Ustyantseva I.M., Kulagina E.A., Aliev A.R., Goloshumov N.P., Agadzhanyan V.V.

Regional Clinical Center of Miners’ Health Protection, Leninsk-Kuznetsky, Russia

The problem of sepsis as a complication of various abnormal processes is still actual medical task [1, 2]. Due to variety of clinical manifestations of sepsis, it is difficult to estimate the initial symptoms. Therefore, it  is important to determine the early clinical and laboratory signs. The improvement in techniques of laboratory diagnosis certainly promotes the collection of such information and accelerates sepsis diagnosis [4, 5]. So, quantitative estimation of functional activity of various populations of leukocytes can be performed with analyzers of XN series during standard general blood analysis [4, 6].
Currently, one can observe gradual transformation of understanding of interpretation of hematological parameters of inflammation (activated neutrophils and lymphocytes) in conditions of real clinical practice.

In some recent published studies, we showed a possibility for use of extended inflammatory parameters of hematological analysis (NEUT-RI, NEUT-GI, AS-LYMP) in critically ill patients in express diagnosis of sepsis and in prediction of sepsis outcome [6, 7]. It has been shown that early changes in NEUT-RI and NEUT-GI are associated with the risk of nosocomial infection, which is registered later [8]. Monitoring of activated neutrophils and lymphocytes allows estimation of intensity of systemic inflammation and generalization of infectious process [6, 7, 8].

– to present a clinical case of complex diagnostic approach with use of monitoring of hematological parameters of inflammation in development of fatal multiple organ dysfunction in a patient with sepsis of high risk group.
The study corresponded to the ethical principles of Helsinki Declare (2013), and to the Rules for Clinical Practice in the Russian Federation (the Order by the Health Ministry of Russia, June 19, 2003, No. 266), with approval from the ethical committee of Regional Clinical Center of Miners' Health Protection, Leninsk-Kuznetsky (the protocol No. 3, January 29, 2020).

A clinical case

A patient T., male, age of 39, was admitted to the admission unit of Regional Clinical Center of Miners' Health Protection, on December 20, 2019. He had some complaints of abdominal pain, blood stool, fatigue and labored breathing.
From the disease history: abdominal pain was increasing gradually within a week. Blood stool appeared on December 20, 2019.

At the moment of examination, the condition was severe and was determined by pain abdominal syndrome. The body temperature was 36.8 °C. The skin was pale and dry. The breathing was vesicular, symmetrical, without rale. The respiratory rate was 24 breaths per minute. Hemodynamics showed a trend to hypotonia. Arterial pressure (AP) was 100/60 mm Hg, heart rate (HR) − 120 beats per minute. The abdomen was not distended; it was symmetrical and did not participate in breathing. It was tensed when palpated, and painful in all regions. The liver was not enlarged. The spleen was not palpated. There were some peritoneal symptoms. Peristalsis was not auscultated. Kidney punch was negative. Urination was frequent. Rectal examination: collapsed hemorrhoids; no infiltrates and masses. Blood stool.

Chest X-ray examination was conducted. It did not show any visible infiltrative changes or signs of hydro- and pneumothorax. Abdominal X-ray examination showed free gas in abdominal cavity under the anterior abdominal wall (up to 4.8 cm).

Laboratory examination: severe anemia (red blood cells - 2.02 × 1012/l; hemoglobin (Hb) - 57 g/l, platelets - 304 × 109/l, leukocytes - 7.2 × 109/l, evident relative increase in neutrophils (91.4 %), evident toxic granulation. Hyperazotemia (urea - 16.3 mmol/l, creatinine - 240 µmol/l).

The preliminary diagnosis was made on the basis of data of physical and laboratory examination: "Gastric and duodenal ulcer, perforation, bleeding".

Urgent surgery was conducted: laparotomy, revision, resection of a part of small intestine, abdominal cavity lavage, laparostomy. Plenty of purulence was in the abdominal cavity, in the subhepatic space and in the small pelvis. Conglomeration of lymph nodes was in the region of mesoileum. Two perforations (diameter of 2 and 3 cm) were 20 cm from ileocecal node.

The postsurgical diagnosis: "Necrosis of a part of the ileum, perforation. Purulent lymphadenopathy of mesoileum, lymphadenopathy of retroperitoneal lymph nodes. General purulent-fibrinous peritonitis. Hepatitis C, B 20-24".

For further treatment, the patient was transferred to the intensive care unit.

In the early postsurgical period, the severity of condition was determined by: 1) surgery volume; 2) systemic inflammatory response syndrome (leukopenia - 3.41 × 109/l, neutrophil deviation - 19 %,
рСО2 - 28 mm Hg, temperature - 35.7 °C); 3) anemia (Hb - 68 g/l); 4) hyperglycemia - 17.9 mmol/l; 5) hyperazotemia (urea - 17.5 mmol/l, creatinine - 219 µmol/l); 6) infection (Klebsiella pneumonia – bacteriological analysis of abdominal discharge and bronchoalveolar lavage fluid (BALF); 7) concurrent basic pathology (hepatitis C, B 20-24).
Analgesia and sedation were performed with narcotic analgetics, targeted antibiotic therapy - with ceftriaxone (2 g, 2 times per day), metrogyl (0.5 g, 3 times per day).

Adequate oxygen delivery and tissue perfusion persisted at the background of anemia correction (average daily transfusion -600 ml of packed red blood cells, and 700 ml of fresh frozen plasma) and water-electrolyte metabolism at the background of daily infusion of crystalloid solutions of 3,000-4,500 ml. Artificial lung ventilation was conducted with consideration of concept of safe ALV, with forced mode with FiO2 of 40 %. Catabolism correction included combined parenteral nutrition.

The figure 1 shows the time trends of organ insufficiency (SOFA) and laboratory parameters in the patient T.

On the second day, the patient's condition was worsening despite of treatment. There were arterial hypertension, respiratory failure, episodic hyperthermia, general purulent-fibrous peritonitis, intestinal paresis, renal failure (hyperazotemia − urea 22 mmol/l, creatinine 250 µmol/l), intense intoxication. SOFA was 7 points (Fig. 1).

Figure 1. Time course of hematological parameters of inflammation, PCT and CRP in the patient T

Note: immature granulocytes (IG), neutrophil reactivity intensity (NEUT-RI), neutrophil granularity (NEUT-GI), procalcitonin (PCT), C-reactive protein (CRP), SOFA.

Normal range of values: IG 0- 0.6 % [5], NEUT-RI 36.0- 62.4 FI, NEUT-GI 134.0- 163.2 SI [10].
Laboratory values: anemia (Hb - 84 g/l), thrombocytopenia (88 × 109/l), relative neutrophilia (66 %) with high amount of immature granulocytes (IG - 19.9 %). At the same time, some changes in additional inflammation parameters were found which supposed a severe bacterial infection: significant increase in NEUT-RI - 90.9 FI, AS-LYMP - 0.07 × 109/l (Fig.1). High levels of procalcitonin (PCT - 7 ng/ml) and C-reactive protein (CRP - 157 mg/l) were found. Bacteriological examination of BALF showed Klebsiella pneumoniae. On the basis of clinical picture, the diagnosis was made: "Sepsis" (Fig. 1).

Relaparotomy, revision, intestinal anastomosis, lavage, and laparostomy were performed on the third day. Subsequently, the severity of condition was determined by sepsis (Klebsiella pneumoniae was found in multiple inoculations of abdominal discharge, and in bacteriological analysis).

At the background of intensive care, the patient showed some trends to gradual worsening. The condition was severe and unstable on the fourth day. There was progression of respiratory and renal failure (hyperazotemia (urea - 24 mmol/l, creatinine - 270 µmol/l)) and organ injuries (SOFA = 9) (Fig. 1).

 The results of laboratory examinations showed some negative trends (Fig. 1). On the fourth day, high levels of PCT (5.53 ng/l), CRP (200 mg/l), relative amount of neutrophils (95 %) and immature granulocytes (18.1 %), and significant increase in NEUT-RI (100.1 FI) were observed (Fig. 2B). At the same time, NEUT-GI and AS-LYMP did not show any differences from normal values. Along with persistent anemia, it could be associated with hemopoiesis due to exhaustion of backup capabilities of the body (Fig.2B).

Figure 2. Scattergrams of hematological parameters of inflammation describing the time course of activated cellular populations of leukocytes in the patient T. on the day 1 (A), 4 (B) and 6 (C)


Note: Sysmex XN1000 (Sysmex Co., Japan), lateral scattering along axis X (SSC), lateral fluorescence along axis Y (SFL). Activated neutrophils – NEUT-RI value characterized by high intensity of fluorescence, of blue color.

On the seventh day, the condition was extremely severe, with negative time trends by means of increasing multiple organ insufficiency. Consciousness was depressed to coma. Body temperature was 36.5 °C. ALV was in forced mode with FiO2 of 50 %. Unstable hemodynamics was maintained with dopamine infusion (15 µg/kg/min) at the background of AP of 80/40 mm Hg, and HR of 80-70 per min.
Laboratory values: anemia (Hb - 102 g/l), leukopenia (leukocytes - 1.72 × 109/l), thrombocytopenia (platelets - 15 × 109/l); hyperazotemia (urea - 39 mmol/l, creatinine - 339 µmol/l); bilirubin (total - 37.3 µmol/l, direct - 25.9 µmol/l), high PCT (6.8 ng/ml), CRP (167 mg/ml); intense increase in level of immature granulocytes (to 27.9 %) (Fig. 1)and NEUT-RI (to 113 FI) (Fig. 2C).

Organ insufficiency was manifested in view of respiratory and renal failure, and vascular dysfunction. Maximal SOFA was 16. Despite of intensive care, the patient died on the seventh day at the background of increasing multiple organ failure and septic shock. The histological examination of surgical materials showed intestinal tuberculosis, perforation, and peritonitis.

The postmortem diagnosis: HIV of 4B stage; secondary diseases: progressing generalized tuberculosis with lung involvement: disseminated lung tuberculosis at progression phase; tuberculosis colitis: infiltrative ulcerous tuberculosis of the ileum, with perforation. Complications: ongoing generalized purulent-fibrous peritonitis; multiple organ insufficiency; sepsis; septic shock".


According to the modern opinions on systemic inflammation of infectious origin, patients should be estimated with consideration of PIRO: estimation of predisposition (P) to sepsis, presence of an infectious agent (1), clinical manifestations (R) organ dysfunction (O).
Presence of massive infection site and sepsis in combination with viral infection (hepatitis C, B20-B24)
  determined high probability of fatal multiple organ disorders.

Concerning the infectious agent in this patient, it was common multiple-resistant gram-negative Klebsiella pneumoniae, which was the cause of generalized purulent peritonitis, and was the main cause of bacteriemia. The clinical manifestations of the infectious process were anemia, a trend to hypothermia (up to 35.5 °C), keukopenia, lympho- and thrombocytopenia, high levels of PCT and CRP.

Organ failure was manifested as renal and respiratory failure, and vascular dysfunction. Maximal SOFA was 16.
During follow-up, the patient showed some trends to gradual increase in intense leukopenia with significant increase in neutrophils (up to 95 %) and immature granulocytes (IG) (from 16.3 % to 27.9 %). It supposed intense inflammation and infection since abnormal left deviation is characterized by release of immature granulocytes in peripheral blood. It shows active response of bone marrow to infectious-inflammatory process [9, 10] (Fig. 1).

The analysis of results of extended inflammatory parameters showed that development of inflammatory response and sepsis was characterized by intense high activation of neutrophils. So, NEUT-RI exceeded the normal range by 61.3 % on average at the background of the reference level of NEUT-GI over the whole follow-up (Fig. 2 A, B, C). The bacterial infection was also confirmed by a single increase in AS-LYMP (to 0.7 %) on the second day.

The time course of laboratory values of hematological analysis with use of extended inflammation parameters (decreasing relative count of neutrophils along with increasing amount of IG, high activation of NEUT-RI, and decreasing amount of lymphocytes were accompanied by gradual increase in thrombocytopenia, and it did not exclude the presence of extracellular infection at the background of viral (hepatitis C, B20-B24) and registered bacterial infection (Klebsiella pneumoniae)).

The final diagnosis of tuberculosis colitis (caused by M. tuberculosis), with perforation and peritonitis, was confirmed by histological study of surgical materials with Ziehl-Nelsen staining for acid-resistant bacteria.


The presented clinical case is the example of possible use of monitoring of NEUT-RI, NEUT-GI, IG and AS-LYMP for estimation of intensity of systemic inflammation, infectious process generalization, and organ failure progression. The high increase in NEUT-RI and IG in the blood can determine the risk of multiple organ disorders at the background of bacterial and viral infection. 

Information on financing and conflict of interest

The study was conducted without sponsorship.
The authors declare the absence of any clear or potential conflicts of interests relating to publication of this article.


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