Physio-metabolic and clinical consequences of wearing face masks-Systematic review with meta-analysis and comprehensive evaluation

Abstract

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/display_record.php?ID=CRD42021256694, identifier: PROSPERO 2021 CRD42021256694.

Keywords: MIES syndrome; adverse (side) effects; health risk assessment; long-term adverse effects; mask; masks and N95 respirators; risk-benefit; surgical mask.

Figure 1

PRISMA flow chart of the systematic review. From initial 2168, fifty-four studies were later included in the qualitative synthesis. Finally, 37 studies were evaluated statistically in the meta-analysis (quantitative analysis).

Figure 2

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 N95) are evaluated. If studies examine two different mask types in parallel, the corresponding studies are marked: □ = surgical mask ■ = N95 mask. (A) Blood oxygen is significantly lowered in mask use. In the subgroup analysis this could also be found for N95 mask use. From the pooled analysis, it seems, that N95 mask may be responsible for a larger SpO₂ drop than surgical masks. In studies evaluating both conditions (surgical and N95 mask) the N95 mask yielded always lower O₂-values than the surgical masks. (B) In the pooled analysis, blood carbon dioxide (PtCO₂, ETCO₂, and PaCO₂) 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 N95 mask use. In studies evaluating both conditions (surgical and N95 mask) the N95 mask yielded always higher CO₂-values than the surgical masks.

Figure 3

Forest (left) and funnel plots (right) of meta-analysis of physiological respiratory outcomes while wearing a face mask. (A) Shows results for ventilation (V_E), (B) for respiratory rate (RR). All face mask types are initially considered together, later subgroups (surgical and N95) are evaluated. If studies examine two different mask types in parallel, the corresponding studies are marked: □ = surgical mask ■ = N95 mask. (A) Breathing volume is significantly lowered in mask use in the pooled analysis. This could be found for general, for surgical, and N95 mask use. In studies evaluating both conditions (surgical and N95 mask) the N95 mask yielded always lower ventilation (V_E) than the surgical masks. (B) No statistical difference could be found regarding respiratory rate in mask use in the pooled analysis, even in the subgroup analysis (not shown).

Figure 4

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 N95) are evaluated. If studies evaluate two different mask types in parallel, the corresponding studies are marked: □ = surgical mask ■ = N95 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 N95 mask) the N95 mask yielded always higher SBP than the surgical mask, however this effect was not statistically significant. (B) For the N95 mask condition a low significance for a slight increase in heart rate could be found. In studies evaluating both conditions (surgical and N95 mask) the N95 mask yielded always higher HR than the surgical mask, and this effect was statistically significant.

Figure 5

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 N95) are evaluated. If studies examine two different mask types in parallel, the corresponding studies are marked: □ = surgical mask ■ = N95 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 N95 mask use but not for surgical mask use. In studies evaluating both conditions (surgical and N95 mask) the N95 mask yielded higher temperatures than the surgical mask, 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.

Figure 6

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 = 373. All face mask types are initially considered together, later subgroups (surgical and N95) are evaluated. If studies examine two different mask types in parallel, the corresponding studies are marked: □ = surgical mask ■ = N95 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 N95 mask use. A pooled analysis comparing both conditions (surgical mask and N95 mask) resulted in statistically significant higher discomfort rates for the N95 mask than the surgical mask. (B) An overall significance for itching could be found for mask use. Also in N95 mask use the perceived itching was statistically significantly elevated according to the pooled subgroup analysis. (C) In studies evaluating both conditions (surgical and N95 mask) the N95 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 N95 mask) the N95 mask yielded always higher humidity perception rates than the surgical mask. A pooled analysis resulted in a statistical significance for higher humidity perception in N95 masks than surgical masks.

Figure 7

Results comparing the N95 to the surgical mask in the meta-analysis. Forest (left) and funnel plots (right) of meta-analysis of diverse outcomes while wearing a N95 mask vs surgical mask are shown. (A) Depicts the biochemical, (B) the cardiorespiratory outcomes, and (C) the subjective sensations outcomes. N95 mask leads to measurably less favorable results compared 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), CO₂ and systolic blood pressure (both increases), but in those comparisons not statistically significant due to too few includable studies.

Figure 8

Forest (left) and funnel plots (right) of meta-analysis of pooled symptom prevalence while wearing a face mask. Headache (62%), acne (38%), skin irritation (36%), shortness of breath (33%), heat (26%), itch (26%), voice disorder (23%), and dizziness (5%) while wearing a mask are significant in the evaluated population (n = 8,128).

Figure 9

Summary of pooled meta-analytic evaluation of biochemical (A) and physical effects (B) during face mask use. The height of the bars reflects the SMD (standard mean difference), their error bars correspond to the confidence intervals. (A) For carbon dioxide rise in the blood there is a medium effect size of >0.5 and for oxygen drop a small effect size of >0.2 regarding the standard mean difference values thresholds according to Cohen (102). (B) For elevated Humidity and Temperature rise under the face mask there is a strong effect size of ≥0.8. The meta-analytical statistical data were as follows: Oxygen (SpO₂): SMD −0.24, 95% CI −0.38 to −0.11, Z = 3.53, p = 0.0004; Carbon dioxide (PtCO₂, ETCO₂, and PaCO₂): SMD +0.64, 95% CI 0.31 to 0.96, Z = 3.86, p = 0.0001; Humidity: SMD +2.24, 95% CI 1.32 to 3.17, Z = 4.75, p < 0.00001; Temperature: SMD +0.8, 95% CI 0.23 to 1.38, Z = 2.72, p = 0.008.

Figure 10

Summary of pooled meta-analytic evaluation of cardiorespiratory effects during face mask use. The height of the bars reflects the SMD (standard mean difference), their error bars correspond to the confidence intervals. Clear effects for a decrease in ventilation and tidal volume are illustrated, no effect for respiratory rate and weak to low effect for increase in heart rate and systolic blood pressure. For ventilation there is a medium effect size of >0.5 with a small effect size of >0.2 for tidal volume of the standard mean difference values according to Cohen (102). The meta-analytical statistical data were as follows: Ventilation: SMD −0.72, 95% CI −0.99 to −0.46, Z = 5.36, p < 0.00001; Tidal volume: SMD −0.37, 95% CI −0.63 to −0.11, Z = 2.82, p = 0.005; Respiratory rate: SMD +0.01, 95% CI −0.29 to 0.30, Z = 0.08, p = 0.94; Heart rate: SMD +0.11, 95% CI −0.05 to 0.28, Z = 1.34, p = 0.18; Systolic blood pressure: SMD +0.17, 95% CI 0.03 to 0.32, Z = 2.39, p = 0.02.

Figure 11

Illustration of the duration of studies in which measurements were made on mask effects (physical, biochemical, and physiological) in 934 participants. The median is 18 min (yellow dotted line) with an interquartile range of 50. The study with the longest experimental duration included 21 subjects, corresponding to 2.2% 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 45.8 min with standard deviation of 69.9). Therefore, the mean is not an appropriate parameter to characterize this distribution.

Figure 12

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 difference), their error bars correspond to the confidence intervals. Five out of 6 complaint categories (83%) are above the strong effect size threshold of >0.8 of the standard mean difference values according to Cohen (102). The meta-analytical statistical data were as follows (SMD = standard mean difference): Itch: SMD +1.57, 95 %CI −0.08 to 3.23, Z = 1.86, p = 0.06; Shortness of breath: SMD +1.46, 95% CI 0.42 to 2.50, Z = 2.75, p = 0.006; Discomfort: SMD +1.16, 95% CI 0.58 to 1.73, Z = 3.94, p < 0.0001; Exertion: SMD +0.9, 95% CI 0.57 to 1.23, Z = 5.31, p < 0.00001; Humidity: SMD +0.9, 95% CI 0.34 to 1.46, Z = 3.17, p = 0.002; Heat: SMD +0.77, 95% CI 0.29 to 1.26, Z = 3.11, p = 0.002.

Figure 13

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: 62% (95% CI 48–75%), Z = 8.77, p < 0.00001; Acne: 38% (95% CI 22–54%), Z = 4.58, p < 0.00001: Skin irritation: 36% (95% CI 24–49%), Z = 5.61, p < 0.00001; Shortness of breath: 33% (95% CI 23–44%), Z = 6.28, p < 0.00001; Heat: 28% (95% CI 15–0.37%), Z = 4.72, p < 0.00001; Itch: 26% (95% CI 15–36%), Z = 4.77, p < 0.00001; Voice disorder 23% (95% CI 2–43%), Z = 2.15, p < 0.03; Dizziness 5% (95% CI 1–9%), Z = 2.5, p = 0.01.