significance due to a limited number of patients (Table 3 and Additional file 1: Fig. S1). Herein, the proportion of a positive MDRO was higher in non-survivors than those in survivors. However, the presence of MDRO was no longer significantly associated with long-term mortality after adjusting for disease severities and the other covariates, and more studies are warranted to further explore the long-term impact of drug-resistant organisms among critically ill patients in the future. Intriguingly, the mortality impact of culture positivity in critically ill patients mainly existed within approximately 6 months of ICU admission, and the finding appears in line with studies have discovered that the altered microbiome in patients with critical illness tended to be restored approximately 6 months after critical illness [32, 33].

In this study, we found that 1.4% (64/4488) of critically ill patients had Candidemia, and invasive fungal infection is currently an increasing threat among critically ill patients in Taiwan and the world [34]. The aforementioned relatively high prevalence of invasive fungal infection in this study may at least partly result from the high proportion of immunocompromised patients [35]. Given that immunocompromised status appeared to be a crucial predictor for long-term mortality in the present study, we hence further explored the modification effect of immunocompromised status on the association between culture positivity and long-term mortality in critically ill patients. Intriguingly, we found that the association between culture positivity and mortality was stronger in patients without immunodeficiency than that in immunocompromised patients (Additional file 1: Table S1).

There are limitations that merit discussion. First, data from this single-centre study may not be generalisable to other healthcare settings. However, the data analysed are real-world data obtained in routine critical care, and the issue of generalisation should be at least partly mitigated. Second, the causal inference could not be drawn given the observation nature of this study. Third, sampling bias might be a concern given that decisions for the microbiological test were made by individual intensivists; however, the administration of intensivists in the study hospital should mitigate the aforementioned concern. Fourth, we could not delineate true, colonised, or contaminated pathogens in this claims-based research.

In conclusion, the identification of early determinants for long-term mortality is a research niche in critical care medicine. Currently, there are discrepant evidences regarding the association between culture positivity and outcome, particularly long-term outcome, in critically ill patients. We linked two databases and found that culture positivity in the blood, respiratory tract and urinary tract were associated with long-term mortality in critically ill patients. Our findings highlight the previous under-recognised role of culture positivity in critically ill patients, and more studies are warranted to clarify the biological mechanisms.