the utility of peripheral blood leucocyte ratios as biomarkers in infectious diseases CORD-Papers-2022-06-02 (Version 1)

Title: The utility of peripheral blood leucocyte ratios as biomarkers in infectious diseases: A systematic review and meta-analysis
Abstract: Summary Objectives To assess the utility of the neutrophil:lymphocyte (NLR) lymphocyte:monocyte (LMR) and platelet:lymphocyte ratios (PLR) as infection biomarkers. Methods PubMed/MEDLINE Embase and Cochrane databases were searched to identify eligible articles. Studies of diagnosis severity or outcome were included. PROSPERO systematic review registration CRD42017075032. Results Forty studies were included reporting on bacterial and viral infections malaria and critical illness due to sepsis. Ten studies reported an association of higher NLR with bacteraemia supported by meta-analysis of patient-level data (five studies n = 3320; AUC 0.72 p<0.0001) identifying a cut-off of >12.65. Two studies reported an association with lower LMR and diagnosis of influenza virus infection in patients with respiratory tract infection. Meta-analysis of patient-level data (n = 85; AUC 0.66 p = 0.01) identified a cut-off of 2.06. The directionality of associations between NLR and outcomes in heterogeneous cohorts of critically ill adults with sepsis varied. Potential clinical utility was also demonstrated in pneumonia (NLR) pertussis (NLR) urinary tract infection (NLR) diabetic foot infections (NLR) and Crimean Congo Haemorrhagic Fever (PLR). Longitudinal measurement of LMR during respiratory virus infection reflected symptoms and NLR during sepsis and bacteraemia predicted mortality. Conclusions Peripheral blood leucocyte ratios are useful infection biomarkers with the most evidence related to diagnosis of bacteraemia and influenza virus infection. In critical illness due to sepsis a signal towards an association with NLR and outcomes exists and NLR should be evaluated in future stratification models. Longitudinal measurement of ratios during infection could be informative. Overall these biomarkers warrant further recognition and study in infectious diseases.
Published: 2019-05-31
Journal: Journal of Infection
DOI: 10.1016/j.jinf.2019.02.006
DOI_URL: http://doi.org/10.1016/j.jinf.2019.02.006
Author Name: Russell Clark D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/russell_clark_d
Author Name: Parajuli Arun
Author link: https://covid19-data.nist.gov/pid/rest/local/author/parajuli_arun
Author Name: Gale Hugo J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/gale_hugo_j
Author Name: Bulteel Naomi S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bulteel_naomi_s
Author Name: Schuetz Philipp
Author link: https://covid19-data.nist.gov/pid/rest/local/author/schuetz_philipp
Author Name: de Jager Cornelis P C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/de_jager_cornelis_p_c
Author Name: Loonen Anne J M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/loonen_anne_j_m
Author Name: Merekoulias Georgios I
Author link: https://covid19-data.nist.gov/pid/rest/local/author/merekoulias_georgios_i
Author Name: Baillie J Kenneth
Author link: https://covid19-data.nist.gov/pid/rest/local/author/baillie_j_kenneth
sha: 35eb9c5003982927c0f06c47747604749e72a0e1
license: els-covid
license_url: https://www.elsevier.com/about/policies/open-access-licenses/elsevier-user-license
source_x: Elsevier; Medline; PMC
source_x_url: https://www.elsevier.com/https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 30802469
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/30802469
pmcid: PMC7173077
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173077
url: https://doi.org/10.1016/j.jinf.2019.02.006 https://www.ncbi.nlm.nih.gov/pubmed/30802469/ https://api.elsevier.com/content/article/pii/S0163445319300556 https://www.sciencedirect.com/science/article/pii/S0163445319300556
has_full_text: TRUE
Keywords Extracted from Text Content: patients NLR ≤2.06 CRD42017075032 Peripheral blood leucocyte monocyte platelet Crimean Congo neutrophil foot lymphocyte AHF human lymphocytes APACHE II human metapneumovirus P. falciparum gastrointestinal melaena VZV marrow Bordetella pertussis blood tonsillitis Patients CAP B-cells peripheral blood extract liver leucocytes H. pylori gastritis ribavirin Fournier's gangrene varicella zoster virus intra-abdominal platelet NS1 antigen angiotensin receptor blocker CNS organ lactate ≥10 HPIV-3 https://www.crd.york.ac.uk/prospero/display _ creatinine cancer serum sodium urease BP children WCC foot urine urogenital heart pleural fluid UTI facial nerve HBV coronaviruses Fournier Gangrene Severity Index gastric biopsy peripheral blood lymphocyte toxin A × 10 9 CCHF human parainfluenza virus 3 serum bicarbonate T-cells solid cancers 1-5 ACE neutrophils DNSI urinary tract Bell's Palsy patients Peripheral blood B Youden's J ulcerative colitis Gram lymphocyte adenosine deaminase patient monocyte AP stool Fournier's CRP AUC brain NLR minimal/no pulmonary serum potassium Neutrophil blood cultures radiologically-confirmed deep neck space RTI individuals HCV serum creatinine lung neutrophil Helicobacter pylori tissue intra-cerebral leucocyte creatinine ≥0.3 E. coli H. pylori intraabdominal vesico-ureteric reflux RSV parenchymal lesions procalcitonin Escherichia coli biopsyconfirmed C. difficile peripheral blood leucocyte ≥50 human rhinovirus haematocrit Intra-abdominal peripheral blood cell S. pneumoniae gastritis Peripheral blood leucocyte UC erythrocyte monocytes Fig. 2 APTT urea breath acute kidney cell corticosteroids PCRconfirmed DMSA VUR bowel ∼50 humans survivors ≤2.06 Streptococcus pneumoniae herpes simplex virus C-reactive submandibular abscess CRP Bell's palsy title/abstracts embolism CRD42017075032 malignancies RHS endotypes urea renal Supplementary Table 1 Crimean Congo monocyte lymphocyte
Extracted Text Content in Record: First 5000 Characters:Objectives: To assess the utility of the neutrophil:lymphocyte (NLR), lymphocyte:monocyte (LMR) and platelet:lymphocyte ratios (PLR) as infection biomarkers. Methods: PubMed/MEDLINE, Embase and Cochrane databases were searched to identify eligible articles. Studies of diagnosis, severity or outcome were included. PROSPERO systematic review registration CRD42017075032. Results: Forty studies were included, reporting on bacterial and viral infections, malaria, and critical illness due to sepsis. Ten studies reported an association of higher NLR with bacteraemia, supported by meta-analysis of patient-level data (five studies, n = 3320; AUC 0.72, p < 0.0 0 01) identifying a cut-off of > 12.65. Two studies reported an association with lower LMR and diagnosis of influenza virus infection in patients with respiratory tract infection. Meta-analysis of patient-level data ( n = 85; AUC 0.66, p = 0.01) identified a cut-off of ≤2.06. The directionality of associations between NLR and outcomes in heterogeneous cohorts of critically ill adults with sepsis varied. Potential clinical utility was also demonstrated in pneumonia (NLR), pertussis (NLR), urinary tract infection (NLR), diabetic foot infections (NLR) and Crimean Congo Haemorrhagic Fever (PLR). Longitudinal measurement of LMR during respiratory virus infection reflected symptoms and NLR during sepsis and bacteraemia predicted mortality. Conclusions: Peripheral blood leucocyte ratios are useful infection biomarkers, with the most evidence related to diagnosis of bacteraemia and influenza virus infection. In critical illness due to sepsis, a signal towards an association with NLR and outcomes exists, and NLR should be evaluated in future stratification models. Longitudinal measurement of ratios during infection could be informative. Overall, these biomarkers warrant further recognition and study in infectious diseases. Infection biomarkers can be used as adjuncts to inform differential diagnosis (e.g. distinguishing bacterial from viral infection), as prognostic markers to stratify patients into sub-groups and endotypes, 1 and to monitor the response to antimicrobial therapy to guide duration. Canonical biomarkers include the total white cell count (WCC) and C-reactive protein (CRP). For over ten years there has been increasing interest in the use of procalcitonin as a biomarker for discrimination of bacterial from viral infection, and to assess response to antimicrobial therapy. Meta-analyses of clinical trials indicate that procalcitonin results can reduce antimicrobial usage and improve outcomes in respiratory tract infections with similar findings in critically ill patients with presumed bacterial sepsis in the intensive care unit (ICU). 2 -4 However, procalcitonin measurement is currently expensive and is not universally available. In contrast, the full blood count is a cheap, fast and ubiquitous laboratory investigation. Automated counters provide a differential WCC, enumerating circulating leucocytes including neutrophils, lymphocytes and monocytes, but these parameters are usually interpreted in isolation. During sepsis, apoptosis of B-cells and T-cells causes lymphocyte depletion, and peripheral blood lymphopenia is associated with mortality and nosocomial infection. 5 -9 Lymphopenia is also associated with the presence of bacteraemia and can be a better predictor than neutrophil and total WCC. 10 Peripheral blood neutrophilia during sepsis, involving demargination and enhanced marrow recruitment, combined with systemic neutrophil activation, can contribute to inflammatory tissue damage and organ failure. 11 It is therefore biologically plausible that the neutrophil:lymphocyte ratio (NLR) and other leucocyte ratios could be informative biomarkers in patients with infection, reflecting underlying immune (dys)function, at least in peripheral blood. The ready availability and low cost of such indices would make them particularly helpful in low-and middle-income countries. In these settings, patient stratification to identify those requiring higher levels of care and discrimination of bacterial/non-bacterial infection to aid antimicrobial stewardship would be especially valuable. This paper systematically reviews the literature evaluating the diagnostic and prognostic utility of the NLR and other peripheral blood leucocyte ratios (lymphocyte:monocyte and platelet:lymphocyte ratios; LMR and PLR respectively) in patients with infections. The PRISMA Statement has been followed in the conduct and reporting of this systematic review. 12 The protocol was registered with the PROSPERO international prospective register of systematic reviews (CRD42017075032, available at https://www.crd.york.ac.uk/prospero/display _ record.php? RecordID=75032 ). Briefly, the following key words were used to search the PubMed/MEDLINE, Embase and Cochrane databases on 25th June 2017: monocyte, lymphocyte, neutrophil, platelet, ratio, infection, sepsis, bacteraemia. We included observatio
Keywords Extracted from PMC Text: UC Patients acute kidney B-cells Neutrophil UTI41 corticosteroids p<0.05 neutrophils CRP AUC tonsillitis urea breath erythrocyte p<0.001).53 × creatinine ≥0.3 malignancies serum potassium gastric biopsy facial nerve haematocrit children brain extract herpes simplex virus minimal/no HBV human VZV renal embolism ≥50 urea Bordetella pertussis adenosine deaminase cancer human rhinovirus organ pulmonary –20 blood cultures serum creatinine RSV APACHE II ≥10 melaena p<0.01).44 Fournier Gangrene Severity Index liver parenchymal lesions Fournier's gangrene.47 Fournier's CRP H. pylori monocyte mortality.20 Patients ≤2.06 title/abstracts toxin A UTI House–Brackmann blood Intra-abdominal intra-cerebral Supplementary Table 1 WCC48 urease H1N1 influenza urinary tract heart Fournier's WCC lactate lymphocyte bowel p<0.01 angiotensin receptor blocker AP serum bicarbonate un-selected ICU patients.19 survivors human parainfluenza virus 3 1.1–2.0 peripheral blood cell C. difficile P. falciparum creatinine HCV platelet intra-abdominal Bell's Palsy coronaviruses procalcitonin H. pylori gastritis review.12 RTI urogenital vasopressor-requirement controls.33 RHS ICU22 low- p<0.001).42 endotypes,1 recovery32 NS1 antigen patients Thailand.55 P. Helicobacter pylori DMSA RSV.35 LMR <2 CRD42017075032 HPIV-3 " radiologically-confirmed deep neck space outcomes.50 peripheral blood lymphocyte BP VUR B Escherichia coli CAP.21 leucocytes foot lung human metapneumovirus gastrointestinal patient somnolence29 vesico-ureteric reflux E. coli CCHF peripheral blood CNS neutrophil leucocyte lymphocytes ribavirin AHF solid cancers p<0.001).54 varicella zoster virus ACE cell humans pleural fluid CAP serum sodium NLR T-cells DNSI Bell's palsy APTT marrow ulcerative colitis ∼50 S. pneumoniae tissue Gram individuals Youden's J Streptococcus pneumoniae sub-mandibular abscess C-reactive stool peripheral blood leucocyte pertussis40 urine monocytes CAP,13 gastritis
Extracted PMC Text Content in Record: First 5000 Characters:Infection biomarkers can be used as adjuncts to inform differential diagnosis (e.g. distinguishing bacterial from viral infection), as prognostic markers to stratify patients into sub-groups and endotypes,1 and to monitor the response to antimicrobial therapy to guide duration. Canonical biomarkers include the total white cell count (WCC) and C-reactive protein (CRP). For over ten years there has been increasing interest in the use of procalcitonin as a biomarker for discrimination of bacterial from viral infection, and to assess response to antimicrobial therapy. Meta-analyses of clinical trials indicate that procalcitonin results can reduce antimicrobial usage and improve outcomes in respiratory tract infections with similar findings in critically ill patients with presumed bacterial sepsis in the intensive care unit (ICU).2, 3, 4 However, procalcitonin measurement is currently expensive and is not universally available. In contrast, the full blood count is a cheap, fast and ubiquitous laboratory investigation. Automated counters provide a differential WCC, enumerating circulating leucocytes including neutrophils, lymphocytes and monocytes, but these parameters are usually interpreted in isolation. During sepsis, apoptosis of B-cells and T-cells causes lymphocyte depletion, and peripheral blood lymphopenia is associated with mortality and nosocomial infection.5, 6, 7, 8, 9 Lymphopenia is also associated with the presence of bacteraemia and can be a better predictor than neutrophil and total WCC.10 Peripheral blood neutrophilia during sepsis, involving demargination and enhanced marrow recruitment, combined with systemic neutrophil activation, can contribute to inflammatory tissue damage and organ failure.11 It is therefore biologically plausible that the neutrophil:lymphocyte ratio (NLR) and other leucocyte ratios could be informative biomarkers in patients with infection, reflecting underlying immune (dys)function, at least in peripheral blood. The ready availability and low cost of such indices would make them particularly helpful in low- and middle-income countries. In these settings, patient stratification to identify those requiring higher levels of care and discrimination of bacterial/non-bacterial infection to aid antimicrobial stewardship would be especially valuable. This paper systematically reviews the literature evaluating the diagnostic and prognostic utility of the NLR and other peripheral blood leucocyte ratios (lymphocyte:monocyte and platelet:lymphocyte ratios; LMR and PLR respectively) in patients with infections. The PRISMA Statement has been followed in the conduct and reporting of this systematic review.12 The protocol was registered with the PROSPERO international prospective register of systematic reviews (CRD42017075032, available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=75032). Briefly, the following key words were used to search the PubMed/MEDLINE, Embase and Cochrane databases on 25th June 2017: monocyte, lymphocyte, neutrophil, platelet, ratio, infection, sepsis, bacteraemia. We included observational studies and clinical trials where the ratios were measured in peripheral blood from humans of any age with viral, bacterial or parasitic infections. Case reports, conference abstracts and review articles were excluded. We accepted both clinical and microbiological diagnoses of infection, which had to be distinguished from evidence of systemic inflammation alone (e.g. elevated CRP or presence of systemic inflammatory response syndrome (SIRS) alone was insufficient). The type of infection had to be reported (syndrome, organ system involved or organism) and the ratio had to be quantified numerically. We included studies reporting the following data: diagnosis of infection (compared to healthy controls, non-infectious diagnosis or alternative infection); severity of infection (any measure) and outcome of infection (any measure). Due to possible confounding effects on the ratios, we excluded studies conducted exclusively in patients with active cancer, chronic liver disease (including HBV and HCV infection), HIV or immunosuppression. We excluded studies using non-routine laboratory techniques to quantify peripheral blood cell counts or diagnose infection. Specifically, investigative use of PCR for bacterial diagnosis was excluded. Individuals of any age were included and results presented refer to adults unless otherwise stated. All title/abstracts returned from the database search (Fig. 1 ) were reviewed by two authors (CDR and HJG) independently to assess the need for full text review. Full text articles were reviewed independently by the same two authors to assess eligibility. Reasons for exclusion were recorded. A data extraction proforma was constructed, iteratively modified, then used to extract data from included studies by two authors (CDR and AP). Risk of bias in patient selection and outcomes reporting was assessed (Supplementary Fig. 1). Synthesis
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