The COVID-19 pandemic


In December 2019, an outbreak of pneumonia of unknown origin was reported in Wuhan, Hubei Province, China. Pneumonia cases were epidemiologically linked to the Huanan Seafood Wholesale Market. Inoculation of respiratory samples into human airway epithelial cells, Vero E6 and Huh7 cell lines, led to the isolation of a novel respiratory virus whose genome analysis showed it to be a novel coronavirus related to SARS-CoV, and therefore named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a betacoronavirus belonging to the subgenus Sarbecovirus. The global spread of SARS-CoV-2 and the thousands of deaths caused by coronavirus disease (COVID-19) led the World Health Organization to declare a pandemic on 12 March 2020. To date, the world has paid a high toll in this pandemic in terms of human lives lost, economic repercussions and increased poverty. In this review, we provide information regarding the epidemiology, serological and molecular diagnosis, origin of SARS-CoV-2 and its ability to infect human cells, and safety issues. Then we focus on the available therapies to fight COVID-19, the development of vaccines, the role of artificial intelligence in the management of the pandemic and limiting the spread of the virus, the impact of the COVID-19 epidemic on our lifestyle, and preparation for a possible second wave.


  • SARS-CoV-2
  • rRT-PCR
  • COVID-19
  • cytokine storm
  • pneumonia
  • ACE2
  • serology

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  1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the seventh human coronavirus, was discovered in Wuhan, Hubei province, China, during the recent epidemic of pneumonia in January 2020 [1,2]. Since then, the virus has spread all over the world, and as of 20 May 2020, it has infected 4,806,299 people, and caused 318,599 deaths [3]. SARS-CoV-2 as well as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) cause severe pneumonia with a fatality rate of 2.9%, 9.6% and ∼36%, respectively [4–6]. The other four human coronaviruses, OC43, NL63, HKU1 and 229E, generally cause self-limited disease with mild symptoms [7].

In this review, we summarize the state of art of COrona VIrus Disease 19 pandemic (COVID-19, as defined by the World Health Organization [WHO] in February 2020), including the origin of SARS-CoV-2, its ability to infect human cells, epidemiology, clinical pathological and laboratory findings, molecular and serological diagnosis and safety issues. We also provide information on available therapies, vaccine development, and the potential role of artificial intelligence in the governance of health care systems and its usefulness in fighting the COVID-19 outbreak.

  1. Origin of SARS-CoV-2

Since the discovery of the novel coronavirus, SARS-CoV-2, scientists have debated its origin [8]. It has been speculated that SARS-CoV-2 is the product of laboratory manipulations. However, genetic data does not support this hypothesis and shows that SARS-CoV-2 did not derive from a previously known virus backbone [9].

Genomes analysis and comparison with previously known coronavirus genomes indicate that SARS-CoV-2 presents unique features that distinguish it from other coronaviruses: optimal affinity for angiotensin converting enzyme 2 (ACE2) receptor and a polybasic cleavage site at the S1/S2 spike junction that determines infectivity and host range [8,10].

SARS-CoV-2 is highly similar to bat SARS-like coronaviruses [2] and bat might be the reservoir host. RaGT13 is ∼96% identical to SARS-CoV-2 with some differences in the spike receptor binding domain (RBD) that could explain the differences in ACE2 affinity between SARS-CoV-2 and SARS-like coronaviruses.

The polybasic cleavage site of SARS-CoV-2 is not present in pangolin beta-coronavirus, which share similarities with SARS-CoV-2. Also, the sequence of RBD of the spike protein (S) suggests that it arose from a natural evolutionary process [8].

Estimates of the most recent common ancestor of SARS-CoV-2 date the epidemic to between late November 2019 and the beginning of December 2019, which is compatible with the first reported cases [11]. Thus, there was unnoticed human transmission after the zoonotic event and before the acquisition of the polybasic furin cleavage site [8].

  1. Epidemiology

3.1. Disease presentation

Patients with SARS-CoV-2 infection may present symptoms ranging from mild to severe with a large portion of the population being asymptomatic carriers. The most common reported symptoms include fever (83%), cough (82%) and shortness of breath (31%) [12]. In patients with pneumonia, chest X-ray usually shows multiple mottling and ground-glass opacity [12,13].

Gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain are described in 2–10% of the patients with COVID-19 [12,14], and in 10% of patients, diarrhea and nausea precede the development of fever and respiratory symptoms [12].

COVID-19 patients usually show decrease lymphocyte and eosinophils counts, lower median hemoglobin values as well as increases in WBC, neutrophil counts, and serum levels of CRP, LDH, AST, and ALT [15]. Moreover, initial CRP serum levels have been reported to be an independent predictor for the development of severe COVID-19 infection [16,17].

Although the main target of coronavirus infection is the lung, the wide distribution of ACE2 receptors in organs [18] may lead to cardiovascular, gastrointestinal, kidney, liver, central nervous system and ocular damage that has to be closely monitored [19].

The cardiovascular system is often affected, with complications including myocardial injury, myocarditis, acute myocardial infarction, heart failure, dysrhythmias, and venous thromboembolic events, and monitoring with high sensitivity cardiac troponin may be useful [20].

Patients presenting with acute respiratory distress syndrome may worsen rapidly and die of multiple organ failure [12] induced by the so-called “cytokine storm”.

Indeed, a cytokine profile resembling the secondary hemophagocytic lymphohistiocytosis syndrome has been described in severe COVID-19 cases, and is characterized by increased interleukin (IL)-2, IL-7, granulocyte colony stimulating factor, interferon-γ inducible protein-10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis factor-α [11]. In addition, elevated levels of ferritin and IL-6 are predictors of fatality, and death is likely due to hyperinflammation induced by the virus [21]. Based on this evidence, tocilizumab (IL-6 receptor blockade) is administered to patients with COVID-19 pneumonia and elevated serum IL-6 to reduce inflammation in the lungs.

Elevation of D-dimer levels has been associated with the severity of COVID-19. Subjects with severe COVID-19 have significantly higher values of D-dimer than those without (weighted mean difference 2.97 mg/L; 95% CI: 2.47–3.46 mg/L) [22]. The elevated D-dimer levels may reflect the risk of disseminated coagulopathy in patients with severe COVID-19, which may require anticoagulant therapy [22].

The Italian Agency of Medicine (AIFA) has recently approved a clinical trial (INHIXACOVID19 study) in which enoxeparin is given subcutaneously to patients with COVID-19 to prevent thromboembolism-related complications. Heparin also has antiviral activity. It is known for its ability to prevent viral infection including coronaviruses infection. Indeed, heparin has a structure similar to that of heparan sulfate that is present on mammalian cellular surfaces and that is utilized by coronaviruses to enter cells [23,24]. In the presence of heparin, the interaction of the S protein with heparan sulfate may be blocked, thus preventing cell entry.

Furthermore, heparin may inhibit proteases involved in virus infectivity [25]. Indeed, SARS-CoV-2 entry requires the cleavage of the S1–S2 subunits followed by the fusion of S2 to the cell membrane. The latter requires the action of host proteases such as cathepsins, cell surface transmembrane protease/serine proteases (TMPRSS), furin, trypsin and factor Xa that are inhibited by heparin.

The course of COVID-19 disease in children is generally asymptomatic or mild compared to that seen in adults, for reasons that are yet to be clearly elucidated. Nonetheless, severe and fatal cases have been reported in children. Clinical laboratory data in children is quite different from adults as reported in a recent meta-analysis that showed an inconsistent alteration of the leukocyte index [26]; however, elevations in the levels of CRP, procalcitonin and LDH were also found in children with severe disease. Interestingly, creatine kinase-MB was elevated in one-third of patients and this raised the suspicion of cardiac involvement in COVID-19 pediatric patients, as recently reported [27].

3.2. SARS-COV-2 transmission

As with other respiratory viruses, SARS-CoV-2 transmission occurs with high efficacy and infectivity mainly through the respiratory route. Droplet transmission is the main recognized route, although aerosols may represent another important route [28,29]. Estimates of the reproduction number (R0) of SARS-CoV-2 range from 1.4 to 2.5 [Statement on the meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV),] to 2.24–3.58 [30].

Similar to SARS-CoV, the oral-fecal route may be another route of transmission of the virus. SARS-CoV-2 RNA has been detected in the stool of patient with COVID-19 pneumonia [31]. Therefore, sewage may have a role in the transmission of SARS-CoV-2. In light of that, technical treatment such as biosorbents capable of retaining and inactivating the virus should be considered [32].

SARS-CoV-2 has been detected in saliva of infected individuals [33]; this can be attributed to the presence of ACE2 receptors in epithelial cells lining the salivary gland ducts [34].

In some studies, patient urine has been tested for SARS-CoV-2 viral RNA. Amongst these studies, the pooled rate of RNA positivity was about 5–6%; nevertheless, the duration of viral shedding in urine samples as well as the infectivity of urine remains to be established [35].

SARS-CoV-2 RNA has also been detected on inanimate surfaces such as door handles and the surface of cell phones in residential sites of patients with confirmed COVID-19. Thus, individuals who have come into contact with infected surfaces could be infected if they touch their eyes, mouth or nose [29].

The vertical transmission of SARS-CoV-2 is debated; a series of nine pregnant women with confirmed COVID-19 showed no mother to child transmission. In addition, SARS-CoV-2 was not detected in breast milk, indicating that the virus cannot be transmitted with breastfeeding [36]. Nevertheless, a newborn with elevated IgM against SARS-CoV-2 born to a mother with COVID-19 has been recently reported. IgM antibodies along with IgG antibodies were detected 2 h after delivery. Il-6 and IL-10 were also elevated, while polymerase chain reaction (PCR) performed on consecutive nasopharyngeal swabs from 2 h to 16 days of age was always negative. Considering that IgM cannot cross the placenta and be transferred to the fetus, it could be hypothesized that the infant was infected in utero even if amniotic fluid was not tested for SARS-CoV-2 RNA [37].

Finally, the eyes may be a route of transmission of SARS-CoV-2. SARS-CoV-2 RNA was detected in ocular swabs of a patient with confirmed COVID-19 3 days after onset of symptoms and at 27 days when a nasopharyngeal swab tested negative by PCR. Interestingly, the virus from an ocular swab was propagated in Vero E6 cells, suggesting that ocular secretions could be infectious [38]. Although no conclusive data is available, goggles should be worn when examining patients with suspected or confirmed COVID-19 [39].

3.3. SARS-CoV-2 incubation period

Determination of the incubation period of SARS-CoV-2 infection is crucial for determining the duration of quarantine, to evaluate the efficacy of entry screening and contact tracing. Based on a Weibull distribution, it was estimated that the mean incubation period is 6.4 days (95% confidence interval (CI): 5.6–7.7), with a range of 2.1–11.1 days (2.5th–97.5th percentile) [40]. Similar estimates have been made by other authors. In a study by Lauer et al. [41], it was estimated that the median incubation period was 5.1 days (95% CI, 4.5–5.8 days), and that 97.5% of infected individuals would develop symptoms within 11.5 days (CI, 8.2–15.6 days) of infection. Therefore, the 14-day period of active monitoring recommended by health authorities is justified by the evidence [42,43]. Longer monitoring can be required in particular cases. It was estimated that 101 out of every 10,000 cases (99th percentile, 482) may develop symptoms after 14 days of active monitoring or quarantine [41].

  1. Viral testing

4.1. Reverse real-time PCR assays

Suspected cases of SARS-CoV-2 infection are confirmed by detection of specific and unique viral sequences using a reverse real-time PCR (rRT-PCR) assay. Immediately after the declaration by the Chinese Health Authorities, on 7 January 2020, that the pneumonia outbreak in Wuhan was caused by a novel coronavirus, a European network of laboratories developed an rRT-PCR protocol based on the alignment and comparison of available bat-related coronavirus and SARS-CoV genome sequences plus five sequences from the novel coronavirus SARS-CoV-2 that were released by the Chinese authorities [44]. Three rRT-PCR assays were developed. The first line assay targets the E gene common to the coronaviruses belonging to Sarbecovirus subgenus and encoding the envelope protein. The second assay targets the RdRp gene encoding the RNA-dependent-RNA-polymerase. This assay contains two molecular probes: one reacts with the SARS-CoV and SARS-CoV-2 RdRp gene, while the second one (RdRP_SARSr-P2) reacts with SARS-CoV-2 RdRp gene. The third assay targets the N (nucleocapsid) gene. This protocol was adopted in 30 European countries [45].

Recently, a new PCR protocol targeting a different region of the RdRp/Hel gene showed a higher sensitivity and specificity than the RdRP_SARSr-P2 assay [46].

The US Centers for Disease Control and Prevention (CDC) protocol targets the N gene of SARS-CoV-2. Two primer/probe sets directed toward different regions of N gene were selected. In addition, a primer/probe set that detects the human RNase P gene in control samples and clinical specimens is included ( Revision 3, 30 March 2020).

Although amplification tests are sensitive, some infections are missed. The reasons for this may be the quality of the collected specimen, time of collection (very early phase of infection or too late during infection), viral load below the limit of detection of the assay, incorrect handling of the specimen or shipping issues. In the case of low viral load in the upper respiratory tract, a deeper specimen may be required to make a diagnosis [47]. Indeed, in SARS and MERS patients, viral RNA in the upper respiratory tract peaked in the first 7–10 days after symptoms onset, while in the lower respiratory tract, viral RNA was still detected 2–3 weeks after disease onset [47,48]. Repeat testing can also be performed in the case of nasopharyngeal swabs initially being negative as this increases the chance of detecting SARS-CoV-2 in the nasopharynx [49].

Several real-time PCR assays obtained the CE mark for in vitro diagnostics and are available on the market. Table 1 summarizes the gene targets, the technical features of the assays and the validated specimen types of the real-time PCR assays cleared by the Italian Ministry of Health.

Table 1. Real-time PCR assays cleared by the Italian Ministry of Health for detection of SARS-CoV-2.

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Point of care tests (POCT) such as Xpert® Xpress SARS-CoV-2 (Cepheid, Sunnyvale, CA, USA) QIAstat-Dx Respiratory 2019-nCoV Panel (QIAGEN, Hilden, Germany), and Simplexa™ COVID-19 Direct kit (DiaSorin Molecular LLC, Cypress, CA, USA) deliver results in about 30-60 min. They do not require skilled technicians and the hands-on time is less than 1 min. These tests can be very useful when clinicians have to make rapid treatment decisions.

A sensitive rRT-PCR assay could be performed on pooled samples. In the present situation where shortage of reagents can be a problem, sample pooling can be a valid alternative to allow the screening of a large number of people in a short time frame. In a recent study, a positive single sample could be detected in a pool of up 32 samples with an estimated false negative rate of 10% [50]. Pooled screening could be implemented to detect SARS-CoV-2 in the community [50,51].

A recent paper showed that in confirmed COVID-19 patients, saliva may be a more sensitive specimen for SARS-CoV-2 detection than nasopharyngeal swab. The authors also reported less variability in self-sample collection of saliva compared to nasopharyngeal swabs. This observation could open the way to at-home self-administered sample collection for large-scale screening of SARS-CoV-2 [52].

The use of urine for diagnostic purposes is still the object of debate. The receptor ACE2, which is used by SARS-CoV-2 to infect human cells, is present not only in the respiratory tract but also in the urogenital system: renal proximal tubule cells, bladder urothelial cells, Leydig cells and cells in the testicular seminiferous ducts in testis [53]. Indeed, patients with COVID-19 may present with kidney damage (proteinuria, elevated serum creatinine, high urea) or severe acute kidney failure. Damage to the reproductive system may occur as well [53]. Taken together, these data suggest that the urogenital system may represent a route of transmission of SARS-CoV2. Some authors reported the identification of the virus in urine [54]. Nevertheless, to date, there is insufficient evidence that urine can be used as a biological specimen for COVID-19 diagnosis.

4.2. CRISPR-Cas12-based lateral flow assay for detection of SARS-CoV-2

Recently, a CRISPR-Cas12-based assay called SARS-CoV-2 DNA endonuclease-targeted CRISPR Trans Reporter (DETECTR) has been developed for the diagnosis of SARS-CoV-2 infection. This assay performs simultaneous reverse transcription and isothermal amplification of RNA extracted from nasopharyngeal or oropharyngeal swabs using loop-mediated amplification (RT-LAMP) [55], followed by Cas12 detection of coronavirus sequences. Detection of the virus is confirmed by cleavage of a reporter molecule. The assay targets the E and N regions but unlike the CDC assay, this one does not target the N1 and N3 regions. Amplification of the E region allows the identification of three SARS-like coronaviruses [SARS-CoV-2 (accession NC_045512), bat SARS-like coronavirus (bat-SL-CoVZC45, accession MG772933) and SARSCoV (accession NC_004718)], whereas the N region specifically detects SARS-CoV-2.

The DETECTR assay can be run in 30–40 min and is visualized on a lateral flow strip. The test is positive if both E and N genes are detected or presumptive positive if either E or N gene is detected. The limit of detection (LOD) of this DETECTR assay is 10 copies/µl vs 1 copy/µl for the CDC assay. The positive predictive agreement and the negative predictive agreement of DETECTR assay versus the CDC assay were 95% and 100%, respectively [56].

4.3. Viral load in respiratory samples

Viral load determination performed on nasopharyngeal swabs demonstrated that mild clinical cases had a lower viral load in their respiratory specimens compared with severe cases. The mean viral load in severe cases was 60-fold higher than mild cases. Stratification of the data in relation at the time of sampling after disease onset showed that delta cycle threshold (delta Ct) values were significantly lower in severe cases than mild cases in the first 12 days of disease. In mild cases, viral clearance occurred earlier and after 10 days, 90% of the patients repeatedly tested negative by PCR. By contrast, PCR was still positive at day 10 or beyond in all severe cases. These preliminary data suggest that determination of SARS-CoV-2 load may be useful for monitoring the patients with COVID-19 disease and for predicting prognosis and assessing disease severity [57].

  1. Serology

Several serological assays, including enzyme-linked immunosorbent assays (ELISA), chemiluminescence assays (CLIA), rapid antibody tests, and western blotting, have been developed since the beginning of the SARS-CoV-2 pandemic. The ELISA test developed by Wantai Biological Pharmacy Enterprise Co. (Beijing, China) detects total antibody, IgM and IgG against SARS-CoV-2 [58]. Total antibodies were detected based on a double-antigen sandwich immunoassay using recombinant antigens containing the RBD of the S protein of SARS-CoV-2 as the immobilized antigen and horse radish peroxidase (HRP) as the conjugated antigen. The IgM μ-chain capture method was used to detect IgM antibodies (IgM-ELISA), using the same HRP-conjugate RBD antigen as in the double-antigen sandwich immunoassay. The IgG antibodies were detected by an indirect ELISA test (IgG-ELISA) based on the recombinant nucleoprotein antigen. The specificity of the assays was determined by testing plasma samples of healthy individuals collected before the SARS-CoV-2 outbreak, and was 99.1%, 98.6% and 99.0% for total antibody, IgM and IgG, respectively [58]. Comparing the results obtained by real-time PCR with those generated by the antibody assays in the first week of illness, PCR showed a higher sensitivity than antibodies assays, 66.7% vs 38.3%. However, from days 8 to 12, the sensitivity of the antibody tests overtook that of the RNA test, and in the late phase of disease, the sensitivity of the antibody tests increased even further compared to the RNA test [58]. Nevertheless, to date, all the international professional organizations, the US Food and Drug Administration and the CDC do not recommend that serology tests be used for diagnosis.

Other research groups developed ELISA assays that used as antigens a modified full-length S protein and the RBD of SARS-CoV2. Using this approach, COVID-19 seroconverters were identified as early as 3 days post symptom onset. Similarly, an antibody test designed to detect E and N antigens detected IgM within one week from disease onset. IgM was detectable for about a month and then gradually disappeared, while IgG was detected after 10 days and was detected for a longer period of time [59].

Using a magnetic chemiluminescence enzyme immunoassay, 100% of patients with COVID-19 were found to be IgG positive 19 days after symptom onset. The median day for both IgG and IgM seroconversion was 13 days post symptoms. Seroconversion for IgM and IgG occurred simultaneously or sequentially. Three groups of patients were identified: patients with synchronous seroconversion of IgG and IgM, patients with IgM seroconversion earlier than IgG seroconversion, and patients with IgG seroconversion earlier than IgM seroconversion. IgM and IgG plateaued 6 days after the first determination. Interestingly, screening of close contacts of patients with COVID-19 showed that few individuals with negative RT-PCR and no symptoms tested positive to IgG and/or IgM, confirming that serology can help in obtaining better estimates of the spread of SARS-CoV-2 [60].

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Italy was the first country engaged in fighting SARS-CoV-2 pandemic after China. This is the reason we wrote this review with our Chinese colleagues. We thank them for their support that came from their experience, for their scientific contribution, and for their friendship.

Disclosure statement

No potential conflict of interest was reported by the author(s).

ACE2 angiotensin converting enzyme 2
AI artificial intelligence
ARDS acute respiratory distress syndrome
CatL cathepsin L
CRRT continuous renal replacement therapy
CDC Centers for Disease Control and Prevention
CI confidence interval
CLIA chemiluminescence assays
COVID-19 Corona virus disease 19
ECMO extracorporeal membrane pulmonary oxygenation
ELISA enzyme-linked immunosorbent assays
HCoV human coronavirus
ICU Intensive Care Unit
IL interleukin
MERS-CoV middle East respiratory syndrome coronavirus
POCT point of care test
PCR polymerase chain reaction
RBD receptor binding domain
rRT-PCR reverse real-time PCR
S protein spike protein
SARS-CoV severe acute respiratory syndrome coronavirus
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
TCM traditional Chinese medicine
TMPRSS surface transmembrane protease/serine protease
WHO World Health Organization


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