Age-related differences in symptoms, diagnosis and prognosis of bacteremia

The incidence of sepsis in humans has been shown to increase with age [1–3]. Elderly patients are at particular risk for bacteremia and sepsis owingto multiple factors such as comorbid illnesses, immunosenescence, malnutrition,instrumentation and institutionalization [4]. Previous studies have identified age as an independent risk factor fordeath due to sepsis [3, 5, 6] and for severe bloodstream infections [7–12], although conflicting results are also reported [13].

The clinical presentation of sepsis is often atypical in elderly patients,complicating and potentially delaying diagnosis [4]. A decline in general health and unspecific functional deterioration,such as reduced ability to perform daily tasks, may be the only symptoms of severeillness, including sepsis [14]. Possible effects of age-related biological changes upon the clinicalcourse or prognosis of sepsis are not well described. In addition, it is not knownwhether atypical presentation is predictive of severe sepsis or death whenestablished criteria for sepsis and organ failure are used.

To address the special challenges regarding clinical evaluations of elderly patientswith severe infection we studied 1) the clinical presentation and severity relatedto age, 2) age linked differences in prognostic sensitivity of C-reactive protein(CRP) and systemic inflammatory response syndrome (SIRS) for early organ failure,and 3) whether age and age-related clinical presentation are additional risk factorsfor early organ failure and death, in a mixed group of patients withcommunity-acquired bacteremia caused by E. coli or S.pneumoniae.

Between 1994 and 2004, 1150 patients had a blood culture positive for eitherE. coli or S. pneumoniae. Of these, 759 hadthe positive blood culture drawn on the day of admission or the following day. For79 patients the clinical data was either unavailable or inadequate for analyses. Intotal, a cohort of 680 patients was eligible for the study.

The CRP values at admission were significantly correlated to the number of failingorgans within one day after admission (r_s = 0.13,p = 0.001). Figure 1 shows the prognosticsensitivity with 95% confidence intervals of initial CRP value and of SIRS atdifferent cut-off values in predicting ≥1 organ failure by age group. Theprognostic sensitivity of a CRP value above 200 mg/L was lower in the middleage group than in the youngest group, whereas no age-associated differences wereseen at cut-off value 80 mg/L. The prognostic sensitivity of SIRS-2 was lowerthan that of SIRS-3 for the two oldest age groups, but not for the youngest agegroup.

Figure 2 displays Kaplan Meier plots of one-year survivalcurves by age group, number of failing organs and microbial agent. There weresignificant differences in one-year survival for age and number of failing organs(p < 0.001 for both), but not for type of bacteria(p = 0.75).

In this material, comprising nearly 700 patients with bacteraemia caused byE. coli or S. pneumoniae, several resultsindicate that age affects the clinical presentation, diagnostic markers, and outcomeof severe infection.

Elderly patients more often presented with “atypical” symptoms likeconfusion, falls, malaise, incontinence and immobility, whereas“classical” symptoms of infection were more common among youngerpatients. The ED doctor’s impression of decline in general health was also amore frequent sign among the older patients. This reflects the general perception ingeriatric care [25], but has, to our knowledge, not previously been confirmed in a largecohort of bacteremic patients. Older patients die earlier during hospitalizationthan younger patients [3], and are more rarely transferred to an intensive care unit (ICU) [13], both also found in our study. We speculate whether advanced age to someextent reduces the chances of patients receiving proper clinical monitoring andtimely antibiotic treatment. In contrast, in our results there was no associationbetween age and the degree of missing data for bilirubin, arterial lactate andinternational standardized ratio (results not shown), indicating that the adequacyof monitoring was the same, irrespective of age.

Despite the efforts to broaden the understanding of sepsis diagnosis beyond SIRS,this entity is still used as rule in criteria for transfer to ICU and for aggressivetreatment. Elderly patients’ subtle presentation of infection makes thesensitivity of SIRS a matter of concern. Studies of the prognostic value of SIRS insepsis are scarce due to the fact that SIRS itself is generally part of theinclusion criteria. One study of ICU-patients with bacteremia caused byPseudomonas aeruginosa and Enterococcus found no differencesin SIRS between elderly and younger patients [26]. In our material, the sensitivity for organ failure of three SIRScriteria was lower than that of two criteria in the elderly, whereas the confidenceintervals overlapped in the younger patients. If absence of SIRS is used as anexclusion criterion for tight observation and aggressive treatment, a prognosticsensitivity of about 60% is hardly satisfactory, and this finding is clearlyclinically relevant.

The usefulness of CRP in sepsis diagnosis has been questioned [27]. A recent meta-analysis on a mixed group of ICU patients found that earlyCRP did not predict outcome, whereas CRP at Day 2 following admission did [28]. Another study recently found that CRP is a useful marker of sepsisresolution [29]. In our study, CRP at cut-off value 80 m mg/L was not associated toin-hospital mortality within 14 days after admission, whereas CRP at cut-off value200 mg/L was, but only in the univariate analysis. Interestingly, we found that thesensitivity of a high CRP-level in the diagnosis of organ failure in bacteraemia islower in elderly patients than in younger patients.

Age was clearly associated with both early organ failure and in-hospital mortality,reflecting the findings of other studies [3, 5, 6]. It is possible that these findings could have been confounded byage-associated clinical presentation hampering the diagnostic work-up and thetimeliness of treatment, rather than age being considered a risk factor in itself.Early diagnosis of sepsis is a prerequisite for early goal directed therapy, whichimproves outcome [30]. Decline in functional status, together with fever, defined by lowercut-off values than those used in SIRS and SAPS [15, 16], are important criteria for suspecting infection in older patients [31]. Decline in functional status includes new or increasing confusion,incontinence, falling, deteriorating mobility, reduced food intake, or failure tocooperate with staff, which partly corresponds to “atypical symptoms”assessed in our study. It might constitute a problem that such “softvariables” are not included in mortality-prediction rules for elderly EDpatients with infection [32]. Our study indicates that such clinical presentations may be associatedwith severity of infection, though not statistically significant in the multivariatefull model.

A subtle presentation may complicate the diagnosis of infections in elderly patients [33]. In our material, clinical judgment on general health in the EDindependently predicted organ failure. The International Sepsis DefinitionConference in 2001 acknowledged the value of clinical judgment: “Few,if any, patients in the early stages of the inflammatory responseto infection are diagnosed with sepsis via four arbitrary criteria.Instead the clinician goes to the bedside, identifies a myriad ofsymptoms and regardless of an evident infection declares the patient to“look septic” [21]. The updated Surviving Sepsis Campaign guidelines acknowledge clinicaljudgment even stronger: “Recommendations from these guidelines cannotreplace the clinician’s decision-making capability whenhe or she is provided with at patients’ unique set of clinicalvariables”. However, studies on the effectiveness of clinicaljudgment in predicting prognosis are scarce. Several studies on severe infection andsepsis did not include “soft” variables, and instead focused onbiomarkers and score systems.

Traditionally, prognostication in critical illness has relied heavily upon measuresof acute physiological derangements upon admission to ICU, as scoring systems do notintegrate pre-hospital functional status, severity of comorbid illness, disabilityor frailty [34]. Cancer, diabetes or cardiovascular disease are the most importantfactors for health-related quality of life after critical illness [35]. Comorbidity, quantified by the Charlson comorbidity index, is aprognostic factor for in-hospital mortality [36]. In our study, the number of comorbid illnesses and comorbiditydichotomized at ≥ 1 illness were independently associated to early organfailure and in-hospital mortality, respectively.

The main strength of the study was that patients were recruited non-selectively andfrom a mixed group of hospital patients. All patients who were admitted to thehospital over more than a decade were included in the study population. A majorweakness is that data were retrospectively collected. Thus, systematic informationon adequacy of antimicrobial treatment was missing and was therefore omitted fromthe analyses. Furthermore, the validity of the estimated number of failing organsmay be uncertain. We may have overestimated organ failure because we did not excludefailure in the organ that was considered primary source for infection. Conversely,organ failure may also have been underestimated because data on liver function andhematological markers as well as markers of peripheral perfusion wereunsystematically registered and therefore excluded. The survival curve by number offailing organs (the middle part of Figure 2), however, isvery similar to 1-year survival curves found by others [37]. We identified leukopenia as a risk factor for poor prognosis in themultivariate models, which corresponds well with neutropenia being one of theclinical risk factors for mortality in sepsis found in several trials [38]. We believe these findings support the importance of the“geriatric-focused results” found in our study.

Elderly patients with bacteremia more often present with atypical symptoms andreduced general condition. SIRS have poorer sensitivity for identifying severeinfection in these patients, and should be less emphasized when assessing the riskof sepsis in elderly patients. Advanced age and comorbidity are risk factors forboth early organ failure and in-hospital mortality. An uncertain clinicalpresentation, however, does not seem associated with in-hospital mortality.Irrespective of age, simple observations such as the subjective judgment of declinein general health, as well as single aspects of SIRS such as tachypnea,hyperventilation and leukopenia, alongside with indicators of organ failure, arecrucial when evaluating patients with possible severe infection. Because theclinical presentation is often atypical in advanced age, these clinical evaluationsmay be seen as keys to safer care for elderly patients with severe infection.