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Archives of Academic Emergency Medicine. 2020; 8(1): e74

REV I EW ART I C L E

The Potential Role of Super Spread Events in SARS-COV-2 Pandemic; a Narrative Review Anthony M. Kyriakopoulos1∗, Apostolis Papaefthymiou2,3, Nikolaos Georgilas4, Michael Doulberis3,5, Jannis Kountouras3

1. Department of Research and Development, Nasco AD Biotechnology Laboratory, Piraeus 18536, Greece.

2. Department of Gastroenterology, University Hospital of Larisa, Larisa 41110, Greece.

3. Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, 54642 Macedonia, Greece.

4. Department of Nephrology, Agios Pavlos Hospital of Thessaloniki, Thessaloniki 55134, Macedonia, Greece.

5. Division of Gastroenterology and Hepatology, University Medical Department Kantonsspital Aarau, Aarau 5001, Switzerland.

Received: August 2020; Accepted: August 2020; Published online: 21 September 2020

Abstract: Coronaviruses, members of Coronaviridae family, cause extensive epidemics of vast diseases like severe acute respiratory syndrome (SARS) and Coronavirus Disease-19 (COVID-19) in animals and humans. Super spread events (SSEs) potentiate early outbreak of the disease and its constant spread in later stages. Viral recombination events within species and across hosts lead to natural selection based on advanced infectivity and resistance. In this review, the importance of containment of SSEs was investigated with emphasis on stopping COVID-19 spread and its socio-economic consequences. A comprehensive search was conducted among literature avail- able in multiple electronic sources to find articles that addressed the "potential role of SSEs on severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic" and were published before 20th of August 2020. Overall, ninety-eight articles were found eligible and reviewed. Specific screening strategies within potential su- per spreading host groups can also help to efficiently manage severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) epidemics, in contrast to the partially effective general restriction measures. The effect of SSEs on previous SARS epidemics has been documented in detail. However, the respective potential impact of SSEs on SARS-COV-2 outbreak is composed and presented in the current review, thereby implying the warranted effort required for effective SSE preventive strategies, which may lead to overt global community health benefits. This is crucial for SARS-COV-2 pandemic containment as the vaccine(s) development process will take considerable time to safely establish its potential usefulness for future clinical usage.

Keywords: Pandemics; epidemics; coronavirus; severe acute respiratory syndrome coronavirus 2; disease outbreaks; cost of illness; mass vaccination

Cite this article as: Kyriakopoulos AM, Papaefthymiou A, Georgilas N, Doulberis M, Kountouras J. The Potential Role of Super Spread Events

in SARS-COV-2 Pandemic; a Narrative Review. Arch Acad Emerg Med. 2020; 8(1): e74.

1. Introduction

Severe acute respiratory syndrome (SARS) has periodically

emerged as epidemics and its natural history could be uti-

lized as a "compass" to comprehend and manage the cur-

rent pandemic of SARS-COV-2. SARS-COV-2 the etiologic

agent of the novel coronavirus disease 2019 (COVID-19), be-

∗Corresponding Author: Anthony M. Kyriakopoulos; Department of Research and Development, Nasco AD Biotechnology Laboratory, 11 Sachtouri Str, Pi- raeus 18536, Greece. Email: [email protected], Fax : 00309210818032

longs to RNA coronavirus family (Coronaviridae) and is a

zoonotic coronavirus that has crossed species barriers to in-

fect human (1-3). The initially investigated strains of COVID-

19 exhibited low potential for transmissibility and infectiv-

ity, similar to SARS coronavirus (SARS-COV ) (1-4). Moreover,

SARS epidemic was potentiated due to super spread events

(SSEs), which led to unexpected elevation of the basic re-

production numbers as calculated via associated epidemiol-

ogy equations (5). Specifically, SSEs resulted from secondary

contacts of carriers (6, 7). Infected individuals, as mediators

of SSEs, represent the initial cluster of viral transmission (8);

thus, inducing an exponential secondary contamination (4).

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A. M. Kyriakopoulos et al. 2

Although the prediction and subsequently the prevention of

SSEs seems to be complicated, the virus, host, environmen-

tal, and mass behaviors determine relative approaches to

prevent and control SSEs; core community health programs

can inhibit and decrease the incidence and the effect of SSEs

(9).

Nevertheless, horizontal austerity measures, such as recom-

mending or compelling individuals to self-isolate at home,

which might cause serious social and psychological burden,

and quarantine, also leading to loss of income due to so-

cial distancing, are associated with negative psychological

and religious effects, which can be long lasting (10), thereby

leading to serious instability of the global society. Prolonged

social isolation and loneliness are associated with increased

mortality (11).

Currently, limited piece of information exists regarding the

effect of SSEs on coronavirus epidemics. The aim of this nar-

rative review is to mainly focus on the potential impact of

SSEs on large outbreaks of coronavirus. The development of

an emergency SARS-COV-2 vaccine has its potential useful-

ness and/or limitations and may result in severe health out-

comes, which prompts better screening for SSEs in order to

control coronavirus pandemics.

2. Method

2.1. Methodological approach

To avoid, in most respects, literature selection bias (12), mul-

tiple electronic sources: Medline/PubMed, SciFinder, Sci-

ence Direct and Goggle Scholar as well as ResearchGate and

General (Google) were investigated via queries with a non-

restricted time frame reaching the 20th of August 2020. Ini-

tial investigation of SSEs and SARS, SSEs and MERS, and

SSEs and COVID-19, gave narrative results from PubMed.

The selected literature, which is included in the study, is

presented in table 1. Same items were also searched in

all other mentioned sources. The scope of the study was

not only to investigate the transmission of SARS-COV-2 due

to SSEs, its comparison with SARS-COV-1 and MERS-COV,

but also to assess the general global impact due to SSEs by

COVID-19. Therefore, further literature investigation was

performed using the same electronic sources. Further in-

vestigation was made on: a) the prevention of SSEs by

coronaviruses causing SAR-1, MERS and COVID-19, b) the

socio-economic relation of SARS-COV-1, MERS and COVID-

19 due to SSEs, c) the austerity caused by SSEs of COVID-

19, and d) the relation of SSEs containment to future vac-

cination programs. For further investigation, the follow-

ing items were searched: "SARS, MERS and COVID-19 Epi-

demic Prevention", "SARS MERS and COVID-19 Infectiv-

ity and Pathogenicity", "Coronavirus SSE Prevention", SSE

Coronavirus Crisis and Socio-economics", "Holy Cup Reli-

gion and Transmission of Pathogens and SSEs", and "Coro-

navirus Immunity and Vaccination".

2.2. Selection process

Screening Process and Eligibility Criteria Studies providing an adequate determination of an SSE re-

lated to SARS, MERS and COVID-19 were primarily screened

and selected by two reviewers (authors) blinded to one an-

other. The results were thereafter cross-matched and du-

plicates were removed. Based on this primary search, the

socio-economic impact of coronavirus, produced by SSEs,

was extrapolated by two other reviewers (authors). Following

this initial selection stage, further screening was performed

by all reviewers, using the previously described search items

to identify parameters determining the global impact of

COVID-19 due to SSEs. Identified parameters included the

global impact of immunity and vaccination, the holy cup and

religion transmission, and the austerity caused by COVID-19

and other coronavirus epidemics due to restrictions applied.

All search results were cross-matched to remove duplicates

and thereafter, exclusion and inclusion criteria were applied.

Exclusion and Inclusion Criteria After removing the duplicates, review was conducted on titles

and abstracts. Also, a decision was made to remove "news

press opinions". Computational model methodologies pro-

ducing contradictory results, studies with wrong interpreta-

tion of SSEs, and studies with non-clear-cut results were also

removed. Studies using the interpretation "a super spread-

ing individual, known as the index case, produces a cluster

of SARS, MERS, and COVID-19 secondary infections" were

included. A second exclusion criterion was applied. In this

stage, peer reviewed literature of recent dates, studies as-

sessing SARS, MERS, and COVID-19 epidemiology measures,

studies on COVID-19 restriction measures producing social

and economic austerity, articles discussing the perspective

for future vaccination and population immunity, and finally

genetic studies on coronaviruses causing SARS, MERS, and

COVID-19.

3. Results

By following the described methodology, on Med-

line/PubMed: a) 23 articles were found on SARS and MERS

and SSE, and b) 11 articles were found on COVID-19 and

SSEs. Out of: a) 13 of the 23 articles on SARS and MERS and

SSE, and b) 7 out of the 11 articles on COVID-19 and SSE were

deemed relevant hits. After applying the exclusion criteria,

12 articles from the first category, and 4 from the second

category were included in the study. Suitable articles found

by searching, which were selected and reviewed for each

part, are illustrated in figure 1. Further investigation in all

other electronic sources described, using the same method-

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3 Archives of Academic Emergency Medicine. 2020; 8(1): e74

Table 1: Literature included from PubMed search for SSEs* in relation to coronavirus outbreaks

Literature included in review for SARS∧ and MERS! in relation to SSEs* Authors and Year Type of article** Study description

Chowell et al. (2015)(51) Comparative research Investigation of relation between SSEs for SARS and MERS trans- mission in nosocomial outbreaks

Al Tawfig et al. (2020) (38) Commentary Demonstration of a stochastic model of transmission of SARS virus

Shaw (2006) (55) Perspective review Implementing efficient intensive care practices to avoid hospital transmission

Chen et al. (2006) (96) Original research Case control study

Investigation of SSE likelihood during hospital transmission

Sung et al. (2009) (97) Original research Case control study

Investigation of SSEs occurring in hospital and prevention strate- gies

Li et al. (2004) (54) Original research Case control study

Investigation of factors contributing to SSEs for prevention and control of disease

Riley (2003) (5) Original research Cross sectional study

Analysis of SARS epidemiology in Hong Kong

Stein (2011) (98) Perspective review Analysis of SARS transmission leading to SSE

Gormely et al. (2017) (52) Original research Model for prevention of pathogen transmission via sanitary plump- ing systems

Lau (2004) (53) Perspective review Implementation of SSE containment with vaccination programs Literature included in review for COVID-19 in relation to SSEs Cave (2020) (56) Perspective review Call for clear epidemiologic definition for SSEs

Xu (2020) (57) Original research Retro- spective cohort study

Analysis of SSEs during COVID-19 in China

Kwok (2020) (58) Original research Analysis of SSE influence in the nature of COVID-19 epidemic Zhang (2020)(21) Original research Description of SSE importance in COVID-19 epidemic ! Severe Acute Respiratory Syndrome; ∧ Middle East Respiratory Syndrome; &Coronavirus Disease-19; *Super Spread Events; **When clearly indicated in article, the type of study is also mentioned.

Table 2: The search results of literature related to COVID-19& global impact due to SSEs*

Search Item Medline/PubMed Other electronic sources**

Number of arti- cles retrieved

Number of arti- cles included

SARS!, MERS∧, and COVID-19 epidemic prevention 42 3589 139 17 SARS, MERS, and COVID-19 infectivity and pathogenicity 672 3812 145 18 Coronavirus SSE prevention 10 627 151 22 SSE, coronavirus crisis, and socio-economics 4 3181 89 11 Holy Cup religion and transmission of pathogens and SSEs 0 15 4 4 Coronavirus immunity and vaccination 73 20975 1175 9 &Coronavirus Disease-19; *Super Spread Events; ** Science Direct, SciFinder, and Google Scholar; !Severe Acute Respiratory Syndrome; ∧Middle East Respiratory Syndrome

ology, increased the number of the included literature to a)

17 and b) 14, for their respective categories of search. Studies

included from PubMed in these categories of searches are

briefly described and listed in table 1. Further, assessing the

general global impact of SSEs related to COVID-19, using all

the mentioned sources, via the same methodology, led to the

inclusion of a) 10 articles related to genetic analysis of SARS-

COV-1 and MERS-COV and SARS-COV-2, b) 5 articles related

to super spread events, c) 2 articles related to austerity, d)

18 articles related to infectivity and pathogenicity of SARS,

MERS and COVID-19, e) 17 articles related to prevention of

SSEs concerning human coronaviruses, f ) 9 articles related

to socio-economic impact, and g) 9 articles related to im-

munity and future vaccination. Table 2 illustrates the initial

numbers of hits using all search items in all sources, and the

final number of articles reviewed in each category.

4. Discussion

4.1. Insights to SSEs

The involvement of SSEs in SARS extensive outbreaks (1, 4, 5,

13-17), necessitates urgent elucidation as global tranquility is

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A. M. Kyriakopoulos et al. 4

Figure 1: Method followed for PubMed search and literature selection regarding SSE in relation to a) SARS-1, MERS and b) COVID-19 out-

breaks.

disturbed by COVID-19 pandemic. Epidemiological research

has proposed that the outbreak was related to a seafood mar-

ket in Wuhan (Hubei, China), underlining the ongoing risk

of viral transmission from animals to induce severe diseases

in humans. Metagenomic RNA sequencing of bronchoalve-

olar lavage fluid from a patient with pneumonia identified a

novel RNA virus strain from the Coronaviridae family (called

SARS-COV-2); and phylogenetic analysis (by introducing the

widely used in silico protein screening) (18-21) of the com-

plete viral genome (29,903 nucleotides) disclosed that the

virus was most closely connected (89.1% nucleotide similar-

ity) with a group of SARS-like coronaviruses (genus Betacoro-

navirus, subgenus Sarbecovirus) formerly isolated from bats

in China (18-22). Insights from previous reports by Menach-

ery et al. (23) (Menachery et al., 2015), pointed out that the

2002-2003 emergence of SARS-CoV introduced the possibil-

ity of viruses of animal origin causing epidemics in human

populations. Conclusions from their study revealed, as pre-

vious studies had demonstrated (1, 5, 13, 15), that closely

related SARS-like viral genes were traceable in Chinese bat

populations. Authors claimed that these viruses were capa-

ble of infecting humans, by selective adaptations or adjust-

ments, and thereby, causing a new epidemic (23). Enhance-

ment of virulence is also attributed to these adaptations due

to acquisition of spike protein via adaptive mutations (24).

Continuous viral random mutations are possible through in-

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5 Archives of Academic Emergency Medicine. 2020; 8(1): e74

Figure 2: Flow of genetic variation of coronaviruses leading to increase of virulence and pathogenicity; epidemiologic steps for specific and

targeted diagnosis to prevent super spread events. Blue arrows point to the flow of genetic variation across gene pools where genetic variation

occurs, i.e. a) between hosts of the same species, b) between hosts of different species by crossing the species barrier, spreading to c) humans

and subsequently to super spreader individuals, where disease transmission is potentiated. Grey arrows point to specific identifications that

can lead to effective interventions with the potential to control the disease spread.

termediate host transmission, until a deadly virus develops,

as illustrated in Figure 2. Recent evidence revealed that re-

combination within intermediate hosts has contributed to

development of SARS-COV-2 (1, 24). Asian outdoor markets

could constitute the ideal places for continuous viral muta-

tion exchanges (25). As presented in Table 3, the best way to

circumvent continuous virus production is targeted surveil-

lance; to at least stop the overspreading by SSEs (2, 3, 22, 26).

This has also been proposed by Menachery et al. (23).

4.2. SARS epidemics and SARS-COV-2 pandemic

SARS-COV-2 is accountable for the unprecedented COVID-

19 pandemic (27), and the interplaying mechanisms involved

in the pathophysiology of COVID-19 include SARS-COV-2

virulence, host immune response, and complex inflamma-

tory reactions (28). Emerging data, also, imply that the reser-

voirs of SARS-COV-1 infection may be similar to COVID-19

(1, 4, 5, 13, 29), as remarkable similarities exist between SARS

and swine acute diarrhea syndrome (SADS) in topographi-

cal, temporal, environmental and etiological backgrounds.

However, the increasing coronavirus variety and spread in

bats were recognized as a potential target to diminish future

epidemics that might impend livestock, community health,

and financial progress (30). Probably, identification of an-

imal and insect vectors that transmit the disease, identifi-

cation and control of alternative routes of transmission like

fecal-oral route, and identification of super spreader patient

groups could help minimize the epidemiological extent com-

pared to the one observed for SARS-COV-2 infection world-

wide. Lessons from SARS epidemic taught us that the key to

control is minimizing the time from the diagnosis of infection

to prompt hospital isolation and diminishing the probability

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A. M. Kyriakopoulos et al. 6

Table 3: Key clinical and laboratory screening functions to appropriately forecast, prevent, and confront SARS! Coronavirus 2, and future

coronavirus epidemic waves

Specific Clinical and Laboratory Investigation Validated techniques to be used Forecasting of pre-symptomatic infection To estimate the probability of a major outbreak, use simulations

of stochastic compartmental epidemic models. Use of diagnostic tests to detect asymptomatic susceptibility and pre-symptomatic infectivity

Estimation of Super Spread Events of current and previous coron- avirus epidemics

Introduction of individual reproductive number. Integrated and computational analysis of the influence of individual variation by binomial distribution and use of branching process analysis of dis- ease data.

Genetic characterization of inpatient viral isolates to identify in- termediate animal hosts facilitating the infection

Next generation sequencing of samples and cultured viral isolates to obtain full sequence and phylogenetic analysis application.

Environmental detection and continuous sewage monitoring RT-qPCR# screening on sewage systems, vectorsÙĹ and potential air transmission. Autopsies and detection of serology conversion of potential vectors.

Heptad repeat region screening for positive selection Computer simulation models to detect positive selection events e.g. codeml branch-site Test coupled with Bayes empirical Bayes procedure, and mixed effects model of evolution.

Receptor recognition analysis of ACE-II+ to identify origin of cross- species and human to human transmissions coronaviruses

Genetic sequencing and phylogenetic analysis of ACE-II to provide origin and efficiency of cross-species and human to human trans- mission and identification of intermediate hosts.

!Severe Acute Respiratory Syndrome; #Reverse Transcriptase Quantitative Polymerase Chain reaction; +Angiotensin-converting enzyme-II.

Table 4: Potential groups of coronavirus super spreaders within the human population*

Population Group Potential route of transmission Hepatitis B and C virus positive patients Airborne Pulmonary tuberculosis positive patients Airborne HIV! positive patients Airborne, urine & fecal-oral (98) Patients receiving hemodialysis Airborne (droplets by nebulizer) and fecal-oral MRSA# Staphylococcus aureus acquisition Constant Worn Glove Contact Transmission Rhinovirus co-infections Airborne Gastrointestinal (Salmonella enteritis) co-infections Fecal – oral Frequent contact with wild animal reservoirs (including domestic animals) and birds**

Airborne and fecal – oral

Construction area workers Air particles Sewage system workers*** Fecal – oral *In both community and hospital environments. **Including slaughter houses, pet shops, animal and bird collectors and breeders, cow, and pig farmers. ***Including workers coming in contact with environment contamination. !Human Immunodeficiency Virus, #Methicillin Resistant Staphylococcus aureus.

of another SSE (5).

4.3. The 20/80 rule as applied to SARS

The typically recognized 20–80 rule or the so-called "Pareto

rule", states that 20% of efforts lead to 80% of results (31).

More specifically, this comprises a principally convenient

state when tackling infectious diseases and is applied to in-

vestigate infection transmission, and initially among cattle

farms. In this regard, Woolhouse et al. (17) reported that tar-

geted actions concerning disease control and prevention in

20% of the farms that mainly supplied the basic reproduc-

tion number (Ro) decreased spread by 80% (32). Focusing

on the COVID-19 virus, Ro is a sign of virus transmissibility,

denoting the average figure of novel infections caused by an

infectious individual in a totally naive population. For R0 >

1, the number of infected people tends to increase, whereas

for R0 < 1, transmission is likely to stop; Ro represents a

chief model in the epidemics, signifying the risk of an infec-

tious mediator with regard to epidemic spread (33). Recent

data indicate that the estimated mean Ro for COVID-19 is al-

most 3.28, with a median of 2.79 and the interquartile range

(IQR) of 1.16, which is substantially higher than WHO’s es-

timation of 1.95. However, due to biased methodology, Ro

for COVID-19 is expected to be about 2–3, which is approxi-

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7 Archives of Academic Emergency Medicine. 2020; 8(1): e74

mately consistent with the WHO estimate (33). SSEs appear

to be a main limitation of the Ro concept. Ro, when calcu-

lated as a mean or median value, does not include the het-

erogeneity of transmission between infected individuals (4);

two infective agents with equal R0 estimates might have no-

ticeably diverse patterns of transmission. Moreover, the goal

of a Health Care System is to achieve Ro <1, which is prob-

ably only phenomenally feasible in certain conditions with-

out scheduled prevention, recognition, and response to SSEs

(9). Naturally, epidemics follow the aforementioned 20 / 80

rule (17). Specifically, in human population, due to heteroge-

neous exposure to infectious agent, the 20% core population

may transmit the disease, widely. For SARS, the rate might

have been even lower than 20% (4). The increased infec-

tious potential of a small population subgroup seems to be

related to immunodeficiency, such as in hemodialysis, can-

cer, immunosuppressive therapies (4, 5, 15, 34). Additionally,

facilitation of disease spread and transmission due to vec-

tor exposure has been investigated in relation to cockroaches

(35). Possible mechanical transportation by rats and cat (13,

36) and air transmission (37) in SARS-COV-1 have also been

studied. Other animals capable of being SARS-COV-2 carri-

ers (excluding mice and rats), like pigs, ferrets, cats, and non-

human primates have recently been introduced (3), and con-

tamination of sewage with SARS-COV-2, has probably pre-

ceded COVID-19 outbreak in France (29). All these agents

may contribute to a minimum of 80% of the total transmis-

sion potential (17), maybe even more (4, 5). Table 4 displays

possible super spreader groups; thus, indicating screening

targets to prevent SSEs. SARS epidemic taught us that control

programs were inefficient in controlling the epidemic within

a population, and failed to identify and provide a targeted

infection diagnosis in groups causing potential SSEs (5, 17).

On the other hand, SARS-COV-2 having the ability to cause a

pandemic rather than an epidemic, resulted in an increased

number of cases and deaths; albeit having a lower mortal-

ity rate than SARS coronavirus (2). SSEs during COVID-19

may involve not only one city, but also a whole country or

many countries, requiring investigation of their effects on a

national or international level (2, 38, 39).

4.4. Prevention of SSEs

Preventing and decreasing COVID-19-related SSEs necessi-

tates the decryption of the mechanism through which SARS-

COV-2 spreads through super spreader individuals, for exam-

ple within healthcare facilities (7, 9). Healthcare facilities are

essential for prevention and control of SSEs (9). SSE preven-

tion may enable us to even overcome initial low COVID-19

virus infectiveness. The capability of the virus to produce

SSEs troubles the epidemiological attempts to restrict viral

spread only by isolating individuals at high risk and perform-

ing obsolete isolation at home for the general population as

carried out in countries such as Greece (5). During the SARS

epidemic in China (Beijing) and Singapore, the vast major-

ity of infected individuals were barely infective and only 6%

of the population was highly infectious, in contrast to many

published SARS models (4, 5). Other ways of potential coro-

navirus transmission between hosts may provide explana-

tions for enormous outbreaks (16). It should not be disre-

garded that coronaviruses cause both respiratory and intesti-

nal infections and share common evolutionary roots with

hepatitis viruses (40, 41). Passing the cross-species barrier

and genetic adaptation within hosts may promote virulence

of coronaviruses in humans (14). This, prompts to specifi-

cally identify potential super spreader groups within popula-

tions through targeted diagnosis. Some of these groups are

listed in Table 2. For this purpose, a usual infection must

be distinguished from a super spread infection (4, 5). Dur-

ing SARS epidemic, the coronavirus infectiousness mostly

occurred in the late stages of infection (5, 17), whereas in

COVID-19, viruses are transmitted even in pre-symptomatic

stages (42). As with Influenza A virus subtype H1N1 trans-

mission (43), accurate diagnosis of COVID-19 in potentially

asymptomatic super spreaders may help contain the magni-

tude of large outbreaks (44).

In the case of Diamond Princess Cruise ship, an early-

assessed R0 of 14.8 (âL’́L4 times higher than the R0 in the epi-

center of the outbreak in Wuhan, China) was decreased to an

assessed effective Ro of 1.78 following on-board isolation and

quarantine processes (45). Similarly, in China (Wuhan) the

application of non-pharmaceutical interventions in the so-

ciety, including a cordon sanitaire of the town; interruption

of community transport, school, and most employment; and

termination of all community events decreased the Ro from

3.86 to 0.32 over a 5-week period (46). Nevertheless, these

strategies could not be maintained.

Emerging research evidence (29) regarding sewage contam-

ination that preceded Paris COVID-19 epidemic is pointing

to the reports of 2003 from the health department of Hong

Kong (35, 36), the noble work by Ng (13), and urge for ex-

tensive environmental monitoring (29, 37) to prevent future

COVID-19 relapses. However, the flow of genetic variation

may be even more complex as illustrated in Figure 2. There-

fore, advanced clinical and laboratory monitoring is required

to prevent SSEs and thereafter, new coronavirus epidemics.

Assembly of key functions and screening techniques of ref-

erence centers is presented in Table 3. Newer therapeu-

tic agents and protocol applications are promising (47), al-

though probably carrying the possibility of resistance state

(48). First, these also require specific diagnostic and surveil-

lance strategies to overcome any unknown adverse epidemi-

ology consequences (48). Inhibiting wild meat markets and

related consumption of wild meat by creating vivid cam-

paigns could be a critical for interrupting the introduction of

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A. M. Kyriakopoulos et al. 8

coronaviruses crossing from animals to the human popula-

tion, as was the case for SARS (1, 4, 5) and Middle East respi-

ratory syndrome (MERS) (49) epidemics, and probably now

for COVID-19 pandemic (1-3). Furthermore, the food pro-

duction process requires radical reconsideration, concerning

the industrial environment of current food production and

serious violations of natural ecosystems (50). Current indus-

trial procedures for preparing food increasingly favor condi-

tions where viral evolution produces new mutations and in-

creased rates of mutations (25), thus raising the probability

of new and more infectious viral strains. In SARS and MERS

epidemics, the role of SSEs in vigorously distributing the

epidemics has been substantially proven (51-55). The new

COVID-19 epidemiology evidence also adequately highlights

the important role of SSEs in homeland of China (21, 56,

57), although surprising evidence from neighboring coun-

tries show the unlikely role of SSE in the spread of the disease

(58).

4.5. Effective molecular screening of SARS-COV-2 and socioeconomic relations

The Coronaviridae family is characterized by a positive-sense

single-stranded RNA genome. Mouse hepatitis virus is a rep-

resentative member of the family (41). Additionally, human

hepatitis E virus also has a positive-sense single stranded

RNA genome and shares a common evolution pathway with

coronaviruses (40). Hepatitis-related incidents were de-

scribed for SARS (59). The genetic recombination of these

viruses within arbitrary intermediate hosts produced conta-

gious strains that are extremely pathogenic to humans (40,

60). In this respect, the relation of SARS-COV genetic se-

quences isolated from human, civets, and bats permitted us

to find the reason for such a dangerous epidemic, which af-

fected people on a worldwide scale in 2003 (61). Moreover,

the unpredictable epidemic of MERS-COV posed a serious

risk to the health of communities worldwide. These under-

scored the necessity for further research of the virus epidemi-

ology and pathophysiology to develop successful therapeu-

tic and preventive medications against MERS-COV infection

(62). While SARS-COV-2 is genetically and structurally con-

nected with MERS-COV, it has its own exclusive structures

which are responsible for its quick spread throughout the

world (60).

Specifically, variations in coronavirus pathogenicity within

different species (63) make the understanding of SARS epi-

demics even more unclear through their capability to over-

come the barrier for cross species transmission, which also

alters their infectivity status (14, 64). As a result, boosting the

pathogenic behavior of coronavirus strains, within species

(65), and across species barriers (49), which is a reflection

of their positive adaptation to rapid recombination events

(49). The recent MERS epidemic revealed the tendency of

the strain to genetically adapt and produce greater outbreaks

(49) as occurred in SARS epidemic in 2003 (66). However,

mainly for socioeconomic reasons, alarm signals were ig-

nored until recently (67). A new phylogenetic analysis tech-

nique employed on clustered COVID-19 strains displayed a

geographic variation preference in infectivity and pathogen-

esis (39). This is probably due to predominating strain’s ten-

dency to cause an SSE as an outcome of a multi- factorial epi-

demic process presented in Figure 2 (23, 24). Marked SSEs for

COVID-19 have already been fully characterized and warrant

urgent investigation (23, 24). As presented in Tables 3 and

4, each way of transmission should be investigated. Hetero-

geneity of epidemic characteristics across nations (39) im-

plies that in this way we may minimize coronavirus trans-

mission. Therefore, salvation of national economic catastro-

phes will also be achieved in this way (66). Thus, the whole

Biomedical Science machinery needs to perform targeted di-

agnosis of SSEs and share the obtained experience. Sub-

sequently, central authorities will no longer need excessive

non-specific contact measures, which will in turn normalize

both societal and economic activities.

4.6. SSE-related large outbreaks and uncon- trolled austerity

On the other hand, improper understanding of how COVID-

19 spreads resulted in societal imbalance due to arbitrary re-

striction of social and religious life including Holy Commu-

nion Cup. It has been consecutively demonstrated by ex-

pert research that the Holy Cup (Chalice) and the Holy Cloth

are not sources or pathways, for potential spreading of in-

fectious diseases including Human Immunodeficiency virus

(HIV ) (68), Hepatitis B virus (HBV ) (69) as well as other com-

municable pathogens (70). Specifically, a review (69), con-

sidered other 129 relative studies. In this review, the possi-

bilities that the shared communion cup can act as a vehicle

for indirect transmission of human immunodeficiency virus,

since it was detected in the saliva of infected individuals, was

investigated. It was emphasized that although for bacterial

contamination, the alcoholic content of the wine, the mate-

rial that the cup is made of, or the practice of partially ro-

tating the cup, cannot stop the occasional transmission of

microbes, the microbial transmission was considerably re-

duced by the intervening use of a cloth to swab the lip of

the cup between communicants. Notably, it was emphasized

that transmission means not an obligatory inoculation or in-

fection. Furthermore, it was also emphasized that out of the

epidemiology of microbes transmitted via saliva, particularly

for the transmission of the herpes viruses, the indirect trans-

mission is rare, and indeed transmission is highly possible by

other means than by the saliva. It was also emphasized that

neither hepatitis B virus nor human immunodeficiency virus

infection can be transmitted by saliva, rendering their indi-

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9 Archives of Academic Emergency Medicine. 2020; 8(1): e74

rect transmission also less likely by inorganic objects. Finally,

the study concluded that no episode of disease transmission

has ever been reported as a result of the shared communion

cup use, and that there was not any scientific evidence that

the communion cup practice should be abandoned due to

the possible risk of spreading of any infection (71, 72). Like-

wise, Kingston et al. (68), by considering 44 relative papers,

also concluded that there is no evidence that the Holy Com-

munion Cup spreads infections. Moreover, more recent esti-

mations also demonstrated that no infections have ever been

observed as a result of religious rituals including Christian

Common Communion chalice practice (70); whereas, data of

previous studies implied that saliva could play a role in HBV

transmission, are likely to be trivial (69). Similarly, recent ev-

idence indicate that, although HBV DNA and HCV RNA can

be discovered in the saliva of infected patients, they seem un-

likely to transmit infection (72). It should be noted that, as in

the case of coronavirus (73, 74), HBV also exists in many body

fluids including saliva, nasopharyngeal fluid or tears by mea-

sures of qualitative and PCR methods (75).

The detection of HBV DNA in saliva motivated our study

group to investigate the potential viral transmission through

the Holy Communion Cup. Two successive retrospective

studies were conducted to investigate the role of Holy Com-

munion as an independent risk factor of HBV dispersion.

The first preliminary study included patients from our reg-

istry of those with chronic hepatitis B under entecavir ( Jannis

Kountouras-personal communication) treatment (76), and

in the next step, the relative registry of another Depart-

ment of the same Hospital was incorporated. Other param-

eters studied, the substantial independent categorical vari-

able to evaluate our hypothesis was the patients’ occupation,

thereby introducing two sub-groups; priests and non-priests.

This classification was performed based on a standard active

and perpetual exhibition (at least once weekly) of priests to

many people’s saliva, as a part of the grounded process of

the Holy Communion Cup. The control group comprised of

the aggregate of Orthodox priests in Greece (10,338) and the

rest general population (10,680,866) at that timeframe. Ap-

proval of the Institutional Ethics Committee was obtained

and all predispositions of the Helsinki Declaration were ful-

filled. The reservoir database did not include any personified

information (name, ID number, etc.) and thus no informed

consent was required. Pearson’s chi-squared test with 1 de-

gree of freedom was performed to evaluate whether there

was a statistically significant difference between the frequen-

cies of HBV infection in case and control groups and statisti-

cal significance was set at p <0.05.

The first single-centre registry included 71 patients and one

(1.4%) of them was a priest. Chronic hepatitis B was signifi-

cantly more frequent among non-priests compared to priests

(x2 (1, N=71)=12.65, p <0.05). The extended sample (N=429)

included the registry of another Department and an aggre-

gate of four (0.93%) priests were diagnosed with chronic hep-

atitis B. Likewise, the chi-square test revealed that non-priest

subjects were more likely to suffer from chronic hepatitis

from HBV infection compared to priests (x2 (1, N=429) =

31, p <0.001). In conclusion, both of our analyses indicated

a lower prevalence of HBV chronic hepatitis among priests

when compared to other occupations.

4.7. Coronavirus vaccination and relationship with SSEs

Currently, vaccines for COVID-19 are in pre-clinical devel-

opment, and no final clinical phase has been ended due

the recent emergence of the disorder. Many global enti-

ties have stated their plans to produce a vaccine for COVID-

19. According to the WHO, 41 candidate vaccines are be-

ing produced for COVID-19 as of March 13, 2020 (77). Im-

portantly, for production of highly effective and safe COVID-

19 vaccines, features such as the possibility of the induction

of antigen-dependent enhancement (ADE) and additional

severe opposing effects previously detected with SARS and

MERS should be considered. ADE is a phenomenon that oc-

curs when non-neutralizing antibodies against proteins of a

virus increase, also increasing virus infectivity (78). In this

regard, coronaviruses can escape the immunity provided by

inactivated or recombinant protein vaccines via fast evolu-

tion (79). The problem with live attenuated vaccines is that

the coronavirus can recover its virulence via serial passages

in cell culture or in vivo (80). Moreover, vaccination in an-

imals and humans could facilitate, rather than inhibit, the

pathogenesis of the targeted viruses. This can be the con-

sequence of an ADE phenomenon. This underlines a mech-

anism by which specific antibodies facilitate infection with

the targeted virus, or cell-based augmentation, a process re-

sulting in an allergic inflammatory response induced by im-

munopathology (81, 82).

Many experimental SARS-CoV-1 vaccines have been formu-

lated from whole inactivated viruses, due to their advan-

tage of large-scale production, multiple epitope presentation

and high conformation stability (83). One such vaccine uses

viruses from AY71A217 strain of SARS-CoV-1, which are dou-

ble inactivated using formalin and UV irradiation, the so-

called double-inactivated virus (DIV ) vaccine (84). Although

DIV had initially been demonstrated to induce neutralizing

antibodies and to protect against SARS-CoV-1 viral replica-

tion, both in tissue culture and in young mice, it soon became

apparent that older mice suffered from vaccine-induced im-

mune pathologies, including failure to contain viral replica-

tion, augmented clinical disease and associated symptoms,

and increased inflammatory response and eosinophilic in-

flux (84, 85). In this respect, there is an overlap between the

immunopathologic responses connected with coronavirus

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A. M. Kyriakopoulos et al. 10

disease and vaccination, and the role of T helper (Th) 17

cells in immune augmentation and eosinophilic lung im-

munopathology; host Th17 polarized inflammatory reac-

tions portray an important role in the pathophysiology of

COVID-19 pneumonia and edema (86, 87). Eosinophilic

pathology, indicating increased pathogenesis and disease

severity in the elderly, has been attributed to the nucleocap-

sid (N) protein, despite the incorporation of multiple SARS-

CoV-1 antigens in the DIV (82, 84). This is on grounds that

the N protein is a strong modulator of innate immunity, also

acting as an interferon antagonist, and therefore, it has the

capability to induce inflammation with subsequent immune

pathology in situations of heterologous viral challenge or in

immune senescence, where patients fail to mount effective

immune responses against the disease (84, 88). The route of

transmission is important to be established for SARS COV-

2. As seen with other important infectious diseases of a)

air borne transmission such as tuberculosis (89), b) orofe-

cal transmission such as HEV (90) and c) blood transmis-

sion such as HBV and hepatitis D virus (91), even if effi-

cient vaccination is established, understanding of SSEs is

still important. Recent research data on the immune re-

ceptors used by coronaviruses, which reflect their ability to

propagate in the human population, imply that complex im-

mune reactions are responsible for a cell to cell transmis-

sion. In addition to ACE-II receptor, as is the case with SARS-

COV, MERS-COV (92) and possibly for SARS-COV-2 (92, 93),

viruses use complex receptor recognition systems common

to immunopathology damage mechanisms in coronavirus-

infected individuals, which clearly define the clinical out-

come (94). Therefore, application of vaccines that may inter-

fere with antibody-mediated infection by coronaviruses (95)

without true epidemiologic containment of coronaviruses, to

restrict genetic adaptation events and inevitably producing

an SSE, may be a miscellaneous attempt. However, synergy

of SSE prevention measures with proper vaccination can pro-

vide a robust attempt for disease containment.

5. Limitations

This study aimed to perform a literature review. Although

effort was made to decrease the risk of bias of results via

double-blind screening of literature and employment of mul-

tiple electronic search engines, bias cannot be eliminated

due to incomplete retrieval of identified research and biased

estimations of included literature conclusions and methods

used. Outcome of the study may also contain biased estima-

tions originating from wrong interpretation of super spread-

ing individuals in literature reviewed for SARS, MERS, and

COVID-19 outbreaks. Although the importance of SSEs in

COVID-19 was recognized by this study, more data from fu-

ture accumulated epidemiology studies are needed to justify

these findings.

6. Conclusion

Taken all together, management of SSEs is mandatory to

yield efficient control over SARS-CoV-2. This is achievable

through early diagnosis of pre/asymptomatic infected indi-

viduals within potential super spreading groups. Prevention

of outbreaks is more essential, especially due to the lack of

efficient vaccination and therapeutic protocols, which ne-

cessitates efficient monitoring, as SARS-COV-2 virus follows

complex infectious patterns. The SARS-COV-2 epidemiolog-

ical models that do not take SSEs into consideration seem to

lead to confusing results with high uncertainty. SARS-CoV-

2 causes prolonged "pandemics" through complex adapta-

tion routes. Currently, in addition to the high technology uti-

lized for diagnosis, clinical observation is indispensable to

deeply comprehend SSEs and prohibit further outspread of

COVID-19. Reference laboratories with efficient and accred-

ited molecular and serological diagnosis must be inter-linked

between countries. All these parameters could contribute to

avoiding a second blind unjustified response that character-

ized the first COVID-19 pandemic spread. Understanding the

epidemiology of COVID-19 through SSEs could be preventive

for future epidemics. A systematic meta-analysis research

methodology, when COVID-19 epidemiology data accumu-

late further, would be advisable to confirm the conclusions

of this study.

7. Declarations

7.1. Ethics approval and consent to participate

This study did not involve the participation of any humans or

animals as it was based only on literature research.

7.2. Consent for publication

All authors agree to publish this manuscript.

7.3. Availability of data and materials

All data used for this manuscript are available upon request

7.4. Competing interests

All authors declare that they have no competing interests.

7.5. Funding

No funding or grant was received for this study.

7.6. Acknowledgements

We thank our families for providing moral assistance to ac-

complish this study.

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11 Archives of Academic Emergency Medicine. 2020; 8(1): e74

7.7. Author contribution

AK inspired the conception and drafted the initial

manuscript. JK revised substantially the manuscript, in-

tellectual content and provided disclosed data for HBV

investigation. AK and JK made the primary double-blind

search. AP, JK, AK, MN, and NG, made all other searches.

AP contributed to the immunology aspect of manuscript.

AP and NG aided in the clinical part and preparing the

final version of the manuscript. MD contributed to biblio-

graphical search and revision of the manuscript. All authors

contributed to the English editing of the manuscript. âĂČ

7.8. Abbreviations

SARS: Severe acute respiratory syndrome.

SARS-COV-2: Severe acute respiratory syndrome coronavirus

-2.

SSEs: Super spread events.

COVID-19: Coronavirus disease 2019.

SADS: Swine acute diarrhea syndrome.

Ro: Basic reproduction number.

IQR: Interquartile range.

MERS-COV: Middle East Respiratory Syndrome coronavirus.

HIV: Human Immunodeficiency virus

HBV: (Human) Hepatitis B virus

HCV: (Human) Hepatitis C virus

ADE: Antigen dependent enhancement

DIV: Double Inactivated virus

Th: T helper (cell)

RT-qPCR: Reverse transcriptase quantitative polymerase

chain reaction

ACE-II: Angiotensin converting enzyme II

MRSA: Methicillin resistant Staphylococcus aureus

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