IssueSep 20

Expanding the Frontier in Covid Testing

As infection mounts the need for rapid and reliable diagnostics (Covid Testing) increases

“You cannot fight a fire blindfolded. And we cannot stop this pandemic if we don’t know who is infected. We have a simple message for all countries: test, test, test,” Dr Tedros Adhanom Ghebreyesus, WHO Director-General, famously said. Nowhere is this (Covid Testing) more evident than in India, where the Covid-19 cases are still rising. Recently, India’s single-day tally (78,761) reported on August 30, surpassed the one-day increase of 77,299 reported by the United States on 17 July. While, the Indian Council for Medical Research (ICMR) has said that, India is ramping up testing (10 lakhs test per day), experts say that testing per million remains low. Noted virologist Dr Shahid Jameel, CEO, Wellcome Trust/DBT India Alliance has said that among the top 10 virus infected countries, testing per million is among the lowest in India. “We are still finding one positive in every 11 to 12 tests. This number should be one in 20 simply and means that testing is still sub-optimal and the outbreak is growing,” he said.With Covid cases still rising in many parts of the country expanding access to testing is the only way to limit the spread of COVID-19 in the community. ICMR has ensured that specific testing platform are made available addressing general testing (RT-PCR), high-throughput testing (COBAS), testing at remotest places and PHCs (TrueNAT, CBNAAT), in containment areas (rapid antigen testing) and for large number and migrant population testing (pooled sample testing). Dr Balram Bhargava, Director General, ICMR said that in a diverse country like India, for equitable access to testing, optimisation of resources based on the evolving epidemic is an essential part of the sustainable scaling up. Starting with one single laboratory at the National Institute of Virology (NIV) in Pune, Maharashtra, as on 21st August 2020 the total number covid-19 specific testing laboratories count has reached 1511. Among these are 983 dedicated government laboratories and 528 private.

RT-PCR

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As soon as the pandemic broke-out in Wuhan, China a number to institutes took it on themselves to identify the virus. It was the efforts of such scientist that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was identified and became the backbone of accurate testing. To help battle the surging coronavirus epidemic, several manufacturers made Covid-19 reverse transcription polymerase chain reaction (RT-PCR) based tests at breakneck speed. The first diagnostic assay to be published by the WHO as a guideline for COVID-19 diagnostic detection was developed at the German Center for Infection Research in January 2020. Since then impressive progress has been made in diagnosing Covid-19 infections. TrueNat is one of the first tests to be made and deployed in India. “Truenat is the first POC, WHO endorsed – RTPCR multi – assay platform that has decentralised and democratised molecular diagnostic testing right upto the CHC/PHC levels,” says Sriram Natarajan, Founder Director and CEO, Molbio Diagnostics. “As of now, there are more than 2500 systems in use in both the private and public sector markets in India,” he adds.

Dr Chandrashekhar Nair, Chief Technical Officer, Molbio Diagnostics said, “The gene targets for the CVID -1 9 testing are as per the WHO guidelines. The Truenat Beta COV targets the E gene and acts as a screening assay, confirming the negatives. In contrast, the Truenat SARS COV 2 targets the RdRp gene that confirms the positives, found positive by the Truenat Beta COV assay.”

The company is also working on a third assay. “The third assay, Truenat COVID 19, will have both the E & ORF 1a genes which will confirm both negatives and positives in the same assay,” Dr Nair said. “This assay will be launched in the market in the first half of September,” he added.Although, RT-PCR tests are hailed for their sensitivity and have widely been used for early detection of Covid-19, it has its limitations. “RT-PCR requires skilled personnel and sophisticated equipment. These equipment are often expansive and have to be housed in temperature and air circulation controlled rooms,” says a renowned molecular pathologist from Kolkata. “The failure to detect virus in infected patients is a huge problem in places that do a large number of tests daily. The correct operation of the test is crucial,” he reiterates.

The turn-around times of 24-hrs also limits the use of RT-PCR in rapid, point-of-care applications. There are a number of challenges for RT-PCR in India but the main one is the shortage of reagents and the number of unreliable reagent manufacturers mushrooming everywhere.

Antigen tests

In June, 2020, ICMR issued an advisory on rapid antigen test for Covid-19, endorsing a stand-alone antigen detection kit called Standard Q COVID-19 Ag detection kit. An antigen test detects viral proteins which are found on the surface of the virus than nucleic acids. The viral proteins detected would reveal if the person is currently infected with the virus.Antigen based tests gained precedence in countries with rising infection that needed a reliable point-of-care rapid detection test with good sensitivity. Weapon of mass testing, rapid antigen test has become a tool for test, track and treat strategy. A quick test is also needed at healthcare settings to allay anxiety and fear of healthcare workers. Antigen tests are far less complex technology than molecular testing and a fraction of the cost of RT-PCR testing.

However, there have been concerns regarding the accuracy of the tests. Earlier in July, the media reports talked about the false negative test. Besides, to know how well the diagnostic test picks out the infection, it’s important to share data and get it analysed by both government and non-government scientists. India does not share data on the number of tests conducted by different methods. According to expert estimates 25-30 per cent of the country’s daily tests now are rapid antigen tests.The human factor is also very important in diagnosing diseases. “Doctors use their expertise to analyse the patient and judge the probability of the occurrence of a disease. Clinical correlation is also important,” the pathologist quoted above said. “No assay manufacturer gives 100% guaranty for their tests. When these tests are validated they are done in ideal lab conditions, but on ground realities are different. Many factors can affect the accuracy of tests like the timing of test, sample collection and handling etc,” he added.

Antibody tests

Antibody tests are blood based assays for covid-19 testing. Antibody-based tests detect antibodies made in response to the particular organism, in this case SARS-CoV-2. This information tells us if a person has been exposed to the virus previously. In the light of new information on asymptomatic patients and community transmission, antibody test for Covid-19 seems like a good option.Antibody tests are important because of the recent increase interest in convalescent plasma therapy. These tests are also well suited for sero-survey, screening of high-risk groups and trace clusters. However, the tests have had a roller coaster ride over the past month, with many researchers questioning the accuracy of commercially available antibody tests. India saw antibody based tests as early as April, 2020 but soon was rejected because of a number of reports of false negatives.

In fact, India stopped testing for two days on April 21-22 because of wide variations in the imported antibody test results. Following this ICMR published a list of validated and approved antibody test. The apex research body also announced a self-made test, COVID Kavach ELISA IgG kits and shared the technology for mass production.However, a couple of days later a number of manufacturers’ and importers’ license was cancelled following a similar action by the United States Food and Drug Administration (US FDA). Taking a que from USFDA the Central Drugs Standard Control Organisation (CDSCO), DCGI, cancelled kit import licences of three firms and suspended those of 15 others. Later, these kits were validated by ICMR and continue to be available in the Indian market.

Extending the Frontier

On August 15, 2020 the saliva based test developed by Yale School of Public Health received US FDA approval. The emergency use authorization was given to SalivaDirect COVID-19 diagnostic test, which uses a new method of processing saliva samples when testing for COVID-19 infection.

This is the fifth test that the FDA has authorized that uses saliva as a sample for testing. Testing saliva eliminates the need for nasopharyngeal swabs, which have also been prone to shortages, and alleviates the patient discomfort associated with these swabs. Since the saliva sample is self-collected under the observation of a healthcare professional, it could also potentially lower the risk posed to healthcare workers responsible for sample collection.

Vivalytic VRI (viral respiratory tract infections) array is a universal test kit developed by Bosch Healthcare Solutions in collaboration with Randox Laboratories to rapidly detect a SARS-CoV-2 (Covid-19) virus infection in patients. The test is world’s first multiplex molecular diagnostic tests that can identify COVID-19 and distinguish it from nine other respiratory infections with similar symptoms, like influenza. Incidentally, this device is still awaiting authorisation from Indian government to be deployed on field.

At this moment none of the authorities around the world have authorised any at-home, sensitive, disposable test for COVID-19, similar to a pregnancy test. Even though companies have been developing such kits, finger-prick IgG, IgM based tests home kits, have been pulled up for mislabelling and fraudulent by the US FDA . Several companies working in this area have put their plans on hold till they get clarity from the authorities on the use of such kits.

Accelerating Availability

Scientists uncover new information on SARS-CoV-2 every day and doctors are baffled with new clinical findings that have changed the way they manage Covid-19. Even then, efforts are underway around the globe to increase testing. Governments are working to scale up daily testing and overcoming bottlenecks in testing, as well as focusing on research into the development of new, superior tests. Ramping up of testing facility across India is at the core of increasing testing per day in India. ICMR has said that it ensured the availability of specific testing platform to address general testing (RT-PCR), high-throughput testing (COBAS), testing at remotest places and PHCs (TrueNAT, CBNAAT), in containment areas (rapid antigen testing) and for large number & migrant population testing (pooled sample testing).

ICMR has said that it established COVID-19 testing labs even in the remotest parts of the country that have difficult terrain. For example, ICMR has established COVID-19 testing lab at an altitude of 18 thousand feet in Leh, Ladakh. Apart from this, the scope of testing has been expanded by setting up a lab at Port Blair, Andaman & Nicobar. The ultimate goal is that testing should be available to everyone in need and no one should be left behind, the apex body said.

Myriad uncertainties still surround the trajectory of the epidemic. On the positive side, containment efforts have yielded good results in some affected countries, but in India the challenge before us is enormous.

 

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