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Home My WebLink About2023_04_20 SSchumacher_Adverse mask effects1 Subject:FW: Adverse mask effects and their overlap with long CV symptoms ‐‐‐‐‐Original Message‐‐‐‐‐ From: Stephen Schumacher <sol@solmaker.com> Sent: Thursday, April 20, 2023 3:48 PM To: Board of Health <boh@co.jefferson.wa.us> Cc: jbuhler@jeffersonhealthcare.org; mready@jeffersonhealthcare.org; mdressler@jeffersonhealthcare.org; Kees Kolff <kkolff@jeffersonhealthcare.org>; bmccomas@jeffersonhealthcare.org Subject: Adverse mask effects and their overlap with long CV symptoms ________________________________ ALERT: BE CAUTIOUS This email originated outside the organization. Do not open attachments or click on links if you are not expecting them. ________________________________ https://www.frontiersin.org/articles/10.3389/fpubh.2023.1125150/full Dear Jefferson Board of Health, At bottom is the new systematic review of 2,168 studies on adverse medical mask effects that I attempted to summarize in public comment today. Our health officer misunderstood this study to be saying "masks cause long covid", so here are brief excerpts to clarify what the study is actually saying: "This systematic review comprehensively revealed ample evidence for multiple adverse physio‐metabolic and clinical outcomes of medical face masks, with worse outcomes in the case of N95 masks. This can have long‐term clinical consequences, especially for vulnerable groups e.g., children, pregnant, older adult, and the ill. Besides transient and progressive hypoxemia, hypercarbia, and individualized clinical symptoms our findings are in line with reports on face masks caused down‐stream aberrations (e.g., oxidative stress, hypercapnia, vasoconstriction, pro‐inflammatory response, immunosuppression etc.) at the organ, cellular and microbiome levels and support the MIES (Mask Induced Exhaustion Syndrome). "Regarding the numerous mask symptoms an important question arises: Can masks be responsible for a misinterpreted long‐COVID‐19‐syndrome after an effectively 2 treated COVID‐19 infection? Nearly 40% of main long‐COVID‐19 symptoms overlap with mask related complaints and symptoms described by Kisielinski et al. as MIES ike fatigue, dyspnea, confusion, anxiety, depression, tachycardia, dizziness, and headache, which we also detected in the qualitative and quantitative analysis of face mask effects in our systematic review. It is possible that some symptoms attributed to long‐COVID‐19 are predominantly mask‐related. Further research on this phenomenon needs to be conducted." So the issue is that harmful effects and systemic exhaustion induced by masks (as confirmed in these 2,168 reviewed studies) may get misdiagnosed as long CV in many cases, given how strongly their symptom sets overlap. This may also explain the strange cases of claimed long CV absent any positive test results. Given these serious adverse impacts to wearing masks, I agree with this review's conclusion that "in the absence of strong empirical evidence of mask effectiveness, mask wearing should not be mandated." Likewise, I urge that Jefferson Healthcare stop mandating its staff to wear mask when dealing with non‐immunocompromised patients, contrary to Mayo Clinic policy: https://newsnetwork.mayoclinic.org/discussion/mayo‐clinic‐to‐ease‐universal‐face‐mask‐requirement/ Yours truly, Stephen Schumacher Port Townsend, WA ‐‐‐ https://www.frontiersin.org/articles/10.3389/fpubh.2023.1125150/full TYPE Systematic Review PUBLISHED April DOI ./fpubh.. OPEN ACCESS EDITED BY Francisco Antunes, Universidade de Lisboa, Portugal REVIEWED BY Cecilia Acuti Martellucci, University of Ferrara, Italy Beny Spira, University of São Paulo, Brazil *CORRESPONDENCE Kai Kisielinski kaikisielinski@yahoo.de Pritam Sukul pritam.sukul@uni-rostock.de SPECIALTY SECTION This article was submitted to Environmental health and Exposome, a section of the journal Frontiers in Public Health RECEIVED December ACCEPTEDFebruary PUBLISHED April CITATION Kisielinski K, Hirsch O, Wagner S, Wojtasik B, Funken S, Klosterhalfen B, Kanti Manna S, Prescher A, Sukul P and Sönnichsen A () Physio-metabolic and clinical consequences of wearing face masks—Systematic review with meta-analysis and comprehensive evaluation. Front. Public Health :. doi: ./fpubh.. COPYRIGHT ©Kisielinski, Hirsch, Wagner, Wojtasik, Funken, Klosterhalfen, Kanti Manna, Prescher, Sukul and Sönnichsen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Physio-metabolic and clinical consequences of wearing face masks—Systematic review with meta-analysis and comprehensive evaluation Kai Kisielinski *, Oliver Hirsch , Susanne Wagner , Barbara Wojtasik , Stefan Funken , Bernd Klosterhalfen , Soumen Kanti Manna , Andreas Prescher , Pritam Sukul *and Andreas Sönnichsen Orthopaedic and Trauma Surgery, Clinical Medicine, Private Practice, Düsseldorf, Germany, Department of Psychology, Fachhochschule für Oekonomie und Management (FOM) University of Applied Sciences, Siegen, Germany,Veterinary Medicine, Wagner Medical Science Liason (MSL) Management, Blankenfelde-Mahlow, Germany,Department of Genetics and Biosystematics, Faculty of Biology, University of Gda´nsk, Gdansk, Poland,Internal Medicine, Clinical Medicine, Private Practice, Moers, Germany,Institute of Pathology, Dueren Hospital, Dueren, Germany,Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India,Institute of Molecular and Cellular Anatomy (MOCA), Rhine-Westphalia Technical University of Aachen, Aachen, Germany,Rostock Medical Breath Research Analytics and Technologies (ROMBAT),Department of Anesthesiology and Intensive Care, University Medicine Rostock, Rostock, Germany,Internal Medicine, Clinical Medicine, Private Practice, Gesundheit für Österreich e.V. (Health for Austria), Vienna, Austria Background:As face masks became mandatory in most countries during the COVID- pandemic, adverse eects require substantiated inves tigation. Methods:A systematic review of , studies on adverse medical mask eects yielded publications for synthesis and studies fo r meta-analysis (on n =,,m =,,f =,, age =.±.). The median trial duration was only min (IQR =) for our comprehensive evaluation of mask induced physio-metabolic and clinical outcomes. Results:We found significant eects in both medical surgical and N masks, wit h a greater impact of the second. These eects included decreased SpO (overall Standard Mean Dierence, SMD = −., % CI = −. to −.,p <.) and minute ventilation (SMD = −., % CI = −. to −.,p <.), simultaneous increased in blood-CO (SMD = +., % CI =.–., p <.), heart rate (N: SMD = +., % CI =.–.,p =.), systolic blood pressure (surgical: SMD = +., % CI =.–.,p =.), skin temperature (overall SMD = +. % CI =.–.,p =.) and humidity (SMD +., % CI =.–.,p <.). Eects on exertion (overall SMD=+.,surgical =+.,N =+.),discomfort(SMD =+.),dyspnoea (SMD = +.), heat (SMD = +.), and humidity (SMD = +.) were significant in n =witharobustrelationshiptomaskwearing(p <.to p<.).Pooled symptom prevalence (n =,) was significant for: headache (%,p <.), acne (%,p <.), skin irritation (%,p <.), dyspnoea (%,p <.), heat (%,p <.), itching (%,p <.), voice disorder (%,p <.), and dizziness (%,p =.). Discussion:Masks interfered with O -uptake and CO -release and compromised respiratory compensation. Though evaluated wearing durations are shorter than daily/prolonged use, outcomes independently validate mask-induced exhaustion-syndrome (MIES) and down-stream physio-metabolic disfunctions. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. MIES can have long-term clinical consequences, especially for vulnerable groups. So far, several mask related symptoms may have been misinterpreted as long COVID- symptoms. In any case, the possible MIES contrasts with the WHO definition of health. Conclusion:Face mask side-eects must be assessed (risk-benefit) against the available evidence of their eectiveness against viral transm issions. In the absence of strong empirical evidence of eectiveness, mask wearin g should not be mandated let alone enforced by law. Systematic review registration:https://www.crd.york.ac.uk/prospero/display_ record.php?ID=CRD ,identifier:PROSPEROCRD. KEYWORDS masks and N respirators, surgical mask, adverse (side) eects, l ong-term adverse eects, health risk assessment, MIES syndrome, risk-benefit, mask Introduction In most countries, the uses of medical face masks have been restricted to professionals for decades (1). In the health- care setting, masks constituted a mandatory self-protective and third-party protective measure for medical personnel prior to COVID-19 pandemic (2) based on the assumption of ecacy of masks in reducing transmission of pathogens, especially bacteria (3). The eectiveness of masks in all healthcare settings was debatable even before 2020 (4,5). In 2020, many scientists and leaders started to believe that the use of masks could also provide protection against viral transmission, although evidence for the eectiveness of this measure was only weak (6). Since the pandemic began, a large number of studies tried to assess the antiviral eectiveness of masks, with hardly conclusive results (7,8). During the 2019 SARS-CoV-2 outbreak face masks were deployed as a mandatory public health measure for the general population in many countries around the world (9), making them oneofthemostimportantuniversallife-styleattributesthatdirectly aect how we breathe. As with any other preventive measure and/or intervention, masks also have speciﬁc disadvantages. While certain properties may have justiﬁed their invention and application in the past, e.g., retention of bacteria during surgical wound care and operations (1,2), at present the question needs to be addressed as to the long-term eects widespread mask wearing may have on normal breathing. It is noteworthy that the compulsory wearing of masks for the entire population provided good research conditions for studying the adverse eects of mask wearing (10–17). Various volatile metabolites are produced through biochemical and metabolic pathways and their concentrations in exhaled breath provide immediate physiological (18,19), metabolic (20,21), and pathological (22,23) signs with the possibility of monitoring various processes and interventions including therapies (24,25). A recent observational study reported continuous respiratory and hemodynamic changes along with corresponding alteration in exhaled volatile metabolites (viz. potentially originate at the cellular/organ levels and via microbial metabolic processes) and has raised signiﬁcant concerns upon the immediate, progressive, transient, and long-term side-eects of FFP2/N95 and surgical masks in adults (aged between 20 and 80 years) at rest (26). Recently, the harmful eects of masks were highlighted in a large scoping (non-systematic) review (14) that has summoned for a systematic review with comprehensive evaluation of mask induced adverse consequences. Though some important systematic reviews regarding masks and their eects already exist (27–30), they are predominantly restricted to healthy and sportive individuals (27,29). Due to the exclusion of children, pregnant women and diseased patients from these evaluations and conclusions (28,31), the reviews do not provide sucient evidence that masks can be safely used the general population. Moreover, the application of ﬁxed statistical models (27), use of narratives rather than quantitative analysis and statistics (despite claiming to be systematic) (32), focus on health care workers (31), as well as comparing the dierent mask types without any baseline/control group (31) were ubiquitous limitations of those studies. Physiological systematic reviews based purely on physiological eects of masks limit data interpretations to normal physio-metabolic ﬂuctuations i.e., beyond the domain of pathophysiological compensatory mechanisms (especially in the older individuals and those with diminished compensatory reserves) and/or acute/chronic subliminal changes in the human microbiome (28,30). In addition, other studies have not addressed subjectiveprevalenceofsymptomsanddiscomfortduringmaskuse and concomitant physical changes such as heat and temperature in detail (27,29). Therefore, the systematic reviews available to date neither address possible symptoms of mask use for the general population nor their exact prevalence. In addition, the transferability of the outcomes of said systematic reviews to the general population is very limited and they do not fulﬁll the actual requirements of clinical and inclusive evaluation, especially from the views and perspectives of medical practitioners. Including young, old, healthy and ill people to the systematic analysis of physiological, metabolic, and clinical data would increase our understanding about the impact of mask-wearing on the general population. In contrast to the above-indicated studies, our systematic review is aimed to quantify the FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. biochemical/metabolic, physical, physiological changes along with the appearance of subjective and clinical symptoms in face mask users and analyze them from a clinician’s and physician’s holistic perspective. Materials and methods Registration This meta-analysis was registered with the international prospective register of systematic reviews (PROSPERO) under the record CRD42021256694 at the National Institute for Health Research (NIHR) and performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement (33). Inclusion and exclusion criteria Theaimwastostudyadverseeectsoffacemasksonmetabolic, physiological, physical, psychological, and individualized parameters. The use of cloth masks, surgical masks and N95/FFP-2 masks were the intervention of interest. Humans of all ages and genders, who were evaluated in controlled intervention studies and observational studies have been included in our comprehensive evaluation. Case reports, narrative reviews, case series and expert opinions were excluded. The main outcomes considered were peripheral oxygen saturation (SpO2), carbon dioxide levels in blood, temperature, humidity, heart rate, respiratory rate, tidal volume and minute ventilation, blood pressure, exertion, dyspnea, discomfort, headache, skin changes, itching, psychological stress, and symptoms during the use of face masks. Literature retrieval strategy First, a comprehensive search term was developed. Then, PubMed, Embase, and Cochrane Library databases were searched. Thesearchwasperformeduntil31stDecember2021.Therewereno restrictions in publication date. Literature that was neither English nor German language was excluded. Additionally, forward-looking data was considered for discussion, but not included in the meta- analysis. Preprints that have been published in journals in the meantime have been given the appropriate references. Literature screening and data extraction Search terms were created according to the criteria deﬁned in the PICO scheme (34). The speciﬁc search terms were: (face mask∗[tw], FFP1 [tw] FFP2 [tw], FFP3 [tw], N99 [tw], N97 [tw], N95 [tw], respiratory protective device ∗[tw], air-purifying respirator∗[tw], surgical mask ∗[tw]) and (risk ∗or adverse eect ∗[tw], adverse event ∗[tw], side eect ∗[tw], psycho ∗[tw], hypoxia [tw], hypercapnia [tw], headache [tw], dead space [tw], safety [tw], carbon dioxide [tw]), not infants, not neonatal, not newborn, not endoscopy, not CPAP, not intubate ∗, not propofol, not resuscitation, not mechanical ventilation [tw], not fetus. The asterisk in the search algorithm here “ ∗” stands for the extension of the spelling with dierent possible letter combinations (e.g., face mask∗with ∗=s, or ∗=ed, or ∗=ing). The abbreviation “[tw]” stands for title word. The retrieved titles and abstracts were then screened and assessed for predeﬁned inclusion criteria by at least three authors. Study design, methodology, interventions, primary and secondary outcomes and language were evaluated using the web-based program Rayyan—a web and mobile app for systematic reviews (35).Fulltextsofallpotentiallyrelevantarticleswereindependently assessed for inclusion by two authors. Full-text exclusions and reasons have been documented. Data of included full texts were extracted: Author and year, type of study, aim of the study, intervention/control, sample size, follow-up, outcomes, funding, setting/country, age, sex, comorbidities, medications, functional status and cognitive status of participants, results, main ﬁndings, and limitations. Descriptive data was extracted by one author and checked by another author. If discrepancies occurred or authors disagreed, a senior author was involved in and a consensus was found (36). Risk of bias assessment of the included studies The quality assessments were carried out using various tools, depending on the type of study. If systematic reviews and meta- analyses were included, these were assessed using the AMSTAR- 2 checklist (37). Interventional studies were examined using the manual “Assessment of the risk of bias in clinical studies” from the Cochrane Collaboration (Cochrane RoB-2) (38). Observational studies were checked with the CASP (Critical Appraisal Skills Program) using standardized forms (39). Statistical analysis A meta-analysis was carried out, if at least two studies with the same research question were found among the randomized, non-randomized controlled trials, and observational studies. A subgroup analysis was conducted, where possible, for dierent mask types (N95/surgical) and even compared the mask types with each other (N95 vs. surgical mask). The program “RevMan- 5.4.1,” which was developed for Cochrane Reviews was used. As we anticipated a considerable between-study heterogeneity - the random eects model was used to pool eect sizes (40). The results were graphically depicted in forest plots. Subgroup analyses were performed and a Q-test was calculated to examine signiﬁcant subgroup dierences. Study heterogeneity was assessed using Cochrane’s Q-test, T2 according to DerSimonian and Laird (41), and I² according to Higgins and Thompson (42). Where possible, a funnel plot was created to investigate publication bias. If this showed an abnormal result and there were at least 10 studies evaluating the same question, Egger’s test (43) was carried out. For the analysis of metabolic and physiological changes all controlled intervention studies in which measurements were FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh..TABLE A (A–C) Overview of included studies. (A) Randomized controlled trials, (B) non-randomized controlled trials, and (C) observational studies.ReferencesStudy designIntervention/controlSamplesizeTimeOutcomes(A) Included randomized controlled trialsBertoli et al. (50)Randomized, two-period cross-overself-control trialWearing N95 respirator vs. no facemask during indirectcalorimetryN=105minoxygen consumption (VO2), carbon dioxide production (VCO2), and Resting EnergyExpenditure (REE)Butz (51)Blinded, randomized cross over studyWearing two types of surgical masks vs. no maskN=1530minCO2under masks, PtCO2(partial transcutaneous CO2pressure) while wearing masks for30min, HR, RR (respiratory rate), and SpO2Dirol et al. (52)Prospective randomized cross-overstudySix-minutes walking test (6 MWT) with and without surgical mask.Mask-discomfort questionnaire was applied before and after6MWT with the maskN=1006minRR, HR, SpO2, EtCO2, and discomfort questionnaireFikenzer et al. (53)Prospective cross-over studyWearing no mask (nm) vs. surgical mask (sm) vs. FFP2/N95 mask(pm), cardiopulmonary and metabolic responses monitoredbyergo-spirometry and impedance cardiographyN=1210minFVC (forced vital capacity), FEV1 (forced expiratory volume in1s), Tienau index, peakexpiratory ﬂow (PEF), HR, stroke volume, cardiac output, arterio-venous oxygen contentdierence, systolic blood pressure (SBP), diastolic blood pressure (DBP), ventilation inliters/minute (VE), RR, tidal volume (VT), pH, partial pressure of carbon dioxide(PaCO2), partial pressure of oxygen (PaO2), lactate Pmax, Pmax/kg, VO2max/kg, heartrate recovery (HRR): HRR-1min, HRR-5min. Discomforts (VAS):humid, hot, breathresistance, itchy, tight, salty, unﬁt, odor, fatigue, and overall discomfort.Georgi et al. (54)Prospective randomized cross-overstudyWearing no mask (nm) vs. community vs. surgical mask vs.FFP2/N95 mask (treadmill: baseline, 50, 75, and 100W)N=249minHR, RR, SBP, DBP, PtCO2, SpO2, and main symptoms questionnaireGoh et al. (55)Randomized, two-period cross-overself-control trialWearing N95 respirator vs. wearing N95 respirator with microfanvs. wearing no facemask during common physical activitiesN=10615minEtCO2, comfort level with visual analog scale (VAS)Hua et al. (47)Prospective randomized crossover trialTwo and 4h after donning the masks, adverse reactions andperceived discomfort and non-compliance were measured.N=20240minSkin parameters: Skin hydration, transepidermal water loss, erythema, pH, and sebumsecretionKim et al. (56)Randomized and self-control trialWearing N95 respirator (partly with exhalation valve) vs. wearingno facemask (NM) during a low-moderate work-rate (5.6km/h)N=2060minHR, RR, transcutaneous carbon dioxide, and SpO2Kim et al. (57)Randomized and two-periodcontrolled trialWearing N95 respirator and no mask during 1h of mixedsedentary activity and moderate exercise during pregnancy vs.non-pregnant womenN=16 vs. 1660minSBP, DBP, mean arterial pressure, HR, stroke volume, cardiac output, total peripheralresistance, RPE, SpO2, and PtCO2Kim et al. (58)Randomized and self-control trialWearing N95 respirator vs. wearing P100 respirator vs. wearing nomask during 1h of treadmill exercise (5.6km/h) in anenvironmental chamber (35◦C, relative humidity 50%)N=1260minFit factor, rectal temperature, mean skin temperature, facialskin temperature underrespirator, SpO2, PtCO2, HR, RR, breathing comfort, thermal sensation, and exertion(Borg scale)Mapelli et al. (59)interventional, prospective,randomized, double-blind, andcross-over studyWearing no mask surgical mask or N95 mask and performingconsecutive cardiopulmonary exercise tests (CPETs) at least 24hapart but within 2 weeksN=1210minVentilation (VE), Oxygen intake VO2, VCO2production, respiratory gases, exspiratoryO2(ETO2) and exspiratory CO2(ETCO2), heart rate (HR), hemoglobin saturation(SaO2), blood pressure (DBP and SBD), dyspnea (Borg scale), spirometry, maximalinspiratory pressure (MIP), and maximal expiratory pressure (MEP)Roberge et al. (60)Randomized and two-periodcontrolled trialWearing an N95 FFR during exercise and postural sedentaryactivities over a 1-h period on pregnant women vs. controlN=22/2260minCore temperature, cheek temperature, abdominal temperature, HR, RR, RPE, andperceived heat (RHP)Wong et al. (61)Randomized and two-periodself-controlled trialWearing a facemask vs. not wearing a facemask during gradedtreadmill (10% slope) walking at 4km/h for 6minN=236minHR and RPEZhang et al. (62)Prospective randomized cross-overstudyExercises (cycle ergometer) with and without surgical masks(mask-on and mask-o) were analyzedN=718minTest duration, maximum power, RPE score, Borg dyspnea scale,Oxygen consumption (V.O2), carbon dioxide production (V.CO2), metabolic equivalent (MET), respiratoryexchange rate (RER), and percentage of oxygen uptake at anaerobic threshold (AT) inpredicted maximal oxygen uptake, inspiratory time (Ti), expiratory time (Te), RR, VT, VE,end-tidal oxygen partial pressure (EtO2), EtCO2, oxygen ventilation equivalent(VE/V.O2), and carbon dioxide equivalent (VE/VCO2)FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh..TABLE B Included nine non-randomized controlled trials.ReferencesStudy designIntervention/controlSamplesizeTimeOutcomesBharatendu et al.(63)Cross-sectional self-control trialWearing N95 respirator vs. no facemaskN=1545minMean ﬂow velocity (MFV), pulsatility-index, end-tidal carbon dioxide partialpressure (EtCO2)Coniam (64)Two-period controlled trialWearing surgical masks (WM) vs. no facemask (NM) duringoral examinationN=18610minPronunciation, vocabulary, grammar, comprehensibility, andaudibilityEpstein et al. (65)Multiple cross-over, self-controltrialWearing N95 respirator vs. wearing surgical mask vs. nofacemask during maximal exercise testN=1618minHR, RR, SpO2, rated perceived exertion (RPE), and end-tidal carbon dioxide(EtCO2)Lee and Wang (66)Two-period self-controlled trialWearing N95 respirator vs. no facemask duringrhinomanometryN=1430 secInspiration breathing resistance increment, expiration breathing resistanceincrement, breathing volume decrementRoberge et al. (67)Multiple cross-over andself-control trialWearing an N95 FFR vs. N95 FFR with exhalation valve vs.no mask during 1-h treadmill walking sessions, at 1.7miles/h and at 2.5 miles/hN=1060minFFR dead space gases, CO2saturation, O2saturation, RR, VT, VE, and HRRoberge et al. (68)Two-period self-control trialWearing a surgical mask for 1h during treadmill exercise at5.6km/h vs. the same exercise with no maskN=2060minCore temperature, cheek temperature, abdominal temperature,HR, RR, RPE,and Perceived heat (RHP)Scarano et al. (69)Two-period self-controlled trialWearing a surgical mask for 1h vs. wearing N95 respiratorfor 1h vs. baselineN=2060minHumidity, heat, breathing diculty, discomfort, mask touching, and perioraltemperatureShenal et al. (70)Multiple cross-over self-controlledﬁeld trialWearing one of seven respirators or medical mask during an8-h working period vs. no maskN=27480minDiscomfort and RPETong et al. (71)Two-period self-controlled trialBreathing through N95 mask materials during rest andexercise of predetermined intensity vs. breathing ambient airN=1950minOxygen consumption (VO2), carbon dioxide production (VCO2), VT, RR, VE,expired oxygen (FeO2), expired carbon dioxide (FeCO2), inspired oxygen (FiO2),and inspired carbon dioxide (FiCO2)FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh..TABLE C Included observational studies.ReferencesStudy designIntervention/controlSamplesizeTimeOutcomesBeder et al. (72)Longitudinal and prospectiveobservational studyWearing surgical mask during major operations vs. baselineN=5360–240minSpO2(oxygen saturation), HR (heart rate)Choudhury et al.(73)Prospective cohort studyWearing N95 respirator during light work vs. wearing fullPPE during heavy work vs. baselineN=75240minHR, SpO2, Perfusion Index (PI), RPE (rated perceived exertion), and modiﬁedBorg scale for dyspnoeaFoo et al. (74)Survey studySelf-administered questionnaire healthcare workersN=322480minPrevalence of adverse skin reactionsForgie et al. (75)Cross-sectional survey studySelf-administered questionnaireN=80Not givenMask/shield preferenceMask results, shield resultsHeider et al. (76)Cross-sectional survey studyValidated Voice Handicap Index (VHI)-10 questionnaireand self-administered questionnaireN=221480minVocal symptoms, Spanish validated Voice Handicap Index (VHI)-10questionnaireIslam et al. (77)Prospective cross-over self-controlstudyWearing FFP2 (N95) mask for 30min under sittingcondition in an air-conditioned roomN=1030minSaha Institute of Nuclear Physics, Department of Atomic Energy, Government ofIndiaJafari et al. (78)Cross-sectional studySelf-administered questionnaire, SpO2, HR, and venousblood samplesN=243240minRR, HR, SpO2, and salivary metabolic signatureKao et al. (79)Prospective observational studyWearing N95 respirator during hemodialysis vs. baselineN=39240minHR, RR, systolic blood pressure (SBP), diastolic blood pressure (DBP), PaO2, andPaCO2discomfort ratesKlimek et al. (80)Cross-sectional survey studyVisual Analog Scales (VAS) to document patient-reportedsymptoms and diagnostic ﬁndingsN=46120minVisual Analog Scales (VAS) to document patient-reported symptoms of rhinitisor rhinorrhea. mucosal irritation, secretion and edema in nasal endoscopy wasgradedKyung et al. (81)Prospective panel studyWearing N95 respirator during 6-min walking test vs.baselineN=976minSBP, DBP, HR, RR, EtCO2, and SpO2Lan et al. (82)Cross-sectional survey studySelf-administered questionnaireN=542360minPrevalence of adverse skin reactionsLi et al. (83)Prospective observational studyExercise on a treadmill while wearing the protectivefacemasksN=10100minHR, temperature and humidity (outside and inside the facemask), SBP, DBP,mask outer humidity, face microclimate humidity, chest microclimate humidity,mask outside temperature, face microclimate temperature, face skin temperature,chest microclimate temperature, subjective sensations: humidity, heat, breathresistance, itching, tightness, feeling salty, feeling unﬁt,feeling odorous, fatigue,and overall discomfortLim et al. (84)Survey studySelf-administered questionnaireN=212240minPrevalence of headachesLuckman et al. (85)Survey study using onlineexperimental settingSelf-administered questionnaire and experimental onlinesettingN=400Not givenRisk compensation with reduced physical distancing (standing, sitting, andwalking)Matusiak et al. (86)Cross-sectional survey studySelf-administered questionnaireN=876Not givenDiculty in breathing, warming/sweating glasses misting up, slurred speech, anditchMo (87)Retrospective observation crossover cohort studyWearing surgical mask vs. not wearing: compare to formerhospitalizations. Including criteria: Patients who werehospitalized three or more times and at least two timesbefore mask mandatesN=237minVital signs: temperature, HR, RR, SBP, DBP, serum and blood gasanalysis,inpatient days. Clinical parameters, including ion concentration of serum, vitalsigns, inﬂammation markers, and artery blood gas.Naylor et al. (88)Survey studySelf-administered online questionnaires.N=129Not givenEects of certain aspects of lockdown, including face masks, social distancing,and video calling, on participants behavior, emotions, hearingperformance,practical issues, and tinnitus.Ong et al. (89)Cross-sectional survey studySelf-administered questionnaire.N=158360minPPE usage patterns, occupation, underlying comorbidities(Continued)FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh..TABLE C (Continued)ReferencesStudy designIntervention/controlSamplesizeTimeOutcomesPark et al. (90)Prospective cohort studyWearing KF94 respirator for 6h vs. baselineN=21360minSkin temperature increase, skin redness, skin hydration, sebum level, skinelasticity, and trans-epidermal water lossPifarré et al. (91)Prospective trialNo mask baseline vs. mask baseline. Subjects wearing a maskimmediately after a 21-ﬂex test performed the RuerprotocolN=85–7minPaO2, PaCO2, SpO2, and HRProusa (92)Cross-sectional survey studySelf-administered questionnaireN=1,010Not givenWearing time, discomfort stress, tricks, psychovegetativecomplaints, positivefeelings, aggression, and depressionRamirez-Morenoet al. (93)Cross-sectional study in healthcareworkersSelf-administered questionnaireN=306420minWork type, type of face mask, number of hours worn per day (SD). pre-existingheadache, comorbidity, other symptoms, Sleep disturbance, loss ofconcentration, irritability, photophobia, sonophobia, and sickness/vomitingRebmann et al. (94)Multiple cross-over andself-control trialWearing only an N95 or an N95 with mask overlay for a12-h shift vs. baselineN=10720hSBP, DBP, CO2saturation, SpO2, HR, headache, nausea, light-headedness, andvisual challengeRosner (95)Cross-sectional study in healthcareworkersSelf-administered questionnaireN=343360minAcne, headache, skin breakdown (nose bridge, cheeks, chin,behind ears), andimpaired cognitionSukul et al. (26)Two-period controlled trialWearing a surgical or N95 mask during rest (young tomid-aged adults were measured for 30min and older adultswere measured for 15min)N=3015–30minExhaled breath proﬁles within mask space by high-resolution real-timemass-spectrometry (PTR-ToF-MS): Aldehydes, hemiterpene, organosulfur,short-chain fatty acids, alcohols, ketone, aromatics, nitrile, and monoterpene.Hemodynamic parameters: SpO2, PETCO2, HR, RR, SBP, DBP, cardiac ouput,exhaled oxygen, and humidity.Szczesniak et al.(96)Survey studySelf-administered online questionnaireAfter mask restrictions vs. before mask restrictionsN=1,476vs. 564Not givenEmployment status, place of residence, worktime per week, somatic symptoms,anxiety and insomnia, social dysfunction, and depressionSzepietowski et al.(97)Survey studySelf-administered online questionnaireN=2,307Not givenItch, mask types used, and duration of mask use per dayTechasatian et al.(98)Prospective cross-sectional surveystudySelf-administered questionnaireN=833480minFactors associated with adverse skin reaction, risk factors for adverse skinreaction, dierences between HCW, and non-HCWThomas et al. (99)Two-period controlled trialComparing the ability to accurately record 20 randomizedaviation terms transmitted over the radio by a helicopteremergency medical services (HEMS) pilot wearing a surgicalfacemask and six dierent N95s with and without theaircraft engine operatingN=3Not givenAccurately record 20 terms transmitted over the radio by (HEMS) pilot wearing asurgical facemask or N95 maskToprak and Bulut(100)Prospective observational studysurgical vs. N-95 maskn=149 vs.n=148N=29735minMaternal vital signs: SBP, DBP, HR, RR, fever centigrade, and SpO2Tornero-AguileraandClemente-Suárez(101)Two-period controlled trialWearing a surgical facemask vs. not wearing a facemaskduring 150min university lessonsN=50150minMental fatigue perception, reaction time (ms) SpO2, mean RR (ms), mean HR(bpm) square root of the mean value of the sum of squared dierences of allsuccessive R-R intervals (RMSSD; ms), low frequency (LF) and high-frequency(HF) normalized units (n.u.), SD1 (ms), and SD2 (ms)AT, anaerobic threshold; DBP, diastolic blood pressure; EtCO2, end-tidal CO2partial pressure; ESRD, end stage renal disease; TEWL, trans-epidermal water loss; FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; HCW, health care worker; HD,hemodialyis; HR, heart rate; MEP, maximal expiratory pressure; TMET1, metabolic equivalent; MIP, maximal inspiratory pressure; PEF,peak expiratory ﬂow; PetCO2, end-tidal carbon dioxide pressure; PetO2, end-tidal oxygen pressure; PI, perfusion index; PPE,personal protective equipment; PtCo2, partial transcutaneous CO2pressure; RER, respiratory exchange ratio; RPE, rated perceivedexertion; RR, respiratory rate; RR, respiratory rate; SaO2, hemoglobin oxygen saturation; SBP, systolic blood pressure; SpO2, oxygensaturation; Te, expiratory time; Ti, inspiratory time; Ttot, Inspiratory+expiratory time; TV, tidal volume; V·CO2, carbon dioxide production; V·O2, oxygen uptake; VE, ventilation in liters/min; VE, ventilation; VT, tidal volume. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. taken during physical activity with face masks were included. We excluded resting conditions since these are not particularly representative for real life settings. Additionally, we excluded pre-post studies to ensure study-comparability. In addition, by excluding rest situations of the mostly healthy study participants, our approach was able to represent the possible eects better in older adults and ill individuals (e.g., with compromised compensation mechanisms), all of whom are a signiﬁcant part of the general population. This also helped to reduce heterogeneity (I2). Neither for the results of the systolic blood pressure (SBP) nor the temperature did we follow this approach. Studies in whichmeasurementsweretakenduringrestandmoderatephysical activity were included in the meta-analysis of the physical outcome on SBP to obtain an evaluable number of studies and to ensure a better comparability and lower heterogeneity (exclusion of heavy load exercise conditions). In order to gather more available data for evaluating the temperature, we included two pre-post studies containing a resting condition using valid methodology and exact temperature measurements. This clearly reduced the heterogeneity index I2. For the meta-analysis of the resultant CO2-blood-content the joint evaluation of dierent experimental CO 2 measurements (PtCO2, ETCO2, and PaCO2) in mmHg was justiﬁed by the following facts: 1) “ETCO2 and PtCO2 measurements both provide an estimation of PaCO2” (44). 2) “End-tidal CO2 (ETCO2) has been considered as a reliable estimate of arterial PCO2, in healthy subjects” (45). 3) “PtCO2 reliably reﬂects PaCO2, irrespective of sensor location” (46). 4) “Transcutaneous CO2 (PtCO2) devices provide another option for the continuous non-invasive estimation of PaCO2, overcoming the limitations posed by end-tidal CO2 analysis” (45). 5) “ETCO2 monitoring tends to underestimate PaCO2 levels” (44). For meta-analysis of measured sensations, all studies in which measurements were mainly taken during physical activity were included. This helped to ensure comparability, lower heterogeneity and the above mentioned aims to draw conclusions on the general population under conditions resembling real life settings. However, an exemption was made for the sensation “discomfort:” To allow evaluable study numbers, we included one pre-post study with resting condition, however, with valid methodology and exact discomfort evaluations (47). Even if this study had not been included, the result would be signiﬁcant and unambiguous, however with a slightly larger 95% CI. Our systematic review also referenced studies aiming to assess the prevalence of sensations and symptoms under mask use. Therefore, we conducted an additional meta-analysis of these observational studies to document the pooled prevalence in mask use. Prevalence was calculated as total number of symptoms per 100 mask wearers. In studies where the standard error (SE) was not reported, we calculated it from the prevalence using the following formula: SE =√p (1-p) / n with a 95% CI =p ±1.96 X SE; where, p =Prevalence. This statistical approach to quantify a pooled prevalencefromobservationalstudieshasbeenpreviouslyreported (48). Meta-analysis was performed using RevMan (Version 5.4.1). The heterogeneity of each meta-analysis was assessed and then the random eects model was used to calculate the pooled prevalence. We conducted subgroup analysis where possible for mask type (N95/surgical). Funnel plots were used to study the possibility of publication bias as described above. The inclusion of observational studies, particularly for the prevalence analysis in our meta-analysis is justiﬁed because these are particularly suitable to investigate exposures that are dicultorimpossibletoinvestigateinrandomizedcontrolledtrials (RCTs), e.g., air pollution or smoking. In addition, observational studies are important to investigate causes with a long latency period, such as carcinogenic eects of environmental exposures or drugs (49). Thus, possible adverse long-term eects of masks, i.e., comparable to the environmental hazards, appeared to be particularly detectable through observational studies. Finally, the random statistical control calculations of our results were performed for quality assurance via the R software (R Foundation for Statistical Computing, Vienna, Austria, version 4.0.1) and packages metafor, dmetar, meta (36). Knapp-Hartung adjustments to control for the uncertainty in the estimate of the between-study heterogeneity were used in these calculations which are controversial as they result in wider conﬁdence intervals and are also suspected to be anti-conservative even though the eects are very homogeneous (36). Results General findings Literature characteristics Of the 2,168 screened records, 54 studies were included for qualitative analysis (see extraction tables,Table 1) and 37 for statistical meta-analysis (Figure 1). Among the 54 studies, 23 were intervention studies, and 31 were observational studies. The 23 intervention studies consisted of 14 randomized controlled trials (RCTs) and nine non-randomized controlled trials (nRCTs). Of the 31 observational studies, 17 works raised measured values, and 14 were questionnaire studies. Quality appraisal The quality of the studies was not very homogeneous. The quality assessment identiﬁed some studies with low and average quality, which were excluded from the meta-analysis. We included only high-quality studies in our meta-analysis of RCTs and nRCTs. The quality of the included observational studies is predominantly good.Tables 2A–D summarizes the results of the quality appraisal of the included research papers. Mask type Of the 37 meta-analytically evaluated studies, 31 examined the N95 mask, 19 the surgical mask with one not reporting on the speciﬁc type of mask due to the predominantly psychological research topic. There were 14 Studies evaluating both mask types (surgical and N95) and we compared the results in a separate meta- analysis (see below, Meta-analysis of N95 mask vs. surgical mask). FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE PRISMA flow chart of the systematic review. From initial , fi fty-four studies were later included in the qualitative synthesis. Finally, studies were evaluated statistically in the meta-analysis (quantitative analysis). Participants and time In order to conduct the meta-analysis 8,641 subjects were included, totaling 22,127 individual measurements/surveys. This population consisted of young (age =34.8 ±12.5) and predominantly female subjects (m =2,482,f =6,159). Physiological, physical, and biochemical data was used in the meta-analyses comprising of 934 participants and 3,765 experimental measurements. Thepooledprevalencedatawasdrawnfromastudypopulation of n =8,128 and included 17,383 data entries. Most of the 37 studies, evaluated in meta-analyses included healthy participants. Twelve studies were conducted in health care workers (32%). Two studies (5%) included chronic obstructive pulmonary disease (COPD), one study on hemodialysis patients, another study included children (3%) and four studies involved pregnant women (11%). The median experimental time of the studies included in the meta-analyses (mostly controlled trials) on physiological, physical, and chemical face mask eects was 18min with an interquartile range (IQR) of 50min (min.: 6min, max.: 360min). There was a major variation in mask wearing durations with several outliers leading to a large standard deviation (mean of 45.8min with a standard deviation of 69.9min). Therefore, the mean was not an appropriate parameter to characterize this distribution). The study with the longest experimental duration (360min, observational) included only 21 healthy participants, which corresponds to 2.2% of the total population studied (n =934). Interestingly, the studies on symptoms (including many observational studies) had signiﬁcantly longer observation times and a mean of 263.8 ±170.3min (median 240, IQR 180) in a total of n =8,128 participants. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. Qualitative evaluation Ofthe54includedstudies,51reportednumerousadversemask eects across multiple clinical disciplines, as already compiled in a previous scoping review (14). Also 14 of the 17 studies, which were not included in the meta-analysis reported those numerous mask eects. Overall, our systematic review found mask related symptoms that can be classiﬁed under the previously described Mask-Induced Exhaustion Syndrome (MIES) (14), with typical changes and symptoms that are often observed in combination. Among the included 54 studies (Table 1), we detected and compiledreportsonfrequentlystatisticallysigniﬁcantphysiological and psychological changes (p <0.05) belonging to the MIES such as: -increase in breathing dead space volume (60,65). -increase in breathing resistance (53,59,66,67,83). -increase in blood carbon dioxide (26,51–58,60,62,63,65,68,71, 81,87,91,94). -decrease in blood oxygen saturation (26,52–54,57–60,62,67,71, 72,79,81,91,94,100,101). -increase in heart rate (26,52,56,57,60,61,67,68,72,81,83,94, 100,101). -decrease in cardiopulmonary capacity (53,59,62). -changes in respiratory rate (52–54,56,59,60,62,68,79,81,100). -shortness of breath and diculty breathing (47,52–54,58,68,69, 73,79,81,83,86,87,92,94). -headache (54,63,73,78,82,84,89,92–95). -dizziness (54,79,81). -feeling hot and clammy (52,53,58,60,68,69,83,86). -decreased ability to concentrate (101). -decreased ability to think (81,94,95,101). -drowsiness (95). -impaired skin barrier function (47,74,95). -itching (47,52,53,74,80,82,83,86,97,98). -acne, skin lesions and irritation (47,68,74,81,82,86,95,98). -false sense of security (85,96). -overall perceived fatigue and exhaustion(52–54,57–62,68,70,71, 73,79,83,94). Moreover, we could objectify additional symptoms of the MIES as follows: - decrease in ventilation (53,59,62). -increase in blood pressure (26,52,53,59,62,81,83,87,100). -increase of measured temperature of the skin under the mask (58,68,69,90). -increase of measured humidity of the air under the mask (58,69, 90). - communication disturbance (86,88,94,95,99). - voice disorder (76,86). -perceived discomfort (47,52,53,69). -increased anxiety (75,88,92). -increased mood swings or depressive mood (75,76,88,92). and: -changes in microbial metabolism (lower gut and oral)(26,77). However, three studies (6% of the included papers) describe the absence of adverse or even positive mask eects (50,64,96). Results of the meta-analysis In the meta-analytic evaluation, we found biochemical, physiological, physical, and perceptual symptoms with face mask use. We were also able to meta-analyze the pooled prevalence of symptoms. These results are presented in detail below. Meta-analysis of biochemical eects of face masks SpO and face masks The results are summarized in Figure 2A. In a pooled analysis, blood oxygen saturation resulted signiﬁcantly lowered during mask use. This could be found for general mask use (p =0.0004, SMD = −0.24, 95% CI −0.38 to −0.11,Z =3.53,I2 =0%). The Eggers’ test did not indicate the presence of funnel plot asymmetry [t(df=11)= −0.70,p =0.50]. This was also conﬁrmed in the subgroup analysis for N95 mask use (p =0.001, SMD = −0.3, 95% CI −0.49 to −0.12,Z =3.19, I2 =0%), but not for surgical mask use [p =0.08, SMD = −0.17, 95% CI (−0.37; 0.02),Z =1.77,I2 =0%]. However, seven of nine studies in the N95 mask meta-analysis were presumably because of the limited sample size. From the pooled analysis, it seems that N95 mask use may be responsible for a larger SpO2 drop than surgical masks. In a separate meta-analysis of pre-post studies an equally signiﬁcantdropinSpO2 wasfoundwhenusingamask(p =0.0001, SMD = −1.24, 95% CI −1.87 to −0.61,Z =3.87,I2 =80%) and especially in the subgroup of N95 masks (p =0.02, SMD = −1.24, 95% CI −2.26 to −0.22,Z =2.37,I2 =89%), yet with a high heterogeneity. Blood CO content and face masks The results are summarized in Figure 2B. In a pooled analysis, blood carbon dioxide content was found to be signiﬁcantly elevated in mask use. This was found for general maskuse(p =0.0001,SMD =0.64,95%CI0.31to0.96,Z =3.86,I2 =81%).TheEggers’testdidnotindicatethepresenceoffunnelplot asymmetry[t(df=11)=−0.87,p =0.40].Thiswasalsoconﬁrmedfor N95 mask use (p =0.003, SMD =0.78, 95% CI 0.28 to 1.29,Z = 3.02,I2 =84%) and also for surgical mask use (p <0.001, SMD = 0.42, 95% CI 0.24 to 0.59,Z =4.65,I2 =0%). There was no signiﬁcant dierence between the pooled eect sizes of N95 and surgical masks [Q(df=1)=3.09,p =0.08]. Further separate pooled evaluations were also carried out for PtCO2, ETCO2, and PaCO2, for each surgical and N95 masks with a signiﬁcant increase in blood CO2 with predominantly low heterogeneity. Even in a separate meta-analysis of pre-post studies with high heterogeneity, a signiﬁcant increase in blood carbon dioxide FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. TABLE A Quality appraisal of randomized trials (Cochrane RoB too l++).Selection biasPerformancebiasDetection biasAttrition biasReporting biasReferences. Random sampling. Allocation blinding.Blindingforintervention. Evaluation blinding. Incomplete data. Selective reporting. Other bias Bertoli et al. (50)LR LR HR HR LR UC LR Butz (51)LR LR HR LR UC UC UC Dirol et al. (52)LR LR HR LR LR LR LR Fikenzer et al. (53)LR LR HR LR LR LR LR Georgi et al. (54)LR LR HR LR LR UC LR Goh et al. (55)LR LR HR LR LR LR LR Hua et al. (47)LR LR HR LR UC UC LR Kim et al. (56)HR LR HR LR LR LR LR Kim et al. (57)LR LR HR LR LR UC LR Kim et al. (58)LR LR HR LR LR UC LR Mapelli et al. (59)LR LR HR LR LR UC LR Roberge et al. (60)LR LR HR LR LR UC LR Wong et al. (61)LR LR HR LR LR UC LR Zhang et al. (62)LR LR HR LR LR LR LR (A)Shows the quality analysis of RCTs with Cochrane RoB tool++. LR =low risk; HR=high risk; UC=Unclear. TABLE B Quality appraisal of non-randomized controlled trials (C ASP checklist).References. Clear focus?. Appropriate methods?. Recruitmentcomprehensible?. Valid measurement ofexposure?. Valid measurement ofoutcome?. Equality of groups?. Confounders taken intoaccount?. Sucient size andsignificance of theeect?. Credibility of the results?. Transferability to otherpopulations? clear focus?. Comparability withexisting evidence? Bharatendu et al. (63)Y Y Y Y UC Y Y Y UC Y UC Coniam (64)UC N Y Y Y UC UC Y Y Y UC Epstein et al. (65)Y Y Y Y Y Y UC N Y Y Y Lee and Wang (66)Y Y Y Y N Y Y N UC Y UC Roberge et al. (68)Y Y Y Y Y Y Y Y N Y Y Roberge et al. (67)Y Y Y Y Y Y Y N Y Y Y Scarano et al. (69)Y Y Y Y Y Y UC Y Y Y UC Shenal et al. (70)Y Y Y Y Y Y Y Y Y Y UC Tong et al. (71)Y Y Y Y N Y Y Y Y Y UC (B)Lists the results of the quality analysis of nRCTs with CASP checklist, Y=yes, N=no, UC=unclear. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. TABLE C Quality appraisal of the observational studies (CASP c hecklist).References. Clear focus?. Appropriate methods?. Recruitment comprehensible?. Valid measurement of exposure?. Valid measurement of outcome?. Equality of groups?. Confounders taken into account?. Sucient size and significanceof the eect?. Credibility of the results?. Transferability to other populations?clear focus?. Comparability with existing evidence? Beder et al. (72)Y Y N Y Y UC N Y Y Y Y Choudhury et al. (73)Y Y Y Y Y N Y Y Y N N Islam et al. (77)Y Y Y Y Y Y UC Y UC Y Y Jafari et al. (78)Y Y Y Y Y Y UC Y Y N UC Kao et al. (79)Y Y Y Y Y Y Y Y Y N UC Klimek et al. (80)Y Y Y Y Y Y UC Y Y Y UC Kyung et al. (81)Y Y Y Y Y Y Y Y Y N UC Li et al. (83)Y Y Y Y Y Y Y UC Y Y UC Luckman et al. (85)Y UC N Y Y Y Y Y Y Y UC Mo (87)Y Y Y Y Y UC UC Y Y Y Y Park et al. (90)Y Y Y Y Y Y N Y Y Y UC Pifarré et al. (91)Y Y Y Y Y Y Y Y Y Y UC Rebmann et al. (94)Y Y Y Y Y Y N N Y N Y Sukul et al. (26)Y Y Y Y Y Y Y Y Y Y UC Thomas et al. (99)Y Y Y Y Y N Y Y Y Y UC Toprak and Bulut (100)Y Y Y Y Y UC N Y Y N Y Tornero-Aguilera and Clemente-Suárez (101) Y Y Y Y Y Y N Y Y Y Y (C)Is on the quality analysis of observational (non-questionnaire) studies with CASP checklist, Y=yes, N=no, UC =unclear. content was found when using a mask (p =0.003, SMD =1.44, 95% CI 0.49 to 2.39,Z =2.97,I2 =94%) and also in the subgroup ofN95masks(p =0.02,SMD =1.51,95%CI0.24to2.78,Z =2.34, I2 =96%). Interestingly, 11 of 17 showed no statistically signiﬁcant eect. Thestudiesthatshowedstatisticallysigniﬁcanteectsdieredfrom those that showed no certain eects as they either included N95 and/or pregnant women or children. The study by Dirol et al. (52) is an exception but has a sample size of n =100 for surgical masks. Apparently, it takes N95 masks and vulnerable populations or appropriately large samples in surgical masks to make the eects more quantiﬁable. Predictably, in the surgical mask meta-analysis, studies with non-signiﬁcant results were of small sample size, with a mean of n =24 and a median of n =14. The advantage of a meta-analysis is to combine several imprecise eects into a more precise overall eect (36). Meta-analysis of physiological eects of face masks Ventilation (VE) in L/min and face masks The results are summarized in Figure 3A. Despite compensatory mechanisms, breathing volume (L/min) was signiﬁcantly lowered during mask use in the pooled analysis. Thiswasnotonlyveriﬁedforgeneralmaskuse(p <0.001,SMD = −0.72,Z =5.36, 95% CI −0.99 to −0.46,I2 =0%) in studies evaluated with an overall low heterogeneity (I2 =0), but also for surgical (p <0.001, SMD = −0,54, 95% CI −0.94 to −0.35,Z = FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh..TABLE D Quality appraisal of the questionnaire studies (CASP checklist).Study designValidity andreliabilityQuestionnairequalityQuestionnairedesignSampleDistributionand responseAnalysisResultsSummary andrecommendationReferencesWas a questionnaire studyan appropriate method?Are the results valid andrealistic?Does the questionnaireused provide reliableresults?Were sample questionsprovided?Are the questionsformulated in a clear andunderstandable way?Details on how thequestionnaire wasprepared?Was the questionnaireprepared in an appropriatemanner?Was the sample sucientlylarge and representative?Was information providedon how the questionnairewas made available?Was information providedon response rates andexclusion criteria?Waspotentialresponsebiasdiscussed?Were the results analyzedappropriately?Were all relevant resultspublished?Were both significant andnon-significant resultspublished?Were results adequatelyinterpreted?Does the summary reflectthe results of the study?Were the results placedin context with existingliterature?Foo et al. (74)YYUCNUCNUCYYYNYYYYYYForgie et al. (75)YYYYYYYYYYNUCYNYYYHeider et al. (76)YYYYYYYYYYYYYYYYYLan et al. (82)YYUCNUCNUCYYYNYYYYYYLim et al. (84)YYUCNUCNUCYNYNYYYYYYMatusiak et al. (86)YYUCNUCYYYYYNYUCYYYYNaylor et al. (88)YYYYYYYYYYYYYYYYNOng et al. (89)YYUCNUCNUCYYYNYYYYYYProusa (92)YNYYYYYNYNNYYYNYUCRamirez-Morenoet al. (93)YYUCNUCYYYYYNYYYYYYRosner (95)YYUCNUCNUCYYNNYYYYYYSzczesniak et al. (96)YNUCNUCNUCYYNNYUCNNYYSzepietowski et al.(97)YYUCNUCYYYYNNYYYYYYTechasatian et al.(98)YYUCNUCNUCYYNNYYYYYY(D)Documents the quality analysis of the questionnaire studies usingthe CASP checklist, Y=yes, N=no, UC=unclear.FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Forest (left)and funnel plots (right)of meta-analysis of blood oxygenation and blood carbon dioxide outcomes while wearing a face mask. All face mask types are initially considered together, later subgroups (surgical and N) are evaluated. If studies examine two diere nt mask types in parallel, the corresponding studies are marked:=surgical mask =N mask.(A)Blood oxygen is significantly lowered in mask use. In the subgroup analysis this could also be found for N mask use. From the pooled an alysis, it seems, that N mask may be responsible for a larger Sp O drop than surgical masks. In studies evaluating both conditions (surgical and N mask) the N mask yielded always lower O -values than the surgical masks. (B)In the pooled analysis, blood carbon dioxide (PtCO , ETCO , and PaCO ) is significantly elevated in mask use. This could be found for general mask use and in the subgroup analysis for surgical mask, and also for N mask use. In studies evaluating both conditions (surgical an d N mask) the N mask yielded always higher CO -values than the surgical masks. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Forest (left)and funnel plots (right)of meta-analysis of physiological respiratory outcomes while wearing a face mask.(A)Shows results for ventilation (VE),(B)for respiratory rate (RR). All face mask types are initially considered together, later subgroups (surgical and N) are evaluate d. If studies examine two dierent mask types in parallel, the corr esponding studies are marked:=surgical mask =N mask.(A)Breathing volume is significantly lowered in mask use in the pooled analysis. This could be found for general, for surgical, and N mask use. In studies evaluating both conditions (surgical and N mask) the N mask yielded always low er ventilation (VE) than the surgical masks.(B)No statistical dierence could be found regarding respiratory rate in mask use in the pooled analysis, even in the subgroup analysis (not shown). 4.32,I2 =0%) and N95 mask use (p =0.0007, SMD = −1.06, 95% CI −1.68 to −0.45,Z =3.39,I2 =0%). Both studies had an overall low heterogeneity (I2 =0). On average, masks reduced respiratory minute volume by −19% according to our meta-analysis, and by as much as −24% for N95 masks; the dierence between surgical and N95 masks was −10% respiratory minute volume. Respiratory rate and face masks The results are summarized in Figure 3B. Interestingly, no statistical dierence regarding respiratory rate was found in mask use in the pooled analysis. Even in the subgroups containing N95 and surgical masks, no dierence compared to the no mask condition could be found. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Forest (left)and funnel plots (right)of meta-analysis of the physiological cardiovascular outcomes systolic blood pressure (SBP) and heart rate (HR). All controlled intervention studies in which measurements were taken during physical activity with face masks were included (exclusion of rest situation and pre-post studies). All face masks types are initially considered together, later if possible subgroups (surgical and N) are evaluated. If studies evaluate two dierent mask types in parallel, the cor responding studies are marked:=surgical mask =N mask.(A)Systolic blood pressure is elevated in the mask condition and also for the subgroup of surgical mask. In studies evaluating both conditions (surgical and N mask) the N mask yielded always higher SBP than the surgical mask, how ever this eect was not statistically significant.(B)For the N mask condition a low significance for a slight increase in heart rate could be found. In studies evaluating both conditions (surgical and N mask) the N mask yielded always higher HR than the surgical mask, and this eect was stati stically significant. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. Systolic blood pressure and masks The results are summarized in Figure 4A. A signiﬁcant elevation in systolic blood pressure was found for mask users with p =0.02, SMD =0.17, 95% CI 0.03 to 0.32,Z = 2.39 and I2 =0% in the pooled analysis. It was a small eect and in nine out of 10 studies insigniﬁcant, including two with higher n in each case. The Eggers’ test does not indicate the presence of funnel plot asymmetry [t(df=8),p =0.27]. This was veriﬁed in the subgroup analysis for surgical masks (p =0.02, SMD =0.21, 95% CI 0.03 to 0.39,Z =2.33,I2 =0%). In studies evaluating both mask types (surgical and N95) the N95 mask always yielded a higher SBP than the surgical mask. However, this eect was not statistically signiﬁcant. There was no signiﬁcant dierence between the pooled eect sizes of N95 and surgical masks [Q(df=1)=0.98,p =0.32]. Heart rate and masks The results are summarized in Figure 4B. No statistically signiﬁcant dierence regarding the heart rate during mask use was found in the pooled analysis. The Eggers’ test did not indicate the presence of funnel plot asymmetry [t(df=14),p =0.94]. However, in the subgroup analysis containing surgical and N95 masks, only for the N95 mask condition a weak signiﬁcance for a slight increase in heart rate could be found (p =0.02, SMD = 0.22, 95% CI 0.03 to 0.41,Z =2.30 and low heterogeneity of studies with I2 =0).Therewasnosigniﬁcantdierencebetweenthepooled eect sizes of N95 and surgical masks [Q(df=1)=1.26,p =0.26]. Meta-analysis of physical eects of face masks Skin temperature and face masks The results are summarized in Figure 5A. Skin covered by mask had a signiﬁcantly higher temperature during rest and activity. This could be found for general mask use (p =0.005, SMD =0.80, 95% CI 0.23 to 1.38,Z =2.81.I2 =72%), for N95 mask use (p =0.02, SMD =0.72, 95% CI 0.12 to 1.32,Z =2.35,I2 =55%), but not for surgical mask use (p =0.21, SMD = 0.96,Z =1.26,I2 =90%). Humidity and face masks The results are summarized in Figure 5B. The dead space covered by mask had a signiﬁcantly higher humidity in the pooled analysis. This could be found for general mask use with p <0.001, SMD =2.24, 95% CI 1.32 to 3.17,Z =4.75 and I2 =50%. Meta-analysis of measured symptoms and sensations during face mask use Discomfort and face masks The results are summarized in Figure 6A. Perceived discomfort was signiﬁcantly higher in mask use during rest and activity in the pooled analysis. This could be found for general mask use (p <0.001, SMD = 1.16, 95% CI 0.58 to 1.73,Z =3.94,I2 =74%), for N95 mask use (p <0.001, SMD =1.98, 95% CI 1.37 to 2.59,Z =6.34,I2 =0%) as well as for surgical mask use (p <0.001, SMD =0.71, 95% CI 0.46 to 0.96,Z =5.58,I2 =0%). Itch and face masks The results are summarized in Figure 6B. In N95 mask use, the perceived itching was signiﬁcantly elevated (p =0.003, SMD =2.65, 95% CI 1.21 to 4.09,Z =3.6,I2 =83%) during activity according to the pooled subgroup analysis. Exertion and face masks The results are summarized in Figure 6C. Perceived exertion is signiﬁcantly higher in mask use during activity in the pooled analysis. This could be found for general mask use (p <0.001, SMD = 0.90, 95% CI 0.58 to 1.23,Z =5.31.I2 =71%), for N95 mask use (p =0.002, SDM =1.19, 95% CI 0.43 to 1.95,Z =3.06,I2 =81%) as well as for surgical mask use (p <0.001, SMD =0.63, 95% CI 0.40 to 0.87,Z =5.29,I2 =24%). The Eggers’ test indicates the presence of funnel plot asymmetry [t(df=10)=2.68,p =0.02]. For N95 mask use (p =0.002, SDM =1.19,Z =3.06,I2 =81%) and this result was conﬁrmed for surgical mask use too (p <0.001, SMD =0.63, Z =5.29,I2 =24%). There was no signiﬁcant dierence between the pooled eect sizes of N95 and surgical masks [Q(df=1)=1.97,p =0.16]. Shortness of breath and face masks The results are summarized in Figure 6D. Perceived shortness of breath was signiﬁcantly higher during mask use during activity in the pooled analysis (p =0.006, SMD = 1.46, 95% CI 0.42 to 2.50,Z =2.75,I2 =86%). Perceived heat and face masks The results are summarized in Figure 6E. Perceived heat is signiﬁcantly higher during mask use with physical activity in the pooled analysis (p =0.002, SMD =0.70, 95%CI 0.28 to 1.13,Z =3.27,I2 =62%). InthesubgroupanalysiscontainingsurgicalandN95masksthe heat perception was increased in both mask types, but only for the surgical mask condition a statistical signiﬁcance for an increase in heat perception could be found (p =0.008, SDM =0.61, 95% CI 0.16 to 1.06,Z =2.66,I2 =50%). Perceived humidity and face masks The results are summarized in Figure 6F. Perceived humidity was signiﬁcantly higher in mask use during activity according to the pooled analysis (p =0.002, SMD =0.90, 95% CI 0.34 to 1.46,Z =3.17,I2 =53%). FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Forest (left)and funnel plots (right)of meta-analysis of physical outcomes while wearing a face mask.(A)Shows results for temperature of skin,(B) for air humidity underneath the face mask. All mask types are initially considered together, later subgroups (surgical and N) ar e evaluated. If studies examine two dierent mask types in parallel, the correspondin g studies are marked:=surgical mask =N mask.(A)Skin covered by mask has a significantly higher temperature during rest and activity. This could be found for general mask use and for N mask use but not for s urgical mask use. In studies evaluating both conditions (surgical and N mas k) the N mask yielded higher temperatures than the surgical ma sk, but this could not be analyzed further due to lack of further studies comparing both conditions.(B)The dead space covered by mask has a significantly higher air humidity in the pooled analysis. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Forest and funnel plots of meta-analysis of measured discomfort (A), itch (B), exertion (C), shortness of breath (D), perceived heat (E), and humidity (F)during face mask use (VAS, Likert-scales or similar) in an evaluated population of n =. All face mask types are initially considered together, later subgroups (surgical and N) are evaluated. If studies ex amine two dierent mask types in parallel, the corresponding s tudies are marked:= surgical mask =N mask.(A)Perceived discomfort is significantly higher in face mask use in the pooled analysis. This could be found for general mask use, in the subgroup analysis for surgical-, and for N mask u se. A pooled analysis comparing both conditions (surgical mask and Nmask) resulted in statistically significant higher discomfort rates for the N mask than the surgical mask.(B)An overall significance for itching could be found for mask use. Also in N mask use the perceived itching wa s statistically significantly elevated according to the pooled subgroup analysis.(C) In studies evaluating both conditions (surgical and N mask) the N mask yielded always higher exertion rates than the surgical masks.(D) Perceived shortness of breath is significantly higher in mask use in the pooled analysis.(E)Perceived heat is significantly higher in the pooled analysis. (F)Perceived humidity is significantly higher in mask use. The subgroup analysis revealed a statistical significance for an increase in humidity perception using a surgical mask. In studies evaluating both conditions (surgical and N mask) the N mask yielded always higher humidity perception rates than the surgical mask. A pooled analysis resulted in a statistical significance for higher humidity perception in N masks than surgical masks. The subgroup analysis containing surgical and N95 masks was completed merely for surgical masks due to lack of studies on N95 masks. In the surgical mask subgroup a statistical signiﬁcance for an increase in humidity perception could be found (p <0.001, SMD =0.63, 95% CI 0.36 to 0.90,Z = 4.6,I2 =0). Meta-analysis of N mask vs. surgical mask The results are summarized in Figures 7A–C. TheN95maskledstomeasurablyworseeectscomparedtothe surgical mask. The blood oxygenation was signiﬁcantly decreased when using a N95 mask compared to a surgical mask with p = FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Results comparing the N to the surgical mask in the meta-anal ysis. Forest (left)and funnel plots(right)of meta-analysis of diverse outcomes while wearing a N mask vs surgical mask are shown.(A)Depicts the biochemical,(B)the cardiorespiratory outcomes, and (C)the subjective sensations outcomes. N mask leads to measurably less favorable results com pared to the surgical mask, significantly for oxygenation (decrease), heart rate (increase), discomfort and humidity (both increases). This trend was also evident for minute volume (decrease), CO and systolic blood pressure (both increases), but in those comparisons not statistically significant due to too few includable studies. FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. 0.003, SMD = −0.53, 95% CI −0.88 to −0.18,Z =2.98,I2 = 37%. The heart rate (p =0.01, SMD =0.25, 95% CI 0.05 to 0.45, Z =2.47,I2 =0%), the perception of discomfort (p =0.02, SMD =3.07, 95% CI 0.52 to 5.61,Z =2.36,I2 =95%) and humidity (p =0.02, SMD =0.59, 95% CI 0.09 to 1.10,Z =2.32,I2 = 0%) increased when the N95 mask was compared to the surgical mask. This trend was also evident for blood content of CO2, minutevolume,exertion,heat,shortenedbreath,andsystolicblood pressure, but was not statistically signiﬁcant due to the limited available studies. Meta-analysis with pooled prevalence of symptoms during face mask use The results are summarized in Figure 8. Headache was the most frequent symptom among n =2,525 subjects, with a prevalence of 62% for general mask use (p < 0.001, 95% CI 0.48 to 0.75), up to 70% with N95 masks (p < 0.001, 95% CI 0.52 to 0.88). Additionally, the prevalence of acne in n =1,489 evaluated mask users was quite high, at 38% (p <0.001, 95% CI 0.22 to 0.54), and skin irritation in n =3,046 mask users had a similar prevalence of 36% (p <0.001, 95% CI 0.24 to 0.49). Shortness of breath was highly prevalent in n =2,134 general mask users, with 33% (p <0.001, 95% CI 0.23 to 0.44), up to 37% for N95 (p =0.01, 95% CI 0.07 to 0.67). Itching was also present in 26% of n =5,000 subjects (p < 0.001, 95% CI 0.15 to 0.36), with a sharp dierence between the 51% of N95 (p <0.001, 95% CI 0.47 to 0.55) and the 17% of surgical masks (p <0.001, 95% CI 0.09 to 0.26). These results were conﬁrmed in control calculations using the R software. Furthermore, voice disorders, assessed in n =1,097, were 23% prevalent (p =0.03, 95% CI 0.02 to 0.43), although with high heterogeneity of the studies. Finally, dizziness had a prevalence of only 5% (p =0.01, 95% CI 0.01 to 0.09), however it was investigatedinonly n=153subjects,thereforethisﬁndingrequires further studies. Discussion Besides possibly providing protection against the transmission of pathogens, face masks undoubtedly impede natural breathing. Such respiratory impairments due to the “new-normal” lifestyle under the present global pandemic have imposed potential adverse eects on our usual external (airways, lungs) and internal (cellular) respiration, aecting a wide range of physio-metabolic processes within various organ systems and/or at cellular levels (14,26). Ensuing consequences were eventually observed at the physical, psychological and social levels along with certain clinical symptoms in the individual human beings (14). In this systemic review, we applied meta-analysis and comprehensive evaluations of physio-metabolic, physical, psychological and clinical burdens of wearing face masks in the general population. Restricting breathing through face masks has turned out to be a fundamental, incisive intervention with possible negative eects on public health. Physio-metabolic burden of masks Our meta-analysis clearly depicts that masks, and especially the N95 masks, signiﬁcantly restrict O2 uptake and hinder CO2 release. Based on the meta-analytic eect sizes deﬁned by Cohen (102), the eect size for CO 2 retention (as per PtCO2, ETCO2, and PaCO2 outcomes) is medium for all mask types and is larger for N95 masks. The eect size for O 2 uptake disturbance (as per SpO2 outcome) is relatively smaller but highly signiﬁcant (p =0.0004;Figures 2A,B,9A). Such respiratory gas-exchange discrepancy can be attributed to the constantly increased dead space ventilation volume (14,60,65,103,104) (i.e., continuous rebreathing from the masks dead space volume) and breathing resistance (14,53,59,66,67,83). Continuous CO2 rebreathing causes the right-shift of hemoglobin-O2 saturation curve. Since O2 and CO2 homeostasis inﬂuences diverse down-stream metabolic processes, corresponding changes toward clinically concerning directions may lead to unfavorable consequences such as transient hypoxemia and hypercarbia, increased breath humidity, and body temperature along with compromised physiological compensations etc. Transient hypoxemia A progressive decrease in SpO2 is observed with respect to the duration of wearing a mask (26,52,56,58,72,73,81,91, 105). The decline in SpO2 levels conﬁrmed in our systemic- review supports the onset and progression of oxidative stress (via signiﬁcantly increased exhaled breath aldehydes—originating from lipid peroxidation) reported by Sukul et al. (26). Studies have shown that oxidative stress (under hypoxic conditions) can inhibit cell-mediated immune response (e.g., T-lymphocytes, TCR CD4 complex, etc.) to ﬁght viral infections, which may gradually lead to immune suppression (106,107). Arterial hypoxemia increases the level of the hypoxia inducible factor-1 (HIF-1 ), which further inhibits T-cells and stimulates regulatory T-cells (107). This may set the stage for contracting any infection, including SARS-CoV-2 and making the consequences of that infection much more severe. In essence, masks may put wearers at an increased risk of infection and severity (106–108). A recent review (109) by Serebrovska et al. discusses a possible link between HIF-1 activation and cell entry of SARS-CoV-2. If the cell is already under oxidative stress, activation of HIF-1 may suppress important adaptive mechanisms e.g., autophagy or proteasomal proteolysis is leads to the induction of necrosis and excessive cytokine production.Sturrocketal.(110)demonstratedthattheSARS-CoV- 2 receptor (e.g., ACE2 and TMPRSS2) expression by primary type II alveolar epithelial cells increased signiﬁcantly following exposure to hypoxic environments in vivo and in vitro. Furthermore, recent research has demonstrated that the cellular entry of SARS-CoV-2 also depends on many other receptor paths/routes (e.g., CD147, CD147—spike proteins etc.), mediated by HIF-1 upregulation (111–114). Therefore, the eect of even mild hypoxemia for an extended span may promote an infection risk along with metabolic stress e.g., due to altered pH via respiratory acidosis. In line with that, Sukul et al. (26) observed a signiﬁcant decrease in FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Forest (left)and funnel plots (right)of meta-analysis of pooled symptom prevalence while wearing a face mask. Headache (%), acne (%), skin irritation (%), shortness of breath (%), heat (%), itch (%), voice disorder (%), and dizziness (%) while wearing a mask are significant in the evaluated population (n =,). FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Summary of pooled meta-analytic evaluation of biochemical (A)and physical eects (B)during face mask use. The height of the bars reflects the SMD (standard mean dierence), their error bars correspond to t he confidence intervals.(A)For carbon dioxide rise in the blood there is a medium eect size of >. and for oxygen drop a small eect size of >. regarding the standard mean dierence values thresholds a ccording to Cohen ().(B)For elevated Humidity and Temperature rise under the face mask there is a strong eect size of ≥.. The meta-analytical statistical data were as follows: Oxygen (SpO ): SMD −., % CI −. to −.,Z =.,p =.; Carbon dioxide (PtCO , ETCO , and PaCO ): SMD +., % CI . to .,Z =.,p =.; Humidity: SMD +., % CI . to .,Z =.,p <.; Temperature: SMD +., % CI . to .,Z =.,p =.. exhaled volatile metabolites (e.g., organosulfur and short-chain fatty acids) originating from the lower gut microbiota during face mask use—indicating anaerobiosis, metabolic acidosis and possible immunosuppression. Even marginal local eects of masks on salivary metabolites in young and healthy adults have indicated alteration of microbial metabolic activity (77). The ﬁndings of Spira (16) from European data show that mask use correlates with increased morbidity and mortality, which could be due to the above-discussed possible processes. Moreover, prolonged hypoxic conditions and low oxygen levels pave the way for immunosuppression and inﬂammation, which may promote the growth, invasion and spread of cancers (114–116). However, further experimental studies are needed to prove that hypoxemia under long-term mask use may result in quantiﬁable changes in HIF-1 and immunosuppression—especially in older adults, ill/comorbid and/or immunocompromised individuals. Transient hypercarbia In line with the increased dead space ventilation and consistently decreasing SpO2 level, CO2 inhalation elevates progressively during the course of wearing a mask, causing transient hypercarbia (26,52,56,58,81,91,105). Very recent experimental data exist on CO2 concentrations of concern in the air breathed while wearing masks, especially in children (117,118). Systemic CO2 concentration exerts an important inﬂuence on the intra- and extracellular pH. CO2 passes quickly through the cell membranes to form carbonic acid, which releases protons and in excess causes acidosis (119–121). With a prolonged CO2 burden the body uses the bones (CO2 storage) to regulate the blood pH: bicarbonate and a positive ion (Ca 2+, K +, and Na+) are exchanged for H +. Accordingly, kidney and organ calciﬁcation were frequently seen in animal studies on low-level CO2 exposure (122,123). Additionally, CO2 in relationship with chronic and/or intermittent long-term exposure might induce pathological states by favoring DNA alterations and inﬂammation (124,125). Moreover, inﬂammation is reported to be caused by low-level CO2 exposure in humans and animals (125– 129). Even slightly elevated CO2 induces higher levels of pro- inﬂammatory Interleukin-1 , a protein involved in regulating immune responses, which causes inﬂammation, vasoconstriction and vascular damage (128). In addition, carbon dioxide is also known as a trigger of oxidative stress caused by reactive oxygen species (ROS) (124) including oxidative damage to cellular DNA (124,125). FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Summary of pooled meta-analytic evaluation of cardiorespiratory eects during face mask use. The height of the bars reflects the SMD (standard mean dierence), their error bars correspond to t he confidence intervals. Clear eects for a decrease in ventilation and tidal volume are illustrated, no eect for respiratory rate and weak to low eect for increase in heart rate and systolic blood pressure. F or ventilation there is a medium eect size of >. with a small eect size of >. for tidal volume of the standard mean dierence values according to Cohen (). The meta-analytical statistical data were as follows: Ventilation: SMD −., % CI −. to −.,Z =., p<.; Tidal volume: SMD −., % CI −. to −.,Z = .,p =.; Respiratory rate: SMD +., % CI −. to ., Z=.,p =.; Heart rate: SMD +., % CI −. to .,Z= .,p =.; Systolic blood pressure: SMD +., % CI . to .,Z =.,p =.. Altogether, the possible damaging mechanism of CO2 aecting tissues is based on the conditions of oxidative stress and acidosis with increased inﬂammation and apoptosis as described above (124,126–131). In the long term, therefore, this could be possible during mask use even at blood-CO2 levels that do not reach the thresholds. In spontaneously breathing subjects in a sitting position, exhaled CO2 proﬁles mirror the endogenous isoprene exhalation (18,132). Signiﬁcant and progressively decreased breath isoprene recently observed in adults (26) indicates the deoxygenation driven sympathetic vasoconstriction in the peripheral compartments (133). Prolonged deoxygenation and CO2 re-breathing therefore, may eventually lead to pulmonary vasoconstriction that may hinder blood-CO2 levels to reach the thresholds. For instance, Sukul et al. also reported the presence of signiﬁcant hyperventilation state in older adults aged ≥60 years before wearing a face mask for the participation in experiments. This indicates a compromised respiratory compensation of precedent mask use (which was obligatory due to pandemic regulations at that time) by these subjects. Physical burden of masks: Humidity and skin temperature Together with the immune-inhibiting mechanisms mentioned above, we found some other possible deleterious mask eects that impede healthy natural breathing. The most prominent and extreme eect was found in the increase of air humidity and skin temperature within the dead space of the mask (Figures 5, 9B). Increased humidity and temperature can increase droplet and aerosol generation, which facilitate liquid penetration through the mask mesh. This not only increases the chance of microorganism (fungal and bacterial pathogens) growth on and in masks (134– 136)causingincreasedriskforaccumulationoffungalandbacterial pathogens (134,136) including mucormycosis (137), but also leading to re-breathing of viruses that may be trapped and enriched within the moisturized mask meshwork. Therefore, these conditions within masks are favorable for pathogenic growth and are unfavorable for good/systemic microbiota i.e., individual speciﬁc. As a result, the isolation of people with masks for extended periods can attain conditions for new and individual speciﬁc strains formations/mutations of pathogens—to which other people in the environment will be susceptible and/or not immune. Additionally, the high concentration of microbiome in masks can be a potential source of infection for the population. The ﬁndings of Fögen (11) using data from the USA which shows that mask use correlates with an increased mortality (case fatality rate of COVID-19) could be due to these processes. This phenomenon could also explain the similar ﬁgures found by Spira (16) in the EU. Compensatory physiological mechanisms Our meta-analytically quantiﬁed CO2-rise and O2-depletion (Figures 2,9A) with mask use certainly needs physiological compensations (Figures 3,4,10). Interestingly, the compensatory responses to mask wearing (e.g., rise in heart rate, changes in respiratory rate and/or minute ventilation etc.) was lower (absent or even reverse) than expected (122,138,139). In former human experiments with low level 1-2% CO2 exposure to breathing air – which corresponds to measured values during mask use (140)—an increased respiratory minute volume (VE) of >34% was detected (122).Incontrasttothatandaccordingtoourresultsundermasksa signiﬁcantly decreased VE by −19% on an average and up to −24% under N95 masks occurs despite face mask driven CO2 exposure (140). VE was even 10% lower for the N95 than for the surgical masks (Figure 3A). However, it appears to have no acute clinical impactintheshorttermanddoesnotexceednormalvaluesofSpO2 and systemic CO2 although these may become problematic in the long run. A compensatory higher arterial PaCO2 and bicarbonate levels execute the buering of inhaled CO 2. Interestingly, during chronic breathing of low CO2 concentrations (in the no-mask condition), due to compensatory mechanisms, e.g., lowered blood pH, increased respiratory rate and VE (122) and an acclimatization occurs(122,138,139,141,142).Inmaskusers,thosecompensatory mechanisms however seem to dier or get disturbed (e.g., no rise in respiratory rate, heart rate and simultaneous fall in VE). Health FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Illustration of the duration of studies in which measurements were made on mask eects (physical, biochemical, and physiologic al) in participants. The median is min (yellow dotted line) with an interquartile range of . The study with the longest experimen tal duration included subjects, corresponding to .% of the total population studied.Striking not only is a very short trial time compared to the everyday scenarios workday and school attendance (see interrupted, auxiliary lines in blue and red), but also a strongly deviating mask exposure duration with outliers (mean of .min with standard deviation of .). Therefore,the mean is not an appropriate parameter to characterize this distribution. risks should be considered despite the mask related compensation attempts (140). During face mask use a rise in the arterial PaCO2 is possible in the long term (26,52,81,91,105). Although, PaCO2 generally remains at a sub-threshold level in healthy mask users (105,138), concerning pathological changes can occur in older (>60 years) and sick people (26,87). Our ﬁndings depicted an absence of typical compensatory reactions to transient hypercarbia thereby implying a suppression of a physiological response owing to the unusual conditions of wearing a mask. The reasons behind this phenomenon, i.e., the absence of a rise in the respiratory rate and ventilation, remain unclear. The simultaneous change in the adverse direction (CO2 rise and simultaneous O2 fall with concomitant dead space- and resistance enlargement caused by the mask) may be responsible for this. The drop in SpO2 and the rise in CO2 (PtCO2, ETCO2, and PaCO2) with no major changes in the heart rate in our meta-analysis also transpires to be an unexpected reaction. Sukul et al. (26) reported altered breathing patterns, respiratory resistance and discomfort under medical masks. Adults younger than 60 years of age described slow breathing (slow and deep inspiration and expiration) under masks, whereas shallow/thoracic breathing (breathing with increased inhalation duration and eort), respiratory resistance and dyspnea was portrayed by those ≥60 years of age. Fittingly, altered breathing patterns/kinetics, progressive changes toward deoxygenation, hypercarbia and insigniﬁcant changes in the respiratory and heart rate transpired to be surprising mask outcomes in our present results (hypercapnia-like eects). Thus, prolonged masks use may lead to hypercapnic hypoxia like conditions. While short and acute hypercapnic hypoxia like conditions in healthy individuals can promote positive eects (sport, training, etc.) (143–145), a chronic/prolonged hypercapnic hypoxia (as also known from sleep apnea) is toxic for the renal (146), nervous (147), and cardiovascular system (148) in the long run—causing metabolic syndrome (14) as well as additional eects on cognitive functions (149). N mask compared to surgical mask In line with recent ﬁndings by Kisielinski et al. (14) and Sukul et al. (26), the present results clearly show that N95 masks lead to signiﬁcantly more pronounced and unfavorable biochemical, physiological and psychological eects (Figure 7) than surgical masks. Altogether, the results in blood oxygenation, discomfort, heart rate, CO2, exertion, humidity, blood pressure, VE, temperature, dyspnea, and itching etc. can be attributed to the larger (almost doubled) dead space and higher breathing resistance of the N95 mask (14). Compared to the surgical mask upon the short-term eects, N95 masks could impose elevated health risks under extended use. Interestingly, recent data from a large multi- country RCT study show no signiﬁcant dierences between the two mask types in terms of SARS-CoV-2 infection rates (150). FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Summary of pooled meta-analytic evaluation of face mask-wearing sensations measured with standardized Borg-. Likert-, VAS-scales, or similar. The height of the bars reflects the SMD (standard mean dierence), their error bars correspond to the confidence intervals. Five out of complaint categories (%) are above the strong eect size threshold of >. of the standard mean dierence values according to Cohen (). The meta-analytical statistical data were as follows (SMD =standard mean dierence): Itch: SMD +., %CI −. to .,Z =.,p =.; Shortness of breath: SMD +., % CI . to .,Z =.,p=.; Discomfort: SMD +., % CI . to .,Z =.,p<.; Exertion: SMD +., % CI . to .,Z =.,p<.; Humidity: SMD +., % CI . to .,Z =.,p=.; Heat: SMD +., % CI . to .,Z =.,p =.. Nevertheless, there was long enforcement of N95 masks in e.g., Austria and Germany (9). Short mask experiment times It is noteworthy to say that in studies with short assessment times neither correspond to real-life conditions nor do they exclude short- or long-term compensatory mechanisms, e.g., obvious for CO2-rebreathing. Short mask experiments are also unable to show long-term changes. However, immediate compensatory mechanisms can hide further adverse reactions (122,138,140). Therefore, longer observation times can lead to clearer values that are closer or above the thresholds due to the attenuation or collapse of transient physiological mechanisms. The experimental studies used here examined important outcomes only had a median examination time of 18min (Figure 11). Heterogeneous studies with small sample sizes yielded signiﬁcant and medium to strong results (Figures 10,12). Nevertheless, experimental studies with longer assessment periods are needed. The observational studies included in the present analysis on symptoms were conducted over signiﬁcantly longer periods (median 240min, IQR 180) and are able to consider cumulative and long-term eects. It is known that observational studies are far more precise in ﬁnding negative eects and are particularly suitable to investigate exposures (e.g., air pollution or smoking) that are dicult or impossible to investigate in randomized controlled trials (RCTs). In addition, observational studies are important to investigate causes with a long latency period, such as toxicological and carcinogenic eects from environmental exposures or drugs (49). The longest period of included studies was 8 months with an averaged of wearing the mask 8h per day (observational study), however with the shortest study with a 5min examining/exposition time (controlled trial). Possible sub-threshold impact of masks—The low-dose long-term eect on health In contrast to our study, most of the recent systematic reviews (27–31) have only analyzed a few outcome threshold values without considering comprehensive eects, exposure time and the susceptibility of the exposed organisms and tissues. Therefore, their recommendations e.g., masks are harmless and safe for everybody etc. appears to be superﬁcial, non-medical, non-holistic, and misleading. In accordance with conclusions of Sukul et al., Fikenzer et al., and Zhang et al. (26,53,62), we have found hints to deleterious eects even without exceeding physiological threshold values and we have interpreted these data as a risk for individuals with suppressed compensatory mechanisms such as in older individuals and sick subjects with cardiorespiratory diseases, infection, diabetes, cancer, and other comorbidities. Sukul et al. (26) were able to show that the unfavorable eects are more pronounced in the older adults (aged: 60–80 years). Moreover, they could provide evidence for toxic eects of face masks including oxidative stress, immunosuppression, deoxygenation and hypercarbia induced vasoconstriction and altered systemic microbial activity. Even with CO2 and SpO2 levels that do not exceed the limits, many clinical researchers have also found troubling results in face mask wearers. Neurologists observed changes in MRI brain signal baseline level due to face mask use (15). Wearing a surgical mask for merely 9min increased end-tidal CO2 causing mild hypercapnia. This was responsibleforacompensatoryincreaseincerebralbloodﬂowwith morphological changes similar to that of a CO2 gas challenge or holding your breath. In patients with aneurysms or brain tumors this phenomenon could be deleterious. Another study showed a pathologic and altered brain metabolism while wearing a N95 mask for 6h (17). The MRI imaging revealed a signiﬁcant drop in brain oxygenation. A more than 50% drop in oxygenation in the cingulate gyrus (cognition circuit) after 6h of mask use was associated with clinical symptoms of a confused state in 80% of the subjects above 35 years. The authors even concluded that the FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. FIGURE Representation of symptom prevalence in % during face mask use as the area of the circles. Along the X-axis, the main recorded symptoms are listed. The higher the prevalence, the bigger the circles and the more often the symptoms. The Y-axis gives the probability of non-random occurrence of the symptoms and includes the statistical Z-value. Thus, the higher the circles are arranged, the more robust is the relationship to face mask wearing. The meta-analytical statistical data were as follows: Headache: % (% CI –%),Z =.,p <.; Acne: % (% CI –%),Z =.,p<.: Skin irritation: % (% CI –%),Z =.,p<.; Shortness of breath: % (% CI –%),Z =.,p<.; Heat: % (% CI –.%),Z = .,p <.; Itch: % (% CI –%),Z =.,p < .; Voice disorder % (% CI –%),Z =.,p <.; Dizziness % (% CI –%),Z =.,p =.. generalpopulationshouldnotwearaN95mask.Thisphenomenon of brain deoxygenation could be dangerous for people with altered brain functions when on medication, after a transient ischemic attack (TIA) or stroke, respectively. Ophthalmologicalstudiesindicatedriskofretinaldamagefrom long-term use of masks. N95 masks reduced the vascular density in the vascular plexus even under resting conditions as early as after 60min(151).Here,thedropinSpO2 andincreaseinbloodpressure weresigniﬁcantbutwithinthenormalphysiologicalrange.Another study reported a signiﬁcant mask-induced increase in intraocular pressure (IOP) after ∼5min of wearing (12). Thus, wearing masks may counteract the therapy aiming to reduce the IOP and can exacerbate irreversible long-term vision problems in individuals with glaucoma. Numerous other studies have shown that the long- term eects, leading to deleterious clinical outcome may result from prolonged mask wearing (15,17,151,152). Such eects are comparable to sick building syndrome (SBS) (153), cigarette smoking and other chronic, slightly toxic inﬂuences relevant to the general population. In accordance with our present analysis and precedent scoping review (14), mask-related changes in leaning toward pathological values can lead to illness and clinical consequences, just like chronically, repeated subliminal harmful environmental events. Occupational diseases deﬁned by the International Labor Organization (ILO) and that are in accordance with the worker’s compensation act in Germany illustrates the potential harm caused by chronic exposure to subthreshold environmental factors (154). Numerous examples of these principles can be found in the literature concerning pharmacology, toxicology, clinical and occupational medicine and even in psychology (155–164). Many other toxicological and environmental health examples are presented in the recent scoping review by Kisielinski et al. (14), which refers to MIES (Mask-Induced Exhaustion Syndrome). Such subliminal chronical changes and harmful eects in the long run arecomparableto thesickbuildingsyndrome(SBS)(153),cigarette smoking(165),saltydiet(166),aluminumenvironmentalpollution (167), low-level lead exposure (168), organochlorine pesticides and polychlorinated biphenyl exposure (169), or even the so-called climate change exposure (170). Altogether, even the subliminal changes due to face mask use can become clinically relevant. Overlapping of face mask eects (MIES) with long-COVID- symptoms Regarding the numerous mask symptoms an important question arises: Can masks be responsible for a misinterpreted long-COVID-19-syndrome after an eectively treated COVID-19 infection? Nearly 40% of main long-COVID-19 symptoms (171) overlap with mask related complaints and symptoms described by Kisielinski et al. as MIES (14) like fatigue, dyspnea, confusion, anxiety, depression, tachycardia, dizziness, and headache, which we also detected in the qualitative and quantitative analysis of face mask eects in our systematic review. It is possible that some symptoms attributed to long-COVID-19 are predominantly mask-related. Further research on this phenomenon needs to be conducted. Complaints and symptoms under mask use and the WHO definition of health Amongst the perceived sensations with mask use only six symptoms (exertion, discomfort, shortness of breath, humidity, heat, and itch) could be meta-analyzed and have resulted in predominantly strong eect sizes (Figure 12). In the pooled prevalence analysis, we included eight main symptoms namely headache, acne, skin irritation, shortness of breath, heat, itch, voice disorder, and dizziness (Figure 13) out of which all were signiﬁcant in the evaluated population (Figure 8). There are many more reported in the literature. However, these could not be meta-analyzed due to the low number of comparable studies on those particular complaints. In the included literature additional reported mask related symptoms were: rhinitis (80), diculties to think and to concentrate (81,94,95,101), drowsiness (95), communication disorder (88,94,99), depression and mood swings (75,76,88,92), anger (92), perceived discomfort (47,52,53,69), anxiety(75,88,92),andanoverallperceivedfatigueandexhaustion (52–54,57–62,68,70,71,73,79,83,94). All of these mask-related symptoms contradict a state of wellbeing and health as deﬁned by the WHO. According to the FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. WHO; “health is a state of complete physical, mental, and social wellbeing and not merely the absence of disease or inﬁrmity” (172). Based on our ﬁndings, the use of face mask in the hope of maintaining health is unfortunately contradicting the WHO’s deﬁnition of health. Regarding all the possible side eects of mask and their still unproven ecacy against viral transmission within the general population (5,10,173,174), health seems not to be substantially preserved by wearing face masks. So far, only two randomized controlled mask trials for prevention of SARS-CoV-2 infection in the general population have been published: one high quality study from Denmark, Europe (175), and the other from Bangladesh with biased results and a lot of inconsistencies (176). Based on a Bayesian random-eects meta-analysis of these two trials, the posterior median for relative risk was 0.91 (95% credible interval 0.63–1.33, 73% probability of some beneﬁts with very limited evidence) (177). Recent data from a large multi-country RCT study show no signiﬁcant dierences between the surgical and N95 mask in terms of SARS-CoV-2 infection rates (150). Asides, there is evidence that COVID-19 rates have been able to expand swiftly when omicron hit (178) even in societies where mask use was assiduously followed—as in Korea, Taiwan, Hong Kong, and Singapore (179). The paucity in high-quality mask studies is unfortunate. Seeing the overall weak evidence for ecacy of masks against viral transmission within the general population (5,10,173, 174,180–184), face masks have to be evaluated appropriately in the sense of the Hippocratic Oath and as per the Primum nihil nocere (above all do not harm). To avoid at all costs that the damage causedbypreventiveortherapeuticmeasuresbecomesgreaterthan that caused by the disease itself, should be the credo of all those involved in the containment of the crisis, including politicians and the so-called experts. Medical decisions can only be made on the basis of comprehensive knowledge on a patient’s overall condition, individualized case history, considering all previous illnesses and interventions, physical and mental predispositions, and his/her socio-economic state, etc. When it comes to medical decision- making in a sick person, the weighing of therapeutic measures for the beneﬁt of the patient against the side eects of the therapy is to be evaluated dierently than a prophylactic procedure in healthy people. If wrong decisions are made in the selection of preventive measures in healthy individuals, or if they are improperly applied, the consequences are usually much more severe and liability claims are often unavoidable. From a standardization point of view the ﬁltration ecacy of mask for viruses remains hypothetic and not in line with the established standards. There are national and international standards for bacteria ﬁltration eciency (BFE) for medical masks since decades, for example the EU-EN 14683, or the USA-ASTM F2101. They are the prerequisites for general approval. However, since 2020 (i.e., nearly 3 years), no comparable standard/testing of masks for viruses does yet exist. Given the fact, that medical masks (surgical and N95) increase particle exhalation in the smallest size range of 0.3–0.5µm, shifting the geometric mean diameter toward smaller sizes (longer in air) compared to no mask conditions (185) doubts arise. Such scientiﬁc facts are pointing toward the nebulization eect of masks, which could be an add-on for their weakness against viral transmission in general. Limitations Our systematic review rarely discussed the inhaled toxins associated with the mask. Inhalation and ingestion of toxic substances, which are ingredients of the masks, are also of importance in evaluating this pandemic non-pharmaceutical intervention (NPI). In addition, our work has not extensively studied the microbial colonization of masks and the consequences of contamination by microorganisms for the wearer. In our meta-analysis ETCO2 and PtCO2 have been used as an approximationofPaCO2 (44–46).Therefore,therealPaCO2 values could be slightly higher or lower. The median exposure period for most studies evaluating physio-metabolic mask adverse eects was 18min.Therearefewexperimentalstudiesevaluatingmaskadverse eects for longer periods that would more closely reﬂect real-world use. Therefore, the negative physio-metabolic and clinical eects of the face masks may well be worse than we have determined. Based on the studies conducted during the pandemic, the control groups without masks were mostly the same individuals, or individuals who were not mask abstinent for too long (general mask requirement) (186), so the mask-no-mask dierences may be mitigated. Because of the rapid ﬂow of science, new relevant papers have certainly appeared that we were unable to consider in the meta-analysis as they appeared after the period of our data search (search limitation to 31.12.2021). The most important and relevant observational studies were considered for this analysis thereby addressing the physio-metabolic and clinical eects. Numerouspsychologicalandsocialeectscouldnotbeassessed analytically as too few relevant and evaluable studies were available. However,thesimplestandclearestfacemaskharms,overandabove the physiological and clinical discussed here, are the psychological and social ones—impeding communication visually and verbally (187–189), disturbed facial expressions and misinterpretation of emotions (190), with the consequence of impeded early childhood learning (191). Conclusion This systematic review comprehensively revealed ample evidence for multiple adverse physio-metabolic and clinical outcomes of medical face masks, with worse outcomes in the case of N95 masks. This can have long-term clinical consequences, especially for vulnerable groups e.g., children, pregnant, older adult, and the ill. Besides transient and progressive hypoxemia, hypercarbia, and individualized clinical symptoms our ﬁndings are in line with reports on face masks caused down-stream aberrations (e.g., oxidative stress, hypercapnia, vasoconstriction, pro-inﬂammatoryresponse,immunosuppressionetc.)attheorgan, cellular and microbiome levels and support the MIES (Mask Induced Exhaustion Syndrome). From our point of view, while a short application of the mask seems to be less harmful, longer and long-term use may cause shift toward the pathophysiological direction with clinical consequences even without exceeding physiological thresholds (O2 and CO2). FrontiersinPublicHealth frontiersin.org Kisielinski et al../fpubh.. So far, several MIES symptoms may have been misinterpreted as long COVID-19 symptoms. Inanycase,thepossibleMIEStriggeredbymaskscontrastswith the WHO deﬁnition of health. The exact threshold of harmless and non-pathogenic time wearing a mask should exclusively be determined by further intensiveresearchandstudies.Duetotheultimatelackofexclusion of the harmfulness of mask wearing, mask use by the general public should be discouraged. In the sense of eectiveness of face masks in the real-world setting (cost-beneﬁt), the mask should show a beneﬁt in terms of reduced respiratory infections, e.g., in healthcare through fewer consultations or hospitalizations (192). Unfortunately, this was not the case, e.g., in Germany (193) and USA (194), where mask mandates were ubiquitous (9). Additionally, there is evidence that COVID-19rateshavebeenabletoexpandswiftlywhenomicronhit (178) even in societies where mask use was assiduously followed— as in Korea, Taiwan, Hong Kong, and Singapore (179). From the above facts, we conclude that a mask requirement must be reconsidered in a strictly scientiﬁc way without any political interference as well as from a humanitarian and ethical point of view. There is an urgent need to balance adverse mask eects with their anticipated ecacy against viral transmission. In the absence of strong empirical evidence of mask eectiveness, mask wearing should not be mandated let alone enforced by law. Data availability statement The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors. Author contributions KK, AS, and OH: conceptualization and methodology. KK and OH: software. KK, OH, SW, BW, SF, AP, BK, SK, PS, and AS: formal analysis and writing—review and editing. KK, OH, SW, BW, PS, and AS: investigation. KK, SW, SF, BK, AP, PS, and AS: physio-metabolic and clinical interpretations. KK, OH, PS, and AS: writing—original draft preparation. 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