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Infection/ Inflammation HAEMATOLOGY | OCTOBER 2017* WHITE PAPER INFECTION/ INFLAMMATION Novel haematological parameters for rapidly monitoring the immune system response Patients with inflammatory disease are common on hospital The clinical value of haematological inflammation wards. When patients are suspected of having an inflam- parameters in managing inflammatory diseases mation, it is important to rapidly differentiate between var- Sysmex’s XN-Series analysers offer a set of haematological ious possible conditions. You need to distinguish between inflammation parameters that lets one quantitatively inflammations caused by infections and those that are not, assess the activation status of neutrophils (NEUT-RI, and determine the responsible pathogen and the patient’s NEUT-GI), immature granulocytes (IG) and activated lym- immune response status in case of an infection. Next, treat- phocytes (RE-LYMP, AS-LYMP). ing physicians need to determine the appropriate therapy for their patients and avoid the overuse of antibiotics. The innate immune system is an initial, non-specific line of defence against pathogens. Its main function is to identify Correctly diagnosing suspected inflammations and infec- and remove foreign substances by specialised white blood tions by clinical examination, biochemical markers and cells (WBC) and further activate the adaptive immune sys- microbiological blood cultures is costly and time-consuming. tem through a process of presenting the pathogens’ antigen. A fast initial indication would be beneficial since this can Typically, activated neutrophils (increased NEUT-RI, in - point out the appropriate diagnostic tests, avoid unneces- creased NEUT-GI), immature granulocytes (IG), reactive sary follow-up tests, and help start or modify treatment lymphocytes (RE-LYMP) and T cell-independent plasma faster. Haematological inflammation parameters obtained cells (AS-LYMP) are found in this phase of infection. Gen- from a routine blood count on Sysmex’s XN-Series analysers erally, the change in value of these parameters depends on can provide quantitative information about the inflamma- the nature of the inflammatory stimulus, severity and stage tory reaction of the patient’s immune system. of the infection. * Revision of the original article published in March 2017 1 | 5 Sysmex white paper Infection/inflammation | October 2017 The innate immune response triggers the adaptive immune Table 1 summarises the haematological inflammation response, which can be divided into an early cell-mediated parameters with their respective units. The parameters let immune response and a later humoral immune response. one quantify: The cell-mediated response is characterised by an increase in activated T lymphocytes and NK-cells. The humoral n activated lymphocytes, response is typically characterised by activated B lympho- n immature granulocytes and cytes (plasma cells). Activated B lymphocytes can be quan- n the activation status of neutrophils. tified with the parameter AS-LYMP (antibody-synthesizing lymphocytes). All activated lymphocytes (including plasma Several recent studies have shown that these parameters cells) are quantified with the parameter RE-LYMP (total are valuable for detecting and monitoring infections and reactive lymphocytes). inflammations [1 – 8]. The structural neutrophil parameters NEUT-RI and NEUT-GI obtained from the XN-Series could The combination of the RE-LYMP and AS-LYMP parameters predict the appearance of later-stage infection markers provides additional information about the cellular activation such as the presence of immature granulocytes, suggesting of the innate and adaptive immune response. The increased that these neutrophil parameters can be used to detect fluorescence values of these cell populations recorded dur- early-stage bacterial infections [1]. Furthermore, an ongoing ing analysis indicate both increased cellular activity and study (manuscript in preparation) found that both RE-LYMP changes in the membrane composition, and so indicate and AS-LYMP counts were mainly increased in viral infec- whether there is a cell-mediated or humoral immune re - tions [2]. RE-LYMP counts were only increased in some sponse to pathogens. This supports differentiation between bacterial infections and AS-LYMP counts were only mildly viral and bacterial infections, or between acute and subsiding increased in bacterial infections (unspecific T-independent infections, or whether there is an inflammatory condition plasma cells). Another study on children younger than five without an infection. years found that NEUT-RI was increased in patients with Table 1 A summary of haematological inflammation parameters with their respective immunological interpretation, units and reference intervals. Cell populations and/ Description Immunological Parameter Unit Reference or their characteristics interpretation interval Total reactive This includes activated B and Increased in innate and RE-LYMP# Cells/L 0 – 0.5 x 109/L lymphocytes T lymphocytes recognised adaptive cell-mediated by an increased fluorescence immune response RE-LYMP%i % 0 – 5% intensity compared to that of common lymphocytes. Antibody-synthesizing These are exclusively activated Increased in innate and AS-LYMP# Cells/L 0 Cells/L lymphocytesii B lymphocytes recognised by adaptive humoral the markedly increased fluo - immune response AS-LYMP%i % 0% rescence intensity compared to that of common lymphocytes. Granularity of A measure of the cytoplasmic Increased in early innate NEUT-GI: Scatter 142.8 – 159.3 neutrophils granularity of the neutrophil immune response Neutrophil Granularity Intensity (SI) SI [1] population, representing their Intensity response to inflammatory processes. Reactivity of A measure of the fluorescence Increased in early innate NEUT-RI: Fluorescence 39.8 – 51.0 neutrophils intensity of the neutrophil immune response Neutrophil Reactivity Intensity (FI) FI [1] population, representing their Intensity metabolic activity. Immature granulocytes The total of metamyelocytes, Indicates the severity IG# Cells/L 0 – 0.06 x 109/L myelocytes and promyelocytes of the early innate are counted as a single pop - immune response IG%i % 0 – 0.6% [9] u lation, separately from the common neutrophils. i As a percentage of all WBC ii When antibody-synthesizing lymphocytes (AS-LYMP) are present, they are also included in the total reactive lymphocytes (RE-LYMP). 2 | 5 Sysmex white paper Infection/inflammation | October 2017 bacterial infections compared to controls [6], whereas only Case study: Early innate immune response RE-LYMP and AS-LYMP counts were significantly higher in to intracellular bacteria patients with viral infections than in patients with bacterial infections. Moreover, in this study the AS-LYMP parameter Case history provided the same discrimination power between viral A 23-year old man with an intermittent fever visited his and bacterial infections as procalcitonin. Stiel et al. (2016) physician three days after the initial onset of fever. The showed that the NEUT-RI parameter has a high sensitivity man reported the following symptoms: shortness of breath, and specificity for diagnosing disseminated intravascular productive cough, abdominal pain, diarrhoea, night sweats coagulation in patients with septic shock [7]. Oehadian et and malaise. Considering the man’s symptoms, the physi- al. (2015) studied the differential diagnostic possibilities of cian suspected pneumonia and ordered a complete blood atypical lymphocyte research parameters (RE-LYMP and count with white blood cell differential analysis to investi- AS-LYMP are derived from them) and found that they can gate the possible cause of infection. help in the differentiation of dengue from leptospirosis and enteric fever [8]. Laboratory results Table 2 An overview of the laboratory results obtained from the Sysmex XN-Series haematology analyser. WBC parameters Data RBC parameters Data PLT parameters Data WBC (109/L) 2.98 RBC (1012/L) 3.96 PLT-I (109/L) 244 NEUT# (109/L) 2.50* HGB (g/L) 102 PLT-F (109/L) 231 LYMPH# (109/L) 0.29* HCT (L/L) 0.312 PDW (fL) 11.4 MONO# (109/L) 0.17* MCV (fL) 78.8 MPV (fL) 11.2 EO# (109/L) 0.01* MCH (pg) 25.8 P-LCR (%) 30.7 BASO# (109/L) 0.01 MCHC (g/L) 327 PCT (L/L) 0.0027 IG# (109/L) 0.02* RDW-SD (fL) 42.2 IPF# (109/L) 4.2 RE-LYMP# (109/L) 0.03 RDW-CV (%) 14.6 IPF (%) 1.8 AS-LYMP# (109/L) 0.02 NRBC# (109/L) 0.00 NEUT% 84.0* NRBC% 0.0 WBC Flag(s) LYMPH% 9.7* MicroR (%) 8.3 Lymphopenia MONO% 5.7* MacroR (%) 3.3 Left Shift? EO% 0.3* HYPO-H (%) 1.6 e Atypical Lympho? BASO% 0.3 HYPER-He (%) 0.3 * result marked as unreliable § research parameter IG% 0.7* RET# (109/L) 22.6 RE-LYMP% 1.0 RET% 0.57 AS-LYMP% 0.6 IRF (%) 5.1 NEUT-GI (SI) 145.5 RET-He (pg) 29.8 NEUT-RI (FI) 60.7 Delta-He (pg) 3.8 FRC# (1012/L)§ 0.0851 FRC%§ 2.15 3 | 5 Sysmex white paper Infection/inflammation | October 2017 Case interpretation The XN analysis results of the young man with fever and charides. These can be released from the cell walls of certain clinical focus on the lungs revealed a leucopenia with a bacteria, and bind to the B cell receptor. relative increase in neutrophils (NEUT/LYMPH = 8.5). The neutrophils showed an increased activation – The overall results exclude an extracellular bacterial infection, NEUT-RI = 60.7 FI – and combined with the low concentra- non-pathogenic inflammation and viral infection. The final tions of AS-LYMP (0.6 %), the results indicate an early diagnosis of suspected tuberculosis was made by positive innate immune response to intracellular bacteria. chest X-ray.
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