Clinical Features and Diagnosis of Sepsis
Sepsis is a systemic disease with a variety of clinical manifestations. The initial symptoms of sepsis are non-specific and include malaise, tachycardia, tachypnea, fever, and sometimes hypothermia. Although most patients with sepsis have an elevated white cell count, some patients present with a low white cell count, which in general is a poor prognostic sign. A band count in excess of 5-10% has been reported to have a high specificity (92%) but low sensitivity for the diagnosis of sepsis (43%)  Other clinical manifestations include altered mental status, hypotension, respiratory alkalosis, metabolic acidosis, hypoxemia with acute lung injury, thrombocytopenia, consumptive coagulopathy, proteinuria, acute tubular necrosis, intra-hepatic cholestasis, elevated transaminases, hyperglycemia and hypoglycemia. Patients may present with clinical features of a localized site of infection, such as cough, tachypnea, or sputum production due to pneumonia; flank pain and dysuria with urinary tract infection, or abdominal pain with intra-abdominal infection.
The manifestations of sepsis can sometimes be quite subtle, particularly in the very young, the elderly and those patients with chronic debilitating or immunosuppressing conditions. These patients may present with normothermia or hypothermia. The failure to generate a temperature greater than 99.6oF (37.5oC) in the first 24 hours of clinical illness, has been associated with an increased mortality rate. An altered mental state or an otherwise unexplained respiratory alkalosis may be the presenting feature of sepsis. The signs and symptoms of systemic inflammation are not useful in distinguishing infectious from non-infectious causes of SIRS.
Blood cultures are considered to provide a clinical gold standard for the diagnosis of bacterial infections. However, blood cultures are only positive in between 20-30% of patients with sepsis; moreover, it takes 2 to 3 days before the results become available. Molecular diagnostic techniques that do not depend on the growth of organisms in culture may offer distinct advantages over current microbiological methods. SeptiFast (Roche Diagnostics, Germany) was the first real-time PCR-based system approved for clinical use. A meta-analysis from 41 phase III diagnostic accuracy studies, reported a sensitivity and specificity for SeptiFast compared with blood culture of 0.68 and 0.86 respectively. More recently advanced PCR followed by electrospray ionization mass spectrometry (PCR/ESI-MS) has been described which can detect more than 800 relevant pathogens in a single assay and which can be completed in approximately 6 hours. The Rapid Diagnosis of Infection in the Critically ill (RADICAL) study was a prospective observational multicenter study which evaluated 529 patients with suspected infection using the PCR/ESI-MS technology. PCR/ESI-MS detected a pathogen in 35% of blood samples compared to 11% for conventional blood culture. These techniques hold great promise for the early detection of blood stream infection allowing for early targeted antibiotic therapy.
A number of bio-markers have been evaluated as adjunctive methods to improve the diagnosis of sepsis. Procalcitonin (PCT) has to date been the most useful bio-marker to aid in the diagnosis of sepsis. PCT, a propeptide of calcitonin, is normally produced in the C-cells of the thyroid. In healthy individuals, PCT levels are very low (<0.01 ng/ml). In patients with sepsis, however, PCT levels increase dramatically, sometimes to more than several hundred nanograms per milliliter. The test is not perfect and should always be interpreted in the clinical context together with other diagnostic tests. Furthermore, early in the course of a patients’ disease the PCT may be low only to increase dramatically within a few hours. The time course of the PCT level is as important as the absolute level (see below). Wacker et al performed a meta-analysis to evaluate the diagnostic accuracy of PCT. In this meta-analysis the sensitivity was 0·77 (95% CI 0·72–0·81), the specificity was 0·79 (95% CI 0·74–0·84) and the area under the ROC curve was 0·85 (95% CI 0·81–0·88). This diagnostic accuracy is better than any other single test to diagnose sepsis. A PCT > 0.5 ng/ml is highly suggestive of a bacterial infection while a level <0.1 ng/ml makes this diagnosis less likely. It should be noted that patients with fungal infections usually have much lower or “normal” PCT levels. In addition to being a very useful test to diagnose bacterial sepsis, the trend in the PCT level is useful for deciding when to discontinue antibiotics.[8,9] Furthermore, the trend in the PCT is strongly predictive of outcomes, with a persistently high level being associated with a poor outcomes. The PCT clearance (PCT-c) calculated using the following formula: initial PCT minus PCT at 96 hours, divided by the initial PCT multiplied by 100 is highly predictive of microbiological cure and patient outcome. [75,76] In patients being treated with the vitamin C, hydrocortisone and thiamine protocol the trajectory of the PCT levels (and the PCT clearance) is critically valuable in determining an adequate response to antimicrobial agents and adequate source control. In patients treated with this “cocktail” the PCT time-course is absolutely predictable, with an exponential fall in the PCT level once the “cocktail” is started (see graph). In patients in whom this pattern is not seen, either inadequate source control, wrong antibiotic(s) or a new infection is highly likely.
Due to the lack of specific criteria to diagnose sepsis this diagnosis is often delayed. The early detection and treatment of sepsis are the most important factors for improving the outcome from this condition. However, for many patients admitted to hospital there is frequently a long delay before the diagnosis of sepsis is made. Furthermore, it is not uncommon for febrile patients to be sent home from the Emergency Department or the physician’s office with the diagnosis of “flu” only to return hours or days later in overt septic shock. The diagnosis of sepsis therefore requires a high index of suspicion, a comprehensive clinical evaluation together with supportive laboratory tests including appropriate microbiological cultures, a complete blood count with differential, and when available PCT levels. It is important to emphasize that unlike PCT, lactate is not a specific “sepsis test”. An elevated lactate is a useful marker of disease severity in patients with sepsis, and sepsis should be considered in the differential diagnosis of patients with an elevated lactate level.
Any one of the following features alone or in combination are suggestive of bacterial sepsis:
- Fever > 38.3oC or hypothermia (< 36oC)
- Heart rate > 120 /min (sinus tachycardia)
- Systolic BP < 90 mmHg
- PCT > 0.5 ng/ml
- Bandemia > 5%
- Lymphocytopenia < 0.5 x 103ul
- Thrombocytopenia < 150 x 103uL
- Increased neutrophil/lymphocyte ratio (greater than 10:1)
- Cavallazzi R, Bennin CL, Hirani A et al. Is the band count useful in the diagnosis of infection? An accuracy study in critically ill patients. J Intensive Care Med 2010; 25:353-57.
- Dark P, Blackwood B, Gates S et al. Accuracy of LightCycler SeptiFast for the detection and identification of pathogens in the blood of patients with suspected sepsis: a systematic review and meta-analysis. Intensive Care Med 2015; 41:21-33.
- Bacconi A, Richmond GS, Baroldi MA et al. Improved sensitivity for molecular detection of bacterial and Candida infections in blood. J Clin Microbiol 2014; 52:3164-74.
- Vincent JL, Brealey D, Abidi NE et al. Rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections. Crit Care Med 2015; 43:2283-91.
- Wacker C, Prkno A, Brunkhorst FM et al. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13:426-35.
- Schuetz P, Chiappa V, Briel M et al. Procalcitonin algorithms for antibiotic therapy desisions. A systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011; 171:1322-31.
- Brodska H, Malickova K, Adamkova V et al. Significantly higher procalcitonin levles could differentiate Gram-negative sepsis from Gram-positive and fungal sepsis. Clin Exp Med 2014; 13:165-70.
- Matthaiou DK, Ntani G, KOntogiorgi M et al. An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithm in adult critically ill patients. Intensive Care Med 2012; 38:940-949.
- Kopterides P, Siempos IL, Tsangaris I et al. Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: A systematic review and meta-analysis of randomized controlled trials. Crit Care Med 2010; 38:2229-41.
- Schuetz P, Maurer P, Punjabi V et al. Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients. Crit Care 2013; 17:R115.
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