Cochrane recently published a review of studies looking at the accuracy of COVID-19 antibody tests. Here we summarise the main conclusions of the first review which provides authentic information to policy makers worldwide including those in India to make them aware of the status of the technology and the improvements needed for its proper use.

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In the effective management of COVID-19, public health agencies are taking many urgent steps. Carrying out antibody tests in large sections of selected groups of people is an important element in this endeavour. A few months ago our capability was to carry out only about 100 tests per day. With the introduction of rapid tests the total number now is over 200,000 per day. With the present rate at which the virus is spreading across the country, the number of tests may also be scaled up.

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COVID-19 pandemic has spread globally with indescribable and unpredictable adverse impacts on all spheres of human activity. As on June 28, 2020, COVID-19 caused 10,086,690 cases and 5,01,392 deaths worldwide. India recorded 5,29,577 confirmed cases and 16,103 deaths till that day. The Government of India, the state governments and associated agencies are closely following the developments and are coordinating their endeavours to face the pandemic. “Test, Track and Treat” are the most crucial steps. Presently, the agencies are ramping up the facilities to achieve these objectives. Comprehensive testing is an important element.

A related development is that on June 25, 2020, Cochrane, the globally respected, independent organisation that reviews evidence from research to inform health decision-making, published a review of studies looking at the accuracy of COVID-19 antibody tests. This is the first version of the review. The review team is continuously updating it and other reviews to provide a critical summary of the worldwide evidence supporting use of tests for COVID-19 over the months to come. This 310-page review is one of six planned, that cover the range of tests and characteristics being considered in the management of COVID-19.

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Importance of these tests

Why are these tests important public health tools? They help to identify individuals with previous COVID-19 disease. This enables assessment of the spread of infection and the need for public health interventions. The review summarises research evidence available up until the end of April 2020 to see whether these tests are accurate enough to diagnose disease in people with or without symptoms of COVID-19; we can also use them to find out whether someone already has had the disease.

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The search

The experts from the University of Birmingham led Cochrane researchers from universities across the world to search through 10,965 unique references on COVID-19 available at the end of April 2020 to find studies that reported results of antibody tests in groups of people known to have (or have had) COVID-19 and others known not to have had COVID-19 infection.

They identified 54 studies reporting test results for 15,976 samples. These studies took place in Asia (38), Europe (15), and in both USA and China (1). Most of them were from China and were carried out in people who had been admitted to hospital and likely to have had severe disease.

As soon as the virus causing COVID-19 enters the body of patients, their immune system responds by developing proteins called antibodies in the blood. They attack the virus. Detecting antibodies in people’s blood may indicate whether they currently have COVID-19 or have had it previously. Whilst detecting current infection is usually done using swab tests within the first 5 days of illness, they may miss infection and are not available to all.

The reviewers looked at three types of antibodies, IgA, IgG and IgM. Most tests measured both IgG and IgM, but some measured a single antibody or combinations of the three antibodies. Data were only available for 27 tests, a fraction of the over 279 (as on May 21, 2020) tests in the market. From this list, the European Union approved: 185; US Food and Drug Administration: 8; China: 7.

Data were available on both laboratory-based tests, which require blood samples taken from the veins, and point-of-care tests, which can use finger-prick blood samples. There was not enough data to compare the accuracy of different tests. The authors plan to update this review over the next few months to provide a more complete summary of the research evidence as it accumulates.

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Sensitivity and timeliness of the test

The researchers found that the sensitivity (the proportion of the people who have had COVID-19 that the test can detect) of antibody testing is very closely related to when the test is performed.

The reviewers also found that tests only wrongly diagnosed COVID-19 in 1% to 2% of people without COVID-19.

A press release from Cochrane illustrated some typical results. In a sample of 1000 people where 200 people (20%) really have COVID-19 (this is typical of workers in a hospital setting where COVID-19 patients have been treated):

• 193 people would receive a positive test result but 10 (5%) of those people would not have COVID-19 (known as a false positive result)
• 807 people would receive a negative test result but 17 (2%) of those people would have COVID-19 (known as false negative result)
• In a population where COVID-19 was more common there would be more false negatives and fewer false positives.

The press release clarified:

“Studies showed that antibody tests may have a role in diagnosing COVID-19 in patients who have had COVID-19 symptoms for two or more weeks but who have not had a swab (PCR) test or tested negative despite COVID-19-like symptoms.”

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Quality of the studies

About the quality of the studies, the researchers had several concerns:

1. Firstly, the studies were small and did not report their results fully.
2. Secondly, many papers included multiple samples from the same patients.
3. Thirdly, more than half of the studies were made available before they had been through peer review (publications known as ‘preprints’).
4. Fourthly, in one important UK study the biomarker manufacturers did not approve the identification of the tests that had been evaluated.

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Implications of this review

Dr. Jac Dinnes, who worked on the review with the University of Birmingham team asserted that the design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. He clarified,

“Studies must report data broken down by time since onset of symptoms. Action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan to update this review regularly as more studies are published."

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Experts comments

From Science Media Centre, Dr. Alexander Edwards, Associate Professor in Biomedical Technology, Reading School of Pharmacy, University of Reading, said that he found the most helpful element of this well-structured systematic review is in organising and clearly laying out the critical questions that must be answered by antibody test trial data.

“The painstaking methodology of translating sets of different published data into evidence-based medicine and policy is vital to ensure we make best use of the tests and tools that are available. Systematic reviews are a major part of this, and it’s therefore very important work.” he added.

Dr. Hayley Jones, Senior Lecturer in Medical Statistics, University of Bristol, stated that with the current proliferation in new antibody tests for SARS-CoV-2, establishment of this ‘living’ (i.e. to be continuously updated) systematic review of test accuracy is an important initiative.

“Data on the accuracy of 27 different tests were found and tabulated, but the data on each individual test was scarce: in particular, only three tests had estimates of sensitivity (how good the test is at detecting previous SARS-Cov-2 infection among people who were previously infected?) based on more than 100 samples. We need more data than this to be confident about a test’s accuracy. Because of the lack of data on particular tests, the authors have at this stage focused on combined results across multiple antibody tests. Going forwards, when the review is updated, it will be important to estimate how different tests compare with each other, as some may be much less accurate than others.” he suggested.

“The data also make it very clear that most, if not all, commercially available tests are not sufficiently accurate to warrant their use outside of the healthcare setting.” Professor Eleanor Riley, Professor of Immunology and Infectious Disease, University of Edinburgh, who is not associated with the study cautioned.

Admittedly, specialists must have now found ways to remove the frailties of the tests.

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Antibody tests in India

According to media reports as of May 18, 2020 the strategy of the Indian Council of Medical Research (ICMR) was to test symptomatic individuals, but restricted it to those in hospitals, containment zones and hotspots, contacts of a confirmed COVID-19 case, healthcare and frontline workers, and those with history of international travel. Presently, ICMR is recommending tests of all symptomatic persons without any qualifiers.

The ICMR advisory quoted,

“Since test, track and treat is the only way to prevent spread of infection and save lives, it is imperative that testing should be made widely available to all symptomatic individuals in every part of the country and contact tracing mechanisms for containment of infection are further strengthened. ICMR advises all concerned State Governments, Public and Private Institutions to take required steps to scale up testing for COVID-19 by deploying combination of various tests.”

On June 26, 2020, a day after the Cochrane review published its study on antibody tests, The Financial Times quoted the concerns of some consultants and virologists from across the UK who argued that there was presently no valid clinical reason for large scale testing, test performance has not yet been adequately assessed and testing risked inefficient use of scarce resources. They criticised the decision on rapid rollout of antibody testing in England in a letter published in The British Medical Journal (The BMJ, June 24,2020). May be ICMR may have sound reasons to use the test optimally in India.

The Press Information Bureau (PIB) reports that the tests are widely used; the total number of all samples (including those for antibody tests) tested on June 27, 2020 is 2, 20,479 in 24 hours.

The present Cochrane Review titled “Antibody tests for identification of current and past infection with SARS-CoV-2” provides authentic information to the policy makers worldwide including those in India to make them aware of the status of the technology and the improvements needed for its proper use.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a freelance science journalist and a former Secretary of the Atomic Energy Regulatory Board. He is available at ksparth@yahoo.co.uk