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Association of a high PCT level (PCT > 1.44 ng/mL) with or without presence of fever for the diagnosis of PBI was then investigated. All episodes with a PCT level of more than 1.44 ng/mL (defined using ROC curves, see above) and fever were PBI episodes. The presence of one of these 2 markers was associated with 46% of PBI episodes. No afebrile patient with PCT level less than 1.44 ng/mL had a PBI.
Procalcitonin (PCT) and fever as markers of proven bacterial infection at admission. Results are shown in percent of episode with proven bacterial infection over total episode presenting both (100%), either one (46%) or none (0%) of PCT >1.44 ng/mL and fever. PCT is expressed in ng/mL. Fever is retained in case of temperature > 38 °C
This is the first study to assess the diagnostic performance of different sepsis markers to predict proven bacterial infection for patients with DKA, admitted in ICU. Fever and high PCT (threshold above 1.44 ng/mL at D0) at ICU admission may help to identify patients with proven bacterial infection in the context of DKA.
The only clinical marker was temperature. Presence of fever on D0 and D2 was higher in PBI episodes as reported in previous studies . Nevertheless, in episodes without PBI, body temperature ranged from 32.9 °C till 38.7 °C on D0. This huge variation may be explained by thermoregulatory function impairment in diabetic patients . Hypothermia (temperature
Other classical sepsis markers were also found to be inefficient in our study to differentiate PBI episodes from those without PBI. We found a high WBC level on D0 (mostly composed of neutrophil polynuclears) in episodes without PBI. Such leukocytosis, as high as 57.0 G/L, has already been reported in several case reports [25, 26]. This result leads to reconsider the usefulness of WBC to predict bacterial infection at admission. Recently, the NLCR was proposed to be a more useful diagnostic tool than other blood tests to identify patients with bacterial infection . However, in our study we did not highlight any difference for this marker between both groups at admission.
In early management of DKA, traditional clinical (hypothermia) and biological (WBC, NLCR) signs of bacterial infection proved to be ineffective, probably because of the reported correlation between hyperglycemia crisis and inflammatory response. In non-diabetic patients, induced hyperglycemia led to an amplification of interleukin-6 (IL-6) and other pro-inflammatory markers . Adding low doses of insulin avoids these alterations even with persistent hyperglycemia . Compared with healthy controls, an induced hyperglycemia in diabetic patients results in a more pronounced secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-6 . Apart from any bacterial infection, TNF-α is known to induce the release of large amount of PCT in both animals  and humans . These data may explain the increase of both PCT and WBC in episodes without PBI on D0. Combining PCT and presence of fever may help to be more specific. Indeed, only PBI episodes presented both signs, whereas there was no PBI episode with the absence of both signs (Fig. 3). On D2, after administration of insulin and correction of glycemia, the near normalization of PCT and WBC in episodes without PBI may be explained by the correction of this inflammatory state, allowing to distinguish two different patterns: episodes with and without PBI. In the former group, episodes of fever occur and high levels of PCT, WBC, neutrophil count and NLCR still persist on D2. In the latter, there is a decrease, if not a normalization, of all the aforementioned markers following the correction of glycemia. Thus, on D0, infection status could be based on PCT level and presence of fever regardless of WBC or hypothermia occurrence. On D2, after normalization of glycemia, usual markers recover their discriminating potential and can enable the reassessment of antibiotic prescriptions if started on D0.
At admission, our study showed that WBC, neutrophils count and hypothermia should not be taken into account in the diagnosis process of infection in diabetes ketoacidosis patients admitted in intensive care unit. Only fever and PCT (with a higher threshold than usual: 1.44 ng/mL) may help distinguish patients with and without PBI. By combining those two markers reduction of antibiotic misuse may be possible.
Sepsis markers in episodes with proven bacterial infection at admission and day 2 (Univariate analysis). Table S2. Sepsis markers in episodes without proven bacterial infection at admission and day 2 (Univariate analysis). Figure S1. Receiver operating characteristics curve of procalcitonin at day 2. Figure S2. Receiver operating characteristics curve of whole blood count and temperature on day 2.
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