10.14639/0392-100X-suppl.1-42-2022-01
The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has once again stigmatised the importance of airborne pathogens and their clinical, social and public health impact. Respiratory viruses are transmitted between individuals when the pathogen is released from the upper airways or from the lower respiratory tract of an infected individual. Airborne transmission is defined as the inhalation of the infectious aerosol, named droplet nuclei which size is smaller than 5 mm and that can be inhaled at a distance up to 2 metres. This route of transmission is relevant for viral respiratory pathogens, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS)-CoV, influenza virus, human rhinovirus, respiratory syncytial virus (RSV) and other respiratory virus families that differ in viral and genomic structures, susceptibility of a population to the infection, severity, transmissibility, ways of transmission and seasonal recurrence. Human respiratory viruses generally infect cells of the upper respiratory tract, eliciting respiratory signs and symptoms, sometimes without the possibility to differentiate them clinically. As seen by the current Coronavirus Disease 2019 (COVID-19) pandemic, human respiratory viruses can substantially contribute to increased morbidity and mortality, economic losses and, eventually, social disruption. In this article, we describe the structural, clinical and transmission aspects of the main respiratory viruses responsible for endemic, epidemic and pandemic infections.
text/xml
1827-675X
2103
en
Nicola Petrosillo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
health system
New endemic and pandemic pathologies with interhuman airborne transmission through ear, nose and throat anatomical sites
Text.Serial.Journal
https://www.actaitalica.it/
42
Annual congress report
2022-04-26
2022-04-06
2022-04-28
2022-04-28
S5-S13
1
Nicola Petrosillo
2022/04/26
10.14639/0392-100X-suppl.1-42-2022-01
S5
Infection Control & Infectious Disease Service, University Hospital Campus Bio-Medico, Rome, Italy
1827-675X
health system
S13
New endemic and pandemic pathologies with interhuman airborne transmission through ear, nose and throat anatomical sites
https://www.actaitalica.it/article/download/2103/762
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42(SUPPL.1):S5-S13; doi: 10.14639/0392-100X-suppl.1-42-2022-01




New endemic and pandemic pathologies
with interhuman airborne transmission through ear,
nose and throat anatomical sites
Nuove patologie endemiche e pandemiche con trasmissione aerea interumana
attraverso siti anatomici di orecchio, naso e gola
Francesco Di Gennaro1, Nicola Petrosillo2
1
 Clinic of infectious Diseases, University of Bari, Aldo Moro, Bari, Italy; 2 Infection Control & Infectious Disease Service, University
Hospital Campus Bio-Medico, Rome, Italy


SUMMARY
The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic
has once again stigmatised the importance of airborne pathogens and their clinical, social
and public health impact. Respiratory viruses are transmitted between individuals when
the pathogen is released from the upper airways or from the lower respiratory tract of an
infected individual. Airborne transmission is defined as the inhalation of the infectious
aerosol, named droplet nuclei which size is smaller than 5 mm and that can be inhaled
at a distance up to 2 metres. This route of transmission is relevant for viral respiratory
pathogens, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle
East respiratory syndrome (MERS)-CoV, influenza virus, human rhinovirus, respiratory
syncytial virus (RSV) and other respiratory virus families that differ in viral and genomic
structures, susceptibility of a population to the infection, severity, transmissibility, ways of
transmission and seasonal recurrence. Human respiratory viruses generally infect cells of
the upper respiratory tract, eliciting respiratory signs and symptoms, sometimes without the
possibility to differentiate them clinically. As seen by the current Coronavirus Disease 2019
(COVID-19) pandemic, human respiratory viruses can substantially contribute to increased
morbidity and mortality, economic losses and, eventually, social disruption. In this article,
we describe the structural, clinical and transmission aspects of the main respiratory viruses
responsible for endemic, epidemic and pandemic infections.                                          Received: February 3, 2022
                                                                                                    Accepted: February 10, 2022
KEY WORDS: SARS, MERS, SARS-CoV-2, COVID-19, H1N1, RSV, pandemic, health
system
                                                                                                    Correspondence
                                                                                                    Francesco Di Gennaro
RIASSUNTO                                                                                           Clinic of Infectious Diseases, University of Bari,
L’attuale pandemia di SARS-CoV-2 ha ancora una volta stigmatizzato l’importanza dei                 Aldo Moro, p.zza G. Cesare 3, 70123 Bari, Italy
patogeni respiratori e il loro impatto clinico, sociale e di salute pubblica. I virus respiratori   E-mail: francesco.digennaro1@uniba.it
si trasmettono tra gli individui quando l’agente patogeno viene rilasciato dalle vie aeree
superiori o dal tratto respiratorio inferiore di un individuo infetto. La trasmissione per via        How to cite this article: Di Gennaro F, Petrosillo
aerea è definita come l’inalazione di particelle aereosolizzate infette di dimensioni inferiori       N. New endemic and pandemic pathologies with
a 5 mm, che può essere inalato a una distanza fino a 2 metri. Questo modo di trasmissione             interhuman airborne transmission through ear,
è rilevante per gli agenti patogeni respiratori virali, tra cui il coronavirus della sindrome         nose and throat anatomical sites. Acta Otorhi-
respiratoria acuta grave (SARS-CoV), la sindrome respiratoria del Medio Oriente (MERS)-               nolaryngol Ital 2022;42(SUPPL.1):S5-S13.
CoV, il virus dell’influenza, il rinovirus umano, il virus respiratorio sinciziale (RSV) e altre      https://doi.org/10.14639/0392-100X-sup-
                                                                                                      pl.1-42-2022-01
famiglie di virus respiratori che differiscono per strutture virali e genomiche, suscettibilità
delle popolazioni all’infezione, gravità, trasmissibilità, modi di trasmissione e ricorrenza
                                                                                                    © Società Italiana di Otorinolaringoiatria
stagionale. Questi virus respiratori umani generalmente infettano le cellule del tratto re-         e Chirurgia Cervico-Facciale
spiratorio superiore, suscitando segni e sintomi respiratori, a volte senza la possibilità di
essere differenziati clinicamente. Come evidenziato dall’attuale pandemia di COVID-19, i                           OPEN ACCESS
virus respiratori umani possono sostanzialmente contribuire ad aumentare la morbilità e la
mortalità, con un notevole impatto sociale ed economico. In questo articolo, descriviamo            This is an open access article distributed in accordance with
                                                                                                    the CC-BY-NC-ND (Creative Commons Attribution-Non-
gli aspetti strutturali, clinici e di trasmissione dei principali virus respiratori responsabili    Commercial-NoDerivatives 4.0 International) license. The
di infezioni endemiche, epidemiche e pandemiche.                                                    article can be used by giving appropriate credit and mentio-
                                                                                                    ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: SARS, MERS, SARS-CoV-2, COVID-19, H1N1, RSV, pandemia, sistemi                       only in the original version. For further information: https://
sanitari                                                                                            creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                              S5
F. Di Gennaro, N. Petrosillo




Introduction                                                    ed by the coevolution of hosts and viruses. Although it is
                                                                early in the co-evolutionary history of SARS-CoV-2 and
The current SARS-CoV-2 pandemic has once again stigma-          the human host, complementary theoretical insights into
tised the importance of airborne pathogens and their clini-     the dynamics of host-pathogen interactions are becoming
cal, social and public health impact. Respiratory viruses are   relevant, e.g., the possibility of endemic equilibria 6.
transmitted between individuals when the pathogen is re-        Drivers of disease dynamics can be conceptualised as a
leased from the upper airways or from the lower respiratory     sequence of rings in a chain of infection which, in turn,
tract of an infected individual 1. Actually, pathogen drop-     relates to the life cycle of the pathogen and present dif-
lets released from respiratory events are the primary means     ferent opportunities for intervention. The first link in the
of dispersion and transmission of organisms that colonise       chain of infection is the pathogen itself. SARS-CoV-2 is
or/and infect the upper airways. During breathing, talk-        an RNA virus, with the potential for high rates of muta-
ing, singing, shouting, coughing and sneezing, individuals      tion and recombination and therefore a high diversity of
harbouring pathogens in the upper airways may produce           genotypes 7. Mutations may contribute to enhancement of
small saliva particles (droplets) and aerosols containing       viral proliferation and infection as well as escape from host
those pathogens 2-4. Airborne transmission is defined as the    immune attack 8.
inhalation of the infectious aerosol, named droplet nuclei      The chain of infection can be interrupted at the point of
which size is smaller than 5 mm and which can be inhaled        the reservoir, including other hosts (primary, intermediate)
at a distance of up to 2 metres. This way of transmission is    and the wider environment. Currently there is no evidence
relevant for viral respiratory pathogens, including severe      of animal reservoirs for SARS-CoV-2, and therefore no
acute respiratory syndrome coronavirus (SARS-CoV),              ongoing transfer to humans, other than from the original
Middle East respiratory syndrome (MERS)-CoV, influenza          hypothesised primary host (bats) in China. SARS-CoV-2
virus, human rhinovirus, respiratory syncytial virus (RSV)      can survive in the abiotic environment with half-lives of
and other respiratory virus families that differ in viral and   up to nine days, depending on the nature of the substrate
genomic structures, susceptibility of the populations to the    and the temperature 9. Coronaviruses can persist in aqueous
infection, severity, transmissibility, ways of transmission     solutions for several weeks, again with a strong inverse cor-
and seasonal recurrence.                                        relation with temperature 10. Various disinfectants are effec-
These human respiratory viruses generally infect cells of       tive at inactivating the virus and therefore the abiotic envi-
the upper respiratory tract, eliciting respiratory signs and    ronment is a potential target for disruption of COVID-19
symptoms, sometimes without the possibility to differenti-      dynamics 11.
ate them clinically. As seen by the current COVID-19 pan-       The third ring is represented by the transfer of the virus be-
demic, human respiratory viruses can substantially contrib-     tween human hosts, which has been the main target of con-
ute to increase morbidity and mortality, economic losses        trol measures, including use of masks, reduction of social
and, eventually, social disruption 5.                           activities, contact tracing, quarantine and physical/social
                                                                distancing. As with other viruses transmitted through the
Methods                                                         respiratory route, SARS-CoV-2 is primarily transmitted by
                                                                droplets, airborne route and contact with contaminated sur-
To carry out this narrative review we searched PubMed,          faces and fomites (which in turn relate to the properties of
Scopus, Google Scholar, EMBASE, Cochrane Library, and           the abiotic environment), and by aerosol formation during
WHO websites from 1950 to January 2022 to identify arti-        invasive respiratory procedures. Some concern has been
cles discussing structural, clinical and transmission aspects   raised by the respiratory shedding of virus which peaks at
of the main respiratory viruses responsible for endemic,        the end of the first week after infection, just before and as
epidemic and pandemic infections.                               symptoms are developing 12. Although testing of convales-
                                                                cent COVID-19 patients has provided evidence for persis-
The chain of transmission for pathogens                         tent RNA shedding, there is no suggestion of chronic carri-
transmitted through the airborne route:                         ers of SARS-CoV-2.
                                                                The last ring of the chain of infection is represented by the
the case of COVID-19                                            characteristics of the susceptible human host. Host deter-
Predicting changes in the spread of COVID-19 requires un-       minants are an important ring in the chain of transmission
derstanding of the interaction between natural processes,       for infectors and infectees. Indeed, for infectors, tissue
such as host immunity, and interventions such as physical       and cellular tropism for virus replication can be important
distancing. A framework for natural processes is provid-        determinants for contagiousness and transmission of res-



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                                                                            Interhuman airborne transmission through ENT anatomical sites




piratory viruses. Whereas SARS-CoV replicates mainly              Below we describe the structural, clinical and transmission
in epithelial cells of the alveoli, SARS-CoV-2 replicates         aspects of the main respiratory viruses responsible for en-
predominantly in upper respiratory ways and in the bron-          demic, epidemic and pandemic infections.
chial epithelium, thus explaining its more efficient trans-
mission 13. The Omicron variant of SARS-CoV-2 appears             Coronaviruses
to be more efficient in transmission because tropism for
the epithelial cells of the otolaryngological anatomic sites      Coronaviruses (CoVs), enveloped positive-sense RNA vi-
seems higher than for the Wuhan and Delta variants 14. As         ruses, were isolated for the first time in 1960 as disease-
a consequence, host nasal or throat viral shedding is an im-      causing agents in humans. There are four genera (alpha,
portant determinant for contagiousness and transmission.          beta, gamma, and delta), with alpha and beta receiving the
For influenza A virus, however, otolaryngological site            most attention due to their propensity to cross animal-hu-
viral shedding alone seems does not completely explain            man boundaries and to cause relevant human diseases.
household transmission 15. Other factors have been hypoth-        There are seven known beta human Coronaviruses
esised, including the presence of superspreaders, and pr-         (HCoVs), including Severe Acute Respiratory Syndrome
esymptomatic shedding. For SARS-CoV-2, levels of viral            (SARS)-CoV (SARS-CoV), Middle East Respiratory Syn-
shedding seem to be similar between presymptomatic and            drome (MERS)-CoV (MERS-CoV), SARS-CoV hCoV-
symptomatic infected individuals, thus determining a silent       HKU1, and hCoV-OC43, as well as hCoV-NL63 and
presymptomatic transmission and a consistent fraction of          hCoV-229E from the genus alfa.
infected individuals from asymptomatic COVID-19 indi-             The coronaviruses hCoV-HKU1, hCoV-OC43, hCoV-NL63
viduals 16,17.                                                    and hCoV-229E cause asymptomatic or moderate respira-
Another important point is the fact that pre-existing immu-       tory and gastrointestinal infections, accounting for 5-30%
nity and vaccination can “modulate” viral shedding from           of common colds 24. However, attention to this family of
infectors 18-20. In the recent forth wave of the COVID-19 pan-    viruses only began with the first global outbreak caused by
demic, highly sustained by Omicron, boostering by a third         the SARS-CoV in 2002. To date, only three highly patho-
vaccine administration can partly explain the higher rate of      genic and lethal hCoVs are known, namely SARS-CoV,
asymptomatic or paucisymptomatic SARS-CoV-2 infected              MERS-CoV and SARS-CoV-2 25. In this section we will
individuals, who manifest only congestion, runny nose and         summarise structural, transmission and clinical findings of
sore throat. Passive immunisation in early infected COV-          this family of viruses.
ID-19 patients has been shown to decrease the rate of hospi-
talisation for COVID-19 in acute and intensive care units 21.     SARS and MERS
Similarly, new antivirals have been introduced in clinical
practice to decrease the viral load in early infected individu-   SARS was the first new disease of the 21st century of global
als 22. Fully vaccination coverage, new vaccines and mono-        interest. The virus was first identified in Foshan, Guangdong
clonal antibodies targeted against new variants are probably      Province, China, in mid-November 2002. However, only
the main steps to reduce the burden of susceptible hosts.         in February 2003 did the virus spread to Hong Kong, and
From the side of infectees, tissue-specific expression of vi-     through international air travel it rapidly spread worldwide 26.
ral receptors angiotensin-converting enzyme 2 (ACE-2) 23          The association of the first SARS-CoV patients with wild
or glycosylation and glycan expression in the upper and           animal markets in Guangdong strengthens the hypothesis
lower respiratory tract may determine not only the most           that SARS-CoV emerged from wild animals (including
prevalent clinical manifestations, but also may affect con-       palm civets) sold at these markets 27. To confirm this, a CoV
tagiousness, as the case of virus-laden aerosols infecting        strain with a homology similarity of almost 99.9% was iso-
predominantly the nasal cavity 23.                                lated from palm civets at wild animal markets able to pass
Human genetic factors can also influence susceptibility           their hosts to humans causing human-to-human transmis-
to SARS-COV-2, including effects via blood group, HLA             sion 28. Also, as epidemiological criteria supporting this
genotypes and fibroblasts. The major genetic risk factor for      hypothesis, almost 80% of SARS-CoV patients claimed
severe SARS-CoV-2 infection and hospitalisation seems to          to have had contact with palm civets during the sporadic
be related to variations on human chromosome 3. Finally,          occurrence in Guangdong 29. Furthermore, other authors
the role of innate immunity against COVID-19 is under             found that farmed palm civets were free of SARS-CoV,
study, since exposure to microbial signals and to cytokines       while those sold in animal markets showed high IgG levels
trains myelomonocytic cells with enhanced effector func-          for SARS CoV 30. This corroborates the role of palm civ-
tion against microbial agents.                                    ets in the origin of disease.



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SARS-CoV is both contagious and virulent. Moreover, due                                     MERS-CoV is a zoonotic virus that infects people through
to its incubation period of up to 10 days, it can be spread                                 direct or indirect contact with ill dromedary camels, ac-
worldwide by asymptomatic carriers travelling worldwide                                     cording to several studies 35,37. MERS-CoV has been con-
with no symptoms 31. By the end of the pandemic in June                                     firmed in dromedaries in the Middle East, Africa and South
2004, there were 8422 cases worldwide with 916 deaths                                       Asia 38. The virus’s origins are unknown, although based
(11% mortality rate) 32. In Table I, we summarise the main                                  on the examination of multiple viral genomes, it is thought
findings.                                                                                   to have originated in bats and been transferred to camels at
The virus is spread from person to person through droplets                                  some point in the distant past.
produced by coughing and sneezing. In addition, infection                                   Both SARS and MERS have an average incubation pe-
can spread through contact with contaminated droplets on                                    riod of 5-days, and 95% of patients who develop symp-
surfaces 33. Fortunately, numerous studies have shown that                                  toms within 13 days after exposure. In both infections,
regularly used disinfectants such as Clorox, 75% ethanol                                    cough, asthenia, headache, fever, cold, cough and myalgia
and fixatives such as formaldehyde and paraformaldehyde                                     are common symptoms 39,40. Also, diagnostic confirma-
cause the virus to lose its infectivity 34.                                                 tion with a nasopharyngeal molecular swab with real-time
In September 2012, eight years after the first SARS-CoV out-                                Polymerase Chain Reaction (RT-PCR) can be facilitated
break, a new Coronavirus classified as MERS-CoV (Middle                                     by accurate history, which enhances the possibility of in-
East Respiratory Syndrome) was identified in Saudi Arabia 35.                               fection 41,42. MERS patients have a higher radiological in-
The first MERS cases were reported in Jordan in April 2012,                                 volvement (90-100%) than SARS patients (60-10%). This
but it was confirmed only later 36. So far, all MERS infections                             is linked to a higher need for intensive care and a higher
have been linked to travel or stays in or around the Arabian                                incidence of acute respiratory distress syndrome (ARDS)
Peninsula. Most MERS-CoV cases have been reported in                                        in MERS patients than with SARS 43,44. The fatality rate for
Middle Eastern countries, including Saudi Arabia, the United                                MERS, which is around 34%, is consistently higher than
Arab Emirates, Qatar, Oman, Kuwait and Iran 35.                                             the 9.6% mortality rate for SARS.
There were 2578 laboratory-confirmed cases of Middle                                        Diabetes, hypertension, renal failure and neoplasia are
East respiratory syndrome (MERS) from 2012 to 2018.                                         among the comorbidities that worsen the condition in both
Larger outbreaks occurred in South Korea in 2015 and                                        SARS and MERS patients. Furthermore, different studies
Saudi Arabia in 2018, with fatality rates of 34.3% in both                                  have revealed that older age and male sex are risk factors of
cases 37.                                                                                   poor outcome for both diseases 43,44.


Table I. Main characteristics of SARS-CoV, MERS, SARS-CoV2, VRS and H1N1.
                              SARS-CoV                 MERS                                   SARS-CoV-2                          RSV                           H1N1
 First isolation            16 November 2002,              4 April 2012, Zarqa,           7 December 2019,               1955, United States            1918, United States
                               Foshan, China                      Jordan                     Wuhan, China
 Family                   Betacoronavirus, lineage       Betacoronavirus, lineage       Betacoronavirus, lineage           Paramyxoviridae               Orthomyxoviridae
                                      B                              C                               B
 Host receptor                      ACE2                      DPP4 or CD26                         ACE2                        CX3CR1                       Sialic acid
 Reservoir and origin           Palm civets                Dromedary camels                       Unclear                    Chimpanzees                       Pigs
 Genome                             RNA                             RNA                            RNA                           RNA                           RNA
 Mode of                    Respiratory droplet,           Respiratory droplet,           Respiratory droplet,                Respiratory               Respiratory droplet,
 transmission                     Contact                         Contact                        Contact                                                     Contact
 Mortality rate                     9.6%                          34.3%                            4.4%                        < 1%                        0.03-0.8%
 Diagnosis                        rRT-PCR                        rRT-PCR                         rRT-PCR                        EIA                          rRT-PCR
 Blood test results          Lymphopenia and                  Lymphopenia,                   Lymphopenia,               Lymphopenia, ­AST,­ALT,         Lymphocytosis and
                                leukopenia                  thrombocytopenia               thrombocytopenia,                   ­PCR                        leukopenia
                                                                                               leukopenia,
                                                                                                   ­LDH
 Long sequalae                        Yes                            Yes                            Yes                            No                            No
 Vaccine                              No                             No                             Yes                            No                            Yes
ACE2: Angiotensin-converting enzyme 2; DPP4 or CD26: Dipeptidyl peptidase-4 (DPP4), also known as CD26 (cluster of differentiation 26); CX3CR1:C-X3-C Motif Chemokine Receptor
1; RNA: Ribonucleic acid; rRT-PCR: Reverse transcription polymerase chain reaction; EIA: enzyme immunoassay; SARS: Severe acute respiratory syndrome; MERS: Middle East
respiratory syndrome; SARS CoV2: Severe acute respiratory syndrome coronavirus 2; VRS: Respiratory syncytial virus; ALT: alanine aminotransferase; AST: aspartate aminotransferase;
PCR: polymerase chain reaction.




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                                                                            Interhuman airborne transmission through ENT anatomical sites




Furthermore, follow-up studies on SARS and MERS pa-                  cells such as neutrophils and monocytes release high
tients have showed that long-term sequalae occur in nearly           amounts of pro-inflammatory cytokines such as interleu-
20-60% of individuals with asthenia, chronic tiredness, re-          kin-6, interleukin-1 and tumour necrosis factor, which
duced lung function and worse quality of life at two years           are linked to disease severity and death 60,61;
after infection 44-46. Anxiety, post-traumatic stress disorder    2. hypoxaemic respiratory failure: some of the distinctive
and impaired performance at work are also reported in 20%            clinical features found in individuals with COVID-19
of MERS and SARS patients 47,48.                                     include the direct cytotoxic effects of the virus and the
                                                                     virus-induced reduction in surfactant levels, resulting in
SARS-CoV-2                                                           atelectasis. The pulmonary derangement of the disease is
                                                                     characterised by hypoxaemia, which occurs without any
The SARS-CoV-2 pandemic began when a significant                     indication of respiratory distress (‘silent hypoxemia’) 62;
number of atypical pneumonias were reported in December           3. COVID-19-related hypercoagulability: the cytokine
2019 in Wuhan, China 49. Within weeks, a new coronavirus             storm and virus-induced endothelial dysfunction work
was isolated: SARS-CoV-2. After only few months, the vi-             together in this process with a significant risk of throm-
rus had spread to 114 countries and on March 11th, 2020,             bosis in lungs or extrapulmonary areas 63,64.
the WHO declared SARS-CoV-2 as a global pandemic 50.              4. SARS CoV-2 has a 5-day incubation period, like SARS-
To date, exactly 2 years after the start of the pandemic,            CoV and MERS, with clinical features ranging from
more than 390 million cases with more than 5.7 million               asymptomatic to severe patterns, where interstitial pneu-
deaths are reported 51. No country in the world is virus free,       monia evolves into ARDS causing high mortality 65. Cur-
with significant direct and indirect impact on mortality and         rently, the mortality rate is of about 4%, but the global
control of other communicable and non-communicable dis-              scenario for this disease is changing with the start of the
eases, due to a major impact on health services, with outpa-         vaccination campaign in December 2020 66 and the ap-
tient services severely disrupted 52,53.                             pearance of new virus variants.
SASR-CoV-2 is a single-stranded RNA virus with posi-              Going beyond the acute phase, there is increasing evidence
tive polarity (28-32 kb). The virus has four structural pro-      about long COVID syndrome, with symptoms related to
teins: Spike (protein S), which allows the virus to bind to       COVID-19 persistent for 12 weeks after the acute infection
the membranes of the host cells, Envelope (protein E) and         episode. In particular, asthenia, myalgia, reduced working
Membrane (protein M) combine to form the Nucleocapsid             capacity can persist in 30-60% of cases 67. Also, anxiety
(protein N) capsid, which holds the genome. The S-glyco-          and depression related to previous SARS-CoV-2 infection
protein is what determines the virus’ specificity for respira-    appear to be frequent 68.
tory epithelial cells; in fact, it is known that SARS-CoV-2       In addition, multiple variants of the Wuhan type (Alpha,
can bind the ACE-2 receptor, which is expressed by cells in       Delta, Gamma, Mu, Zeta, Omicron, and many more) have
the capillaries of the lungs 54,55.                               been identified in the last two years of the pandemic 69,70,
The specific origin of the new coronavirus is unclear, and        which has an influence on both clinical management and
no theory has been ruled out. A possible zoonotic aetiol-         global health policy, which we will not address in this paper.
ogy has been postulated by several ideas proposed in early
investigations (such as SARS and MERS) 56. In particular,
Bungarus multicinctus, a highly venomous snake trafficked
                                                                  H1N1
in the Wuhan wet market, was suspected by several sci-            H1N1 influenza was first isolated in military troops during
entists to be the source of the disease. Since most of the        the 1918-1919 pandemic in the United States. One third
first affected people worked in that market, it was suspected     of the world’s population was affected, around 50 million
that an early strain of the virus had arrived and spread to       people died globally, of whom about 675,000 in the United
the province and adjacent territories. However, another zo-       States 71. Subsequent outbreaks of H1N1 swine flu were
onotic option might be the Malaysian pangolin, which is           recorded in the United States in 1976 and more recently
also sold in the Wuhan market 57-59.                              in April 2009, when a reassortant triple strain of influenza
It is known that SARS-CoV-2 has more of an indirect cy-           (H1N1) caused 2000 deaths in Mexico 72.
totoxic action than direct cytotoxicity. In fact, the action of   Influenza viruses are very unstable RNA viruses and can be
the virus is decoded in this triple activity:                     found in wild animals as reservoirs, allowing genetic muta-
1. cytokine storm: dysregulated or overactive immune re-          tions and reassortments 73. Currently circulating in humans
    sponses can cause significant systemic damage. In the         as seasonal influenza, H1N1 and H3N2 74 are subtypes of
    patient’s lung tissue and peripheral blood, mononuclear       influenza A that originated in birds and pigs 75.



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Until 1979, these strains had been the only one present in      with typical respiratory signs and symptoms, which may
Europe isolated from pig farms and with a clear lineage         be accompanied by lethargy, irritability and poor nutrition.
relationship to the 1918 pandemic virus 75. Subsequently,       Nasopharyngeal washes or tracheal secretions are better
since the 1980s, new strains of H1N1 swine influenza have       specimens for confirming RSV than nasal swabs, although
been isolated, such as the H1avN1 virus, showing rapid and      nasal swabs are the most widely used due to their conveni-
persistent adaptation in mammals 76. Subsequent viral re-       ence. Because of the short timeframe (less than 30 minutes),
assortments led to the development of different genotypes       low cost and objective end point, enzyme immunoassay is
such as H1N2 (H1huN2) with a higher capacity for gene           the quick detection test most used. A chest X-ray may show
reassortment and spreading 77.                                  a radiological image of pneumonia, with enhancement of
Crucial for the pathogenesis of the virus is the HA pro-        the bronchial pattern. In addition, especially in children ad-
tein, which is capable of drift and anti-hygienic shifts due    mitted to intensive care, concomitant battery overinfection
to the flexibility of the viral RNA-dependent RNA poly-         is frequent. The mortality rate is low, below 0.5/0.8%, but
merase 78. Indeed, previous pandemics are thought to have       with higher mortality in low-income countries due to the
been caused by changes in the HA protein, including re-         scarcity of resources and neonatal intensive care 87,88.
assortments and mutations between animals and humans.
Clinically, influenza has a short incubation period of about    Conclusions and recommendations
2 days (range, 1-5 days). The clinical presentation may
range from moderate to severe patterns, with fever, cough,      In the last 20 years we have experienced three different
bacterial overinfection and, in severe circumstances, acute     Coronavirus pandemics with progressively greater spread
respiratory distress syndrome (ARDS) and acute respira-         and impact on life and health systems, and learned to live
tory failure 79.                                                with RSV and H1N1 epidemics.
The H1N1 virus is now a common human flu virus with             Some reflections can be drawn from this:
low mortality rate (0.03-0.8%), which is related to comor-      • training on epidemic preparedness and response must
bidities and age of patients 80. The use of the 2009 H1N1          be an integral part of the educational and cultural back-
influenza virus vaccine has recently been approved, with           ground of health workers in order to always be prepared
positive implications for pandemic containment, patient            for what is no longer a sporadic or episodic event;
outcomes and maintenance of healthcare systems 81.              • a One Health approach, with high respect for nature and
                                                                   animals, is the basis for the prevention of infectious dis-
                                                                   eases. Deforestation, the use of exotic animals as food or
Respiratory syncytial virus, RSV                                   medicine and intensive animal husbandry may be at the
The human respiratory syncytial virus (RSV) is an envel-           root of current pandemics and responsible for future ones;
oped, non-segmented negative-strand RNA virus of fam-           • the indirect impact on other diseases cannot be neglect-
ily Paramyxoviridae able to cause respiratory tract infec-         ed. Health systems must have plan to avoid disruption of
tions especially in children with a seasonality between            diagnostic and therapeutic pathways;
December and February and between April and May 82,83. It       • team working should be central in the health section.
was first isolated in chimpanzees in 1955 and subsequently         Respiratory pathogens require a strong co-operation of
in infants with severe pulmonary disease 83.                       different specialists: infectious diseases specialists, mi-
The clinical presentation varies from mild infection of the        crobiologists, ENT specialists, pulmonologists and epi-
upper respiratory tract or otitis media to severe and life-        demiologists. Only thinking system-wide and working
threatening involvement of the lower respiratory tract 84.         together will it be possible to tackle current and future
The most common form in infants is bronchiolitis, with a           pandemics;
hospitalisation rate of about 3%. Preterm delivery, chronic     • vaccination is proving to be one of the most successful
lung disease of prematurity, low birth weight, Down syn-           strategies in the fight against SARS-CoV-2. Allowing
drome together with other chromosomal abnormalities, and           vaccination worldwide, including in low-income coun-
neuromuscular dysfunction are also risk factors for RSV-           tries, is necessary for justice but also to avoid the emer-
related hospitalisation or worsening of the condition and          gence of new variants;
admission to the critical care unit 85. RSV symptoms peak       • development of therapeutic strategies is a key pillar to
around day 5 and usually improve after 7-10 days. Due to           improve the outcome of our patients;
the prolonged recovery of the ciliated cells, the cough may     • developing cost-effective point-of-care tests can be cru-
last for up to four weeks 86. The diagnosis of acute bronchi-      cial for widespread diagnosis in remote areas, more in-
olitis is clinical and microbiological based on presentation       vestments are needed on this field;



S10
                                                                                          Interhuman airborne transmission through ENT anatomical sites




• long-term effects on patients and healthcare personnel                    8
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                                                                                 variations associated with mortality rate of COVID-19. J Hum Genet
  must be constantly monitored;                                                  2020;65:1075-1082 https://doi.org/10.1038/s10038-020-0808-9
• strengthening networks of molecular genomics labora-                      9
                                                                                 Riddell S, Goldie S, Hill A, et al. The effect of temperature on per-
  tories worldwide is indispensable for nipping future epi-                      sistence of SARS‑CoV‑2 on common surfaces. Virol J 2020;17:145.
  demics in the bud.                                                             https://doi.org/10.1186/s12985-020-01418-7
                                                                            10
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Conflict of interest statement                                                   and other coronaviruses in the environment and on common touch sur-
                                                                                 faces and the influence of climatic conditions: a review. Transbound
The authors declare no conflict of interest.                                     Emerg Dis 2021;68:296-312. https://doi.org/10.1111/tbed.13707
                                                                            11
                                                                                 Kampf G, Todt D, Pfaender S, et al. Persistence of coronaviruses on
Funding                                                                          inanimate surfaces and their inactivation with biocidal agents. J Hosp
This research did not receive any specific grant from fund-                      Infect 2020;104:246-251. https://doi.org/10.1016/j.jhin.2020.01.022
ing agencies in the public, commercial, or not-for-profit
                                                                            12
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sectors.                                                                    13
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                                                                                 competence, and innate immune responses of the coronavirus SARS-
Authors’ contributions                                                           CoV-2 in human respiratory tract and conjunctiva: an analysis in
FDG and NP conceived the idea. Both authors reviewed                             ex-vivo and in-vitro cultures. Lancet Respir Med 2020;8:687-695.
                                                                                 https://doi.org/10.1016/S2213-2600(20)30193-4
the literature, drafted the manuscript, critically revised, and             14
                                                                                 Shuai H, Chan JFW, Hu B, et al. Attenuated replication and
approved the final version before submission. Both authors                       pathogenicity of SARS-CoV-2 B.1.1.529 Omicron. Nature 2022;
have read and agreed to the published version of the manu-                       603:693-699. https://doi.org/10.1038/s41586-022-04442-5
script.                                                                     15
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The research was conducted ethically, with all study pro-                        MERS-CoV viral load dynamics, duration of viral shedding, and in-
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