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Archived 2: Evidence to support safe return to clinical practice by oral health professionals in Canada during the COVID-19 pandemic: A report prepared for the Office of the Chief Dental Officer of Canada

July 2021 update

Contents

Preparation of this update

This evidence synthesis was prepared for the Office of the Chief Dental Officer of Canada, based on a comprehensive review under contract by the following:

Raphael Freitas de Souza, Faculty of Dentistry, McGill University
Paul Allison, Faculty of Dentistry, McGill University
Lilian Aboud, Faculty of Dentistry, McGill University
Martin Morris, Library, McGill University

Foreword to the third update

By Dr James Taylor, Chief Dental Officer of Canada

July 13, 2021

Following the successful completion of the original document on 31 July 2020, the Office of the Chief Dental Officer of Canada (OCDOC) commissioned McGill University to produce three updates during the year following the first report. This is the third of those update reports, covering relevant literature published between March 1st and June 30th, 2021. It is intended as an addendum to the original document and its previous updates, and should thus be used in conjunction with them. This 3rd update document will reside alongside the original report and the 1st and 2nd updates in the public domain, to be accessible to decision makers as they carry out their respective responsibilities.

As with the original document and its previous updates, McGill University drafted a comprehensive knowledge update concerning key issues that inform the provision of oral health care by relevant providers in Canada during the COVID-19 pandemic. The OCDOC then reconvened the representative multidisciplinary knowledge-based group from the national oral health professional and federal government health domains. The group's role was to work collaboratively to contribute to the generation of a single high-level national evidence update document by the team from McGill.

The organizations participating in this collaboration included:

Federal Health Portfolio

National oral health regulatory federations

National oral health professional associations

National oral health academic association

OCDOC mandate: to advance population-level oral health through health promotion, disease prevention and professional/technical guidance with an emphasis on vulnerable populations.

Introduction

During May and June 2020, a research team completed a rapid review of the literature to support the safe practice of Canadian dental professionals during the COVID-19 pandemic. Following input from stakeholders on the draft report in mid-July, the report was finalized and submitted July 31 and then published on the Canada.ca website in both official languages in September 2020. The review covered literature published from January 1, 2000, to June 30, 2020. With the rapid pace of new publications linked to the COVID-19 pandemic, the Chief Dental Officer of Canada determined that updates to the report were needed three times during the year following the first report. These updates covered scientific literature published between July 1, 2020, and October 31, 2020, between November 1, 2020, and February 28, 2021, and finally between March 1, 2021, and June 30, 2021. This is the third (and last) of those update reports adding relevant literature published during the period March 1st to June 30th 2021. The results of the two previous updates are found in this document and are identified as such.

This update document uses the same structure as the original report, addressing the same nine questions. In response to each question, we include: the rationale for the question (the same as the previous report); the summary response provided in the previous report; and then a summary of the new literature. The references are only those identified for the relevant update period and appended tables contain only material from newly identified references. Readers should return to the original report and previous updates for lists of references and other material pertinent to those documents.

Project goal

To create a knowledge product around which the Office of the Chief Dental Officer of Canada can convene a representative knowledge-based group of the national oral health professional domain, in order to generate a single high-level national expert document which Canada's oral health regulatory authorities may then choose to consult in developing consistent guidance for their respective registrants at the Provincial/Territorial level. Further, educators, program officials and policy makers may also choose to consult this document as they carry out their respective responsibilities.

When reading this report it is important to recognize three essential points:

This document focuses on evidence that is categorized as high quality using internationally recognized hierarchies of evidence Footnote 1 Footnote 2 Footnote 3. These are in descending order:

  1. Systematic reviews and meta-analyses
  2. Randomised controlled trials with definitive results (confidence intervals that do not overlap the threshold clinically significant effect)
  3. Randomised controlled trials with non-definitive results (a point estimate that suggests a clinically significant effect but with confidence intervals overlapping the threshold for this effect)
  4. Cohort studies
  5. Case-control studies
  6. Cross sectional surveys
  7. Case reports
  8. Expert opinion

Specific objectives

  1. To update the previously published comprehensive review of the literature concerning key issues that inform the provision of oral health care by relevant providers in Canada during the COVID-19 pandemic. Those key areas are:
    1. Which patients are at greater risk of the consequences of COVID-19 and so consideration should be given to delaying elective in-person oral health care?
    2. What are the signs and symptoms of COVID-19 that oral health professionals should screen for prior to providing in-person health care?
    3. What evidence exists to support patient scheduling, waiting and other non-treatment management measures for in-person oral health care?
    4. What evidence exists to support the use of various forms of personal protective equipment (PPE) while providing in-person oral health care?
    5. What evidence exists to support the decontamination and re-use of PPE?
    6. What evidence exists concerning the provision of aerosol-generating procedures (AGP) as part of in-person oral health care?
    7. What evidence exists to support transmission mitigation strategies during the provision of in-person oral health care?
    8. What evidence exists to support space ventilation strategies that reduce the risk of transmission?
    9. What evidence exists to support the disinfection of surfaces in spaces in which oral health care is provided?
  2. To prepare a written report documenting the updated findings of the aforementioned literature searches. The report is prepared in a manner that provides clear and concise information to decision-makers (individuals providers or organizational) highlighting where strong to no levels of scientific evidence exist to support different approaches.

Methods used to identify and include relevant literature

The same methodological approach was used for this update as was used in the original report and previous updates. In summary, search words and phrases were identified for each of the above topic areas a) to i), and searches were performed for English language articles, in standard scientific literature databases for the period March 1 to June 30, 2021. Two steps were then used to include publications in this report/process: i) step 1 was a review of abstracts to decide on the relevance of publication content for the topic areas; and ii) step 2 was to include only those publications reporting the results of prospective cohort studies, randomized controlled trials, systematic reviews and/or meta-analyses. Steps 1 and 2 were done by one author and a random number of publications were reviewed in the same way by a second author so as to ensure reliability of the findings. An additional, separate search was performed of the bibliography supporting relevant national, provincial and state guidelines concerning oral health care provision during the COVID-19 pandemic in Canada and the USA. Any publications identified in this bibliography that were not in our aforementioned search, but which fulfilled the quality criteria in step 2 and were published during the relevant period were also included in this update report.

With respect to step 1, concerning relevant subject areas, as well as searching for COVID-19 and SARS-CoV-2, we also searched for similar respiratory tract viruses such as SARS, MERS, H1N1 and influenza. In reporting the results of our work, we have made clear whether the evidence concerns COVID-19, SARS-CoV-2, SARS, MERS, H1N1, influenza and sometimes other pathogens. In reality, much of the work reported is in the form of systematic reviews that cover a range of relevant pathogens and diseases. In the updates, for questions with a robust body of evidence about COVID-19, we did not update evidence about other respiratory diseases or viruses (indicated for a topic when applicable).

With respect to step 2, concerning the inclusion of only that evidence fulfilling certain levels of quality, this was taken to enable this review to focus only on strong evidence in support of various approaches and concepts. This means that any evidence we highlight is of high quality. However, where we state that there is no evidence using our quality criteria, it does not mean there is no evidence at all, rather it means that evidence that exists is not of high enough quality to be included in our review. This is particularly important to note in the context of the current pandemic wherein there are a very high number of publications emerging from rapidly performed research, which for good reasons, may not be of the quality ideally desired. There are also many documents containing the opinions of experts, which are valuable in the circumstances, but which are recognized to be low in the hierarchy of quality of evidence.

Report structure

This report will address each of topics a) to i) in turn. For each topic, we provide the rationale for the question (which is the same as in the original report and previous updates); the summary response provided in the previous updates; and then a summary of the new literature, stating how strong the evidence is. The main body of the report contains only these summaries; however, each topic has an appendix containing a tabular summary of included papers, with summary data where appropriate. Readers of this report who are interested in more detailed information will need to access the relevant papers themselves. We also make clear where evidence is related to COVID-19/SARS-CoV-2 or related to similar respiratory tract viruses such as SARS, MERS, H1N1 and influenza. Finally, where pertinent, we refer readers to relevant Health Canada websites.

Summary of update report

First update

This section provides an overview of the findings reported in the different sections. For more detailed information and for the references, see the relevant sections.

We identified a large number of new systematic reviews and meta-analyses concerning the symptoms of people diagnosed with COVID-19 and the risk factors for serious consequences such as hospitalization, ventilation and death among those patients. Many of these reviews and analyses confirmed data presented in the previous report. The evidence is strong that the most common signs and symptoms experienced by people diagnosed with COVID-19 are fever, cough, fatigue and muscle aches, shortness of breath, sputum, headache, sore throat and gastrointestinal symptoms, including diarrhea. New strong evidence has emerged reporting loss of sense of smell and altered sense of taste as common symptoms. With respect to risk factors for serious consequences of COVID-19, the evidence is strong for increased risk among people with cardiovascular diseases, hypertension, diabetes, chronic respiratory diseases, liver and kidney diseases, obesity and smokers. Newly added risk factors are people with cancer and cerebrovascular conditions. In terms of sociodemographic factors, the evidence is strong that increased age augments the risk of serious consequences, with this increased risk beginning to emerge particularly for those 60 years and older. There is now good evidence in the international literature indicating men being at increased risk for COVID-19 and its consequences, although it is not clear why - is it biological or because of their work, socializing habits and/or smoking and alcohol consumption? However, it is important to note that in Canada, the incidence of COVID-19 is higher in women. There is also some evidence to indicate that when studies control for socioeconomic factors, there are no racial differences in serious consequences for COVID-19.

While the evidence concerning the disease itself is increasingly strong, the evidence supporting different interventions pertinent to oral health care remains minimal and weak and relatively little work has been published in the period since the first report. In terms of clarifying guidance for oral health professionals, one systematic review highlights the categories of actions in pre-treatment, during treatment and post-treatment phases of care that organizations around the world have concentrated on, although this does not mean the relevant actions are based on evidence, rather that these are common areas to consider. Another review of guidelines for dental care during the pandemic noticed an increasing focus on preventive and non-Aerosol Generating Procedures (AGPs) and another highlighted the need to develop an evidence-based classification of AGPs and non-AGPs in dentistry rather than the theoretical approaches used thus far.

In terms of PPE, the picture remains unclear in terms of evidence directly related to oral health care, although the evidence does suggest using combined forms of facial covering (e.g., face visor and N95 mask) is better than just one, as no single interventions are fully effective in preventing transmission. There is emerging evidence that N95 masks can be microwaved and re-used at least once without loss of function but there remains no evidence supporting various mitigating approaches such as use of pre-treatment mouthwash, rubber dam and high-volume evacuation. There is evidence that chlorhexidine mouthwash reduces bacterial colony-forming units but none on this or other mouthwashes concerning viruses or disease transmission.

There is emerging evidence concerning the risk factors for Health Care Workers (HCWs) contracting COVID-19, plus the impacts of the disease on them, which are both relevant in terms of considering how to mitigate risks and impacts. Suggestions concerning reducing hours and increasing mental support services have been made for HCWs.

Second update

This section provides an overview of the findings reported in the different sections. For more detailed information and for the references, see the relevant sections.

Our second update identified another large collection of systematic reviews and meta-analyses documenting comorbidities that increase the risk of severe complications in case of infection by SARS-Cov-2. Most results are similar and/or complementary to previous versions of this report (e.g., higher risk for severe COVID-19 in individuals with hypertension, cardiac lesions and diabetes mellitus), but we have also highlighted reports that clarify risk related to pregnant women (the authors recognize that use of the term pregnant women is not gender inclusive. However, the systematic reviews on pregnant women referenced in this evidence synthesis did not include gender diverse people who are pregnant, limiting findings referenced to pregnant women only), who are at higher risk of the same complications for other individuals, including severe COVID-19 and ICU admission. Neonates can be affected negatively if born to mothers who are COVID-19-positive, including lower weight at birth and more frequent admission to a neonatal unit. Many reviews reinforce well-established evidence concerning COVID-19 signs and symptoms, but some reviews introduce a new concept of major relevance in our field: oral mucosal lesions associated to COVID-19.

Newer systematic reviews highlight the effective use of telehealth approaches to reduce in-person dental appointments, provide patient information and train professionals. They also reinforce the need for specific COVID-19 questionnaires before dental care, ventilated waiting rooms/common spaces, social distancing and regular disinfection of non-treatment and operatory areas but evidence does not support the use of laboratory screening tests for SARS-Cov-2 in dental care settings.

Other reviews compared different masks and respirators and suggested that FFP3 and FFP2 may be comparable to N95 to protect professionals from COVID-19. Again, face shields with lateral protection seem essential for dental care providers, combined with at least type 3 medical masks or respirators. However, there is little evidence to support different methods to reuse PPE, with recommended use only in cases of shortage.

A hierarchy of risk for contamination was suggested by evidence identified in this update, with higher risk associated with the use of ultrasonic scalers, high-speed handpieces, air-water syringe, air polishers, as well as handpieces and lasers for oral surgery (including extractions and osteotomy). Reviews have recommended the use of alternative techniques to minimise aerosols (e.g., atraumatic restorative treatment with hand instruments and silver diamine fluoride instead of conventional restorative treatment), and pre-appointment use of several types of mouthwashes to minimize risks of transmission.

Little evidence was gathered to support the use of air cleaning systems as a means to mitigate the transmission of COVID-19 in dental operatory rooms. More studies are still needed to determine disinfection methods for surfaces and objects in an oral healthcare facility, although a novel finding, however, is the efficacy of sodium hypochlorite as a disinfecting medium for impressions and dental prostheses.

Third update

The findings of this last update include several confirmatory SRs regarding comorbidities and conditions linked to a higher risk for fatal and severe COVID-19, further strengthening the evidence in this domain. We identified new information about certain conditions, which can lead to worse outcomes in case of SARS-CoV-2 infection, including psychiatric disorders, obstructive sleep apnea, pulmonary aspergilosis, multiple sclerosis and Parkinson's disease. Besides previously identified and now well-known signs and symptoms of COVID-19 (e.g., fever, cough, olphactory loss), there is some evidence that the condition may sometimes lead to skin manifestations.

This update identified some limited evidence in support of specific telehealth-based approaches to limit the presence of patients during the pandemic, as well as artificial intelligence for patient screening to decide whether in-person appointments are appropriate. We also identified a classification system that is usable by oral healthcare providers to assist people who might test positive for COVID-19.

New evidence to support the use of different PPE was limited and confirmed some of the findings of our previous updates. No new studies concerning the reprocessing and re-use of PPEs were eligible for this update, in line with the current non-recommendation of those approaches due to sufficient supplies. In this context, it is important to recognize that while re-use of certain PPE was considered at the beginning of the pandemic when supplies were often short, it is now not recommended to re-use PPE in Canada.

Included studies reinforced the need for adequate ventilation and filtration to control contamination during AGPs, with optimal results in hospital settings by combining both. Few studies have approached space ventilation strategies directly, but some provide specific recommendations based on the use of natural ventilation, air vents and filtering units. The time to remove aerosols seems to reduce considerably if ventilation is combined with filtering units.

The mitigation and management of aerosols specific to oral health care settings is still based on limited evidence, although the following website provides a good overview of how people acquire COVID-19. However, in this most recent update, we identified new evidence to support some pre-procedural mouthwashes, rubber dam and high-volume evacuators. Included studies recommend the minimization of aerosols as much as possible in different dental treatments, including the use of hand scalers and manual excavation instead of high-speed handpieces where viable. New evidence has emerged that high-power lasers may result in a considerable volume of particles in the air; thus, studies suggest more complex barrier methods when they are used, both in clinical and laboratory settings.

Finally, limited evidence supports a wide array of surface disinfecting agents against SARS-CoV-2, but also reminds us that this virus is able to survive for several days on vinyl, steel and glass, which are common materials in any oral healthcare environment. Given the paucity of evidence on SARS-CoV-2, the reader may opt to refer to previous studies on other enveloped viruses for further information on those agents:

Report results

a. Which patients are at greater risk of the consequences of COVID-19 so consideration should be given to delaying elective in-person oral health care?

a.1. Findings from the first update

We identified multiple systematic reviews, meta-analyses and a few cohort studies adding to the knowledge and understanding of which patient groups are at greater risk of severe consequences of having COVID-19. The large majority of these studies confirmed findings we described in the previous report. Nevertheless, there have been some important additional findings with strong evidence supporting them. Recently published reviews and meta-analyses confirmed the increased risk for serious consequences of COVID-19 including hospitalization, ventilation and death for people with cardiovascular diseases Footnote 4 Footnote 5 Footnote 6 Footnote 7 Footnote 8 Footnote 9 Footnote 10 Footnote 11 Footnote 12 Footnote 13 Footnote 14 Footnote 15 Footnote 16 Footnote 17, hypertension Footnote 4 Footnote 5 Footnote 6 Footnote 7 Footnote 8 Footnote 9 Footnote 10 Footnote 11 Footnote 12 Footnote 17 Footnote 18 Footnote 19 Footnote 20,respiratory diseases Footnote 5 Footnote 7 Footnote 10 Footnote 11 Footnote 12 Footnote 18 Footnote 21 Footnote 22 Footnote 23, diabetes Footnote 4 Footnote 5 Footnote 7 Footnote 8 Footnote 10 Footnote 11 Footnote 19 Footnote 20 Footnote 21 Footnote 24 Footnote 25 Footnote 26 Footnote 27 Footnote 28, liver Footnote 12 Footnote 29 Footnote 30 Footnote 31 and kidney diseases Footnote 5 Footnote 8 Footnote 11 Footnote 12 Footnote 14 Footnote 22 Footnote 32 Footnote 33 Footnote 34 Footnote 35 Footnote 36 Footnote 37 Footnote 38 Footnote 39 plus for smokers Footnote 18. New information adds to the list of at-risk people who are obese Footnote 20 Footnote 40 Footnote 41 Footnote 42 Footnote 43, have cancer Footnote 11 Footnote 44 Footnote 45 Footnote 46 Footnote 47 and cerebrovascular conditions Footnote 10 Footnote 11 Footnote 12 Footnote 13 Footnote 17 Footnote 48 Footnote 49 Footnote 50 Footnote 51.

Concerning age and sex, again there has been additional high-quality evidence published. It is clear that increased age increases the risk of serious consequences Footnote 20 Footnote 49 Footnote 52 Footnote 53 with one review clarifying that the peak increase in risk is for serious consequences starts to occur for those 50-59 years of age but the largest risk increase is for the 60-69 year olds compared to those in their 50s, although the risk keeps increasing with older age Footnote 52. With respect to sex, it is now clear from the international literature that the incidence of COVID-19 is greater in men than women Footnote 10 Footnote 19 Footnote 54 Footnote 55. However, it is important to note, as shown on the webpage COVID-19 epidemiological and economic research data, that in Canada, the incidence of COVID-19 is higher in females compared to males, although this varies by age group. In terms of disease outcomes, again the international literature shows men are at increased risk for serious consequences of COVID-19 including death Footnote 20 Footnote 54 Footnote 56 Footnote 57 Footnote 58. However, these studies also pointed out that it is not clear why men are at greater risk for worse outcomes. They could be at increased risk because of the nature of their work, their socializing habits, their smoking, alcohol consumption and/or levels of comorbidities Footnote 20 Footnote 58. In Canada, there have been more hospitalizations and deaths among women but more men admitted to intensive care units (again see COVID-19 epidemiological and economic research data. It is also important to recognize that certain groups in the population face greater risk due to social, economic and occupational vulnerabilities. Further research needs to be performed to better understand the different levels of risk experienced by various groups in the population.

Canada COVID-19 daily epidemiology report. Further research needs to be performed to better understand this phenomenon.

With respect to COVID-19 in pregnancy, the evidence remains relatively limited because the numbers are considerably smaller than in the broader population studies. Nevertheless, there is limited, emerging evidence that pregnant women with COVID-19 are at increased risk for complications with their pregnancy Footnote 59 Footnote 60 Footnote 61 Footnote 62. There is also emerging limited evidence concerning the problems suffered by neonates who are COVID-19 positive Footnote 59 Footnote 60 Footnote 63 Footnote 64 Footnote 65. With respect to the possibility of vertical transmission from mother to foetus, one systematic review reported zero such cases Footnote 64 while two others reported rates of 2-3.2% of neonates testing positive for SARS-Cov-2 among babies born to mothers who were also SARS-Cov-2 positive Footnote 61 Footnote 66.

a.2. Findings from the second update

This second update returned several systematic reviews (SRs) within this topic. As for the November 2021 update, most of those SRs confirm previous strong evidence regarding the risk for complications of COVID-19 associated with now well-known comorbidities. Probably the most studied comorbidity linked to higher risk of severe COVID-19, ICU admission and death is hypertension, which was identified by 49 new SRs Footnote 67 Footnote 68 Footnote 69 Footnote 70 Footnote 71 Footnote 72 Footnote 73 Footnote 74 Footnote 75 Footnote 76 Footnote 77 Footnote 78 Footnote 79 Footnote 80 Footnote 81 Footnote 82 Footnote 83 Footnote 84 Footnote 85 Footnote 86 Footnote 87 Footnote 88 Footnote 89 Footnote 90 Footnote 91 Footnote 92 Footnote 93 Footnote 94 Footnote 95 Footnote 96 Footnote 97 Footnote 98 Footnote 99 Footnote 100 Footnote 101 Footnote 102 Footnote 103 Footnote 104 Footnote 105 Footnote 106 Footnote 107 Footnote 108 Footnote 109 Footnote 110 Footnote 111 Footnote 112 Footnote 113 Footnote 114 Footnote 115. Twenty-six SRs further confirm the higher rates of severe COVID-19 among CVD patients, with a higher risk for ICU admission and death Footnote 67 Footnote 68 Footnote 69 Footnote 71 Footnote 72 Footnote 74 Footnote 76 Footnote 77 Footnote 78 Footnote 81 Footnote 82 Footnote 84 Footnote 86 Footnote 87 Footnote 88 Footnote 91 Footnote 92 Footnote 98 Footnote 99 Footnote 101 Footnote 107 Footnote 113 Footnote 114 Footnote 115 Footnote 116 Footnote 117. Specific CVD and conditions tackled by recent SRs include congestive heart failure Footnote 10 Footnote 75 Footnote 107 Footnote 118 Footnote 119 Footnote 120 Footnote 121, cardiac arrythmia Footnote 75 Footnote 119 Footnote 120 Footnote 122, myocardial injury Footnote 119 Footnote 123, history of heart transplant Footnote 124, general Footnote 89 Footnote 125 Footnote 126 and acute cardiac injury Footnote 67 Footnote 75 Footnote 97 Footnote 110 Footnote 120 Footnote 123 Footnote 127 Footnote 128 Footnote 129 Footnote 130, and coronary heart disease Footnote 93 Footnote 103 Footnote 105 Footnote 115 Footnote 131. In all cases, the risk of severe COVID-19 and subsequent death raises considerably.

As found in previous versions of this report, a history of respiratory diseases raises the risk for severe COVID-19 and death (six SRs) Footnote 69 Footnote 105 Footnote 114 Footnote 132 Footnote 133 Footnote 134.Specific conditions associated with increased risk for poor outcomes of COVID-19 were asthma (11 SRs) Footnote 72 Footnote 85 Footnote 88 Footnote 91 Footnote 94 Footnote 100 Footnote 133 Footnote 135 Footnote 136 Footnote 137 Footnote 138 Footnote 139, COPD (15 SRs) Footnote 67 Footnote 77 Footnote 84 Footnote 86 Footnote 90 Footnote 98 Footnote 113 Footnote 114 Footnote 116 Footnote 140 Footnote 141 Footnote 142 Footnote 143 Footnote 144 Footnote 145 and ARDS (12 SRs) Footnote 67 Footnote 71 Footnote 72 Footnote 108 Footnote 110 Footnote 120 Footnote 130 Footnote 146 Footnote 147 Footnote 148 Footnote 149 Footnote 150. Three SRs suggest higher risk for severe COVID-19 in patients with a history of pneumonia Footnote 73 Footnote 112 Footnote 133. This update also reinforces findings for diverse types of cancer Footnote 67 Footnote 69 Footnote 72 Footnote 84 Footnote 86 Footnote 88 Footnote 94 Footnote 100 Footnote 101 Footnote 103 Footnote 107 Footnote 113 Footnote 114 Footnote 116 Footnote 151 Footnote 152 Footnote 153 Footnote 154 Footnote 155 Footnote 156 Footnote 156 Footnote 157 Footnote 158 Footnote 159 Footnote 160 Footnote 161 Footnote 162 Footnote 163, cerebrovascular diseases Footnote 67 Footnote 69 Footnote 72 Footnote 77 Footnote 84 Footnote 86 Footnote 88 Footnote 113 Footnote 114 Footnote 115 Footnote 164 Footnote 165 Footnote 166 Footnote 167, acute Footnote 67 Footnote 86 Footnote 120 Footnote 123 Footnote 130 Footnote 168 Footnote 169 Footnote 170 Footnote 171 Footnote 172 Footnote 173 Footnote 174 Footnote 175 Footnote 176 Footnote 177 Footnote 178 Footnote 179 and chronic kidney diseases (including patients who received transplants and hemodialysis) Footnote 67 Footnote 69 Footnote 82 Footnote 86 Footnote 88 Footnote 94 Footnote 100 Footnote 103 Footnote 105 Footnote 107 Footnote 113 Footnote 116 Footnote 140 Footnote 142 Footnote 169 Footnote 174 Footnote 175 Footnote 178 Footnote 179 Footnote 180 Footnote 181 Footnote 182 Footnote 183, being linked to severe COVID-19 and higher odds for death. A history of diabetes mellitus has been associated with a higher risk of severe COVID-19 and consequences like cerebrovascular accidents, ICU admission, invasive ventilation and mortality Footnote 67 Footnote 68 Footnote 69 Footnote 70 Footnote 71 Footnote 72 Footnote 73 Footnote 74 Footnote 76 Footnote 77 Footnote 78 Footnote 80 Footnote 81 Footnote 82 Footnote 84 Footnote 86 Footnote 87 Footnote 88 Footnote 90 Footnote 91 Footnote 92 Footnote 93 Footnote 94 Footnote 95 Footnote 96 Footnote 97 Footnote 98 Footnote 99 Footnote 100 Footnote 101 Footnote 102 Footnote 103 Footnote 104 Footnote 105 Footnote 106 Footnote 107 Footnote 108 Footnote 110 Footnote 112 Footnote 113 Footnote 114 Footnote 115 Footnote 116 Footnote 132 Footnote 142 Footnote 184 Footnote 185 Footnote 186 Footnote 187 Footnote 188 Footnote 189 Footnote 190.

More specific findings of this update include a higher severity of and mortality through COVID-19 among individuals affected by dementia Footnote 191 Footnote 192 Footnote 193 Footnote 194 and other nervous system diseases Footnote 164 Footnote 195; liver disease (mostly chronic) Footnote 67 Footnote 69 Footnote 113 Footnote 114 Footnote 196 Footnote 197 Footnote 198 Footnote 199 Footnote 200 Footnote 201 Footnote 202 Footnote 203; and thromboembolism, both arterial Footnote 204 Footnote 205 Footnote 206 Footnote 207 Footnote 208 Footnote 209 and venous Footnote 210 Footnote 211 Footnote 212 Footnote 213 Footnote 214 Footnote 215 Footnote 216 Footnote 217 Footnote 218 Footnote 219 Footnote 220 Footnote 221. Evidence seems less consensual regarding autoimmune disease, with conflicting results Footnote 88 Footnote 100 Footnote 222.

Important factors linked to severe COVID-19 outcomes include advanced age Footnote 69 Footnote 71 Footnote 72 Footnote 78 Footnote 79 Footnote 90 Footnote 101 Footnote 105 Footnote 106 Footnote 109 Footnote 134 Footnote 141 Footnote 180 Footnote 206 Footnote 223 Footnote 224 Footnote 225 Footnote 226 Footnote 227, obesity Footnote 94 Footnote 96 Footnote 100 Footnote 101 Footnote 114 Footnote 142 Footnote 190 Footnote 228 Footnote 229 Footnote 230 Footnote 231 Footnote 232 Footnote 233 Footnote 234 Footnote 235 Footnote 236 and smoking (current or previous) Footnote 67 Footnote 77 Footnote 78 Footnote 81 Footnote 86 Footnote 94 Footnote 103 Footnote 104 Footnote 145 Footnote 237 Footnote 238 Footnote 239 Footnote 240 Footnote 241 Footnote 242 Footnote 243 Footnote 244 Footnote 245 Footnote 246, all of which were mentioned in our previous reports. Interestingly, a history of bariatric surgery seems protective against COVID-19-related death and hospital admission Footnote 247 Footnote 247. In this update, we found no evidence for the role of a specific sex/gender as a risk factor for complications of COVID-19 Footnote 67 Footnote 69 Footnote 71 Footnote 72 Footnote 73 Footnote 77 Footnote 78 Footnote 79 Footnote 87 Footnote 90 Footnote 92 Footnote 101 Footnote 103 Footnote 104 Footnote 105 Footnote 130 Footnote 141 Footnote 223 Footnote 226 Footnote 248 Footnote 249 Footnote 250 Footnote 251 Footnote 252. Regarding the role of race in COVID-19 outcomes, some SRs suggest modest differences in the risk for severe disease and mortality with higher risk among Asians compared other groups Footnote 71 Footnote 253 Footnote 254 Footnote 255. Interestingly, newer SRs suggest different risks to acquire COVID-19 in people with different blood types, the highest risk being for those with blood type A and Rh-positive; however, the odds for severe COVID-19 and death are the highest among blood type AB individuals Footnote 256 Footnote 257 Footnote 258.

Stronger evidence is now emerging concerning pregnant women, neonates and children. Pregnant women are at higher risk for hospital admission (including ICU and invasive ventilation) if affected by COVID-19, compared to non-pregnant women Footnote 259 Footnote 260 Footnote 261 Footnote 262. The risk is further increased if some of the abovementioned conditions are present, e.g., obese women, increased maternal age, pre-existing hypertension and diabetes Footnote 259 Footnote 263. Neonates are at higher risk for complications if their mothers are COVID-19-positive, including admission to a neonatal unit, low birth weight and fetal distress, besides the possibility of acquiring the disease from their mothers (vertical transmission) Footnote 259 Footnote 260 Footnote 261 Footnote 263 Footnote 264 Footnote 265 Footnote 266 Footnote 267 Footnote 268. Regarding children, although they are less prone to complications from COVID-19 Footnote 148 Footnote 269 Footnote 270 Footnote 271 Footnote 272 Footnote 273 Footnote 274, a history of cancer Footnote 275 or obesity Footnote 276 increases the risk for severe disease in this age group. We found no evidence fulfilling our inclusion criteria concerning the association between congenital and genetic syndromes (e.g., Down syndrome, intellectual disabilities) with the outcomes of COVID-19. This as a major knowledge gap that should be explored in future prospective studies.

We found moderate evidence suggesting more complications with COVID-19 among individuals who have tuberculosis, influenza, chronic hepatitis, HIV, rheumatic diseases, intestinal diseases, dyslipidemia, secondary infections and vitamin D insufficiency. Also, individuals who underwent surgical procedures while affected by COVID-19 seem to face higher mortality rates Footnote 277.

A good document summarizing the key risk factors for severe COVID-19 disease can be found at: People who are at high risk for severe illness from COVID-19.

a.3 Findings from the third update

Fourteen SRs with meta-analyses endorse the higher risk of severe COVID-19 and subsequent mortality among people with cardiovascular disease (CVD) Footnote 278 Footnote 279 Footnote 280 Footnote 281 Footnote 282 Footnote 283 Footnote 284 Footnote 285 Footnote 286 Footnote 287 Footnote 288 Footnote 289 Footnote 290 Footnote 291. Hypertension is again highlighted as a risk condition in people who might test positive for COVID-19, with higher odds of ICU admission and death (15 SR with meta-analysis Footnote 278 Footnote 279 Footnote 292 Footnote 280 Footnote 281 Footnote 282 Footnote 293 Footnote 294 Footnote 295 Footnote 283 Footnote 284 Footnote 285 Footnote 287 Footnote 290 Footnote 291). Other specific CVD linked to a higher risk of severe and lethal COVID-19 were congestive heart failure Footnote 296 Footnote 297 Footnote 289 Footnote 298), cardiac arrythmias Footnote 299 Footnote 297 Footnote 300 Footnote 298, myocardial and cardiac injuries Footnote 298 Footnote 301 Footnote 293, ST- Segment Elevation Myocardial Infarction (STEMI) Footnote 302 Footnote 303, acute cardiac injury Footnote 288 Footnote 289 Footnote 290 Footnote 298 Footnote 304, coronary heart disease Footnote 297 Footnote 295, and both left and right ventricular dysfunction Footnote 305 Footnote 306. Moreover, the occurrence of cardiac arrest in COVID-19 patients results in more frequent mortality compared to patients who do not test positive for the virus Footnote 305.

Six new SRs with meta-analyses further endorsed previous evidence that pre-existing respiratory diseases in general can increase the risk for severe COVID-19 outcomes and subsequent mortality Footnote 279 Footnote 292 Footnote 304 Footnote 281 Footnote 22 Footnote 293. The same can be stated for specific respiratory diseases, i.e., asthma Footnote 307 Footnote 308 Footnote 309 Footnote 310 Footnote 311 Footnote 312, COPD Footnote 307 Footnote 313 Footnote 304 Footnote 308 Footnote 282 Footnote 297 Footnote 295 Footnote 284 Footnote 314 Footnote 310 Footnote 285 Footnote 290 Footnote 291, ARDS Footnote 278 Footnote 315 Footnote 280 Footnote 281 Footnote 22 Footnote 295 Footnote 288 Footnote 290, obstructive sleep apnea Footnote 316, and pulmonary aspergillosis Footnote 317 Footnote 318.

A large body of evidence confirms the link between diabetes mellitus and severe and lethal COVID-19 Footnote 278 Footnote 319 Footnote 320 Footnote 279 Footnote 292 Footnote 280 Footnote 281 Footnote 321 Footnote 282 Footnote 322 Footnote 293 Footnote 323 Footnote 294 Footnote 295 Footnote 324 Footnote 325 Footnote 283 Footnote 326 Footnote 327 Footnote 284 Footnote 319 Footnote 328 Footnote 285 Footnote 287 Footnote 329 Footnote 290 Footnote 291 Footnote 330. People with cancer are also at higher risk for the same poor outcomes, with even higher mortality during active chemotherapy Footnote 307 Footnote 331 Footnote 332 Footnote 333 Footnote 280 Footnote 304 Footnote 282 Footnote 334 Footnote 293 Footnote 335 Footnote 331 Footnote 336 Footnote 284 Footnote 337 Footnote 338 Footnote 291 Footnote 330.

Six SRs and meta-analyses concluded that cerebrovascular diseases in general are linked to higher odds for severe COVID-19 Footnote 279 Footnote 282 Footnote 293 Footnote 295 Footnote 287 Footnote 291. Two SRs with meta-analyses came to the same conlsusion for dementia, with higher mortality rates for people with this condition Footnote 339 Footnote 340.

A single SR with meta-analysis concluded that patients with certain psychiatric disorders (i.e., mood disorders, schizophrenia, schizotypal and delusional disorders) may be at higher risk to become infected by SARS-CoV-2 Footnote 341. The same patients may be at higher risk of severe and lethal COVID-19 outcomes, at least when they are in advanced age or have comorbidities.

A single SR with meta-analysis provided evidence that COVID-19 increases the odds of developing Guillain-Barré syndrome, although this remains rare Footnote 342. Acute liver lesions were also identified as potential complications of COVID-19 by two SRs with meta-analyses Footnote 22 Footnote 288.

Again, chronic Footnote 292 Footnote 304 Footnote 282 Footnote 293 Footnote 295 Footnote 324 Footnote 343 Footnote 344 Footnote 283 Footnote 345 Footnote 287 Footnote 291 and acute kidney diseases Footnote 304 Footnote 281 Footnote 22 Footnote 295 Footnote 346 Footnote 347 Footnote 345 Footnote 288 Footnote 290 Footnote 348 were highlighted as risk factors for severe COVID-19 and subsequent hospital admission and death. Severe COVID-19 was also more frequent among people with liver disease Footnote 278 Footnote 304 Footnote 349 Footnote 293 Footnote 350.

Ten SRs with meta-analyses point out that current and previous smokers are at higher risk of death if infected by SARS-CoV-2 Footnote 278 Footnote 304 Footnote 281 Footnote 321 Footnote 351 Footnote 352 Footnote 293 Footnote 297 Footnote 295 Footnote 291. Twelve SRs with meta-analyses identified obesity as a risk factor for severe COVID-19, hospitalization (including ICU admission and invasive ventilation) and death, even in young patients Footnote 353 Footnote 354 Footnote 355 Footnote 356 Footnote 357 Footnote 295 Footnote 324 Footnote 358 Footnote 359 Footnote 360 Footnote 287 Footnote 361.

Age was again confirmed as a risk factor for severe COVID-19 and mortality, mostly in the presence of comorbidities Footnote 339 Footnote 292 Footnote 362 Footnote 304 Footnote 363 Footnote 364 Footnote 293 Footnote 297 Footnote 294 Footnote 324 Footnote 284 Footnote 365 Footnote 288 Footnote 290 Footnote 291). Three SRs with meta-analyses described Black and East Asian individuals as being at higher risk of COVID-19, with a non-Caucasian ethnicity being linked to a higher risk of consequent mortality Footnote 363 Footnote 321 Footnote 293. Two SRs with meta-analyses highlighted that seroprevalence of SARS-CoV-2 varies considerably among different regions of the world, with highest rates in Southeast Asian, African and Eastern Mediterranean regions Footnote 363 Footnote 293.

Arterial thrombosis has been linked to higher risks of severe and fatal COVID-19 Footnote 366 Footnote 296 Footnote 367 Footnote 368 Footnote 369 Footnote 370, while venous thrombosis (including pulmonary embolism) was highlighted as a risk factor for ICU admission among COVID-19 patients Footnote 371 Footnote 372 Footnote 217 Footnote 373 Footnote 374.

Some SRs with meta-analyses link pre-existing conditions to worse outcomes among COVID-19 patients, including higher mortality with dyslipidemia Footnote 375 and hemoglobinopathies Footnote 376. Diseases and conditions linked to a higher risk of lethal and severe COVID-19 included multiple sclerosis Footnote 377, Parkinson's disease Footnote 378, femoral and hip fractures Footnote 379 Footnote 380, rheumatic diseases Footnote 381, immunosuppression Footnote 333 Footnote 330, previous HIV infection Footnote 382 Footnote 383 Footnote 384 Footnote 385 Footnote 386 and different degrees of frailty Footnote 387 Footnote 388 Footnote 389 Footnote 390. The previous use of NSAIDs exerted no difference on the course of COVID-19, however Footnote 391.

Nutritional issues (i.e., deficiencies of vitamin D Footnote 392 Footnote 393 Footnote 394 Footnote 395 Footnote 396 Footnote 397 and micronutrients Footnote 398) were identified by some SRs with meta-analyses as being correlated with severe and/or fatal COVID-19.

An emerging issue refers to the recurrence of COVID-19, which was described in 15% of a sample of 3,644 patients by a SR with meta-analysis Footnote 399.

Pregnant women with COVID-19 were slightly more likely to be admitted to ICU, particularly with increased maternal age, high body mass index and comorbidities Footnote 400 Footnote 281 Footnote 401 Footnote 402 Footnote 294 Footnote 403. Neonates born to women with COVID-19 were more likely to be admitted to neonatal units and have lower birth weight (1 SR with meta-analysis Footnote 281). Two SRs with meta-analyses concerning COVID-19 in children stated that, although the prevalence is lower than in adults Footnote 294, comorbidities like cancer can increase the risk for severe and fatal infection in this group Footnote 333.

b. What are the signs and symptoms of COVID-19 that oral health care professionals should screen for prior to providing in-person health care?

b.1. Findings from the first update

We identified multiple systematic reviews and meta-analyses plus prospective cohort studies adding to the now strong literature on the signs and symptoms of COVID-19. The additional literature we identified largely confirmed the summary and list of symptoms provided in the earlier report (fever, cough, shortness of breath, fatigue and muscle weakness and aches, headache and digestive symptoms such as diarrhea Footnote 5 Footnote 9 Footnote 10 Footnote 19 Footnote 404 Footnote 405 Footnote 406 Footnote 407 Footnote 408 Footnote 409), although notable new information has been added. This includes new signs and symptoms now recognized as among those often shown by people with COVID-19, including anosmia (lost sense of smell; 39-88%) Footnote 406 Footnote 407 Footnote 410 Footnote 411 and dysgesia (altered sense of taste; 81%) Footnote 411. There were also important additions to the previous list of signs and symptoms, including loss of appetite (34%) Footnote 5, myocardial injury (16%) Footnote 412, dizziness (6%) Footnote 19 and confusion/agitation (5%) Footnote 407. On top of this, there has been additional literature concerning symptoms experienced by children with COVID-19, including fever (53%), cough (39%) and sore throat (14%) Footnote 413. The evidence concerning the symptoms experienced by pregnant women with COVID-19 remains relatively limited compared to the general population but new information now available includes estimates of the proportion of pregnant women with viral pneumonia (71-89%) Footnote 60, fever (44-63%) Footnote 60 Footnote 65 Footnote 414, cough (36-71%) Footnote 60 Footnote 65 Footnote 414, dyspnea (13-34%) Footnote 65 Footnote 414 and myalgia or fatigue (11%) Footnote 60.

b.2. Findings from the second update

This second update found a large body of evidence confirming previously described signs and symptoms of COVID-19, including fever, cough, dyspnea, sore throat, muscle pain, headache, abdominal pain, diarrhea, agitation/confusion, dizziness, loss of appetite, as well as olfactory and gustatory impairment. Ischemic strokes also seem more frequent among COVID-19 patients Footnote 115 Footnote 164 Footnote 415 Footnote 416 Footnote 417 Footnote 418 Footnote 419.

Newly described findings include expectoration with blood (hemoptysis), chest pain and tightness Footnote 67 Footnote 69 Footnote 130 Footnote 420, and ocular manifestations (conjunctival symptoms) Footnote 421. Specific laboratory and imaging findings can be seen in COVID-19 patients (please refer to Appendix B for more information).

Of special interest for oral healthcare providers, a single SR describes oral mucosal lesions associated with COVID-19 Footnote 422. Patients may present irregular ulcers, small blisters and petechiae affecting palate, tongue, lips, gingiva or buccal mucosa. Desquamative gingivitis was also observed. Whereas mild cases seem to develop oral mucosal lesions before or at the onset of respiratory symptoms, patients who required medication and hospital admission may have those lesions between 7 and 24 days after symptoms started.

A good document concerning signs and symptoms of COVID-19 can be found at the following link: COVID-19 signs, symptoms and severity of disease: A clinician guide.

b.3 Findings from the third update

This third update found several SRs with meta-analyses confirming previous information about the signs and symptoms of COVID-19. Fever is highlighted as one of the most common signs, reaching a medium grade for almost half of the cases Footnote 280 Footnote 377 Footnote 281 Footnote 423 Footnote 424 Footnote 293 Footnote 297 Footnote 294 Footnote 365 Footnote 425 Footnote 291.

Newer signs to consider include cutaneous manifestations, often morbilliform, varicelliform, and urticarial Footnote 426. COVID-19 also has been linked to neurological symptoms Footnote 427 Footnote 425 Footnote 428 and higher pulse rate Footnote 291.

We also identified recent SRs with meta-analyses quantifying asymptomatic patients as being 31% of COVID-19-positive nursing home residents Footnote 364 and 5% to 12.9% of children Footnote 281 Footnote 429 Footnote 430.

As the pandemic evolves, new data on long-term, post-COVID-19 symptoms were reported by a single SR with meta-analysis Footnote 431. After recovery from COVID-19, 55% of patients report chronic fatigue and pain, while almost a quarter report neurological complaints and olfactory dysfunctions (24% each), and abdominal breathing (21%).

c. What evidence exists to support patient scheduling, waiting and other non-treatment management measures for in-person oral health care?

c.1. Findings from the first update

Again, several relevant systematic reviews were identified. One relevant publication reviewed COVID-19 transmission risk and protection protocols published by organizations in countries throughout the world and in academic journals Footnote 432. They categorized the approaches they found common to all protocols in these publications into pre-, during and post-dental treatment measures as per Table 1 below. It is important to note that this summary of factors common to all reviewed dental COVID-19 protocols does not necessarily reflect any evidence to support their inclusion, or exactly what the advice for each factor is, rather it is a list of factors in dental COVID-19 dental protocols that were common to all review publications.

Table 1. Measures recommended in dental protocols identified in systematic review by Banakar et al Footnote 432.
Stage of care Measures recommended
Pre-dental treatment
Before entering a dental office
At the dental office		 Patient triage, identification potential COVID-19 cases, delay of non-urgent dental care, management of dental appointments, active and culturally safe screening of dental staff.
Active and culturally safe screening of patients, physical distancing in the dental office, cleaning and disinfection measures for patients, use of facemasks by everyone entering the dental office, patient education, use of personal protective equipment (PPE) by the dental team and management of the dental operatory room.
During dental treatment Maintaining hand hygiene, offering preoperative anti-microbial mouth rinse to patients, using rubber dams, high-volume saliva ejectors, and extraoral dental radiographs, using 4-handed dentistry, avoiding aerosol-generating procedures, one-visit treatment and environmental cleaning and disinfection procedures.
Post-dental treatment Cleaning and disinfecting reusable facial protective equipment, as well as management of laundry and medical waste.

This list of factors to consider and the categorization of the stages of pre-, during and post-dental treatment was very similar to those documented in two other systematic reviews on the subject Footnote 433 Footnote 434. A review of guidelines for pediatric dentistry during the COVID-19 pandemic published throughout the world made similar observations but in addition, focused on the need for preventive and non-AGPs Footnote 435. The authors mentioned focusing on using approaches including telehealth, using fluoride varnish and resin or sealing non-cavitated caries, using atraumatic restorative technique (ART), interim therapeutic restorations, indirect pulp capping, the Hall technique and silver diamine fluoride Footnote 435.

c.2. Findings from the second update

Some included studies bring new information about telehealth, reaching moderate levels of evidence. The possibility of reducing physical contact and providing continuous care makes telehealth appropriate, with potential to reduce COVID-19-related morbidity and mortality Footnote 436. Oral health-specific approaches were highlighted as useful for the present pandemic by two reviews Footnote 437 Footnote 438. Examples of contributions by teledentistry include fewer in-person appointments and remote triage of the elderly, with good cost-effectiveness and acceptability by patients, caregivers, families and care facilities Footnote 439. The use of remote appointments was also highlighted as favorable for evaluating cleft lip and palate patients, including their post-treatment follow-up Footnote 440. Generic telehealth methods have been pointed as a way to guarantee better access to care during a lockdown Footnote 441 and to evaluate chronic pain patients in certain circunstances Footnote 442. One review suggested that the use of mobile apps in health care can increase the effectiveness of tasks such as training personnel and managing patients at risk or with symptoms of COVID-19 Footnote 443.

Recommended practices for patient management before entering the dental office include triage of possibly infected patients Footnote 444 Footnote 445 and restricting dental treatment to urgent care during high levels of infectious disease in the local community Footnote 438. In-office approaches should include active screening with temperature measurement, minimum number of patients in waiting rooms, physical distancing, good ventilation and no shared objects among waiting patients and staff Footnote 444 Footnote 445 Footnote 446 Footnote 447. Emergency treatment of COVID-19 patients should follow high levels of personal protection and be conducted within specifically equipped facilities Footnote 445. A recent review questions the use of laboratory tests (e.g., ELISA and rapid serological assays) for SARS-Cov-2 in an oral healthcare setting, and recommend simpler approaches instead, including an interview, checking temperature to rule our possible active COVID-19 cases and strict infection control Footnote 448.

In terms of disinfection of dental operative settings, disinfecton/cleaning of dental chairs after each patient is recommended, while disinfecton/cleaning of all other surfaces (e.g., operatory light, counters and delivery units) twice a day is also recommended Footnote 445. Personal belongings and jewelry should not be worn by dental professionals during patient management. Another review suggests cleaning and disinfection of waiting and treatment areas between patients, including doorknobs, chairs, floor, desks, restrooms and elevators Footnote 444.

c.3 Findings from the third update

Moderate evidence from SRs confirm the usefulness of teledentistry and telehealth-based approaches during the pandemic. New evidence concerning promising uses include the surveillance of oral epithelial dysplasia Footnote 449 and speech therapy interventions in children with palatal clefts Footnote 450. A prospective study highlights the potential use of artificial intelligence for the screening of dental patients to minimize emergency service overuse and thus COVID-19-related risks Footnote 451.

An SR Footnote 452 recommends three criteria to use in the context of providing emergency care in a hospital setting when the emergency care has to be provided prior to receiving the result of a diagnostic test. These criteria help assign relevant patients to high risk of having COVID-19 versus low risk of having COVID-19. Relevant patients are considered as high risk of having COVID-19 in the presence of one of more of the following criteria:

  1. fever plus one or more sign/symptom of respiratory disease and previous stay in an area reporting local transmission of COVID-19 disease within 14 days prior to symptom onset;
  2. any acute respiratory illness and contact with a confirmed COVID-19 case within 14 days prior to symptom onset; or
  3. severe respiratory infection requiring hospitalization, without an etiology that fully explains the clinical presentation.

After application of the three criteria, people who are presumptive for COVID-19 are confirmed by COVID-19 RT-PCR test and chest imaging Footnote 452. Those tests should be done before admission in the surgical ward when possible; the absence of conclusive tests should lead the patient to be treated as a patient with COVID-19.

At the dental office, recommended approaches during the pandemic remain similar to what was reported in our previous updates. This includes using remote approaches, limited scheduling and postponing treatment during the active phases of the pandemic Footnote 424 Footnote 453 Footnote 454, using COVID-19 screening questionnaires and emergency care under negative pressure or isolation Footnote 424 Footnote 453, and prioritizing non-aerosol procedures (e.g., caries excavation in children) Footnote 455. A new recommendation refers to waste disposal, which should be preferably done in double-layer, yellow, leak-resistant clinical waste bags, with a "gooseneck" knot Footnote 454.

Recommendations for masks and frequent handwashing as a prevention method by the population in general and patients visiting health care settings remain. An SR with meta-analysis Footnote 456 concerning the prevention of influenza demonstrated optimal transmission prevention with 5 to 10 handwashings daily, whereas 10 or more did not result in further effect. A new SR did not reveal a significant preventive effect for influenza if face masks used by people in the community is the only public health measure Footnote 457.

An SR provided relevant data about the most frequent environments for the transmission of COVID-19, with these being public travel, 58.1%; close contacts, 43.1%; and community spread, 27.4% Footnote 294. Those aspects, besides the potential transmission by fomites Footnote 458 Footnote 424 Footnote 459, should be kept in mind for infection control and patient screening. In terms of oral health care staff adopting appropriate preventive measures, a recent randomized RCT among dental students demonstrated that a behavioural intervention based on "dissonance induction" (i.e., making a subject recognize inconsistencies between COVID-19 prevention guidelines and their beliefs/practices) was more effective than an intervention based on "assessment reactivity" (i.e., enquiring about preventive behaviour to elicit future attention to adequate COVID-19 prevention practices) in students adopting preventive measures Footnote 460. In this study, the group of students intervened by "assessment reactivity" performed like a negative control group (i.e., no behavioural intervention).

Important information about the transmission of COVID-19 and means to prevent or reduce transmission can be found at these two websites:

d. What evidence exists to support the use of various forms of personal protective equipment (PPE) while providing in-person oral health care?

d.1. Findings from the first update

We identified several systematic reviews with relevant information. One investigated the use of powered air-purifying respirators (PAPR) compared to N95 masks and other devices in the prevention of viral infection of health care workers, focusing on SARS-Cov-2, SARS-Cov-1, MERS and Ebola viruses. This review reported no difference in HCW infection rates using PAPR versus other respirator devices. They did note however, increased heat tolerance for HCWs using PARP but more difficulty communicating and with mobility Footnote 461. Another review investigated the benefits for oral and maxillofacial surgeons of using N95 versus surgical masks when performing AGPs Footnote 462. They concluded that most studies comparing the two showed no difference in infection rates of HCWs but there was some evidence suggesting that N95 masks may be better when performing an AGP with a patient known to be COVID-19 positive or whose status is unknown Footnote 462. Another review of N95 and surgical masks and eyewear use in dental care reported that combined use of two or more measures (for example, mask and facial visor) is effective as a barrier to aerolized microbes, although this can be affected by multiple factors such as airflow dynamics, aerolized particle size, prolonged wearing and wetness of masks and poor fit. Importantly, they noted that no intervention on its own has been demonstrated effective at preventing infection Footnote 463. We identified no research evidence that referred specifically to KN95 masks.

Another review investigated the physical and mental health impacts of COVID-19 on HCWs during the pandemic Footnote 464 and reported that working in a high-risk setting, having a COVID-19-diagnosed family member, inadequate hand hygiene, improper PPE use, close contact with patients ≥ 12 times daily, extended contact hours (≥15 daily) and unprotected exposure are associated with increased risk of COVID-19-related impacts for HCWs Footnote 464. They also noted that prolonged PPE usage led to cutaneous manifestations and skin damage, that HCWs experienced high levels of depression, anxiety, insomnia and distress, and that female HCWs and nurses are disproportionately affected Footnote 464. All this suggests the need for vigilance with infection control procedures, shorter work hours and mental health support for HCWs Footnote 464.

d.2. Findings from the second update

Again, this update identified several relevant new SRs. This update found moderate evidence regarding protection of health care workers against COVID-19. In general, reviews stress the critical role of proper donning and doffing of PPE Footnote 465 Footnote 466. Again, reviews highlight the adversities of prolonged use of PPE, with skin damage on the nasal bridge being the most common problem Footnote 467.

Several reviews approached specific PPE items, including:

Despite the evidence that complex PPEs and procedures (e.g., PAPR, doffing after sanitation) may be more protective in ideal settings, we lack data about their performance in diverse "real life" scenarios. Future studies should clarify whether more complexity may lead to higher risk of inadequate use of PPEs and thus higher risk of contamination in oral healthcare settings.

Several reviews compared N95 to medical masks Footnote 444 Footnote 445 Footnote 466 Footnote 468 Footnote 470. General findings show that N95 masks may be superior in moderate- to high-risk clinical settings, with further reduction in the risk of COVID-19 infection and other respiratory viruses. Some reviews recommend that dental professionals, including oral and maxillofacial surgeons, should wear N95 masks when small-sized aerosolized particles are expected Footnote 466. Although face masks (medical or not) may reduce primary respiratory infection risk Footnote 472, COVID-19-specific studies are still needed.

The Health Canada website also has information concerning PPE.

d.3 Findings from the third update

In general, this third update has found few sources of evidence dealing with PPE for patient care, but included some data about complications for health care workers (including oral health professionals, nurses and physicians) e.g., headache, dry skin, dyspnoea, hyperhidrosis and dermatitis Footnote 473 Footnote 474.

Updated evidence still supports face masks as important to reduce the risk of acquiring COVID-19 among the general population Footnote 475. For health professionals, data resonate with previous updates by indicating that conventional surgical masks may not be an effective barrier for health professionals during the use of AGPs Footnote 476, compared to N95 respirators Footnote 477. The recommendation of gowns and gloves as relevant protection methods against acquiring COVID-19 remain, as observed with SARS-CoV-1 and SARS- CoV-2 Footnote 477.

e. What evidence exists to support the decontamination and re-use of PPE?

e.1. Findings from the first update

We identified one additional systematic review on this subject Footnote 478. The review investigated the use of microwave and heat-based decontamination of N95 masks and found that microwave irradiation may provide safe and effective viral decontamination for N95 masks while conserving function but that autoclaving did not do the latter so is not supported. The authors did however note that more research needs to be performed in "real world settings" to confirm their conclusions Footnote 479.

e.2. Findings from the second update

Few included sources of evidence approached possible ways to re-use PPE. One scoping review did not recommend routine decontamination of facemasks, but rather in situations of shortage only Footnote 466. Some specific decontamination methods before re-use of masks include:

e.3 Findings from the third update

We identified no new sources of evidence under this topic for the 3rd update. In this context, it is important to note that re-using and reprocessing PPE in Canada was only, considered at the beginning of the pandemic when there were shortages of certain PPE. Re-use and reporocessing of PPE is no longer recommended in Canada.

Relevant information from Health Canada can be found at:

f. What evidence exists concerning the provision of aerosol-generating procedures (AGP) as part of in-person oral health care?

f.1. Findings from the first update

We identified two systematic reviews with relevant subject matter published during the period July to October inclusive. One systematic review confirmed that SARS-Cov-2 is present in saliva and as well as sputum and the nasopharynx and concluded that saliva could be used to test for COVID-19 Footnote 480. Another rapid systematic review was performed with the aim of classifying aerosol generating procedures (AGPs) Footnote 481. They identified a list of procedures with strong agreement in the literature that they were AGPs. This list did not include dental procedures and the authors hypothesized that this non-inclusion of dental procedures is because they comprise a wide range of acts some of which are AGPs and others are not Footnote 481. This raises the important point that the dental professions need to identify AGPs versus non-AGPs within dental procedures and this needs to be based on sound principles and science. This is important because it has implications for the use of PPE and other interventions while performing dental procedures.

We identified two systematic reviews with relevant subject matter published during the period July to October inclusive. One systematic review confirmed that SARS-Cov-2 is present in saliva and as well as sputum and the nasopharynx and concluded that saliva could be used to test for COVID-19 Footnote 480. Another rapid systematic review was performed with the aim of classifying aerosol generating procedures (AGPs) Footnote 481. They identified a list of procedures with strong agreement in the literature that they were AGPs. This list did not include dental procedures and the authors hypothesized that this non-inclusion of dental procedures is because they comprise a wide range of acts some of which are AGPs and others are not Footnote 481. This raises the important point that the dental professions need to identify AGPs versus non-AGPs within dental procedures and this needs to be based on sound principles and science. This is important because it has implications for the use of PPE and other interventions while performing dental procedures.

f.2. Findings from the second update

We identified limited evidence regarding this topic. Three reviews indicate that wastewater can be a source of infection by SARS‐Cov‐2 Footnote 482 Footnote 483 Footnote 484, although we identified no study fulfilling our inclusion criteria with recommendations for oral healthcare settings. Even with the paucity of direct evidence, it seems reasonable to highlight the importance of the careful management of water processors and sedimentation tanks in dental offices and laboratories, whose interior should be seen as a potential reservoir of the virus.

Regarding transmission by droplets, particles smaller than 5 μm can move beyond 8 meters and stay suspended for more than 2 hours Footnote 446. Environmental conditions may affect the viability of SARS-Cov-2, with longest lifespan at low temperatures and high humidity.

Two SRs recommend a hierarchy of contamination risk for dental procedures, as follows Footnote 485 :

High-risk procedures also include laser surgery and osteotomies, commonly used in oral and maxillofacial surgery Footnote 462 Footnote 486 Footnote 487.

f.3 Findings from the third update

A limited body of evidence refers to AGP in this third update, with most sources focusing on transmissibility itself. Two SRs reinforce the role of sustained speaking and breathing (not only coughing or loud speech) as potential sources of air droplets contributing to airborne transmission of COVID-19 Footnote 488 Footnote 489. Saliva itself can be considered as a potential carrier of SARS-CoV-2. A new SR highlighted a sensitivity of 83% for detecting COVID-19 with the saliva of symptomatic patients (compared to 97% and 87% from bronchoalveolar secretion and nasopharygeal swabs, respectively) Footnote 490. Another SR reported good contamination control in a hospital setting providing care for people who test positive for COVID-19 with the combination of negative pressure isolation rooms, strict PPE and sterilisation protocols and structured training for care provision Footnote 476.

Specific studies on oral health care include a SR comparing high- and low-power lasers, with more aerosol generation with the first Footnote 491. According to the authors, when using high-power lasers in dental offices and laboratories oral health care providers should consider more complex infection control procedures.

As in previous updates, we identified evidence concerning other infectious agents (SARS, MERS, H1N1, influenza and bacteria) resulting in recommendations by authors of these studies of a hierarchy of procedures to use during the pandemic, Footnote 492 Footnote 455 Footnote 454. These include preferring manual caries excavation and hand scaling rather than high-speed handpieces and ultrasonic scaling, whenever possible.

g. What evidence exists to support transmission mitigation strategies during the provision of in-person oral health care?

g.1. Findings from the first update

As previously mentioned, we identified a systematic review confirming that SARS-Cov-2 is present in saliva and as well as in sputum and the nasopharynx Footnote 480. This is important to consider in the context of this topic concerning mitigating strategies. We also identified several systematic reviews published in the relevant period investigating a number of mitigating strategies during the provision of dental care and other health care procedures. A Cochrane review looked at a range of mitigating strategies including high volume evacuation, dental isolation combination systems, rubber dam and disinfectants, including disinfectant coolants Footnote 493. The authors observed that all the studies included in their review investigated interventions' effects on colony forming units of bacteria, not viruses or respiratory disease transmission. They nevertheless concluded that there was probably benefit in using all the tested interventions but that the evidence to support them was weak Footnote 493. Another Cochrane review investigated the potential protective effect against COVID-19 transmission of health care workers using antimicrobial mouthwashes and/or nasal sprays and identified no studies, although they did note a few relevant on-going randomized trials Footnote 494. Another systematic review investigated the specific question "Does hydrogen peroxide mouthwash (at any concentration) have a virucidal effect?" and identified no research fulfilling their quality criteria addressing this question, thereby concluding that there is no evidence to support the use of hydrogen peroxide mouthwash to control viral load Footnote 495. A rapid systematic review noted the possible beneficial effect of hypertonic saline nasal washes and mouth washes to mechanically reduce viral load and so potentially reduce risk of transmission from patients with COVID-19 to others Footnote 496. Finally, another systematic review investigated the potential benefits of anti-microbial mouthwashes in managing COVID and found no clinical studies, only in vitro evaluations of chlorhexidine, povidone-iodine and C31G. The review noted that all these mouthwashes demonstrated reduced viral load in in vitro studies but recognized the lack of clinical evidence Footnote 497.

In summary, there remains no evidence concerning interventions to mitigate viral or COVID-19 transmission during dental treatments but there is good evidence supporting Chlorhexidine mouthwash reducing bacterial load (this was identified in the previous version of this report). Evidence for other interventions is weak and equivocal.

g.2. Findings from the second update

Newer systematic and scoping reviews indicate different methods to mitigate contamination during dental treatment, although evidence could be classified as limited. Two SRs recommend the use of chemomechanical caries removal, extraoral radiographs and hand scalers whenever possible Footnote 444.

High-volume evacuators (HVE) have also been recommended as a valid approach to reduce contamination during AGP, although included reviews gathered data from studies about bacterial contamination Footnote 444 Footnote 447 Footnote 466 Footnote 498. The same has been stated for the use of a rubber dam, which is another effective method to reduce airborne particles and thus microbial contamination Footnote 445 Footnote 466 Footnote 447 Footnote 498.

Some of the reviews and clinical studies included in this update approach the use of different antimicrobial mouthrinses to reduce contamination in the mouth and pharynx. In general, the pre-procedural use of those mouthrinses is considered a valid method to reduce contamination by aerosols during dental treatment Footnote 444 Footnote 466 Footnote 498 Footnote 499, although the real benefit in COVID-19 patients remains unclear Footnote 500. Povidone- iodine (PVP-I) and essential oils (EO) showed efficacy against SARS-CoV-2 in a small RCT (5 participants/mouthwash), when used as a prophylaxis for viral spread. In that trial, participants recruited from a COVID-19 reference center used either substances for 4-6 days (gargling for 30 sec, 3x/day), reaching negative viral load in most cases at 4 days Footnote 501. There is evidence that reinforces the virucidal effect of PVP-I against other respiratory viruses Footnote 502, whereas EO, chlorhexidine (CHX) and cetylpyridinium chloride (CPC) mouthrinses are able to reduce airborne bacteria during AGP Footnote 498.

A recent RCT displays promising results for CPC-, dipotassium glycyrrhizinate- and tranexamic acid-based mouthrinses used 3x daily for 7 to 10 days before dental implant placement, as methods to reduce airborne bacterial contamination Footnote 503. Finally, a systematic review states that there is no evidence to support whether mouthwashes containing chlorine compounds, including chlorine dioxide and sodium chlorite, can prevent or manage COVID-19 Footnote 504.

g.3 Findings from the third update

Evidence concerning methods to mitigate contamination during dental procedures remains limited. Besides some interventions mentioned above (avoiding/minimizing AGPs, including minimal use of high-speed handpieces, air-water syringe and ultrasonic scalers), two SRs enforce the advantage of high-volume evacuators whenever possible Footnote 454Footnote 505. One of those reviews state that the use of rubber dam along with a high-volume evacuator will further reduce the risk of contamination Footnote 454.

A few SRs and clinical studies suggest some benefit from mouthrinses before dental procedures. Agents tested against SARS-CoV-2 and with potential advantage include: povidone-iodine, hydrogen peroxide, chlorhexidine digluconate, ColdZyme, cetylpyridinium chloride, and essential oils Footnote 506 Footnote 507 Footnote 508 Footnote 509.

h. What evidence exists to support space ventilation strategies that reduce the risk of transmission?

h.1. Findings from the first update

We identified one systematic review published in the relevant period and with pertinent information Footnote 493. This Cochrane systematic review of multiple interventions to reduce aerosols during dental procedures reported one study with only two participants suggesting a stand-alone ventilation system may reduce aerosols during cavity preparation and ultrasonic scaler use Footnote 493. It also reported another study with 50 participants suggesting laminar flow with a HEPA filter may reduce aerosols at 76cm from the floor and 20-30cm from a patient's mouth. However, they stated that no studies reported on viral contamination or disease transmission, rather they concerned bacterial contamination and the evidence was of low certainty Footnote 493.

h.2. Findings from the second update

In the period, there were just three SRs and a scoping review about ventilation as a way to reduce COVID-19 transmission. Air purifiers with HEPA filters and room ventilation (30 min) between patients have been recommended as a protocol to reduce the risk of infection, as well as irradiation with UVC Footnote 444 Footnote 445. Recommendations for HEPA filters included at least 99.995% retention for particles of 0.01 µm or more Footnote 510. In case of emergency dental treatment of COVID-19-positive patients, the operatory room should be under negative pressure or continuous air exchange Footnote 447. Although the role of air exchange is recommended for any patient Footnote 483, the exact degree of protection provided by those approaches is still unclear. Recommended air exchange rates depend on whether the patient is diagnosed with COVID-19, with at least 1.5 and 6.0 air change/hr for negative and positive patients, respectively Footnote 510.

h.3 Findings from the third update

Only a single SR Footnote 454 and 1 prospective study Footnote 511 approached this topic, with limited evidence regarding air cleaning in dental offices. The authors of those studies recommended the following measures to prevent cross-infection by SARS-CoV-2: (i) adequate natural ventilation of the operatory and waiting area, (ii) placing supply-air vents in the waiting area to promote air flow from clean areas into potentially contaminated spaces, (iii) return-air vents in the operatory or waiting room, and (iv) properly directed extractor fans (not towards doors), and fixed-split and portable air conditioning (without recirculation) without incorporated humidifiers Footnote 454.

Both references Footnote 454 Footnote 511 recommend the use of portable high efficiency particulate air (HEPA) filtration units in operating rooms. HEPA units should be adjacent to the patient's chair, but not behind professionals. One of the studies reported complete removal of aerosols in 4 to 12 minutes by combining a HEPA unit with ventilation, whereas the latter alone would take 30 minutes Footnote 511.

i. What evidence exists to support the disinfection of surfaces in spaces in which oral health care is provided?

i.1. Findings from the first update

We identified one additional systematic review covering surface disinfection published during this period Footnote 512. This review investigated the use of surface decontamination against SARS-Cov-2 and against airborne pathogens and directly transmitted viral pathogens in dental settings. They found no evidence that fulfilled their quality criteria concerning SARS-Cov-2. However, they reported finding good quality evidence that 70% ethanol and 0.5% sodium hypochlorite used as surface disinfectants reduce the possibility of surface transmission of respiratory viruses. They recommended applying these disinfectants on surfaces for 1 minute to reduce the risk of contamination with SARS-Cov-2 Footnote 512.

i.2. Findings from the second update

This second update gathered more SRs about this topic than the previous update. Moderate evidence suggests the disinfection of impressions, trays and dental prostheses with 1% NaOCl for 1 minute as a way to reduce SARS-CoV infectivity Footnote 513. A scoping review reinforces the need for routine disinfection of any dental prosthetic material with intermediate level disinfectants as well as methods to mitigate patients' gag reflex (e.g., proper suction and anaesthesia) Footnote 447.

Some reviews gathered limited evidence that certain disinfectants may reduce contamination by bacteria and other respiratory viruses on diverse surfaces, including door handles, chairs, desks and other surfaces that may touched regularly. The most frequent disinfectants studied were 0.1% sodium hypochlorite, 62-70% isopropyl alcohol, 0.5% hydrogen peroxide Footnote 444 Footnote 445 Footnote 514. Single SRs indicated successful viral inactivation with glutaraldehyde and iodine-containing detergents Footnote 514, whereas 0.05-0.2% benzalkonium chloride and 0.02% chlorhexidine digluconate were less able to inactivate various coronaviruses Footnote 483. Finally, irradiation by ultraviolet-C (UV-C) has been stated as an effective method to inactivate pathogenic bacteria Footnote 515 and viruses Footnote 514. Most of those agents may be useful against SARS-Cov-2, although this second update could not gather any direct evidence.

It is important to note that Health Canada has lists of surface disinfectants and hand sanitizers that it states are supported by evidence and likely to be effective against SARS-CoV-2. However, since disinfecting agents may damage dental materials and equipment and other surfaces, it is important to review their compatibility before use.

i.3 Findings from the third update

Four SRs provided limited evidence regarding surface disinfecting agents of potential use in oral healthcare environments against SARS-CoV-2 Footnote 516 Footnote 459 Footnote 454 Footnote 517. The virus can survive up to 28 days at room temperature over certain surfaces (i.e., polymer and paper banknotes, vinyl, steel and glass); thus, those surfaces should receive special attention. Dangerous viral loads can remain for up to 21 days on most of those surfaces. This can be mitigated by low temperatures combined to low humidity, and sunlight.

An SR recommended disinfecting surfaces ideally 10 or more minutes after AGPs, as a fallow time to permit the settling of suspended viral particles. It also recommends a combination of 70-80% ethanol (minimum 1-minute exposure time) + 0.5% hydrogen peroxide + freshly prepared 0.1% (1 g/L) sodium hypochlorite, to be used at 2-3-hour intervals Footnote 454.

Specific disinfectants successfully tested against SARS-CoV-2 include 1% sodium hypochlorite, which can also be used to flush water lines (2 min between patients and 1L by the end of the day), but not on lithium disilicate restorations (reason: decrease in bonding) Footnote 454. Another SR highlights that combining n-propyl or isopropyl alcohols to detergents may not be a good approach, since they result in more skin irritation than the agents separately Footnote 517.

Two SRs also suggested there is some limited evidence to support the previously mentioned usefulness of the following agents/methods against other viruses: vaporized hydrogen peroxide Footnote 518, 2% glutaraldehyde, 0.25% peracetic acid, and autoclaving Footnote 454.

As with previous updates, we refer readers to Health Canada's website on surface disinfectants and hand sanitizers:

Glossary of abbreviations

Abbreviation
Explanation
AGP
Aerosol-generating procedures
CDC
Centers for Disease Control and Prevention
CFU
Colony-Forming Unit (count of viable bacteria)
CHX
Chlorhexidine
COVID-19
Coronavirus disease 2019
HCP
Health Care Professionals
HCW
Health Care Worker
HVE
High-Volume Evacuation
H1N1
Influenza A
ICU
Intensive Care Unit
IgM
Immunoglobulin M
MD
Mean Deviation (statistical analysis)
MERS
Middle East Respiratory Syndrome
PPE
Personal Protective Equipment
RCT
Randomized Controlled Trials
RR
Risk Ratio (statistical analysis)
SARS
Severe Acute Respiratory Syndrome
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus-2
SR
Systematic Review
TMD
Temporomandibular disorders
UVGI
Ultra-violet Germicidal Irradiation

Appendix A: Key findings for topic a) patients at greater risk of the consequences of COVID-19

The following diseases, conditions and groups have strong evidence for risk.

Heart diseases and conditions

Cardiovascular disease (CVD)
Main finding Source

Higher risk for COVID-19:
(i) severity: odds 1.79 to 3.37x greater, RR= 3.00
(ii) mortality: odds 3.15 to 4.85x greater

Severe heart disease
(i) mortality: odds 0.67x greater

Prevalence: 5% to 16%

 SR and meta-analysis: Abate at al. Footnote 278; SR and meta-analysis: Cheng at al. Footnote 279; SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Hatmi et al. Footnote 281; Meta- analysis: Hoang et al. Footnote 282; SR and meta-analysis: Mirjalili et al. Footnote 283; SR and meta-analysis: Parohan et al. Footnote 284; Meta- analysis: Sinclair et al. Footnote 285; SR and meta-analysis: Szarpak et al.Footnote 286; SR and meta-analysis: Thakur et al. Footnote 287; SR and meta-analysis: Tiruneh et al. Footnote 288; SR and meta-analysis: Toloui et al. Footnote 289; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Yue-liang et al. Footnote 291

Congestive heart failure
Main finding Source

Higher risk for COVID-19:
(i)severity: 19.07%
(ii) mortality: 47.8%, odds 2.70x greater, RR=5.13

Prevalence in patients with COVID-19: 14.4% to 85%

Meta-analysis: Greca et al.Footnote 296;
SR and meta-analysis: Lee KH et al. Footnote 297; SR and meta-analysis: Toloui et al.Footnote 289; SR and meta-analysis: Zhao YH et al. Footnote 298

Cardiac arrythmias
Main finding Source

Higher risk for COVID-19:
(i) severity: RR=12.1
(ii) mortality: 40.3%, odds 1.95x greater, RR=3.8

Prevalence in patients with COVID-19: 15.3% to 18%

 SR and meta-analysis: Garcia-Zamora et al. Footnote 299; SR and meta-analysis: Lee KH et al. Footnote 297; SR and meta-analysis: Tondas et al. Footnote 300; SR and meta-analysis: Zhao YH et al. Footnote 298

Myocardial injury
Main finding Source

Higher risk for COVID-19:
(i) mortality: 61.7%

Prevalence in patients with COVID-19: 21.2%

 SR and meta-analysis: Zhao YH et al. Footnote 298

Cardiac injury
Main finding Source

Higher risk for:
(i) severe COVID-19: RR: 1.80
(ii) mortality: odds 6.87x greater

 SR and Meta-analysis: Dy et al. Footnote 301; SR and meta-analysis: Kim et al. Footnote 293

ST - segment elevation myocardial infarction (STEMI)
Main finding Source
Patients with ST-Segment Elevation Myocardial Infarction (STEMI): mortality 1.17 to 1.52x greater SR and meta-analysis: Chew et al. Footnote 302; SR and meta-analysis: Rattka et al.Footnote 303

Acute cardiac injury
Main finding Source

Higher risk for COVID-19:
(i) severity: 19.46%, odds 3.48x greater
(ii) mortality: odds 25.16x greater, RR= 6.91

Prevalence in patients with COVID-19: 1% to 6.4%

 SR and meta-analysis: Goel at al. Footnote 304; SR and meta-analysis: Tiruneh et al. Footnote 288; SR and meta-analysis: Toloui et al. Footnote 289; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Zhao YH et al. Footnote 298

Coronary heart disease
Main finding Source

Higher risk for COVID-19:
(i) severity: odds 2.87x greater
(ii) mortality: odds 2.70x greater

 SR and meta-analysis: Lee KH et al. Footnote 297; SR and meta-analysis: Li X et al. Footnote 295

Cardiac arrest
Main finding Source

Higher risk for COVID-19:
(i) mortality: 89.9%
(ii) compared with non- infected COVID-19: odds 2.34x greater

 SR and meta-analysis: Ippolito et al. Footnote 305

Ventricular dysfunction
Main finding Source

Higher risk for COVID-19:
(i) mortality: 48.5% vs 27.4% in patients with or without right ventricular dysfunction (odds 3.10x greater)
(ii) mortality: 56.3% vs 30.6% in patients with or without ventricular dilatation (odds 2.43x greater)
(iii) mortality: 52.9% vs 14.8% in patients with or without right ventricular dysfunction (odds 5.75x greater)

 SR and meta-analysis: Ippolito et al. Footnote 305; SR and meta-analysis: Paternoster et al.Footnote 306

Hypertension
Main finding Source

Higher risk for COVID-19:
(i) severity: 35.9%, odds 1.98 to 3.11x greater, RR= 1.70 to 2.02
(ii) ICU admission: 15%
(iii) mortality: odds 2.67 to 3.67x greater

Prevalence: 15% to 32.2%

 SR and meta-analysis: Abate et al. Footnote 278; SR and meta-analysis: Cheng at al. Footnote 279; SR and meta-analysis: Du et al. Footnote 292; SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Hatmi et al. Footnote 281; Meta- analysis: Hoang et al. Footnote 282; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Li J et al.Footnote 294; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Mirjalili et al.Footnote 283; SR and meta-analysis: Parohan et al. Footnote 284; Meta- analysis: Sinclair et al. Footnote 285; SR and meta-analysis: Thakur et al.Footnote 287; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Yue-liang et al. Footnote 291

Respiratory diseases and conditions

Respiratory disease (general)
Main finding Source

Higher risk for COVID-19:
(i) severity: odds 1.98 to 5.67x greater; RR=1.55
(ii) mortality: odds 3.72x greater

Prevalence in patients with COVID-19: 7% to 34%

 Meta-analysis:SR and meta-analysis: Cheng at al. Footnote 279; SR and meta-analysis: Du et al. Footnote 292; SR and meta-analysis: Goel at al.Footnote 304; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Khateri et al. Footnote 22; SR and meta-analysis: Kim et al. Footnote 293

Respiratory disease (asthma)
Main finding Source

Higher risk for COVID-19:
(i) poor outcomes: odds 0.92x greater
(ii)severity: 2.3% vs 2.2% for non-severe patients (odds 1.04 to 1.13x greater)
(iii) mortality: odds 0.87 to 0.96x greater
(v) incidence of asthma with age in COVID-19 patients: odds 0.77x greater

Prevalence in patients with COVID-19: 3%, odds 0.08x

 SR and meta-analysis: Alkhatami et al. Footnote 307; SR and meta-analysis: Gulsen et al. Footnote 308; SR and meta-analysis: Kaur A et al. Footnote 309; SR and meta-analysis: Reyes et al.Footnote 310; SR and meta-analysis: Soreoto et al.Footnote 311; SR and meta-analysis: Wu T et al. Footnote 312

Chronic obstructive pulmonary disease (COPD)
Main finding Source

Higher risk for:
(i) severe COVID-19 (risk difference: odds 2.88x to 8.35x greater, RR= 3.63 to 4.22
(ii) severity: 5.2% vs 1.4% for non-severe patients (odds 2.58x greater)
(iii) ICU admission (odds 1.35x greater)
(iv) COVID-19 mortality: 30% (odds 2.29 to 3.55x greater, RR= 3.18)
(v) mortality associated with males: RR= 1.20

Prevalence in patients with COVID-19: 2.2%

 SR and meta-analysis: Alkhatami et al. Footnote 307; SR and meta-analysis: Gerayeli et al. Footnote 313; SR and meta-analysis: Goel at al. Footnote 304; SR and meta-analysis: Gulsen at al.Footnote 308; Meta- analysis: Hoang et al. Footnote 282; SR and meta-analysis: Lee KH et al. Footnote 297; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Parohan et al.Footnote 284; SR and meta-analysis: Rabbani et al.Footnote 314; SR and meta-analysis: Reyes et al. Footnote 310; Meta- analysis: Sinclair et al.Footnote 285; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Yue-liang et al.Footnote 291

Acute respiratory distress syndrome (ARDS)
Main finding Source

Higher risk for COVID-19:
(i) severity: 26% to %; odds: 39.59x to 42.69x greater
(ii) mechanical ventilation: MDM:-7.0
(iii) ICU admission: MDM: 3.1
(iv) mortality: odds 1.25 to 62.85x greater, RR =7.99

Prevalence in patients with COVID-19: % to 30.93%

 SR and meta-analysis: Abate et al. Footnote 278; SR and meta-analysis: Dmytriw et al. Footnote 315;SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Khateri et al. Footnote 22; SR and meta-analysis: Li X et al.Footnote 295; SR and meta-analysis: Tiruneh et al.Footnote 288; SR and meta-analysis: Wu Y et al. Footnote 290

Diabetes mellitus
Main finding Source

Higher risk for COVID-19:
(i) severity: 10.8% to 48%, odds 1.60 to 3.39x greater, RR= 1.54 to 2.10
(ii) mortality: 82%, odds 0.54 to 2.60x greater, RR= 1.3

Comparing diabetic vs non-diabetic patients:
(i) severity: 34.8% vs 22.8% (odds 1.43x greater)
(ii) mortality: 20% to 21.3% vs 6.1% to 11% (odds 1.82 to 2.3x greater)
(iii) ARDS as complication: 34.4% vs 17.2% (odds 2.38x greater)
(iv) Acute Cardiac Injury as complication: 22% vs 12.8% (odds 2.59x greater)
(v) AKI as complication: 19.1% vs 10.2% (odds 1.97x greater)

COVID-19 is associated with diabetic ketoacidosis (DKA), hyperglycaemic hyperosmolar state (HHS) and euglycemic DKA (EDKA)

Prevalence of mortality among diabetic patients in:

  1. Europe: 28%
  2. United States: 20%
  3. Asia: 17%

High to moderate certainty of evidence for associations among diabetes and COVID-19:
(i) between male sex (odds 1.28x greater)
(ii) older age (>65 years) (odds 3.49x greater)
(iii) pre-existing comorbidities:
- cardiovascular disease (odds 1.56x greater)
- CKD (odds 1.28x greater)
- COPD (odds 1.40x greater)

Prevalence in patients with COVID-19: 9.55% to 48%

 SR and meta-analysis: Abate et al. Footnote 278; SR and meta-analysis: Saha et al. Footnote 319; SR and meta-analysis: Chamorro-Pareja et al. Footnote 320; SR and meta-analysis: Cheng at al. Footnote 279; SR and meta-analysis: Du et al. Footnote 292; SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Hewitt et al. Footnote 321; Meta- analysis: Hoang et al. Footnote 282; SR and meta-analysis: Kaminska et al. Footnote 322; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Lazarus et al. Footnote 323; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Li Y et al. Footnote 324; SR and meta-analysis: Lontchi-Yimagou et al. Footnote 325; SR and meta-analysis: Mirjalili et al.Footnote 283; SR and meta-analysis: Palaiodimos et al.Footnote 326; SR and meta-analysis: Papadopoulus et al. Footnote 327; SR and meta-analysis: Parohan et al. Footnote 284; SR and meta-analysis: Saha et al. Footnote 319; SR and meta-analysis: Schlesinger et al. Footnote 328; Meta- analysis: Sinclair et al. Footnote 285; SR and meta-analysis: Thakur et al. Footnote 287; SR and meta-analysis: Varikasuvu et al. Footnote 329; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Yue-liang et al. Footnote 291; SR and meta-analysis: Zhang L et al. Footnote 330

Cancer
Main finding Source

Higher risk infection in patients with COVID-19 with different types of cancer:
(i) lung cancer:2.1%

Higher risk for COVID-19:
(i) severity: 16%, odds 1.48 to 2.73x greater, RR=1.64 to 2.91
(ii) mortality: 1% to 41%, odds 0.20 to 3.54x greater
(iii) mortality of patients > 60 years with cancer and COVID-19:
(iv) mortality of patients with comorbidities, cancer and COVID-19:

  • Hypertension: odds 1.6x greater
  • Cardiovascular diseases: odds 2.2x greater
  • COPD: odds 11.4x greater

(v) mortality lung cancer: 18% to 60%, odds 1.47 to 1.8x greater
(viii) mortality in patients with active chemotherapy: odds x greater
(ix) mortality hematological cancer: 37.48%
(x) mortality breast cancer: 14.2%

Prevalence in patients with COVID-19: odds 0.07x
-in Europe: odds 0.22x greater
-in Asia-Pacific: odds 0.04x greater
-in North America: odds 0.05x greater
- patients > 60 years with cancer and COVID-19: odds 0.10x greater
- patients ≤60 years with cancer and COVID-19: odds 0.05x greater

 SR and meta-analysis: Alkhatami et al. Footnote 307; SR and meta-analysis: Lei et al. Footnote 331; SR and meta-analysis: Kamal et al. Footnote 332; SR and meta-analysis: Belsky et al. Footnote 333; SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Goel at al. Footnote 304; Meta- analysis: Hoang et al. Footnote 282; SR and meta-analysis: Kaur H et al.Footnote 334; SR and meta-analysis: Kim et al.Footnote 293; SR and meta-analysis: Kong et al. Footnote 335; SR and meta-analysis: Lei et al.Footnote 331; SR and meta-analysis: Liu GE et al. Footnote 336; SR and meta-analysis: Parohan et al. Footnote 284; SR and meta-analysis: Tagliamento et al. Footnote 337; SR and meta-analysis: Venkatesulu et al. Footnote 338; SR and meta-analysis: Yue-liang et al.Footnote 291; SR and meta-analysis: Zhang L et al. Footnote 330

Cerebrovascular diseases and conditions
Main finding Source

Higher risk for COVID-19:
(i) severity: odds 2.47 to 3.92x greater, RR= 2.12 to 2.86

Prevalence in patients with COVID-19: 43%

 SR and meta-analysis: Cheng at al.Footnote 279; Meta- analysis: Hoang et al. Footnote 282; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Li X et al.Footnote 295; SR and meta-analysis: Thakur et al. Footnote 287; SR and meta-analysis: Yue-liang et al. Footnote 291

Nervous system disease (dementia)
Main finding Source

Higher risk for COVID-19:
(i) poor outcomes: in elderly adults with COVID-19 (odds 2.96x greater)
(ii) mortality in elderly patients with hip fracture: RR=1.13
(iii) mortality rates of dementia vs non-dementia elderly adults with COVID-19: 39% vs 20%

 SR and meta-analysis: Alcock et al. Footnote 339; SR and meta-analysis: Saragih et al. Footnote 340

Kidney diseases

Chronic kidney disease (CKD)
Main finding Source

Higher risk for COVID-19:
(i) severity: odds 1.27 to 4.24x greater, RR= 1.76 to 2.00
(ii) hospitalization: odds 4.29x greater
(iii) mortality: 19.18%, odds 0.55 to 5.58x greater

Prevalence in patients with COVID-19: 4.5% to 9.7%

 SR and meta-analysis: Du et al. Footnote 292; SR and meta-analysis: Goel at al. Footnote 304; Meta- analysis: Hoang et al. Footnote 282; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Li Y et al. Footnote 324; SR and meta-analysis: Lin YC et al. Footnote 343; SR and meta-analysis: Menon et al. Footnote 344; SR and meta-analysis: Mirjalili et al.Footnote 283; SR and meta-analysis: Singh Jet al Footnote 345; SR and meta-analysis: Thakur et al. Footnote 287; SR and meta-analysis: Yue-liang et al. Footnote 291

Acute kidney disease (AKI)
Main finding Source

Higher risk for COVID-19:
(i) severity: 20%, odds 8.28 to 16.013x greater
(ii) hospitalization: 10%
(iii)mortality: odds 13.52 to 22.86x greater

Prevalence in patients with COVID-19: 7% to 12.78%

 SR and meta-analysis: Goel at al. Footnote 304; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Khateri et al. Footnote 22; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Menon et al.Footnote 346; SR and meta-analysis: Nasiri et al. Footnote 347; SR and meta-analysis: Singh J et al.Footnote 345; SR and meta-analysis: Tiruneh et al. Footnote 288; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Xu et al. Footnote 348

Smoking
Main finding Source

Higher risk to severe COVID-19:
- current smokers: odds 0.74 to 1.40x greater, RR= 1.23
- Compared to never-smokers, patients with a smoking history: odds 1.53x greater
- Underlying Cardiovascular Disease: 9.7%, odds 2.87x greater

Higher risk to ICU admission: 24%

Higher risk to COVID-19 mortality:
- current smokers: 43%, odds 1.79x greater, RR= 1.19 to 2.19
- previous smoking history (ex-smoking): odds 1.91x greater
- compared to former smokers, current smokers' patients: increased mortality COVID-19 (RR= 2.19)
- median age: 77 years
- female: 48%

Prevalence in patients with COVID-19: 9% to 14%

 SR and meta-analysis: Abate et al.Footnote 278; SR and meta-analysis: Goel at al. Footnote 304; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Hewitt et al. Footnote 321; SR and meta-analysis: Hou et al. Footnote 351; SR and meta-analysis: Kang et al. Footnote 352; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Lee KH et al. Footnote 297; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Yue-liang et al.Footnote 291

Obesity
Main finding Source

Higher risk for COVID-19:
(i) poor outcome or hospitalization: odds 1.51 to 1.73x greater
(ii) severity: odds 1.31 to 3.03x greater
(iii) severity: associated with visceral fat area (odds 1.9x greater)
(iv)severity when associated with comorbidities: odds 1.56x greater
(iii) ICU admission: odds 1.35 to 2.81x greater; SMD 0.46
(iv) invasive mechanical ventilation: SMD 0.38; odds 1.77x greater
(v) in younger patients: odds 3x greater
(vi) associated to ARDS: odds 2.89x greater

Higher risk for COVID-19 mortality:
(i) odds: 0.96 to 3.52x greater

Prevalence in patients with COVID-19: 25%

 SR and meta-analysis: Bansal et al. Footnote 353; SR and meta-analysis: Chowdhury et al. Footnote 354; Meta- Analysis: Das et al. Footnote 355; SR and meta-analysis: Foldi et al. Footnote 356; SR and meta-analysis: Helvaci et al. Footnote 357; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Li Y et al. Footnote 324; SR and meta-analysis: Pranata et al. Footnote 358; Meta-analysis: Pranata et al. Footnote 359; SR and meta-analysis: Seidu et al.Footnote 360; SR and meta-analysis: Thakur et al. Footnote 287; SR and meta-analysis: Zhang X et al. Footnote 361

Liver diseases and conditions

Liver diseases (general)
Main finding Source

Higher risk for COVID-19:
(i) severity: 32%; odds 1.02x greater, RR=1.84.

Metabolic dysfunction-associated fatty liver disease
Higher chance for COVID-19:
(i) severity: 28%

Non-alcoholic fatty liver disease
(i) severity: 36%, odds 2.60x greater
(ii) ICU admission: 24%, odds 1.66x greater
(iii)mortality: odds 1.01x greater

 SR and meta-analysis: Abate et al. Footnote 278; SR and meta-analysis: Goel et al. Footnote 304; SR and meta-analysis: Hegyi et al. Footnote 349; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Singh A et al. Footnote 350

Acute liver diseases
Main finding Source
Prevalence in patients with COVID-19: 19% to 22.8% SR and meta-analysis: Khateri et al. Footnote 22; SR and meta-analysis: Tiruneh et al. Footnote 288

Effect of age
Main finding Source

Prevalence of COVID-19:
(i) <20 years: 20% lower than that of working age adults (20-64 years) RR=0.77
(ii)20 years: 2.1%
(iii)20 - 49 years: 5.8%
(iv)50-64 years: 5.2%
(v) ≥65 years: 2.6%
(vi) ≥65 years: lower than that of working age adults (20-64 years) RR=0.76
(vii) Among aged care residents: 45%

High risk for severe COVID-19:
(i) age>=60 years (51%, odds 2.62 to 5.73x greater)
(ii) age ≥65 vs <65 years old (odds 4.59x greater)

Associated to:
- diabetes: 22.95%
- hypertension: 48.95%
- cardiovascular diseases: 19.95%

High risk for severe COVID-19 (ICU admissions):
(i) age ≥60 years: 22%
(ii) Among aged care residents: 37%

High risk for COVID-19 mortality:
(i) age ≥60 years: 11%, odds 6.00x greater, MD= 13.32
(ii) age ≥60 years with hip fracture: 34% (9% in non-infected patients), RR=4.42 for early mortality
(iii) age ≥70 years: 86.6%, odds 3.61x greater
(iv) age >= 70 and < 70 years with CKD and COVID-19 (odds 8.69x greater) than in the >= 70 years (odds 2.44x)
(v) age >= 80 years: 84.4%
(vi) advanced age + frailty: odds 1.79x greater
(vii) Among aged care residents: 23%
(viii) older age: odds 1.05x greater

SR and meta-analysis: Alcock et al. Footnote 339; SR and meta-analysis: Du et al. Footnote 292; SR and meta-analysis: Dumitrascu et al. Footnote 362; SR and meta-analysis: Goel at al. Footnote 304; SR and meta-analysis: Chen X et al. Footnote 363; SR and meta-analysis: Hashan et al.Footnote 364; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Lee KH et al. Footnote 297; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Li Y et al. Footnote 324; SR and meta-analysis: Parohan et al. Footnote 284; SR and meta-analysis: Singhal et al. Footnote 365; SR and meta-analysis: Tiruneh et al. Footnote 288; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Yue-liang et al. Footnote 291

Effect of sex
Main finding Source
High risk for severe COVID-19:
(i) male: 58.1% to 65.09%, odds 1.31 to 1.51x greater; RR 1.02 to 1.26
(ii)male vs. female: 7% vs. 6.6%, odds 1.50x
High risk for COVID-19 mortality:
(i) male: 37% (odds 1.54 to 1.72x greater, RR= 1.67)
(ii) female: odds 0.97x greater		 SR and meta-analysis: Abate et al.Footnote 278; SR and meta-analysis: Du at al. Footnote 292; SR and meta-analysis: Goel at al. Footnote 304; SR and meta-analysis: Chen X et al.Footnote 363; SR and meta-analysis: Zaki et al. Footnote 458; SR and meta-analysis: Kim et al.Footnote 293; SR and meta-analysis: Lee KH et al. Footnote 297; SR and meta-analysis: Li J et al.Footnote 294; SR and meta-analysis: Li X et al. Footnote 295; SR and meta-analysis: Li Y et al. Footnote 324; SR and meta-analysis: Parohan et al. Footnote 284; Meta- analysis: Sinclair et al. Footnote 285; SR and meta-analysis: Wu Y et al. Footnote 290; SR and meta-analysis: Yue-liang et al.Footnote 291; SR and meta-analysis: Zhang L et al. Footnote 330

Effect of race
Main finding Source

Prevalence of COVID-19:
- Black: RR 2.70
- Asian: RR 1.91, odds 0.06x greater
-non-Hispanic white: odds 0.30x greater
-Hispanic: odds 0.27x greater
-non-Hispanic black: 0.15x greater
- others or unknown: odds 0.21x greater

- White: lower risk of infection compared with Black and Asian people.
- Compared with non-Hispanic white, Hispanic ethnicity was associated with a lower risk of the critical outcome (RR= 0.83).
- Compared with non-Hispanic white, non-Hispanic black was not associated with a lower risk of the critical outcome (RR= 0.84).
- Compared with non-Hispanic white, Asian ethnicity was not associated with a lower risk of the critical outcome (RR= 1.33).

Higher risk for COVID-19:
(i) mortality: Non-Caucasian ethnicity RR=1.67

 SR and meta-analysis: Chen X et al.Footnote 363;SR and meta-analysis: Hewitt et al. Footnote 321; SR and meta-analysis: Kim et al. Footnote 293

Arterial thrombosis/coagulopathies
Main finding Source

Higher risk for COVID-19:
(i)mortality: odds 2.39x greater
(ii) mortality: hypercoagulability (23.1%)
(iii) thrombotic events + comorbidities: 85%
(iv) thrombotic events + Elevated D-dimer: 70%
(v) thrombotic events + Cardiovascular complications: 100%
(vi) Platelet count and D-dimer level were significant predictors of disease severity and
older men had higher risks of severe coagulopathic disease
(vii) Disseminated intravascular coagulation

  • Prevalence: 3%
  • Mortality: odds 2.46x greater

Prevalence in patients with COVID-19: 22%

 SR and meta-analysis: Gabbai-Armelin et al. Footnote 366; Meta-analysis: Greca et al. Footnote 296; Meta-analysis: Mitra et al. Footnote 367; Meta-analysis: Moonla et al.Footnote 368; SR and meta-analysis: Xiong et al. Footnote 369; SR and meta-analysis: Zhou X et al. Footnote 370

Venous thromboembolism (VTE), vein thrombosis (DVT) and/or pulmonary embolism (PE)
Main finding Source

Prevalence in patients with COVID-19:
- VTE: 18% to 26%
- DVT: 14% to 15.43%
- PE: 4.85% to 11%
- PE with or without DVT: 12%

Higher risk for COVID-19, ICU admission:
- VTE: 24%
- DVT: 7%
- PE: 19%

 Meta- analysis: Birocchi et al. Footnote 371; SR and meta-analysis: Gratz et al.Footnote 372; SR and meta-analysis: Porfidia et al. Footnote 217; SR and meta-analysis: Ng et al. Footnote 373; SR and meta-analysis: Sarfraz et al. Footnote 374

HIV
Main finding Source

Higher risk for COVID-19:
(i) severity: 2.5%, RR= 1.24
(ii) hospitalization: 28.4%
(iii) ICU admission: 3.5%
(iv)mortality: 5.3% to 14.1%, odds 1.19x greater, RR= 1.78
(v) HIV + COVID+ hypertension: 24%
(vi) HIV + COVID+ diabetes: RR= 0.96
(v) HIV + COVID+ chronic cardiac disease: RR= 5.2
(v) HIV + COVID+ CKD: RR= 8.43

Prevalence in patients with COVID-19: 0.9% to 1.2%

  • United States: 1.43%
  • Spain: 0.26%
  • China: 0.99%
 SR and meta-analysis: Haryanto et al.Footnote 382; SR and meta-analysis: Lee et al. Footnote 383; SR and meta-analysis: Liang et al. Footnote 384; SR and meta-analysis: Ssetongo et al.Footnote 385; SR and meta-analysis: Ssetongo 2 et al.Footnote 386

Vitamin D insufficiency
Main finding Source
Higher risk for COVID-19:
(i) severe: odds 1.75 to 2.57x greater, RR= 2.00
(ii) ICU admission: odds 0.36x greater
(iii)mortality: odds 1.05 to 3.08x greater, RR= 2.45
(iv) mortality in male gender: odds 0.93 to 1.22x greater
(v) mortality in diabetic patients: odds 0.88x greater
(vi) not statistically significant when reviewed 31 studies (8209 patients).
(vii) individuals with Vitamin-D deficiency were 80% more likely to acquire COVID-19 infection as compared to those who have sufficient Vitamin D levels (odds 1.80x greater)		 SR and meta-analysis: Akbar et al. Footnote 392; SR and meta-analysis: Bassatne et al.Footnote 393;SR and meta-analysis: Kazemi et al.Footnote 394; SR and meta-analysis: Oscanoa et al. Footnote 395; SR and meta-analysis: Shah et al.Footnote 396; SR and meta-analysis: Teshome et al. Footnote 397

Frailty patients
Main finding Source

Impact of clinical frailty scale (CFS) sub-categories (1-3, 4-5 and 6-9), by increasing severity of frailty and to identify factors associated with increased mortality from COVID-19:

  • CFS 4- 5 patient group had significantly increased mortality when compared to patients with CFS 1-3 (odds 1.95x greater)
  • CFS 6- 9 patient group had mortality increase when compared to patients with CFS 1-3 (odds 3.09x greater)
  • male gender, Ischaemic Heart Disease, Hypertension and Chronic Kidney Disease were associated with increased COVID-19 mortality.
  • Frailty was significantly associated with increased risk of all-cause mortality among patients with COVID-19 (odds 1.81x greater)
  • Prevalence frailty + COVID-19: 51%
  • Severity: odds 691.76x greater
  • Hospitalization: odds 2.62x greater
  • Mortality: odds 1.99x greater
  • Most common:
  • Age 60-70 years (odds 1.85x greater)
  • Age ≥70 years (8.45x greater)
  • Male (odds 1.88x greater)
  • Occupation of retirees (odds 4.27x greater)

SR and meta-analysis: Kastora et al. Footnote 387; SR and meta-analysis: Yang et al.Footnote 388; SR and meta-analysis: Zhang XM et al. Footnote 389; SR and meta-analysis: Zhao J et al. Footnote 390

Pregnant women
Main finding Source

Higher risk for severe COVID-19:
(i) ICU admission: 6.9%

Higher risk for COVID-19 pregnant mortality:
(i) 1.3%, odds 1.37x greater
(ii) obesity: RR 2.48
(iii) gestational diabetes: RR 5.71
(iv) asthma: RR 2.05

Compared with mild COVID-19, severe COVID-19 was strongly associated with:
(i)preeclampsia: odds 4.16x greater)
(ii) preterm birth: odds 4.29x greater
(iii) gestational diabetes: odds 1.99x greater
(iv) low birth weight: odds 1.89x greater

Pre-existing maternal comorbidity, higher risk for:
(i) admission to ICU: RR= 5.09
(ii) invasive ventilation: RR= 4.34
(iii) mortality: RR= 2.26

Delivery in pregnant women with COVID-19:
(i) spontaneous preterm birth: 26.8% to 52.45%, odds 1.82x greater
(ii) stillbirth: odds 1.28 to 2.11x greater
(iii) preeclampsia: 6.2%, odds 1.33x greater
(iv) caesarean section: 58.3% to 86.66%
(v) vaginal delivery: 25%
(vi)fetal death: 4.6% to 7%
(vii) abortion: 16.7%
(viii) post-partum hemorrhage: 39.1%
(ix) premature rupture membrane: 20.7%
(x) fetal growth retardation: 11.7%
(xi) obstetric complications: 51.7%

Pregnant women vs non-pregnant women
(i) Pregnant women with COVID-19 were less likely to be obese (RR= 0.68)
(ii) Pregnant women with COVID-19 were less likely to have a smoking history (RR= 0.32)
(iii) non-pregnant women with COVID-19- had a higher frequency of comorbidity compared to COVID-19-infected pregnant women:
-chronic cardiac disease (RR= 0.58)
- renal disease (RR= 0.45)
- malignancy (RR= 0.82).
(iv) pregnant women were significantly higher risk for:
- ICU admission (RR= 2.26)
- invasive mechanical ventilation (RR= 2.68)

SR and meta-analysis: Chmielewska et al. Footnote 400; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Karimi et al. Footnote 401; SR and meta-analysis: La Verde et al. Footnote 402; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Wei et al. Footnote 403

SR and meta-analysis: Khan et al.Footnote 519

The following diseases, conditions and groups have limited to moderate evidence for risk.

Obstructive sleep apnea
Main finding Source
Higher risk for COVID-19:
(i) poor outcome: odds 1.72x greater
(ii) severity: odds: 1.70x greater
(ii) mechanical ventilation: odds 1.67x greater
(iii) ICU admission: odds 1.76x greater
(iv) mortality: odds 1.74x greater		 SR and meta-analysis: Haryanto et al. Footnote 316

Pulmonary aspergillosis
Main finding Source
Higher risk for COVID-19:
(i) ICU admission: 54.9%
(ii) mortality: 10.2% to 51.2%, odds 2.83x greater		 SR and meta-analysis: Mitaka et al. Footnote 317;SR and meta-analysis: Singh S et al. Footnote 318

Effect of demographic region
Main finding Source
Seroprevalence in the general population:
Higher risk for COVID-19:
- South- East Asia (India): 19.6%
- Asia: RR= 1.42
- Africa: 16.3%
- Eastern Mediterranean: 13.4%
- Americas: 6.8%
-North America: RR= 1.23
- Europe: 4.7%, RR= 1.19
- Western Pacific: 1.7%		 SR and meta-analysis: Chen X et al.Footnote 363; SR and meta-analysis: Kim et al.Footnote 293

Mental disorders
Main finding Source

COVID-19 patients suffered from:
(i) Mood disorders: 43.1%
(ii) Schizophrenia, schizotypal and delusional disorders: 16.1%

Higher risk for COVID-19:
(i) poor outcomes: in elderly adults with COVID-19)
(ii)severity: odds 1.76x greater
(iii) mortality: odds 1.52x greater
(iv)mortality:

  • Mood disorders: 15.9%
  • Schizophrenia, schizotypal and delusional disorders: 22.3%

Among COVID-19 patients with mental disorders + comorbidities:
(i)diabetes: 24.5%
(ii)hypertension: 35.4%
(iii)CVD: 11.5%
(iv)cerebrovascular disease: 9.1%
(v) CKD: 9.6%

 SR and meta-analysis: Toubasi et al. Footnote 341

Guillain- Barre Syndrome (GBS)
Main finding Source

(i) Compared with non-infected contemporary or historical controls, patients with SARS-CoV-2 infection (odds 3.27x greater)
(ii) In SARS-CoV-2-infected patients, olfactory nerve involvement: 41.4%
(iii) In SARS-CoV-2-infected patients, olfactory or concomitant cranial nerve involvement: 42.8%

Prevalence in patients with COVID-19: 0.15%, 15 cases per 100,000 SARS-CoV-2 infections

 SR and meta-analysis: Palaiodimu et al. Footnote 342

Use of non-steroidal anti-inflammatory drugs (NSAIDs)
Main finding Source
(i) No difference in the hazard for the development of a fatal course of COVID-19 between NSAID users and non-NSAID users (odds 0.73 to 0.86x greater) SR and meta-analysis: Kow et al. Footnote 391

Dyslipidemia
Main finding Source

Higher risk for:
(i) mortality: 60%, odds 1.69x greater

Prevalence in COVID-19 patients: 17.5%

 SR and meta-analysis: Zuin et al. Footnote 375

Multiple sclerosis
Main finding Source
Higher risk for:
(i) severe COVID-19: odds x greater
(ii) hospitalization: 20.7%
(iii) ICU admission: odds x greater
(iv) mortality: 3%		 SR and meta-analysis: Barzegar et al.Footnote 377

Parkinson's disease
Main finding Source
Higher risk for:
(i) poor outcomes: odds 2.64x greater
(ii) severe COVID-19: odds 2.61x greater
(iii) mortality: RR= 2.63		 SR and meta-analysis: Putri et al.Footnote 378

Femoral fractures
Main finding Source
Higher risk for:
(i) severe COVID-19: odds x greater
(ii)mortality: among patients with and without COVID-19 (odds 6.31x greater)
(iii) mortality: surgically treated patients with COVID-19 (odds 5.99x greater)
(iv) mortality: among patients with hip fracture (34.74%, RR= 4.59)
(v) mortality: among patients with hip fracture 30-day (38%)		 SR and meta-analysis: Patralekh et al.Footnote 379; Meta-analysis: Raheman et al.Footnote 380

Immunosuppressed patients
Main finding Source
Higher risk for COVID-19:
(i) severity: 16%
(ii) ICU admission: 8%
(iii) mortality: 2%		 SR and meta-analysis: Belsky et al.Footnote 333; SR and meta-analysis: Zhang L et al. Footnote 330

Rheumatic diseases
Main finding Source
Higher risk for COVID-19:
(i) severity: odds 1.53x greater
(ii) hospitalization: 1.36x greater
(iii)ICU admission: odds 1.94x greater
(iii) mortality: odds 1.29x greater		 SR and meta-analysis: Wang Q et al. Footnote 381

Hemoglobinopathies
Main finding Source
Higher risk for COVID-19:
(i) mortality: odds 1.07x greater
Prevalence in patients with COVID-19: odds 4.4x		 SR and meta-analysis: Haghpanah et al.Footnote 376

Micronutrient deficiency
Main finding Source

Higher risk for COVID-19:
(i) ICU admission: odds 0.26x greater

Incidence among COVID-19 patients: odds 0.37x

 SR and meta-analysis: Wang MX et al.Footnote 398

COVID-19 recurrence
Main finding Source
Of 3,644 patients recovering from COVID-19 and being discharged:
-15% patients were re-positive with SARS-CoV-2 during the follow-up.
- Among recurrence cases, it was estimated 39% subjects underlying at least one comorbidity.		 SR and meta-analysis: Hoang et al.Footnote 399

Neonates
Main finding Source
Higher risk for neonates born to mothers with COVID-19:
(i) admitted to the neonatal unit (67.06%)
(ii) low birth weight: 42.8%		 SR and meta-analysis: Hatmi et al.Footnote 281

Children
Main finding Source

Higher risk for COVID-19:
(i) ICU admission: 8.1%
(ii) mechanical ventilation: 5.99%
(iii) mortality: 3.8%
(iv) mean age: 4.6 years
(v) 50.3% males

Pediatric patients with cancer and COVID-19:
- risk of severity: 24%
- risk of mortality: 9%

Pediatric patients with comorbidities and COVID-19:
Higher risk for:
(i) severity: 5.1%
(ii) severity in obese: RR=2.87
(iii) mortality: RR=2.81

SR and meta-analysis: Li J et al. Footnote 294

SR and meta-analysis: Belsky et al.Footnote 333

General considerations
Main finding Source
COVID-19 mortality rates (general):
-14% to 17.1%
-for general patients admitted to the hospital (excluding critical care): 11.5%
-for patients with critical illness: 40.5%		 SR and meta-analysis: Macedo et al. Footnote 520; SR and meta-analysis: Wu Y et al. Footnote 290

Appendix B: Key findings for topic b) clinical signs and symptoms of COVID-19

The following signs, symptoms, groups and situations have strong evidence for risk.

Fever
Main finding Source

High risk for COVID-19:
(i) severity: odds 0.79 to 1.96x greater
(ii) patients with Multiple Sclerosis: 69.8%
(iii) associated with chills: 14.45%
(iv) HIV patients: 71.1%
(v) elderly patients: 83.95%

Prevalence of:

  • Medium grade fever: 44.33%
  • Low grade fever: 38.16%
  • High grade fever: 14.71%

Prevalence in patients with COVID-19: 78.1% to 92%

 SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Barzegar et al. Footnote 377; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Islam et al. Footnote 423; SR and meta-analysis: Amiri et al. Footnote 424; SR and meta-analysis: Kim et al.Footnote 293; SR and meta-analysis: Lee KH et al.Footnote 297; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Singhal et al. Footnote 365; SR and meta-analysis: Vakili et al.Footnote 425; SR and meta-analysis: Yue-liang et al. Footnote 291

Cough
Main finding Source

High risk for COVID-19:
(i) severity: odds 0.65 to 1.45x greater
(ii) patients with Multiple Sclerosis: 63.9%
(iii)elderly patients: 60.95%

Prevalence in patients with COVID-19: 14% to 73%

 SR and meta-analysis: Cares-Marambio et al. Footnote 521; SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Barzegar et al. Footnote 377; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Amiri et al. Footnote 424; SR and meta-analysis: Kim et al.Footnote 293; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Singhal et al. Footnote 365; SR and meta-analysis: Vakili et al. Footnote 425; SR and meta-analysis: Yue-liang et al.Footnote 291

Dyspnea or shortness of breath
Main finding Source

High risk for COVID-19:
(i) severity: odds 4.20 to 8.68x greater, RR= 2.90
(ii) patients with Multiple Sclerosis: 39.5%
(iii) elderly patients: 42.95%

Prevalence in patients with COVID-19: 32.6% to 48.96%

 SR and meta-analysis: Booth et al.Footnote 522; SR and meta-analysis: Cares-Marambio et al. Footnote 521; SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Barzegar et al. Footnote 377; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Li J et al. Footnote 294;
SR and meta-analysis: Singhal et al. Footnote 365; SR and meta-analysis: Vakili et al. Footnote 425; SR and meta-analysis: Yue-liang et al. Footnote 291; SR and meta-analysis: Zhang L et al.Footnote 330

Myalgia or fatigue (muscle ache)
Main finding Source

High risk for COVID-19:
(i) severity: odds 1.40 to 4.82x greater, RR= 1.43
(ii) patients with Multiple Sclerosis: 51.2%

Prevalence in patients with COVID-19: 13% to 52%

 SR and meta-analysis: Booth et al.Footnote 522; SR and meta-analysis: Cares-Marambio et al. Footnote 521; SR and meta-analysis: Giri et al. Footnote 280; SR and meta-analysis: Barzegar et al.Footnote 377; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Amiri et al. Footnote 424; SR and meta-analysis: Kim et al.Footnote 293; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Vakili et al.Footnote 425; SR and meta-analysis: Yassin et al.Footnote 428; SR and meta-analysis: Yue-liang et al.Footnote 291

Headache
Main finding Source

High risk for COVID-19:
(i) severity: odds 1.36x greater

Prevalence in patients with COVID-19: 6% to 12.1%

 SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Amiri et al. Footnote 424; SR and meta-analysis: Vakili et al. Footnote 425; SR and meta-analysis: Yassin et al. Footnote 428; SR and meta-analysis: Yue-liang et al. Footnote 291

Gastrointestinal symptoms

General
Main finding Source

Higher chance for COVID-19:
(i) severity: odds 2.07x greater
(ii) ICU admission: odds 1.01x greater
(iii) mortality: 3.5%, odds 0.92x greater
(iv) mortality: China (0.9%), USA (10.8%)

Prevalence in patients with COVID-14.8%

 SR and meta-analysis: Bolia et al.Footnote 523; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Menon et al. Footnote 524; SR and meta-analysis: Shehab et al.Footnote 525

Diarrhea
Main finding Source

High risk for COVID-19:
(i) severity: odds 3.97x greater

Prevalence in patients with COVID-19: 7.8% to 19.08%

 SR and meta-analysis: Bolia et al. Footnote 523; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Shehab et al.Footnote 525; SR and meta-analysis: Zarifian et al.Footnote 526

Abdominal pain
Main finding Source

High risk for COVID-19:
(i) severity: odds 2.76x greater

Prevalence in patients with severe COVID-19: 4.5%, odds 7.17x greater

 SR and meta-analysis: Hatmi et al.Footnote 281; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Yue-liang et al. Footnote 291

Nausea and vomiting
Main finding Source

High risk for COVID-19:
(i)severity: odds 15.55x greater

Prevalence in patients with COVID-19: 4.7% to 19.7%

 SR and meta-analysis: Bolia et al.Footnote 523; SR and meta-analysis: Booth et al.Footnote 522; SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Li J et al. Footnote 294; SR and meta-analysis: Shehab et al. Footnote 525; SR and meta-analysis: Vakili et al.Footnote 425; SR and meta-analysis: Zarifian et al. Footnote 526

Chill
Main finding Source
High risk for COVID-19:
(i)severity: odds 2.30 to 6.32x greater		 SR and meta-analysis: Booth et al.Footnote 522; SR and meta-analysis: Yue-liang et al. Footnote 291

Anosmia/hyposomnia
Main finding Source

Prevalence in patients with COVID-19: 18.3% to 38.2%, odds 10.21x greater

When compared with patients with Olfactory dysfunction (OD), patients without OD:
High risk for COVID-19:
(i) hospitalization: odds 5.28x greater
(ii)Mechanical Ventilation: odds 7.01x greater
(iii) mortality: odds 7.0x greater

 SR and meta-analysis: Goshtasbi et al.Footnote 527; SR and meta-analysis: Mutiawati et al.Footnote 528; SR and meta-analysis: Vakili et al.Footnote 425; SR and meta-analysis: Yassin et al. Footnote 428

Gustatory impairment
Main finding Source
Prevalence in patients with COVID-19: 19.6% to 5.4% SR and meta-analysis: Vakili et al.Footnote 425; SR and meta-analysis: Yassin et al.Footnote 428

Anorexia or loss of appetite
Main finding Source

High risk for COVID-19:
(i) severity: odds 0.58 to 2.25x greater, RR=2.07

Prevalence in patients with COVID-19: 10.2% to 28.9%

 SR and meta-analysis: Kim et al. Footnote 293; SR and meta-analysis: Vakili et al.Footnote 425; SR and meta-analysis: Yue-liang et al. Footnote 291; SR and meta-analysis: Zarifian et al.Footnote 526

Nasal congestion
Main finding Source
Prevalence in patients with COVID-19: 3.7% to 22% SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Amiri et al. Footnote 424

Stroke
Main finding Source

Higher chance for COVID-19:
(i) severity: in patients with acute ischemic stroke vs non-severe patients (RR=2.91)
(ii) ICU admission: in patients with acute ischemic stroke vs non-severe patients (RR=4.47)
(iii) mortality: hemorrhagic stroke (44.72%) and ischemic stroke (36.23% to 38%)

Prevalence in patients with COVID-19:
-ischemic stroke: 1.11% to 1.7%
-hemorrhagic stroke: 0.46%
-ischemic stroke (71.58%) was more prevalent than hemorrhagic stroke (28.42%)

 SR and meta-analysis: Lu et al. Footnote 529; SR and meta-analysis: Syahrul et al. Footnote 530; SR and meta-analysis: Tan et al.Footnote 531

Dizziness
Main finding Source
High risk for COVID-19:
(i) severity: RR=2.06
Prevalence in patients with COVID-19: 6.7% to 11.3%		 SR and meta-analysis: Kim et al. Footnote 293;
SR and meta-analysis: Vakili et al.Footnote 425; SR and meta-analysis: Yassin et al.Footnote 428

Chest pain or chest tightness
Main finding Source

High risk for COVID-19:
(i) severity: odds 4.09x greater

Prevalence in patients with COVID-19: 16%

 SR and meta-analysis: SR and meta-analysis: Cares-Marambio et al. Footnote 521; SR and meta-analysis: Yue-liang et al. Footnote 291

Sputum
Main finding Source
High risk for COVID-19:
(i) severity: odds 11.40x greater
(ii) mortality: odds 2.08x greater		 SR and meta-analysis: Booth et al. Footnote 522; SR and meta-analysis: Zhang L et al. Footnote 330

Laboratory abnormalities
Main finding Source
- Fibrinogen: MD 0.42
- C- reactive protein: MD 35.74; odds 3.99x greater risk for severe disease
- Ferritin: MD 506.15
- Procalcitonin: MD 0.07, odds 2.91 to 5.28x greater risk for severe disease
- Leukocytosis: odds 3.44x greater risk for severe disease
- Lymphocytopenia: odds 4.39x greater risk for severe disease
- Aspartate aminotransferase: odds 3.02x greater risk for severe disease
- Lactic dehydrogenase: odds 8.33x greater risk for severe disease		 SR and meta-analysis: Chaudhary et al. Footnote 532; SR and meta-analysis: Haryanto et al.Footnote 533; SR and meta-analysis: Heidari- Beni et al. Footnote 534; Meta- analysis: Huang et al. Footnote 535; SR and meta-analysis: Kiss et al. Footnote 536; SR and meta-analysis: Yue-liang et al.Footnote 291; SR and meta-analysis: Zarifian et al.Footnote 526; SR and meta-analysis: Zhang L et al.Footnote 330

D-dimer (elevated)
Main finding Source
Higher risk for COVID-19:
(i) severity: 77%, MD 0.43 to 0.60
(ii) mortality: 75%		 SR and meta-analysis: Chaudhary et al.Footnote 532; SR and meta-analysis: Haryanto et al.Footnote 533; SR and meta-analysis: Zhan et al. Footnote 537; SR and meta-analysis: Zhao R et al. Footnote 538

Neurological symptoms
Main finding Source
- Prevalence in COVID-19 patients: (i)severity: 31%
(ii) mortality: 6.2%
(iii) most prevalent comorbidity: cerebrovascular disease (2.5% to 4.3%)		 SR and meta-analysis: Tandon et al. Footnote 427; SR and meta-analysis: Vakili et al. Footnote 425; SR and meta-analysis: Yassin et al.Footnote 428

Pregnant women

Fever
Main finding Source

Higher risk for COVID-19 mortality:
Fever alone: 100%

Comparing pregnant women and non-pregnant women with COVID-19: The risk of experiencing fever (RR= 0.74)

 SR and meta-analysis: Karimi et al. Footnote 401; SR and meta-analysis: Khan et al. Footnote 519

Cough
Main finding Source
Higher risk for COVID-19 mortality:
cough alone: 100%		 SR and meta-analysis: Karimi et al. Footnote 401

Dyspnea
Main finding Source
Higher risk for COVID-19 mortality: 58.3% SR and meta-analysis: Karimi et al. Footnote 401

Myalgia or fatigue
Main finding Source

Higher risk for COVID-19 mortality: 50%

Comparing pregnant women and non-pregnant women with COVID-19: The risk of experiencing myalgia (RR= 0.92)

 SR and meta-analysis: Karimi et al.Footnote 401; SR and meta-analysis: Khan et al. Footnote 519

Diarrhea
Main finding Source
Comparing pregnant women and non-pregnant women with COVID-19: The risk of experiencing diarrhea (RR= 0.40) SR and meta-analysis: Khan et al.Footnote 519

Gastrointestinal symptoms
Main finding Source
Higher risk for COVID-19 mortality: 8.3% SR and meta-analysis: Karimi et al.Footnote 401

Chest discomfort
Main finding Source
Comparing pregnant women and non-pregnant women with COVID-19: The risk of experiencing chest discomfort (RR= 0.86) SR and meta-analysis: Khan et al.Footnote 519

Headache
Main finding Source

Prevalence in COVID-19 patients:
6%

Comparing pregnant women and non-pregnant women with COVID-19: The risk of experiencing headache (RR= 0.77)

 SR and meta-analysis: Hatmi et al.Footnote 281; SR and meta-analysis: Khan et al. Footnote 519

Expectoration
Main finding Source
Comparing pregnant women and non-pregnant women with COVID-19: The risk of experiencing expectoration (RR= 0.45) SR and meta-analysis: Khan et al.Footnote 519

Sore throat
Main finding Source
Higher risk for COVID-19 mortality: 8.3% SR and meta-analysis: Karimi et al. Footnote 401

Children

Multisystem inflammatory syndrome (MIS-C)
Main finding Source

Common:
- gastro-intestinal symptoms (84.3% to 87.3%)
- neurologic symptoms (22.9%)
- cardiovascular symptoms (45% to 31%)
- myocarditis (55.3% to 61.8%)
- coronary vessel abnormalities (17.2%)
- ventricular dysfunction (38%)
- coronary aneurism (20% to 21.7%)
- ECG abnormalities (28.1%)
- Cardiac arrythmias (33.3%)
- shock (65.8%),

Prevalence in COVID-19 patients:
- prevalence in Hispanic patients: 34.6%
- prevalence in Black patients: 31.5%

High risk for:
(i)mortality: 1% to 1.9%

 SR and meta-analysis: Dhar et al.Footnote 539; SR and meta-analysis: Haghighi- Aski et al. Footnote 540; SR and meta-analysis: Yashuara et al.Footnote 429

Fever
Main finding Source
Common (45.86% to 47%) SR and meta-analysis: Islam et al.Footnote 423; SR and meta-analysis: Mansourian et al. Footnote 541

Cough
Main finding Source
Common (37%) SR and meta-analysis: Mansourian et al.Footnote 541

Gastro-intestinal symptoms
Main finding Source
Common (87.3%) SR and meta-analysis: Yashuara et al. Footnote 429

Diarrhea
Main finding Source
Common (19%) SR and meta-analysis: Mansourian et al. Footnote 541

Dyspnea
Main finding Source
Common (odds 6.61x greater) Meta-analysis: Zhou B et al.Footnote 430

Pharyngalgia
Main finding Source
Common (13%) SR and meta-analysis: Mansourian et al. Footnote 541

Laboratory abnormalities
Main finding Source
Common:
- lymphopenia (9%)
- lymphocytosis (26%)
- neutropenia (34%)
- D-dimer (36%)
-low oxygen saturation (38%)		 SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Mansourian et al.Footnote 541

Radiological features
Main finding Source
Common:
- abnormal chest X-ray (odds 3.33x greater)		 Meta-analysis: Zhou B et al. Footnote 430

General considerations
Main finding Source
- 5% to 12.94% were asymptomatic
- 79.6% presented mild/moderate symptoms
-7.46% presented severe symptoms
- the mean age 9.3 years		 SR and meta-analysis: Hatmi et al. Footnote 281; SR and meta-analysis: Yashuara et al. Footnote 429; Meta-analysis: Zhou B et al.Footnote 430

The following diseases, conditions and groups have limited to moderate evidence for risk.

Dysgeusia
Main finding Source
Prevalence in patients with COVID-19: 36.6%, odds 8.61x greater SR and meta-analysis: Mutiawati et al. Footnote 528

Ageusia
Main finding Source
Prevalence in patients with COVID-19: 49.8% SR and meta-analysis: Hatmi et al. Footnote 281

Expectoration
Main finding Source
High risk for COVID-19:
(i) severity: odds 1.36x greater		 SR and meta-analysis: Yue-liang et al.Footnote 291

Rhinorrhea
Main finding Source
Prevalence in patients with COVID-19: 7.5%, SR and meta-analysis: Li J et al.Footnote 294

Cutaneous manifestations
Main finding Source

Prevalence in patients with COVID-19:
-morbilliform (30.6%)
-varicelliform (18.8%)
-urticarial (13.2%)
-chilblains- like (12.5%)
-acro- ischemic (9%)

The most common: morbilliform, varicelliform, and urticarial

 SR and meta-analysis: Lee et al.Footnote 426

Impairment of consciousness (also termed "confusion," "agitation" or "delirium")
Main finding Source

High risk for COVID-19:
(i) mortality: odds 1.50 to 2.39x greater

Prevalence in patients with COVID-19: 27%

 SR and meta-analysis: Pranata et al. Footnote 542

Lymphopenia/lymphadenopathy
Main finding Source
High risk for COVID-19:
(i) severity: 32%		 SR and meta-analysis: Hatmi et al. Footnote 281

Thrombocytopenia
Main finding Source
High risk for COVID-19:
(i) mortality: odds 7.37x greater
(ii) mortality Thrombocytopenia + ARDS: odds 3.49x greater
Prevalence in patients with COVID-19: 12.4%		 SR and meta-analysis: Zong et al. Footnote 543

Radiological features
Main finding Source
High risk for COVID-19:
(i)severity: bilateral lung involvement with severe clinical presentation: odds 3.44x		 SR and meta-analysis: Hashemi- Madani et al.Footnote 544

Vital signs outcomes
Main finding Source
- Prevalence in critical COVID-19 patients:
(i) Higher body temperature: VDM=0.29
(ii) Higher body pulse: VDM= 4.19		 SR and meta-analysis: Yue-liang et al.Footnote 291

Asymptomatic
Main finding Source
- Prevalence in COVID-19 patients: (i) Among aged care residents: 31% SR and meta-analysis: Hashan et al. Footnote 364

Long-term symptoms
Main finding Source
Prevalence in patients post-COVID-19 infection:
- abdominal lung functions: 20.7%
- neurological complaints: 24.13%
- olfactory dysfunctions: 24.13%
- specific widespread symptoms (chronic fatigue and pain): 55.17%		 SR and meta-analysis: Salamanna et al.Footnote 431

Appendix C: Key findings for topic c) non-disease-specific approaches to assist with non-treatment patient management measures for in-person oral health care

The following approaches and settings have moderate evidence for risk.

Teledentistry
Main finding Source

Oral epithelial dysplasia (OED):
Remote consultations with patient-provided clinical photographs may be a useful way of maintaining a level of surveillance in this group of patients. (89-100% agreement).

Children with Cleft Palate:
The use of telepractice for providing speech pathology interventions for children with cleft palate is useful, as audiovisual materials, the use of interactive videos for speaking children and educational videos for parents.

SR and meta-analysis: McCarthy et al.Footnote 449

SR: Palomares-Aguilera et al. Footnote 450

Telehealth
Main finding Source

Telehealth or virtual care clinics to evaluate patients with fracture: 18% to 100% of efficiency

Remote consultations in general practice are likely to be used more by younger, working people, non-immigrants, older patients, and women.
Internet-based consultations more used by younger, affluent, and educated groups.

Telehealth is important during COVID-19 pandemic and after, for Otolaryngologists, due the risk of infection resulting from the examination of the head and neck and AGP due to the predilection of viral particles for the nasal cavities and pharynx.

Clinical Swallowing outcomes via Telehealth: Investigated the reliability of outcome measures derived from clinical swallowing tele-evaluations in real-world clinical practice.
Advantages:
- reliability were "excellent" for most raters across all tasks (ICCs of.63 and 1.00)
- Subjective observations of oral intake and objective measures taken can be reliably measured via telehealth in clinical practice.
Disadvantages:
- infrequent instances of suboptimal video quality
-reduced camera stability
-camera distance
-obstruction of the patient's mouth during tasks.

SR: Murphy et al. Footnote 545

SR: Parker et al. Footnote 546

SR: Samarrai et al. Footnote 547

Prospective study : Borders et al.Footnote 548

Artificial intelligence
Main finding Source

Artificial Intelligence techniques optimize on clinical settings in terms of quality, accuracy and most importantly time:
- early screening
- diagnosis
- prognosis of the disease

Were identified in total:
-14 models for screening
- 38 diagnostic models for detecting COVID-19
- 50 prognostic models for predicting ICU need, ventilator need, mortality risk, severity assessment or hospital length stay.

Use of screening algorithm, within a newly integrated Electronic Health Record (EHR).
Advantages:
- stratify risk in order to identify patients who are likely to have a poor outcome if care is delayed;
- reduce patients with non-emergent needs seeking care in the emergency rooms;
- prevent overuse of dental emergency services;
- follow up visit to the dental emergency clinic post screening was 30% with or without algorithmic usage;
- when utilizing the algorithm, the rates of patients that did need emergency care based on Acuity Level was 63%.

SR: Adamidi et al. Footnote 549

Prospective study: Perelman et al.Footnote 451

Hospital environment
Main finding Source

Management of emergency surgical patients under COVID-19 pandemic:
A patient is defined "suspected" for COVID-19 infection if he presents:

  • fever and at least one sign/symptom of respiratory disease and a history of travel to or residence in a country area or territory reporting local transmission of COVID-19 disease during the 14 days prior to symptom onset;
  • any acute respiratory illness, having been in contact with a confirmed COVID-19 case in the last 14 days prior onset of symptoms;
  • severe respiratory infection, with no other etiology that fully explains the clinical presentation, requiring hospitalization.

Suspected clinical diagnosis of COVID-19 is confirmed through:

  • The COVID-19 RT-PCR test
  • The chest imaging that includes chest radiograph, computed tomography scan or lungs ultrasound.
 SR: De Simone et al. Footnote 452

Dental office

Before entering a dental office
Main finding Source

Identification of suspected patients or carriers of COVID-19:
(i) Urgent dental care: pharmacological and phone tracking with video treatment.
(ii) Elective dental care postpone of treatment for 14 days or/and initial screening via telephone.
(iii) only maintaining urgency treatments in positive epidemiological areas for the COVID-19 disease

Orthodontic procedures:
(i)limited scheduling of patients.

SR and meta-analysis: Amiri et al. Footnote 424; Scoping review: Lourenço et al. Footnote 453

SR: Singh et al. Footnote 454

At the dental office
Main finding Source

Patient Assessment
- As soon as the patient is scheduled for dental treatment, a comprehensive medical history, screening questionnaire for COVID-19, and true emergency questionnaire should be completed.
- 72,2% of the authors, suggested either an epidemiological and clinical questionnaire or a simple clinical exam.
-Emergency dental care: using negative pressure rooms or rooms for isolation of airborne infection.

Pediatric Dentistry:

(i)Greater rigor in the use of PPE may cause strangeness for children.
(ii) the management of patient's behavior before and during the treatment and new approaches to perform the procedures will be demanded.
(iii)non-aerosol techniques and minimally invasive procedures will be preferable.

Orthodontic Procedures:
(i)limiting the number of HCP during procedure.
Endodontic Procedures:
(i) endodontists demonstrated adequate knowledge of main
symptoms of COVID-19 and the risks of infection during dental procedures (98.5%).
(ii) Most professionals
have suspended elective dental care during quarantine;
while, about half of them, performed only emergency
procedures in their workplaces.
(iii) in their daily
practice, 72.1% of endodontists
implemented biosecurity measures in preventing
COVID-19.

SR and meta-analysis: Amiri et al. Footnote 424; Scoping review: Lourenço et al. Footnote 453

SR: Sales et al. Footnote 455

SR: Singh et al. Footnote 454

SR : Sarria- Guzman et al. Footnote 550

Post dental treatment
Main finding Source
Waste management
Clinical waste should segregate in double-layer yellow leak-resistant clinical waste bags (with a "gooseneck" knot).		 SR: Singh et al. Footnote 454

Specific precautions

Frequent handwashing
Main finding Source

Existing data pooled from RCTs reveal a reduction in occurrence of Influenza with the Handwash with facemask in community settings: 64.9%

Effect of disease prevention
Could reduce the risk of disease infection:
- hand washing more than 4 times/day compared to not (odds 0.61x greater)
- hand washing ≤4 times/day compared with hand washing 5-10 times/day (Odds 0.75x greater)
- hand washing ≤4 times/day compared with hand washing >10 times/day (odds 0.65x greater)
- hand washing ≤10 times/day with hand washing >10 times/day (odds 0.59x greater)
No statistically significantly reduce the risk of disease infection:

  • hand washing more than 10 times/day compared to 5-10 times/day (odds 0.86x greater)

Patients could not identify the symptoms, routes of transmission or prevention actions against SARS-CoV-2 infection. The only preventive measures indicated were washing hands and sanitize with alcohol.

SR and meta-analysis: Aggarwal et al. Footnote 457

SR and meta-analysis: Xun et al.Footnote 456

SR: Sarria- Guzman et al. Footnote 550

Masks or respirators
Main finding Source
Existing data pooled from RCTs do not reveal a reduction in occurrence of Influenza with the use of facemask alone in community settings: 10.9% SR and meta-analysis: Aggarwal et al. Footnote 457

Specific settings, general considerations
Main finding Source

-COVID-19 incubation period is similar SARS: median 5- 6 days but can take up to 14 days to show symptoms.
-COVID-19 meantime between symptoms onset and hospitalization: median 4.4 days.
-fomite transmission was examined in high-frequency touch surfaces (circulating banknotes, disposable chopsticks, hospital staff PPE, and others).

The status of dentists and other oral health practitioners' knowledge, attitude, and awareness about COVID-19:
(i) 85.5% of the dentists had a high level of awareness about virus transmission modes
(as sneezing, coughing, shaking hands, and contacting infected surfaces).
(ii)80.7% of the dentists gave the correct answers to the questions related to virus transmission modes.
(iii) 79.9% of the dentists had a positive attitude about virus transmission modes (like continuous handwashing, social distancing, and mask wearing).

The common mode of COVID-19 transmission:
-travel related: 58.1%
-close contacts: 43.1%
-community spread: 27.4%

RCT done among 1517 undergraduate dental students tested the effectiveness of 'dissonance induction' (DI) and 'assessment reactivity' (AR) in improving adherence to World Health Organization (WHO) measures as compared to a control group:
- DI group were found to be significantly higher (15.11 ± 4.1) compared to the AR (13.13 ± 2.01) and control (12.87 ± 2.97) groups
- DI is an easy intervention to bring an immediate and significant change in adherence to precautionary measures.

Scoping review: Zaki et al.Footnote 458; SR and meta-analysis: Amiri et al. Footnote 424;
SR: Onakpoya et al. Footnote 459

SR and meta-analysis: Jafari et al.Footnote 551

SR and meta-analysis: Li J et al. Footnote 294

RCT: Chandu et al. Footnote 460

Appendix D: Key findings for topic d) PPE for providing in-person healthcare

The following personal protective approaches have limited to moderate evidence for risk, though strong evidence for SARS-CoV-2 and other diseases.

Risk factors for health care workers (HCW)
Main finding Source

Adverse events among HCW due to PPE use during the COVID-19:
- headache (55.9%)
- dry skin (54.4%)
- dyspnoea (53.4%)
- pressure injuries (40.4%)
- itching (39.8%)
- hyperhidrosis (38.5%)
- dermatitis (31.0%; 0.6 to 6.7 cases per 10 000 person/year)

Factors related with a greater risk of adverse events among HCW due to PPE use during the COVID-19:
- females had a higher risk of adverse events (odds 1.87 to 3.20x greater)
- comorbidities such as diabetes mellitus, obesity, pre-existing headache, and smoking
- the longer duration of shifts wearing PPE (odds 1.24 to 4.26x greater)

 SR and meta-analysis: Galanis et al. Footnote 473; SR: Larese Filon et al. Footnote 474

Risk factors for oral health care workers

General
Main finding Source
Adverse events among HCW due to PPE use during the COVID-19:
- occupational contact dermatitis: Higher incidence compared to other HCWs.
For dentists (11 cases per 10 000 person/year)
For dental technicians (13.8 cases per 10 000 person/year)		 SR: Larese Filon et al. Footnote 474

Face masks
Main finding Source
Wearing face masks may reduce COVID-19 infection risk (RR=0.12) SR: Tabatabaeizadeh Footnote 475;

Surgical masks
Main finding Source
Conventional surgical masks do not offer protection against high-risk AGPs. R: Sobti et al. Footnote 476

N95 masks
Main finding Source
Significantly protective of HCW from contracting SARS-CoV-1 and SARS- CoV-2: odds 0.11x greater SR and meta-analysis: Chan et al.Footnote 477

Gowns
Main finding Source
Significantly protective of HCW from contracting SARS-CoV-1 and SARS- CoV-2: odds 0.59x greater SR and meta-analysis: Chan et al.Footnote 477

Gloves
Main finding Source
Significantly protective of HCW from contracting SARS-CoV-1 and SARS- CoV-2: odds 0.39x greater SR and meta-analysis: Chan et al. Footnote 477

Appendix E: Key findings for topic e) decontamination and re-use of PPE

Decontamination and personal protective approaches have no new information for evidence for risk.

Appendix F: Key findings for topic f) the provision of aerosol-generating procedures (AGP)

The following aerosol-generating procedures have limited evidence for risk in relation to SARS-CoV-2.

Droplet transmission
Main finding Source

-Coughing: 82% of the droplet nuclei produced when coughing is within a sufficiently small range (0.74-2.12 micrometres, μm) to contribute to airborne disease transmission. Coughing increases the contagiousness, especially in close contact, of symptomatic cases relative to asymptomatic ones.
- Speaking: the particles generated by speaking tend to involve a broader size distribution, including some particles that are larger in size than produced by other aerosol-generating behaviours in the 3.5 and 5 μm range. The viral transmission of influenza can occur from speaking but it is untested as to whether the finding applies to COVID-19.
- Breathing: 42% of a large proportion of particles produced during breathing were of diameters < 0.8μm, of which size and concentration tend to be unaffected by such environmental factors as temperature and humidity. The viral transmission of influenza strains can occur through breathing-related activities.
- Sustained phonation: particles between 3.5 and 5 μm in size became more prominent in sustained phonation compared to speech and other explored AGPs.
- Loud phonation: the act of voicing loudly does not seem to have an impact on the size of particles generated.

Highly infectious COVID-19 individuals shed tens to thousands of SARS-CoV-2 virions/min via droplets and aerosols while breathing, talking and singing.

Overall sensitivity of respiratory specimens for COVID-19 detection among symptomatic patients:
(i)97% for bronchoalveolar
(ii)92% for double naso/oropharyngeal swabs
(iii)87% for nasopharyngeal swabs
(iv)83% for saliva
(v) 82% for DTS
(vi)44% for oropharyngeal swab

SR: Chacon et al.Footnote 488; SR: Chen et al. Footnote 489

SR and meta-analysis: Khiabani et al.Footnote 490

Bio-aerosol transmission/contamination
Main finding Source

Medical interventions:
No have studies examining transmissibility with other safety protocols, nor any studies quantifying the risk of aerosol generation with nasopharyngeal or oropharyngeal swabs for detection of SARS-CoV-2.
Bio-aerosol transmission/contamination associated with nasopharyngeal or oropharyngeal swab testing:
Using a dedicated sampling room with negative pressure isolation room, PPE, strict sterilisation protocols, structured training with standardised collection methods and a structured collection and delivery system= 0% HCW infection rate among eight nurses conducting over 11 000 nasopharyngeal swabs.
Most orthopaedic procedures are high-risk AGPs.

SR: Agarwal et al.Footnote 552

SR : Sobti et al. Footnote 476

Consensus of AGP on oral and dental procedures
Main finding Source

The use of laser in Dentistry:

  1. high-power lasers form more aerosols than low-power lasers
  2. high-power lasers need to be controlled to minimize the risks of cross-infection.
 SR: Lago et al.Footnote 491

The following aerosol-generating procedures have limited evidence for risk in relation to SARS, MERS, H1N1, influenza and bacteria.

Consensus of AGP on oral and dental procedures
Main finding Source

During dental periodontal procedures:
Hierarchy of procedure contamination risk:
(i) Higher: Higher power settings
(ii) Moderate: Ultrasonic scaling, air polishing and prophylaxis procedures produce contamination (splatter, droplets and aerosol) in the presence of suction, with a small amount of evidence showing droplets taking between 30 min and 1 h to settle.
(iii) Lower: hand scaling
(iv) Distribution of contamination varied in relation to operator position
(v) Distribution of contamination was found on the operator, patient and assistant with higher levels around the head of the operator and the mouth and chest of the patient

During pediatric procedures:
(i) non-aerosol techniques and minimally invasive procedures will be preferable.

During Orthodontic procedures:
(i) avoiding or restricting AGPs whenever possible;
(ii) avoiding the use of high-speed dental handpieces, air-water syringe and ultrasonic scalers;
(iii) using rubber dams and HVE during AGPs;
(iv) utilization of the 4-handed or 6-handed cooperation technique;
(v) avoiding intraoral radiographs like IOPA or occlusal views that can stimulate gag reflexes and induce coughing;
(vi) using handpieces with anti-retractive valves.

SR: Johnson et al. Footnote 492

SR: Sales et al. Footnote 455

SR: Singh et al. Footnote 454

Appendix G: Key findings for topic g) mitigation strategies (for example, rubber dam, mouth rinses etc.) during the provision of in-person oral health care

The following interventions have limited evidence for risk in dental procedures in relation to SARS-CoV-2.

Mouth rinse solutions

Different types of solution
Main finding Source

(i) The main oral antiseptics that have been tested against SARS-CoV-2 were:
- PVP-I
- H2O2 
- chlorhexidine digluconate (CHX)
- ColdZyme
- CPC.

 SR: Mateos-Moreno et al. Footnote 506

Povidine-iodine (PVP-I)
Main finding Source

(i)The current evidence supports the virucidal properties of 0.5% PVP-I is effective in reducing SARS-CoV-2 in the nasal cavity, nasopharynx, oral cavity, and oropharynx.
(ii)The preoperative use of PVP-I mouthrinse/gargle is important in preventing the spread of infection during the COVID-19 pandemic.
(iii) PVP-I have been tested against other coronaviruses and SARS-CoV-2.

The effect of decreasing salivary load with PVP-I and CPC mouth-rinsing was observed to be sustained at 6 h time point. Within the limitation of the current study, the use of PVP-I and CPC formulated that commercial mouth-rinses may be useful as a pre-procedural rinse to help reduce the transmission of COVID-19.

SR: Chopra et al.Footnote 507; SR: Mateos-Moreno et al.Footnote 506

RCT: Seneviratne et al.Footnote 508

Hydrogen Peroxide (HP)
Main finding Source
(i) Nose/mouth/throat washing with hydrogen peroxide may enhance those local innate responses to viral infections and help protect against the current SARS-CoV-2.
(ii)HP have been tested against other coronaviruses and SARS-CoV-2.		 SR: Mateos-Moreno et al.Footnote 506

Chlorhexidine (CHX)
Main finding Source

CHX is a simple and safe addition to current COVID-19 prevention.
Using CHX as an oral rinse and posterior oropharyngeal spray in hospitalized COVID-19 patients:
(i) SARS-CoV-2 was eliminated from the oropharynx of patients who used CHX as an oral rinse (62.1%) versus of the control group patients (5.5%).
(ii) Patients who used a combination of oral rinse and oropharyngeal spray, 86.0% eliminated oropharyngeal SARS-CoV-2, versus 6.3% of control patients.
(iii) CHX have been tested against SARS-CoV-2.

 Prospective Cohort Study : Huang et al. Footnote 509; SR : Mateos-Moreno et al.Footnote 506

Cetylpyridinium chloride (CPC)
Main finding Source
(i) CPC have been tested against other coronaviruses and SARS-CoV-2. SR: Mateos-Moreno et al.Footnote 506

The following interventions have limited evidence for risk in dental procedures in relation to other coronaviruses and bacteria.

General considerations
Main finding Source
Various risk reduction interventions that have been consistently recommended:
(i)avoiding or restricting AGPs whenever possible;
(ii)avoiding the use of high-speed dental handpieces, air-water syringe and ultrasonic scalers;
(iii)limited scheduling of patients;
(iv)limiting the number of HCP during procedure;
(v)using rubber dams and HVE during AGPs;
(vi)utilization of the 4-handed or 6-handed cooperation technique;
(vii)avoiding intraoral radiographs like IOPA or occlusal views that can stimulate gag reflexes and induce coughing;
(viii)using handpieces with anti-retractive valves.		 SR: Singh et al. Footnote 454

High‐volume evacuator
Main finding Source

(i) HVE used with intraoral evacuator (Iso Vac) was found to be most effective in mitigating spatter.
(ii) HVE+ rubber dam: reduces the contamination risk.

(i)During oral prophylaxis using ultrasonic scalers, the use of HVE+ intraoral suction device resulted in significant reductions in CFUs compared with the use of the intraoral suction device alone (P <.001).
(ii)The highest amounts of CFUs were found in the operating zone and on patients during HVE and combination treatment periods.

SR: Singh et al. Footnote 454

RCT: Suprono et al. Footnote 505

Rubber dam
Main finding Source
(i) During AGPs procedures dental treatment: the use with HVE reduces the contamination risk. SR: Singh et al. Footnote 454

Laser
Main finding Source
The use of laser in Dentistry: low-power lasers form less aerosols than high-power lasers but must be protected to minimize the risks of cross-infection. SR: Lago et al. Footnote 491

Mouth rinse solutions

Different types of solution
Main finding Source

(i) The main oral antiseptics that have been tested against other coronaviruses are:
- povidone-iodine (PVP-I)
- essential oils
- cetylpyridinium chloride (CPC)
-sodium bicarbonate
- sodium chloride
-baby shampoo
-hydrogen peroxide (H2O2).

 SR: Mateos-Moreno et al. Footnote 506

Hydrogen peroxide (HP)
Main finding Source
(i)HP is produced physiologically by oral bacteria and plays a significant role in the balance of oral microecology since it is an important antimicrobial agent. SR: Mateos-Moreno et al.Footnote 506

Essential oil (EO)
Main finding Source
(i) EO have been tested against other coronaviruses. SR : Mateos-Moreno et al. Footnote 506

Appendix H: Key findings for topic h) space ventilation strategies to reduce the risk of transmission

The following ventilation settings have limited evidence for risk in relation to SARS-CoV and microorganisms.

Air cleaning systems in dental office
Main finding Source

Preventive engineering control measures that may reduce the risk of infection:
(i)ensuring adequate natural ventilation of the operatory and waiting area with new air,
(ii)allowing air flow from the clean area into the less clean area by placement of supply-air vents in reception or corridor area
(iii)return-air vents in the waiting area or rear of the patient operatory,
(iv) portable high efficiency particulate air (HEPA) filtration units placed adjacent to the patient's chair, but not behind the dental healthcare personnel.
(v)use of properly directed extractor fans (not towards doors), fixed-split and portable air conditioning (without recirculation) without incorporated humidifiers.

(i)Aerosol accumulation may occur in dental treatment rooms with poor ventilation.
(ii) Accumulated aerosol particles could not be removed by ventilation alone within 30-min in rooms with Equivalent ventilation provided by the PAC (ACHvent<15).
(iii)Addition of Portable Air Cleaner (PAC) with a HEPA filter significantly reduced aerosol accumulation and accelerated aerosol removal.
(iv)Accumulated aerosols could be completely removed in 4 to 12-min by ventilation combined with PAC.
(iv)Effectiveness of the PAC was especially prominent in rooms with poor ventilation.

SR: Singh et al. Footnote 454

Prospective study : Ren et al. Footnote 511

Appendix I: Key findings for topic i) disinfection of surfaces in spaces in which oral health care is provided

The following approaches and interventions have limited to moderate evidence for risk in relation to SARS-CoV-2.

General considerations
Main finding Source

(i) The longest SARS-CoV-2 survival time is 28 days at room temperature (RT) on different surfaces:
-polymer banknotes
- vinyl
- steel
- glass
- paper banknotes.
(ii) SARS-CoV-2 human infection from contaminated surfaces, dangerous viral load on surfaces for up to 21 days was determined on:
-polymer banknotes
-steel
-glass
- paper banknotes.
(iii) For viruses other than SARS-CoV-2, the longest period of survival was 14 days, on:
- glass.

(iv) Environmental conditions can affect virus survival:
-low temperatures and low humidity: support prolonged survival of viruses on contaminated surfaces independently of surface type.
- exposure to sunlight: reduces the risk of surface transmission.

- Laboratories reported the highest frequency of contaminated surfaces (20.5%, 17/83).

SR: Marzoli et al. Footnote 516

SR: Onakpoya et al. Footnote 459

Disinfection methods
Main finding Source
(i)Surface inactivation of SARS-CoV-2 can be achieved by standard disinfection methods involving the use of: 70-80% ethanol (minimum 1-minute exposure time) + 0.5% hydrogen peroxide + freshly prepared 0.1% (1 g/L) sodium hypochlorite, at 2-3-hour intervals.
(ii)A fallow period or minimum post AGP downtime of 10 minutes has been recommended to allow for settling of larger droplets before initiation of environmental cleaning.
(iii) Heat-automated high-level disinfection using washer-disinfector may be employed for decontamination of photographic retractors.		 SR: Singh et al.Footnote 454

Disinfectants

Chlorine
Main finding Source

- 1%NaOCl solution for 1 minute: reduce SARS-CoV infectivity and to minimize the risk of cross-contamination through prosthetic materials;
- 1%NaOCl solution: increase in surface roughness and color alteration on acrylic resin (not clinically significant);
- 1% NaOCl solution: decrease in bonding strength on lithium disilicate.

Flushing dental unit water lines for at least 2 minutes at patient intervals or sucking about 1 L of 1% sodium hypochlorite through the suction line at the end of the day reduces the risk of cross-contamination.

SR: Singh et al. Footnote 454

SR : Singh et al. Footnote 454

Alcohols
Main finding Source
- n-propanol alone: low irritation potential
- 60% n-propanol: significant damage effects of repeated exposure in healthy (as well as atopic skin in vivo)
- n-propanol or isopropanol + detergents: greater irritation potential, compared with a quantitatively identical application of the same irritant alone.		 SR and meta-analysis : Tasar et al.Footnote 517

Detergents
Main finding Source
- n-propanol or isopropanol + detergents (ie, sodium lauryl sulfate): greater irritation potential for frequent handwashing with detergents, compared with a quantitatively identical application of the alcohol alone. SR and meta-analysis : Tasar et al. Footnote 517

The following approaches and interventions have limited evidence for risk in relation to different viruses and bacteria.

Disinfectants

Hydrogen peroxide
Main finding Source

Efficacy of Vaporized Hydrogen Peroxide (VHP) fogging against dental environment pathogens:

  • VHP generation was effective for the bacteria and some viruses.
  • aerosolized hydrogen peroxide found a greater log kill with the use of VHP generators.
  • The VHP generators can play a role in dental bio-decontamination.
 SR: Ahmed et al. Footnote 518

Glutaraldehyde
Main finding Source
Sterilization and disinfection of orthodontic armamentarium: cold sterilization using 2% glutaraldehyde for heat-sensitive items: orthodontic markers, ultrasound bath and thermal disinfection. SR: Singh et al.Footnote 454

Peracetic acid
Main finding Source
Sterilization and disinfection of orthodontic armamentarium: cold sterilization using 0.25% peracetic acid for heat-sensitive items: orthodontic markers, ultrasound bath and thermal disinfection. SR: Singh et al. Footnote 454

Autoclaves
Main finding Source
Sterilization and disinfection of orthodontic armamentarium:
- autoclave sterilization preferably for pliers, arch wires and minis crews.
-high-level chemical disinfection or cold sterilization using 2% glutaraldehyde or 0.25% peracetic acid for heat-sensitive items such as orthodontic markers; ultrasound bath and thermal disinfection.		 SR: Singh et al. Footnote 454

Appendix J: Methods used to identify and include relevant literature

This report was structured as a rapid review of the evidence to support safe provision of oral health care during the COVID-19 pandemic. Different search strategies were tailored for nine key areas ("a" to "i"); available evidence was divided according to those key areas.

J.1. Eligibility criteria

J.1.1. Study types and design

This report and subsequent updates included studies in the field of COVID-19/SARS-CoV-2, but extended inclusion to studies on closely related respiratory viruses (key areas "c" to "i"), comprising SARS, MERS, H1N1, influenza, common cold and sometimes other pathogens. For questions with a robust body of evidence about COVID-19, we did not update evidence about other respiratory diseases or viruses (key areas "a" and "b"). Eligible study designs were: systematic reviews (SR) (with meta-analysis or not), scoping reviews, randomized controlled trials (RCT) and prospective cohort studies. We considered only manuscripts written in English as potential sources of study data.

The large amount of included studies for key areas "a" and "b" led us to stricter criteria, as detailed at session J.3.2.1. The paucity of literature on SARS-CoV-2 infection control has led us to extend inclusion criteria for key areas "f", "g", "h" and "i". Therefore, studies related to airborne bacterial contamination were also included for those areas.

J.1.2. Types of conditions and interventions

Each key review area approached a distinct set of conditions and/or interventions of relevance for oral health care. In brief, those were conditions leading to higher risk of morbidity or mortality by COVID-19, approaches to protect healthcare professionals and patients from infection in different moments (i.e., physical distancing, aerosol-generating procedures, asepsis/disinfection and PPE). We expect conditions and interventions of relevance for the viruses mentioned above to be potentially relevant for COVID-19/SARS-CoV-2, even if as with poorer generalizability - studies reporting them would be considered as weaker sources of evidence.

Specific conditions and interventions were:

  1. Comorbidities and other health conditions able to increase the risk of COVID-19-related complications, including death;
  2. Clinical signs and symptoms expected with COVID-19 and observable by dental professionals before rendering in-person care;
  3. Non-treatment approaches to provide in-person dental care, including patient scheduling, waiting and others (for example, teledentistry-based interventions);
  4. Different PPE for in-person dental care, based on studies from different areas of health (not restricted to dental professions);
  5. Decontamination of PPE, aiming at their possible re-use;
  6. Aerosols generated by dental procedures, and their relevance for the transmission of COVID-19;
  7. Methods to mitigate cross-infection by aerosols during in-person provision of oral health care, including rubber dam and pre-operatory mouth washes;
  8. Spatial ventilation strategies to reduce the risk of transmission;
  9. Disinfection of surfaces where oral health care is provided.

Since, at the time of preparing this review, there is no available vaccine for COVID-19, we have not considered that kind of intervention. We did not include prophylactic antiviral regimens for the same reason, for either patients or health care professionals. Since there is potential for vaccines and antivirals to become parts of dental professionals' routine after their development, we may consider including them in future updates.

J.1.3. Outcomes

This review considered any outcome related to the severity of COVID-19 as relevant, including signs/symptoms, complications and incident comorbidities, disease-specific severity indexes, and survival/death. Whenever relevant, measures of contamination (for example, % contaminated per group, or microbial counts on disinfected surfaces) and adverse effects (for example, rash caused by prolonged mask wearing) were considered.

Whenever relevant for each study key area, a brief description of patient and professional perception was provided. This would be done quantitatively (by numbers, for example, % of dentists who disinfect impressions before sending to the laboratory) or qualitatively (by a concise narrative of key perceptions).

J.2. Search strategy

J.2.1. Electronic searches

We performed systematic literature searches separated by key areas in the following databases: CINAHL, Embase (Ovid), MEDLINE (Ovid) and SCOPUS, restricting our search to a period of 4 months (March 1 2021 and June 30 2021). Different search strategies were prepared for key areas "a" to "i" and adapted for each database. Given their similar nature, some pairs of key areas employed a single search (i.e, "a"+"b"; "c"; "d"+"e"; "f"+"g"; "h" and "I"), totalling six searches.

Please refer to Appendix J table at the end of this appendix for the terms used in the electronic searches.

J.2.2. Researching other resources

We reviewed the list of references of all papers included in the report to identify other potentially relevant studies ("reference mining").

J.3. Data collection and analysis

J.3.1. Selection of studies

Two researchers (L.A. and R.S.) examined the titles and abstracts from each search to decide on their exclusion. A third researcher (P.A.) tackled any disagreement between the two reviewers during the selection of titles and abstracts.

Potential inclusion (including cases of insufficient information for exclusion) led to the revision of full text versions by two researchers (R.S. and P.A.). For full text selection, any disagreement was decided by a consensus meeting with a third researcher (L.A.). Although we always reached consensus, the third researcher would have the final decision in cases of persisting disagreement.

In the case of having two or more manuscripts describing the same study, those references would count as a single included study.

J.3.2. Data extraction, management and quality of studies

Studies were classified according to the level of evidence provided: SR>RCT>prospective cohort. Scoping reviews were considered due to the breadth of information rather than strength of evidence. Since this is a rapid review on a vast number of key areas, no in-depth quality assessment was performed - instead, we classified sources of evidence as "strong", "limited" or "none" for each specific condition/intervention.

J.3.2.1 Eligibility criteria for key areas A and B

Our search yielded several redundant studies for key areas A and B. That led us to restrict our eligibility criteria, by including only systematic reviews, with meta-analyses or not. As decision criteria for inclusion, this report considered as a systematic review just those studies with:

  1. a well-defined goal and/or research question, based on participant/patient type, exposure and outcome variables;
  2. systematic study selection, by using reproducible methods (including clear search strategy and eligibility criteria);
  3. quality assessment of reviewed literature (for example, application of standard quality assessment questionnaires for clinical studies);
  4. any strategy to synthetize obtained data (including meta-analysis) or at least a critical description primary study data, if studies cannot be pooled.

Primary studies for key area A were restricted to prospective ones. This enabled us to focus on high-level evidence. The latter restriction was not applied to key area B, given the non-analytical nature of the question.

Scoping reviews were still eligible for key areas C to I, to achieve broader information for those areas with more scarce evidence. Retrospective studies were excluded from this update, however.

J.4. Description of studies

J.4.1. Results of the search

The search strategy retrieved 4,486 study titles and abstracts. After examining those references, 4,269 clearly did not meet the inclusion criteria and were excluded. Two hundred and seventeen full text reports of potentially relevant studies were obtained for further evaluation. After excluding 15 full reports, our sample totaled 202 study reports.

According to each section, articles were included. Appendix J table shows the selection of the publication for inclusion in the systematic review.

Appendix J table: Yield of the six electronic search strategies, in terms of the number of reports

Key areas Total Excluded Included
A + B 1,485 1,309 176
C 635 614 21
D + E 448 443 5
F + G 603 589 14
H 1,077 1,075 2
I 238 233 5
No data No data No data Total = 223Footnote *
Footnote *

Several articles were included for more than one topic (e.g.: 14 articles were identified for topics A and B; 7 articles for two or more different topics) hence the total in the table surpasses 100% of the included articles (n = 223 and 202, respectively).

Return to footnote * referrer

J.4.2. Included studies

Regarding study design, the majority of our inclusions were SR and/or meta-analyses (n=193, 95.5%). We have also included five Prospective Cohort Studies (n=5, 2.48%), two scoping reviews (n=2, 1%), as well two RCT (n=2, 1%).

J.4.3. Measures of treatment effect and unit of analysis issues

Included studies underwent qualitative analysis and separate data extraction, without further efforts for quantitative synthesis. Please refer to the main document and Appendices A to I for the description and results of included studies.

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M. Sepandi, M. Taghdir, Y. Alimohamadi, S. Afrashteh, H. Hosamirudsari, Factors Associated with Mortality in COVID-19 Patients: A Systematic Review and Meta-Analysis, Iran J Public Health 49(7) (2020) 1211-1221.

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M. Vakhshoori, M. Heidarpour, D. Shafie, M. Taheri, N. Rezaei, N. Sarrafzadegan, Acute Cardiac Injury in COVID-19: A Systematic Review and Meta-analysis, Arch Iran Med 23(11) (2020) 801-812.

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Y. Zhou, Q. Ren, G. Chen, Q. Jin, Q. Cui, H. Luo, K. Zheng, Y. Qin, X. Li, Chronic Kidney Diseases and Acute Kidney Injury in Patients With COVID-19: Evidence From a Meta-Analysis, Front Med (Lausanne) 7 (2020) 588301.

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Z.H. Wu, Y. Tang, Q. Cheng, Diabetes increases the mortality of patients with COVID-19: a meta-analysis, Acta Diabetol 58(2) (2021) 139-144.

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J. Yang, C. Tian, Y. Chen, C. Zhu, H. Chi, J. Li, Obesity aggravates COVID-19: An updated systematic review and meta-analysis, J Med Virol (2020).

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A.Y. Soeroto, A. Purwiga, H.P.E.H.P. Emmy, R.M.A. Roesli, Asthma does not increase COVID-19 mortality and poor outcomes: A systematic review and meta-analysis, Asian Pac J Allergy Immunol (2021).

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S. Saha, R.H. Al-Rifai, S. Saha, Diabetes prevalence and mortality in COVID-19 patients: a systematic review, meta-analysis, and meta-regression, J Diabetes Metab Disord (2021) 1-12.

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L. Palaiodimos, N. Chamorro-Pareja, D. Karamanis, W. Li, P.D. Zavras, K.M. Chang, P. Mathias, D.G. Kokkinidis, Diabetes is associated with increased risk for in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis comprising 18,506 patients, Hormones (Athens) 20(2) (2021) 305-314.

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Y.C. Lin, T.S. Lai, S.L. Lin, Y.M. Chen, T.S. Chu, Y.K. Tu, Outcomes of coronavirus 2019 infection in patients with chronic kidney disease: a systematic review and meta-analysis, Ther Adv Chronic Dis 12 (2021) 2040622321998860.

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T. Menon, S.A.Q. Gandhi, W. Tariq, R. Sharma, S. Sardar, A.M. Arshad, R. Adhikari, F. Ata, S. Kataria, R. Singh, Impact of Chronic Kidney Disease on Severity and Mortality in COVID-19 Patients: A Systematic Review and Meta-analysis, Cureus 13(4) (2021) e14279.

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Footnote 345

J. Singh, P. Malik, N. Patel, S. Pothuru, A. Israni, R.C. Chakinala, M.R. Hussain, A. Chidharla, H. Patel, S.K. Patel, R. Rabbani, U. Patel, S. Chugh, A. Kichloo, Kidney disease and COVID-19 disease severity-systematic review and meta-analysis, Clin Exp Med (2021).

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T. Menon, R. Sharma, S. Kataria, S. Sardar, R. Adhikari, S. Tousif, H. Khan, S.S. Rathore, R. Singh, Z. Ahmed, The Association of Acute Kidney Injury With Disease Severity and Mortality in COVID-19: A Systematic Review and Meta-Analysis, Cureus 13(3) (2021) e13894.

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N. Nasiri, S. Rahmati, A. Etminan, H. Sharifi, A. Bazrafshan, M. Karamouzian, A. Sharifi, Kidney Complications of COVID-19: A Systematic Review and Meta-Analysis, J Res Health Sci 21(1) (2021) e00503.

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Z. Xu, Y. Tang, Q. Huang, S. Fu, X. Li, B. Lin, A. Xu, J. Chen, Systematic review and subgroup analysis of the incidence of acute kidney injury (AKI) in patients with COVID-19, BMC Nephrol 22(1) (2021) 52.

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P.J. Hegyi, S. Vancsa, K. Ocskay, F. Dembrovszky, S. Kiss, N. Farkas, B. Eross, Z. Szakacs, P. Hegyi, G. Par, Metabolic Associated Fatty Liver Disease Is Associated With an Increased Risk of Severe COVID-19: A Systematic Review With Meta-Analysis, Front Med (Lausanne) 8 (2021) 626425.

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A. Singh, S. Hussain, B. Antony, Non-alcoholic fatty liver disease and clinical outcomes in patients with COVID-19: A comprehensive systematic review and meta-analysis, Diabetes Metab Syndr 15(3) (2021) 813-822.

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Footnote 356

M. Foldi, N. Farkas, S. Kiss, F. Dembrovszky, Z. Szakacs, M. Balasko, B. Eross, P. Hegyi, A. Szentesi, Visceral Adiposity Elevates the Risk of Critical Condition in COVID-19: A Systematic Review and Meta-Analysis, Obesity (Silver Spring) 29(3) (2021) 521-528.

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N. Helvaci, N.D. Eyupoglu, E. Karabulut, B.O. Yildiz, Prevalence of Obesity and Its Impact on Outcome in Patients With COVID-19: A Systematic Review and Meta-Analysis, Front Endocrinol (Lausanne) 12 (2021) 598249.

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R. Pranata, M.A. Lim, I. Huang, E. Yonas, J. Henrina, R. Vania, A.A. Lukito, S.A. Nasution, I. Alwi, B.B. Siswanto, Visceral adiposity, subcutaneous adiposity, and severe coronavirus disease-2019 (COVID-19): Systematic review and meta-analysis, Clin Nutr ESPEN 43 (2021) 163-168.

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R. Pranata, M.A. Lim, E. Yonas, R. Vania, A.A. Lukito, B.B. Siswanto, M. Meyer, Body mass index and outcome in patients with COVID-19: A dose-response meta-analysis, Diabetes Metab 47(2) (2021) 101178.

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X. Zhang, A.M. Lewis, J.R. Moley, J.R. Brestoff, A systematic review and meta-analysis of obesity and COVID-19 outcomes, Sci Rep 11(1) (2021) 7193.

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F. Dumitrascu, K.E. Branje, E.S. Hladkowicz, M. Lalu, D.I. McIsaac, Association of frailty with outcomes in individuals with COVID-19: A living review and meta-analysis, J Am Geriatr Soc (2021).

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M.R. Hashan, N. Smoll, C. King, H. Ockenden-Muldoon, J. Walker, A. Wattiaux, J. Graham, R. Booy, G. Khandaker, Epidemiology and clinical features of COVID-19 outbreaks in aged care facilities: A systematic review and meta-analysis, EClinicalMedicine 33 (2021) 100771.

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S. Singhal, P. Kumar, S. Singh, S. Saha, A.B. Dey, Clinical features and outcomes of COVID-19 in older adults: a systematic review and meta-analysis, BMC Geriatr 21(1) (2021) 321.

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P.R. Gabbai-Armelin, A.B. de Oliveira, T.M. Ferrisse, L.S. Sales, E.R.O. Barbosa, M.L. Miranda, K.B. Salomao, F.L. Brighenti, COVID-19 (SARS-CoV-2) infection and thrombotic conditions: A systematic review and meta-analysis, Eur J Clin Invest 51(6) (2021) e13559.

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S. Mitra, R.R. Ling, I.X. Yang, W.H. Poon, C.S. Tan, P. Monagle, G. MacLaren, K. Ramanathan, Severe COVID-19 and coagulopathy: A systematic review and meta-analysis, Ann Acad Med Singap 50(4) (2021) 325-335.

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C. Moonla, D. Sosothikul, T. Chiasakul, P. Rojnuckarin, N. Uaprasert, Anticoagulation and In-Hospital Mortality From Coronavirus Disease 2019: A Systematic Review and Meta-Analysis, Clin Appl Thromb Hemost 27 (2021) 10760296211008999.

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S. Birocchi, M. Manzoni, G.M. Podda, G. Casazza, M. Cattaneo, High rates of pulmonary artery occlusions in COVID-19. A meta-analysis, Eur J Clin Invest 51(1) (2021) e13433.

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Footnote 372

J. Gratz, M. Wiegele, M. Maleczek, H. Herkner, H. Schochl, E. Chwala, P. Knobl, E. Schaden, Risk of Clinically Relevant Venous Thromboembolism in Critically Ill Patients With COVID-19: A Systematic Review and Meta-Analysis, Front Med (Lausanne) 8 (2021) 647917.

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J.J. Ng, Z.C. Liang, A. Choong, The incidence of pulmonary thromboembolism in COVID-19 patients admitted to the intensive care unit: a meta-analysis and meta-regression of observational studies, J Intensive Care 9(1) (2021) 20.

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A. Sarfraz, Z. Sarfraz, A.A. Razzack, G. Patel, M. Sarfraz, Venous Thromboembolism, Corticosteroids and COVID-19: A Systematic Review and Meta-Analysis, Clin Appl Thromb Hemost 27 (2021) 1076029621993573.

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M. Zuin, G. Rigatelli, C. Bilato, C. Cervellati, G. Zuliani, L. Roncon, Dyslipidaemia and mortality in COVID-19 patients - a meta-analysis, QJM (2021).

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M. Barzegar, O. Mirmosayyeb, M. Gajarzadeh, A. Afshari-Safavi, N. Nehzat, S. Vaheb, V. Shaygannejad, A.H. Maghzi, COVID-19 Among Patients With Multiple Sclerosis: A Systematic Review, Neurol Neuroimmunol Neuroinflamm 8(4) (2021).

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C. Putri, T.I. Hariyanto, J.E. Hananto, K. Christian, R.F.V. Situmeang, A. Kurniawan, Parkinson's disease may worsen outcomes from coronavirus disease 2019 (COVID-19) pneumonia in hospitalized patients: A systematic review, meta-analysis, and meta-regression, Parkinsonism Relat Disord 87 (2021) 155-161.

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M.K. Patralekh, V.K. Jain, K.P. Iyengar, G.K. Upadhyaya, R. Vaishya, Mortality escalates in patients of proximal femoral fractures with COVID-19: A systematic review and meta-analysis of 35 studies on 4255 patients, J Clin Orthop Trauma 18 (2021) 80-93.

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S. Kastora, G. Kounidas, S. Perrott, B. Carter, J. Hewitt, P.K. Myint, Clinical frailty scale as a point of care prognostic indicator of mortality in COVID-19: a systematic review and meta-analysis, EClinicalMedicine 36 (2021) 100896.

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N.A. Mohamed, N. Baharom, W.S.W. Sulaiman, Z.Z. Rashid, W.K. Ken, U.K. Ali, S.N. Othman, M.N. Samat, N. Kori, P. Periyasamy, N.A. Zakaria, A.N.K. Sugurmar, N.E.M. Kazmin, C.X. Khee, S.M. Saniman, I. Isahak, Early Viral Clearance among COVID-19 Patients When Gargling with Povidone-Iodine and Essential Oils: A Clinical Trial, International Medical Journal 27(6) (2020) 651-654.

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B.L. Cavalcante-Leao, C.M. de Araujo, I.B. Basso, A.G. Schroder, O. Guariza-Filho, G.C. Ravazzi, F.M. Goncalves, B.S. Zeigelboim, R.S. Santos, J. Stechman-Neto, Is there scientific evidence of the mouthwashes effectiveness in reducing viral load in COVID-19? A systematic review, J Clin Exp Dent 13(2) (2021) e179-e189.

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R. Bolia, A. Dhanesh Goel, M. Badkur, V. Jain, Gastrointestinal manifestations of pediatric coronavirus disease and their relationship with a severe clinical course: A systematic review and meta-analysis, J Trop Pediatr (2021).

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M. Shehab, F. Alrashed, S. Shuaibi, D. Alajmi, A. Barkun, Gastroenterological and hepatic manifestations of patients with COVID-19, prevalence, mortality by country, and intensive care admission rate: systematic review and meta-analysis, BMJ Open Gastroenterol 8(1) (2021).

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K. Goshtasbi, J. Pang, B.M. Lehrich, M. Vasudev, J.L. Birkenbeuel, A. Abiri, E.C. Kuan, Association Between Olfactory Dysfunction and Critical Illness and Mortality in COVID-19: A Meta-analysis, Otolaryngol Head Neck Surg (2021) 1945998211017442.

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F. Heidari-Beni, A. Vahedian-Azimi, S. Shojaei, F. Rahimi-Bashar, A. Shahriary, T.P. Johnston, A. Sahebkar, The Level of Procalcitonin in Severe COVID-19 Patients: A Systematic Review and Meta-Analysis, Adv Exp Med Biol 1321 (2021) 277-286.

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B. Haghighi Aski, A. Manafi Anari, F. Abolhasan Choobdar, R. Zareh Mahmoudabadi, M. Sakhaei, Cardiac abnormalities due to multisystem inflammatory syndrome temporally associated with COVID-19 among children: A systematic review and meta-analysis, Int J Cardiol Heart Vasc 33 (2021) 100764.

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R. Pranata, I. Huang, M.A. Lim, E. Yonas, R. Vania, R.A.T. Kuswardhani, Delirium and Mortality in Coronavirus Disease 2019 (COVID-19) - A Systematic Review and Meta-analysis, Arch Gerontol Geriatr 95 (2021) 104388.

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J.C. Borders, J.S. Sevitz, J.B. Malandraki, G.A. Malandraki, M.S. Troche, Objective and Subjective Clinical Swallowing Outcomes via Telehealth: Reliability in Outpatient Clinical Practice, Am J Speech Lang Pathol 30(2) (2021) 598-608.

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