key: cord-1005999-d7g5xnq9
authors: Tahmasebi, Safa; Khosh, Elnaz; Esmaeilzadeh, Abdolreza
title: The outlook for diagnostic purposes of the 2019‐novel coronavirus disease
date: 2020-05-26
journal: J Cell Physiol
DOI: 10.1002/jcp.29804
sha: 89fc8782d0457e7e2af99ee33d9f0eb8a3ff3322
doc_id: 1005999
cord_uid: d7g5xnq9

At the end of December 2019, a novel acute respiratory syndrome coronavirus 2 (SARS‐CoV2) appeared as the third unheard of outbreak of human coronavirus infection in the 21st century. First, in Wuhan, China, the novel SARS‐CoV2 was named by the World Health Organization (WHO), as 2019‐nCOV (COVID‐19), and spread extremely all over the world. SARS‐CoV2 is transmitted to individuals by human‐to‐human transmission leading to severe viral pneumonia and respiratory system injury. SARS‐CoV2 elicits infections from the common cold to severe conditions accompanied by lung injury, acute respiratory distress syndrome, and other organ destruction. There is a possibility of virus transmission from asymptomatic cases as active carriers, in addition to symptomatic ones, which is a crucial crisis of COVID‐19 that should be considered. Hence, paying more attention to the accurate and immediate diagnosis of suspected and infected cases can be a great help in preventing the rapid spread of the virus, improving the disease prognosis, and controlling the pandemic. In this review, we provide a comprehensive and up‐to‐date overview of the different types of Clinical and Para‐clinical diagnostic methods and their practical features, which can help understand better the applications and capacities of various diagnostic approaches for COVID‐19 infected cases.

First, in Wuhan, China, SARS-CoV2 arose as a new viral infection, and is currently named Coronavirus Disease 2019 . New

Coronavirus (MERS-CoV) and SARS-CoV are different strains of coronaviruses belonging to the β-coronavirus cluster (P. . SARS-CoV2, the chief pathogen of the human respiratory system, is the third zoonotic coronavirus disease and the third major medical crisis with a different genome from SARS-CoV.

SARS-CoV2 is mostly transmitted by respiratory system droplets, gastric tract, and close human interaction, and is located in the nasal mucosa, mouth, and lungs of exposed individuals. Of note, middleaged and elderly individuals, as well as patients with chronic or autoimmune underlying diseases, are most susceptible to be infection by SARS-CoV2. Incredibly, coronavirus has become a critical challenge in global public health due to rapid development and extreme spread by active carriers in human-to-human transmission (Riou & Althaus, 2020) . Clinically, COVID-19 brings about very severe respiratory infections and lethal sickness the same as SARS and MERS. Besides respiratory system injury, COVID-19 hurts various organs, including the kidney, liver, gastrointestinal, and neurologic systems (Yin & Wunderink, 2018) . Structurally, the coronavirus is characterized as an enveloped, nonsegmented, and single-stranded Safa Tahmasebi and Elnaz Khosh contributed equally to this study. RNA virus. The structure is composed of an Envelope (E), Nucleocapsid (N), Membrane (M), and Spike (S) proteins. Both E and M proteins have a central role in virus assembly and release of the virus (Schoeman & Fielding, 2019; Sheikh, Al-Taher, Al-Nazawi, Al-Mubarak, & Kandeel, 2020) . The S protein, an immense multipurpose viral transmembrane protein, induces immune responses by mediating the virus attachment to host receptors (F. Li, 2016) . The N protein, a multifunctional protein, is identified as a viral RNA silencing suppressor. The N protein has a substantial role in viral transcription and replication and is involved in packaging the encapsidated genome into virions. Regarding the overexpression and high immunogenicity of N protein, it can be considered as a potential diagnostic target for SARS-CoV2 detection (Hurst, Koetzner, & Masters, 2009 ).

After exposure, the virus enters into target cells and acts by binding to its receptor, the so-called angiotensin-converting enzyme 2 (ACE2). ACE2 is present on type I and II alveolar epithelial cells of healthy lung tissue. Also, it has been reported that organ failure can occur all over the body if organ cells express ACE2. The interaction between SARS-CoV2 and ACE2 leads to overexpression of ACE2 resulting in alveolar cell detriment, interstitial and alveolar edema, respiratory system failure, and ARDS (Y. . Among various laboratory abnormalities, lymphopenia with or without leukocyte irregularities is commonly observed as a major para-clinical criterion of COVID-19 infected patients (L. . According to SARS-CoV2 immunopathogenesis, lymphopenia is characterized by a decrease in lymphocytes, particularly CD8+ T cells and a slight increase in neutrophils (Wan et al., 2020) .

Moreover, it has been found that SARS-CoV2 can indirectly infect immune cells, mostly T cells, and macrophages, and elicits their destruction. Increased frequency of infected immune cells, lymphopenia, and high levels of inflammatory cytokines are considered as the most related elements to COVID-19 immunopathogenesis . In this regard, elevated levels of pro-and inflammatory cytokines, including tumor necrosis factor-α (TNF-α), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP-1A), monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein-10 (IP-10), interleukin-1 (IL-1), IL-2, IL-6, IL-7, and IL-10 have been documented in COVID-19 patients with severe conditions, which generate the cytokine storm. It seems that the cytokine storm is the primary phenomenon of virus pathogenesis leading to inflammation, lung injury, ARDS, and other organ failures (Wan et al., 2020) .

Hence, there is a critical need for the detection of the infected or suspected cases as soon as possible to apply the appropriate treatments for COVID-19 and prevent the spread of virus. For this reason, in this review, we will focus on the im- 

The importance of different diagnostic methods of COVID-19 has been emphasized in many studies. Several studies have been designed or are underway to investigate the efficacy of COVID-19 diagnostic methods, and have been listed in Table 1 and IgG antibodies or viral antigens. Recently, the use of serological tests to rule out or confirm the infection, specifically in negative NAATs has been suggested due to the ease of use, quick presentation of results, as well as acceptable specificity and sensitivity. Contrarily, viral culture does not need to be used for detection due to the research aspect of culture. However, it can be applied to determine the contagiousness of the infection, the presence of the virus at different surfaces, and study the efficacy of various treatments on cultured cells.

In the following, we have described in detail the different types of diagnostic methods in the two general clinical and para-clinical categories.

Sample collection is an important procedure that should be done correctly to achieve accurate diagnostic results. With regard to the transmission of the SARS-CoV2 through the respiratory tract, fecaloral, and body fluids, anal swabs, oral swabs, and blood samples are different methods of sample collection for diagnosis of the novel coronavirus (W. Zhang et al., 2020) . A recent study has analyzed repeated sample collection from positive cases, which showed that 15 infected patients still had a virus after days of receiving treatments. They further reported that they might have more positive oral swabs on the first day of sampling, and more positive anal swabs on the late period of sampling. Notably, prolonged positive stool samples are not correlated with the severity of the disease, and some positive Zhang et al., 2020) . Also, they evaluated the levels of IgM and IgG antibodies in samples on Day 0 and Day 5. The positive rate of IgM shifted from 50% to 81%, and the positive rate of IgG shifted from 81% to 100%. On the basis of a high detection rate of antibody titers, it is beneficial to assess both serological and molecular tests in suspected patients.

One of the latest studies has analyzed 1,070 samples collected from different sites of 205 infected patients. The specimens were collected from the pharynx, urine, feces, sputum, blood, and nasal. 

The Centers for disease control (CDC) have reported that the newly prevalent virus has mild to severe clinical manifestations in many cases and sometimes leads to death (CDC). In the suspected patients, symptoms almost appear as fever, cough, fatigue, pneumonia, and respiratory distress; whereass some symptoms such as rhinorrhea, diarrhea, hemoptysis, headache, and phlegm-producing cough are rare in these patients (Adhikari et al., 2020 in the lung to the medullary cardiorespiratory center through synapseconnected routes. It seems that the infection of the nervous system could be a reason for the respiratory failure of the coronavirus.

According to research, the average time interval from the onset of initial symptom to dyspnea is 5 days, that to admission in hospital is 7 days, and that to receive intensive care is 8 days. This latency time interval is enough for the virus to penetrate the nervous system and They selected the ORF1b and N genes as highly conserved targets.

SARS coronavirus nucleic acids wereconsidered as positive controls.

As a result, the respiratory specimens of two infected patients 8 | TAHMASEBI ET AL.

showed positive results after detectionby two RT-PCR assays, in which the N gene assay revealed significant sensitivity 10 times more than the ORF1b gene in positive specimens. Overall, the findings of this study suggest using the N-RT-PCR as a screening assay and the ORF1b-RT-PCR as a confirmatory assay.

From decades ago, pooling diagnostic tests have been developed to optimize detection time, save on reagents, and quickly detect large numbers of suspicious or contaminated cases in infectious disease.

Beneficially, intricate equipment and additional training are not required in the use of these tests (Nguyen, Bish, & Aprahamian, 2018) .

Pooling has been evidenced for RT-qPCR, which would allow to RT-PCR to detect the low-concentration RNA with further optimization (Arnold et al., 2013) . 

It should be noted that there is a possibility of a positive RT-PCR result in COVID-19 recovered patients. With this point of view, a study evaluated four treated COVID-19 patients from Wuhan, China, by rRT-PCR to confirm whether they could return to work. The patients' recovery was confirmed by rehabilitation criteria, including normal temperature over 3 days, relieved respiratory difficulties, and confirmed CT imaging based on recovered acute exudative lesions.

Finally, confirmation of two separated negative RT-PCR results led to hospital discharge and discontinuation of quarantine. Accordingly, RT-PCR assays were carried out on throat swabs of patients using BioGerm kits, 5-13 days after hospital discharge, and discontinuation of quarantine, all of which were positive (Lan et al., 2020) . Surprisingly, the results revealed that a proportion of rehabilitated patients

can be virus carriers and should continue the quarantine protocol for about 5 days more. Also, the RT-PCR assay should be reevaluated to confirm the complete remission of treated patients.

Several advantages of RT-PCR assays make them potent and effective diagnostic techniques for COVID-19 infection. The RT-PCR assay is identified as a practical diagnostic approach used to confirm the COVID-19 positive cases (Roberts et al., 2015) . It has the capability of precise and reproducible determination of infected cases.

Also, it can be employed to quantify the presence or absence of viral RNA and viral load in patients' specimens. In plasma therapy, selection and confirmation of COVID-19 recovered patients, as appro- 

According to a report, in one SARS-CoV2 infected patient with both RT-qPCR and NGS, the positive results were not confirmedby TAHMASEBI ET AL.

| 9

RT-qPCR testing within 3 weeks before obtaining the BALF . This data suggests the high FNR or inconsistency of R 

Laboratory screening tests (laboratory findings) based on assessing the biological and chemical factors in blood would be helpful for better determination of COVID-19 infected patients, although they do not have higher specificity and sensitivity (Table 3) Moreover, a higher level of D-dimer was also detected in patients with severe conditions (Bangash, Patel, & Parekh, 2020; F. Zhou et al., 2020) . The procalcitonin level is mostly normal in COVID-19

patients, but a higher-level was reported in bacterial co-infection.

Increased levels of pro-and inflammatory cytokines in the serum of infected COVID-19 patients also were reported in several studies, which is considered as the main reason for the cytokine storm (C. Huang et al., 2020) . In addition to the laboratory findings as mentioned above, detecting the lymphocyte subsets and their levels in the blood samples of patients would provide valuable information for better diagnosis of infection. In a study, Wan et al. (2020) In a systematic review and meta-analysis study (Pormohammad et al., 2020) , investigating the available laboratory data among 2,361 SARS-CoV2 patients, the results demonstrated 13.3% leukocytosis, 26% leukopenia, and 62.5% lymphopenia. Furthermore, among 2,200 patients, increased levels of platelets (thrombocytosis) and CRP were reported in 91% and 81% of patients, respectively. Also, a case report study by W. Han et al. (2020) neutrophils. Consequently, despite the nonspecific findings of blood count and parameters in diagnosing COVID-19 infected patients, these laboratory findings would be helpful in early detection of infected cases in combination with highly specific and sensitive approaches, such as CT imaging and RT-PCR assay. 

Following the exposure to SARS-CoV2, the host immune system releases the IgM and IgG antibodies against the virus. First, IgM appears in the initial exposure to response to SARS-CoV2 antigens and is involved in the primary immune responses; however, IgG is also engaged in secondary immune responses. IgM is the first produced antibody with low concentration, low affinity, and limited maintenance time, which is disappeared at the end of the infection.

Contrarily, IgG is later secreted with high concentration, affinity, and maintenance time, and also persists after infection recovery.

Accordingly, IgM detection indicates acute infection, and IgG is a diagnostic index of previous, middle, or late infection. Thereby, developing ELISA tests for detecting these anti-SARS-CoV2 antibodies would help early detection of positive cases at least a few weeks after infection onset. Interestingly, a large number of suspected cases can be identified in a short time with simple facilities and acceptable sensitivity/specificity rates, as well as a low rate of false-negative results.

In one study, W. Zhang et al. (2020) Another study by Liu, Liu, Wang, and Zheng (2020) was performed to analyze the diagnostic values of IgM and IgG antibodies against the N protein of SARS-CoV2 in 238 hospital admitted patients with confirmed or suspected SARS-COVID-19 infection.

Surprisingly, the ELISA findings indicated that suspected cases were positively contaminated by SARS-CoV2. They also detected the IgM and IgG in 194 cases, with a 81.5% positive rate, which was considerably more than the RT-PCR assay (64.3%). Additionally, it was found that ELISA detected suspected patients who had negative RT-PCR results with a 78.8% positive rate for IgM and IgG.

W. measured the produced IgM, and IgG antibodies against nucleocapsid protein (rN) and spike protein (rS) of SARS-CoV2 in 214 COVID-19 confirmed patients using the ELISA.

Successfully, rN-based IgM and IgG were detected in 68.2% and 70.1% of patients, respectively. Besides this, rS-based IgM and IgG were discovered in 77.1% and 74.3% of patients, respectively. Findings also reported that positive rates of IgM/IgG were 80.4% and 82.2% for rN-and rS-based detections, respectively. Furthermore, it was found that rS-based detection of IgM had a higher sensitivity than rN-based detection.

In an investigation by Amanat et al. (2020) , ELISA was developed using recombinant antigens originating from the spike protein (SP) of SARS-CoV2. They showed that screening and identification of COVID-19 seroconverters were possible as early as 3 days following the symptom onset with high sensitivity and specificity. As expected, no reactivity was observed in individuals who were not exposed to SARS-CoV2 and were completely naive for SP. By reliance on these details, exposed/immune and naive people can be easily distinguished. In a related study by Stadlbauer et al. (2020) , a detailed protocol was provided for the expression of antigens derived from the spike protein that can be used as a substrate for setting up ELISA and other immunological assays. They claimed that the presented protocol was adapted to local needs, including research, diagnostic, and clinical laboratories. With respect to the applications of ELISA in detecting the anti-SARS-CoV2 IgM/IgG antibodies based on the findings mentioned above, it is considered as an applicable serological assay for the detection of COVID-19 with high sensitivity and specificity.

In one study, Long et al. (2020) whereas, after 20-22 days, the IgM had an around 94.1% positive rate. They also found that the IgM and IgG titers were gradually increased within 3 weeks after onset of the symptoms; however, IgM indicated a slight decrease after more than 3 weeks. Moreover, it was understood that in patients with a severe condition, IgG and IgM titers were more remarkable than those with the non-severe condi- In another investigation, 

The LFA, a qualitative immunoassay, is another potent serological technology used to detect the COVID-19 infected cases with a rapid, simple, and low-cost procedure. LFA acts based on a paper-based platform for quantifying multiple analytes in a sample within According to a study conducted for an antigen rapid test, the findings demonstrated the high sensitivity of detecting the N antigen derived from SARS-CoV in the early stages of the infection, which was a useful early diagnostic approach for SARS-CoV (Che et al., 2004; Di et al., 2005) . In a pre-peer reviewed study (Diao et al., 2020) , a cohort of 239 participants with suspected SARS-CoV2

infection was included to detect the viral antigen. Accordingly, the nucleocapsid protein (NP) of SARS-CoV2 was evaluated in nasopharyngeal swab and urine sample within 10 minutes using a fluor- infections, it confirms the advantage of early detection of the serological tests compared with RT-PCR. Also, the importance of specimen quality for the serological assays is less stringent compared with RT-PCR assays. Importantly, false-negative results derived from sampling quality are fewer in using antibodies for serological diagnosis (Xiao, Wu, & Liu, 2020) . On the basis of this, it has been suggested that using serological assays provides the facility of early diagnosis of positive cases even with an improper sample collection and unsatisfied molecular examinations.

As another benefit, a broad scale of infection diagnosis is achieved using the ELISA technique that detects the antibodies by automatic devices. Moreover, ELISA provides the feasibility of identifying a large number of infected cases in a quick turnaround time.

The other limitations of RNA-based assays that led to the critical necessity to use ELISA include requiring upscale and expensive lab facilities, restrictive biosafety levels, low or middle detection sensitivity and specificity, different sampling locations, and technical experts. Another essential issue is the ease of using serological tests in the clinical laboratory of any hospital, as opposed to the molecular approach that requires a specific and well-equipped laboratory.

Notably, reporting on the very mild or asymptomatically infected cases, as a large population without viral RNA-based testing, is another critical aspect that should be considered. Hence, detection of the specific IgG antibody, as a large-scale seroepidemiological study, would help understand the true scale of human-to-human transmission and report the accurate rate of COVID-19 infected cases (Xiao et al., 2020) . Promisingly, these types of applicable diagnostic tests would contribute to the early detection of infected or suspected cases and prevent the spread of the virus.

Recently, the new Abbott ID NOW COVID-19 test has received emergency use authorization (EUA) from the FDA to detect the novel coronavirus (SARS-CoV2), as the fastest available molecular TAHMASEBI ET AL.

| 15 point-of-care test. The Abbott ID NOW test is identified as a rapid, isothermal, and instrument-based, system that can be used for the qualitative identification of infections. Interestingly, this approach has a unique isothermal nucleic acid amplification technology that provides molecular results in a short time, which lets clinicians make evidence-based clinical decisions during a patient visit. Accordingly, it has been reported that the Abbott ID NOW assay presents positive results in as few as 5 min and negative results within 13 min, based on the rRT-PCR assay. Moreover, for the detection of Influenza A&B, Strep A and respiratory syncytial virus (RSV), ID NOW is the pioneer molecular point-of-care platform (Abbott, 2020) .

With regardto the current outbreak of the novel coronavirus (2019-nCoV) worldwide, arisen from Wuhan, China, it is critically required to

identifypractical strategies for precise diagnostic methods and appropriate treatment choices. The rapid human-to-human transmission of SARS-CoV2, even by asymptomatic carriers has led to an intensive health disaster. The most common clinical manifestations of the disease are fever, cough, and dyspnea. Some complications such as ARDS, acute kidney injury, and liver damage may also occur during the process of the disease, which can cause death, subsequently.

Additionally, the elevated levels of pro-and inflammatory cytokines elicit the cytokine storm phenomenon, which has proved to be a prominent reason for respiratory system destruction.

The typical laboratory abnormalities in COVID-19 patients include lymphopenia, hypoalbuminemia, and increased levels of CRP, ESR, LDH, AST, ALT, and D-dimer. Although the characteristics of clinical features and abnormal laboratory finding results can guide healthcare workers toward a primary diagnosis, the final detection of the COVID-19 patients is confirmed by spiral lung CT scans, molecular assays, and serological tests. Mostly, bilateral and peripheral GGOs and/or occasional consolidations have been observed in radiological findings of lung involvements. Indisputably, initial chest CT could be performed as a potential diagnostic modality in symptomatic cases, especially at the early stages of the disease. Of note, it should be considered that some suspected patients may have no CT findings; therefore, repeated CT imaging and other diagnostic techniques would assist in ruling out or confirming the suspected individuals. The other applicable confirmation methods are RNA-based molecular assays, among which the rRT-PCR test is a gold-standard approach.

Despite the rapid and definite diagnosis of the infected cases, high-FNR, lengthy procedure, and the necessity of intricate equipment restricts the utilization of the RT-PCR assays compared with CT imaging. Recently, serological techniques have been developed as another quick diagnostic test based on detecting SARS-CoV2specific IgM/IgG antibodies with high sensitivity and specificity. Besides this, it is worth noting that the accurate process of sample collection, sampling clinical specimens from multiple sites, and different detection rates of positive specimens should be considered to achieve the most accurate test results for COVID-19 diagnosis.

In conclusion, the profound comprehension of various application aspects of the diagnostic approaches, their advantages and disadvantages, as well as their appropriate administration could lead to taking efficacious steps forward to prevent the virus outbreak, manage the current pandemic state, contribute to infected patients' recovery, and subsequently promote public health.

The authors would like to dedicate this study to healthcare workers, which are struggling with the novel coronavirus.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest.

S. T. and E. K. H. contributed to data gathering, writing the primary draft of the manuscript, and designing figures and tables. A. E. contributed to the hypothesis, correspondence, scientific and structural editing, and verifying the manuscript before submission.

n/a ORCID Abdolreza Esmaeilzadeh http://orcid.org/0000-0002-5402-3967

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