INNOVATIVE LABORATORY TECHNOLOGIES IN DIAGNOSIS OF SEPSIS

Ustyantseva I.M.1,2, Khokhlova O.I.,1, Goloshumov N.P.1, Agadzhanyan V.V.1,2

1Regional Clinical Center of Miners’ Health Protection, Leninsk-Kuznetsky, Russia
2Novosibirsk Research Institute of Traumatology and Orthopedics named after Ya.L. Tsivyan, Novosibirsk, Russia

 INNOVATIVE LABORATORY TECHNOLOGIES IN DIAGNOSIS OF SEPSIS

Despite of success in diagnosis and treatment of sepsis, this condition remains one of the main problems in modern medicine, because it is the main cause of mortality in patients in the intensive care units all over the world [9, 25]. The study by M.M. Levy et al. (2012) showed that the hospital mortality from sepsis varied from 28.3 to 41.1% in the Northern America and Europe [16]. There are some findings showing that treatment of sepsis costs more than 20 billion USD among the total costs for admissions in USA in 2011 [23]. Each hour of delay in treatment causes the increase in sepsis-related mortality approximately by 8 % [19]. Sepsis can be unrecognized in many cases [18].
Historically, sepsis was diagnosed on the evidences of persistent bacteremia (septicaemia). However sepsis determination has been changing in concordance with the progress in understanding the pathological physiology. So, during the Consensus Conference of American College of Chest Physicians/ Society of Critical Care Medicine (ACCP/SCCM) in Chicago in 1992, the term bacteremia was excluded, and some definitions and criteria (Sepsis-1, 1991) by Bone R.C. et al were accepted [8]. According to these definitions, sepsis is a pathologic process, which is based on the body response in view of generalized (systemic) inflammation to an infection of various origin (bacterial, viral, fungal) - Systemic Inflammatory Response Syndrome (SIRS). Moreover, local inflammation, sepsis, severe sepsis and septic shock are considered as the various forms of intensity of the body’s inflammatory response to the infectious process [1, 8]. Severe sepsis and septic shock are the most severe forms of such response and are accompanied by disorders of functions, which are distant from the main infectious and inflammatory process of the systems and organs [8]. SIRS is diagnosed in presence of more than one criterion (the table 1). Currently, SIRS criteria (two and more) are used for identification of sepsis.

Table 1. Diagnostic criteria of sepsis and organ dysfunction

Sepsis diagnostic criteria

ACCP/SCCM
(1992 г.)

SCCM/ESICM/ACCP/САР/SIS (2001 г.)*
Surviving Sepsis Campaign (SSC12)**

ICDSSS (Sepsis-3) (2016 г.)
qSOFA***

Main parameters

Infection

+

+

 

Temperature

< and/or > 38.0°C

< and/or >38.3 °C

 

Heart rate (beats per min)

> 90

> 90 or  > 2 SD above age standard

 

Respiratory rate (breaths per min)

> 20

> 30

> 22 

Systolic arterial pressure (mm Hg)

 

 

≤ 100

 

 

 

Disordered consciousness

Inflammation values

White blood count

> 12 000/ mcl
and/or < 4000/mcl,
and/or  > 10% of immature white blood cells

> 12 000/
and/or < 4000/ mcl,
and/or > 10% of immature white blood cells

 

C-reactive protein

DR

> 2 SD above standard

 

Procalcitonin

DR

> 2 SD above standard

 

Tissue perfusion values

Hyperlactataemia

DR

above laboratory standard (> 1 mmol/l)

 

Note:
SCCM – Society of Critical Care Medicine; ESICM – The European Society of Intensive Care Medicine; ACCP – The American College of Chest Physicians; ATS – the American Thoracic Society; SIS – the Surgical Infection Society; DR – disregarded.

*Levy M.M., Fink M.P., Marshall J.C., Abraham E. [et al.], 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference //Crit Care Med. 2003. Vol. 31, № 4. Р. 1250-1256.
**Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign:International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. //Crit Care Med. 2013. Vol. 41. P. 580-637.
***Singer M., Deutschman C.S., Seymour C.W. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) //JAMA. 2016. Vol. 315, №. 8. P. 801-810.


The concept by Bone R.C. et al [8] was revised several times. In 2001, during SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference (Sepsis-2), some changes were done, for example, the recommendation to use the term multiple organ dysfunction syndrome (MODS) – a clinical syndrome, which is characterized by development of acute, potentially reversible dysfunction of organs, which are not directly involved into the primary pathological process. Also the list of the diagnostic criteria was supplemented [15].
In 2012, during revision of Surviving Sepsis Campaign (SSC12), the list of the signs, the symptoms and the laboratory values (C-reactive protein, procalcitonin, glucose, lactate) confirming a possible presence of sepsis was updated [10].
Insufficient specificity and sensitivity of SIRS criteria were subsequently accepted as a significant limitation, resulting in further revision of the term sepsis [13, 26]. In 2014, the group of 19 experts in intensive care, surgery, infectious disease and pulmonology was initiated. After two years of research work, they offered the clinical implementation of the new definitions [25]. The definitions were presented during 45th congress of Society of Critical Care Medicine (SCCM) on February 23, 2016 [21]. They include the new notion – Quick SOFA (Quick Sequential Organ Failure Assessment) (the table 1), excluding the SIRS notion from definitions sepsis and severe sepsis, and sepsis was offered to define as a life-threatening dysfunction caused by dysregulated response to infection.
In 2016, the work group of SCCM recommended to call the new definitions as Sepsis-3, 1991 and 2001 definitions as Sepsis-1 and Sepsis-2 correspondingly [21]. The necessity of future changes is accented.
The offer for exclusion of the symptoms of systemic inflammatory response syndrome (SIRS) caused the mixed response in the medical society, despite of approval from 31 public societies. It is determined by the fact that the definitions of ACCP/SCCM 1991 are basic for most national and international recommendations [8]. According to S.Q. Simpson (2018), there are not any proven advantages of the new principles of the consensus, and SIRS criteria should remain the important component of the diagnostic process [20]. Therefore, there is not any uniform opinion on necessity and appropriateness of transition to the definitions of Sepsis-3.
One should note that the last revision of ICD-10 included the SIRS criteria into the sections R57.2 – septic shock, R65 (0-5) – systemic inflammatory response syndrome, with subsequent detalization. According to the letter of Russian Health Ministry, these changes are recommended for use in the territory of Russia (the Letter of RF Health Ministry, December 5, 2014, No.13-2/1664) [3]. In 2016, Saint-Petersburg Society of Specialists in Sepsis developed the clinical recommendations for diagnosis and treatment of severe sepsis and septic shock in the medical and preventive facilities of Saint Petersburg [2].
Therefore, sepsis is one of the key clinical problems of the modern age that is determined by its high incidence and mortality in the world. Currently, one of the main problems is identification of techniques, which allow improving the accuracy, reproducibility and/or clinical value of sepsis diagnosis. There is not any gold standard for diagnostics.  Therefore, the clinicians still rely on the range of the traditional and new biomarkers for distinction between patients with infection and without it [14]. The ideal biomarker should correspond to SMART concept: specific and sensitive, M – measurable, A – available and affordable, R – responsive and reproducible, T – timely.
In our previous works, we showed the high diagnostic sensitivity and specificity of some laboratory tests (increase in blood lactate [4, 5], lipopolysaccharide-binding protein (LPS-BP), interleukin-6 and -8 (IL-6, IL-8), C-reactive protein (CRP), procalcitonin (PCT) [6], and significant decrease in apolipoprotein B (ApoB) [7]. It allowed recommending these values as the markers of infectious process generalization and development of septic complications. However the correct estimation of the supposed inflammation and infection according to results of clinical examination, biochemical markers and microbiological studies is a time-consuming and expensive process. Availability of the test and the rapidness of result are important in conditions of time deficiency and possible underestimation of the patient’s condition. Currently, the new line of hematological cytometers has been developed. They allow calculating and differentiating the various populations of leukocytes, as well as quantitative estimation of their maturity and activity according to intensity of fluorescent signal and degree of diffusion. There are some publications showing the usefulness of these hematological parameters for sepsis [11, 17, 22, 24].
Therefore, the use of the new diagnostic parameters of inflammation becomes valuable in diagnostic analysis.
Objective – to estimate the possibility of use of extensive inflammation parameters of the automatic hematologic analysis (activated neutrophils and lymphocytes) for diagnosis of septic complications in critically ill patients. 

MATERIALS AND METHODS

17 patients were examined (12 men (70.6 %), 5 women (29.4 %), mean age of 56 ± 3.8) in the intensive care unit of Regional Clinical Center of Miners’ Health Protection, Leninsk-Kuznetsky. 3 patients suffered from severe traumatic brain injury, 4 – polytrauma, 2 – acute disorder of cerebral perfusion by hemorrhagic type, 1 – phlegmon, 1 – large bowel obstruction, 1 – paraproctitis, 4 – severe pneumonia, 1 – acute pancreatitis.
The patients were distributed into the groups depending on the signs of sepsis, which were identified in concordance with Sepsis-1 [8] and Sepsis-3 [21]. The main group included the patients with confirmed sepsis (n = 7). The comparison group included the patients without sepsis (n = 10). The study program was realized with laboratory techniques on the days 1-3 after admission to the intensive care unit.
The samples of peripheral venous blood in the tubes with K3EDTA (Becton Dickinson) were studied with the Sysmex XN-1000 hematological analyzer (Sysmex, Co., Japan) during 2 hours after sampling.
The main parameters were  estimated including the count of leukocytes, absolute and relative amount of neutrophils, immature granulocytes (IG), as well as the extended parameters of inflammation (NEUT-GI – neutrophil granularity intensity, NEUT-RI – neutrophil reactivity intensity,  RE-LYMP – reactive lymphocytes, AS-LYMP – antibody-synthesizing cells).
The blood serum samples were estimated for C-reactive protein (CRP) with use of immunoturbidimetric test and procalcitonin (PCT) with immune chemical method with Cobas 6000 (Roche, Switzerland).
The statistical analysis of the results was conducted with IBM SPSS Statistics 20. Distribution of the values was estimated with visual estimation of frequency histograms. Since most part of the data had the distribution differing from the normal one, the results were presented as (Me) (LQ-UQ), where Me – median, (LQ-UQ) – interquartile range (LQ – 25 %, UQ – 75 %).
The intergroup differences in the quantitative signs were identified with Mann-Whitney’s non-parametric test. The differences were statistically significant for p < 0.05. The correlation relationships between the signs were described with Spearman's rank correlation coefficient (ρ).
The study was approved by the ethical committee of Regional Center of Miners’ Health Protection and corresponded to WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects, and the Rules for Clinical Practice in the Russian Federation confirmed by the order by Health Ministry of the Russian Federation, June 19, 2003, No.266. 

RESULTS AND DISCUSSION

The study showed some consistent changes between the groups according to PCT and CRP: the patients of the main group showed the increase in the levels of these biomarkers 6.5 and 2.7 times correspondingly as compared to the comparison group, confirming the sepsis diagnosis (the table 2). At the same time, the general amount of leukocytes, neutrophils and immature granulocytes did not differ. The analysis of the extended parameters of inflammation showed that the development of inflammation response in the critically ill patients of the main group was characterized by higher NEUT-RI with unchanged NEUT-GI than in the comparison group (by 37.1 %, p < 0.001). At the same time, the insignificant increase in AS-LYMP was found, testifying the course of bacterial infection.

Table 2. Laboratory values of inflammation in critically ill patients

 

Main group
(n = 7)

Comparison group
(n = 10)

р

Leukocytes, abs. 109/l

10.6 (7.30-4.81)

14.4 (12.46-16.88)

0.88

Neutrophils, abs. 109/l

9.6 (6.42-12.77)

11.4 (9.55-14.38)

0.23

Neutrophils, %

88 (86.3-90.5)

83 (78.3-87.7)

0.043

IG, abs., 109/l

0.15 (0.070-0.250)

0.12 (0.080-0.187)

0.364

IG, %

1.7 (0.80-3.30)

0.8 (0.57-1.15)

0.07

NEUT-RI, FI

73 (63.9-80.1)

53 (61.8-55.0)

< 0.001

NEUT-GI, SI

154 (148.7-159.3)

155 (151.2-160.2)

0.813

AS-LYMP, abs. 109/l

0.03 (0.020-0.070)

0 (0.0-0.0)

0.01

AS-LYMP, %

0.3 (0.10-0.70)

0 (0.0-0.0)

0.01

RE-LYMP, abs. 109/l

0.08 (0.050-0.12)

0.15 (0.020-0.21)

0.364

RE-LYMP, %

0.8 (0.50-1.00)

1.0 (0.17-1.67)

0.536

Procalcitonin, ng/ml

3.9 (0.90-56.36)

0.6 (0.32-0.78)

0.001

CRP, mg/l

282 (198.9-384.1)

103 (96.5-108.2)

< 0.001

Note: IG – immature granulocytes; NEUT-RI – intensity of responsiveness of neutrophils; NEUT-GI – intensity of granulosity of neutrophils; FI – fluorescence intensity; SI – spattering intensity; AS-LYMP – antibodies which synthesize lymphocytes; RE-LYMP – reactive lymphocytes; CRP – C-reactive protein.

The correlation analysis showed the strong direct relationships between the levels of NEUT-RI, PCT and CRP (Spearman's rank correlation coefficient = 0.642, p = 0.005 and ρ = 0.774, p < 0.001).
The study by R.J. Dinsdale et al showed the similar results in the burn patients: the significant increase in NEUT-RI with development of septic complications, and low discrimination ability to differ septic and non-septic patients for NEUT-GI [11].
It is known that neutrophils take the leading position in antimicrobial protection. In sepsis, the higher pathogenetical role is related not to the general count of neutrophils in the blood, but to presence of cellular subpopulation, phenotype and level of activation stimulating the tissue injury. According to the existing definition, the beginning of organ dysfunction presents the signs of sepsis. It can be caused by excessive activation of the complement and actions of neutrophils against the host which are accompanied by healthy tissue injury. Conversely, persistent inflammation can lead to decreasing sensitivity of neutrophils and components of the complement, promoting the contagion [12].
Therefore, estimation of functional activity of neutrophils is important alongside with quantitative values. SYSMEX XN technologies allow rapid collection of such data, accelerating the diagnosis of sepsis.

Clinical case

The patient B., age of 61, was admitted to the admission department of Regional Clinical Center of Miners’ Health Protection on January 6, 2018. He had some complaints of thickness and pain in the perianal regional, absent defecation more than 5 days, general uneasiness, increasing body temperature up to 38 °C. The examination showed a round, painful formation (10 cm diameter). The laboratory examination: leukocytosis with relative and absolute neutrophilia (16.6 × 109/l and 14.92 × 109/l correspondingly), hyperbilirubinemia (total bilirubin – 42.3 mcM/l), hyperazotemia (creatinine – 160 mcM/l, urea – 15.2 mmol/l).
The presumptive diagnosis was made on the basis of physical and laboratory examination: “Acute purulent pelviorectal periproctitis. Toxidrome”. The patient was admitted to the surgical department No.1. After admission, the surgery was carried out: opening, revision and draining of the abscess. Antibacterial therapy (ciprofloxacin 0.4 g, 3 times per day) was conducted. The further surgical treatment included laparotomy, laparostomy, revision, necrectomy. Debridement of the purulent focus was performed several times. Despite the treatment, the condition of the patient was worsening. Arterial hypotension, respiratory embarrassment, decreasing diuresis (less than 50 ml/h), events of gastrointestinal paresis, anemia and episodic hyperthermia were observed. The laboratory examination showed persistent neutrophilia with increasing count of immature granulocytes (January 9, 2018 – 0.48 × 109/l, January 11, 2018 – 0.34 × 109/l). At the same time, some changes in the additional parameters of inflammation testifying the course of severe acute bacterial infection were noted: NEUT-RI – 76.4 FI, AS-LYMPH – 0.09 × 109/l.
The diagnosis was made on the basis of the clinical picture and the data of the examination: “Sepsis”. For further treatment, the patient was transferred to the intensive care unit. The diagnosis was confirmed by the levels of procalcitonin (2.12 ng/l) and CRP (199 mg/l). Meropenem-sensitive E. coli was separated in the bacteriological examination of the wound discharge. Therefore, this antibiotic was prescribed (1 g, 3 times per day), which subsequently was substituted to the combination of sulperason (4 g, 2 times per day) + amikacin (1.5 g daily).
The patient’s condition was improving at the background of intensive care in the ICU. On January 26, 2018, the condition was of middle severity. The breathing was respiratory and adequate. Hemodynamics was stable. Diuresis was sufficient. The events of intestinal paresis were corrected (from January 19, 2018, enteral administration of fluid with gradual extension was initiated; from January 25 – the table 1 was prescribed). The patient could assimilate nutrition. Peristalsis was active.
The time course of the results of the laboratory examinations corresponded to the positive time course of the patient’s condition. Particularly, the levels of procalcitonin (January 26, 2018 – 1.43 ng/ml), C-reactive protein (92 mg/l), leukocytes, immature granulocytes and NEUT-RI were observed (the figures 1-2 show the scattergrams of time course of distribution of different populations of leukocytes). At the same time, NEUT-GI increased from 159.7 SI (January 11, 2018) to 163.9 and to 167.2 SI (January 17, 2018 and January 26, 2018 correspondingly). Along with persistent anemia, it can be associated with disorders of hematopoiesis as result of depletion of reserves.

Figure 1. The scattergram of distribution of population of leukocytes in the patient B. on the day 3 of the disease

Figure 2. The  scattergram of distribution of population of leukocytes in the patient B. on the day 18 of the disease


The presented case demonstrates that IG and NEUT-RI (available during total clinical analysis of the blood with SYSMEX XN) correlated with severity of the course of purulent-septic process and the levels of the generally accepted inflammation markers (PCT, CRP). It allows using these values both for express diagnosis of sepsis and prediction of outcome. CONCLUSION

Therefore, the identified significant differences in NEUT-RI in the critically ill patients with and without sepsis allow considering this parameter as the perspective diagnostic marker of sepsis. Simplicity, availability and rapidness of results in the standard blood analysis open the possibilities for wide clinical usage. The limitations of the study suppose further large-scale studies.

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