Coronavirus disease 2019 (COVID-19) has created havoc all over the world, and the
disease has taken the lives of millions, mostly in the United States (US) and Europe.[1] The virus has been claimed to originate from bats; thereafter, it passed from bats
to a secondary animal before being transmitted to humans. The COVID-19 is caused by
RNA virus of coronaviridae family and belongs to the β group of Corona viruses (β-CoVs).
The mutated SARS-Corona virus is now named SARS-CoV-2, which was discovered in Wuhan
city of China from a patient afflicted with pneumonia of unknown etiology.[2] Based on the rapid increase in rate of human infection, the World Health Organization
(WHO) classified the disease as a pandemic. To date, more than 3.3 million cases of
COVID-19 have been reported globally, with mortality recorded in 235,000 cases and
the number increasing every minute.[3] Within few weeks of declaring the COVID-19 a pandemic, in vitro diagnostic (IVD)
assays for detection of SARS-CoV-2 were developed.
The first real-time, reverse transcription polymerase chain reaction (RT-PCR) assay
with high-specificity for detection of SARS-CoV-2 RNA via envelope (E) and RNA-dependent
RNA polymerase (RdRp) gene was developed in Germany in early January 2020.[4] Since then, many companies have started manufacturing real-time PCR kits. Till now,
the US Food and Drug Administration (FDA) has offered emergency use authorizations
(EUAs) for COVID-19 diagnostic testing kits from approximately 32 manufactures/distributors.[5]
Due to high-demand of these kits in the US and Europe, and restrictions on international
transport, it has become impossible for the Indian government to remain dependent
only on imported kits in order to test its population of 1.3 billion. Even in the
US and European countries, the demand of RT-PCR kits is not being met by suppliers,
mainly because of lockdowns, leading to restricted production in most of these countries.
In India, more than 21 domestic manufacturers have started production of RT-PCR reagents,
and their concordance with standard RT-PCR Kits has ranged from as low as 10 percent
to as high as 100 percent (https://www.icmr.gov.in/pdf/press_realease_files/ICMR_Press_Release_23032020.pdf).
As the RT-PCR is technology-intensive, it has not been a favorite of small laboratories
and private practitioners. Furthermore, every government, the WHO, and even the common
public has been demanding testing, testing and testing. In March 2020, the FDA issued
a policy to allow development of serological tests. Interestingly, more than 70 test
kit developers notified the agency that they have serological tests available, and
some firms have even started claiming that their serological tests are FDA-approved.[6] Several other companies started manufacturing antibody-based rapid diagnostic test
kits on a large scale.
As always, China was fastest in terms of development of such kits, be it rapid diagnostic
tests (RDTs) for tuberculosis[7] or kits for COVID-19 detection. China’s Guangzhou Wondfo Biotech Co. was the first
company, followed by SD Biotech of South Korea, which started mass production of these
RDTs. The latter started manufacturing these RDTs in its Indian plant along with two
other Indian companies. The Indian Council of Medical Research (ICMR) and Drug Controller
General of India (DCGI), New Delhi, under tremendous public pressure allowed the conditional
import of serological kits. (https://www.icmr.gov.in/pdf/covid/kits/Antibody_based_tests_16042020.pdf). The ICMR and Government of India’s Ministry of Health clearly notified that these
RDTs will be used for surveillance purposes only and not for active case detection.
This step of starting the antibody-based rapid test was met with great enthusiasm
on all platforms.[8]
Subsequently, in the second week of April, ICMR and several state governments procured
hundreds of thousands of RDTs from Wondfo Biotech and other manufactures in China
and South Korea. However, within few days of this conditional import of serological
kits, the Indian markets got flooded with these kits through black marketing. After
field evaluation in third week of April, the ICMR found that these kits gave highly
discordant results when compared with RT-PCR and also posed serious problems in their
sensitivity and specificity. Realizing the backlash of poor accuracy, the Government
of India decided in favor of rolling back the antibody-based tests and return the
consignments to the manufacturers at their own cost.[9]
The biggest concern of using such kits is that the countries or states where these
are used can lead to a false sense of low incidence in their area due to low sensitivity.
The IgM and IgG antibodies which would be detected by these kits will appear only
after 7 to 10 days of infection, which is known as the window period. Furthermore,
during this window period, the patient will remain infectious but asymptomatic and
that may result in amplification of the disease in the community. It is reported that
even after 7 days of appearance of symptoms, the IgM positivity was only in 27.8%
cases, IgG in only 3.3% cases, and a combination of both in 27.8% RT-PCR confirmed
cases. Between 1 to 2 weeks of symptom appearance, this percentage was 48%, 8% and
48%, while after 2 weeks, the detection rates rose to 95.8%, 62.5% and 95.8%, respectively.[10] This clearly shows that the antibody-based assays have very little diagnostic utility
for COVID-19 which is a very acute disease.
The antibody-based kits for COVID-19 diagnosis also show false positive results due
to longer persistence of the IgM and IgG antibodies. Due to the persistence of these
antibodies even in patients who have successfully recovered from the infection, these
RDTs will give false positive results. This may lead to misleading overestimation
of cases in the territory, causing unrealistic phobia and panic situation.[11]
Therefore, these serological kits must be used for surveillance purposes only under
government-controlled conditions. The sale of such kits in the open market will prove
to be devastating. Many small clinics, and even patients if they get access to these
tests, may go into hiding and not disclose and notify the positive results. Only molecular
tests such as RT-PCR must be used for the purpose till the epidemic is over. However,
there is an urgent need to upscale the capacity of molecular biology laboratories
in India, especially for automated high throughput RNA extraction systems. We have
by now realized that the maximum delay in reporting the results occurs on account
of RNA extraction, instead of RT-PCR. Therefore, cartridge-based tests like Xpert
Xpress (Cepheid) with multiple modules or walk-away RT-PCR systems could be the only
answer to meet the test demand.
