Narrative review on century of respiratory pandemics from Spanish flu to COVID-19 and impact of nanotechnology on COVID-19 diagnosis and immune system boosting

The rapidly spreading throughout the existing highly contagious Severe-Acute-Respiratory-Syndrome-2 (SARS-2) or so-called Coronavirus 2019 (COVID-19) disease, reminded us of other pandemics that happened in the last century (H1N1 Spanish flu) and continued in the current century by (SARS, MERS, and COVID-19) [1‐3]. After a series of respiratory viral pandemic diseases that started in 1918–1919 by a mysterious and fatal disease called H1N1 Spanish Flu and some researchers called it Mother of Pandemics [4], due to this pandemic has infected more than a third of the world's population and claimed an approximate 50 million lives, with untypically extreme clinical symptoms in young, formerly disease-free adults, the pandemic has been a major cause of death [5]. In this regard, SARS-CoV-2 and 1918 influenza A/H1N1 viruses have some common properties, such as being of similar basic reproduction numbers (R0), varying from 2 to 4, and similar shedding patterns from infectious patients, and hence likely to have similar generation gaps. In tandem, COVID-19 may have a latency period similar to that of influenza [6]. Then, in the current millennium, the world has witnessed persistent viral attacks from a novel viral family called Coronaviruses (CoVs) [7]. CoVs, containing an Orthocoronavirus subfamily and a Torovirinae subfamily. The Orthocoronavirinae subfamily comprises four genera: the alpha coronavirus, the beta coronavirus, the gamma coronavirus and the delta coronavirus [8]. Beta coronavirus genera encompass from Severe-Acute-Respiratory-Syndrome (SARS), Middle-East-Respiratory-Syndrome (MERS), human CoV-229E (HCoV-229E), HCoV-OC43, and Corona Virus-2019 (COVID-19) [3].

In 2002, 2012 and 2019, the world was attacked by three viral respiratory diseases by the SARS, the MERS and the COVID-19, accordingly. Corona viruses are enveloped, non-segmented, positive-sense, monostranded RNA viruses that show a characteristic appearance under negative-staining electron microscopy [9].

The WHO reported that in the southern Chinese province of Guangdong, on November 2002, no update was received from the Government of China up to the month's end of March, a massive 792 cases and 31 deaths were reported. The ministry of health of China reported more than 8,000 cases.It is estimated that there were 1 thousand cases of disease and about 774 deaths, giving a lethality rate of about 7%. The reservoir host of the infection is thought to be the Asian civet cat (Paguma larvata). It was expected that the host-to-human transmission sites would be open markets, as is the case with the current COVID-19 outbreak. [10]. The global SARS epidemic was successfully controlled in July 2003, and no cases of SARS have been reported since 2004. [11]. The emergence of SARS was followed by MERS as the second most important coronavirus causing a world-wide public health emergency. First appeared in Saudi Arabia (KSA) in 2012 when a patient aged 60 with severe pneumonia [10]. An epidemic of the virus only became apparent in 2014, with a total identified case count of 662 and a case fatality index of 32.97%. From 2014 to 2016, 1364 cases were observed in KSA [10]. Overall, 27 countries have been affected by MERS during the epidemics, in Asia, Europe, the Middle East, and North America. [12]. The cases identified beyond the Middle East, including the South Korea (SK) epidemic in where 186 people have been found to be infected as a result of a supraspreading, have involved transplant recipients who have already been infected in the Middle East. Since 2012, a total of 2494 lab-confirmed cases of MERS have been reported, with 858 associated deaths (case-fatality ratio of 34.4%) [10].

With regard to COVID-19, WHO has raised the risk level of the CoV crisis to "very high" on 28 February 2020. On 11 March, as COVID-19 incidents outside China have increased by a factor of 13 and the number of infected countries has increased threefold to over 118,000 registered cases in 114 different countries, with more than 4,000 fatalities, the WHO declared COVID-19 a global pandemic. Governments around the world are working to put countermeasures in place to hold the potentially deleterious effects. Health organizations are coordinating the flow of information and issuing directives to best minimize the impact of the pandemic threat. Meanwhile, researchers from all over the world are working intensively and information on the transmission mechanisms, the clinical spectrum of the new diagnosis of the disease, prevention and treatment approaches is developing rapidly. Many unknown factors concerning the virus-host dynamic and the progress of the epidemic remain, including the timing of its peak [13].

Nanomaterials (NMs) have specific features that are unique, which characterize them as outstanding materials able to apply in spectrum devices, sensors, and techniques used in virus’s detection, treatment, and virus’s elimination from the environment [14]. A major part of the applications of NMs is to predict and treat viruses in the health care and environment. In this review, we are presenting a brief about some of these uses.

The avian influenza is distinguished for its capacity to contaminate various animal diversity, including species such as bats, birds and mammals. Even though successful interspecies transmission is rare, it plays a pivotal role in the generation of new vectors of the pandemic [14]. In the pandemic of 1918–1919, March 1918 was the start of the spring wave. It spread across the Europe, US, and Asia over the next six months. Although levels of disease were high, mortality rates in most places were not significantly higher than usual. A second or autumn wave spread around the world from September to November 1918 and was very fatal. In many countries, a third wave occurred in early 1919. Contemporary observers concluded from the clinical similarities that they were seeing the same infection disease in successive waves [4]. The mild forms of the epidemics in all three waves were typical of the influenza seen in the 1889 pandemic and the avian flu epidemic and previous inter-pandemic years. In view of this, even the quick progression from uncomplicated influenza infection to fatal pneumonia, characteristic of the autumn and winter waves of 1918–1919, was observed in the few severe cases in the spring wave [4, 15].

Up until 2003, only 2 CoVs, Human CoV 229E (HCoV-229E) and HCoV-OC43 have been known to lead to human disease [16]. It manifests as mild symptoms such as a common cold in adults and more serious illness in infants, the old and immunocompromised people. In November 2002, numerous exceptional cases of "atypical pneumonia" of unexplained reason reported in the city of Foshan, Guangdong Province, In China, where many health staff have been contaminated [17]. This was introduced to Hong Kong on 21 February 2003 by a doctor who dealt with similar cases of SARS in the Chinese mainland, which resulted in widespread of serious pneumonia in Hong Kong and labelled by WHO as “severe-acute respiratory-syndrome” on March 15, 2003 [18, 19]. Months passed, and a number of incidents of SARS have been identified prior to SARS-CoV was identified. A new b-CoV (SARS-CoV) of lineage B was confirmed as the cause of the SARS pneumonia cases on 22 March 2003. The SARS-CoV pandemic has spread to 29 countries and regions. It was clear that the world's health, medical and scientific development communities were not sufficiently prepared for the emergence of SARS. [18]. Human-to-human chains of transmission have emerged in Canada, Toronto, Chinese Taipei, Hong Kong, China, Vietnam Singapore and Hanoi. The SARS epidemic had a short history and the WHO announced the winding down of the SARS epidemic in July 2003 [18].

Ten years since the last sign of SARS-CoV, in June 2012, a man died in KSA of serious pneumonia and kidney weakness [20]. A newly discovered corona-virus, the Middle-East-Respiratory-Syndrome-Coronavirus (MERS-CoV), has been identified from his sputum [21]. A group of severe-respiratory illness cases had emerged in April 2012 in Jordan in a hospital and were diagnosed in retrospect as MERS12, and a group of three MERS infected cases in the UK were detected in September 2012 MERS-CoV has continued to rise and expand outside the "Arabic peninsula”. As a consequence of travel by contaminated individuals; frequently these newly transmitted MERS cases have resulted in hospital-acquired transmission.[22]. In May 2015, the MERS outbreak in SK was triggered by a single returnee from the Middle East and affected sixteen clinics and 186 cases. As of 26 April 2016, 1,728 MERS cases have been confirmed, of which 624 fatalities in 27 different countries [22].

A pneumonia group of cases linked to a recently discovered β-coronavirus appeared in Wuhan, China, in December 2019. On January 12, 2020, the World Health Organization (WHO) designated this coronavirus as the 2019-novel coronavirus (2019-nCoV) (WHO). International Committee proposed naming the newly identified coronavirus as SARS-CoV-2, both reported on 11 February 2020. Chinese scientists rapidly isolated SARS-CoV-2 from a patient on 7 January 2020. They came out to genome sequencing of the SARS-CoV-2. As of 1 July 2021, 91,833 cases of COVID-19 have been confirmed in mainland China including 4636 deaths. The basic reproduction number “R0” of SARS-CoV-2 has been assessed by studies to be around 2.2 or more (range 1.4–6.5), and family pneumonia outbreak groupings add to the proof of a steadily growing COVID-19 epidemic through human-to-human transmission (Fig. 1) [23].

According to the WHO (https://​covid19.​who.​int/​); globally, as of 8:36 pm CEST, 14 April 2022, there have been 500,186,525 confirmed cases of COVID-19, including 6,190,349 deaths, reported to WHO. As of 18 April 2022, a total of 11,307,908,653 vaccine doses have been administered.

Influenza viruses in different species are known to originate in wild waterfowl. (Fig. 2) [24]. Whilst human-pig transmission subtypes have already been shown and substantiated, direct transmission between birds and humans has been less prevalent (as in the case of H9N2 and H5N1 subtypes) but has in some cases resulted in fatalities. [25].

Regarding the reservoir of coronaviridae family which consists of beta-coronavirus that include three pandemics recently (SARS, MERS, COVID-19). Bats are a huge natural reservoir wide range of CoVs, including SARS-CoV-like and MERS-CoV-like viruses (Fig. 2). Following the virus's genomic sequence, COVID-19 was studied, the genome for Bat CoV RaTG13 showed 96.2 percent overall identity of the genome series, indicating the CoV bat Even human SARS-CoV-2 may have the same parentage. In contrast, bats aren't accessible for purchase in this seafood marketplace business. By the way, synchronization of protein sequences and further phylogenetic study revealed similar residues receiver was found in several species, which offered more possibilities for alternate intermediate hosts; For starters, tortoises, pangolin, and snacks [23].

All pandemics respiratory viruses are zoonotic airborne RNA viruses that are rarely transmitted between native forms of humans but could mutate to make human transmission more effective. Frequent and approved transmission routes droppings (> 5 mm diameter, flying Transmission' < 1 m) make contact with the nose with viable viruses, mouth, eyes, or upper airway and 'airborne transmission' where droplets (5 mm diameter) are kernels [27]. 2002 and 2003 were examples of the H1N1 influenza pandemic in SARS and 2009.

The function of 'direct communication of touch' (without the possibility of polluted surfaces) and 'indirect touch propagation' (including infected surfaces) of the distribution of such pandemic potential viruses have been controversial. Nonetheless, various reports and investigations have reported that indirect communication transmission is prevalent. The transmission path for other respiratory viruses, as well as influenza, under certain conditions [26].

Influenza virus replication occurs at the cellular level mainly in the epithelial cells of the intestinal tract in birds and in the epithelial cells of the respiratory tract in humans and other mammals [27]. In humans, ribonucleo-proteins (vRNPs) are subsequently transmitted into the nucleus of the diseased cells, in which viral RNA transcripts and replicates through the enzymatic activity of the viral polymerase complex attached to vRNPs [28]. The replication of viral RNA occurs via a positive intermediate, the complementary ribonucleoprotein complex [29]. Transcription of viral-RNA produces positive-stranded mRNA that is cap-linked and polyadenylated and then exported to the cytoplasm to be translated into viral proteins. [30]. Virus newly synthesised polymerases (PA, PB1,and PB2) and viral NP are imported into the nucleus to increase the rate of viral-RNA synthesis, while the viral membrane proteins HA, NA and M2 are transported and incorporated in the plasma membrane [31].

MERS-CoV and SARS-CoV have a specific coding mechanism in which about two thirds of the “viral RNA” is translated into two giant poly-proteins, while the remaining viral genome is transcribed in one nested series of subgenomic mRNAs [22]. Both pp1a and pp1ab, polyproteins encode sixteen non-structural proteins. (nsp1–nsp16) which bring up the viral replicase transcriptase complex [32]. The polyproteins are cleaved by papain-like protease (PLpro; corresponding to nsp3) two proteases, and The protease, 3C-like protease (3CLpro; corresponding to nsp5). nsps re-arrange membranes derivated from the rough endoplasmic reticulum (RER) into dual-membrane vesicles, in which the virus transcription and replication take place. The exoribonuclease (ExoN) function of nsp14 is a unique feature of coronaviruses, which supplies the correction capacity necessary to sustain a largescale RNA genome without accumulating harmful mutations. MERS-CoV and SARS-CoV transcribe 9 and 12 subgenomic RNAs respectively. These encode the four structural proteins, namely the spike protein (S), envelope (E), nucleocapsid (N),,membrane (M) and several accessory proteins that do not participate in viral replication but interfere with the host's innate immune response or whose function is unknown or misunderstood.

The envelope “E” spike glycoprotein “S” clings to its cellular receptor, angiotensin converting enzyme 2 (ACE2) for SARS-CoV and dipeptidyl peptidase 4 (DPP4) for MERS-CoV. The “viral RNA genome” is delivered into the cytoplasm after membrane fusion, emissions to the host cell membrane or to the endosome membrane. The RNA is unwrapped to permit translation of the two polyproteins, transcription of the subgenomic RNAs and replication of the viral genome. The resulting envelope glycoproteins are introduced into the RER or Golgi membranes; genomic RNA and nucleocapsid proteins coming together to form the nucleocapsids. Virus particles bud in the ER-Golgi intermediate compartment (ERGIC). The virus-containing vesicles then fuse with the plasma membrane to deliver the virus [22].

Regarding COVID-19 (Fig. 3), genomic RNA is utilized as a scaffolding to directly translate polyprotein 1a/1ab (pp1a/pp1ab), which encodes non-structural proteins (nsps) to make the replication-transcription complex (RTC) in double membrane vesicles (DMV). Eventually, a nested set of subgenomic RNAs (sgRNAs) is synthesised by the RTC in a discontinuous mode of transcription. These subgenomic messenger RNAs (sgRNAs) have common 5′-leader and 3′-terminal sequences. and Subsequent acquisition and Transcription termination of a leader RNA occurs at transcriptional regulatory sequences situated between open reading frames (ORFs). These minus-stranded gRNAs act as a template for subgenomic mRNA production.

A typical CoV genome and subgenomes include at minimum six ORFs. The first"ORFs (ORF1a/b), which account for about two-thirds of the total genome length, code for 16 nsps (nsp1-16), with the exception of Gammacorona virus, which has no nsp1. There is a − 1 frame shift between ORF1a and ORF1b, resulting in the production of two polypeptides: pp1a and pp1ab. These polypeptides are treated into 16 nsps by the virus-encoded chymotrypsin-like protease (3CLpro) or master protease (Mpro) and one or two papain-like proteases. Other ORFs on the third of the genome near the 3′-tip encode at least four major structural" proteins: (S), (M), (E) and (N) [33]. Various CoVs encode specific structural and accessory proteins,like the HE protein, the 3a/b protein and the 4a/b protein, in addition to these four basic structural proteins. CoV sgRNAs are used to translate all structural and accessory proteins [34].

Influenza A virus will turn hosts and create newly developed lineage [35]. This infection, known as zoonotic offers a chance to adapt the virus to the next host, and the resulting pandemics. When influenza A virus enters the body, the grippe HA (hemagglutinin) molecule accepts sialic acid (N-acetylneuraminic) around the top of the host cell [36]. HA is a transmembrane type of glycoprotein as homotrimer introduced to the virus sheet. Every monomer is composed of two subunits, HA2 and HA1. In the endosome low pH region, cleaved HA with a fusogenic HA2 stalk domain fusion mediates of the endosomal membrane with the viral membrane, which makes viral entry strong ribonucleoprotein (vRNP) to host cell [37].

The"vRNP complex comprises of 8 single-stranded, negative-sense nucleoprotein (NP) vRNA, and RNAs for influenza-A Polymerase"(PA, PB1, and PB2 compound)[28]. With subsequent fusion, the vRNP complex can be liberated in the cell's cytoplasm, after which it enters the nucleus by successful conveyance [37]. The nucleus is where the RNA synthesis of all influenza viruses takes place. Begin transcription process; RNA polymerase virus binds to highly retained and almost complementary 13 at the end of the 5' nuclear power and 12 at the end of the 3' nucleotide"eight segments. Nevertheless, the polymerase influenza virus has no inherent capping activity. It summarizes RNAs use 5 'host cap pre-mRNAs viral massager A special "cap snatching" mechanism mediation PB1 and PB2 derived from cellular transcriptions protein [28]. Nonstructural NS1 protein affects viral morphogenesis later in the viral replication cycle particles. However, they are not viral structural particles [38].

Receptor identification represents the initial stage of viral infection of host cells and one of the most essential factors in viral infection and pathogenesis [39]. While many other host- and virus-related factors can also influence the efficiency of infection and replication of the virus in a specific host, these factors only come into play once the virus is linked to a cell membrane receiver [40]. Coronaviruses (CoVs) have an enveloped, single-stranded-RNA genome that encodes four membrane proteins, namely spike, membrane, envelope, and nucleocapsid proteins as shown in Fig. 3 [2, 41]. S proteins are important for a viral entry concerning pathogenicity [42]. On the SARS-CoV envelope “E”, a trimeric S mediates the penetration of the virus into host cells. It first links to its host receiver, the angiotensin 2 converting enzyme (ACE2), and fuses the host and virus membranes afterward [43]. A given receptor-binding-domain (RBD) on the “S” SARS-CoV is sufficient to bind with high-affinity to ACE2 [44]. An important element in the pathogenesis of SARS-CoV and cross-species infections has been identified as the RBD/ACE2 binding affinity [45]. The experimental cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike proteins, that might have a significant consequences for the rapid manufacturing of antibodies and vaccines to combat 2019-nCoV, is therefore urgently needed [46].

Virulence factors are considered one of the vital element which plays a prominent role in virus adaption into the host cell [47]. Regarding pandemic influenza, Haemagglutinin (HA) is part of the surface glycoprotein of the virus. with two main roles in the very earliest phase of virus replication: membrane fusion and receptor linking [48]. HAs of high Avian influenza virus pathogen set an important contribution in virulence. They usually have a specific sequence (i.e. a sequence of basic amino acids at the cleavage site that helps to the prevalence of pathogenicity). [49]. This pattern, although it is not reflected in the HA sequence of 1918. Nevertheless, it had been shown that a reasserting virus with the genetic history 1918 HA repeated at a significantly elevated titer in the lungs, and with a large influx of lungs from neutrophils and alveoli macrophages caused severe pulmonary damage. The real 1918 virus with significant morbidity and subsequent death showed similar results. These results indicate an important role in the disease of the 1918 virus for the HA gene [50]. The high-virulence area (s) of HA has not yet been discovered. The other central factor in the 1918 outbreak is virulence. One unusual characteristic of the pandemic of 1918 was that many people have passed away of viral pneumonia; viral flu viruses in the pulmonary system of infected persons usually replicate poorly and often result in life-threatening viral pneumonia [51]. In the pulmonary system of infected filaments and non-human primates, we record an effective replication of the 1918 virus, which contributed to viral pneumonia.

In comparison, the lungs of infected animals did not have a contemporary human H1N1 virus, even though it reproduced in the nasal cavities. Therefore, we conclude that the 1918 virus's capacity to expand in the lungs is related to its high human virulence [51]. It is also noted that high virus titers were based on the NP genes and polymerase in the lungs of infected ferrets in 1918 [52]. Polymerase genes also are significant in the pathogenicity and transmission of the mouse in ferrets [53]. These results strongly involve viral RNA polymerase complex in the successful transmission of the virus to the low respiratory tract and indicate that, in combination with a particular HA, it may be sufficient to induce fatal pneumonia during the pandemic of 1918–1919 [54]. Pathogenicity can also be correlated with other viral factors like the case of pandemic NA, NS1, PB1-F2 and others in 1918. The pro-apoptotic viral protein PB1-F2 needs only the shift in one amino acid at the 66th position to enhance the virulence of the virus in 1918 [51]. The 1918 PB1-F2 expression encourages pulmonary pathology in primary viral and secondary bacterial infections [51].

Respecting beta coronaviruses (SARS, MERS, and COVID-19), they contain E protein consisting of several active motifs between 76 and 109 CoV-dependent amino acids given its limited size [55]. Modification or suppression of E protein in different CoVs resulted in viruses with different phenotypes and unusual interrelationships between the virus and the host including stress induction and protein reactions or changes in concentrations with cellular ion because of E protein ion channel activity [55, 56]. All these practices have an important effect on the pathogenesis of CoV. Furthermore, in COVID-19 “S” is the main defining of cell tropism and therefore interspecies transmission of CoVs, since it binds the virus to a cellular receptor and then catalyzes membrane fusion entry of the virus [57]. The electron-microscopy 3D structure of the 2019-nCoV viral S showed its similarity with the S of the other COVs [57]. The further characteristics of other CoVs may thus be deducted. Viral S is a transmembrane type I transmembrane protein with an n-terminal cleavable signal peptide, a large and highly n-glycosylated e, a transmembrane, and cytoplasmic tail embedded in an S-cyllated residue cluster [57]. The ectodomain has been divided into the highly variable S1 domain between the genera and the S2 domain that is more conserved and catalyzes membrane fusion. The recipient-binding operation causes pathogenicity [58].

The pandemic H1N1 influenza virus in 1918–1919 witness variations in signs and symptoms according to many factors such as the severity of the cases, individual's age, and season [59]. The mild, unclear illness as predominate in the spring herald waves included symptoms of the upper respiratory tract, such as sore throat, nasopharyngitis, and cough, as well as systemic manifestations of fever, myalgia, and prostration (Fig. 4) [60]. Epistaxis has been carried out in both mild and severe cases [61]. The physician reporting Three thousand cases at Camp Fremont noted that epistaxis was a common characteristic of the entire pandemic [60]. This was considered a characteristic of the disease as blood always poured from the nose and mouth of the patient. The duration of moderate illness was generally limited to 72 h. Typically, the cough was not productive. Fever was prevalent up to 104° F. Sometimes sudden and extreme prostration [62]. One definition of the patient as "quickly or almost unexpectedly seized with a sense of prostration that was completely incapable of doing what he could. There was significant respiratory distress in patients with severe illness [62]. Their symptoms included remarkably intense cyanosis, hunger in the air, reduced awareness, and diffuse bubbling rales of highly progressive lung edema (Fig. 4). The cyanosis of heliotropic cyanosis found in some patients before death after the heliotrope flower's deep blue or purple color. Physicians also first note that the lips and ears are intensely blue before focusing on the rest of the face [31]. In a letter to a colleague's doctor, some described the color as purplish-black and one Scottish doctor who works at camp Deven noted that "the men color to white are not easy to distinguish." In the abnormal pigment, a doctor determined that cyanosis is due to extensive exudations in the alveoli preventing proper oxygenation when a repeated spectrographic control of the patient's blood was not found [60]. Two psychiatric conditions related, acute respiratory disturbance. Rapid mortality syndrome (ARDS), and fatal cases were identified of bronchopneumonia. A secondary bacterial infection leading to bronchopneumonia caused the most deaths with pneumonia, except for those killed in 1918 after the epidemic of H1N1 [60]. Initial leukopenia was followed by bronchopneumonia leukocytosis [63]. Brundage and Shanks [64], recorded a median period of 7–10 nights from the onset of illness and several deaths > 15 days after the onset, in conjunction with secondary bacterial pneumonia, for the most affected population.

In the case of SARS, Fever, chilling, rigors, myalgia, dry toxins, dyspnea, malaise, and headache are the main distinguishing clinical features of SRAS [65]. More popular are sore throats, diarrhea, rhinorrhea, nausea, vomiting, and swelling [65]. In 40–70% of SARS patients, watery diarrhea was present. It tended to happen about 7 days after the onset of the disease [18]. Two patients complicated with epileptic status was detected in serum and cerebrospinal fluids. Elderly SARS-CoV infected patients may develop a low appetite, decrease in overall well-being, fall-fracture, and uncertainty, but may not be able to mount febrile responses to some elderly people [66].

In comparison, SARS-CoV infection was usually mild in kids under the age of 12. In contrast, infection in adult children was close to that in adults [67]. SARS-CoV-ac-Quired infection was connected to a lethality rate of 25%. during pregnancy, a high incident of spontaneous abortion, preterm delivery, and delayed development of the intrauterine child without perinatal SARS-CoV infection [18].

Adults who become infected with MERS-CoV may develop a range of illness and disease severity, from asymptomatic to slight, moderate or severe (Fig. 4) [68]. The time of incubation is from 2 to 14 days. Low-grade fever, runny nose, sore throat, dry cough and myalgia can occur in patients with mild infections. Patients with serious infections have acute pneumonia Syndrome of respiratory pain, a multilateral scheme organ failure, and disease. Furthermore, fellow members measure pneumonia progression by scoring the number of chest x-ray lung zones in patients with severe infection, showing abrupt progression after approximately seven days and severity pneumonia. The symptoms peaked afterward about fourteen days. MERS-CoV is greater in the lower respiratory tract samples than in the upper respiratory tract samples. Also, extrapulmonary characteristics are common, including myalgia. Back to half of all MERS-CoV patients, a third of critically ill people, including abdominal pains, nausea, vomiting, and diarrhea, are experiencing acute kidney injury. A third are gastrointestinal, and MERS-CoV in stool can be found [68].

Regarding COVID-19 fatigue and cough is myalgia or tiredness [69], most frequently reported symptoms. Expectoration, headache, haemoptysis and diarrhoea less frequent symptoms [70, 71], and in over half the patients, dyspnea developed (Fig. 4). The results of the blood tests showed that the white cell and lymphopenia were normal or reduced [72]. The typical ICU admission chest CT images were bilateral, multiple lobular, and sub-segment consolidation areas [73]. Non-ICU patients demonstrated bilateral ground-glass opacity and sub-segmental consolidation areas by representative chest CT conclusions [74]. Laboratory studies found that the most frequent symptoms are cough (67.7%), and fever (87.9%) while diarrhoea is uncommon.. 82.1% of ICU admitted patients reported lymphopenia [75].

The exact degree of pandemic morbidity and death from 1918 is not known because influenza does not differ from other respiratory diseases without laboratory confirmation [76]. Autopsy samples analyzed are mostly the pulmonary tissue of the fatalities that died in the autumn of 1918 [77]. There are also missing epidemiological details. The flu was not a reportable disease or illness monitored before the pandemic in any provincial or federal public health organization. After the pandemic death became apparent in the autumn of 1918, In addition, communities began to have physical offices to register cases of influenza [78].

Nevertheless, numerous cases avoided reliable reporting and/or timely reporting. In the American Public Health Journal of January 1919, the editor wrote in several cases that data was incomplete and deceptive because "the demand for intervention was so strong, that very few were willing to focus on research in the future [60]. Reported since the middle of the eighteenth century, significant pandemics have occurred between 10 and 40 years. Of these, the pandemic of "Spanish flu" in 1918 was the worst in the world, killing 20–40 million or more people (Fig. 5) [79].

In 2002 a SARS outbreak originating in Guangdong in China triggered the number-one major infectious disease of the twenty-first century, with 916 deaths among over 8098 patients in 29 countries. Ten years later, 2254 laboratory reported cases of MERS-CoV were declared by the WHO, with 800 deaths in 27 countries, from 2012 to 16 September 2018 [80] (Fig. 5). Significantly, over eighty percent of recent studies in virology and genetics of this infection have demonstrated that both MERS-CoV and SARS bats could be potential natural reservoirs. of confirmed cases of SARS, 22 percent were health workers in China and more than 40 percent were health workers in Canada [81]. Similarly, MERS nosocomial transmission was in the Middle East and in Korea. The cases reported in the Middle-East and North Africa have all contributed to the outbreaks in other countries, and their transmission due to international travel. Both SARS and MERS contributed to massive public health and economic outbreaks [80].

The pandemic of COVID-19 has swept into over 200 countries with notable confirmed cases and deaths. It has caused mental health stress and public panic [127]. The rapid dissemination of COVID-19, which started in China, has been characterized as a pandemic by WHO in March 2020 [128]. In February 2020, Egypt announced its first COVID-19 case. After that, Egypt scaled-up precautionary measures, with a partial lockout beginning in March 2020 [129]. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on nasopharyngeal swabs taken from symptomatic patients, and contacts of confirmed cases traced over the previous two weeks [130]. In individuals with a high suspicion rate, the test was repeated after 48 h [130]. The airport testing included body temperature and clinical assessment and the use of a rapid diagnostic test for severe-acute-respiratory syndrome IgM and IgG for coronavirus 2 [129].

The general public in China has severe anxious behaviors, resulting in a significant shortage of medical supplies. In addition, many frontline medical staff have been overworked for an extended period, which has prevented them from getting sufficient rest. There are indications that mental health problems may be occurring among health workers and survivors during the SARS epidemic [131]. However, the time distribution of the spread of COVID-19 may also commit to the heterogeneity of the disease burden across the US. The size and the time of the epidemiological peak, in particular, determine the required health system's responsiveness to provide proper healthcare. In many cases, it is challenging to obtain accurate data forecasts of the epidemic peak due to limited and often not trustworthy incidence data and the difficulties of modelling the effects of rapidly implemented and modified mitigation efforts [132]. Variability in county-level screening standards and actions, non-pharmaceutical interventions (NPIs) such as social distancing and outbreak initiation, and insufficient laboratory testing data also limit efforts to accurately model epidemic trajectories over several weeks [132]. In addition, projections of the cumulative burden of disease are less constrained by these difficulties. They do not attempt to describe the evolution of an epidemic over time. Even though these projections do not consider the nuance of the intensity and timing of outbreaks, their estimates of the disease burden's spatial footprint contain essential information for resource allocation [132].

During viral pandemics, various strategies have been used to limit the virus's propagation and treat infected and affected patients, such as quarantine, mass gatherings, facemasks, and hygiene [133].

Intravenous immunoglobulin (IVIg) therapy decreases intestinal epithelial cell infectivity. It reduces the growth of the opportunistic Candida albicans (human unicellular-fungal pathogen) in the murine gut in connection with the upregulation of anti-inflammatory cytokines coupled with downregulation of proinflammatory mediators [220].

CoVs cover positive-stranded-RNA viruses relating to the Coronaviridae family [221]. Viral RNA genome sequencing has shown that the virus-producing COVID-19 is phylogenetically linked to the SARS-associated CoV initial separated in Chinese horseshoe bats through 2015–2017. CoVs are extremely deadly with human-to-human communication, which has grievously-produced several losses. Unluckily, we were collectively disappointed to know that the opportunity was apparent, imminent, and important. We declined to ensure that the policies and directives, produced by specialists, can be quickly and efficiently performed in case of a disorder [222, 223].

Nanotoxicity is an evolving field used to assess the unintended hazardous effects of nanoparticles (NPs) on human health. While NPs have become promising tools for a wide range of biomedical applications, their extensive use depends on the assessment of their biosafety [245, 248, 258‐261]. There is increasing interest in assessing the health impact of these materials and expanding knowledge of their cytotoxicity and biocompatibility. Once a new nanomaterial appears, its cytotoxic effect, i.e., the possible alteration of basic cellular functions, is usually evaluated primarily. Nevertheless, the absence of cytotoxicity does not confer to these materials an implicit biocompatibility [262].

This must be assessed as a separate endpoint. The concept of biocompatibility is based on the adequate interaction between the nanomaterial and its biological environment, i.e. the non-existent toxic or immune response of the treated biomaterial (cell, tissue or organism) [262]. Cytotoxicity is generally related to the possible negative impact on a specific cell line. Thus, cytotoxicity is generally assessed first by specific tests conducted in vitro before being assessed in vivo. These tests can be performed in vitro (metabolic activity, cell proliferation and viability, oxidative stress, apoptosis tests, necrosis tests, etc.) and in vivo (behavioral analysis and body weight, biodistribution, biodegradation and clearance, pharmacokinetics, hematology and serum chemistry, histopathology, acute and repeated dose toxicity, reproductive and developmental toxicity, genotoxicity and mutagenicity, etc.) tests [262].

Regardless of whether in vitro or in vivo methods are used, the results of studies conducted on the toxicity of NPs are currently contradictory. Basically, it has been observed that cytotoxicity and biocompatibility are governed by several factors, including the inherent physicochemical properties of nanoparticles and the way they are delivered to the body. For example, a higher toxicity of nanoparticles was observed during oral and intraperitoneal administration compared to intravenous injection. In addition, biocompatibility was highly tissue or organ specific. The cytotoxicity of nanoparticles is also strongly related to physicochemical characteristics such as size, shape, surface area, and charge. All these elements show that the biocompatibility of nanoparticles is highly dependent on several factors, ranging from the intrinsic properties of the particles to the formulation, the biological target, the dose and even the methodology used to assess their toxicity [263].

In general, the smaller the size of the nanoparticles, the greater the cytotoxic effect. One of the hypotheses that could explain the toxicity of small-sized nanoparticles is that it results from the presence of a high surface area compared to their volume. This leads to an increased absorption capacity and may increase the risks of interaction with biomolecules [262, 263]. In addition, the dose of NPs administered to a model organism can also affect their toxicity. Similarly, Coradeghini et al. [264] revealed that the toxicity of Au NPs towards mouse fibroblast cell lines was dose-dependent.

Recently, Donskyi et al.[265], proposed graphene with precise double sulfate/alkyl functionalities as a platform for the inhibition of SARS-CoV-2 and feline coronavirus replication by virtue of viral envelope disruption. Notwithstanding using a wide concentration window (10 to 100 times), the graphene platforms show strong antiviral activity against native SARS-CoV-2 without significant toxicity against human cells. Hence, more research is needed on the effective doses and likely toxic effects of NPs to create a safe environment for humans against extremely dangerous diseases like COVID-19. Therefore, new specific standardization and certification tests (which include evaluation of physicochemical characteristics, sterility, pyrogenicity, bio-distribution and ADME, pharmacokinetics, and in vivo and in vitro toxicity) for preclinical nanosafety and toxicity risk study need to be developed. Efforts to standardize risk assessment procedures for NPs are ongoing and need to be further improved. Currently, nanomaterials are considered in the same way as conventional chemicals. The main efforts to standardize nanotechnology are being developed by the standards development organizations (SDOs).

Biodegradable nanoparticles (BNPs) are novel carriers for the delivery of drug molecules. They are receiving increasing attention due to their ability to serve as viable carriers for the specific delivery of vaccines, genes, drugs and other biomolecules to the body (Fig. 10). BNPs have become popular recently due to their special features such as targeted drug delivery, better bioavailability and therapeutic efficacy to deliver the drug at a constant rate. They offer improved biocompatibility, superior drug/vaccine encapsulation and convenient release profiles for a number of drugs, vaccines and biomolecules for use in a variety of applications in the field of nanomedicine [266‐269].

Polymeric nanoparticles are considered as biodegradable material. They are polymeric colloidal elements of very small size in which a drug of interest can be encapsulated or incorporated into their polymeric network or conjugated or adsorbed onto the layer. Various natural and synthetic polymers are used in the synthesis of biodegradable nanoparticles (Fig. 10), some of the frequently used polymers are chitosan, cellulose, gelatin, gliadin, polylactic acid and polylactic-co-glycolic acid. Nanoparticles have been progressively explored for drug delivery and have enabled sustained kinetic release. Drugs integrated in this system can give better efficacy, decrease drug resistance, reduce systemic toxicity and symptoms, and also improve patient compliance [268].

Recently, Qiao et al. [270], proposed a peptide-based subunit candidate vaccine against SARS-CoV-2 delivered by biodegradable mesoporous silica nanoparticles induced high humoral and cellular immunity in mice. Through this study, seven linear B-cell epitopes and three CD8 + T-cell epitopes were selected from the SARS-CoV-2 spike glycoprotein by immune computational approaches for vaccine design. A nanoparticle-based candidate vaccine (B/T@BMSNs) against SARS-CoV-2 was promptly prepared by encapsulating these ten epitope peptides into BMSNs, accordingly. The BMSNs, endowed with potential biodegradability and excellent in vitro and in vivo safety, demonstrated the ability to efficiently deliver the epitope peptides into the cytoplasm of RAW264.7 cells. Strong humoral and cellular Th1-like immunity was induced by B/T@BMSNs in mice and the 10 selected epitopes were identified as effective antigenic epitopes capable of inducing a robust peptide-specific immune response [270].

To optimize NPs as a delivery system, a better understanding of the different mechanisms of biological interactions and particle engineering is still needed. However, biodegradable NPs seem to be a promising system for drug delivery due to their versatile formulation, sustained release properties, subcellular size, and biocompatibility with various tissues and cells of the body. The development of nanomedicine remains a great challenge and other biodegradable nanomaterials still need to be explored and validated for their potential clinical use. Figure 10 provides a summary of the synthetic routes for biodegradable nanoparticles and their in vivo applications.

During the years 1919, 2002, 2012 and 2019, the world was attacked by four viral respiratory diseases, Spanish flu, SARS, MERS and COVID-19, respectively. Coronaviruses are single-stranded, non-segmented, enveloped, RNA-positive viruses that have a particular appearance under negative-stain electron microscopy. It is well known that wild waterfowl are the source of all influenza viruses in other species. Regarding COVID-19 fatigue and cough is myalgia or tiredness, most frequently reported symptoms. Sputum, headache, hemoptysis, and diarrhea were less frequent symptoms, and in over half the patients, dyspnea developed. During COVID-19 infection both inborn and adaptive immune cells are synergistically-involved in the anti-viral response. A significant increase in neutrophils, leukocytes, and neutrophil lymphocyte ratio has been identified in serious or critical cases of COVID-19 compared to mild cases. From currently available information and clinical expertise, the elderly and people of all ages with serious underlying health problems may be at increased risk of severe illness from COVID-19. The occurrence of pregnancy has been a strong risk factor for increased illness and mortality for both pandemic and seasonal influenza. During viral pandemics, a variety of different approaches were employed to limit or avoid the fast spread of the virus and treat infected patients such as quarantine, mass gatherings, facemasks, and hygiene. Today, anti-viral drugs are key in preventing and treating influenza virus infection and disease. Different medicines and approaches had been used for the treatments against COVID-19 such as remdesivir, favipiravir, ribavirin, chloroquine and hydroxychloroquine, glucocorticoids, teicoplanin and other glycol-peptides, monoclonal or polyclonal antibodies, convalescent plasma, and herbal medications. Vaccination is one of the most powerful ways for disease control and prevention, according to the WHO. A vaccine has the effect of helping the body's immune system to recognise and fight pathogens including the following viruses or bacteria, which then keepsrecognize and combat pathogens such as viruses or bacteria, which then recognize and fights pathogens like viruses or bacteria, thus protecting us from the diseases they induce. Intravenously introduced nanomaterial of natural and inorganic sources is growing attention in clinical sciences. The standard antiviral potential is achieved with NPs with less than 10 nm. In production, the NP's size stabilization (stabilizing or capping agents) process changes the anti-viral power. The NPs surface can be altered with special receptors to be attached with particular targets. In the innate immune system, phagocytosis guided by the stability of the signals of prophagocytic and antiphagocytic on target. This review presents insights about using NMs to give treatment to COVID-19 further, improve the bioavailability of the abused drugs, diminish their toxicity, and improve their performance.