1 Introduction

The year 2019 ended with a fatal outbreak of a novel coronavirus, Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), preliminarily identified as a causative agent of a series of unusual pneumonia cases in Wuhan City, Hubei Province, China. The International Committee on Taxonomy of Viruses (ICTV) permanently named the pathogen SARS-CoV-2 and the disease it caused coronavirus disease 2019 (COVID-19) and declared the crisis a pandemic (Enserink 2020). As per the World Health Organisation (WHO), latest situation report (Sep 14, 2020) at the time of this writing, more than 28.9 million confirmed cases with more than millions of deaths have been reported in 208 countries (Organisation 2020). The first reported case of COVID-19 was in Wuhan, Hubei province with symptoms such as fever, cold, shortness in breath very similar to the common cold in few cases and within a week had a reported cluster cases of acute pneumonia (Nishiura et al. 2020). The Computerized Tomography (CT) scan of the patients revealed slight opacity and difference from the healthy scan of the lungs (Ai et al. 2020).

2.2 CRISPR-Cas based testing

Another aspect to be explored for detecting COVID-19 is making use of CRISPR-Cas gene editing tool which can create wonders in the field of detection (Chekani-Azar et al. 2020). Making use of CRISPR-Cas has been reported for use in medicine and diagnostics over the years. Success in making use of the CRISPR-Cas has enabled to ascertain new systems for targeting and manipulating nucleic acids including those from Cas9, Cas12, Cascade and Cas13 orthologues (Pickar-Oliver and Gersbach 2019; Li et al. 2019). Possibilities of develo** a diagnostic tool for detection of TB is already known using CRISP-Cas technology which lay the foundation for making its use in COVID-19 detection as well (Ai et al. 2019). Very recently, developed SARS-CoV-2 DNA Endonuclease-Targeted CRISPR Trans Reporter (DETECTR) for detection of COVID-19 using CRISPR-Cas12. This developed lateral flow strip could decrease the detection time required by the ongoing RT-PCR testing and aid in better disease management in this crucial time (Broughton et al. 2020). Exploiting the potential of CRISPR-Cas technology fluorescence and colorimetric based detection of COVID-19 was made possible. The technology is named as specific high-sensitivity enzymatic reporter unlocking (SHERLOCK) by making use of recombinase-mediated polymerase pre-amplification of DNA or RNA for detection. The reported technology takes less than an hour to provide results making it one of the potent applicants in the field of diagnosis of COVID-19 (Kellner et al. 2019). An improved version of SHERLOCK was put forward which overcome major challenges of SHERLOCK and is named as STOP (SHERLOCK testing in one pot). The mentioned assay is capable of solely performing extraction, amplification and CRISPR-mediated detection of the viral RNA in a go on a single temperature. Two version are presented as STOP covid version 1 and 2 respectively. STOP covid version 1 is compatible with lateral-flow and fluorescence readouts whereas STOP covid version 2 makes use of magnetic beads concentrated SARS-CoV-2 RNA for detection (Joung et al. 2020). CREST is another pioneering discovery in the field of diagnosis for detection of COVID-19. The CREST stands for (Cas13-based, Rugged, Equitable, Scalable Testing) and has overcome major drawbacks associated with the current diagnostic system of COVID-19. The Cas13 can be used in point of care setting and it would be low cost when compared to traditional lateral flow assay as it doesn’t require antibody conjugates for the detection (Rauch et al. 2020). Another effective use of CRISPR Cas 12 was seen by integrating into a lateral flow system named as iSCAN having potential to be used as effective management system for point of care detection(Ali et al. 2020). AIOD CRISPR assay, made use of a pair of crRNAs to initiate the detection using CRISPR-Cas12a for improved sensitivity. The assay have potential in detecting nucleic acids (DNA and RNA) of SARS-CoV-2 and HIV (Ding and Yin 2020). Integration of lateral flow system along with nucleic acid as a substrate for quick and point of care results can prove to be fruitful amid this pandemic as shown in Fig. 3a. Another perspective to be explored is pairing CRISPR-Cas with electrochemical based sensing as it can help in achieving even lower limit of detection. Can Dincer et.al, reported (CRISPR)/Cas13a-powered microfluidic based electrochemical sensor for detection of cancer reaching a limit of 10 pM on site (Bruch et al. 2019). Such a system should be made available at this crucial time in detection of COVID-19. Development of CRISPR-Cas based on-chip electrical detection of nucleic acid could be the future of detection in COVID-19 screening as it can detect even in femto Molar levels (Hajian et al. 2019).

Fig. 3
figure 3

Lateral flow integration for a Nucleic acid-based testing for COVID 19 detection, b Protein based testing for COVID 19 detection

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2.3 Protein based testing

Along with the on-going nucleic acid-based testing for detection of COVID-19 protein-based detection can also act as an excellent supplement alongside for better mass screening for early measures in a point of care setting. Although nucleic acid, CRISPR-Cas and aptamer-based testing are currently been employed for detection protein-based avenues needs to be explored. Antigen and antibody are the among the major protein-based entities which are already used for detection of several diseases over a long time. Protein-based detection system mostly includes ELISA, chromogenic based or fluorescence-based detection using dye, lateral flow-based detection. Not much was developed until recently since the viral load has reported fluctuating with weeks after detection providing results which are not possibly reproducible when test was made using saliva sample from infected patients. Viral load was highest at the start and subsequently declined at the end (To et al. 2020). Although it can be speculated that antibody-based test can provide more time since antibody can be detected even after a long time in the patient.

2.3.1 Antigen based testing

An antigen test has ability to reveals if a person is presently infected with a pathogen such as the SARS-CoV-2 virus. Antigen tests mostly detect proteins or glycans, such as the spike proteins found on the surface of the SARS-CoV-2 virus. Sona nanotech is one of the pioneers in the filed leading the way of COVID-19 testing by develo** antigen-based test kit for detection. The gold nanorod particles used are CTAB (cetyltrimethylammonium) free hence limiting the toxic risks associated with the use of other gold nanorod technologies in medical applications. It was reported recently that the test attained a positive response to a recombinant whole spike protein control reagent specific to SARS-CoV2 and neither had false positives (Nanotech 2020). Another milestone is reached by E25Bio’s rapid diagnostic which provide results in 15 min by detecting the presence of the virus in the patient sample (Misra 2020). Iceni Diagnostics run by Prof Rob Field, has developed a diagnostic technique that make use of an artificial glycan receptor to detect the novel virus (Iceni Diagnostics Ltd 2020). OraSure envisions is another established name being working on develo** antigen based testing kit (OraSure Technologies 2020). Roche has reported of develo** test having sensitivity of 96.52% and a specificity of 99.68%, based on 426 samples from two independent study centers the test helps in identifying both symptomatic and asymptomatic people with in 15 min (Roche Ltd 2020a). Lately special consideration is being given to point of care antigen testing in order to detect infected person at the earliest and decreasing the chances of mass transfer of the virus (Dinnes et al. 2020). However, it was reported that antigen based detection alone cannot be effective in detection of SARS-CoV-2 (Mak et al. 2020).

2.3.2 Antibody based detection

Major class of immunoglobins includes of IgG, IgM, IgA, IgE and IgD which can contribute in detection of diseases. IgG been the first line of defense initiated as part of the immune response when infected by a pathogen and creates immunological memory to further fight the infection is mostly targeted in detection of COVID-19. Also reported is that IgM appears in the blood of the patient when infected by SARS after 3 to 6 days and IgG can be detected 8 days after the infection occurred (Racine and Winslow 2009; Wan et al. 2003).

IgG and IgA ELISAs in conjunction with the EURO Lab workstation (Euroimmun, Lübeck, Germany). EUROIMMUN enzyme-linked immunosorbent assay (ELISA) for semi-quantitative detection of IgA and IgG antibodies in serum and plasma samples using recombinant S1 domain of the SARS-CoV-2 spike protein as antigen is reported demonstrates excellent sensitivity for detection of IgA and IgG antibodies from samples collected ≥3 days and ≥ 4 days, respectively, after COVID-19 diagnosis by PCR (Beavis et al. 2020). Other ELISA based IgG and IgA showed specificity of 91.9% and 73.0% 12 and 11 days after symptom onset (Jääskeläinen et al. 2020). Many industries as well have developed ELISA based detection kit for COVID-19 like Epitope diagnostic, Inc. and Eagle bioscience although tests are yet to be approved by FDA for use. Eagle bioscience test kits are now available for use in the US for detection (Epitope Diagnostics 2020; Bioscience 2020). Making use of protein for detection is known and adopted for development over decades but recently making use of neutralizing antibody had been adopted to fight against the novel coronavirus. The antibody targets the spike protein of the virus which is made up of two subunits the S1 and S2. The S1 subunit is necessary for entry into the host cell while S2 subunit helps in fusion of the cellular and viral membrane. SARS-CoV-2 binds the receptor human angiotensin-converting enzyme 2 (ACE2) (Wang et al. 2020a).Considering the fact that neutralizing antibodies have great potential to fight the diseases making its use in disease diagnosis could be the near future. On evaluation of IgM/IgG based detection kit the highest specificity was reported for the Wantai SARS-CoV-2 Total Antibody ELISA followed by 93% for the Euroimmun IgA ELISA and 96% for the Euroimmun IgG ELISA with sensitivities of 90%, 90%, and 65%, respectively (Lassaunière et al. 2020).

Development of lateral flow strip for detection makes use of antigen-antibody reaction. Here the reaction occurs on the nitrocellulose membrane. Once the sample is added into the strip the antigen interacts with the already loaded capture antibody for detection through capillary action. The gold nanoparticle-conjugated antibody is present near the sample port to interact with the sample for the formation of the visible color change after formation of the immunocomplex. Making use of lateral flow assay for diseases detection which makes use of antigen-antibody for detection can be a better alternative for COVID-19 diseases management. Lateral flow assay(LFA) is well established in terms of diseases detection and been used for more than a decade as shown in Fig. 3b (Bahadir and Sezgintürk 2016).

Building on this concept various lateral flow strip has been developed lately (Li et al. 2011; Martinez et al. 2008). Table 1 represents the available list of commercial SARS-CoV-2 in-vitro diagnostic assays.

Table 1 List of commercial SARS-CoV-2 in vitro diagnostic assays given an EUA from the FDA as of 9 May 2020
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4 Conclusion and future prospect

The development and research have ramped up at a greater speed than ever in the field of diseases diagnosis due to COVID-19 outbreak leading to an increase in the mortality rate each day in an unpredictable manner. Still countries are struggling to speed up testing due to the laborious and expensive RT-PCR lab technique, which often require centralized services. Few RT-PCR based innovative diagnostic methods are in the developmental stage which detect viral materials in different ways such as gene editing tool CRISPR. But, need of the hour in this pandemic is the development and establishing innovative diagnostic tool which would be easy to use, accurate, sensitive and point of care. Although point of care serological tests (lateral flow immunoassay based) is readily available in the market for COVID-19 detection but still the quality of commercial kits needs to be re-evaluated due to occurrence of false positive results. The lateral flow-based immunoassay has advantages over RT-PCR in develo** nations were the facilities for RT-PCR set up is scare. However, the lateral flow immunoassay does not give an explicit picture of the severity of the disease but can help as an aid the detection alongside with RT-PCR technique.

With the available technology, the diagnosing of the disease could be a menace shortly. Although the process of technology development is hurtling up day by day integrating them for a better output is essential. In our view, following developments can make an advanced COVID -19 detection tools (Fig. 5): 1) Making isothermal amplification-based LFA could be one of the alternatives in hand to overcome the problem with current lateral flow assay of giving false negative results. 2) Paper-based device with real-rime simultaneous detection of multiple DNA targets can be developed for highly sensitive and specific detection, 3) Nanotechnology intervention in the pipeline of disease detection can be potentially fruitful, 4) Development needs to be made in making use of microfluidic devices for development of new prototype for early point of care detection of the novel virus. Even screening of close biomarkers for development of accurate and precise diagnostics kit is necessary, 5) Efforts need to be made for technology forward approach by integrating it to smartphone mobile devices which are omnipresent in nature, 6) Making CRISPR-Chip based electrical detection can help us to detect the analyte even at lower concentration, 7) Development of novel face mask which in turn is integrated with an sensor can help in detecting even lower limit of virus 8) Making use of electrochemical based device as it can detect even narrow antigenic load. There is also possibility to explore the development of point-of-care tests with multiplex assays and breathe analyzer. With integration with technology it will be easy not only to identify the people suffering and also take measure as early as possible for better diseases management.

Fig. 5
figure 5

Future prospects of COVID-19 diagnosis

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Research in the field of COVID-19 is evolving quickly and new data are generated each day. Some referenced manuscripts are preprints and have not been peer-reviewed.