Periodontitis and circulating blood cell profiles: a systematic review and meta-analysis

•Periodontitis is associated with hematologic changes (SORT A recommendation).•Higher leukocyte, neutrophil, and erythrocyte sedimentation rates are the most common findings.•Periodontitis treatment was a decrease in leukocyte levels. Periodontitis chronic inflammatory disease local systemic implications. Evidence suggests consistent periodontitis. Our aim to critically appraise available evidence on hemogram, leukogram, thrombogram alterations otherwise healthy patients suffering from periodontitis when compared controls. For this systematic review (SR), we searched MEDLINE, Web of Science, EMBASE, Cochrane Library (CENTRAL) for studies published up June 2020. Both observational interventional baseline standard levels were included. Outcomes interest values impact these outcomes. Upon risk bias assessment, data extraction both qualitative quantitative (standardized mean differences) analyses performed. Random-effects meta-analyses performed provide pooled estimates. The Preferred Reporting Items Systematic Reviews Meta-analyses (PRISMA) guidelines followed (PROSPERO Reg. No. CRD42020164531). total 45 studies, eight intervention 37 case–control identified after final search 3,012 titles. Following quality 43 articles deemed have low bias, two moderate risk. confirmed that white red cell lineages. Severe greater blood counts (mean difference [MD] = 0.53, 95% confidence interval [CI]: 0.26–0.79) larger number neutrophils (MD 7.16%, CI: 5.96–8.37) lower platelet volume 0.30 fL, 0.49 ?0.10) participants. Nonsurgical periodontal (WBC) 0.28 109/L, ?0.47 ?0.08) (Strength Recommendation Taxonomy [SORT] recommendation). Higher WBC levels, higher neutrophil rate, volumes count findings. association between could be causal nature. Further assessment determine whether causes circulating cells identify molecular mechanisms underlying associations warranted. Inflammation key host immune response triggered by variety factors including pathogens, damaged cells, toxic substances [1Chen L Deng H Cui et al.Responses inflammation-associated diseases organs.Oncotarget. 2018; 9: 7204-7218Crossref PubMed Scopus (1347) Google Scholar]. Cells humoral initiated new stimulus identified. Monitoring body inflammation has over years been possible thanks cellular biomarkers [2Watson J De Salis I Salisbury C Hamilton W ‘I'm fishing really’—Inflammatory marker testing primary care: study.Br Gen Pract. 2016; 66: e200-e206Crossref (22) Scholar], among which rate (ESR) considered reliable affordable surrogates. When acute resolves ensues, important implications can occur [3Furman D Campisi Verdin E al.Chronic etiology across life span.Nat Med. 2019; 25: 1822-1832Crossref (871) Scholar,4Franceschi Garagnani P Parini Giuliani Santoro Inflammaging: immune–metabolic viewpoint age-related diseases.Nat Rev Endocrinol. 14: 576-590Crossref (838) It recognized all noncommunicable diseases, diabetes cardiovascular basis. An understanding triggering urgently needed as it affect onset progression well their complications. major multifactorial caused dysbiotic dental biofilm [5Roberts FA Darveau RP Microbial protection virulence tissue function polymicrobial communities: symbiosis dysbiosis.Periodontol 2000. 2015; 69: 18-27Crossref (59) Scholar] characterized progressive destruction periodontium [6Papapanou PN Sanz M Buduneli N al.Periodontitis: consensus report Workgroup 2 2017 World Workshop Classification Periodontal Peri-Implant Diseases Conditions.J Clin Periodontol. 45: S162-S170Crossref (404) one leading tooth loss worldwide [7Petersen PE Ogawa global burden disease: towards integration prevention control.Periodontol 2012; 60: 15-39Crossref (426) Scholar,8Kassebaum NJ Bernabé Dahiya Bhandari B Murray CJL Marcenes Global severe 1990–2010: meta-regression.J Dent Res. 2014; 93: 1045-1053Crossref (1003) an exaggerated gingival distinctive infiltrate plethora pro-inflammatory mediators not only confined tissues but also involved [9Ebersole JL Dawson Emecen-Huja al.The war: microbes immunity.Periodontol 2017; 75: 52-115Crossref (84) Scholar,10Ebersole Graves CL Gonzalez OA al.Aging, inflammation, immunity disease.Periodontol 72: 54-75Crossref (94) Systemic repercussions result comprehensively explored revised [11Jepsen S Caton JG Albandar JM al.Periodontal manifestations developmental acquired conditions: 3 S219-S229Crossref (126) Scholar,12Chan Pasternak GM West MJ place examination referral general medicine.Periodontol 74: 194-199Crossref (10) Hence reasonable hypothesize such might observed using recent linked lineage parameters [13França LF de da Silva FRP di Lenardo al.Comparative analysis patients: results obtained meta-analysis.Arch Oral Biol. 97: 144-149Crossref confirming preliminary altered iron ferritin controls [14Chakraborty Tewari Sharma RK Narula SC Effect non-surgical therapy serum levels: study.J 85: 688-696Crossref (18) Scholar, 15Latha Thirugnanamsambandan Arun R Masthan KMK Malathi Rajesh Serum level patients.J Pharm Bioallied Sci. 7: S184-S189PubMed 16Guo LN Yang YZ Feng salivary hepcidin type mellitus.BMC Health. 18: 1-9Crossref 17Leite FRM Nascimento GG Scheutz F López smoking periodontitis: meta-regression.Am Prev 54: 831-841Abstract Full Text PDF (147) 18Nibali Darbar U Rakmanee T Donos Anemia clinical studies.J 90: 1252-1259Crossref (13) Similarly, appear present [18Nibali 19Temelli Yetkin Ay Z Aksoy al.Platelet indices distribution width) correlations inflamed surface area coronary artery pilot 89: 1203-1212Crossref 20Zhan Y Lu Meng Wang X Sun Hou role platelets responses generalized aggressive periodontitis.J 44: 150-157Crossref (14) 21Anand PS Sagar DK Mishra Narang Kamath KP Anil Total differential peripheral generalised periodontitis.Oral Heal Dent. 443-450PubMed undertake critical appraisal protocol registered PROSPERO (ID: CRD42020164531) according Handbook Interventions [22Higgins JPT Green version 5.1.0 (updated March 2011). Collaboration, 2011Google hereby reported PRISMA (Appendix S1, see Supplementary Data, online only, at www.exphem.org) [23Liberati Altman DG Tetzlaff statement reporting reviews evaluate health care interventions: explanation elaboration.PLoS 2009; 6e1000100Crossref (9479) following PI(E)CO questions adopted:1.“Do controls?”2.“Do nonsurgical (NSPT)?” respective statements:1.Otherwise (Patients, P); (Intervention/Exposure, E); no (Comparison, C); (Outcome, O) (detailed under Data Extraction Process Items).2.Otherwise (patients, (intervention/exposure, (comparison, posttreatment Items). Studies eligible inclusion based criteria:1.Observational (cross-sectional case–control) individuals without periodontitis.2.Interventional (randomized controlled trials [RCTs] [CCTs]) or periodontitis.3.Only clear case definition.4.Only (hemogram, thrombogram).5.Studies other comorbidities. Interventional may included address 1 if they comparing Only 2. Detailed strategies conducted databases PubMed, Central Register Controlled Trials (CENTRAL), Science until syntax used: (periodontitis OR gingivitis (periodontal [MeSH])) AND (Hematologic Tests [MeSH] Blood Cell Count Erythrocyte Leukocyte Platelet Coagulation International Normalized Ratio Partial Thromboplastin Time Thrombelastography Prothrombin Thrombin Whole Grouping Crossmatching Sedimentation Bone Marrow Examination Aggregation Indices Fibrin Clot Lysis FIGLU Test Hematocrit Hemoglobinometry Osmotic Fragility Function Bleeding Retraction Mean Volume Schilling ferritin). No restrictions year publication language applied. Gray literature through appropriate registers. Four periodontology journals hand-searched (Journal Clinical Periodontology, Journal Periodontology 2000, Research) any additional articles. Authors contacted necessary and/or clarification reports. Study selection assessed independently investigators (JB VM), who titles abstracts retrieved studies. Interexaminer reliability full-text computed (? statistics), disagreements resolved discussion third author (SBH). Electronic study characteristics, first author's name, design, year, country, exclusion criteria, definition, age, participants, gender, habits, values. All extracted reviewers (VM JB). With respect consistency, expressed units: WBC, lymphocyte, monocyte, eosinophil, 109/L; hematocrit, widths (RDWs) percentages; (RBC) 109/?L; corpuscular (MCV) (MPV) fL; hemoglobin concentration (MCHC) g/dL; (MCH) pg; ESR mm/h; ?g/dL; ng/mL. exposure, found multiple definitions lack consistency hampered interpretation data. subgrouped confident nonconfident definition previously criteria [24Muñoz Aguilera Suvan Buti al.Periodontitis hypertension: meta-analysis.Cardiovasc 2020; 116: 28-39Crossref (98) established (European Federation American Academy Periodontology) definitions. Confident follows: (at least 30% sites attachment [CAL] ?4 mm) [25Armitage G Development classification system conditions.Ann 1999; 4: 1-6Crossref (3439) Scholar]; different teeth CAL 6 mm site probing pocket depth (PPD) 4 (CDC/AAP definition) [26Eke PI Page RC Wei Thornton-Evans Genco RJ Update population-based surveillance 83: 1449-1454Crossref (645) interdental detectable more nonadjacent teeth, buccal oral ?3 pocketing >3 [27Tonetti MS Greenwell Kornman KS Staging grading FRAMEWORK proposal definition.J S149-S161Crossref (405) five ?6 mm. definitions, considered: community index need (CPITN) score 3/4 quadrant; “alveolar bone loss” measurements PPD/CAL; unclear diagnostic Newcastle–Ottawa (NOS) Scale cohort used calibrated reviewer appraising cross-sectional calibration purposes, random sample 10 re-assessed days later (agreement 0.96). seven nine stars (RoB), six RoB, fewer than high RoB. Any dispute second (JB). ROBINS-I tool (Risk Bias Non-randomized studies—interventions) [28Sterne JA Hernán MA Reeves BC al.ROBINS-I: assessing non-randomised interventions.BMJ. 355: 4-10Google Continuous means deviations (SD) analyzed (MD) (CI). units standardized converted appropriately mentioned earlier. If median interquartile range selected SD calculated formula [29Hozo SP Djulbegovic Hozo Estimating variance median, range, size sample.BMC Med Res Methodol. 2005; 5: 1-10Crossref In analysis, irrespective individual definition. Subgroup meta-analysis estimates DerSimonian–Laird random-effects strategy [30Schwarzer Carpenter JR Rücker Meta-analysis R. Springer, 2015Crossref We Version 3.4.1 calculate model described [31Schwarzer Meta: Package meta-analysis.R News. 2007; 40-45Google forest plots meta package I2 Cochrane's Q statistic inspect statistical heterogeneity (p < 0.1), ?2 test overall homogeneity tests two-tailed, ? set 0.05. Further, provided weight percentage given each study. ?10 Overall CIs. sensitivity explore influence MD approach (which allows data) versus employing ratio (RoM) (permits direct cases attenuates eventual within estimates) [32Friedrich JO Adhikari NKJ Beyene method alternative differences analyzing continuous outcome variables meta-analysis: simulation study.BMC 2008; 8: 32Crossref (171) 33Friedrich geometric analyze outcomes comparison arithmetic empiric simulation.Stat 31: 1857-1886Crossref (26) 34Higgins White Anzures-Cabrera skewed data: combining log-transformed rawscales.Stat 28: 6072-6092Crossref (257) 35Friedrich methods.J Epidemiol. 2011; 64: 556-564Abstract (109) Then, priori defined RoB examined estimates, meta-regression toward smokers (through periodontitis/without periodontitis) sex (men-to-women ratio). separating nonsevere compare and, hence, infer severity. employed Strength (SORT) strength [36Newman MG Weyant Hujoel JEBDP improves adopts Guidelines reviews.J Evid Based 147-150Crossref (33) 6,107 possibly relevant publications. After removal duplicates, 3,197 manuscripts 2,860 excluded abstracts. Of 158 remaining full text search/eligibility, another 114 S2, Data). synthesis (Figure 1). Good interexaminer screening recorded 0.915, 0.929–0.943). Scholar,18Nibali Scholar,37Zhan activation platelet–leukocyte interaction Leukoc 100: 1155-1166Crossref 38Zimmermann Hagenfeld Diercke K al.Pocket bleeding dental, lifestyle, socioeconomic variables: cross-sectional, multicenter feasibility German National Cohort.BMC 15: (31) 39Sharma Astekar Metgud Soni Verma Patel C-reactive protein, lipid metabolism link disease.Biotech Histochem. 577-582Crossref (9) 40Kumar BP Khaitan Ramaswamy Sreenivasulu Uday Velugubantla RG Association count—a control Exp 6: 214-217Crossref 41Pereira LC JCR Rêgo JMC al.Apolipoprotein E, atherosclerosis: review.Arch 98: 204-212Crossref 42Anumolu VSH Srikanth Paidi Evaluation relation anemia estimation parameters: Indian Soc 20: 265-272PubMed 43Gani Mallineni SK Ambalavanan Ramakrishnan Deepalakshmi Emmadi Estimation interleukin-6, count, smear South population.West J. 61: 826-831PubMed 44Gaddale Mudda Karthikeyan Desai SR Shinde Deshpande Changes components Investig 59-64Crossref 45Anand Ashok reduced levels.J 49: 719-728Crossref 46Pej?i? Kesi? Peši? Mirkovi? Stojanovi? stages periodontitis.Acta Croat. 50: 159-167PubMed 47Monteiro AM Jardini MAN Alves al.Cardiovascular 80: 378-388Crossref (80) 48Papapanagiotou Nicu EA Bizzarro activation.Atherosclerosis. 202: 605-611Abstract (67) 49Shi Xu al.Systemic markers 79: 2340-2346Crossref (42) 50Bizzarro Van Der Veld