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Asymptomatic or mildly symptomatic COVID-19 patients with craniomaxillofacial injuries have an increase risk of surgical site infection

  • Author Footnotes
    1 Equal contribution
    Poramate Pitak-Arnnop
    Correspondence
    Corresponding author at: Klinik für MKG-Chirurgie, Universitätsklinikum Marburg, UKGM, Baldingerstr., 35043 Marburg, Germany.
    Footnotes
    1 Equal contribution
    Affiliations
    Department of Oral and Maxillofacial Surgery, University Hospital of Giessen and Marburg, UKGM GmbH, Campus Marburg, Faculty of Medicine, Philipps-University of Marburg, Marburg, Germany
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    1 Equal contribution
    Chatpong Tangmanee
    Footnotes
    1 Equal contribution
    Affiliations
    Department of Statistics, Chulalongkorn Business School, Bangkok, Thailand
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  • Author Footnotes
    1 Equal contribution
    Chayawee Muangchan
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    1 Equal contribution
    Affiliations
    Department of Internal Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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    2 Equal contribution
    Jean-Paul Meningaud
    Footnotes
    2 Equal contribution
    Affiliations
    Department of Plastic, Reconstructive, Aesthetic and Maxillofacial Surgery, Henri Mondor University Hospital, AP-HP, Faculty of Medicine, University Paris-Est Créteil Val de Marne (Paris XII), Créteil, France
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    2 Equal contribution
    Andreas Neff
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    2 Equal contribution
    Affiliations
    Department of Oral and Maxillofacial Surgery, University Hospital of Giessen and Marburg, UKGM GmbH, Campus Marburg, Faculty of Medicine, Philipps-University of Marburg, Marburg, Germany
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      Abstract

      Purpose

      To evaluate the association between “asymptomatic or mildly symptomatic”, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (AS/MS-COVID) and surgical site infection (SSI) after craniomaxillofacial injury (CMFI) repair.

      Methods

      Using a case-control study design with a match ratio of 1:4, we enrolled a cohort of AS/MS-COVID cases with CMFI immediately treated during a one-year interval. The main predictor variable was SARS-CoV-2 infection (yes/no), and the outcome of interest was SSI (yes/no). The other variables were demographic, clinical, and operative. Appropriate statistics were computed, and P < 0.05 was considered statistically significant.

      Results

      The case group comprised 257 cases (28.8% females; 13.2% aged ≥ 60 years; 10.5% with fractures; 39.7% involved nasal/oral/orbital tissue [viral reservoir organs, VROs]; 81.3% blunt trauma; 19.1% developed SSI [vs. 6.8% in the control group]) with a mean age of 39.8 ± 16.6 years (range, 19-87). There was a significant relationship between SARS-CoV-2 infection and SSI events (P < 0.0001; odds ratio, 3.22; 95% confidence interval, 2.17 to 4.78). On subgroup analysis, SSIs significantly increased with age ≥ 60 years, presence and treatment of fracture, contamination with VROs, and prolonged antibiotic use (PAU). However, multiple linear regression analysis confirmed the positive effect only from old age, contact with VROs, and PAU (relative risk = 1.56, 2.52, and 2.03; r = 0.49; P = 0.0001).

      Conclusion

      There is a significant 2.8-fold increase in SSIs among AS/MS-COVID cases, especially those aged ≥ 60 years and/or injured to VROs, and thereby, require PAU.

      Keywords

      Introduction

      Elective surgical procedures have often been postponed or cancelled during the coronavirus disease 2019 (COVID-19) pandemic (as recommended by the AO CMF authors

      Pitak-Arnnop P, Sirintawat N, Tangmanee C, et al. Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients. J Stomatol Oral Maxillofac Surg (in press) doi: 10.1016/j.jormas.2022.01.006.

      ) because they may be at high risk of viral transmission. Microvascular alterations due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were found to cause SSIs at both donor and recipient sites in free fibular flap reconstruction.
      • Inouye D.
      • Zhou S.
      • Clark B.
      • et al.
      Two cases of impaired wound healing among patients with major head and neck free-flap reconstruction in the setting of COVID-19 infection.
      Our recent study, nevertheless, demonstrated the absence of nosocomial SARS-CoV-2 infection among hospital personnel in contact with asymptomatic COVID-19 patients undergoing midfacial fracture repair

      Pitak-Arnnop P, Sirintawat N, Tangmanee C, et al. Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients. J Stomatol Oral Maxillofac Surg (in press) doi: 10.1016/j.jormas.2022.01.006.

      , suggesting that craniomaxillofacial injury (CMFI) care in asymptomatic or mildly symptomatic COVID-19 patients (AS/MS-COVID) could be safe. Moreover, several studies rejected the association between SARS-CoV-2 infection and surgical site infections (SSI) such as after hand surgery
      • Baldwin A.J.
      • Jackowski A.
      • Jamal A.
      • et al.
      Risk of surgical site infection in hand trauma, and the impact of the SARS-CoV-2 pandemic: A cohort study.
      , caesarean births

      McLaren R Jr, London V, Narayanamoorthy S, et al. Cesarean birth morbidity among women with SARS-CoV-2. Am J Perinatol (in press) doi: 10.1055/s-0041-1739430

      , or appendectomy
      • Huamán Egoávil E.
      • LaGrone L.
      • Ugarte Oscco R.
      • et al.
      SARS-CoV-2 infection is not associated with a higher rate of post-operative complications in adult appendectomy patients in Peru: Cross-sectional study.
      .
      To the best of our knowledge, there is currently inadequate scientific evidence through well controlled epidemiologic studies that explore the association between SSI events after CMFI treatments in COVID-19 patients. The aim of this study was to assess the risk that AS/MS-COVID poses in the development of SSI in patients undergoing CMFI repair. This patient group were our research interest because they are the majority of COVID-19 patients in Germany, i.e. 67%

      Rommel A, Lippe EV, Plass D, et al. COVID-19-Krankheitslast in Deutschland im Jahr 2020 – Durch Tod und Krankheit verlorene Lebensjahre im Verlauf der Pandemie. BURDEN 2020 Study Group. Dtsch Arztebl Int 2021;118:145-51. doi: 10.3238/arztebl.m2021.0147.

      , and may visit emergency departments (or could be treated without the diagnosis of SARS-CoV-2 infection). We hypothesised that the presence of AS/MS-COVID increased the risk of SSI after CMFI surgery significantly. Our specific purposes were 1) to identify a cohort of AS/MS-COVID patients with CMFI and estimate SSIs, 2) to assess additional risk factors for SSIs, and 3) to construct a clinically relevant predictive model of disease (i.e. SSI in relation to the presence of AS/MS-COVID).

      Materials and Methods

      Study Design and Sample Description

      The investigators designed and implemented a retrospective case-control, chart review study, which was approved by the institutional review board. The ethical principles of the declaration of Helsinki

      World Medical Association. The declaration of Helsinki – Ethical principles for medical research involving uman subjects. Available from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed February 2, 2022.

      and the STROBE statement

      University of Bern Institute of Social and Preventive Medicine. The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement. Available from: https://www.strobe-statement.org/. Accessed February 2, 2022.

      were followed throughout the study.
      Eligible cases must meet five conditions: having 1) ≥ 18 years of age, 2) SARS-CoV-2 infection tested twice as reported by our previous work

      Pitak-Arnnop P, Sirintawat N, Tangmanee C, et al. Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients. J Stomatol Oral Maxillofac Surg (in press) doi: 10.1016/j.jormas.2022.01.006.

      , 3) the American Society of Anesthesiologists (ASA) physical status classification system I or II without any conditions that could impair the wound healing and/or increase an SSI risk, such as diabetes mellitus (DM)

      American Society of Anesthesiologists’ Committee on Economy. ASA physical status classification system. Available from: https://www.asahq.org/standards-and-guidelines/asa-physical-status-classification-system. Accessed February 2, 2022.

      , 4) mildly symptomatic (i.e. mild flu-like symptoms such as throat soreness, running nose, taste and/or smell loss, or diarrhoea)

      Rommel A, Lippe EV, Plass D, et al. COVID-19-Krankheitslast in Deutschland im Jahr 2020 – Durch Tod und Krankheit verlorene Lebensjahre im Verlauf der Pandemie. BURDEN 2020 Study Group. Dtsch Arztebl Int 2021;118:145-51. doi: 10.3238/arztebl.m2021.0147.

      or asymptomatic COVID-19, and 5) immediate CMFI treatments during a one-year period in a German Level I Trauma Centre of a regional hospital group comprising seven hospitals in six “hot-spot” locations (> 65,000 confirmed cases during the study period). The term “immediate treatment” refers to appropriate patient care at patient’s hospital arrival (e.g. simple wound closure directly in the emergency department) until the first 24 hours of hospital stay (e.g. facial fracture repair which may be postponed due to operating room capacity).
      • Shah I.
      • Gadkaree S.K.
      • Tollefson T.T.
      • et al.
      Update on the management of craniomaxillofacial trauma in low-resource settings.
      • Lander D.P.
      • Lee J.J.
      • Kallogjeri D.
      • et al.
      The impact of treatment delay on malunion and nonunion after open reduction of mandible fractures.
      We identified “cases” via International Classification of Disease (ICD-10) diagnostic codes and Operation and Procedure Classification System (OPS) codes within the front-end anonym electronic medical records of the hospital database. A list of ICD and OPS codes used to identify potential cases is summarised in Table 1.
      Table 1International Classification of Disease (ICD-10) diagnostic code and Operation and Procedure Classification System (OPS) code used to identify potential subjects for the case group (available from: https://www.icd-code.de/).
      ICD codesDiagnosis
      S02.0, S02.1, S02.2, S02.3, S02.4, S02.5, S02.6, S02.7, S02.8Craniomaxillofacial fractures
      S00.01, S00.21, S00.31, S00.41, S00.51Craniofacial abrasion wounds
      S00.04, S00.24, S00.34, S00.44, S00.54Foreign bodies in craniofacial region
      S00.05, S00.1, S00.35, S00.45, S00.55Craniofacial bruising/contusion
      T14.4Multiple nerve injuries
      T14.5Multiple vascular injuries
      T14.6Muscular and fascial injuries
      J34.8Diseases of nose and paranasal sinuses, e.g. septal haematoma
      T1.0, S01.0, S01.1, S01.2, S01.3, S01.4, S01.5, S01.7Open wounds in craniofacial region
      K13.1Cheek and lip biting
      H05.0Acute inflammation of orbit
      H01.9Inflammation of eyelids
      H10.2Acute conjunctivitis
      S05.0Conjuntival injury and corneal abrasion
      H02.0Entropium
      H02.1Ektropium
      H02.4Eyelid ptosis
      S05.1Contusion of globes and orbital tissue
      S03.0Temporomandibular joint luxation
      OPS codesTreatments
      5-760.13, 5-760.14, 5-760.23, 5-760.24, 5-760.43, 5-760.44, 5-760.63, 5-760.64Lateral midfacial (i.e. zygomatic arch or complex) fracture repair
      5-761.13, 5-761.14, 5-761.33, 5-761.34, 5-761.43, 5-761.44Central midfacial (i.e. maxillary, nasoorbitoethmoidal) fracture repair
      5-762.13, 5-762.14, 5-762.53, 5-762.54Combined centro-lateral midfacial fracture repair
      5-092.2, 5-086. 5-086.1, 5-086.30Posttraumatic oculoplastic procedures
      5-764.13, 5-764.14, 5-764.23, 5-764.24, 5-764.3, 5-764.43, 5-764.44, 5-765.13, 5-765.14, 5-765.23, 5-765.24, 5-765.33, 5-765.34, 5-765.43, 5-765.44, 5-765.72, 5-765.73, 5-765.74Mandibular fracture repair
      5-766.0, 5-766.1, 5-766.2, 5-766.3, 5-766.4, 5-766.5, 5-167.0, 5-167.1, 5-167.2Orbital fracture repair
      5-168.xOptic nerve decompression
      5-164.0Releasing of retrobulbar haematoma
      5-767, 5-767.0, 5-767.1, 5-767.2, 5-767.3, 5-767.4Frontal fracture repair
      5-892.00, 5-892.04, 5-892.05, 5-892.1, 5-892.10, 5-892.14, 5-892.15Haematoma releasing of head and neck region (other than for retrobulbar haematoma) with/without drainage
      5-896.00, 5-896.04, 5-896.05, 5-896.10, 5-896.14, 5-896.15Débridement of head and neck region
      5-928.00, 5-928.01, 5-928.01, 5-928.02, 5-928.03, 5-928.04, 5-928.05, 5-928.0hSimple wound closure of head and neck region
      5-769.0, 5-769.1, 5-769.2, 5-769.3, 5-769.4, 5-769.5, 5-769.6Dental occlusion control, placement or removal of intermaxillary fixation
      5-056.0Neurolysis/decompression of cranial nerve outside skull
      5-774.7, 5-774.70, 5-774.71, 5-774.72, 5-774.8Plastic reconstruction and augmentation of maxilla
      5-779.0, 5-779.1Reduction of temporomandibular joint luxation
      Subjects were excluded if 1) CMFI surgery was unnecessary, such as closed, non-displaced, isolated nasal fractures, 2) COVID-19 symptoms were moderate to severe (e.g. high fever, coughing, pneumonia, or requiring intensive medical care)

      Rommel A, Lippe EV, Plass D, et al. COVID-19-Krankheitslast in Deutschland im Jahr 2020 – Durch Tod und Krankheit verlorene Lebensjahre im Verlauf der Pandemie. BURDEN 2020 Study Group. Dtsch Arztebl Int 2021;118:145-51. doi: 10.3238/arztebl.m2021.0147.

      , and 3) treatment was delayed (≥ 14 days posttrauma), and may cause more complications.
      • Shah I.
      • Gadkaree S.K.
      • Tollefson T.T.
      • et al.
      Update on the management of craniomaxillofacial trauma in low-resource settings.
      • Lander D.P.
      • Lee J.J.
      • Kallogjeri D.
      • et al.
      The impact of treatment delay on malunion and nonunion after open reduction of mandible fractures.
      Based on the hospital database in a 10-year interval before the COVID, four CMFI control cases were randomly recruited for each included case, and matched by gender, age (± 5 years), injury, and treatment types. We used a control-to-case ratio of 4:1 to increase the statistical power of the study, while ratios greater than 4:1 have little additional impact on power.

      Boston University School of Public Health. Case-control studies. Available from: https://sphweb.bumc.bu.edu/otlt/MPH-Modules/EP/EP713_Case-Control/. Accessed on February 2, 2022.

      Study Variables

      The primary predictor variable was SARS-CoV-2 infection (yes/no). The main outcome of interest was SSI (yes/no), defined by the US Centers for Disease Control and Prevention (CDC) as an infection related to an operative procedure that occurs at or near the surgical incision (or traumatic open wounds) within 30 days of the procedure (including trauma surgery), or within 90 days if prosthetic materials is implanted at surgery.

      National Healthcare Safety Network, Centers for Disease Control and Prevention (CDC). Surgical site infection event (SSI) 2022. Available from: https://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf. Accessed on February 2, 2022.

      The other variables were demographic, clinical, and operative. The demographic variables were gender (female/male) and age (adjusted into binary according to the old age cut-off value: 18-59 vs. ≥ 60 years). The clinical variables were injury mechanism (blunt vs. sharp/penetrating trauma) and location (presence of facial fracture or soft-tissue wound; contact with nasal/oral/orbital tissue which is a viral reservoir and may increase intensive viral dispersion

      Pitak-Arnnop P, Sirintawat N, Tangmanee C, et al. Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients. J Stomatol Oral Maxillofac Surg (in press) doi: 10.1016/j.jormas.2022.01.006.

      • Pitak-Arnnop P.
      • Meningaud J.P.
      • Sirintawat N.
      • et al.
      A German AWMF’s S2e/realist synthesis and meta-narrative snapshot of craniomaxillofacial manifestations in COVID-19 patients: Rapid living update on 1 January 2021.
      [yes/no]). The operative variables were treatment (fracture repair vs. simple wound closure), prolonged antibiotic use (PAU) ≥ 72 hours (yes/no), and hospital stay (yes/no).

      Data Management and Statistical Analysis

      Anonymous data were compiled using a data abstraction form and analysed by two software tools: MedCalc® (Ostend, Belgium) to estimate the risk of SSI after CMFI treatments, and G Power 3 for Windows (Düsseldorf, Germany) for the post hoc power analysis. We calculated odds ratios (OR), P values, 95% confidence intervals (CI), and relative risks (RR) using conditional logistic regression, which accounted for matching factors. The conditional logistic regression function was employed to test each independent variable separately and calculate the crude risk of SSI for each specific factor. We selected those variables that were significant at P < 0.05 for further multivariate linear regression analyses.

      Results

      There were 257 “case” patients and 1,028 controls were included for analysis. Within the “case” group, there were 74 females, 34 subjects aged ≥ 60 years, 27 with facial fractures requiring immediate treatments such as due to retrobulbar haematoma or as a part of polytrauma surgery [others underwent delayed treatment after COVID-19 healed], 102 (39.7%) with CMFI in contact with nasal/oral/orbital tissue [viral reservoir organs, VROs], and 209 (81.3%) with blunt trauma. The mean age was 39.8 ± 16.6 years (range, 19-87). All of the 257 “cases” were postoperatively admitted to an isolated room for ≥ 14 days from the diagnosis or the first symptom until the absence of COVID-19 symptoms for ≥ 48 hours “and” two negative COVID-19 tests were confirmed irrespective of treatments received, as recommended by the German Robert Koch Institute (RKI) for Disease Control and Prevention.

      Robert Koch-Institut. COVID-19: Entisolierung von Patient/-innen im stationären Bereich sowie Bewohner/-innen in Alten- und Pflegeheimen. Available from: https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Entlassmanagement.html. Accessed February 2, 2022.

      49 (or 19.1%) “cases” and 70 (6.8%) controls had an SSI (P = 0.0001; OR, 3.22; 95% CI, 2.17 to 4.78).
      On subgroup analysis, age ≥ 60 years, presence and treatment of fracture, contact with VROs, and PAU were significant risk factors of SSI development (R > 1.0). RR of gender, injury mechanism (i.e. blunt trauma) and hospital stay were close to 1.0, indicating no effect on the outcome (probably chance findings) (Table 2).
      Table 2Cohort characteristics grouped by surgical site infection (SSI), and bi- and multivariate analyses.
      ParametersTotal*(n = 1,285)SSI(n = 119)Non-SSI(n = 1,166)P-value(OR; 95% CI)RR
      Demographic
      Female370 (28.8)40 (10.8)330 (89.2)0.241.25
      Males915 (71.2)79 (8.6)836 (91.4)(1.28; 0.86 to 1.92)
      Females: case group74 (5.8)11 (14.9)63 (85.1)0.211.52
      Females: control group296 (23)29 (9.8)267 (90.2)(1.61; 0.76 to 3.39)
      Age ≥ 60 year170 (13.2)82 (48.2)88 (51.8)< 0.000114.54
      Age < 60 years1,115 (86.8)37 (3.3)1,078 (96.7)(27.15; 17.4 to 42.36)
      Age ≥ 60 years: case group34 (2.6)23 (67.6)11 (32.4)0.0131.56
      Age ≥ 60 years: control group136 (10.6)59 (43.4)77 (56.6)(2.73; 1.23 to 6.04)
      Clinical
      Sharp/penetrating trauma240 (18.7)22 (9.2)218 (90.8)1.00.99
      Blunt trauma1045 (81.3)97 (9.3)948 (90.7)(0.99; 0.61 to 1.6)
      Blunt trauma: case group209 (16.3)18 (8.6)191 (91.4)0.461.22
      Blunt trauma fracture: control group836 (65.1)59 (7.1)777 (92.9)(1.24; 0.72 to 2.15)
      Presence of fracture135 (10.5)21 (15.6)114 (84.4)0.0121.83
      Soft tissue injury only1,150 (89.5)98 (8.5)1,052 (91.5)(1.98; 1.19 to 3.29)
      Presence of fracture: case group27 (2.1)12 (44.4)15 (55.6)< 0.00015.33
      Presence of fracture: control group108 (8.4)9 (8.3)99 (91.7)(8.8; 3.17 to 24.42)
      Contact with VROs510 (39.7)88 (17.3)422 (82.7)< 0.00014.31
      No contact with VROs775 (60.3)31 (4)744 (96)(5; 3.27 to 7.67)
      Contact with VROs: case group102 (7.9)34 (33.3)68 (66.7)< 0.00012.52
      Contact with VROs: control group408 (31.8)54 (13.2)354 (86,8)(3.28; 1.99 to 5.41)
      Operative
      Fracture repair135 (10.5)21 (16.8)114 (84.4)0.0121.83
      Simple wound closure1,150 (89.5)98 (8.5)1,052 (91.5)(1.98; 1.19 to 3.29)
      Fracture repair: case group27 (2.1)12 (44.4)15 (55.6)< 0.00015.33
      Fracture repair: control group108 (8.4)9 (8.3)99 (91.7)(8.8; 3.17 to 24.42)
      Prolonged antibiotic use305 (23.7)95 (31.1)210 (68.9)< 0.000112.72
      No prolonged antibiotic use980 (76.3)24 (2.4)956 (97.6)(18.02; 11.24 to 28.89)
      Prolonged antibiotic use: case group61 (4.7)32 (52.5)29 (47.5)0.00012.03
      Prolonged antibiotic use: control group244 (19)63 (25.8)181 (74.2)(3.17; 1.78 to 5.65)
      Hospital stay418 (32.5)76 (18.2)342 (81.8)< 0.00013.67
      No hospital stay867 (67.5)43 (5)824 (95)(4.26; 2.87 to 6.32)
      Hospital stay: case group257 (20)49 (19.1)208 (80.9)0.61.14
      Hospital stay: control group161 (14.8)27 (16.8)134 (83.2)(1.17; 0.7 to 1.96)
      Overall (whole cohort)
      Case group257 (20)49 (19.1)208 (80.9)< 0.00012.8
      Control group1,028 (80)70 (6.8)958 (93.2)(3.22; 2.17 to 4.78)
      Note: VRO – viral reservoir organ; OR – adjusted odds ratio; 95% CI – 95% confidence interval; RR – relative risk. Categorical data are presented as number (percentage); * – Percentages in this column were calculated by the total subjects (n = 1,285). Statistically significant P-values are indicated in bold typeface, and the risk factors were determined by relative risk values (RR > 1.0) and presented with bold and italic typeface.
      Multiple linear regression analysis confirmed the positive effect only from old age, contact with VROs, and PAU (RR = 1.56, 2.52, and 2.03; r = 0.49; P = 0.0001). There are moderate positive correlations between SSI events in older AS/MS-COVID patients and VRO-contamination and PAU. Despite technically positive and negative correlations arising from presence and treatments of fractures, the relationships between SSI events in elderly patients with SARS-CoV-2 infection and these parameters were weak (r = 0.087 and -0.009) (Table 3).
      Table 3Multivariate linear regression analysis of study variables.
      Predictor variablesEstimateStandard errorr2rP-value
      Age ≥ 60 years0.18750.104N/AN/AN/A
      Presence of fracture0.1250.25430.00760.08720.63
      Contact with viral reservoir organ0.43750.12380.32620.57110.0014
      Fracture repair-0.43750.28860.0001-0.00910.14
      Prolonged antibiotic use0.50.1310.27570.52510.0007
      r20.5548
      r0.4934
      Overall P-value0.0001
      Note: SSI – surgical site infection; N/A – not applicable. Statistically significant P-values are indicated in bold typeface.
      The post hoc power estimate was 99.9% with an effect size of 0.5 and α = 0.05, suggesting nearly 100% chance of our research results with their real effect.

      Discussion

      This study is novel in using a scientific method to assess SSI events after CMFI repair in AS/MS-COVID patients. We found that these patients were 2.8 times more likely to suffer from SSIs, when compared to non-COVID patients. Hence, COVID-19 patients, albeit asymptomatic or mildly symptomatic, aged ≥ 60 years and/or with injury in contact with VROs require particular attention, when they have CMFI.
      It has been well known since the first pandemic wave that older people are severely affected through acute respiratory distress syndrome (ARDS) and high death rates. Patients at this age are prone to infections (i.e. SAS-COV-2 infection and others such as SSIs) and noncommunicable chronic diseases due to physiological changes especially chronic proinflammatory state and a decreased function of innate and acquired immunity. They often have frailty, sarcopenia, disability, cognitive decline, anxiety, depression, and so on, promoting negative progression of the disease.
      • Córdova L.D.S.
      • Vega A.P.M.
      • Luján-Carpio E.
      • et al.
      Clinical characteristics of older patients with COVID-19: A systematic review of case reports.
      In this study, we followed the United Nation (UN)’s definition of older persons, which accepts the chronological age of 60 years as the cut-off value.

      Kowal P, Dowd JE. Definition of an older person. Proposed working definition of an older person in Africa for the MDS Project. Geneva: World Health Organization; 2001. doi: 10.13140/2.1.5188.9286.

      However, a systematic review by Córdova et al.
      • Córdova L.D.S.
      • Vega A.P.M.
      • Luján-Carpio E.
      • et al.
      Clinical characteristics of older patients with COVID-19: A systematic review of case reports.
      revealed that age ≥ 80 years was consistent with progressive physiological changes and clinically relevant. We, therefore, did a further analysis using this cut-off and found that AS/MS-COVID patients aged ≥ 80 years were nearly 2 times more likely to develop SSIs than those aged 60-79 years (11/11 [or 100%] vs. 12/23 [or 52.2%]; P = 0.0058; 95% CI, 1.3 to 2.83; RR, 1.92). Because we included ASA I-II patients only, SSIs in older patients with comorbidities and/or moderate to severe COVID-19 could be much higher and necessitate further investigations.
      SARS-CoV-2 has a broad affinity for angiotensin-converting enzyme 2 (ACE2) on cell surfaces for entering host cells. ACE/ACE2 balance disruption and activation of the rennin-angiotensin-aldosterone system caused by SARS-CoV-2 lead to disease progression, especially in patients with comorbidities, such as DM and cardiovascular diseases.
      • Beyerstedt S.
      • Casaro E.B.
      • Rangel É.B.
      COVID-19: Angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection.
      • Menachery V.D.
      • Gralinski L.E.
      Coagulation and wound repair during COVID-19.
      The binding of SARS-CoV-2 to ACE2 increases levels of angiotensin II (Ang II), a potent vasoconstrictor and pro-inflammatory molecule which exerts oxidative stress, mitochondrial dysfunction, endothelial cell damage, hypercoagulation and thrombosis (via free radical generation), and jeopardise proper neovascularisation for wound healing.
      • Inouye D.
      • Zhou S.
      • Clark B.
      • et al.
      Two cases of impaired wound healing among patients with major head and neck free-flap reconstruction in the setting of COVID-19 infection.
      High levels of serum plasminogen activator inhibitor-1 (PAI-1) and D-dimers are consistent with microthrombi observed in COVID-19 patient autopsies.
      • Menachery V.D.
      • Gralinski L.E.
      Coagulation and wound repair during COVID-19.
      Clinically, Inouye et al.
      • Inouye D.
      • Zhou S.
      • Clark B.
      • et al.
      Two cases of impaired wound healing among patients with major head and neck free-flap reconstruction in the setting of COVID-19 infection.
      reported free flap failure in patients with SARS-CoV-2, and Talmor et al.
      • Talmor G.
      • Grube J.G.
      • Eloy J.A.
      • et al.
      Nasoseptal flap necrosis after endoscopic skull base surgery in the setting of COVID-19 pandemic.
      described pedicled nasoseptal flap necrosis and failure due to SARS-CoV-2 infection. A systematic review by Chen et al.
      • Chen D.
      • Zhou H.
      • Yang Y.
      • et al.
      The adverse effects of novel coronavirus on diabetic foot patients: A protocol for systematic review and meta analysis.
      concluded that SARS-CoV-2 reduces a cure rate of diabetic feet, and increases healing time, amputation and mortality rates.
      Our recently published meta-narrative review
      • Pitak-Arnnop P.
      • Meningaud J.P.
      • Sirintawat N.
      • et al.
      A German AWMF’s S2e/realist synthesis and meta-narrative snapshot of craniomaxillofacial manifestations in COVID-19 patients: Rapid living update on 1 January 2021.
      and prospective study

      Pitak-Arnnop P, Sirintawat N, Tangmanee C, et al. Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients. J Stomatol Oral Maxillofac Surg (in press) doi: 10.1016/j.jormas.2022.01.006.

      highlighted that not only the airway and oral cavity but ocular surfaces (which could be infected via the nasolacrimal duct) are VROs, and could host high viral density causing local microvascular pathology and poor wound healing. CMFI involving VROs are therefore a prominent risk factor for SSIs, which are significantly higher than surgery without VRO-contact, such as hand surgery
      • Baldwin A.J.
      • Jackowski A.
      • Jamal A.
      • et al.
      Risk of surgical site infection in hand trauma, and the impact of the SARS-CoV-2 pandemic: A cohort study.
      , caesarean births

      McLaren R Jr, London V, Narayanamoorthy S, et al. Cesarean birth morbidity among women with SARS-CoV-2. Am J Perinatol (in press) doi: 10.1055/s-0041-1739430

      , or appendectomy
      • Huamán Egoávil E.
      • LaGrone L.
      • Ugarte Oscco R.
      • et al.
      SARS-CoV-2 infection is not associated with a higher rate of post-operative complications in adult appendectomy patients in Peru: Cross-sectional study.
      (49/257 [19.1%] vs. 20/556 [3.6%] vs. 1/43 [2.3%] vs. 4/58 [6.9%]; P < 0.00001). Minimally invasive techniques could be an alternative for surgery involving VROs to reduce the surgical access size and viral splattering

      Pitak-Arnnop P, Sirintawat N, Tangmanee C, et al. Inanimate surface contamination of SARS-CoV-2 during midfacial fracture repair in asymptomatic COVID-19 patients. J Stomatol Oral Maxillofac Surg (in press) doi: 10.1016/j.jormas.2022.01.006.

      • Pitak-Arnnop P.
      • Meningaud J.P.
      • Sirintawat N.
      • et al.
      A German AWMF’s S2e/realist synthesis and meta-narrative snapshot of craniomaxillofacial manifestations in COVID-19 patients: Rapid living update on 1 January 2021.
      , e.g. Meningaud and Pitak-Arnnop’s endoscope-assisted retrocaruncular approach for medial orbital wall and nasoorbitoethmoidal fractures.
      • Meningaud J.P.
      • Rigolet A.
      • Ernenwein D.
      • et al.
      La voie d’abord rétro-caronculaire assistée par endoscopie pour le traitement des fractures de la paroi interne de l’orbite: étude préliminaire.
      • Meningaud J.P.
      • Pitak-Arnnop P.
      • Bertrand J.C.
      Endoscope-assisted repair of medial orbital wall fractures using a retrocaruncular approach.
      A recent systematic review by Pitak-Arnnop

      Pitak-Arnnop P. An evidence-based approach to antibiotic prophylaxis for oral, craniomaxillofacial plastic/head and neck surgical procedures. J Clin Pharm Ther (in press) doi: 10.1111/jcpt.13618.

      suggested that facial fracture and contaminated/clean-contaminated wound repair require antibiotics up to 3 and 5 days, respectively, while clean facial wounds need no antibiotic prophylaxis. PAU is reasonable in the circumstances of AS/MS-COVID patients with SSI. Inouye et al.
      • Inouye D.
      • Zhou S.
      • Clark B.
      • et al.
      Two cases of impaired wound healing among patients with major head and neck free-flap reconstruction in the setting of COVID-19 infection.
      found that SSIs in COVID-19 patients were intensified by secondary bacterial infections, which emerge from Staphylococcus aureus (75%), Escherichia coli (58.3%), Klebsiella pneumonia (41.6%), Pseudomonas aeruginosa (33.3%) as well as Acinetobacter baumannii, Streptococcus pneumonia, and Haemophilus influenza (25%).
      • Abu-Rub L.I.
      • Abdelrahman H.A.
      • Johar A.A.
      • et al.
      Antibiotics prescribing in intensive care settings during the COVID-19 era: A systematic review.
      These populations should, therefore, be recognised as high-risk and are SSI-prone via acquired immune compromise, poor microcirculation, and infected surgical sites (if involve VROs), and may benefit from human recombinant soluble ACE2 (hrsACE2).
      • Inouye D.
      • Zhou S.
      • Clark B.
      • et al.
      Two cases of impaired wound healing among patients with major head and neck free-flap reconstruction in the setting of COVID-19 infection.
      In other words, PAU could be rational if rigorously selected AS/MS-COVID patients with CMFI are treated before COVID-19 cures.
      The strengths of this study are related to the case-control design, wherein each “case” patient had their matched controls, and the strict inclusion and exclusion criteria. There are, however, some limitations associated with this study that merit consideration. First, while the design was retrospective case-cohort, the study was not randomised a priori. The decision to treat CMFI was made on the basis of operator, patient and hospital factors. Moreover, it has been evidenced that there is an increase in wound dehiscence and SSIs on the mask-covered face (due to frictional trauma by a mask) after Mohs micrographic surgery and parotidectomy during the COVID-19 pandemic.
      • Erickson S.P.
      • Foshee J.P.
      • Baumann B.C.
      • et al.
      Mohs surgical site infection rates and pathogens for the mask-covered face during the COVID-19 pandemic versus the pre-COVID era.
      • Bonavolontà P.
      • Troise S.
      • Arena A.
      • et al.
      The use of personal protective equipment during the COVID-19 pandemic: The effects on surgical wounds healing after parotid gland surgery.
      Because of the retrospective nature, the correlation between the use of a mask and wound dehiscence and SSIs in our cohort was not monitored and is beyond our study’s aim. Another potential shortcoming is an inclusion of ASA I-II patients only, which is probably unrealistic. Older patients often have comorbidities, suggesting that this study’s generalisability (external validity) reduces, while internal validity increases. Additionally, the analyses herein did not assess the effect of radiographic and laboratory changes due to SARS-CoV-2 infection on SSI events and severity because of heterogeneous patient management protocols. The “cases” might have different, albeit usually negative, radiographic and laboratory changes.

      Rommel A, Lippe EV, Plass D, et al. COVID-19-Krankheitslast in Deutschland im Jahr 2020 – Durch Tod und Krankheit verlorene Lebensjahre im Verlauf der Pandemie. BURDEN 2020 Study Group. Dtsch Arztebl Int 2021;118:145-51. doi: 10.3238/arztebl.m2021.0147.

      • Córdova L.D.S.
      • Vega A.P.M.
      • Luján-Carpio E.
      • et al.
      Clinical characteristics of older patients with COVID-19: A systematic review of case reports.
      Lastly, it is unknown whether and how SARS-CoV-2 creates local tissue alterations and subsequent SSIs. Bench research should be performed to answer this unresolved question.

      Conclusions

      AS/MS-COVID patients with CMFI have a 2.8-fold increase in the SSI, especially elderly patients injured in contact with VROs, and require PAU. In other words, close surveillance of SSI using appropriate measures, such as C-reactive protein, is recommend in AS/MS-COVID patients with CMFI. The presence and treatments of facial fractures in this patient group elicit positive and negative, albeit weak, correlations with SSI events, respectively. All CMFI patients should, therefore, be preoperatively tested for SARS-CoV-2 infection until the pandemic ends. We refer interested readers to a triage protocol for CMFI patients during the COVID-19 pandemic proposed by Wunsch and Pitak-Arnnop.
      • Wunsch A.
      • Pitak-Arnnop P.
      Strategic planning for maxillofacial trauma and head and neck cancers during COVID-19 pandemic—December 2020 updated from Germany.
      Conflict of Interest
      Nil
      Ethics statement/confirmation of patient permission
      Approved by the institutional review board. All patients consented that we can use their anonymous data for research.
      Authors’ Declarations
      Funding: Nil
      Conflicts of interest/Competing interests: The authors indicate full freedom of investigation and manuscript preparation. They have no conflict of interest relevant to this article to disclose.
      Availability of data and material: Deidentified individual participant data are not available. Based on the current patient data protection law in Germany, open access to the raw data is not allowed. The datasets generated and analysed during this study are available from the corresponding author upon reasonable request.

      Authors’ contributions:

      Conception and design: P.P., C.T., C.M., J-P.M., A.N.
      Acquisition, analysis and interpretation of data: P.P., C.T., C.M.
      Drafting and revising the work: : P.P., C.T., C.M., J-P.M., A.N.
      Final approval of the work: : P.P., C.T., C.M., J-P.M., A.N.
      Agreement to all aspects of the work: P.P., C.T., C.M., J-P.M., A.N.

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