SYSTEMATIC REVIEW article
https://www.frontiersin.org/articles/10....23.1125150/full
Front. Public Health, 05 April 2023
Sec. Environmental health and Exposome
Volume 11 - 2023 | https://doi.org/10.3389/fpubh.2023.1125150
Physio-metabolic and clinical consequences of wearing face masks—Systematic review with meta-analysis and comprehensive evaluation
Kai Kisielinski1*, Oliver Hirsch2, Susanne Wagner3, Barbara Wojtasik4, Stefan Funken5, Bernd Klosterhalfen6, Soumen Kanti Manna7, Andreas Prescher8, Pritam Sukul9* and Andreas Sönnichsen10

1Orthopaedic and Trauma Surgery, Clinical Medicine, Private Practice, Düsseldorf, Germany
2Department of Psychology, Fachhochschule für Oekonomie und Management (FOM) University of Applied Sciences, Siegen, Germany
3Veterinary Medicine, Wagner Medical Science Liason (MSL) Management, Blankenfelde-Mahlow, Germany
4Department of Genetics and Biosystematics, Faculty of Biology, University of Gdańsk, Gdansk, Poland
5Internal Medicine, Clinical Medicine, Private Practice, Moers, Germany
6Institute of Pathology, Dueren Hospital, Dueren, Germany
7Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
8Institute of Molecular and Cellular Anatomy (MOCA), Rhine-Westphalia Technical University of Aachen, Aachen, Germany
9Rostock Medical Breath Research Analytics and Technologies (ROMBAT), Department of Anesthesiology and Intensive Care, University Medicine Rostock, Rostock, Germany
10Internal 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-19 pandemic, adverse effects require substantiated investigation.

Methods: A systematic review of 2,168 studies on adverse medical mask effects yielded 54 publications for synthesis and 37 studies for meta-analysis (on n = 8,641, m = 2,482, f = 6,159, age = 34.8 ± 12.5). The median trial duration was only 18 min (IQR = 50) for our comprehensive evaluation of mask induced physio-metabolic and clinical outcomes.

Results: We found significant effects in both medical surgical and N95 masks, with a greater impact of the second. These effects included decreased SpO2 (overall Standard Mean Difference, SMD = −0.24, 95% CI = −0.38 to −0.11, p < 0.001) and minute ventilation (SMD = −0.72, 95% CI = −0.99 to −0.46, p < 0.001), simultaneous increased in blood-CO2 (SMD = +0.64, 95% CI = 0.31–0.96, p < 0.001), heart rate (N95: SMD = +0.22, 95% CI = 0.03–0.41, p = 0.02), systolic blood pressure (surgical: SMD = +0.21, 95% CI = 0.03–0.39, p = 0.02), skin temperature (overall SMD = +0.80 95% CI = 0.23–1.38, p = 0.006) and humidity (SMD +2.24, 95% CI = 1.32–3.17, p < 0.001). Effects on exertion (overall SMD = +0.9, surgical = +0.63, N95 = +1.19), discomfort (SMD = +1.16), dyspnoea (SMD = +1.46), heat (SMD = +0.70), and humidity (SMD = +0.9) were significant in n = 373 with a robust relationship to mask wearing (p < 0.006 to p < 0.001). Pooled symptom prevalence (n = 8,128) was significant for: headache (62%, p < 0.001), acne (38%, p < 0.001), skin irritation (36%, p < 0.001), dyspnoea (33%, p < 0.001), heat (26%, p < 0.001), itching (26%, p < 0.001), voice disorder (23%, p < 0.03), and dizziness (5%, p = 0.01).

Discussion: Masks interfered with O2-uptake and CO2-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. MIES can have long-term clinical consequences, especially for vulnerable groups. So far, several mask related symptoms may have been misinterpreted as long COVID-19 symptoms. In any case, the possible MIES contrasts with the WHO definition of health.

Conclusion: Face mask side-effects must be assessed (risk-benefit) against the available evidence of their effectiveness against viral transmissions. In the absence of strong empirical evidence of effectiveness, mask wearing should not be mandated let alone enforced by law.

Systematic review registration: https://www.crd.york.ac.uk/prospero/disp...=CRD42021256694, identifier: PROSPERO 2021 CRD42021256694.
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 efficacy of masks in reducing transmission of pathogens, especially bacteria (3). The effectiveness 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 effectiveness of this measure was only weak (6). Since the pandemic began, a large number of studies tried to assess the antiviral effectiveness 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 one of the most important universal life-style attributes that directly affect 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 effects 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 effects 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-effects of FFP2/N95 and surgical masks in adults (aged between 20 and 80 years) at rest (26). Recently, the harmful effects 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 effects 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 sufficient 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 different mask types without any baseline/control group (31) were ubiquitous limitations of those studies. Physiological systematic reviews based purely on physiological effects 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 subjective prevalence of symptoms and discomfort during mask use 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 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

The aim was to study adverse effects of face masks on metabolic, 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. The search was performed until 31st December 2021. There were no 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 effect* [tw], adverse event* [tw], side effect* [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 different 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). Full texts of all potentially relevant articles were independently 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 different 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 effects model was used to pool effect sizes (40). The results were graphically depicted in forest plots. Subgroup analyses were performed and a Q-test was calculated to examine significant subgroup differences. 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 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 effects 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 which measurements were taken during rest and moderate physical 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 different experimental CO2 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 prevalence from observational studies has been previously reported (48). Meta-analysis was performed using RevMan (Version 5.4.1). The heterogeneity of each meta-analysis was assessed and then the random effects 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 difficult or impossible to investigate in randomized controlled trials (RCTs), e.g., air pollution or smoking. In addition, observational studies are important to investigate causes with a long latency period, such as carcinogenic effects of environmental exposures or drugs (49). Thus, possible adverse long-term effects 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 effects 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.-- excerpt, rest at link above --

Fascinating.