coronavirus disease 2019 (covid-19): challenges, measures
TRANSCRIPT
Diploma Thesis
Coronavirus Disease 2019 (COVID-19): Challenges, measures, proportionality – an outlook for oral healthcare in a systematic
review
For the attainment of the academic degree
Doktor(in) der Zahnheilkunde (Dr.med.dent.)
at the
University Clinic of Dentistry Vienna, Department of Oral Surgery
Markus Munzig 01542104 Supervisors Univ. Prof. DDr. Andreas Schedle Univ. Prof. DDr. Werner Zechner
_______________________ _______________________
Supervisor Signature Diploma Student Signature
Table of Contents
1 Acknowledgment 4
2 Abstract 5
3 Introduction 7 3.1 Origin and disambiguation of SARS-CoV-2 8 3.2 A Distinction of SARS-CoV-2 and other coronaviruses 9 3.3 Biological aspects and infection mechanism of SARS-CoV-2 11 3.4 Transmission of SARS-CoV-2 12 3.4.1 Significance of SARS-CoV-2 transmission for oral healthcare 15 3.5 Pathophysiology of severe COVID-19 infections 16 3.6 Symptoms of COVID-19 and differential diagnosis 18 3.7 Testing and diagnostics 20 3.8 Pharmacotherapy and oral health-related issues 22 3.9 Epidemiology and developments 26 3.10 Rationale and Aim of Study 28
4 Materials and Methods 29 4.1 Research strategy 29 4.1.1 The general framework, information sources, and data collection process 29 4.1.2 Eligibility criteria 30 4.1.3 Search 30 4.1.4 Study selection 31
5 Results 33 5.1 Recommendations for oral healthcare provision during the COVID-19 pandemic 33 5.2 Standard infection control in oral healthcare regardless of COVID-19 37 5.3 Measures for infection control of SARS-CoV-2 in oral healthcare 38 5.3.1 Approach 1: Elimination of indirect transmission possibilities of SARS-CoV-2 39 5.3.2 Approach 2: Elimination of direct transmission possibilities 42 5.3.3 Approach 3: Administrative intervention: Altering organizational patterns 47 5.3.3.1 Patient assessment 48
5.3.3.2 Treatment of COVID-19 confirmed and suspected patients 50
5.3.3.3 Treatment flowchart 50
5.4 Proportionality and feasibility of measures in oral healthcare practice 53 5.4.1 Approaching proportionality and feasibility of measures 53
6 Discussion 55 6.1 Historic virus outbreaks of an enormous impact compared to the COVID-19 pandemic 55 6.2 Outlook, recommendations, and future pandemic prevention 57 6.2.1 Outlook on the progression of the pandemic 57 6.2.2 Recommendations for oral healthcare 59 6.2.3 Future pandemic prevention 60
7 Conclusion 62
8 List of Abbreviations 63
9. List of References 65
Acknowledgment
4
1 Acknowledgment
To Ute and Michael.
Abstract
5
2 Abstract
The outbreak of the Coronavirus disease 2019 (COVID-19), caused by novel SARS-CoV-2,
has resulted in a global and rapidly progressing pandemic. Even after a year post of its
outbreak, the ever-changing circumstances in its wake incite uncertainty among healthcare
professionals worldwide. The joint efforts against the spreading of the virus are deemed one
of the most significant medical and socio-economic challenges of modern history. Being
frontline suppliers of medical services, oral healthcare professionals currently face the
tremendous need to tackle both potentially infected patients and avoid becoming infectious
themselves. Aerosol generating dentistry procedures and working exceedingly close to likely
entry gates for the virus, such as mouth, nose, and eyes, potentially increase transmission risk
and, therefore, vulnerability for both patient and staff. This additional risk variable in the
equation for patient health, workplace safety, and minimization of transmission risk of SARS-
CoV-2 demand appropriate protection gear and strict behavioral rules to avoid further
aggravation. Hence, what protective measures are reasonable and indispensable in times of
new normality with resurging case numbers, stabilizing, or declining infection ratios? How
can dental healthcare be carried out responsibly, covering the period until a remedy for
COVID-19 is found? This systematic review aims to examine findings regarding
epidemiology, pathogenesis, clinical manifestations, and diagnosis of COVID-19 and
treatment of patients to evaluate prevention, guidelines, and management strategies for oral
healthcare. It is set to determine which measures and steps have to be undertaken, owing to
their effectiveness and proportionality in oral healthcare practice, to provide the most feasible
working environment under such demanding and challenging circumstances. Investigating on
parallels and comparisons to past virus outbreaks and pandemics of similar impact in recent
human history (e.g., SARS-CoV, MERS-CoV) is set to estimate the further course of events
and hence anticipate upcoming challenges in oral healthcare practice. Overall, this review
aims to make a scientifically sound contribution to ensuring patients’ and medical staff’s
health and safety in these challenging times.
Abstract
6
Der Ausbruch der Coronavirus-Krankheit-2019 (COVID-19), verursacht durch das neuartige
SARS-CoV-2, hat zu einer globalen und schnell fortschreitenden Pandemie geführt. Auch ein
Jahr nach dem Ausbruch verunsichern die sich ständig wandelnden Begleitumstände das
medizinische Personal weltweit. Die gemeinsamen Anstrengungen gegen die Ausbreitung des
Virus gelten als eine der größten medizinischen und sozioökonomischen Herausforderungen
der modernen Geschichte. Als Anbieter medizinischer Dienstleistungen an vorderster Front
sieht sich die Zahnmedizin derzeit mit der enormen Notwendigkeit konfrontiert, sowohl mit
potenziell infizierten Patienten umzugehen als auch zu vermeiden, selbst infiziert zu werden.
Aerosolerzeugende zahnärztliche Eingriffe und das Arbeiten in unmittelbarer Nähe von
möglichen Eintrittspforten für das Virus, wie Mund, Nase und Augen, erhöhen potenziell das
Übertragungsrisiko und damit die Anfälligkeit sowohl für den Patienten als auch für das
medizinische Personal. Diese zusätzliche Risikovariable in der Gleichung für die
Patientengesundheit, die Sicherheit am Arbeitsplatz und die Minimierung des
Übertragungsrisikos von SARS-CoV-2 erfordert eine angemessene Schutzausrüstung und
strenge Verhaltensregeln, um eine weitere Zuspitzung zu vermeiden. Welche
Schutzmaßnahmen sind also sinnvoll und unabdingbar in Zeiten neuer Normalität mit
steigenden Fallzahlen und sich stabilisierenden oder rückläufigen Infektionsraten? Wie kann
eine zahnärztliche Versorgung verantwortungsbewusst gewährleistet werden, um den
Zeitraum bis zur Verfügbarkeit eines Heilmittels für COVID-19 zu überbrücken? Diese
systematische Übersichtsarbeit zielt darauf ab, Erkenntnisse über Epidemiologie,
Pathogenese, klinische Manifestationen und Diagnose von COVID-19 sowie die Behandlung
von Patienten zu untersuchen, um Präventions- und Managementstrategien sowie Richtlinien
für die zahnmedizinische Versorgung zu bewerten. Es soll ermittelt werden, welche
praktischen Maßnahmen und Schritte aufgrund ihrer Effektivität und Verhältnismäßigkeit
unternommen werden müssen, um unter diesen anspruchsvollen und herausfordernden
Umständen ein möglichst sinnvolles Arbeitsumfeld zu schaffen. Die Untersuchung von
Parallelen und Vergleiche zu vergangenen Virusausbrüchen und Pandemien mit ähnlichen
Auswirkungen (z. B. SARS-CoV, MERS-CoV) soll den weiteren Verlauf der Ereignisse
abschätzen und damit die kommenden Herausforderungen für die zahnmedizinische Praxis
antizipieren. Insgesamt soll diese Übersichtsarbeit einen wissenschaftlich fundierten Beitrag
zur Gewährleistung der Gesundheit und Sicherheit von Patienten und medizinischem Personal
in diesen herausfordernden Zeiten leisten.
Introduction
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3 Introduction
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), is an infectious disease, which initially was detected in Wuhan
City, China in late 2019 (1). The first cases of initial pneumonia clusters were reported to
health authorities on December 29, 2019, linking them to an unknown virus. This virus was
later classified as SARS-CoV-2, back then and before classification known as 2019-nCoV (2).
After the virus was identified as the causative agent of COVID-19 and successfully isolated
for analysis, its genome was published in early January, identifying it as a novel coronavirus
(3). It is the seventh member of the family of coronaviruses capable of infecting humans (4).
On January 30, 2020, the World Health Organization declared a public health emergency of
international concern over this global pneumonia outbreak. It subsequently spread over more
than 190 countries and regions, infecting at least 64.1 million people and resulting in more
than 1.45 million deaths worldwide as of December 01, 2020, with a still-rising trend in case
numbers (5). The outbreak was formally declared a pandemic by the WHO on March 11.
Governments worldwide began adopting measures to slow the spread of infection, including
social distancing, shutting down public life, and locking down individuals (6). A zoonotic
origin of the virus is implicated by phylogenetic data, as two bat-derived severe acute
respiratory syndromes (SARS)–like coronaviruses are more closely related to SARS-CoV-2
than SARS-CoV and the Middle East respiratory syndrome (MERS)-CoV (7). With further
progression of the pandemic and its swift spread around the globe, community transmission
and family clusters were internationally studied in detail and provided valuable insights into
the existence of person-to-person transmission dynamics (8,9). The reported symptoms of
COVID-19 in an early review range from mild to severe, with fever, dry cough, myalgia,
fatigue, pneumonia, and dyspnea being reported as the most common clinical manifestations
(10). Some people show no symptoms at all, and some 3,5% of severe cases were initially
reported to result in death, especially among elder adult individuals (11). The infection is
spreading significantly faster than pathogens, having caused similar large-scale outbreaks like
SARS, MERS, and Ebola, although being less deadly, regarding current estimates of the
COVID-19 case fatality rate (11,12). The basic reproduction number (R0) of the virus — the
average number of newly infected people by one infected individual — is relatively high and
estimated to be around 3,3 – 3,8 according to the Robert Koch Institute (RKI) and 3.32
Introduction
8
according to a recently published meta-analysis (13,14). Healthcare workers are generally
regarded as exceptionally prone to exposure to SARS-CoV-2, according to the US Centers for
Disease Control and Prevention (CDC), making them potential carriers and spreaders of the
disease through infection (15,16). Over the last months, most countries have applied strict
policies to contain the virus's spread with varying success. Most commonly, these measures
include wearing masks, practice social distancing, and shutting down public life. The explicit
factors and mechanisms regarding the spreading and prevention of COVID-19 and
appropriate measures are subject to numerous ongoing studies. Each day, new information is
published, which gives a more precise outline of the situation. This systematic review aims to
collect, structure, and evaluate the current evidence up December 01, 2020, to picture the best
overview possible.
3.1 Origin and disambiguation of SARS-CoV-2
On February 11, 2020, the International Committee on Taxonomy of Viruses (ICTV)
suggested naming the newly identified coronavirus as "SARS-CoV-2". This decision was due
to taxonomic and phylogenetic considerations as well as its genetic similarity to the virus that
resulted in the outbreak of 2003, which is now called "SARS-CoV-1". WHO hence decided to
name the associated pneumonia as "Coronavirus Disease (COVID19)", alluding to 2019 as
the year of its discovery (17). The outbreak's origin is suspected to be located in the Huanan
Seafood Wholesale Market in Wuhan City. Bats are sold as food on this market, among other
wildlife animals serving as natural virus reservoirs (18). However, other investigations imply
that the first viral transmission to humans might have another origin, after all. They suggest
that this virus may have been circulating in human populations for an extended period before
it gained the ability to cause human diseases through genomic adaptations during undetected
human-to-human infection (19–21). Usually remaining confined in animal populations,
coronaviruses are deemed to have evolved over thousands of years, sometimes resulting in
zoonotic spreads (22). For other coronavirus transmissions in recent history, intermediate
mammalian hosts have been described, such as civet cats in the case of SARS-CoV-1 and
dromedary camels in MERS-CoV (23,24). Genetic investigations of the virus have resulted in
SARS-CoV-2 showing higher sequence homology to Bat-CoV-RaTG13 previously detected
Introduction
9
in Rhinolophus affinis from the Yunnan Province than Bat-SL-CoVZC21 and Bat-SL-
CoVZC45, suggesting that the Chinese chrysanthemum bat is the origin and natural host of
SARS-CoV-2 (25). Interestingly, the evolutionary reservoir of SARS-CoV-1 is assumed to be
in bat populations as well, more precisely in horseshoe bats (26). As early as 2007, there were
warnings of an extensive reservoir of coronaviruses in horseshoe bat populations in China. In
connection with exotic animals' consumption, this was already presented as a "time bomb"
(27). Regarding the intermediary host's question, it is now widely assumed that a Pangolin has
served as the human-transmitting virus carrier (28–30). The South China Agricultural
University has researched more than 1000 metagenomic samples from pangolins and found
that 70% of pangolins contained β-CoV (31). In one case, there even appeared to be
approximately 99% genome sequence homology between SARS-CoV-2 and the consensus
sequence from the pangolin species, implicating that Pangolins are the most likely
intermediate host of SARS-CoV-2 yet (32). Many early patients reportedly have not been
exposed to the markets, which suggests overcoming the animal-human barrier and the
subsequent human-to-human spread (33–36).
3.2 A Distinction of SARS-CoV-2 and other coronaviruses
Coronaviruses were first discovered in the 1960s and are considered a significant cause of
viral respiratory infections globally (37). They generally infect vertebrates, especially
mammals and birds, snakes, and other wild animals (38–40). As of now, coronaviruses are
subdivided into four genera: α- CoV, β-CoV, γ-CoV, and δ-CoV (41,42). While α- and β-
CoVs primarily infest the respiratory, gastrointestinal, and central nervous system of humans
and other mammals, γ- and δ-CoVs mainly infect birds (43–46). Accounting for the recent
discovery of SARS-CoV-2 and the resultant disease COVID-19, there currently are a total of
7 coronaviruses known to be able to infect humans (47)
- Human coronavirus HKU1 (HCoV-HKU1) - Human coronavirus 229E (HCoV-229E) - Human coronavirus OC43 (HCoV-OC43) - Human coronavirus NL63 (HCoV-NL63) - Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1) - Middle East respiratory syndrome-related coronavirus (MERS-CoV)
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- Novel coronavirus SARS-CoV-2
Most coronavirus family members cause mild respiratory symptoms in humans, such as
HCoV-229E and HCoV-OC43, which are likely to account for about 15-29% of relatively
low virulence respiratory pathogens in humans (48,49). Correspondingly, one epidemiological
study holds coronaviruses responsible for approximately 15% of common colds (50). On the
contrary, SARS-CoV-1 and MERS-CoV (both belonging to the β-CoVs and discovered in
2002 and 2012, respectively) are particularly virulent strains and exceptionally pathogenic in
humans, causing severe respiratory diseases and therefore are associated with higher mortality
than other coronaviruses (47,51–55). SARS-CoV-2 is counted to the β-CoVs, too, owing to
the phylogenetic analysis of the viral genome. The observed incubation time of 1-14 days is
similar to SARS-CoV-1 and MERS-CoV, which is around 2-13 days (56). However, its spike
protein structures differ significantly from MERS-CoV and SARS-CoV-1, resulting in a more
efficient entry mechanism into human cells due to its higher affinity to angiotensin-converting
enzyme 2 (ACE2), which will be discussed in detail in the next chapter (57,58). Even though
the nucleotide sequence similarity between SARS-CoV-2 and SARS-CoV-1 is just about
79%, the similarity between SARS-CoV-2 and MERS-CoV is around 50% SARS-CoV-2 is
consequently capable of spreading even faster (53,59–63). A meta-analysis was able to show
that essential laboratory markers for infections such as lactic dehydrogenase, C-reactive
protein, and neutrophils correlate stronger with COVID-19 mortality than with that of SARS
or MERS, respectively (64). It hence comes as no surprise that COVID-19 has already caused
more deaths in about five months than SARS and MERS combined in years (58,65).
In 2012, MERS-CoV was isolated first from a Saudi Arabia patient who died from acute
pneumonia and renal failure (66). In the aftermath, MERS-CoV caused 2494 registered cases
in 27 countries, of which 858 resulted in death – a case-fatality rate of 34.4% (67). On the
contrary, both SARS-CoV-1 and SARS-CoV-2 were first detected in China. SARS-CoV-1 is
associated with a total of 8422 presumed SARS-CoV-1 cases in 32 countries between
November 2002 and August 2003 - a case-fatality rate of 11% (68). In comparison, since
December 2019, SARS-CoV-2 has infected at least 64.1 million people in 190 countries or
regions and caused at least 1.45 million deaths (status: December 01, 2020) – a case-fatality
rate of roughly 2.3% (69). Although the overall number of recovered patients is continuously
increasing, the number of newly confirmed cases and deaths is still surging.
Introduction
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Human coronavirus Incubation period Common clinical symptoms
229E, OC 43 2-5 days General malaise, headache, nasal discharge, sneezing, sore throat, fever, and cough (10–20% of patients)
NL63 2-4 days Cough, rhinorrhea, tachypnoea, fever, hypoxia, obstructive laryngitis
HKU1 2-4 days Fever, running nose, cough, dyspnea
MERS-CoV 2-13 days Fever, cough, chills, sore throat, myalgia, arthralgia, dyspnea, pneumonia, diarrhea and vomiting (30% of patients), acute renal impairment
SARS-CoV-1 2-11 days Fever, myalgia, headache, malaise, chills, nonproductive cough, dyspnea, respiratory distress, diarrhea (30–40% of patients)
SARS-CoV-2 1-14 days Malaise, fever, dry cough, cough, dyspnea, myalgia, fatigue
Fig. I: Comparison of incubation time and clinical symptoms of human coronaviruses (48)
3.3 Biological aspects and infection mechanism of SARS-CoV-2
SARS-CoV-2 is a member of the family of Coronaviridae, a subfamily of Orthocoronavirinae
within the order of Nidovirales (70). Coronaviruses are named based on their characteristic
common feature: Crown-like glycoprotein spikes, called virions, littering their membrane,
which envelops a non-segmented, large, positive-sense single-stranded RNA, with size
between 26,000 – 37,000 bases (10,46,71,72). Currently, four significant proteins have been
identified in coronaviruses: S (spike), E (envelope), M (membrane), and N (nucleocapsid)
proteins (39). They are part of a genomic framework identified as 5′-leader-UTR-replicase-S
(Spike)- E (Envelope)-M (Membrane)-N (Nucleocapsid)-3′UTRpoly (A) tail, which contains
accessory genes at the 3' end (46). Within the membrane, there are also other polyproteins and
nucleoproteins, RNA polymerase, 3-chymotrypsin-like protease, papain-like protease,
helicase, glycoprotein, and accessory proteins (3,4,32,73). The M- and E- proteins are
essential for viral assembly, and the N-protein is essential for RNA synthesis (46,55).
Most importantly, the spike protein (S-protein) is essential for the interaction between the
virus and the target cell: It mediates ACE2 receptor binding and fusion of virus and host cell
membrane (74). The transmembrane ACE2 receptor is found throughout the respiratory tract
on mucosal tissue cells, like the dorsum of the tongue or salivary glands (74,75), which is
why saliva has also been proposed for quick virus diagnostics (76,77). ACE2-positive
epithelial cells of salivary gland ducts were shown to represent an early target of SARS-CoV-
1 infection, which suggests a similar mechanism for SARS-CoV-2 (78). Even though the S-
Introduction
12
protein of SARS-CoV-2 features four amino acid variations than SARS-CoV-1, it can still
bind to the ACE2 receptor of humans, bats, civet cats, and pigs just as SARS-CoV-1 (4,78–
81). After having successfully attached to the ACE2 receptor, the virus inserts its RNA into
the target cell. Through RNA polymerase, the viral RNA can then replicate in the host
cytoplasm. The sheer amount of energy required for this repetitive process eventually forces
the infected host cell into apoptosis, thereby releasing the viral DNA's newly formed copies
(82). It is of elementary understanding that the virus per se is inert and incapable of self-
replication as long as it has not entered and used a target cell to its favor. Therefore, it needs
to "hijack" the human body to remain functional (83). Hence, outside the body, the outer layer
of spike protein structures can easily be disintegrated by commercial standard disinfectants in
less than 5 minutes, rendering the virus virtually incapable of interacting and entering human
cells and thus turning it harmless (84). The ACE2 receptor as a crucial link in the infection
mechanism was identified and confirmed by a recombinant ACE2-Ig antibody, a SARS-CoV-
1-specific human monoclonal antibody, and serum from a convalescent SARS-CoV-1-
infected patient, which can neutralize SARS-CoV-2 (4,85–87). Moreover, the cellular
transmembrane protease, serine subtype 2 (TMPRSS2), positively affects the S-protein
priming of SARS-CoV-2. This observation suggests that people with higher expression of
ACE2 are likely to be more prone to infection with SARS-CoV-2 and that the inhibition of
TMPRSS2 might add to a possible treatment (86,88,89).
3.4 Transmission of SARS-CoV-2
Transmission of SARS-CoV-2 appears to happen predominantly by respiratory microdroplets
and aerosol (90–92). The water envelope of smaller droplets evaporates during sedimentation,
and the resulting droplet nuclei (aerosol) can float in the air for an indefinite time. Diffusion
primarily occurs through sneezing, coughing, and saliva. The length of time virus particles
remain airborne is determined by settling velocity, size, relative humidity, and airflow (90).
Air-floating aerosols were found for up to 3h after release in an experimental laboratory study
(91). Mostly closed rooms with poor ventilation seem to present an additional hazard (93). It
is assumed that these droplets may travel through the air for distances up to several meters
(94,95). Respiratory droplets bigger than 5µm in diameter can spread up to 1m, whereas
Introduction
13
droplet nuclei smaller than 5µm create an aerosol with a diffusion capacity beyond 1m (96).
Given the finding that the nasal cavity and pharyngeal space of infected individuals are
containing a high virus load, oral healthcare-related professions are prone to risking infection
with SARS-CoV-2. Including medical staff in dentistry, oral and maxillofacial surgery, ear,
nose, and throat (ENT) specialists (91,97). The main viral entry points are the nose, mouth,
and eyes. Hypothetical transmission via the orofecal route has been described, too, as viral
RNA was detected in stools and anal swabs (90,96,98,99). However, a study pointed out that
no viable virus could be extracted from stool samples implicating sketchy evidence regarding
this particular transmission possibility (100). Nevertheless, there is evidence suggesting that
transmission through the ocular surface is possible (92).
Generally, virus transmission and subsequent infection are deemed to occur due to prolonged
proximity below 2m to virus carriers, after facial contact with hands that have touched
contaminated surfaces, through contact with a patient's excreta, or airborne virus particles
(8,35,91). These findings are fascinating considering the observation that people are touching
their face on an average of 23 times per hour, with over 40% of these contacts involving the
mucous membranes of the nose and mouth (101). Currently, four likely transmission paths of
SARS-CoV-2 have been described: symptomatic transmission (directly from a COVID-19
patient), pre-symptomatic transmission (directly from a SARS-CoV-2 positive person without
symptoms yet), asymptomatic transmission (directly from a SARS-CoV-2 positive person
who never actually develops symptoms) and environmental transmission (indirect
transmission, untraceable to an index patient) (102). Therefore, asymptomatic patients in the
oral healthcare setting should not be considered healthy during the COVID-19 pandemic. The
average reported incubation time, ranging from the moment of infection with SARS-CoV-2 to
disease outbreak is approximately 5.1 days (CI 95%: 4.5 - 5.8 days), and symptom onset of
infected individuals who develop symptoms is within 11.5 days (CI 95%: 8.2 - 15.6 days)
(103). Since mild symptoms and loss of taste or smell are described among the infection
symptoms with SARS-CoV-2, the identification and definition of truly asymptomatic carriers
are difficult (104–106). Accordingly, the number of unrecorded cases among the population
contributing to a reservoir for unnoticed virus transmission could be high (107,108). About
12.6% of patients have been reported to transmit SARS-CoV-2 before showing symptoms
(109). Another study found that roughly 44% of total transmissions are estimated to be
"hidden transmissions", occurring based on pre-symptomatic index patients spreading the
infection unknowingly (35). While numerous publications support the general possibility of
Introduction
14
infection transmission during incubation time, several studies report cases of asymptomatic
carriers of SARS-CoV-2 and the transmission from asymptomatic index patients to healthy
individuals (35,106,118,110–117). A study published in May 2020 in Nature Medicine
suggests that a large proportion of SARS-CoV-2 infections are due to people who do not have
symptoms themselves, which contributes to the disease's rapid progression. The study points
out that this hallmark clearly distinguishes SARS-CoV-2 from SARS-CoV-1 and MERS-
CoV, as people infected with SARS-CoV-1 or MERS-CoV were at most infectious about one
week after the onset of symptoms. In such cases, it was sufficient to isolate symptomatic
patients. SARS-CoV-2 infectivity, on the other hand, seems to be at its maximum at or just
before the onset of symptoms. Thus, isolating symptomatic individuals is considered
insufficient to limit further spread. In order to determine the viral load, throat samples from
COVID-19-positive patients were analyzed. These samples are significant because most
viruses are excreted through the throat when speaking or coughing. The samples covered a
period from day 1 of the disease to day 32, and it was found that on average, infectiousness
started at 12.3 days (95% CI, 5.9–17 days) before symptom onset and peaked at the onset,
after which the virus levels in the throat decreased steadily. This pattern was observable
regardless of age, sex, the severity of the illness, and the course of the disease (119). The
World Health Organization published a scientific brief on March 27, 2020, stating the lack of
sufficient proof regarding the airborne infection capacities of SARS-CoV-2 (120). However,
in some studies, aerosols containing RNA of SARS-CoV-2 were detected in air samples of
patients' exhaled air or the room air of patient rooms (121–123). Also, the transmission of
SARS-CoV-2 via aerosols has been suggested, and other studies pointed out that aerosols can
spread beyond the usual social distancing instructions of 1.5 to 2 meters due to aerodynamic
effects (124–126). This statement is based on the assumption that the mere presence of viral
RNA in aerosols does not account for its ability to transmit viable viruses per se. The CDC
also points out that the epidemiology of SARS-CoV-2 indicates that a major part of infections
is not spread through airborne transmission but close contact (127). As evidence suggests that
SARS-CoV-2 is transmissible by air during normal talking and breathing, to date, most
countries affected by the pandemic decided to impose precaution measures that prevent
airborne transmissions, such as, e.g., the mandatory use of face masks in public transport,
healthcare institutions, and similar policies (128). In conclusion, the transmission of SARS-
CoV-2 from human to human seems to occur most frequently through direct contact with
respiratory droplets and indirect contact with fomites. Airborne and fecal-oral transmission
Introduction
15
are considered likely, but the conclusive proof is missing yet. A study discussing 1,038 cases
of SARS-CoV-2 in Hong Kong between January 23 and April 28 used contact-tracing data to
identify all local clusters of infection (129). The study points out that merely 19 percent of
cases accounted for a remarkable 80 percent of transmissions, all of them due to social
gatherings. Another 10 percent of cases accounted for the remaining 20 percent of
transmissions - with each of these infected individuals transmitting the virus to only one other
person, perhaps two people, on average, which occurred mostly within households. Another
corollary finding is not less surprising: 70 percent of infected individuals did not pass on the
virus to anyone else. These findings hint at so-called "super spreader"-events where a few
highly contagious individuals serve as the main transmission route (129,130). Regardless of
the transmission dynamics, the viral load of symptomatic and asymptomatic carriers was
about the same (110). In August 2020, a study focusing on viral load was published in the
Lancet, which evaluated nasopharyngeal swab samples. It found that the mean log10 viral
load significantly differed between patients who were alive versus those who had died by the
end of the study period, resulting in a 7% hazard increase for each log adjusted virus amount
per ml, pointing out that high viral load and mortality are related (131).
3.4.1 Significance of SARS-CoV-2 transmission for oral healthcare
Oral healthcare professionals are working in an environment, which intrinsically contains a
particular biohazard threat. They are particularly at risk for virus transmission and contagion
(132,133). However, a recently published meta-analysis of the Cochrane Library concluded
that no studies could be found that explicitly evaluate disease transmission via aerosols in the
dental setting (134). In oral healthcare, standard procedures include face-to-face
communication, the use of sharps and electromedical tools generating aerosols through
nebulization, frequent exposure to blood, saliva, and other body fluids as well as the
occupational proximity to the oropharyngeal region of potentially infectious patients, who can
spread aerosols through coughing and talking without a face mask (75,135–140). Dental
devices such as handpieces operate with high-speed air turbines, effectively mixing water and
air as a coolant and spraying in the patient's oral cavity and creating large amounts of aerosol,
again mixing with potentially infectious tissue particles, microorganisms, blood, and saliva
(141). A study found the most considerable microbiological contamination in the dental
Introduction
16
healthcare practice to occur via splashes and aerosols in a range up to 1m from the oral cavity
(141). Oral healthcare workers (OHCWs) usually maintain proximity of 60cm or less to a
patient's oral cavity during treatment (142). Since other studies indicate that SARS-CoV-2 is
carried in salivary fluids and accumulates on the tongue's dorsum, aerosol-generating
procedures are deemed to be particularly risky (143,144). Mainly, because they contribute to
numerous dental practice procedures, HCoVs can maintain their virulence at room
temperature on surfaces from 2 hours up to 9 days and are more tenacious at 50% relative air
humidity than at 30%, however, without explicitly naming SARS-CoV-2 (137,145).
Accordingly, a dry and clean working environment decreases the persistence of SARS-CoV-2
(137). Even after completing aerosol-generating treatments, the virus can float within the air
of the treatment room for some time, with larger and heavier particles settling faster on
surfaces in the room, turning them into a hazard for transmission via indirect contact
(146,147). Another potential risk factor is implied by the time patients spend very close to
each other in the waiting room in dental offices, which could highly predispose virus
transmission (148). As discussed before, the available data strongly suggests that SARS-CoV-
2 can sustain on surfaces, although with decreasing titers and virality over time. It can remain
intact and viral for up to 4 hours on copper surfaces, up to 24 hours on cardboard, and up to 2
to 3 days on stainless steel and plastic, respectively (91,96,137). Since the minimal infectious
dose of SARS-CoV-2 has not yet been established, cross-infection from a patient to another
person or contamination of medical tools and equipment is conceivable (133). Hence, the
presumed principal infection ways in oral healthcare practice are represented by inhalation of
virus droplets and aerosol, direct contact of nasal, conjunctival, or oral tissue with contagious
patient residues indirect contact through environmental surface contamination (136,137). This
turns out to present a significant concern for dental clinics and hospitals since the procedures
generating those hazards are deeply integrated into the dentistry workflow and cannot be
easily avoided but merely reduced in daily oral healthcare practice (90,137).
3.5 Pathophysiology of severe COVID-19 infections
SARS-CoV-2 almost always attacks the throat first. It nests in the mucous membrane cells
deep in the throat and at the base of the nose. However, unlike the SARS-CoV-1, the new
Introduction
17
coronavirus often first penetrates the throat's mucosal cells to multiply (100). Subsequently,
millions of viruses break out of the mucosal cells that line the throat - often even before an
infected individuum feels sick, sometimes even unnoticed (119). When their throat scratches,
many COVID-19 patients are already at the peak of their infectiousness. The comparison with
SARS-CoV-1, in particular, shows why SARS-CoV-2 is so much more efficient: In the case
of SARS-CoV-1, humans have to cough up the viruses from the depths of the lungs and then
exhale them to be genuinely contagious. Regarding SARS-CoV-2, all that is needed for virus
transmission is a clear throat, a sneeze, or even just a breath (100,119). As the virus descends
from the nasopharyngeal region into the lungs via breathing or shedding of infected throat
tissue, COVID-19 takes its course. The virus uses the ACE2 receptor, which is usually crucial
for regulating blood pressure and water balance to gain lung cells' access. However, it seems
to slow down inflammation in the lung and prevent water accumulation that makes breathing
difficult (149). Whenever the viruses infiltrate cells, they take the ACE2 receptor into the
cell's interior, where it remains ineffective. The more virus is present in the alveoli, the fewer
receptors are found on the lung cells' surface (149). Because the presumed protective effect is
lost, some researchers believe that a vicious circle starts here: If the virus reproduces in the
lung cells, they break down, exhausted by the multiplication of the viruses (150). The immune
system is lured by the intruder and tries to neutralize it. Leucocyte cell swarms migrate from
the blood vessels into the alveoli. These leucocytes produce cytokines that attract other
immune cells, which also produce cytokines in their attempt to attract more immune cells,
respectively - a so-called "cytokine storm" flushes the human body (151,152). Macrophages
secrete enzymes in order to destroy the virus. The enzymes produced by macrophages that are
supposed to fight the viruses also destroy the cells, causing damage to unrelated and healthy
tissue. As a result, the cell walls become porous, and cell fluid enters the alveoli. Cell debris,
sugar molecules, blood cells, proteins, and fibrin stick together and form a solid mass,
impairing oxygen transmission. Thereupon, the blood-air barrier becomes increasingly
impermeable, which reduces blood oxygenation and causes lung fibrosis, edema, and
impaired regeneration. Ultimately, the alveoli collapse, which results in respiratory failure
(153). Another observation that reinforces this effect is that SARS-CoV-2 predominately
attacks type II lung cells, which produce surfactant to keep the alveoli of the lungs open
(154). When these type II lung cells perish, the alveoli face a surfactant shortage within hours
or a few days. Subsequently, they collapse under the weight of the water and the cell mass.
Eventually, entire areas of the lung can collapse, shrinking the functional area and reducing its
Introduction
18
compliance. As an Italian intensive care physician put it, an adult lung can shrink to a "baby
lung" (155). Whereas most patients' immune system is capable of fighting the virus
efficiently, with many not noticing more than only a slight shortage of breath, some
individuals suffer severe respiratory distress syndrome (RDS) and even cardiac arrest as a
consequence. Involvement of the brain stem and thus the respiratory center could also play a
role among these severe courses of COVID-19 (156). The immune reaction that SARS-CoV-2
triggers in the lung tissue causes the blood to coagulate in the pulmonary vessels: Platelets
start secreting fibrin, entangling red blood cells, and forming a blood clot. If a large clot forms
in one of the pulmonary arteries, the right heart ventricle is pumping less, and less blood gets
into the lung tissue, and therefore the oxygenation of blood decreases. If the condition
persists, such a pulmonary embolism can lead to death. If the clot detaches, it can cause a
stroke when it reaches the brain (157). The right ventricle tries to pump more blood by
increasing the stroke volume and frequency to saturate the blood with enough oxygen despite
a weakened lung. This can cause myocardial injury, which then can lead to cardiac arrhythmia
(158). Besides, the myocardium can get inflamed, so it comes as no surprise that heart attacks
were observed in COVID-19 patients (159,160). In some cases, SARS-CoV-2 seems to cause
total loss of smell in patients as one of the first symptoms, implicating a neuroinvasive
potential (156,161,162). How exactly this happens is yet unclear. Viruses such as the herpes
virus are suspected to migrate via olfactory filaments through the ethmoid bone into the
olfactory bulb into the nerve water (156). That might also be the explanation of a SARS-CoV-
2 positive young adult with a virus-negative nasal swab who showed strong neurological
anomalies. Notwithstanding the negative swab, the virus RNA later was found in his spinal
fluid, constituting the first case of meningitis/encephalitis associated with SARS-CoV-2
(163).
3.6 Symptoms of COVID-19 and differential diagnosis
Although various reports indicate that 40-80% of infected individuals could present as
asymptomatic, the most frequent symptoms and clinical conditions of patients with COVID-
19 are body temperatures beyond 37.4 °C, fever, dry cough, sore throat, muscle pain
(myalgia), shortness of breath (dyspnea), fatigue, weakness (asthenia) and headache (164–
Introduction
19
168). General respiratory problems are among the most common complaints manifesting after
a mean incubation period of about five days, ranging from 0-24 days (59,103,118,165).
Abnormal chest x-ray and computer-tomographic abnormalities such as milk-glass-like
shadows are typically found in patients with respiratory restrictions (169). About 50% of
people affected by COVID-19 complain about diminished taste sensation (dysgeusia) as well
as a total loss of taste (ageusia) and a reduced sense of smell (hyposmia), which mainly seems
to occur at a relatively early stage of the disease before hospitalization and can last even after
other symptoms mitigate (170–172). After a data analysis of 1702 people using the COVID
Symptom Tracker app developed in King's College London, 59% of patients who tested
COVID-19 positive reported loss of taste and smell, compared to only 18% of those who
tested negative. It suggests that self-reported loss of taste and smell is a decisive predicting
factor for a positive COVID-19 diagnosis, even more, substantial than self-reported fever
(173). A possible explanation might be the fact that the dorsum of the tongue hosts 96% of the
oral ACE2-positive cells (74). Additionally, a cross-sectional survey of 108 confirmed cases
of COVID-19 in Wuhan found that 46% of the reported patients stated dry mouth as one of
their symptoms, suggesting a direct impact of SARS-CoV-2 on the physiological function of
salivary glands (172). Less frequent symptoms have also been reported, such as nausea,
vomiting, and diarrhea (59). The typical predilection patient hit by a severe form of COVID-
19 is male, with a mean age of about 56 years and pre-existing chronic conditions such as
diabetes, immunosuppression, or cardiovascular impairments (132). He is comparably more
prone to develop symptoms like pneumonia or acute respiratory distress syndrome (59,169–
171). Generally, patients with specific co‐morbidities – such as hypertension, diabetes, and
ischemic heart disease – seem to be more likely to become more seriously ill after infection
with SARS-CoV-2. Changes in ACE2 due to those illnesses or appropriate medication, such
as ACE2 inhibitors or other hypertensiva, are suspected of playing a pivotal role. For
example, circulating amounts of ACE2 are increased in hypertensive and diabetic patients,
possibly contributing to a higher infection risk due to the infection mechanism described
beforehand (174). Concerning the symptoms, COVID-19 has been classified in various
progressive forms: mild, moderate, severe, and critical (175). The mild form consists of
generally mild symptoms, without any radiological signs of pneumonia. The moderate form
includes body temperatures over 37.4 °C, respiratory complaints, and pneumonia with
radiological hallmarks. The severe and critical forms are typically setting in around a week
after infection, including dyspnea and hypoxemia, which can swiftly worsen Acute
Introduction
20
Respiratory Distress Syndrome (ARDS), acidosis and septic shock. In its most harmful form,
COVID-19 can induce severe metabolic alterations, coagulation deficiency, hyper-
inflammation, arrhythmia, acute myocardial injury, acute liver injury, sepsis, multiple organ
failure, and ultimately death in patients; with however only moderate or insignificant rises in
body temperature in severe and critical progressions (62,133,167,176). The prognosis of a
severe course of COVID-19 in patients has been often linked to predictors such as age, sex,
abnormal computed tomography scans, lactic dehydrogenase, lymphocyte count, and C
reactive protein (177). About 81% of disease courses are mild to moderate, and around 14%
of patients experience clinical worsening with the development of dyspnea and hypoxemia,
typically about 7-10 days after the onset of symptoms. In about 5% of cases, there is an
indication for intensive medical therapy, mainly with the necessity for invasive respiratory
therapy due to hypoxemic respiratory failure (167). Since the symptoms of a mild onset of
COVID-19 are unspecific, differential diagnosis is essential. A broad range of infectious
diseases with similar manifestations is to be taken into account, such as, e.g., common cold
(rhinovirus), influenza, parainfluenza, adenovirus, human metapneumovirus (HmPV),
respiratory syncytial virus (RSV), Group A streptococci and Epstein-Barr-virus, as well as
non-infectious respiratory disorders, such as dermatomyositis, cryptogenic organizing
pneumonia and vasculitis (178,179).
3.7 Testing and diagnostics
The most common clinical diagnosis methods of SARS-CoV-2 are rapid antigen detection
testing based on detecting viral protein in the respiratory sample material and real-time
reverse transcription-polymerase chain reaction (rRT-PCR) for direct virus detection. The
latest generation of rapid antigen tests provides quick results on-site, typically within 20
minutes; the rRT-PCR testing method takes about 4-5 hours in a laboratory to obtain results.
Both tests usually are obtained from two simultaneous oro- and nasopharyngeal swabs (180).
If defined requirements are met, antigen tests can be a useful addition to the PCR test
capacities where an assessment of a person's infection status in the early stage of the infection
should be made quickly. Due to the lower sensitivity and specificity of antigen test strips,
antigens of viruses other than SARS-CoV-2 are also recognized, such as other human
coronaviruses, which may trigger false-positive results (181). Hence, these tests' use is only a
Introduction
21
useful supplement to other measures under certain conditions (182,183). Virus genome
detection by rRT-PCR is already possible in the pre-symptomatic phase in various patient
materials, usually about 2-3 days before to 20 days after onset of symptoms, whereas indirect
serological detection via antibodies is not recommended for acute diagnostics but only
possible and useful from day 7-10 after the onset of symptoms due to low seroconversion
rates in the early stage (4,184–188). In the early phase, smears from the upper airways are
particularly suitable as sample material (nasopharyngeal swabs or throat swabs). In later
stages, secretions from the lower airways (e.g., sputum samples) can also be used for
examination and may provide more significant results (143,172,183). Regarding the release of
patients from quarantine, the ct -value (threshold cycle) is a meaningful indicator. It
corresponds to the number of PCR cycles required until the test proves positive and is,
therefore, a measure of the virus concentration in the sample material. A ct-value >30 goes
after current knowledge with a relatively low viral load and loss of growability on a culture
medium, making it a critical threshold for the assumed patient infectiousness (180,189,190).
In most patients, seroconversion occurs in the 2nd week after the onset of symptoms
(184,191,192). Several test kits have been developed by various manufacturers that use serum
plasma or whole blood samples. They deliver results within minutes and with an accuracy of
up to 95%, such as a diagnostic rapid test kit developed by Biolidics (Singapore) and Abbott
Laboratories (USA), which received emergency approval from the US Food and Drug
Administration (FDA) for the fastest SARS-CoV-2 detecting point-of-care test (POCT) yet,
providing positive results in 5 minutes and negative results in 13 minutes (193). Concerning
the verification of a previous SARS-CoV-2 infection, various test formats (ELISA, CLIA)
with different virus antigens (recombinant S or N proteins) are available for the detection of
IgM, IgA, IgG, or total antibodies (192). According to present knowledge, serological
detection of SARS-CoV-2 specific antibodies does not allow a clear statement on the
infectivity, or immune status of a test person since the mere presence of antibodies that bind
to SARS-CoV-2 does not necessarily mean that they are capable of neutralization, or that
protective immunity is provided (181,192). How long the protective immune response against
SARS-CoV2 will last is still unknown, just as the overall duration of immunity and the
eventual possibility of reinfection still needs to be investigated, which both require
longitudinal serological studies that track patients' immunity over a more extended period
(194,195). Primary infection with SARS-CoV-2 has shown to protect rhesus macaques from
later infection, casting doubt on reports that some discharged patients showed re-positivity
Introduction
22
due to reinfection (196). In Austria, the broad establishment of testing facilities is an integral
part of a package of measures to contain the virus's spread. This approach has been
implemented since the beginning of the pandemic, and testing capacities have been expanded.
In addition to the testing of persons suspected of being infected, contact tracing plays a
decisive role in containing the virus's spread, and measures have been taken to increase the
resources for contact tracing and testing of contact persons within the provinces. Therefore,
the Austrian testing strategy is closely linked to measures recommended by the WHO, such as
compliance with hygiene and distance rules, protection of the mouth and nose, contact
tracing, and isolation (189).
3.8 Pharmacotherapy and oral health-related issues
Several now commercially available vaccinations have been filed for emergency approval by
the various national control instances since late 2020 (e.g., BioNTech/Pfizer, Moderna,
Oxford/AstraZeneca, CureVac, Sputnik V) (197,198). On December 21, 2020,
BioNTech/Pfizer's vaccine became the first COVID-19 vaccine approved across the EU
(199). In the published results of the mRNA vaccines' pivotal studies, the efficacy in
preventing symptomatic COVID-19 disease after the second dose was more than 90%
compared to placebo. The values for the BioNTech/Pfizer vaccine "BNT162b2" are similar:
The "New England Journal of Medicine" reports 95 % efficacy (200,201). As of February 28,
2021, 76 vaccine candidates are being investigated in clinical trials in humans at this time,
based on different platforms (e.g., DNA, mRNA, vector, or protein subunit vaccines).
Besides, there are 182 vaccines still in the pre-clinical or exploratory development phase
(197). In Austria, as of February 28, 2021, there currently are three different vaccines
available: BioNTech/Pfizer "BNT162b2", Moderna "mRNA-1273", and
Oxford/AstraZeneca's vector vaccine "ChAdOX1 S", which are administered according to a
scheme following a national vaccination strategy. Usually, the vaccination is provided in two
partial doses at an interval of 21-28 days (BioNTech/Pfizer, Moderna) and 28-84 days
(Oxford/AstraZeneca). How long the protection lasts after these two vaccinations and if
booster vaccinations are necessary is currently unknown (201). More than 400,000 people in
Austria (about 5% of the vaccine-eligible population) have already received a first dose (199).
Introduction
23
According to a large observational study of 1.2 million people conducted by the Israeli
Ministry of Health, the BioNTech/Pfizer vaccine prevents 89.4% of virus transmission due to
a lower viral load. Two weeks after the second dose of the vaccine, 95.8% fewer infections
were found in vaccinated people than in unvaccinated people. One week after the second
dose, efficacy was 91.9%, according to the report. Moreover, the vaccine also provided 99.2%
protection against severe disease and 98.9% protection against fatality two weeks after the
second dose (202). However, it could not be conclusively clarified whether the vaccination
can stop all transmissions or merely reduce the viral load. Besides, the study was not designed
to assess whether the infection is still possible after vaccination. Also, the study does not
allow conclusions to be drawn about the efficacy against newly emerging, more infectious
mutations, also known as Variant of Concern (VOC), e.g., South African variant B.1.351, UK
variant B.1.1.7, Brazil variant B.1.1.248. In general, however, it can be postulated that an
mRNA vaccine (e.g., BioNTech) has decisive advantages over a vector vaccine (e.g.,
AstraZeneca) since it tends to be easier to produce and can therefore also be adapted more
quickly to a mutation (203,204). In early February, Oxford/AstraZeneca revealed a pre-press
report, suggesting that one dose of their vaccine cuts virus transmission by up to 67% due to
viral load reduction. (205). To this end, the Austrian Ministry of Health, in collaboration with
the National Vaccination Commission, presented a vaccination sequence in December 2020
that provides for vaccine administration according to population group (206,207). For this
purpose, seven priority groups were created (very high, high, elevated, moderately elevated,
moderate, low elevated), depending on the risk of exposure, risk of a severe or fatal course,
and system relevance. In the general population, residents of nursing homes and homes for the
elderly and citizens over 80 years of age represent the most critical group. People with pre-
existing conditions or risk factors, such as immunodeficiency, dementia, or dialysis
dependence, fall into the "high" or "elevated" group, depending on their individual risk. With
decreasing age, the risk rating also generally decreases. Medical personnel is prioritized as a
separate group in four subgroups, depending on exposure risk and contact with vulnerable
patients. Oral healthcare professionals are classified among the medical staff with the highest
risk and intensive care staff. The classification under "moderately increased" and "moderate"
risk comprises system-relevant occupational groups outside the healthcare sector, for
example, state administration and the executive branch. After the vaccination of these sectors
is completed, the remaining population will be vaccinated (206,207). On account of the still
low global vaccination coverage, the clinical management of COVID-19 usually comprises
Introduction
24
symptomatic treatment, partially with respiratory assistance and organ support for severe
intensive care cases. Specific antiviral treatment or remedy does not exist yet. However, some
antiviral and antimalarial drugs are administered and tested in clinical trials (208). Some
experimentally or routinely used drugs in treating patients with COVID-19 can cause severe
side effects, but the benefits often offset their disadvantages. In March 2020, the World
Health Organization started a study called "Solidarity" to validate different drugs for the
potential specific treatment of severe COVID-19 complications (209). This clinical trial
includes chloroquine/hydroxychloroquine (an antimalarial and medication for various
autoimmune diseases), Remdesivir (a virostatic), combined Lopinavir, and Ritonavir
(commonly used to treat HIV), and interferon-β (a glycoprotein) (210,211). On July 03, 2020,
the European Commission granted conditional approval for Remdesivir (Veklury®). It is
indicated for COVID-19 pneumonia requiring oxygen (212). Other clinical trials, such as the
"Recovery" trial, are currently testing on additional suggested treatment options like low-dose
dexamethasone (an anti-inflammatory corticosteroid), azithromycin (a commonly used
antibiotic), tocilizumab (an anti-inflammatory), convalescent plasma (collected from donors
who have recovered from COVID-19, contains antibodies against SARS-CoV-2). On June
17, 2020, WHO published a statement concerning the cease of the hydroxychloroquine arm of
the Solidarity Trial to find an effective COVID-19 treatment due to strong evidence from
France ("Discovery" trial) and the UK ("Recovery" trial) as well as a Cochrane review. It
suggests that hydroxychloroquine does not reduce the mortality of hospitalized COVID-19
patients compared to standard treatment (209). However, it still is prescribed for medical
conditions that cause manifestations in the oral cavity, like active rheumatoid arthritis or
systemic and discoid lupus erythematosus (213). The current joint research efforts focus on
developing new drugs and implementing an existing medication, primarily anti-inflammatory,
immunomodulatory, and monoclonal antibodies, to control the immune response associated
with severe cases of COVID-19, rather than directly attacking the virus. The use of
dexamethasone has proven to be a supposedly promising option. After pre-press study results
from Oxford University as part of the "Recovery" trial, it found the corticosteroid to reduce
mortality in hospital patients severely affected by COVID-19 by up to one third (214). As a
result of intensive pharmacotherapy, some patients may suffer from oral problems related to
soft tissues, saliva production, oral neurological sensations, and other problems, even after
full recovery from COVID-19 (215). When assessing the effect and consequences of systemic
pharmacotherapy on the oral health of patients after an intensive hospital stay, it should not be
Introduction
25
underestimated that SARS-CoV-2 features neurotropic and mucosotropic abilities and may
affect the functioning of salivary glands, taste and smell sensations as well as the integrity of
the oral mucosa. These intraoral environment changes are also likely to cause oral microbiota
disbalance (77,216). Apart from the potential aggravation of existing autoimmune conditions
within the oropharyngeal area through dysregulated humoral and cellular mechanisms caused
by virus-triggered hemophagocytic lymphohistiocytosis (also referred to as "cytokine storm"),
it is worth noting that the associated therapeutic measures of severe infections with SARS-
CoV-2 are deemed to contribute to negative changes in oral health potentially. These changes
include opportunistic fungal infections, dry mouth (xerostomia) on account of a decreased
salivary flow, ulcerations, and gingivitis as a consequence of an impaired immune system or a
susceptible oral mucosa, respectively (215).
Fig. II: Administration of Remdesivir and Dexamethasone in temporal relation to respiratory support (167)
no respiratory
supportO₂ supply
high flow O₂ supply,
non-invasive ventilation
invasive ventilation ECMO
Dexamethason
Administration in case of dynamic deterioration; benefit of invasive ventilation greater than with O₂
administration or non-invasive ventilation (see: RECOVERY study)
RemdesivirEarliest possible administration when O₂ is mandatory; no administration beyond the
viral phase
Introduction
26
3.9 Epidemiology and developments
Based on data retrieved from the Johns Hopkins University (JHU) and WHO, as of December
01, 2020, there have been over 64.1 million confirmed cases of COVID-19, along with over
1.45 million confirmed deaths. The infections span across 190 countries, areas, or territories
of all continents except Antarctica. The largest infection centers with the most cases are now
occurring in the USA, followed by India, Brazil, and France. Most deaths due to COVID-19
were recorded in the USA, Brazil, India, Mexico, and the UK (69,217). From the very
beginning of the pandemic, countries around the world have been striving to "flatten the
curve" of the coronavirus pandemic, which involves reducing the number of new COVID-19
cases from one day to the next in order to prevent healthcare systems from becoming
overwhelmed and left without intensive care capacities. A meta-analysis published in August
2020 placed the number of secondary infections caused by a single infection case (also known
as baseline reproduction number R0) at 3.32, excluding single outlier studies with
significantly higher estimated values (13). This value can be interpreted that with an R0 of
about 3, at least two-thirds of all transmissions must be prevented to bring the epidemic under
control. Likewise, potential herd immunity can only be established after about 60-70% of the
population has been infected with the virus and subsequently has formed antibodies
(187,218,219). If R0 decreases below 1, the outbreak will cease itself (136,220). In
comparison, seasonal influenza epidemics have shown a median R0 of around 1.27, and
measles has a substantially higher R0, ranging from 12 to 18, making them far more
contagious than SARS-CoV-2 (221,222). The so-called infection fatality rate (IFR) strongly
depends on age. Roughly speaking, about 0.5 - 1% of overall infected individuals die (167).
According to an overview study carried out at the end of September, the IFR of SARS-CoV-2
is 0.68 (between 0.53 and 0.82). The rate is just above zero (0,04%) for children and young
adults, reaching around 0.4% for the 55-year-olds and 1.3% for the 65-year-olds. 75-year-olds
who fall ill with COVID-19, on the other hand, are already at 4.2% likeliness to die and those
being 85 years old at 14 percent, respectively (65,223–225). The European Centre estimates
the case fatality rate (CFR, of confirmed cases) in Europe for Disease Prevention and Control
(ECDC) to be 3.5% in the median, with a range from 0.6– 17.7% owing to the different
European countries and is based on the number of deaths per confirmed case (11). Increasing
age was shown to be strongly linked to increased risk of fatality, with 0% risk regarding
Introduction
27
children below ten years, about 1% over 60 years, and over 20% in the ninth decade of life
(226). As of December 01, 2020, in Austria, the current case-fatality rate is 1,1%. There have
been registered 282.456 cases of COVID-19 and 3.184 related deaths (227). Owing to these
numbers, SARS-CoV-2 is the least deadly of the three most pathogenic human coronaviruses.
It shows a lower global CFR ( ~3%) than SARS-CoV-1 (~11%) or MERS-CoV (~34%) but a
higher CFR than seasonal influenza (0.04% to 0.15%) according to data from CDC for the
2019 to 2020 season in the US (67,68,228). Nevertheless, owing to the initial case-fatality rate
in Italy of 14.4%, the potential virulence of SARS-CoV-2 has shown to be capable of
overwhelming even advanced healthcare infrastructures (229). As a matter of supporting
governments, general healthcare facilities, and medical professionals worldwide saving the
lives of infected individuals, oral healthcare provision has understandably stepped back and
halted elective dental treatments in order to protect the employees and patients from risks of
potential exposure and disease, maintain social distancing and preserve personal protective
equipment (PPE) for emergency procedures, which in many countries ran critically scarce
during the initial incline of cases (58,165,230). Over the last months of uncertainty, many
internationally renowned institutions focusing on general health and oral healthcare have
supported this approach. They have issued various continuously updated guidelines and codes
of conduct, such as the WHO, the American Dental Association (ADA), the Centers for
Disease Control and Prevention (CDC), and the Austrian Social Ministry, just to name a few
(16,231–233). A UK study conducted during the first infection wave pointed out that 1746
mostly telephone-held patient triages in the oral healthcare realm resulted in 1322 clinical
consultations, with most patients showing no symptoms of COVID-19 and symptomatic
irreversible pulpitis or apical periodontitis as the most frequent diagnoses. Interestingly, no
staff got infected through occupational exposure (234). This absence of cross infections
between OHCWs and patients has also been described in another study (235). In contrast,
after an initial flattening of the infection curve during the summer months, the current resurge
of active case numbers in the general population in Europe increases the pressure on
governments to re-evaluate their measures to contain the pandemic.
Introduction
28
3.10 Rationale and Aim of Study
Early studies focusing on the subject of COVID-19 have shown that healthcare staff is among
the most exposed and disproportionately high affected professionals regarding the spreading
of SARS-CoV-2 (90). Though there exists an increasing number of studies examining the link
between COVID-19 and oral healthcare, they often lack the most recent findings and
developments to contextualize their results due to the rapidly and ever-changing situation
worldwide. Hence, primarily owing to the period reaching from the first infection wave until
the general availability of vaccinations or remedy, the first aim of the present systematic
review is to determine which measures and steps are necessary, effective, and proportional in
order to provide the most feasible working environment in the oral healthcare realm under
such demanding circumstances. With limited clinical evidence and guidelines constantly
evolving, different aspects of partially conflicting approaches to adequate patient management
during the COVID-19-pandemic have to be taken into consideration. Based on the current
global setting and the local situation in Austria, appropriate measures for the oral healthcare
setting will be discussed. The second aim of the study is to examine the possibility of future
prediction to find out whether and how a forecast for the progression of the pandemic can be
made, taking into consideration the course of the previous virus and disease outbreaks that
may seem fit.
Materials and Methods
29
4 Materials and Methods
4.1 Research strategy
4.1.1 The general framework, information sources, and data collection process
Due to time constraints and a continually increasing number of new studies, papers, and
articles focusing on the subject of COVID-19 and oral health-related issues, the PubMed
MEDLINE online database has been chosen as a primary source of information for this
systematic review, along with the Cochrane Library database and Google Scholar. Additional
information was collected from various data sources, including government and public health
institution websites (see below), Google Search, and regional newspaper articles, while
preference was given to publications at the highest administrative level. The search strategy
was outlined using a PICO model (see 4.1.3). Automatic daily updates via E-Mail on new
results of pre-constructed and saved search terms (see 5.1.3) ensured that new findings on the
topic could be included incrementally in this review after critical appraisal. Eligibility criteria
of studies have been kept intentionally broad to check on potentially interesting key sources
of studies not directly focusing on the oral healthcare aspect. To ensure the best scientific
standards, the quality and recency of evidence were assessed for the best possible outcome.
Source papers were sought to coincide with CEBM Evidence Level 4 (Oxford Centre for
Evidence-based Medicine – Levels of Evidence, March 2009), including case series and
analysis with no sensitivity analysis. Publications based on expert opinion without any
supporting evidence were only considered for discussion. The following sources were
consulted to gain additional information on the subject through recommendations and
guidelines with the general objective to identify the best infection prevention and control
strategies: World Health Organization (WHO), American Dental Association (ADA) Centers
of Disease Control (CDC), Johns Hopkins University (JHU), Social Ministry of Austria and
Robert Koch Institute (RKI). To assess feasibility and compliance in implementing protective
measures, ten dentists of the University Clinic of Dentistry Vienna with more than five years
of clinical experience each were consulted (see 5.4.1, Fig. VII). The last date considered for
information adding to this review was December 01, 2020, except for "Pharmacotherapy and
Materials and Methods
30
oral health-related issues" (see 3.8), reflecting upon the latest vaccination strategy
developments in Austria and therefore including information until February 28, 2021.
4.1.2 Eligibility criteria
Due to this review's short-term nature, pre-press samples of studies were included in the
research process. No language or date limits were applied, including Chinese findings
(translated into English via deepl.com). Immediate exclusion criteria refer to papers providing
a mere expert opinion without stated sources or scientific backup (except for discussion) and
publications with context not referrable to the subject.
4.1.3 Search
The electronic search mainly focused on PubMed MEDLINE, conducting complex inquiries
consisting of cross-linked index terms (Medical Subject Headings [MeSH]) combined with
free-text keywords. A PICO model was used to assess the keywords for further investigation:
- Population: Papers, articles, and guidelines for oral healthcare practice during the
COVID-19 pandemic, as well as historical comparison and parallels to similar virus
pandemics
- Intervention: Gaining background knowledge on COVID-19; application of
countermeasures and therapeutic considerations in oral healthcare; outlook for oral
healthcare practice.
- Comparison: Comparison of different official guidelines, interventions, and
recommendations.
- Outcome: Feasibility, proportionality, and effectiveness of measures for transmission
risk reduction in oral healthcare practice; historical comparison and future challenges
In order to account for the different aspects of this systematic review, the conducted search
was split up into three parts with different search terms each:
1. Consequences of SARS-CoV-2 and COVID-19 for oral healthcare and clinical
routine:
Materials and Methods
31
• PubMed search term: ("Dentistry" [Mesh] OR "Oral Health" [Mesh] OR dental
OR dentistry) AND (SARS-CoV-2 OR severe acute respiratory syndrome
coronavirus 2 OR Covid-19 OR 2019-nCoV)
• 151 results (2.5.2020)
2. Prevention, (in-) effectiveness of protective countermeasures in oral healthcare:
• PubMed search term: (prevention OR avoidance OR effectiveness OR
ineffectiveness) AND (SARS-CoV-2 OR severe acute respiratory syndrome
coronavirus 2 OR Covid-19 OR 2019-nCoV) AND ("Dentistry" [Mesh] OR
"Oral Health" [Mesh] OR dental OR dentistry)
• 58 results (2.5.2020)
3. Progression forecast: Historic comparison and parallels to similar virus pandemics:
• PubMed search term: (sars-cov-2 OR severe acute respiratory syndrome
coronavirus 2 OR covid-19 OR 2019-ncov) AND (pandemic or epidemic)
AND (history OR historic OR historical OR comparison OR parallels OR
forecast OR outlook OR prediction) AND (guidelines OR advice OR
recommendations)
• 69 results (2.5.2020)
4.1.4 Study selection
All results of the conducted searches were manually screened to comply with one or more of
the following criteria: A reference on oral health or dentistry; a clear thematic link between
COVID-19 and (oral) healthcare provision; a general focus on the management of the
COVID-19 pandemic or historical comparison of the COVID-19 pandemic to prior virus
outbreaks. During the first search, 278 papers were obtained. The abstracts were reviewed to
identify the papers for which then the full texts were obtained. After applying immediate
inclusion and exclusion criteria, 67 papers remained and were analyzed subsequently. After a
further refined selection, 35 initial articles were obtained finally, which is visualized in the
PRISMA (preferred reporting items for systematic reviews and meta-analyses) flowchart of
study inclusions and exclusions on the next page (Figure II).
Materials and Methods
32
Fig. III: PRISMA flowchart of study inclusions and exclusions
Iden
tific
atio
n Sc
reen
ing
Elig
ibili
ty
Incl
usio
n
• Sources: PubMed, Google Scholar, Cochrane Library, ADA, CDC, JHU, RKI, WHO
• Search terms for PubMed MEDLINE: see 4.1.3
• Publication date: up to 30.11.2020
• Languages: no restriction
278 search results after the first PubMed search on 2.5.2020
• Abstract assessment for eligibility with adequate information
• Application of immediate inclusion and exclusion criteria
• 67 remaining results after first PubMed search
Full text assessment for refined selection and contextual relevance
• 35 final results after first PubMed search
• 425 overall findings up to December 1, 2021
Filtered after first search: 32 results
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33
5 Results
5.1 Recommendations for oral healthcare provision during the COVID-19
pandemic
Despite the widespread transmission of SARS-CoV-2 in the Chinese population and shutting
down oral health-related services to a necessary minimum during the first infection wave, the
demand for urgent dental treatment decreased by only 38% (236). It suggests that dental
emergency services are vital for the community, and the need for urgent dental care within the
population will always be of major concern even during the current pandemic, which,
however, also puts a heavy strain on critical healthcare supply such as PPE (237). In many
countries, a further challenge of logistical nature during the first incline of infections was
avoiding clogged hospital emergency rooms already overloaded with COVID-19 patients or
other emergencies. The consideration was to differentiate between minor dental trauma,
patients with severe dental pain who require drug prescription or similar ambulatory dental
problems, and potentially life-threatening oral health emergencies. The latter comprises head
and neck fascial space infection, facial trauma that may compromise the airway, and
uncontrollable oral tissue bleeding, which have to be referred to oral and maxillofacial
surgery (58,238). This is why institutions like, e.g., the CDC, ADA, and WHO have
developed continuously updated guidelines for dental emergencies and urgent non-emergency
dental procedures, aiming to prevent infections and minimize pain or indisposition.
Postponing elective procedures under certain circumstances is a key recommendation of these
guidelines. Hence, different procedures of urgent dental care got clarified in detail, including
severe dental pain, trauma on account of a fractured, symptomatic tooth, avulsion or luxation
as well as post-operative osteitis, various infections like pericoronitis, dry socket, abscess and
cellulitis, and other urgent restorative procedures (see Figure III) (238,239). When most
dental clinics were closed obliging to official government recommendations, the University of
Rochester Eastman Institute for Oral Health, a US dental clinic that is open seven days a
week, provided a good illustration of how dental clinics offering urgent dental care can help
to ease the burden on the emergency medical sector. It was found that approximately 96% of
patients showing up had moderate to severe pain associated with pulpal or periapical
inflammation, dentoalveolar infections, and trauma. Additionally, research in the conduction
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on teledentistry showed significant benefits for optimizing patient referral and reduced patient
flow (58,240). Since many patients required stronger medication than over-the-counter
analgesics or antibiotics in addition to curative treatment like root channel treatment or
extraction per se, these patients would have most likely contacted the emergency hospital
clinic otherwise, which would have placed additional pressure on the health system (58).
Initially, some state health departments had felt compelled to impose rigorous conditions on
the dental treatment of emergency patients during the current pandemic, such as PPE not
generally available at that time or negative-pressure isolation rooms with high-efficiency
particulate air (HEPA) filtration (16). It became difficult for many dental clinics to comply
with these strict regulations. As a result, many regulations were relaxed or lifted over time,
such as the recommendation to wait 15 minutes before cleaning and disinfecting room
surfaces after completion of clinical care and exit of each patient without suspected or
confirmed COVID-19 (239). After a period of waiting and observing, in which dentists were
called to postpone elective dental treatments and only provide emergency support, institutions
like the ADA and the dental association in Austria and Germany have published a mid-May
statement. It finds that recent studies from China, South Korea, and Italy do not provide any
conclusions on increased infection risks for staff in dental offices (232,241,242). The German
Dental Association (BZAEK) also finds that politically backed restrictions on dental treatment
prohibiting the practice of dentistry, oral and maxillofacial surgery except for emergency
treatment, are not proportionate. The resulting interference with the fundamental freedoms of
the dentists concerned is not justified and, at the same time, the provision of oral healthcare to
the public is jeopardized if the freedom to exercise oral healthcare is at stake (241). The
Austrian Chamber of Dentists (ÖZÄK) agrees with this assessment. It finds that the final
decision of whether these recommendations are implemented remains with the dentist in the
sense of freelance work. Increased numbers of infections were found above all in the general
medical field, ENT, and ophthalmology. However, according to international and national
findings on the spread of COVID-19, there is currently no conclusive evidence that oral
healthcare teams are subject to increased infection rates, nor that dental treatments have
contributed to an increased spread of infection in the population (241). Based on the
information currently available, the conspicuous low infection rate in the oral health sector is
attributed to the consistent implementation of classical protective measures and generally high
hygienic standards (242). As for the current period of this writing, with resurging infection
numbers after the first infection wave, the ÖZÄK released a continuously updated summary
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of general recommendations closely linked to the official recommendations of the RKI (242).
Accordingly, as far as appointments, reception, and waiting room management are concerned,
every patient should be checked for common COVID-19 symptoms of the past two weeks by
telephone or E-mail before the visit and again when entering the premises. These symptoms
include fever, cough, shortness of breath, as well as taste and smell disturbances. In this case,
patients should be informed not to go to the practice or a hospital independently but to call an
official government hotline for medical assistance. If the patient visits a practice, the
physician should advise the patient to leave the practice immediately and arrange for help via
the hotline provided. Appointments should only be made by telephone or E-mail and after
strict time management to avoid crowded waiting rooms. Information about mask obligation
in the practice area should be available. Treatment planning should be designed to maintain
the distance between patients in the reception and waiting area. If possible, distance markings
should be applied. Congestion in the stairwell or aisle area can be avoided if patients are
encouraged to go for a walk or wait in public places at a sufficient distance, where they can be
contacted by telephone as a substitute for calling them personally in the waiting room. The
number of people waiting should be limited as far as possible so that a reasonable distance
can be kept. Persons accompanying adult patients should wait outside the practice, and
patients should be encouraged to touch as few surfaces as possible, including door handles,
for example. Any physical greeting should be avoided, and patients should be advised to keep
their hands clean and disinfected after entering and before leaving the practice. Reception
areas can be separated and protected by an impermeable partition. Surgery and practice rooms
are supposed to be ventilated regularly, and all door handles and publicly accessible buttons
should be disinfected regularly. Patients should also be encouraged to stick to the public
cough and sneeze etiquette, which means that they should turn away when coughing or
sneezing or use a disposable handkerchief or the crook of their arm instead of their palms.
Considering the treatment of patients without symptoms, according to RKI and ÖZÄK, the
transmission of viruses can be prevented in inconspicuous, symptom-free patients by adhering
to the standard hygiene measures (242,243). In the oral healthcare practice, the usual standard
hygiene measures are considered sufficient, consisting of wearing mouth-nose protection and
gloves and performing adequate hand hygiene with the correct application of surgical hand
disinfection, if necessary. These findings, however, are taking into consideration that the
usual exposure time in these facilities is rather short. Wearing mouth-nose protection and
protective goggles reduces the risk of infection from aerosols, blood, and saliva splashes. In
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other words - the standard hygiene regulations in dental surgeries are considered to be
sufficient by the RKI for standard treatment of patients without symptoms, which makes
protective shields, protective gowns, surgical hoods, and respiratory masks not strictly
necessary for patients without symptoms of COVID-19. Since the RKI meanwhile officially
recognized the spread via aerosols, the correct aspiration technique must be strictly observed
to avoid the formation of aerosols as far as possible (14). Accordingly, the indication for the
use of ultrasonic handpieces, powder jet devices (e.g., "Air-Flow"), and air-driven turbines
must be considered as limited (242). Antiseptic mouthwashes can help to minimize the
transmission of infection. However, according to current recommendations, 1% H2O2 solution
is more effective against the current virus than the gold standard chlorhexidine (90,137). The
treatment of patients who are demonstrably infected with SARS-CoV-2 or who are reasonably
suspected to be infected (contact with infected persons, symptoms typical of COVID-19 like
fever or coughing) should generally be postponed until after the end of the disease unless it is
an emergency. These patients are to be referred to further medical assistance via the
government hotline to secure the diagnosis and, if necessary, initiate therapy (242). The risk is
currently estimated to be very high for risk groups and to vary from region to region. With
increasing age and pre-existing conditions, the probability of severe disease progression of
COVID-19 increases. The taking of medical history is therefore vital to limit the risk of
infection. According to current recommendations, this is why and to avoid contact in the
waiting room or practice, any form of treatment for risk groups like multimorbid patients,
elderly seniors, immunocompromised patients, or patients with other severe health problems
should be reduced to an absolute minimum. Concerning employee management, the following
recommendations currently apply in Austria: During breaks in treatment, the recommended
minimum distances between employees should be observed, and at least a mouth-and-nose
protection should be worn when talking to each other as well as during daily work. Team
meetings should be held regularly so that necessary measures and routines can be discussed,
questions clarified, and adjustments made if necessary. (242,244,245).
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Classification Exemplary procedures Management
Dental emergency
Uncontrolled bleeding • Cellulitis or a diffuse soft-tissue bacterial infection with intra-oral or extra-oral swelling that potentially compromises the patient's airway • Trauma involving facial bones, potentially
compromising the patient's airway
Refer to oral and maxillofacial surgery
Urgent dental interventions
to relieve pain
Severe dental pain from pulpal inflammation • Pericoronitis
or third-molar pain • Surgical post-operative osteitis, dry socket dressing changes • Abscess or localized bacterial infection resulting in localized pain and swelling • Tooth fracture resulting in pain or causing soft tissue trauma •
Dental trauma with avulsion/luxation • Dental treatment required before critical medical procedures • Final crown/bridge cementation if the temporary restoration is
lost, broken or causing gingival irritation • Biopsy of abnormal tissue
Primary management: Local anesthetic, pain
management (nonopioid medication, NSAID), antibiotics, endodontic therapy, vital pulp therapy, incision and drainage, replantation of the tooth
Secondary management: Refer to oral and maxillofacial surgery only in case of complications
Other urgent
dental interventions
Extensive dental caries or defective restorations causing
pain • Management with interim restorative techniques if possible (silver diamine fluoride, glass ionomers) • Suture removal • Denture adjustment on radiation/oncology
patients • Denture adjustments or repairs when function impeded • Replacing temporary filling on endo access openings in patients experiencing pain • Snipping or adjustment of an orthodontic wire or appliances piercing or
ulcerating the oral mucosa
Refer to oral and maxillofacial surgery only in case
of complications
Fig. IV: Procedures that may constitute dental emergencies and urgent interventions. Summarized according to ADA "What constitutes a dental emergency?" (238) and "Coronavirus Disease 19 (COVID-19): Implications for Clinical Dental Care" (132).
5.2 Standard infection control in oral healthcare regardless of COVID-19
Even though studies were able to show that awareness and attitudes about infection control
are present in oral healthcare practice, there are low levels of implementation regarding the
same. However, some findings suggest that compliance is possible both in medium and large
practices (246–253). In oral healthcare practice, infection control is all about weighing up
potential risks, as it is not possible to completely rule out the danger of transmission of
airborne infectious diseases, both for the patient and dental team (254). The main objective of
past infection transmission guidelines in dental practice was to avoid blood-borne diseases
(255). Not least due to the spread of SARS-CoV-2 but also because of diseases like hepatitis
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B, measles, and tuberculosis transmittable via aerosol and saliva, new findings on the
spreading via aerosol have come into focus, mainly because dental practices have a large
number of aerosol-generating procedures, established as a part of most treatments (256–258).
However, the oral healthcare setting's aerosol precaution measures are generally less strict
than other healthcare environments since patients are generally considered healthy (259). As a
result, dentistry has always been carried out so that even current guidelines in dental practice
tend to advocate optimal and feasible rather than maximum precautions (142).
5.3 Measures for infection control of SARS-CoV-2 in oral healthcare
The findings discussed under 6.1 confirm that, against previous concerns, the oral healthcare
working environment is not exceptionally prone to the transmission of SARS-CoV-2.
Nevertheless, there is understandable uncertainty among oral healthcare professionals about
the high potential transmissibility and the continuous exposure to patients that might be
contagious without even knowing themselves (260). This assumption that all patients may be
possibly SARS-CoV-2 positive although yet asymptomatic, combined with the fact that
transmission via aerosols is possible, has become somewhat of a starting point for the
development of further and necessary measures worldwide. As discussed before, a substantial
number of individuals with only mild or even no symptoms at all could present the primary
source for the majority of reported cases, also referred to as "super spreaders", and thus could
jeopardize oral healthcare teams to become vectors as well (19,50). On the other hand,
dentists and oral healthcare workers are deemed to contribute to avoiding the health system's
collapse by flattening the epidemic curve through preventive measures (261). Accordingly,
during the first wave of infection, dentists and oral healthcare professionals in many places
only offered emergency care, following the recommended protocols to control cross-infection.
Hence, much of the research published to date has focused on providing an overview of the
recommended cross-infection guidelines (165). The National Institute for Occupational
Safety and Health (NIOSH) in the United States, which investigates safety at work to make
recommendations in this respect, found that measures are generally more effective if they
intervene closer to the virus source than medical staff (142). With not only regard to the oral
healthcare setting, but all healthcare professionals, including dentists, these general measures
and recommendations, for example, include daily monitoring of the temperature and regular
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testing of staff, use of PPE consisting of N95 / FFP2 or N95 / FFP3 masks, gloves, gown or
coverall, face shield, head cover, and rubber boots. Additionally, the implementation of
various communication technologies to keep contact with patients is considered crucial, as
well as social distancing, mobility restriction, diagnostic tests, and isolation of infected
individuals, just to name a few (230,232,243,262–268). These and other approaches to
systematic infection control of SARS-CoV-2 in the existing code of conduct in the oral
healthcare setting and possible adjustments to protect oral healthcare professionals and the
population they serve will be discussed henceforth. The specific treatment recommendation in
different publications can be subsumed in three major approaches, all of whom should be
considered. The first and second approach measures focus on eliminating direct and indirect
transmission possibilities of SARS-CoV-2, respectively, whereas the third approach targets
structural changes in how appointments and treatments are organized. The individual aspects
of these complementary approaches are explained in more detail below.
5.3.1 Approach 1: Elimination of indirect transmission possibilities of SARS-CoV-2
Hand hygiene
After the spread of SARS-CoV in 2003, hand hygiene was the single most important
preventive countermeasure (269). In its current recommendations, the RKI suggests the
consistent implementation of basic hygiene, including hand hygiene, in all areas of healthcare
(243). Since the fecal-oral transmission of SARS-CoV-2 is considered to be a possible hazard,
the importance of hand hygiene for oral healthcare practice is of particular importance and
partially even considered to be the most critical measure for reducing the risk of
microorganism transmission to patients (185,270,271) This means that oral healthcare
professionals should avoid touching their own eyes, mouth, and nose during treatment and
before disinfection. Although adequate hand hygiene is considered a treatment prerequisite,
handwashing compliance is relatively low, making infection control a significant challenge
(272). Improving towards adequate hand hygiene is of utmost importance at this point. To
increase handwashing compliance, the WHO issued a "My five moments of hand hygiene"
protocol. In particular, oral healthcare professionals should wash their hands before
examining the patient, before performing procedures, after touching the patient, after touching
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the environment and potentially contagious equipment, after touching the oral mucosa,
damaged skin or wounds, and after contact with blood, body fluids, secretions and excretions
(90,273). Hand disinfection should be carried out with a disinfectant with proven, at least
limited virucidal effectiveness after taking off the gloves and before leaving the room (243).
Environmental sanitation
The WHO recommends that after every patient treatment in the oral healthcare context of
COVID-19, one cycle of standard cleaning and disinfection according to the standard
operating procedures (SOPs) of the entire treatment area (environmental surfaces) is carried
out, with particular attention to high-use surfaces (274). Accordingly, the regular cleaning and
disinfection of door handles, chairs, reception desks, and phones is imperative as well (231).
Various active substances are biocides concerning human coronaviruses. The ECDC advises
using neutral soap or 70% alcohol for surfaces (275). It was shown how different substances
diminish the infectivity of SARS-CoV-2 by about 4 log10 or more, including ethanol (75%-
95%), 2 -propanol (70% - 100%), the combination of 45% 2-propanol with 30% 1 - propanol,
glutardialdehyde (0.5%-2.5%), formaldehyde (0.7% - 1%) and povidone-iodine (0.23% -
7.5%). Sodium hypochlorite required a minimum concentration of at least 0.21% to be
effective against SARS-CoV-2. On the other hand, hydrogen peroxide was only effective after
one minute at a concentration of 0.5% (137). A significant result is the ineffectiveness of
chlorhexidine against SARS-CoV-2: within 10 min, a concentration of 0.2%, common in
many places and used in regular dental practice, shows no effectiveness against the virus
(276). The virus usually persists on surfaces for a few hours but can last up to several days,
depending on the surface type, temperature, and humidity of the environment, which can best
be avoided by disinfecting surfaces with 0.1% sodium hypochlorite or 62% - 71% ethanol for
at least one minute (137,274,275). The WHO recommends using 70% ethanol for disinfecting
small surface areas and reusable equipment between treatments and equipment sensitive to
chlorine. A solution with 0.1% (1000 ppm) or 0.5% (5000 ppm) sodium hypochlorite is
recommended for surface disinfection or disinfection of large blood or body fluid spills,
respectively (231). It has also been reported that SARS-CoV-2 can be inactivated by
peroxyacetic acid or chloroform and is sensitive to ultraviolet radiation and heat, with
temperatures above 56 degrees Celsius for at least 30 minutes being sufficient (277).
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All medical devices with direct contact with the patient must be used for the related patient
only and must be disinfected after use. Mechanical cleaning with automated washer-
disinfectors is highly recommended in order to avoid contamination through splashing in the
manual cleaning process. If transported in a closed, externally disinfected container, central
reprocessing is possible. Thermal disinfection procedures should be preferred whenever
possible. If this is not possible, disinfectants with proven, at least limited virucidal efficacy
should be used (137,243).
Medical waste
Medical waste, including disposable protective equipment, should be transported as soon as
possible after use from the treatment area to an intermediate storage area. Reusable
instruments and items should be collected instantly after use, pre-treated, cleaned, sterilized,
and stored correctly following the protocol for disinfection and sterilization of dental
instruments (278). Medical and domestic waste from patients with a suspected or confirmed
infection with SARS-CoV-2 should be considered as generally infectious medical waste.
About 15% of healthcare waste generated in patients' oral healthcare is considered hazardous,
may pose health and environmental risks, and should therefore be safely collected in marked,
lined containers and sharp, safe boxes. Special double-layer bin liners should be used for this
purpose, the surface of which should be marked and which must be disposed of in accordance
with the requirements for the disposal of infectious medical waste (90,279).
Anti-retraction handpiece
The air and water hoses of the dental unit create an optimal spreading climate for microbes
such as viruses and bacteria, contaminating the dental unit and thus possibly cause cross-
infection. In this constellation, high-speed dental handpieces without anti-retraction valves,
which expel and suck in foreign bodies and liquids during dental procedures, are problematic.
A study showed that anti-retraction high-speed handpieces could significantly reduce the
absorption and spread of bacteria and hepatitis viruses compared to conventional handpieces
(280). Therefore, the use of these handpieces without anti-retraction function should be
avoided during the current pandemic. This measure is also considered to be useful to avoid
other cross-infections unrelated to COVID-19 (269).
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5.3.2 Approach 2: Elimination of direct transmission possibilities
Preprocedural mouth rinse
To reduce exposure to oral microbes in the saliva, including the possible transmission of
SARS-CoV-2, a pre-procedural mouthwash containing oxidizing agents such as hydrogen
peroxide (H2O2), Cetylpyridinium chloride (CPC), or povidone-iodine (PVP-I) for at least 20
seconds is recommended to safely neutralize the virus, which is susceptible to oxidation
(90,137,231,281–283). Previous studies have shown that SARS-CoV and MERS-CoV were
both highly susceptible to povidone in mouthwash solutions and that povidone-iodine is
suitable for both oral and nasal disinfection of SARS-CoV-2 (281,284–286). This pre-
procedural mouthwash is beneficial when a rubber dam cannot be used (90). Chlorhexidine,
however, which is widely used in dentistry, has in vitro been shown to be ineffective for
reliable deactivation of SARS-CoV-2, albeit showing virostatic tendencies (137,287).
Several in silico studies suggest antiviral effects of essential oils against SARS-CoV-2.
However, neither in vitro nor in vivo studies have been published concerning their antiviral
effects so far (283). Ethanol has been shown to inactivate enveloped viruses within 30
seconds completely and partially inactivate them at 15s above 70% concentration (288).
However, the effect of the ordinary and less toxic concentration of 14-27% in standard mouth
rinsing solutions has not been sufficiently researched (283). In summary, gentle gargling of
the oral cavity and throat for at least 30 seconds has been recommended with either H2O2 1.5-
3%; PVP-I, 0.2-0.5%; or 0.05% CPC (279,287–293). However, as of December 2020, there
are too few in vivo, in vitro, and in silico studies to recommend specific mouth rinses for
intraoral viral load containment.
Rubber dam
Especially in situations where high-speed handpieces and dental ultrasound equipment are
commonly used, the use of a rubber dam can significantly minimize saliva production, blood,
and contaminated aerosols or splashes (286,294,295). For example, using a rubber dam can
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reduce airborne particles in the radius of about 1m around the mouth by 70%. In addition to
the regular suction, an extra-large and high volume suction can be used for aerosol and
splashes to reduce the droplet load further (231,269,295). If rubber dam isolation is not
possible in some instances, manual caries removal and periodontal debridement using a hand
scaler or curette are recommended to reduce aerosol generation as much as possible (90).
Avoidance of retching and coughing
Where possible, procedures that cause gagging or coughing should be avoided altogether.
Accordingly, panoramic radiography or cone-beam computed tomographic imaging should be
preferred over intraoral radiography, if possible. Intraoral sensors should be double-shielded
as well to prevent perforation and cross infection (296,297).
Personal protective equipment for oral healthcare workers
Owing to the last similar SARS-CoV outbreak with vast numbers of acquired infections
among medical professionals, the physical separation of OHCWs and hazard through isolation
or protective gear is of crucial importance (298). Since airborne droplet infection is the main
path of propagating SARS-CoV-2, barrier protection equipment is recommended, especially
in dental clinics and hospitals. In the dental clinic setting, this includes protective goggles,
respiratory masks, gloves, caps, face shields, and protective clothing for particularly high-risk
procedures, the use of which is strongly recommended to all medical staff in the clinical
environment (16,58,90,231,232,243). These measures can be subdivided into three levels of
PPE intervention with distinct features: The primary or standard protection recommended to
all staff in the clinical environment of oral healthcare includes a working cap, disposable
surgical mask, and a regular working outfit (e.g., a white coat), as well as protective goggles
or face shield, and disposable latex or nitrile gloves. The secondary protection marks
advanced protection for dental professionals. It includes the same measures for primary
protection, adding a disposable isolation clothing or surgical clothing layer. The tertiary
protection is meant to provide an additional safety layer for the unlikely event when contact
with patients infected with SARS-CoV-2 is likely or inevitable, adding a second pair of
gloves, protective disposable outerwear layer like isolation clothing, gown, and shoe covers
(58,90,245,299). Owing to PPE and gown use, a current Cochrane review suggests that
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"covering more of the body" results in "better protection". However, it also found insufficient
evidence in the presumption that covering body parts with additional layers automatically
leads to enhanced protection but rather causes less user comfort since donning and doffing
becomes more difficult. Still, it concluded that gowns provide better protection than just an
apron (300). Still, the "CDC donning and doffing guidance" suggests double-gloving, glove
disinfection, and one-step glove and gown removal to increase compliance and reduce
contamination (268,299,300). A suggested sequence for advanced PPE donning is the
following: Disposable shoe cover; followed by a non-valved respirator; surgical headgear; eye
protection; hand sanitization; first pair of gloves; disposable gown; and finally, the second
pair of gloves. Likewise, a suggested sequence for doffing is: Hand sanitization (still with
gloves on); shoe cover, gown, and glove removal; removal of primary gloves; hand
sanitization; removal of headgear, eye protection, and respirator; final hand sanitization (301).
The SARS-CoV-1 outbreak in 2003 showed the importance of proper donning and doffing
when a substantial number of healthcare professionals got infected due to inefficient use of
PPE (269,302,303). As one of the essential protective measures, respiratory masks are subject
to the EU regulation DIN EN 149:2009-08 on personal protective equipment concerning the
basic health protection and safety requirements (304). Referred to as "filtering facepieces",
they are commonly classified as FFP1, FFP2, and FFP3, accounting for their filtering and face
adhesion abilities as well as leakage, skin compatibility, flammability, and respiratory
resistance. (305–307). The leakage of a mask comprises the leakage points on the face, the
leakage at the optional exhalation valve, and the actual filter passage. FFP1 masks may have a
total leakage of no more than 25%, FFP2 masks no more than 11%, and FFP3 masks no more
than 5%. Minimum respective filtration efficiencies are 80%, 94%, and 99% for particle
diameter ranging up to 0.6 µm (304). N95 masks can filter as much as 99.8% of particles with
a diameter of up to 0.1 µm, including SARS-CoV-2 around 0.12 µm (65,308). In the US,
respiratory devices have been classified by the NIOSH, which separates "filtering facepiece
respirators" (FFRs) into nine categories: N95, N99, N100, P95, P99, P100, R95, R99, and
R100 (309). For practical use, it is worth mentioning that FFP2 masks are comparable to an
N95 FFR mask (310). Authenticated masks of either FFP2 or N95 standard are recommended
for general oral healthcare practice during the pandemic (296). Since respiratory masks' filter
capacity decreases over time, they should be replaced accordingly (311). The mask must be
placed correctly over the mouth, nose, and cheeks and be as close to the edges as possible to
minimize air ingress at the sides. Like a surgical mask (SM), conventional mouth-nose
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protection is not equal to a respirator mask and, depending on the type and position, has a
higher leakage, comparable to FFP1 masks. Their principal limitation is due to poor face fit
and the inherent possibility of aerosol aspiration. SMs can filter particles of 0.04 –1.3 µm,
making them suitable for shielding infectious droplets from the release into the environment
and protecting the wearer from macroscopic droplets from the patient's sputum. Vice versa,
they are protecting patients from saliva and respiratory secretion produced by healthcare
workers. SMs are also considered effective protection against contact of mouth and nose with
contaminated hands (133,312). To reduce breathing resistance, respirators are also available
with an exhalation valve, most commonly for FFP3/N99. Although these masks protect the
wearer, they do not protect the people around from potentially contagious exhaled air of an
asymptomatic individuum, thus making them the second choice for medical use and
especially inappropriate for dentistry oral healthcare. Hence, they should not be used by
infectious patients or in the care of patients at risk of infection. Instead, non-valved respirators
should be preferred. As in general medical practice, patients should wear at least one
conventional mouth-nose protection, reducing the amount of aerosol released. It can also warn
patients and staff to think about infection-preventing measures (312). On the other hand,
masks can create a false sense of security, leading to becoming neglectful towards other
essential routines such as hand hygiene. It was also shown that masks used by the virus
receiver achieve lower protection levels than when used by the virus source (307,313). The
patient's mouth-nose protection can be used as long as its functionality is not impaired, e.g.,
due to moisture penetration. However, it should be disposed of as infectious waste when it is
taken off. More elaborate and complex mask systems (FFP2, FFP3) for staff are justified
where either exposure to a patient's cough cannot be avoided, as well as in the case of
prolonged and close contact with the patient during the physical examination, where a high
aerosol concentration must be assumed (312). Since these conditions are met in most dental
practices, it comes as no surprise that also the RKI states that at least FFP2 masks must be
worn following occupational safety regulations when directly treating patients with confirmed
or probable COVID-19 (243). Similarly, the WHO states that during aerosol-generating
procedures such as tracheal intubation, manual ventilation before intubation, non-invasive
ventilation, tracheotomy, cardiopulmonary resuscitation, and bronchoscopy, a mask of at least
FFP2 or N95 standard should be worn. However, there is no explicit mention of dentistry and
oral healthcare (307). Nevertheless, it has been proven that dental drills are subject to
producing aerosols; regular drills mainly cause splatter and little aerosol contaminated with
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bacteria, fungi, blood, and viruses, whereas oral surgery drills have been shown to cause more
aerosol (314–316). As there has already been a mask shortage in the past, strategies have been
developed for a more resource-efficient use of masks and other PPE to ensure regular supply
in healthcare facilities (311). The reprocessing of breathing masks plays a central role in this
process, although this procedure's necessity was again advised against, as there is currently no
supply bottleneck (317,318). According to the CDC, respiratory equipment should be
preferred over face masks as long as they are available. However, their use should be
prioritized for patients where respiratory protection is most important due to specific airborne
pathogens like, e.g., tuberculosis, varicella, and measles (319). In its current interim guidance,
The WHO stated that face shields might be considered an alternative to medical masks in case
of a severe deficiency. However, based on the available evidence, the use of non-medical
masks or fabric masks as an alternative to medical masks is not considered adequate to protect
healthcare workers (230).
Negative air pressure room and ventilation
For excessively aerosol-generating procedures, the advantages of a negative air pressure
room, preferably with HEPA filtration, have been discussed (231). This intervention's idea is
that potentially contaminated air of the treatment room is removed and exhausted through
ventilation while clean air can enter. Although most dental clinics do not feature equipment
alike and the minimum amount of infectious virus particles in room air and the sheer
possibility to generate this amount of aerosol through dental drills are still subject to
investigations, working in such an environment can be advantageous, even though hardly
feasible. In any case, it is helpful to know about the nearest clinic or hospital with a negative
pressure room in case of inevitable treatment of COVID-19-positive patients (16,320). A
considerable reduction and dilution of the virus load can already be achieved by manual,
active ventilation of the rooms, for example, by opening windows (231,296,321). Mechanical
ventilation is helpful and regarded as a complementary measure to support active manual
ventilation. A constant exchange of air in one direction, i.e., a draught, is useful to reduce the
potential virus load in the room air (322).
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5.3.3 Approach 3: Administrative intervention: Altering organizational patterns
The main focus of administrative intervention against transmission and spread of SARS-CoV-
2 is to avoid patient contact where it is not absolutely necessary. For example, physical
barriers like transparent partitions can be imagined at the reception desk for scheduling
appointments. The dental clinic's internal structure should also be assessed and, if necessary,
redesigned to ensure a safe distance at all times, especially in the waiting area (142). Triage at
the entrance area should be used to identify and adequately treat patients with a low risk of
transmission, and at least 1m distance should be maintained at all times between the staff
performing it (231,237,276,323,324). Staff should, however, bear in mind that triage relying
on temperature measurement is unable to distinguish asymptomatic or pre-symptomatic
patients from non-affected individuals. For patients showing signs and symptoms of COVID-
19, oral healthcare should be limited to emergency care, which should only be provided in a
clinic with extended protective measures (16,142,231). The ADA listed some practice-
oriented interim guidance recommendations regarding patient interaction before, during, and
after appointments (232). Before appointments, oral healthcare staff should try to reach out to
patients by telephone and ask questions about their current health status. These questions
should be repeated when patients arrive. For example, in the form of written confirmation to
ensure that nothing has changed in the meantime. Besides, patients' temperature should be
measured before entering the treatment rooms in times of unclear infection conditions.
Infrared cameras or non-contact forehead thermometers have proven to be useful for this
purpose (90). Wearing mouth-nose-masks should be obligatory on arrival at the dental surgery
or dental clinic, and patients should be encouraged to bring their own masks. The number of
people who bring patients to their appointment should be limited to avoid cross-infections and
maintain the widely recommended distance of at least 1m between individuals (325,326).
Older children should come to the treatment room alone if possible, and younger children
should wait at home under appropriate supervision when their parents attend a dental
appointment. During treatment, patients should be asked to wait outside until the dental team
is ready. As the mouth-nose-mask must logically be removed during oral treatment, this
simple measure is designed to reduce the number of people in the potentially infectious area
around the treatment room. During breaks in treatment, the recommended minimum distances
between employees should be observed at all times, and any physical greeting should be
avoided (245). In the surgery and waiting room, toys or magazines should be removed to
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avoid indirect virus transmission. Also, hand disinfectants should be available for patients.
Staff should wipe off after each treatment any objects that patients are prone to touch, such as
pens, clipboards, or furniture. The computer keyboard should be provided with a disposable
cover to be easily cleaned between patients. Depending on the supply situation, it is also
conceivable to exchange PPE between treatment appointments (232). Immunocompromised
patients or patients with severe systemic comorbidities are considered particularly at risk and
should be scheduled for an empty waiting room at the end of the day (327). At the end of
treatment, staff should thoroughly clean the areas where patients have been, using
disinfectants effective against SARS-CoV-2 (232).
5.3.3.1 Patient assessment
Teledentistry
Teledentistry is the use of information technology and telecommunications to provide remote
oral healthcare support. It can be used, e.g., for consultations between clinicians, real-time
face-to-face video conferencing between practitioners and patients, or remote monitoring
(328). In its "Considerations for the provision of essential oral health services in the context of
COVID-19", the WHO states that before their appointments, patients should be screened
either by virtual/remote technology or telephone (231). Equally, in its "Interim Infection
Prevention and Control Guidance for Dental Settings During the COVID-19 Response", the
CDC, too, states that all patients should be screened via telephone for symptoms hinting at
COVID-19. Non-emergent dental treatment should be avoided if the patient reports symptoms
and should be delayed until the patient has recovered. Those in need of urgent dental
treatments are subject to telephone triage, which assesses the patient's oral health condition
and determines whether there are options for in-office treatment. Accordingly, clinicians can
gauge the dental condition and make an informed decision to either defer or provide oral
healthcare (132,239). According to the WHO, the remote assessment of urgent or emergency
patients can be carried out based on "3A" (advice, analgesics, antibiotics) (329). Telephonic
advice can be supported by E-mail, photos, or video conferences, which along with the patient
history, can help manage emergencies and come in useful when providing routine and
preventive oral healthcare (330–333). In a systematic review examining the possibilities of
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remote monitoring of surgical and non-surgical dental patients, teledentistry is seen as a
promising tool, especially concerning reducing waiting times and costs (334). Since it is
estimated that by 2025, mobile internet will be used by over 60% of the world population,
mobile video- and telephone consultations are considered a benefit for community health,
especially among low- and middle-income households (335–338).
Questionnaire
Patients with COVID-19 who are in the acute febrile phase of the disease are not
recommended to visit the dental clinic and will most likely not show up. Should this
nevertheless happen, the OHCW should be able to identify the patient with a suspected case
of COVID-19 infection and avoid treatment. The patient then should be reported to the
Infection Control Department or the Health Department as soon as possible. In addition to
triage and other precaution measures, a questionnaire should be used to screen potentially
infected patients before entering the treatment room. This questionnaire should be part of the
regular patient record and stored. According to various sources, these pre-check routine
questions should include health status, travel history, and recent contacts (90,120,296,334).
Exemplary pre-check questionnaire (90,132,327,339)
1. Do you have a fever, or have you had a fever in the last 14 days?
2. Have you had coughing or breathing difficulties in the last 14 days?
3. Have you traveled to a country or region classified as a risk area by the WHO in the
last 14 days?
4. Have you come into contact with a person with a confirmed COVID-19 infection
within the last 14 days?
5. Have you come into contact with people who are considered infected by the health
authorities and who have had fever or breathing difficulties in the last 14 days?
6. Are there people with fever or respiratory problems within the last 14 days who have
had close contact with you?
7. Have you recently attended meetings or gatherings, or have you had close contact with
many unknown persons?
8. Have you taken any pain medications (e.g., Ibuprofen, Paracetamol, Aspirin)?
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5.3.3.2 Treatment of COVID-19 confirmed and suspected patients
If a patient answers "yes" to any of the screening questions and his or her body temperature is
below 37.3°C, the OHCW should postpone treatment for at least 14 days, if possible. The
patient should be instructed to perform a self-quarantine at home and report any experience of
fever or flu-like syndrome to the local health authorities. If a patient answers "yes" to any of
the screening questions and their body temperature is above 37.3°C, the patient should be
quarantined immediately, and staff should report to the nearest hospital's infection control
department local health authorities. If a patient answers "no" to all screening questions and
their body temperature is below 37.3°C, the OHCW can treat the patient with the additional
protective measures discussed previously and avoid splashing or aerosol forming procedures
as much as possible. If a patient answers "no" to all the screening questions, but his or her
body temperature is not below 37.3 °C, the patient should be referred to the appropriate
department or family physician for further medical care (90). In a report upon the current
measures taken in the Department of Conservative Dentistry and Periodontology in Munich, it
is advised that if the patient has an elevated temperature above 37.3 °C or answers a question
on the checklist in the affirmative, he or she is prompted to perform 30 seconds of hygienic
hand disinfection. A mask is then immediately handed out, and its correct fit over the nose
and mouth is monitored. Next, a medical judgment should be made about whether the patient
requires emergency dental treatment (see Figure IV) or whether treatment can be deferred for
at least 14 days after the initial onset of symptoms. If it is decided that treatment is necessary,
the patient will be given a protective gown (as will the practitioners) and escorted to a
separate isolation room for COVID-19 patients. Great care should be taken to ensure that the
patient does not touch surfaces such as door handles and surfaces (340).
5.3.3.3 Treatment flowchart
In this unprecedented pandemic and the restrictive long-run situation, it is advisable to follow
the latest protocols and instructions of the local dental associations in the respective country,
based on current literature and research (90,132,261,341). Hence, in accordance with the
CDC's dental treatment classification previously mentioned under 5.1, a treatment flowchart
(Figure V) has been developed, taking into consideration the current findings of ADA, CDC,
and WHO. Generally, these findings propose that via telecommunication, the patient's state of
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health should be assessed. For patients without indications of COVID-19, even those at risk,
all treatment measures can usually be carried out by abiding by the standard precaution
measures, depending on the local infection rates. If patients claim to be infected with SARS-
CoV-2, suspect infection, or have had contact with infected persons, a diagnosis by their
family doctor or a government hotline should be obtained as a precautionary measure.
Treatment of patients who are proven or suspected to be infected with SARS-CoV-2 - for
example, through contact with infected persons or symptoms typical of COVID-19 - should
generally be postponed until after the end of the illness, unless it is an emergency (see Figure
IV). Dental treatment that cannot be postponed for patients who have COVID-19 or are
suspected of having it should generally only be carried out in dental treatment centers or
clinics following the measures already described. Should this not be possible in exceptional
cases, the already mentioned extended or tertiary precautions against the transmission of
SARS-CoV-2 must be taken in practice (16,231,232). The following flowchart is based upon
these findings and is supposed to serve as an overview subsuming the already discussed
prerequisites and logical steps necessary to decide upon patient treatment rather than figuring
out a detailed step-by-step worksheet for clinical practice. Such a detailed SOP (standard
operation practices) protocol can, e.g., be found at the Institute of German Dentists (IDZ),
which proposes a short screening questionnaire to determine whether a person has an
infection or is suspected of having one as well as the urgency of treatment. Depending on
these two questions' outcomes, different standard procedures are indicated, which provide
step-by-step guidance on how to proceed (342).
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Fig. V: Patient screening and decision tree flowchart
* subject to unanimous recommendations; currently, the WHO recommends postponing routine treatments "until there has been sufficient reduction in COVID-19 transmission rates from community transmission to cluster cases or according to official recommendations at national, sub-national or local level. The same applies to aesthetic dental treatments […]" (231), which is strongly disagreed by the ADA (343).
** Aerosol generating procedures: e.g., air/water spray, dental cleaning with ultrasonic scaler and polishing, periodontal treatment with ultrasonic scaler; any kind of dental preparation with high or low-speed handpieces, direct and indirect restoration and polishing, definitive cementation of crown or bridge, mechanical endodontic treatment, surgical tooth extraction, implant placement (231).
*** silver-diamine-fluoride / glass ionomer
Patient assessment through telescreening or triage area
• Contactless temperature measuring
• Dry cough, fatigue, ageusia, anosmia other respiratory symptoms
• Epidemiological and travel history
Routine treatment
• Dental cleaning
• Dental caries / defective
restorations
• Asymptomatic tooth extraction
• Broken denture / orthodontic
appliances
Urgent treatment
• Severe dental pain, acute pulpitis
• Painful pericoronitis
• Abscess with swelling and pain
• Painful tooth fracture
• Dental trauma, avulsion, luxation
• Injury due to orthodontic wire
Emergency treatment
• Oral or maxillofacial trauma
• Fractures
• (Potential) airway obstruction
• Fever combined with facial swelling
COVID-19
suspected
• AGP** avoidance if possible
• Staff must wear at least a medical mask, eye protection, fluid resistant gown, gloves
• non-invasive restorative techniques
(SDF / GI *** application)
• Disinfection immediately after procedure
• Staff must wear at least FFP2 / N95 mask, eye protection, fluid
resistant gown, gloves
• Rubber dam, suction
• Treatment preferably in
separate room
• Disinfection immediately after procedure
• Referral to hospital or emergency care center
• Airborne infection transmission precautions and / or isolation room
COVID-19
improbable
• Postpone treatment *
• Patient instruction to present again in case of severe deterioration according to current local guidelines
COVID-19
suspected
COVID-19
improbable
Procedure without aerosol Procedure generates aerosol
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5.4 Proportionality and feasibility of measures in oral healthcare practice
The following table (Fig. VI) is supposed to serve as a short recap of the known SARS-CoV-2
transmission routes and suggested precautions for the oral healthcare setting by the current
interim guidance protocols of ADA, CDC, and WHO (145,231,232,239,274). The further
proportionality, feasibility, necessity, costs, and supply of the proclaimed suggestions are
evaluated based on these findings.
Transmission Example Suggested precautions
Airborne Aerosols, virus particles suspended in the air
Reduction of aerosol-generating procedures (AGPs), FFP2/N95 respirators, room ventilation, negative air
pressure rooms (AIIR), potent suction device
Droplets Sneezing, coughing, talking, physical
proximity
Distancing in the waiting room and among staff, limited
patients per treatment room, surgical masks, rubber dam
Direct transmission Oral and body fluids, direct contact with lesions, cross-infection through touching
Standard and additional PPE (gloves, eye protection, face shield, gown)
Contaminated surfaces Contaminated hands, needles, improperly disinfected working surfaces
Hand hygiene, regular surface disinfection, instrument sterilization, proper donning and doffing
Fig. VI: Transmission routes in oral healthcare and suggested precautions
5.4.1 Approaching proportionality and feasibility of measures
An exciting question about the current pandemic is the question of the proportionality of the
recommended measures. An approximation will be attempted in the following by taking a
closer look at the availability and price of the precautionary measures against SARS-CoV-2
described as well as the relationship between compliance, feasibility, and necessity of the
individual measures (Figure VII), aiming to figure out which of the individual measures are
not only affordable and available but also necessary and feasible. As a benchmark, a regular
clinical operation with COVID-19 prevention measures and readiness to treat infected patients
is assumed, which is supposed to simulate the most realistic clinical circumstances at the
current time. A numerical and quantified analysis of the current preventive measures proves
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rather difficult concerning statistical outcomes due to the lack of data. Hence, the assessment
and placement of the individual measures in the table are based on the frequency, uniformity,
and evaluation of the respective measures in current specialist literature of international
renown (i.e., CDC, WHO, ADA, RKI), on whose findings many national recommendations
are based (231,232,239,243,244). The expertise of ten dentists at the University Dental Clinic
of Dentistry Vienna with at least five years of clinical experience served to assess compliance
and feasibility in the clinical context of oral healthcare. The evaluation of availability is owing
to the current supply and demand in Austria (344,345).
Compliance and/or
feasibility in the clinical context (expert opinion)*
Necessity
(recommendations of CDC, WHO, ADA, RKI)**
Availability
(in dental clinics in Austria, December 01, 2020)***
Cost
(new acquisition / per treatment)
AIIR or air purification low - very low inconsistent AIIR unavailable >1590€ n.a. (1)
Disinfection high - very high very high, consistent available < 1€ p.t. (2)
Eye protection high very high, consistent available < 10€ n.a. (3)
Gloves very high very high, consistent available < 1€ p.t. (4)
Gown low - moderate very high, consistent available < 2€ p.t. (5)
Respirators ≥ FFP2 very high very high, consistent available < 2€ p.t. (6)
Social distancing low - moderate very high, consistent unlimited free
Teledentistry low high, consistent unlimited no additional cost
Treatment delay moderate inconsistent does not apply does not apply
Fig. VII: Comparison of recommended measures
* consensus after consultation of ten dentists with at least five years of clinical experience at the University Clinic of Dentistry Vienna ** (231,232,239,243)
*** (345) (1) https://www.henryschein.at/dental/at-radic8-viruskiller.aspx?sc_lang=de-at&hssc=1 (2) https://www.henryschein.at/at-de/dental/c/reinigung-desinfektion-pflege/haende-waschung-desinfektion
(3) https://www.henryschein.at/at-de/dental/c/arbeitsschutz-hygiene/hand-augenschutz-lupenbrillen (4) https://www.henryschein.at/at-de/dental/p/einweg-glas-kunststoffartikel/einmalhandschuhe-spender/semperguard-latex-puderfrei-innercoated-groesse-xs-packung-100-stueck/421771 (5) https://henryscheinmed.at/s=Schutzmantel%20/#pw_050_00000
(6) https://www.henryschein.at/at-de/dental/p/einweg-glas-kunststoffartikel/mundschutz/atemschutzmaske-ffp2-ohne-klimaventil-packung-20-stueck/12774
Discussion
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6 Discussion
6.1 Historic virus outbreaks of an enormous impact compared to the
COVID-19 pandemic
Although historically, humanity has always been plagued by pandemics and wars, the horror
of some pandemics matches and even exceeds the death toll of the deadliest military conflicts.
For example, the H1N1 influenza virus, also known as Spanish flu, caused between 50 and
100 million deaths in less than a year and infected over 500 million people (346,347). In
1918, this was equivalent to about a third of the world's population (348). In comparison, the
first world war caused around 40 million casualties from 1914 – 1918 (349). When European
conquerors arrived in mainland America in 1520, they also brought the new world's variola
virus, also known as the new world smallpox outbreak. Due to lack of protective immunity,
up to 90% of the local native American population died until 1580 because of smallpox,
measles, and flu waves (350–354). Even though smallpox eradication measures were first
described in 1798, it took almost 180 years to succeed (355). The highest median R0 of the
worst influenza outbreaks before the COVID-19 pandemic in 1918 (Spanish Flu) and 1968
(Hong Kong Flu) were both 1.8, compared to 2.4 - 3.3 during the current pandemic and 1.27
as an average of seasonal influenza (221). A seasonal pattern is not evident in the eight largest
pandemics that have occurred since the early 1700s. Relative to the northern hemisphere,
three started in spring, one in summer, two in autumn, and two in winter (356). After seven of
these outbreaks had an early peak, which subsided within a few months without any human
impact, each of these seven outbreaks reached a second substantial peak about six months
after the first climax (357). After first being diagnosed in 1981, the acquired
immunodeficiency syndrome (AIDS) gradually became a pandemic of zoonotic origin that
resulted in a massive challenge for global health (358). Consequently, healthcare protocols
and protective measures had to be revised, and new protective standards were established
(355,359,360). Also, dentists accustomed to treating their patients without masks, gloves, or
eye protection faced a paradigm shift (361). The feared obstruction of the doctor-patient
relationship was the subject of a 1985 New York Times article, and even as late as 1990, the
American Dental Association attempted to object at court to the mandatory use of protective
equipment (361,362). Since refusal of protective equipment nowadays seems mildly absurd,
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56
AIDS in the 1980s arguably pushed occupational safety considerations like COVID-19 does
today (363). The rise of SARS-CoV-1 in 2003 resulted in global economic damage of an
estimated US$ 30 billion, exceeding the military expenditures of most countries at that time
(364,365). Even more so, the current COVID-19 pandemic has already caused estimated GDP
losses of US$ 76 – 346 billion for 2020 (366). In recent years, wildlife-borne diseases have
repeatedly attracted attention and public interest, illustrating a reality in which it is essential to
be prepared for the outbreak of a global pandemic. Apart from SARS-CoV-2, wildlife
coronaviruses have already been responsible for two other infectious disease outbreaks in the
last 20 years, known as SARS-CoV-1 and MERS-CoV (265). Differences and similarities of
the respective coronaviruses have already been described in section 3.2. It should be noted
that the response speed to pandemics has improved since the appearance of SARS-CoV-1 in
China in 2003. When the WHO issued a global alert, 146 days had already passed since the
first case became known (367). For SARS-CoV-2, it was only six days until the WHO issued
a first report and 32 days until WHO classified the outbreak as a public health emergency
(368,369). Also, virus isolation, virus gene sequence publication, and intermediate host
studies were initiated much quicker than during the 2013 pandemic. Besides, the Chinese
government's response to the current pandemic benefited from the swift international
exchange of research results, the enhanced communication and national research ability, and
the erection of temporary hospitals for immediate help 25 days after the first known case
(265). Nevertheless, by the end of January 2020 and not even one month after the first case
was discovered, the cumulative number of SARS-CoV-2 cases in China had already exceeded
the total global number of previous SARS-CoV-1 cases (370). During the outbreak of SARS-
CoV-1, a large number of healthcare workers were infected through iatrogenic transmission.
In contrast, although there are isolated cases of nosocomial infections in SARS-CoV-2, most
infections occur outside the hospital setting as the pandemic continues to evolve globally
(178).
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57
6.2 Outlook, recommendations, and future pandemic prevention
6.2.1 Outlook on the progression of the pandemic
The WHO estimates that up to 10% of all people worldwide have already been infected with
SARS-CoV-2, which corresponds to about 700 million individuals (371). Officially, only
about 64 million cases have been proven yet. Europe has been in the second infection wave
since October 2020 at the latest, but it is likely to take a different course than the first. It is
expected to be less steep but longer-lasting and hopefully with fewer victims. In particular,
measures such as the consistent wearing of masks or the prohibition or avoidance of large
crowds could positively impact this trend and, according to estimates, save 281,000 lives in
Europe by February 2021. Everything possible should be done to minimize health and social
collateral damage, such as keeping schools open and avoiding a second general lockdown in
many places in March 2020 (372). Based on recent model calculations, the pandemic will
likely last 18 to 24 months (373). European countries discussed whether it would be more
sensible to merely mitigate the spread of the epidemic instead of suppressing it entirely during
the course of the pandemic. This "wave-breaking" approach, partially followed by less strict
lockdown enforcement, has meanwhile been adopted by some countries (374). One argument
in favor of this approach is that it gradually builds up immunity among the population.
Without vaccination, herd immunity will be achieved when 60-70% of the population has
been infected with SARS-CoV-2 (see 3.9). However, this strategy has nevertheless led to
massive overburdening of the health system, with further bottlenecks being likely despite
better preparation after the first wave in spring 2020 (375). A recently published article in
"Nature" suggests that the spread of SARS-CoV-2 is favored by cold, dry conditions and
lower UV radiation through less and weaker sunlight in winter, resulting in peaks (376,377).
The virus also degrades more rapidly on surfaces in warm and humid environments (378).
The condition in houses in winter with warm, dry, and stagnant air of about 20°C is
additionally deemed to support the virus stability (379). In internationally renowned
publications of "Science" and the "Center for Infectious Disease Research and Policy
(CIDRAP)" three possible scenarios for the progression of the pandemic have been outlined
in April/May 2020, which are graphically depicted in Fig. X (380,381):
Discussion
58
- Scenario 1 "Peaks and Valleys": After a first wave, others follow over many months.
These bring similarly high case numbers. These outbreaks become less severe only
gradually because the number of immune people increases after the illness has been
overcome. According to the researchers, the occurrence of the waves can vary
geographically. Depending on the height of the wave peaks, temporary restrictions of
public life would be periodically necessary.
- Scenario 2 "Fall Peak": This scenario is based on the course of the H1N1 ("Spanish
flu") influenza in 1918/19. Pandemics in 1957/58 and 2009/10 also followed this
pattern. Accordingly, a first summit is followed by a much higher one in the following
autumn or winter months. This scenario appears to be the most likely at the time of
this writing since case numbers globally have reached a record high. However, there is
also more testing than ever before. If this scenario proves to be accurate, strict rules
will be needed again in early winter at the latest to avoid overburdening health
systems.
- Scenario 3 "Slow Burn": The first outbreak is followed by a long agitation period with
a repeated flare-up of the epidemic, which, however, never reaches the initial high
again. Again, local differences have to be taken into account when deciding on more
stringent measures. Even though this third pattern has not been observed in previous
influenza pandemics, it was considered a possibility for the current pandemic.
Scenario 1: Peaks and Valleys Scenario 2: Fall Peak Scenario 3: Slow burn
2020 2021 2022 2020 2021 2022 2020 2021 2022 Fig. X: Possible scenarios of the COVID-19 cases development (381)
However, even though prognostic models for the current pandemic are available and generally
showing high discriminative performance, there is reported to be a high risk of bias due to the
exclusion of potentially interesting patients on account of time restraints, non-representative
selection of control patients, and model overfitting. This could lead to optimistic and
Discussion
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misinterpreted performance estimates of these models, making constant international
information exchange and cooperation crucial for a correct outlook assessment (177,382).
6.2.2 Recommendations for oral healthcare
It is evident that OHCWs, as an integral part of the healthcare system, are facing treatment of
SARS-CoV-2 infected emergency patients sooner or later. Making a virtue out of necessity,
OHCWs can be of reliable support in the global fight against the current and future
pandemics. Due to airborne diseases, they are trained in handling barrier techniques, cross-
infection protocols, and management of patients in pain, including vulnerable patients like the
elderly, children, and pregnant women. In particular, OHCWs can simultaneously raise
awareness among staff and patients about the situation's seriousness based on substantial
evidence. They also can identify emergencies that are indicated for dental treatment in the
context of a renewed restricted operation, practice effective telemedicine where necessary,
and ensure that their team is well acquainted with the transmission of COVID‐19 and the
necessary preventive measures, all of which can be helpful to patients and the community as a
whole (58,165). As analyzed under 5.4.1, the measures against COVID-19 with the most
significant compliance in the clinical setting of oral healthcare are respirators, disinfection,
gloves, and eye protection. Due to its sheer infeasibility, AIIR is the least efficient measure
mentioned in current guidelines by the most renowned institutions. However, one of the
biggest problems is that asymptomatic virus carriers cannot be adequately identified and
isolated. At the beginning of the pandemic, this resulted in the treatment of potentially
infectious patients in regular PPE (scrubs, gloves, surgical masks, goggles) instead of
advanced gear due to limited availability and shortages. An important lesson here is that PPE
stocks should be built up beforehand to avoid such bottlenecks in the future. Clinical staff and
asymptomatic patients requiring emergency dental treatment should be tested as soon as
testing capacity can be increased and rapid tests are sufficiently available (340). In the US, for
example, after months of insecurity, elective treatment in oral healthcare has been widely
reassumed after approximately 95% of dental practices have been either fully closed or open
only for emergency care, with similar tendencies worldwide (383). However, the substantial
current increase in the number of cases in Europe does not allow for a clear conclusion on
Discussion
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treatment scope in the coming months. It still depends on local virus dynamics, general
healthcare capacity, diagnostic tests, treatment options, and immunization availability.
As the pandemic is likely to persist for an extended period and may be followed by post-
pandemic outbreaks, risks and feasibility should be carefully weighed when phasing out
additional preventive measures. Since it is impossible to practice social distancing in oral
healthcare, after all, further research should be done on the effectiveness of current
precautions (142,380). Given that even though vaccinations are becoming more and more
accessible, there is currently no cure or comprehensive remedy available for COVID-19, it
would be advisable for OHCWs to focus on the avoidance of aerosol-generating procedures as
a precaution when treating patients, like manual caries excavation instead of drilling and
conventional root canal treatment (165). Glimpsing into a future of recurrent respiratory
disease pandemics, it may be worth considering negative-pressure treatment rooms, at least
for dental clinics and hospitals (58). Moreover, the current pandemic might offer a good
opportunity to discuss the extension of courses in dental schools. They could include
additional tasks for OHCWs that consider natural disasters and pandemics, preparing them to
be active members of health teams in emergency and pandemic situations. Professional
associations could provide training courses to strengthen their role in general healthcare, for
example, on acute care, such as, e.g., life support, phlebotomy, prescription, and
administration of appropriate drugs (165).
6.2.3 Future pandemic prevention
From the consecutive occurrence of SARS-CoV in 2003, H1N1 in 2009, MERS in 2012,
Ebola in 2018, and SARS-CoV-2 in 2020, it can be concluded that global public health
emergencies are no longer one-off events and pandemics of infectious diseases are very likely
to continue to affect us in the future. Thus, fighting pandemics globally and efficiently will
likely continue to stay a major challenge for humanity. Fueled by the dogma of unchecked
economic growth, almost 8 billion people, worldwide travel, megacities, environmental
destruction, and the extensive suppression of nature, ideal conditions have been created for
viruses such as SARS-CoV-2 to develop and spread (384). Although an accurate estimate is
difficult to make, it can be assumed that the financial collateral damage of COVID-19 will far
Discussion
61
exceed the costs of targeted global preparedness for future pandemics (385,386). Besides,
planning for the future spread of diseases could also bring significant benefits beyond the
mere pandemic reference. Advantages are seen in the course of this for basic healthcare,
general living security, research and development, international cooperation and emergency
response, and biosafety management, among others (265). The concrete challenges of the near
future may lie in a better, united, and international pandemic policy, in providing more money
for institutions such as the WHO, and in creating reserve capacity in hospitals, which in many
places have been subject to austerity politics in recent years (384). As a perspective article in
the New England Journal of Medicine put it: "We applaud the $8.5 billion in federal funding
for COVID-19 and the state legislatures that are passing emergency funding bills, but these
steps are akin to ordering the best fire engine possible while your home burns." (387).
Conclusion
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7 Conclusion
The COVID-19 pandemic has revealed significant shortcomings of healthcare systems in their
collective response to a global public health threat. While the role of oral healthcare in
combating this pandemic should not be overestimated, the current situation provides an
excellent opportunity to assess oral healthcare in the context of a public health emergency and
to review the effectiveness of protective measures critically. As many people do not show
signs and symptoms of SARS-CoV-2 infection, every patient should be considered potentially
infectious. Hence, continued strict adherence to high standards of hygiene, review of infection
control protocols, and the use of adequate PPE in oral healthcare practice is imperative to
prevent cross-infection and further spread. As an integral part of the healthcare system, oral
healthcare should actively participate in the fight against public health emergencies.
Concerning the future, the question arises as to how patients and staff can be best protected
and which processes should be improved to make it easier to cope with a similar disease
outbreak, should it occur again. In the medium and long term, hopes of resuming everyday
life now rest on the accelerations of worldwide vaccination coverage and adaption of vaccines
to possible virus mutations. However, we cannot fail to recognize the irony that in our
technological society of artificial intelligence and progress in scientific research, where
complex data networks theoretically give us unlimited access to information and empower us
to act globally, united and interconnected, the most effective response to contain the pandemic
at the moment is still a measure known for several centuries - namely isolation of individuals.
Even though most recommended infection control measures in oral healthcare are effective
and feasible, uniform and universal recommendations are still lacking, mostly owing to
treatment of SARS-CoV-2-positive patients and categorization of treatment need. OHCWs
should continually keep up to date through the respective medical associations and regulatory
agencies, as measures to ensure a safe work environment may change during the COVID-19
pandemic. This imposes that a high degree of personal responsibility of the practicing
physicians towards implementing the measures is assumed as the outbreak proceeds.
List of Abbreviations
63
8 List of Abbreviations
ACE2 Angiotensin converting enzyme
ADA American dentist association
AIIR Airborne infection isolation rooms
ARDS Acute respiratory distress syndrome
BZAEK German Dental Association
DNA Deoxyribonucleic acid
ENT Ear, nose and throat
β-CoVs Beta-coronaviruses
CDC Centers for Disease Control and Prevention
CFR Case fatality rate
CIDRAP Center for Infectious Disease Research and Policy
CLIA Chemiluminescent immunoassay
COVID-19 Corona virus disease 19
CPC Cetylpyridinium chloride
ELISA Enzyme-linked immunosorbent assay
FFP Filtering face piece
FDA US Food and Drug Administration
HCoV-229E Human coronavirus 229E
HCoV-OC43 Human coronavirus OC43
HEPA High-efficiency particulate air
HIV Human immunodeficiency virus
HmPV Human metapneumovirus
IDZ Institute of German Dentists
IFR Infection fatality rate
IgM, A, G Immunoglobulin M, A, G
JHU Johns Hopkins University
ÖZÄK Austrian dentist chamber
OHCW Oral healthcare worker
MERS-CoV Middle East respiratory syndrome-related coronavirus
MeSH Medical subject headings
List of Abbreviations
64
NIOSH National Institute for Occupational Safety and Health
POCT Point-of-care test
PVP-I Povidone-iodone
PPE Personal protective equipment
PRISMA Preferred reporting items for systematic reviews and meta-analyses
R0 Basic reproduction number
RDS Severe respiratory distress syndrome
RKI Robert Koch Institute
RSV Respiratory syncytial virus
RNA Ribonucleic acid
rRT-PCR Real-time reverse transcription polymerase chain reaction
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
SARS-CoV Severe acute respiratory syndrome coronavirus
SM Surgical mask
SOP Standard operating procedure
TMPRSS2 Transmembrane protease, serine subtype 2
UTR Untranslated region
VOC Variant of Concern
WHO World health organization
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