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176 | wileyonlinelibrary.com/journal/jcpe J Clin Periodontol. 2020;47:176–198.© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Received: 12 August 2019 | Revised: 7 December 2019 | Accepted: 14 December 2019 DOI: 10.1111/jcpe.13236 S Y S T E M A T I C R E V I E W Adjunctive laser or antimicrobial photodynamic therapy to non- surgical mechanical instrumentation in patients with untreated periodontitis: A systematic review and meta-analysis Giovanni E. Salvi1 | Alexandra Stähli1 | Julia C. Schmidt2 | Christoph A. Ramseier1 | Anton Sculean1 | Clemens Walter2 Salvi and Stähli contributed equally to the manuscript. 1Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland 2Department of Periodontology, Endodontology and Cariology, University Center for Dental Medicine (UZB), University of Basel, Basel, Switzerland Correspondence Giovanni E. Salvi, Department of Periodontology, School of Dental Medicine, University of Bern, Freiburgstrasse 7, CH- 3010 Bern, Switzerland. Email: giovanni.salvi@zmk.unibe.ch Abstract Aim: To compare the adjunctive effects of lasers or antimicrobial photodynamic therapy (aPDT) to non-surgical mechanical instrumentation alone in untreated peri- odontitis patients. Materials and Methods: Two focused questions were addressed using the Population, Intervention, Comparison and Outcome criteria as follows: in patients with untreated periodontitis, (a) does laser application provide adjunctive effects on probing pocket depth (PPD) changes compared with non-surgical instrumentation alone? and (b) does application of aPDT provide adjunctive effects on PPD changes compared with non-surgical instrumentation alone? Both randomized controlled clinical trials (RCTs) and controlled clinical trials (CCTs) were included. Results of the meta-analysis are expressed as weighted mean differences (WMD) and reported according to the PRISMA guidelines. Results: Out of 1,202 records, 10 articles for adjunctive laser and 8 for adjunctive aPDT were included. With respect to PPD changes, 1 meta-analysis including 2 articles (total n = 42; split-mouth design) failed to identify a statistically significant difference (WMD = 0.35 mm; 95%CI: −0.04/0.73; p = .08) in favour of adjunctive aPDT (wavelength range 650–700 nm). In terms of adjunctive laser application, a high variability of clinical outcomes at 6 months was noted. Two articles included patient-reported outcomes and 10 reported on the presence/absence of harms/ad- verse effects. Conclusions: Available evidence on adjunctive therapy with lasers and aPDT is lim- ited by (a) the low number of controlled studies and (b) the heterogeneity of study designs. Patient-reported benefits remain to be demonstrated. K E Y W O R D S antimicrobial photodynamic therapy, laser, non-surgical periodontal treatment, periodontitis, systematic review mailto: https://orcid.org/0000-0001-5523-3192 https://orcid.org/0000-0002-5631-3300 https://orcid.org/0000-0003-1515-8831 https://orcid.org/0000-0002-5110-2539 https://orcid.org/0000-0003-2836-5477 https://orcid.org/0000-0002-9967-1570 mailto:giovanni.salvi@zmk.unibe.ch http://crossmark.crossref.org/dialog/?doi=10.1111%2Fjcpe.13236&domain=pdf&date_stamp=2020-07-27 | 177SALVI et AL. 1 | INTRODUC TION Non-surgical subgingival mechanical instrumentation aims at elimi- nating the aetiologic factors on the root surface and is considered the standard of care of cause-related therapy in patients with untreated periodontitis (Badersten, Nilveus, & Egelberg, 1984a, 1984b). Subgingival mechanical instrumentation may be performed by either hand and/or power-driven instruments and results in im- proved clinical outcomes such as reduced bleeding on probing (BoP) and decreased probing pocket depth (PPD) (Badersten, Nilveus, & Egelberg, 1984a, 1984b). However, in sites with impaired access such as deep periodontal pockets and furcation areas, residual subgingival calculus and bacterial deposits may remain on the root surface (Caffesse, Sweeney, & Smith, 1986; Oda & Ishikawa, 1989). Therefore, the adjunctive use of lasers and antimicrobial photody- namic therapy (aPDT) has been increasingly investigated as adjunc- tive approaches to non-surgical mechanical instrumentation alone (Mizutani et al., 2016; Schwarz, Aoki, Becker, & Sculean, 2008; Sgolastra, Severino, Gatto, & Monaco, 2013; Sgolastra, Severino, Petrucci, Gatto, & Monaco, 2014). The most common laser applications for periodontal therapy in- clude diode, carbon dioxide (CO2), neodymium-doped: yttrium alu- minium garnet (Nd:YAG), erbium-doped: yttrium aluminium garnet (Er:YAG) and erbium, chromium-doped: yttrium, scandium, gallium, garnet (Er,Cr:YSGG) lasers with wavelengths ranging from 635 to 10,600 nm. All of these wavelengths can be used adjunctively to me- chanical non-surgical instrumentation to debride connective tissue and epithelium within periodontal pockets, inactivate bacteria and ablate subgingival calculus (Eberhard et al., 2003; Jepsen, Deschner, Braun, Schwarz, & Eberhard, 2011). In fact, the Er:YAG laser with a wavelength of 2,940 nm displays high absorption in water and hy- droxide ions thereby providing the possibility to remove subgingival calculus without causing thermal side effects to adjacent tissue (Aoki, Ando, Watanabe, & Ishikawa, 1994; Eberhard et al., 2003; Schwarz et al., 2008). However, to be recommended for clinical applications, adjunctive use of any type of lasers to non-surgical mechanical in- strumentation must yield predictable and safe outcomes superior to those obtained with mechanical instrumentation alone (Cobb, 2017). An additional application of laser photons known as aPDT aims at destroying bacterial cells in periodontal pockets by means of highly reactive oxygen radicals produced by a combination of a low-level laser light in conjunction with a photosensitizer (Dobson & Wilson, 1992). Several oral bacteria are susceptible to low-level laser light in the presence of photosensitizers such as toluidine blue O, methylene blue and malachite green. This procedure is expected not only to reduce both the bacterial burden and inflammation in periodontal tissues but also to provide biostimulatory effects with photonic en- ergy. Conflicting and short-term outcomes of clinical studies, how- ever, were reported when comparing the adjunctive effects of aPDT to non-surgical mechanical instrumentation alone (Pourabbas et al., 2014; Sgolastra et al., 2013). Despite reports of positive outcomes on the use of adjunctive lasers in the management of untreated periodontitis (Qadri, Javed, Johannsen, & Gustafsson, 2015) and aPDT (Meimandi et al., 2017), clinically relevant benefits for the patient need to be systematically appraised. Hence, the aim of the present systematic review was to inves- tigate the adjunctive effects of laser or aPDT to non-surgical peri- odontal therapy in patients with untreated periodontitis after a follow-up of 6 months. 2 | MATERIAL AND METHODS 2.1 | Study registration The review protocol was registered and allocated the identification number CRD42019128262 in the PROSPERO international prospec- tive register of systematic reviews hosted by the National Institute for Health Research (NIHR), University of York, UK, Center for Reviews and Dissemination. 2.2 | Reporting format The Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) were adopted throughout the process of the Clinical Relevance Scientific rationale for the review: Periodontitis is a biofilm- initiated disease and its treatment is accomplished by means of non-surgical mechanical instrumentation. The aim of the present systematic review was to investigate whether or not adjunctive application of laser or antimi- crobial photodynamic therapy (aPDT) provides benefits to non-surgical periodontal therapy alone after a follow-up of 6 months. Principal findings:Evidence on adjunctive therapy with laser or aPDT is limited and heterogeneous. One meta- analysis based on 2 articles (total n = 42; split-mouth de- sign) failed to identify a statistically significant difference (WMD = 0.35 mm; 95%CI: −0.04/0.73; p = .08) in mean PPD changes in favour of adjunctive aPDT with a wave- length range of 650–700 nm. Out of 17 articles, 2 reported on patient-reported outcome measures and 10 reported on presence/absence of harms or adverse effects. Practical implications: Available evidence on adjunctive therapy with lasers and aPDT is limited by (a) the low number of controlled studies and (b) the heterogeneity of study designs. A high variability of clinical outcomes at 6 months was noted. Patient-reported benefits remain to be demonstrated. 178 | SALVI et AL. present systematic review (Moher, Liberati, Tetzlaff, & Altman, 2009; Moher et al., 2015). 2.3 | Population (P), Intervention (I), Comparison (C) and Outcomes (O) (PICO) Population: Patients with untreated periodontitis. Intervention: Adjunctive use of laser or aPDT to non-surgical me- chanical instrumentation by means of hand and/or power-driven instrumentation. Comparison: Non-surgical mechanical instrumentation by means of hand and/or power-driven instrumentation alone. Outcome measures Primary outcome Change in PPD Secondary outcomes Change in clinical attachment level (CAL) Residual PPD Change in BoP Change in plaque level Change in subgingival biofilm composition Change in gingival crevicular fluid (GCF) biomarker levels Patient-reported outcome measures (PROMs) Harms and adverse effects 2.4 | Focused questions The following focused questions were adapted using the PICO cri- teria (Stone, 2002): • In patients with untreated periodontitis, does laser applica- tion provide adjunctive effects on PPD change compared with non-surgical mechanical instrumentation alone? • In patients with untreated periodontitis, does application of aPDT provide adjunctive effects on PPD change compared with non-surgical mechanical instrumentation alone? 2.5 | Search strategy 2.5.1 | Electronic search A comprehensive and systematic electronic search of MEDLINE via PubMed, Scopus and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies in humans published in English up to 9th April 2019. Language was limited to English due to time constraints. The following search terms were used: PubMed search terms: For the search in the PubMed library, combi- nations of controlled terms (MeSH) and keywords were used whenever possible: ("periodontal diseases" [MeSH Terms] OR "periodontitis" [MeSH Terms]) AND ("laser" [All Fields] OR "photodynamic" [All Fields]) AND ("non-surgical" [All Fields] OR "non surgical" [All Fields] OR "scal- ing" [All Fields] OR "root planing" [All Fields] OR "debridement" [All Fields] OR “conventional periodontal therapy” [All Fields]) Scopus search terms: (KEY ("periodontal diseases" OR "periodon- titis")) AND (TITLE-ABS-KEY ("laser" OR "photodynamic")) AND (TITLE-ABS-KEY ("non-surgical" OR "non-surgical" OR "scaling" OR "root planing" OR "debridement" OR “conventional periodontal therapy”)) Cochrane database for randomized controlled trials search terms: (MeSH descriptor: [Periodontitis] explode all trees OR MeSH de- scriptor: [Periodontal Diseases] explode all trees) AND (All text ("laser" OR "photodynamic")) AND (All text ("non-surgical" OR "non-surgical" OR "scaling" OR "root planing" OR "debridement" OR “conventional periodontal therapy”)) 2.5.2 | Manual search A manual search of the reference lists of relevant reviews and sys- tematic reviews on the topics as well as of the reference lists of the included full-text articles was performed. 2.5.3 | Unpublished literature search In order to further identify potential articles for inclusion, grey lit- erature was searched in the register of clinical studies hosted by the US National Institutes of Health (www.clini caltr ials.gov) and in the multidisciplinary European database (www.openg rey.eu). 2.6 | Study design The following study designs were considered: • Randomized controlled clinical trials (RCTs) • Prospective controlled clinical trials (CCTs) • Studies with split-mouth and parallel arms designs 2.7 | Inclusion criteria The following inclusion criteria were applied: 1. Follow-up of 6 months 2. ≥20 patients per treatment arm at 6-month follow-up 3. ≥20 patients at 6-month follow-up for studies with split-mouth design 4. Clinical examination at 6-month follow-up 5. Non-surgical instrumentation by means of hand and/or power- driven instruments http://www.clinicaltrials.gov http://www.opengrey.eu | 179SALVI et AL. 6. Studies including subgingival adjunctive laser application 7. For meta-analysis a. Studies including only 1x non-surgical mechanical instrumen- tation combined with only 1x adjunctive application of lasers or aPDT b. Studies reporting PPD changes between baseline and 6-month follow-up 2.8 | Exclusion criteria The following exclusion criteria were applied: • Studies including patients with treated periodontitis • Referred patients with pre-treated periodontitis • Studies including patients treated in the course of supportive periodontal therapy (SPT) • Studies including the use of ≥2 laser types • Studies including a combination of laser and aPDT application • Abstracts • Letters to editors • Narrative reviews • Case reports • Case series • Insufficient/unclear information not allowing data extraction • No author response to inquiry e-mail for data clarification 2.9 | Screening Screening was performed independently by 4 reviewers (A. S., G. E. S., C. W. and J. C. S.). A Cohen's kappa score was calculated to assess inter-examiner agreement (Landis & Koch, 1977). Eligibility assessment was performed firstly through title and abstract analysis and secondly through full-text analysis. In order to avoid exclusion of potentially relevant articles, abstracts providing unclear results were included in the full-text analysis. If necessary, authors were contacted for clarifications. From all studies of potential relevance, full-text was obtained for independent assessment by 2 reviewers against the stated inclusion criteria. Any disagreement was resolved by discussion among the reviewers. In the event of multiple publica- tions on the same patient sample, relevant data on the primary and secondary outcome measures were extracted from the publication with the 6-month follow-up. 2.10 | Data extraction From the selected articles fulfilling the inclusion criteria, data ad- dressing the primary and secondary outcome measures were ex- tracted in duplicate by two independent reviewers for qualitative and quantitative analysis. 2.11 | Quality assessment The criteria used to evaluate the quality of the selected controlled trials were adopted from the checklist of the Cochrane Center and the CONSORT (Consolidated Standards of Reporting Trials) statement, providing guidelines for the following parameters: (a) sequence generation; (b) allocation concealment method; (c) masking of the examiner; (d) address of incomplete outcome data; and (e) free of selective outcome reporting. The degree of bias was categorized as low risk if all the criteria were met and high risk if two or more criteria were missing (Higgins, Altman, & Sterne, 2011; Moher et al., 2010; Schulz, Altman, Moher, & Fergusson, 2010). Potential impact of risk of bias for sample size calculation, patient selection and reporting was considered for each selected study. 2.12 | Data analysis To assess changes in PPD (i.e. primary outcome) at the 6-month follow-up, mean values and standard deviations were used and ana- lysed with weighted mean differences (WMD) and 95% confidence intervals (CIs). Results documenting PPD change were extracted from RCTs and used to evaluate the potential benefits of adjunctive laser or aPDT therapy. Meta-analyses wereperformed using random effect meth- ods by grouping laser types according to their wavelength. For these meta-analyses, only studies using a single adjunctive application of laser or aPDT (test) and a single episode of non-surgical mechanical instrumentation (control) were included. Forest plots were used to illustrate the outcomes of the meta-analyses. Mean prediction inter- vals and their 95% lower and upper limits were only calculated and reported for meta-analyses including at least 3 studies. The statistical heterogeneity among studies was explored by the I2 index (Higgins, Thompson, Deeks, & Altman, 2003). Statistical significance was set to p < .05. All analyses were per- formed with Review Manager (RevMan Version 5.3. Copenhagen: The Nordic Cochrane Centre). 3 | RESULTS 3.1 | Search A total of 1,202 records were identified through the electronic search. After removal of duplicates, 659 records remained for ab- stract screening. No citations from the manual search and the grey literature search were identified (Figure 1). Upon exclusion of 604 articles based on their abstracts, 55 ar- ticles remained for full-text evaluation. Following exclusion of 38 articles based on full-text analysis (Table 1), 17 articles remained for qualitative and quantitative analysis. 180 | SALVI et AL. An inter-examiner Cohen's kappa score of 0.749 was calculated according to the results from title and abstract screening. 3.2 | Adjunctive laser therapy 3.2.1 | Description of included studies The characteristics of the 10 articles evaluating the adjunctive use of laser are summarized in Table 2 (Dereci, Hatipoglu, Sindel, Tozoglu, & Üstün, 2016; Dilsiz, Canakci, & Aydin, 2013; Eltas & Orbak, 2012a; Euzebio Alves et al., 2013; Hatipoglu et al., 2017; Kamma, Vasdekis, & Romanos, 2009; Kelbauskiene, Baseviciene, Goharkhay, Moritz, & Machiulskiene, 2011; Matarese, Ramaglia, Cicciu, Cordasco, & Isola, 2017; Rotundo et al., 2010; Üstün, Hatipoglu, Daltaban, Felek, & Firat, 2018). 3.2.2 | Study design One article included two experimental and two control groups, re- spectively (Eltas & Orbak, 2012a). Two studies (Kamma et al., 2009; Rotundo et al., 2010) included 3 experimental and 1 control groups, respectively. One study included two experimental groups and one control group (Dilsiz et al., 2013) while the remaining 6 articles in- cluded one experimental group and one control group. Three articles (Dereci et al., 2016; Hatipoglu et al., 2017; Üstün et al., 2018) reported on a parallel-arm design while 7 articles re- ported on a split-mouth design (Dilsiz et al., 2013; Eltas & Orbak, 2012a; Euzebio Alves et al., 2013; Kamma et al., 2009; Kelbauskiene et al., 2011; Matarese et al., 2017; Rotundo et al., 2010). The total number of patients treated was 370 of whom 230 were included in studies with a split-mouth and 140 in studies with a par- allel-arm design, respectively. F I G U R E 1 PRISMA flow chart depicting the selection process | 181SALVI et AL. 3.2.3 | Study samples Sample sizes varied from 24 to 60 patients, and a power calculation was described in 5 of the 10 included articles (Eltas & Orbak, 2012a; Euzebio Alves et al., 2013; Kamma et al., 2009; Kelbauskiene et al., 2011; Rotundo et al., 2010). The mean age of the included patients ranged from 34.9 to 50.5 years. The percentage of females ranged from 33% to 67% and of males from 33% to 66%, respectively. Smokers were reported in 3 articles (Eltas & Orbak, 2012a; Kamma et al., 2009; Rotundo et al., 2010); smokers were excluded in 6 articles (Dilsiz et al., 2013; Euzebio Alves et al., 2013; Hatipoglu et al., 2017; Kelbauskiene et al., 2011; Matarese et al., 2017; Üstün et al., 2018). Two articles re- ported on patients diagnosed with aggressive periodontitis (Kamma et al., 2009; Matarese et al., 2017), 7 articles on patients diagnosed with chronic periodontitis (Dereci et al., 2016; Dilsiz et al., 2013; Eltas & Orbak, 2012a; Euzebio Alves et al., 2013; Hatipoglu et al., 2017; Rotundo et al., 2010; Üstün et al., 2018), and periodontal diag- nosis was not reported in 1 article (Kelbauskiene et al., 2011). All studies were conducted in one centre. One study (Kamma et al., 2009) was conducted in a private dental clinic limited to peri- odontics while the remaining nine studies were conducted in a uni- versity setting. 3.2.4 | Intervention/comparison Five different types of laser were used in the 10 included articles. The use of a diode laser was reported in four articles (Euzebio Alves et al., 2013; Hatipoglu et al., 2017; Kamma et al., 2009; Matarese et al., 2017), Er:YAG laser in one article (Rotundo et al., 2010), Er,Cr:YSGG laser in three articles (Dereci et al., 2016; Kelbauskiene et al., 2011; Üstün et al., 2018), Nd:YAG laser in one article (Eltas & Orbak, 2012a) and potassium titanyl phosphate (KTP) laser in the remaining one article (Dilsiz et al., 2013). In a total of six articles, non-surgical mechanical instrumentation and laser application were reported to be performed in one session (Eltas & Orbak, 2012a; Hatipoglu et al., 2017; Kamma et al., 2009; Matarese et al., 2017; Rotundo et al., 2010; Üstün et al., 2018), while in the remaining four articles (Dereci et al., 2016; Dilsiz et al., 2013; Euzebio Alves et al., 2013; Kelbauskiene et al., 2011) non-surgical mechanical instrumentation and/or laser application was delivered in multiple sessions. With respect to non-surgical mechanical instrumentation, two articles reported the use of hand instruments only (Euzebio Alves et al., 2013; Kamma et al., 2009) and the remaining 8 articles reported a combination of hand and power-driven instruments. In seven articles, the use of local anaesthesia in conjunction with periodontal treatment was reported (Dereci et al., 2016; Eltas & Orbak, 2012a; Euzebio Alves et al., 2013; Hatipoglu et al., 2017; Kamma et al., 2009; Matarese et al., 2017; Üstün et al., 2018); in one article, local anaesthesia was reported to be delivered if needed (Rotundo et al., 2010) whereas lack of information with respect to TA B L E 1 Studies excluded based on full-text analysis and reasons for exclusion First author (year of publication) Reason for exclusion Abduljabbar, Vohra, Kellesarian, and Javed (2017) 4a Al-Falaki, Cronshaw, and Parker (2016) 3 Angelov et al. (2009) 6a Balata et al. (2013) 4a Castro Dos Santos et al. (2016) 3 Ciurescu, Teslaru, Zetu, and Ciurescu (2016) 3 Crespi, Capparè, Toscanelli, Gherlone, and Romanos (2007) 3 Derdilopoulou, Nonhoff, Neumann, and Kielbassa (2007) 4 Dilsiz and Sevinc (2014) 5 Eltas and Orbak (2012b) 5 Franco et al. (2014) 1 Giannelli, Formigli, Lorenzini, and Bani (2012) 3 Giannelli, Formigli, Lorenzini, and Bani (2015) 3 Giannelli, Materassi, Fossi, Lorenzini, and Bani (2018) 3 Grzech-Leśniak, Matys, and Dominiak (2018) 3 Grzech-Leśniak, Sculean, and Gašpirc (2018) 3 Gündogar, Senyurt, Erciyas, Yalim, and Üstün (2016) 3 Hill, Dehn, Hinze, Frentzen, and Meister (2019) 4a Moritz et al. (1998) 1 Obradović et al. (2012) 4 Pesevska, Gjorgoski, Ivanovski, Soldatos, and Angelov (2017) 4 Petrović et al. (2018) 2 Pinheiro et al. (2010) 1 Qadri, Javed, Poddani, Tuner, and Gustafsson (2011) 5 Romero et al. (2017) 3 Roncati, Gariffo, Barbieri, and Vescovi (2017) 1 Ruiz Magaz, Santos Alemany, Hernández Alfaro, and Nart Molina (2016) 4a Saglam, Kantarci, Dundar, and Hakki (2014) 1 Salgado et al. (2017) 1 Sanz-Sanchez, Ortiz-Vigon, Matos, Herrera, and Sanz (2015) 1 Schwarz, Sculean, Georg, and Reich (2001) 3 Schwarz, Sculean, Berakdar, et al. (2003) 3 Schwarz, Sculean, Georg, and Becker (2003) 3 Sculean et al. (2004) 3 Segarra-Vidal et al. (2017) 1 Sjöström and Friskopp (2002) 2 Üstün et al. (2014) 1 Yadwad, Veena, Patil, and Shivaprasad (2017) 3 Note: 1, number of subjects <20; 2, follow-up time <6 months; 3, study protocol does not match with stated focused question; 4, endpoints do not match withstated inclusion criteria; 5, no data at 6-month follow-up; 6, other reasons (e.g. follow-up time unknown). aNo author response to inquiry e-mail for data clarification. 182 | SALVI et AL. the use of local anaesthesia was observed in two articles (Dilsiz et al., 2013; Kelbauskiene et al., 2011). 3.2.5 | Outcomes The outcomes of the 10 articles evaluating adjunctive laser ther- apy are summarized in Table 3. The data of the included RCTs provide an inconclusive picture regarding benefits of adjunctive laser application. Meta-analyses on the primary outcome meas- ure could not be performed for lasers grouped with a wavelength range of 810–980 nm and a wavelength range of 2,780–2,940 nm due to (a) the low number of comparable studies, (b) the hetero- geneity of study designs and/or (c) the lack of reporting of mean PPD changes between baseline and the 6-month follow-up in the original articles. Table 6a summarizes the percentages of studies reporting on secondary outcomes. CAL change (i.e. 100%), Plaque Index change (i.e. 90%) and change in BoP (i.e. 90%) were reported with the high- est frequency. Harms or adverse effects and change in subgingival biofilm composition were reported in four articles (i.e. 40%), while change in GCF biomarkers levels/volumes were reported in three articles (i.e. 30%). Residual PPD and PROMs were reported in one article (i.e. 10%). 3.3 | Adjunctive aPDT 3.3.1 | Description of included studies The characteristics of the eight included articles (Al-Askar et al., 2017; Berakdar, Callaway, Eddin, Ross, & Willershausen, 2012; Betsy, Prasanth, Baiju, Prasanthila, & Subhash, 2014; Bundidpun, Srisuwantha, & Laosrisin, 2018; Dilsiz et al., 2013; Malgikar et al., 2016; Raut, Sethi, Kohale, Mamajiwala, & Warang, 2018; Theodoro et al., 2012) are summarized in Table 4. 3.3.2 | Study design All studies were designed as RCTs. Five out of 8 studies applied a split-mouth design, that is test and control interventions were com- pared within a patient (Berakdar et al., 2012; Bundidpun et al., 2018; Dilsiz et al., 2013; Malgikar et al., 2016; Theodoro et al., 2012). Three studies used two separate patient groups, that is non-surgical me- chanical debridement without (control group) and with adjunctive aPDT treatment (test group) (Al-Askar et al., 2017; Betsy et al., 2014; Raut et al., 2018). None of the included studies was funded by an industrial part- ner. Examiner calibration was reported in six articles (Al-Askar et al., 2017; Betsy et al., 2014; Dilsiz et al., 2013; Malgikar et al., 2016; Raut et al., 2018; Theodoro et al., 2012). A formal power calculation was described in five (Al-Askar et al., 2017; Betsy et al., 2014; Bundidpun et al., 2018; Raut et al., 2018; Theodoro et al., 2012) of the eight included articles. All studies were conducted in a single university or specialist centre. 3.3.3 | Study samples Samples sizes varied from 20 to 88 patients. The total number of pa- tients observed was 331, that is 123 patients received test and con- trol interventions in a split-mouth design, and 208 patients received either mechanical debridement without (104 patients as controls) or with adjunctive aPDT treatment (104 patients as test group). Mean age of included patients ranged from 41 to 59 years, and the propor- tion of females varied from 0% to 65%. In all studies, patients with systemic conditions, pregnant or lactating women and patients who had taken antibiotics in the past 3–12 months were excluded. One study included exclusively pa- tients with medically diagnosed prediabetes (Al-Askar et al., 2017). Smoking was an exclusion criterion in all studies. Dental and periodontal characteristics of the patients included varied considerably between studies. While case definitions and re- quirements in terms of PPD differed among studies, in all studies but 1 (Al-Askar et al., 2017) patients were diagnosed with chronic periodontitis according to the 1999 classification (Armitage, 1999). Nine articles specified a minimum of PPD ≥4–7 mm in at least 3–6 teeth or sites. One article defined the presence of PPD >5 mm and CAL >4 mm without definition of a minimum number of teeth (Raut et al., 2018). Three articles (Berakdar et al., 2012; Dilsiz et al., 2013; Theodoro et al., 2012) called for the presence of BoP. Five arti- cles defined the presence of at least 20 teeth (Betsy et al., 2014; Bundidpun et al., 2018; Dilsiz et al., 2013; Malgikar et al., 2016; Theodoro et al., 2012). The number of tooth sites treated with adjunctive aPDT (test procedure) ranged from 33 to 839 sites. Four articles did not specify the exact number of teeth or sites treated per patient and/or treat- ment arm (Al-Askar et al., 2017; Dilsiz et al., 2013; Malgikar et al., 2016; Raut et al., 2018). In four articles, treated sites were speci- fied in terms of PPD and the presence of BoP (Al-Askar et al., 2017; Berakdar et al., 2012; Betsy et al., 2014; Theodoro et al., 2012). One article reported exclusively single-rooted teeth in the analysis (Betsy et al., 2014). 3.3.4 | Intervention/comparison A diode laser was used in the eight articles included. All articles but 1 (Raut et al., 2018) stated the laser manufacturer which differed among studies. The most commonly used laser tips were fibre optic tips (Betsy et al., 2014; Bundidpun et al., 2018; Dilsiz et al., 2013; Malgikar et al., 2016; Theodoro et al., 2012). In the remaining three articles, the material of the laser tip was not reported. If reported, diameter of the laser tip ranged from 200 to 400 μm. The output | 183SALVI et AL. TA B LE 2 C ha ra ct er is tic s of s tu di es o n ad ju nc tiv e la se r t he ra py to n on -s ur gi ca l m ec ha ni ca l i ns tr um en ta tio n Fi rs t a ut ho r (y ea r) St ud y Ty pe D es ig n n ce nt re In du st ria l F un di ng C al ib ra tio n Pa tie nt ch ar ac te ris tic s n pa tie nt s ( n fe m al e) M ea n ag e ± SD (r an ge ) Pe rio do nt al d ia gn os is Sm ok in g st at us n tr ea te d te et h/ si te s p er tr ea tm en t a rm Ty pe o f p ro be Si te s o f p ro bi ng p er to ot h La se r La se r t yp e (p ro du ct na m e) M at er ia l o f t ip (d ia m et er ) Ph ys ic al d at a La se r p ow er La se r e ne rg y Ir ra di at io n tim e W av el en gt h La se r i nt en si ty La se r d en si ty Tr ea tm en t Fo llo w -u p Ti m e po in ts (m on th s) Tr ea tm en t A dv er se e ff ec ts K am m a et a l. (2 00 9) RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er ca lib ra te d 30 p at ie nt s (1 6 fe m al e) 41 .8 ± 6 .2 A gP 18 s m ok er s, 1 2 no n- sm ok er s O ne q ua dr an t p er p at ie nt (1 s ite p er tr ea tm en t gr ou p pe r p at ie nt a na ly se d) G ol dm an /F ox -W ill ia m s 6 D io de la se r (S m ile Pr o9 80 ™ , Bi ol ite c, J en a, G er m an y) Fl ex ib le g la ss fi br e op tic g ui de (3 00 µ m ) 2 W n. r. 30 s /s ite 98 0 nm 2, 83 0 W /c m 2 94 .3 J/ cm 2 Te st g ro up : S RP (h an d) + la se r C on tr ol g ro up : S RP (h an d) 2 w ee ks – 3 – 6 n. r. n. r. Ro tu nd o et a l. (2 01 0) RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er ca lib ra te d 27 p at ie nt sa (1 8 fe m al e) 50 .5 ± 1 1. 7 C hP 12 s m ok er s (< 10 c ig ar et te s/ da y) , 1 5 no n- sm ok er s 41 9 si te s fo r t es t a nd 4 22 s ite s fo r c on tr ol gr ou p; o ne q ua dr an t p er p at ie nt b n. r. 6 Er :Y AG la se r ( Sm ar t 29 40 P lu s, D EK A M .E .L .A . s rl, C al en za no , F ire nz e, It al y) C on ic fi br e tip (0 .5 m m ) n. r. n. r. n. r. 2, 94 0nm n. r. 15 0 m J/ pu ls e at 10 H z Te st g ro up : l as er + S RP (h an d + ul tr as on ic ) C on tr ol g ro up : S RP (h an d + ul tr as on ic ) 3 – 6 SP T af te r 1 w ee k, 1 , 3 a nd 6 m on th s 2 pe rio do nt al a bs ce ss es in th e te st g ro up , 1 p at ie nt w ith fe ve r, 1 pa tie nt lo st 1 da y of w or k, 1 p at ie nt w ith 1 d ay o f d ai ly li fe in te rf er en ce Ke lb au sk ie ne et a l. (2 01 1) RC T Sp lit -m ou th Si ng le -c en tr e n. r. Ex am in er ca lib ra te d 30 p at ie nt s (1 4 fe m al e) n. r. (2 6– 58 ) Ea rly o r m od er at e pe rio do nt iti s N on -s m ok er s 14 3 te et h fo r c on tr ol a nd 1 35 te et h fo r t es t gr ou p M ea n 8. 4 (1 .3 ) t ee th p er p at ie nt fo r c on tr ol a nd m ea n 9. 5 (2 .2 ) t ee th fo r t es t g ro up (s in gl e- ro ot ed te et h) c PC P 12 (H u- Fr ie dy , U SA ) 6 Er ,C r:Y SG G la se r (W at er la se , B io la se , C ul ve r C ity , U SA ) Fi br e op tic ti p (6 00 μ m ) 1 W n. r. n. r. 2, 78 0 nm n. r. n. r. Te st g ro up : S RP (h an d + ul tr as on ic ) + la se rd C on tr ol g ro up : S RP (h an d + ul tr as on ic ) 2 – 3 – 6 – 12 O H I, su pr ag in gi va l s ca lin g an d po lis hi ng N on e El ta s an d O rb ak (2 01 2a ) RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er ca lib ra te d 52 p at ie nt s (2 6 fe m al e) 43 .5 (3 2– 52 ) C hP 26 s m ok er s, 2 6 no n- sm ok er s 10 4, i. e. 2 te et h pe r p at ie nt n. r. 6 N d: YA G la se r (n .r. ) Fi br e op tic ti p (n .r. ) 1 W , 1 0 H z 10 0 m J 30 s /s ite 1, 06 4 nm n. r. n. r. Te st g ro up : S RP (h an d + ul tr as on ic ) + la se r C on tr ol g ro up : S RP (h an d + ul tr as on ic ) + pl ac eb o la se r 1 – 6 n. r. n. r. (C on tin ue s) 184 | SALVI et AL. Fi rs t a ut ho r (y ea r) St ud y Ty pe D es ig n n ce nt re In du st ria l F un di ng C al ib ra tio n Pa tie nt ch ar ac te ris tic s n pa tie nt s ( n fe m al e) M ea n ag e ± SD (r an ge ) Pe rio do nt al d ia gn os is Sm ok in g st at us n tr ea te d te et h/ si te s p er tr ea tm en t a rm Ty pe o f p ro be Si te s o f p ro bi ng p er to ot h La se r La se r t yp e (p ro du ct na m e) M at er ia l o f t ip (d ia m et er ) Ph ys ic al d at a La se r p ow er La se r e ne rg y Ir ra di at io n tim e W av el en gt h La se r i nt en si ty La se r d en si ty Tr ea tm en t Fo llo w -u p Ti m e po in ts (m on th s) Tr ea tm en t A dv er se e ff ec ts D ils iz e t a l. (2 01 3) e RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er ca lib ra te d 24 p at ie nt s (1 4 fe m al e) 40 .7 ± 7 .3 (3 0– 58 ) C hP N on -s m ok er s 14 4 te et h di st rib ut ed o ve r t hr ee tr ea tm en t gr ou ps Fl or id a Pr ob e (G ai ne sv ill e, U SA ) w ith a n oc cl us al s te nt n. r. K TP la se r ( Sm ar tL ite , D EK A , F lo re nc e, It al y) Fi br e op tic ti p (2 00 µ m ) 0. 8 W n. r. n. r. 53 2 nm n. r. 11 .7 J/ cm 2 Te st g ro up : S RP in tw o se ss io ns w ith in 7 d ay s (u ltr as on ic + h an d) + la se r C on tr ol g ro up : S RP in tw o se ss io ns w ith in 7 d ay s (u ltr as on ic + h an d) + pl ac eb o la se r 6 Pr op hy la xi s af te r 1 a nd 3 m on th s N on e Eu ze bi o A lv es et a l. (2 01 3) RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er ca lib ra te d 36 p at ie nt s (2 3 fe m al e) 46 .8 ± 8 .1 1 (3 7– 64 ) C hP N on -s m ok er s 36 s in gl e- ro ot ed te et h PC PU N C 15 (H u- Fr ie dy ) 6 D io de la se r ( ZA P So ft la se , P le as an t H ill , U SA ) Fi br e op tic ti p (4 00 µ m ) 1. 5 W n. r. 20 s /s ite 80 8 ± 5 nm 1, 19 3. 7 W /c m 2 n. r. Te st g ro up : S RP (h an d) + la se r ( 2 ap pl ic at io ns : 1 d ay an d 1 w ee k af te r S RP ) C on tr ol g ro up : S RP (h an d) + pl ac eb o la se r 1. 5 – 6 SP T at 3 m on th s n. r. D er ec i e t a l. (2 01 6) RC T Pa ra lle l a rm s Si ng le -c en tr e N on e n. r. 60 p at ie nt s (2 9 fe m al e) 43 .7 ± 3 .1 C hP n. r. n. r. W ill ia m s 6 Er ,C r:Y SG G la se r (B io la se , I rv in e, C al ifo rn ia , U SA ) Fi br e op tic ti p RF PT 5– 14 (n .r. ) 1. 5 W , 3 0 H z n. r. n. r. n. r. n. r. n. r. Te st g ro up : S RP (h an d + ul tr as on ic ) 1 tim e + la se r, 3 tim es w ith in 7 d ay s C on tr ol g ro up : S RP (h an d + ul tr as on ic ) 3 ti m es w ith in 7 d ay s + pl ac eb o la se r 1 – 3 – 6 n. r. N on e H at ip og lu e t a l. (2 01 7) RC T Pa ra lle l a rm s Si ng le -c en tr e n. r. n. r. 40 p at ie nt s (2 0f /2 0g ) ( 20 fe m al e) n. r. C hP N on -s m ok er s n. r. n. r. 6 In di um g al liu m al um in iu m ph os ph at e di od e la se r ( Ep ic , B io la se , Ir vi ne , C A , U SA ) Fi br e op tic ti p (3 00 µ m ) 1. 5 W n. r. 20 s /t oo th 94 0 nm n. r. 15 J/ cm 2 Te st g ro up : S RP (h an d + ul tr as on ic ) + la se r C on tr ol g ro up : S RP (h an d + ul tr as on ic ) 1 – 3 – 6 n. r. n. r. TA B LE 2 (C on tin ue d) (C on tin ue s) | 185SALVI et AL. Fi rs t a ut ho r (y ea r) St ud y Ty pe D es ig n n ce nt re In du st ria l F un di ng C al ib ra tio n Pa tie nt ch ar ac te ris tic s n pa tie nt s ( n fe m al e) M ea n ag e ± SD (r an ge ) Pe rio do nt al d ia gn os is Sm ok in g st at us n tr ea te d te et h/ si te s p er tr ea tm en t a rm Ty pe o f p ro be Si te s o f p ro bi ng p er to ot h La se r La se r t yp e (p ro du ct na m e) M at er ia l o f t ip (d ia m et er ) Ph ys ic al d at a La se r p ow er La se r e ne rg y Ir ra di at io n tim e W av el en gt h La se r i nt en si ty La se r d en si ty Tr ea tm en t Fo llo w -u p Ti m e po in ts (m on th s) Tr ea tm en t A dv er se e ff ec ts M at ar es e et a l. (2 01 7) RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er ca lib ra te d 31 p at ie nt s (1 7 fe m al e) 34 .9 ± 1 .2 A gP N on -s m ok er s n. r. (o ne m ax ill ar y qu ad ra nt w ith a t l ea st 6 te et h pe r p at ie nt ) U N C- 15 (H u- Fr ie dy , U SA ) 6 D io de la se r ( W is er La se r, D oc to r s m ile , La m bd a, V ic en za , It al y) Fi br e op tic ti p (3 00 µ m ) 1 W , 5 0 H z n. r. 20 s /t oo th 81 0 nm n. r. 24 .8 4 J/ cm 2 Te st g ro up : S RP (u ltr as on ic ) + la se r C on tr ol g ro up : S RP (u ltr as on ic ) + p la ce bo g el so lu tio n 0. 5 – 1 – 2 – 6 – 12 n. r. n. r. Ü st ün e t a l. (2 01 8) RC T Pa ra lle l a rm s Si ng le -c en tr e N on e n. r. 40 , ( 20 f /2 0g ) ( 19 fe m al e) 45 .8 ± 6 .5 3 (3 6– 59 )f , 4 4. 05 ± 6 .1 6 (3 5– 58 )g C hP N on -s m ok er s n. r. PW D (H u- Fr ie dy , U SA ) 6 Er ,C r:Y SG G la se r (Wat er la se ip lu s, Bi ol as e, Ir vi ne , C A , U SA ) Fi br e op tic ti p RF PT 5– 14 (n .r. ) 1. 5 W , 3 0 H z n. r. n. r. n. r. n. r. n. r. Te st g ro up : S RP (h an d + ul tr as on ic ) + la se r C on tr ol g ro up : S RP (h an d + ul tr as on ic ) 1 – 3 – 6 Su pr ag in gi va l c le an in g af te r 1, 3 a nd 6 m on th s n. r. A bb re vi at io ns : A gP , a gg re ss iv e pe rio do nt iti s; C hP , c hr on ic p er io do nt iti s; E r,C r:Y SG G , e rb iu m , c hr om iu m -d op ed : y tt riu m , s ca nd iu m , g al liu m a nd g ar ne t; Er :Y AG , e rb iu m -d op ed : y tt riu m a lu m in iu m g ar ne t; G aA lA s, a lu m in iu m g al liu m a rs en id e; K TP , p ot as si um ti ta ny l p ho sp ha te ; n , n um be r; n. r., n ot re po rt ed ; N d: YA G , n eo dy m iu m -d op ed : y tt riu m a lu m in iu m g ar ne t; O H I, or al h yg ie ne in st ru ct io ns ; S PT , su pp or tiv e pe rio do nt al th er ap y; S RP , s ca lin g an d ro ot p la ni ng . a 1 p at ie nt lo st to fo llo w -u p (2 6 pa tie nt s w er e in cl ud ed in th e an al ys es ). b F in al ly a na ly se d: 4 05 s ite s fo r t es t a nd 3 99 fo r c on tr ol g ro up . c F in al ly a na ly se d: 5 09 fo r t es t a nd 5 79 fo r c on tr ol g ro up . d L as er a pp lic at io n on ce a w ee k fo r e ac h m ill im et re o f p oc ke t r ed uc tio n (o n av er ag e 3 ap po in tm en ts ). e S tu dy h as 2 te st g ro up s se e Ta bl e 4. f T es t g ro up . g C on tr ol g ro up . TA B LE 2 (C on tin ue d) 186 | SALVI et AL. TA B LE 3 C lin ic al o ut co m e pa ra m et er s of s tu di es o n ad ju nc tiv e la se r t he ra py to n on -s ur gi ca l m ec ha ni ca l i ns tr um en ta tio n. If n ot o th er w is e in di ca te d, p ar am et er s ar e pr es en te d as m ea ns ± S D Fi rs t a ut ho r (y ea r) G ro up Ti m e po in t PP D (m m ) PP D c ha ng e (m m ) C A L (m m ) C A L ch an ge (m m ) BO P (% ) BO P ch an ge (% ) PI (% ) K am m a et a l. (2 00 9) Te st Ba se lin e 6. 67 ± 1 .2 9 – 7. 07 ± 1 .7 1 – 82 .4 – 52 .7 6 m on th s 3. 87 ± 0 .9 2* – 4. 93 ± 1 .6 2* – 24 .3 – 29 .2 C on tr ol Ba se lin e 6. 47 ± 1 .3 6 – 7. 07 ± 1 .5 8 – 81 .6 – 54 .1 6 m on th s 4. 13 ± 1 .0 6* – 5. 20 ± 1 .6 6* – 25 .8 – 32 .6 Ro tu nd o et a l. (2 01 0) Te st Ba se lin e 5. 1 ± 1. 1 – 5. 7 ± 1. 5 – 71 – 63 6 m on th s 3. 9 ± 1. 5 1. 2 ± 1. 6 5. 2 ± 1. 8 0. 5 ± 1. 7 53 – 47 C on tr ol Ba se lin e 5. 2 ± 1. 2 – 6. 1 ± 1. 6 – 73 – 68 6 m on th s 4. 3 ± 1. 7 1. 0 ± 1. 5 5. 6 ± 2. 0 0. 5 ± 1. 8 57 – 48 Ke lb au sk ie ne et a l. (2 01 1) Te st Ba se lin e 4. 33 ± 1 .0 8* * – 4. 47 ± 1 .2 ** – 79 .0 – 3. 5a 6 m on th s – 2. 13 ± 1 .2 4* * – 2. 1 ± 1. 26 ** 10 .5 – 9. 1a C on tr ol Ba se lin e 4. 07 ± 0 .7 9* * – 4. 23 ± 0 .9 2* * – 74 .1 – 3. 7a 6 m on th s – 1. 64 ± 1 .0 6* * – 1. 57 ± 1 .1 1* * 17 .0 – 14 .1 a El ta s an d O rb ak (2 01 2a ) Te st b Ba se lin e 5. 4 ± 0. 8 – 6. 7 ± 1. 1 – – – 1. 9 ± 0. 6c 6 m on th s 3. 8 ± 0. 6 – 6. 4 ± 1. 1 – – – 0. 8 ± 0. 5c C on tr ol b Ba se lin e 5. 4 ± 0. 7 – 6. 6 ± 1. 2 – – – 1. 7 ± 0. 6c 6 m on th s 4. 2 ± 0. 5 – 6. 5 ± 1. 1 – – – 0. 7 ± 0. 5c Te st d Ba se lin e 5. 3 ± 0. 7 – 6. 1 ± 1. 1 – – – 1. 7 ± 0. 8c 6 m on th s 3. 1 ± 0. 5* – 5. 6 ± 1. 0 – – – 0. 6 ± 0. 4c C on tr ol d Ba se lin e 5. 3 ± 0. 8 – 6. 1 ± 0. 9 – – – 1. 8 ± 0. 5c 6 m on th s 3. 6 ± 0. 5* – 5. 8 ± 1. 0 – – – 0. 6 ± 0. 5c D ils iz e t a l. (2 01 3) Te st Ba se lin e 5. 96 ± 0 .9 1 – 7. 75 ± 0 .6 1 – 96 ± 0 .2 0 – 1. 42 ± 0 .5 8e 6 m on th s 3. 92 ± 0 .4 1* 2. 08 ± 1 .0 2 5. 33 ± 1 .0 5* 2. 42 ± 1 .1 4 42 ± 0 .5 0* – 0. 75 ± 0 .4 4e C on tr ol Ba se lin e 5. 83 ± 0 .7 6 – 7. 50 ± 0 .7 2 – 92 ± 0 .2 8 – 1. 46 ± 0 .5 1e 6 m on th s 4. 42 ± 0 .8 8* 1. 42 ± 0 .8 8 6. 04 ± 1 .0 0* 1. 50 ± 0 .8 8 46 ± 0 .5 1 – 0. 71 ± 0 .4 6e Eu ze bi o A lv es et a l. (2 01 3) Te st Ba se lin e 6. 13 ± 1 .3 5 – 6. 91 ± 1 .9 4 – 97 .2 ± 1 6. 6 – 1. 25 ± 0 .9 9c 6 m on th s 3. 63 ± 1 .4 9 2. 56 ± 1 .7 9 5. 33 ± 2 .1 3 1. 70 ± 1 .7 2 40 .1 ± 4 9. 3 57 .1 0. 66 ± 0 .8 8c C on tr ol Ba se lin e 5. 69 ± 0 .9 5 – 6. 50 ± 1 .7 4 – 94 .4 ± 2 3. 2 – 1. 47 ± 0 .9 0c 6 m on th s 2. 93 ± 1 .3 3 2. 76 ± 1 .1 3 4. 30 ± 2 .0 8 2. 10 ± 1 .6 4 33 .6 ± 4 7. 2 60 .8 0. 60 ± 0 .7 7c (C on tin ue s) | 187SALVI et AL. Fi rs t a ut ho r (y ea r) G ro up Ti m e po in t PP D (m m ) PP D c ha ng e (m m ) C A L (m m ) C A L ch an ge (m m ) BO P (% ) BO P ch an ge (% ) PI (% ) D er ec i e t a l. (2 01 6) Te st Ba se lin e 5. 3 ± 1. 8 – 2. 9 ± 0. 6 – 75 .1 ± 7 .2 – 2. 4 ± 0. 5e 6 m on th s 1. 9 ± 0. 7 – 1. 8 ± 0. 5 – 37 .8 ± 7 .7 * – 1. 5 ± 0. 5e C on tr ol Ba se lin e 5. 3 ± 1. 8 – 2. 9 ± 0. 4 – 77 .7 ± 7 .4 – 2. 5 ± 0. 5e 6 m on th s 2. 1 ± 0. 6 – 1. 9 ± 0. 4 – 41 .6 ± 8 .6 * – 1. 5 ± 0. 5e H at ip og lu e t al . ( 20 17 ) Te st Ba se lin e 4. 05 ± 0 .6 4 – 3. 03 ± 0 .6 5 – 75 .9 ± 6 .7 9 – 1. 88 ± 0 .2 7 6 m on th s 1. 88 ± 0 .5 5 – 1. 75 ± 0 .5 8 – 21 .7 ± 8 .1 6* – 1. 25 ± 0 .1 5* C on tr ol Ba se lin e 4. 00 ± 0 .5 3 – 2. 74 ± 0 .5 9 – 74 .8 ± 7 .5 9 – 1. 86 ± 0 .2 8 6 m on th s 1. 95 ± 0 .8 1 – 1. 81 ± 0 .6 0 – 31 .5 ± 7 .2 3* – 1. 41 ± 0 .1 6 M at ar es e et al . ( 20 17 ) Te st Ba se lin e 5. 25 ± 0 .6 6 – 5. 36 ± 0 .3 9 – 75 .2 6 ± 3. 6 – 28 .2 1 ± 5. 12 6 m on th s 2. 24 ± 0 .3 5 3. 19 ± 0 .2 2 – 22 .7 9 ± 4. 2 – 24 .5 5 ± 3. 36 C on tr ol Ba se lin e 5. 18 ± 0 .5 7 – 4. 88 ± 0 .5 5 – 78 .1 2 ± 2. 2 – 28 .5 4 ± 5. 23 6 m on th s 2. 68 ± 0 .2 9 – 3. 11 ± 0 .2 5 – 24 .6 7 ± 3. 2 – 25 .0 4 ± 3. 69 Ü st ün e t a l. (2 01 8) Te st Ba se lin e 3. 88 ± 0 .5 0 – 2. 69 ± 0 .4 7 – 74 .7 5 ± 7. 59 – 1. 72 ± 0 .3 2 6 m on th s 1. 83 ± 0 .8 0 – 1. 76 ± 0 .5 6 – 26 .8 5 ± 7. 39 – 1. 32 ± 0 .1 6 C on tr ol Ba se lin e 3. 97 ± 0 .7 2 – 2. 88 ± 0 .5 8 – 77 .3 0 ± 7. 64 – 1. 78 ± 0 .3 5 6 m on th s 2. 03 ± 0 .7 3 – 1. 76 ± 0 .5 7 – 32 .7 0 ± 7. 55 – 1. 21 ± 0 .1 5 A bb re vi at io ns : B O P, b le ed in g on p ro bi ng ; C A L, c lin ic al a tt ac hm en t l os s; P I, pl aq ue in de x; P PD , p oc ke t p ro bi ng d ep th . a P er ce nt ag e of te et h pr es en tin g vi si bl e pl aq ue . b S m ok er s. c A cc or di ng to S iln es s an d Lö e (1 96 4) . d N on -s m ok er s. e A cc or di ng to L öe (1 96 7) . *p < .0 5; ** p < .0 01 . TA B LE 3 (C on tin ue d) 188 | SALVI et AL. TA B LE 4 C ha ra ct er is tic s of s tu di es o n ad ju nc tiv e aP D T ton on -s ur gi ca l m ec ha ni ca l i ns tr um en ta tio n Fi rs t a ut ho r ( ye ar ) St ud y Ty pe D es ig n n ce nt re In du st ria l f un di ng C al ib ra tio n Pa tie nt ch ar ac te ris tic s n pa tie nt s ( n fe m al e) M ea n ag e ± SD (r an ge ) Pe rio do nt al d ia gn os is Sm ok in g st at us n tr ea te d te et h/ si te s p er tr ea tm en t a rm Si te s o f p ro bi ng p er to ot h La se r La se r t yp e (p ro du ct n am e) M at er ia l o f t ip (d ia m et er ) Ph ot os en si tiz er A pp lic at io n tim e/ si te Ph ys ic al d at a La se r p ow er La se r e ne rg y Ir ra di at io n tim e W av el en gt h La se r i nt en si ty La se r d en si ty Tr ea tm en t Fo llo w -u p Ti m e po in ts (m on th s) Su pp or tiv e th er ap y A dv er se e ff ec ts Be ra kd ar e t a l. (2 01 2) RC T Sp lit -m ou th Si ng le -c en tr e N on e n. r. 22 p at ie nt s (1 0 fe m al e) 59 .3 ± 1 1. 7 (3 8– 74 ) C hP N on -s m ok er s 44 te et h (w ith ≥ 1 si te w ith B oP a nd P PD ≥5 m m ) PC P 12 (H u- Fr ie dy , U SA ) 6 D io de la se r ( Pe rio w av e, O nd in e Bi op ha rm a, V an co uv er , C an ad a) n. r. (6 00 μ m ) M et hy le ne b lu e 0. 00 5% n. r. 15 0 m W n. r. 60 s 67 0 nm n. r. n. r. Te st g ro up : S RP (h an d) + a PD T C on tr ol g ro up : S RP (h an d) 1 – 3 – 6 n. r. N on e Th eo do ro e t a l. (2 01 2) RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er c al ib ra te d 33 p at ie nt s (2 1 fe m al e) 43 .1 2 ± 8. 2 (n .r. ) C hP N on -s m ok er s 33 s ite s (B oP , P PD 5 –9 m m , a pp ro xi m al ) PC P- U N C 15 (H u- Fr ie dy ), oc cl us al s te nt n. r. D io de la se r/ G aA lA s la se r (B io W av e, K on do rt ec h Eq ui pm en t, Sã o C ar lo s, B ra zi l) Fi br e op tic ti p (n .r. ) To lu id in e bl ue O 1 00 µ g/ m l n. r. 30 m W 4. 5 J 15 0 s/ si te 66 0 nm 0. 4 W /c m 2 64 .2 8 J/ cm 2 Te st g ro up : S RP (h an d) + a PD T C on tr ol g ro up : S RP (h an d) 2 – 3 – 6 O H I a nd p ro fe ss io na l pr op hy la xi s (w ee kl y in m on th 1 , b im on th ly in m on th 2 –3 , m on th ly in m on th 4 –6 ) N on e D ils iz e t a l. (2 01 3) a RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er c al ib ra te d 24 p at ie nt s (1 4 fe m al e) 40 .7 ± 7 .3 (3 0– 58 ) C hP N on -s m ok er s 14 4 te et h di st rib ut ed o ve r t hr ee tr ea tm en t gr ou ps Fl or id a Pr ob e (G ai ne sv ill e, U SA ) w ith a n oc cl us al s te nt n. r. D io de la se r/ A lG aA s la se r (D oc to r S m ile d io de , LA M BD A S ci en tif ic a, V ic en za , It al y) Fi br e op tic ti p (3 00 μ m ) M et hy le ne b lu e 1% 3 m in 10 0 m W 6 J 60 s 80 8 nm n. r. n. r. Te st g ro up : F M -S RP (u ltr as on ic ) w ith ou t tim e re st ric tio n + 1 w ee k la te r S RP (h an d) + a PD T C on tr ol g ro up : F M -S RP (u ltr as on ic ) w ith ou t t im e re st ric tio n + 1 w ee k la te r SR P (h an d) + p la ce bo la se r 6 Pr of es si on al p ro ph yl ax is af te r 1 a nd 3 m on th s N on e Be ts y et a l. (2 01 4) RC T Pa ra lle l a rm s Si ng le -c en tr e N on e Ex am in er c al ib ra te d 88 b p at ie nt s (4 4c , 4 4d ) 51 fe m al e (2 2c , 2 9d ) 40 .8 ± 8 .3 c , 38 .4 ± 9 .6 d C hP N on -s m ok er s 10 9c , 1 20 d t ee th (P PD 4 –6 m m , s in gl e- ro ot ed ) W ill ia m s 4 D io de la se r ( C N I O pt o- el ec tr on ic s Te ch . C o. L td , C ha ng ch un , C hi na ) Fi br e op tic ti p (2 00 μ m ) M et hy le ne b lu e 10 m g/ m l 3 m in 1, 00 0 m W n. r. 60 s /s ite 65 5 nm n. r. 60 m W /c m 2 Te st g ro up : F M -S RP (h an d + ul tr as on ic ) w ith ou t t im e re st ric tio n + aP D T C on tr ol g ro up : F M -S RP (h an d + ul tr as on ic ) w ith ou t t im e re st ric tio n 0. 5 – 1 – 3 – 6 n. r. N on e M al gi ka r e t a l. (2 01 6) RC T Sp lit -m ou th Si ng le -c en tr e N on e Ex am in er c al ib ra te d 24 p at ie nt s (9 fe m al e) 36 .7 3 ± 8. 46 e , 34 .3 3 ± 6. 80 f ( 24 –5 5) C hP N on -s m ok er s n. r. U N C− 15 , o cc lu sa l s te nt n. r. D io de la se r ( D en La se ; C hi na D ah en g G ro up , I nc ., Be iji ng C hi na ) Fi br e op tic ti p (4 00 μ m ) M et hy le ne b lu e 1% 3 m in 1, 00 0 m W (5 .0 W pe ak p ow er , w ith 20 0 μs p ul se le ng th + 2 00 μ s pu ls e in te rv al ) n. r. 30 –4 5 s/ si te 98 0 nm n. r. n. r. Te st g ro up : F M -S RP (h an d + ul tr as on ic ) + aP D T (2 4 hr la te r) C on tr ol g ro up FM -S RP (h an d + ul tr as on ic ) 1 – 3 – 6 O H I a ft er 1 , 3 a nd 6 m on th s N on e (C on tin ue s) | 189SALVI et AL. Fi rs t a ut ho r ( ye ar ) St ud y Ty pe D es ig n n ce nt re In du st ria l f un di ng C al ib ra tio n Pa tie nt ch ar ac te ris tic s n pa tie nt s ( n fe m al e) M ea n ag e ± SD (r an ge ) Pe rio do nt al d ia gn os is Sm ok in g st at us n tr ea te d te et h/ si te s p er tr ea tm en t a rm Si te s o f p ro bi ng p er to ot h La se r La se r t yp e (p ro du ct n am e) M at er ia l o f t ip (d ia m et er ) Ph ot os en si tiz er A pp lic at io n tim e/ si te Ph ys ic al d at a La se r p ow er La se r e ne rg y Ir ra di at io n tim e W av el en gt h La se r i nt en si ty La se r d en si ty Tr ea tm en t Fo llo w -u p Ti m e po in ts (m on th s) Su pp or tiv e th er ap y A dv er se e ff ec ts A l-A sk ar e t a l. (2 01 7) RC T Pa ra lle l a rm s Si ng le -c en tr e N on e Ex am in er c al ib ra te d 70 p at ie nt s (3 5c , 3 5d ) 0 fe m al e 45 .7 ± 0 .8 c , 42 .5 ± 2 .6 d n. r. N on -s m ok er s n. r. (≥ 6 si te s w ith P PD ≥ 4 m m p er p at ie nt ) G ra de d pr ob e (H u- Fr ie dy , U SA ) 6 D io de la se r ( Pe rio w av e, O nd in e Bi op ha rm a, V an co uv er , C an ad a) Fl ex ib le ti p M et hy le ne b lu e 0. 00 5% n. r. 15 0 m W n. r. 60 s /s ite 67 0 nm n. r. n. r. Te st g ro up : F M -S RP (u ltr as on ic ) + a PD T C on tr ol g ro up : F M -S RP (u ltr as on ic ) 3 – 6 n. r. n. r. Bu nd id pu n et a l. (2 01 8) RC T Sp lit -m ou th Si ng le -c en tr e N on e n. r. 20 p at ie nt s (1 3 fe m al e) 47 .2 5 ± 8. 91 (3 5– 70 ) C hP N on -s m ok er s 83 9c , 7 89 d s ite s U N C- 15 (H u- Fr ie dy , U SA ) 6 D io de la se r ( H EL BO Ph ot od yn am ic S ys te m s, Se nd en , G er m an y) Fi br e op tic ti p (n .r. ) Ph en ot hi az in e ch lo rid e 1 m in 10 0 m W n. r. 10 s /s ite (6 s ite s pe r t oo th ) 66 0 nm n. r. n. r. Te st g ro up : F M -S RP (u ltr as on ic ) + a PD T (1 w ee k la te r) C on tr ol g ro up : F M -S RP (u ltr as on ic ) 1 – 3 – 6 O H I a nd s up ra gi ng iv al cl ea ni ng a ft er 1 , 3 a nd 6 m on th s N on e Ra ut e t a l.(2 01 8) RC T Pa ra lle l a rm s Si ng le -c en tr e N on e Ex am in er c al ib ra te d 50 p at ie nt sg (2 5c , 2 5d ) 22 fe m al e (9 c , 13 d ) 51 ± 2 .8 3c , 4 6. 90 ± 4 .3 2d C hP N on -s m ok er s n. r. U ni ve rs ity o f N or th C ar ol in a no 15 (H u- Fr ie dy , U SA ) 6 D io de la se r/ G aA lA s la se r (n .r. ) n. r. In do cy an in e gr ee n 5 m g/ m l 1 m in 80 0 m W n. r. 60 s /t oo th 81 0 nm n. r. 5. 4 J/ cm 2 Te st g ro up : S RP (h an d + ul tr as on ic ) + a PD T C on tr ol g ro up : S RP (h an d + ul tr as on ic ) + p la ce bo la se r 6 n. r. N on e A bb re vi at io ns : A lG aA s, a lu m in iu m g al liu m a rs en id e la se r; Bo P, b le ed in g on p ro bi ng ; C hP , c hr on ic p er io do nt iti s; F M , f ul l m ou th ; h an d, h an d in st ru m en ts ; G aA lA s, a lu m in iu m g al liu m a rs en id e la se r; n, nu m be r; n. r., n ot re po rt ed ; O H I, or al h yg ie ne in st ru ct io n; a PD T, a nt im ic ro bi al p ho to dy na m ic th er ap y; P PD , p oc ke t p ro bi ng d ep th ; R C T; ra nd om iz ed c on tr ol le d cl in ic al tr ia l; SR P, s ca lin g an d ro ot p la ni ng . a S tu dy h as 2 te st g ro up s se e Ta bl e 2. b 3 p at ie nt s lo st to fo llo w -u p an d 2 pa tie nt s di sc on tin ue d in te rv en tio n. c T es t. d C on tr ol . e M al es . f F em al es . g 5 p at ie nt s lo st to fo llo w -u p. TA B LE 4 (C on tin ue d) 190 | SALVI et AL. TA B LE 5 C lin ic al o ut co m e pa ra m et er s of s tu di es o n ad ju nc tiv e aP D T to n on -s ur gi ca l m ec ha ni ca l i ns tr um en ta tio n. If n ot o th er w is e in di ca te d, p ar am et er s ar e pr es en te d as m ea ns ± S D Fi rs t a ut ho r ( ye ar ) G ro up Ti m e po in t PP D (m m ) PP D c ha ng e (m m ) C A L (m m ) C A L ch an ge (m m ) BO P (% ) BO P ch an ge (% ) PI (% ) Be ra kd ar e t a l. (2 01 2) Te st Ba se lin e 6. 4 ± 0. 8 – 8. 1 ± 1. 3 – 10 0a – – 6 m on th s – 2. 9 ± 0. 8* – – 13 .6 a – – C on tr ol Ba se lin e 5. 9 ± 0. 8 – 7. 2 ± 1. 2 – 10 0a – – 6 m on th s – 2. 4 ± 0. 6 – – 22 .7 a – – Th eo do ro e t a l. (2 01 2) Te st Ba se lin e 5. 75 ± 1 .4 4 – 6. 52 ± 2 .1 1 – 93 .9 – 90 .9 6 m on th s 3. 42 ± 1 .1 5 – 4. 96 ± 2 .0 7 – 45 .5 – 27 .3 C on tr ol Ba se lin e 5. 81 ± 1 .0 – 6. 23 ± 1 .2 5 – 97 .0 – 93 .9 6 m on th s 3. 1 ± 0. 83 – 4. 25 ± 1 .7 3 – 27 .3 – 15 .2 D ils iz e t a l. (2 01 3) Te st Ba se lin e 5. 88 ± 0 .7 4 – 7. 67 ± 0 .5 6 – 88 ± 0 .3 4 – 1. 50 ± 0 .5 1b 6 m on th s 4. 33 ± 0 .4 8 1. 54 ± 0 .5 9 6. 13 ± 0 .9 9 1. 54 ± 1 .1 0 38 ± 0 .4 9 – 0. 79 ± 0 .4 1b C on tr ol Ba se lin e 5. 83 ± 0 .7 6 – 7. 50 ± 0 .7 2 – 92 ± 0 .2 8 – 1. 46 ± 0 .5 1b 6 m on th s 4. 42 ± 0 .8 8 1. 42 ± 0 .8 8 6. 04 ± 1 .0 0 1. 50 ± 0 .8 8 46 ± 0 .5 1 – 0. 71 ± 0 .4 6b Be ts y et a l. (2 01 4) Te st Ba se lin e 5. 7 (5 .0 –6 .0 ;1 .0 )c – 6. 5 (5 .0 –8 .0 ;1 .4 )c – – – 2. 0 (0 .5 – 3. 0; 0. 8) c, d, * 6 m on th s 3. 0 (2 .0 –6 .0 ;1 .0 )c, * – 4. 0 (2 .6 –7 .0 ;2 .0 )c, * – – – 1. 0 (0 .0 – 2. 5; 1. 0) c, d C on tr ol Ba se lin e 5. 5 (4 .2 –6 .0 ;1 .0 )c – 6. 0 (4 .2 –8 .0 ;1 .7 )c – – – 1. 2 (0 .5 – 3. 0; 1. 0) c, d, * 6 m on th s 4. 0 (2 .0 –6 .0 ;1 .0 )c, * – 4. 5 (2 .0 –7 .0 ;2 .0 )c, * – – – 0. 5 (0 .0 – 2. 0; 0. 5) c, d M al gi ka r e t a l. (2 01 6) Te st Ba se lin e 6. 13 ± 0 .3 8 – 6. 59 ± 0 .5 0 – – – 2. 54 ± 1 .7 0d 6 m on th s 3. 57 ± 0 .4 1* 2. 57 ± 0 .5 3 4. 04 ± 0 .3 7 2. 55 ± 0 .4 4 – – 1. 73 ± 0 .4 9d C on tr ol Ba se lin e 6. 16 ± 0 .4 0 – 6. 63 ± 0 .5 3 – – – 2. 49 ± 1 .7 3d 6 m on th s 3. 65 ± 0 .4 9* 2. 50 ± 0 .5 4 4. 00 ± 0 .3 9 2. 63 ± 0 .4 7 – – 1. 60 ± 0 .5 2d A l-A sk ar e t a l. (2 01 7) Te st Ba se lin e 15 .8 ± 3 .4 e – – – 51 .6 ± 7 .9 – 54 .4 ± 8 .4 6 m on th s 10 .4 ± 2 .5 e – – – 40 .3 ± 5 .6 – 42 .5 ± 6 .7 C on tr ol Ba se lin e 17 .2 ± 3 .4 e – – – 56 .4 ± 9 .3 – 51 .6 ± 7 .5 6 m on th s 13 .6 ± 2 .8 e – – – 44 .5 ± 8 .2 – 47 .2 ± 7 .4 Bu nd id pu n et a l. (2 01 8) Te st Ba se lin e 4. 96 ± 1 .1 1 – 5. 15 ± 1 .5 6 – 85 .5 0 – 3. 01 ± 1 .0 7f 6 m on th s 2. 97 ± 0 .7 4 1. 99 ± 0 .8 9 3. 99 ± 1 .2 3 1. 16 ± 1 .1 6 33 .3 0* 52 .2 0 2. 06 ± 1 .0 9f C on tr ol Ba se lin e 4. 91 ± 1 .0 2 – 5. 01 ± 1 .5 7 – 83 .6 0 – 3. 02 ± 1 .0 8f 6 m on th s 3. 02 ± 0 .8 1 1. 89 ± 0 .9 2 3. 89 ± 1 .3 3 1. 12 ± 1 .1 6 40 .5 0* 43 .1 0 2. 15 ± 1 .0 6f (C on tin ue s) | 191SALVI et AL. power of the lasers ranged from 30 to 1,000 mW with an irradia- tion time of 10 to 150 s per site. Wavelengths of lasers ranged from 655 to 980 nm. In three articles, laser densities were reported and ranged from 5.4 to 60 J/cm2 (Betsy et al., 2014; Raut et al., 2018; Theodoro et al., 2012). Five articles reported the application of methylene blue in different concentrations as photosensitizer, while three articles (Bundidpun et al., 2018; Raut et al., 2018; Theodoro et al., 2012) reported the use of toluidine blue O, phenothiazine chloride or in- docyanine green for laser activation. Application time of the photo- sensitizer per site amounted to 1 min (Bundidpun et al., 2018; Raut et al., 2018) or 3 min (Betsy et al., 2014; Dilsiz et al., 2013; Malgikar et al., 2016), if reported. All studies included test and control groups. In both groups, non-surgical mechanical instrumentation was performed by hand instruments, that is curettes (Berakdar et al., 2012; Theodoro et al., 2012), or power-driven instruments, that is ultrasonic devices (Al- Askar et al., 2017; Bundidpun et al., 2018), or a combination of both (Betsy et al., 2014; Dilsiz et al., 2013; Malgikar et al., 2016; Raut et al., 2018). In all studies but 1 (Dilsiz et al., 2013), non-surgical mechanical instrumentation was performed in one single session. Five articles reported full-mouth instrumentation (Al-Askar et al., 2017; Betsy et al., 2014; Bundidpun et al., 2018; Dilsiz et al., 2013; Malgikar et al., 2016). Treatment in controls consisted of non-surgical mechan- ical instrumentation without adjunctive measures. In two studies, a placebo laser was additionally used in the control group (Dilsiz et al., 2013; Raut et al., 2018). Treatment in the test groups consisted of non-surgical mechanical instrumentation with adjunctive aPDT, which was applied immediately after mechanical instrumentation in five studies (Al-Askar et al., 2017; Berakdar et al., 2012; Betsy et al., 2014; Raut et al., 2018; Theodoro et al., 2012). In three studies, aPDT was applied with a time lag after mechanical instrumentation, that is after 24 hrs (Malgikar et al., 2016) or 1 week (Bundidpun et al., 2018; Dilsiz et al., 2013). In all studies, aPDT was applied once. In all studies, maximum follow-up time amounted to 6 months. None of the included articles reported on PPD measurements and/ or subgingival mechanical debridement within 6 months after initial treatment. Oral hygiene instructions and/or professional prophylaxis were performed after 1, 3 and 6 months in three studies (Bundidpun et al.,2018; Dilsiz et al., 2013; Malgikar et al., 2016) and in weekly to monthly intervals in one study (Theodoro et al., 2012). 3.3.5 | Outcomes The outcomes of the eight studies evaluating the adjunctive use of aPDT are summarized in Table 5. In order to conduct meta-analyses on reported mean PPD changes between baseline and the 6-month follow-up, studies were grouped according to wavelength, fre- quency of mechanical instrumentation (i.e. only 1×) and frequency of aPDT application (i.e. only 1×). Based on the small number of stud- ies in the meta-analysis (i.e. <10), funnel plots were not included to display publication bias.F irs t a ut ho r ( ye ar ) G ro up Ti m e po in t PP D (m m ) PP D c ha ng e (m m ) C A L (m m ) C A L ch an ge (m m ) BO P (% ) BO P ch an ge (% ) PI (% ) Ra ut e t a l. (2 01 8) Te st Ba se lin e 6. 04 ± 0 .8 2 – 5. 80 ± 0 .7 0 – 10 0 – 1. 52 ± 0 .4 6d 6 m on th s 3. 53 ± 0 .5 8* * – 4. 12 ± 0 .7 8* * – 10 * – 0. 60 ± 0 .4 7d C on tr ol Ba se lin e 6. 08 ± 0 .7 3 – 5. 68 ± 0 .6 9 – 10 0 – 1. 48 ± 0 .4 4d 6 m on th s 5. 08 ± 0 .6 6* * – 4. 96 ± 0 .7 3* * – 40 * – 0. 68 ± 0 .4 5d A bb re vi at io ns : B O P, b le ed in g on p ro bi ng ; C A L, c lin ic al a tt ac hm en t l os s; P I, pl aq ue in de x; P PD , p oc ke t p ro bi ng d ep th . a % c as es w ith ≥ 1 to ot h w ith B O P. b A cc or di ng to L öe (1 96 7) . c M ed ia n (ra ng e; in te r- qu ar til e ra ng e) . d A cc or di ng to S iln es s an d Lö e (1 96 4) . e N um be r o f s ite s w ith P PD ≥ 4 m m . f T ur es ky m od ifi ca tio n of Q ui gl ey a nd H ei n (1 96 2) . *p < .0 5; ** p < .0 01 . TA B LE 5 (C on tin ue d) 192 | SALVI et AL. 3.3.6 | Primary outcome: Change in PPD Five studies were excluded from meta-analysis based on the fact that treatment was repeated after one week (Dilsiz et al., 2013), mean PPD changes were not reported (Raut et al., 2018; Theodoro et al., 2012), mean PPD values were not reported (Betsy et al., 2014), and only treated sites with PPD ≥4 mm were reported (Al-Askar et al., 2017). Figure 2 illustrates the results of the meta-analysis for changes in PPD based on two studies with split-mouth design including a total of 42 patients (Berakdar et al., 2012; Bundidpun et al., 2018). No statistically significant difference (WMD = 0.35 mm; 95%CI: −0.04/0.73; p = .08) was observed comparing adjunctive use of aPDT (wavelength range: 650–700 nm) to non-surgical periodontal therapy alone. 3.3.7 | Secondary outcomes Table 6b summarizes the percentages of studies reporting on sec- ondary outcomes. Changes in Plaque Index were reported in all studies. CAL changes and the report of harms or adverse effects represented the second most cited outcomes (i.e. 88%) followed by BoP changes (i.e. 75%). Changes in subgingival biofilm composition were reported in 25% of articles. Patient-reported outcome meas- ures and residual PPD were reported in 1 article each (i.e. 13%), and no article reported on changes in GCF biomarker levels/volumes. 3.4 | Quality assessment The assessment of risk of bias of the included studies is illustrated in Figure 3a,b and was based on the Cochrane Center and CONSORT guidelines (Consolidated Standards of Reporting Trials) to evaluate the quality of RCTs (Moher et al., 2010; Schulz et al., 2010). No sin- gle study demonstrated high risk of bias, and the majority of studies displayed a low or unclear risk of bias. 4 | DISCUSSION The aim of the present systematic review was to investigate the ad- junctive effects of laser application or aPDT to non-surgical peri- odontal therapy of at least 20 patients with untreated periodontitis after a follow-up of 6 months. It should be noted that studies report- ing on laser application or aPDT as a monotherapy as well as studies conducted in treated periodontitis patients and in patients enrolled in supportive periodontal therapy were not considered for the pre- sent systematic review. Moreover, studies reporting on the use of airpolishing devices were not considered as it is not regarded the standard of care for untreated periodontitis patients. The adjunctive use of lasers with eight different wavelengths was identified. The potential benefits compared to control proce- dures were evaluated in 10 studies with a total of 370 patients for adjunctive laser therapy and in eight studies with a total of 331 pa- tients for adjunctive aPDT. The results of one meta-analysis includ- ing two studies with split-mouth design indicated that adjunctive aPDT application to non-surgical periodontal therapy failed to yield statistically significant improvements with respect to mean PPD changes between baseline and the 6-month follow-up. The term “untreated periodontitis” was selected in order to dif- ferentiate adjunctive application of lasers or aPDT between patients with untreated periodontitis and those enrolled in supportive peri- odontal therapy. Moreover, a potential wash-over effect could not be completely ruled out when applying aPDT in studies with a split- mouth design and may bias the outcomes. In addition, keeping in mind the observed great heterogeneity among the studies identified by the systematic search, in particu- lar in terms of laser type, tip diameter, wavelength, photosensitizer, mode of periodontal treatment, number of treated sites, population and several possible combinations of these parameters, a careful attempt was developed to conduct meta-analyses only when PPD changes between baseline and the 6-month follow-up were reported in the original articles. Within the highly heterogeneous set of con- founding variables, a selection of parameters including wavelength, type of laser, single episode of non-surgical periodontal therapy and single application of laser/aPDT for grouping the studies was consid- ered and applied for further analysis in case studies were suitable. Two articles included PROMs, and 10 articles reported the pres- ence/absence of harms or adverse effects. Nine studies did not ob- serve any adverse or side effects (Berakdar et al., 2012; Betsy et al., 2014; Bundidpun et al., 2018; Dereci et al., 2016; Dilsiz et al., 2013; Kelbauskiene et al., 2011; Malgikar et al., 2016; Raut et al., 2018; Theodoro et al., 2012). In one study, two periodontal abscesses oc- curred in the test group (Rotundo et al., 2010). All but one study (Kamma et al., 2009) were performed in a uni- versity setting. Interestingly, no study reported on cost/benefit ratio related to adjunctive laser/aPDT application. F I G U R E 2 Forest plot of the weighted mean change in PPD at 6 months with adjunctive aPDT with diode lasers (wavelength range 650–700 nm; test) compared with non-surgical mechanical instrumentation alone (control) | 193SALVI et AL. TA B LE 6 (a ) F re qu en cy o f r ep or te d se co nd ar y ou tc om es o f i nc lu de d ar tic le s on a dj un ct iv e la se r t he ra py . ( b) F re qu en cy o f r ep or te d se co nd ar y ou tc om es o f i nc lu de d ar tic le s on a dj un ct iv e an tim ic ro bi al p ho to dy na m ic th er ap y (a PD T) Fi rs t a ut ho r ( ye ar ) C A L ch an ge Bo P ch an ge Pl aq ue In de x ch an ge Re si du al P PD Ch an ge s i n su bg in gi va l bi of ilm c om po si tio n Ch an ge s i n G CF b io m ar ke r le ve ls /v ol um es PR O M s H ar m s o r ad ve rs e ef fe ct s (a ) Ü st ün e t a l. (2 01 8) + + + N R N R + N R N R M at ar es e et a l. (2 01 7) + + + N R + + N R N R H at ip og lu e t a l. (2 01 7) + + + N R N R N R N R N R D er ec i e t a l. (2 01 6) + + + N R +N R N R + Eu ze bi o A lv es e t a l. (2 01 3) + + + + + N R N R N R D ils iz e t a l. (2 01 3) + + + N R N R N R N R + El ta s an d O rb ak (2 01 2a ) + N R + N R N R + N R N R Ke lb au sk ie ne e t a l. (2 01 1) + + N R N R N R N R N R + Ro tu nd o et a l. (2 01 0) + + + N R N R N R + + K am m a et a l. (2 00 9) + + + N R + N R N R N R To ta l 10 (1 00 % ) 9 (9 0% ) 9 (9 0% ) 1 (1 0% ) 4 (4 0% ) 3 (3 0% ) 1 (1 0% ) 4 (4 0% ) (b ) Ra ut e t a l. (2 01 8) + + + N R + N R N R + Bu nd id pu n et a l. (2 01 8) + + + + N R N R N R + A l-A sk ar e t a l. (2 01 7) N R + + N R N R N R N R N R M al gi ka r e t a l. (2 01 6) + N R + N R N R N R N R + Be ts y et a l. (2 01 4) + N R + N R N R N R + + D ils iz e t a l. (2 01 3) + + + N R N R N R N R + Be ra kd ar e t a l. (2 01 2) + + + N R N R N R N R + Th eo do ro e t a l. (2 01 2) + + + N R + N R N R + To ta l 7 (8 8% ) 6 (7 5% ) 8 (1 00 % ) 1 (1 3% ) 2 (2 5% ) 0 (0 % ) 1 (1 3% ) 7 (8 8% ) A bb re vi at io ns : + , o ut co m e re po rt ed ; B oP , b le ed in g on p ro bi ng ; C A L, c lin ic al a tt ac hm en t l ev el ; G C F, g in gi va l c re vi cu la r f lu id ; N R, o ut co m e no t r ep or te d; P PD , p oc ke t p ro bi ng d ep th ; P RO M s, p at ie nt - re po rt ed o ut co m e m ea su re s. 194 | SALVI et AL. F I G U R E 3 (a, b) Parameters provided in the Cochrane Center and CONSORT guidelines (Consolidated Standards of Reporting Trials) to evaluate the quality of randomized controlled trials (RCTs) (a) (b) | 195SALVI et AL. The results of the present systematic review are in accordance with those presented in recent narrative reviews on the topic (Cobb, 2017; Mizutani et al., 2016). Collectively, available evidence is lim- ited and highly heterogeneous. If both statistical and clinical significance are considered to be equally important when comparing adjunctive laser therapy or aPDT to non-surgical mechanical instrumentation alone, future RCTs should define which criteria determine clinical significance. Defining PPD changes as the primary outcome has some limitations. The reporting of the percentage of PPDs ≤5 mm or the percentage of PPDs >5 mm would be meaningful from a clinical perspective. Unfortunately, only one study on adjunctive lasers and one study on adjunctive aPDT re- ported on residual PPDs. This is of critical importance when planning dissemination of evidence-based guidelines for periodontal therapy. In this context, guidelines for periodontal therapy should include a list of criteria for the assessment of (a) thresholds of reduction in PPD, BoP and gain in CAL, (b) percentage of residual PPD >5 mm requiring additional periodontal therapy, (c) frequency distribution of sites exhibiting a substantial improvement from baseline with re- spect to PPD, BoP and CAL, (d) harms and adverse events, (e) PROMs and (f) costs of treatment. Ideally, future studies should adopt the CONSORT guidelines, apply sufficient statistical power, use appro- priate randomization and avoid split-mouth designs. It is well known that smoking adversely affects periodon- tal treatment outcomes. Therefore, the results of studies with adjunctive laser application including smokers (Kamma et al., 2009; Rotundo et al., 2010) need to be interpreted accordingly. Furthermore, clinicians should be aware that the evidence on the effects of adjunctive therapy with different types of lasers or aPDT is affected by a number of factors such as: (a) the variation in diag- nosis and risk profiles of patients with untreated periodontitis, (b) the variation in protocols and frequency of non-surgical mechani- cal instrumentation, (c) the variation in laser types/wavelengths, (d) the variation in aPDT protocols and (e) the variation in frequency of application of adjunctive laser or aPDT. Hence, in patients with untreated periodontitis, current evidence on the adjunctive use of lasers or aPDT to non-surgical periodontal therapy is limited and heterogeneous. ACKNOWLEDG EMENTS The authors would like to thank Carin A. Rinne and Silwan Mendes (Basel) for their support in the preparation of the manuscript. CONFLIC T OF INTERE S T The authors do not report any conflicts of interest. ORCID Giovanni E. Salvi https://orcid.org/0000-0001-5523-3192 Alexandra Stähli https://orcid.org/0000-0002-5631-3300 Julia C. Schmidt https://orcid.org/0000-0003-1515-8831 Christoph A. Ramseier https://orcid.org/0000-0002-5110-2539 Anton Sculean https://orcid.org/0000-0003-2836-5477 Clemens Walter https://orcid.org/0000-0002-9967-1570 R E FE R E N C E S Abduljabbar, T., Vohra, F., Kellesarian, S. V., & Javed, F. (2017). Efficacy of scaling and root planing with and without adjunct Nd:YAG laser therapy on clinical periodontal parameters and gingival crevicular fluid interleukin 1-beta and tumor necrosis factor-alpha levels among patients with periodontal disease: A prospective randomized split- mouth clinical study. 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