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Rammya Mathew: We must not be guided by bad science on covid-19

BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m2241 (Published 09 June 2020) Cite this as: BMJ 2020;369:m2241

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Like any medical test, intrepreting a RT-PCR test result for COVID-19 without considering clinical picture is misleading and dangerous

Dear Editors

I am responding to Dr Ashcroft’s rapid response regarding the unwise “blanket management plans without consideration of the clinical picture” involving asymptomatic staff who tested positive from RT-PCR (reverse transcriptase-polymerase chain reaction) test for SARS-COV-2, the coronavirus causing COVID-19.

I can understand his frustration but for the benefit of readers not fully cognisant of the issues involving COVID-19 testing, here is a quick summary:

Current testing standards for COVID-19 involves primarily the testing for genetic material specific to SARS-COV-2 in a swab taken from the naso-pharyngeal region containing respiratory mucus (and/or patient’s own cells). Normally even in a good sample the amount of genetic material is minute, hence the technique of amplifying the number of copies of genetic material fragment specific to the COVID-19 virus so that the lab can detect it.

Hence, there is a chance that a poor sample with insufficient material or when there is not a lot of viral material being produced at an early stage in an infected person, will not get a positive test result, thus the result is false(ly) negative. In the case of RT-PCR test showing false(ly) positive when the person is in fact truly not infected, this can be due to presence of other genetic material similar to that of SARS-COV-2 virus, contamination of sample, human sample processing or data entry/recording mistake or machine error.

It is important to realize that this test does NOT differentiate if the genetic material is from a virus that is capable of infection or if it came from those that are not, ie inactivated. Only by actually testing the sample on cell culture (a far slower and labour intensive process) looking for viral replication to certain standard can it be certain if the virus detected is viable or active. The condition for those testing positive to RT-PCR but actually not-infective and negative to cell culture testing is called RNA shredding and is known to occur within 8-10 days of symptom onset.

Other testing that can be done but thought to be less consistent or accurate is testing for blood antibodies to SARS-COV-2; IgM type reflects body response to early (infective) stage and IgG relates to a later stage in body response and is associated with longer term immunity (but not always).

Generally it is regarded that a person who tested positive to RT-PCR and IgG to SARS-COV-2 at the same time is not considered infectious; the result only reflecting recent previous infection (this advice comes with a caveat as I am only an orthopaedic surgeon!).

However to the staff in the pathology lab, a positive result to either test means the person being tested is regarded as “consistent with infection with SARS-COV-2”. Therefore as in any medical test, the result needs to be correlated with the clinical picture; anyone can read a report but knowing the application and relevance to clinical findings is the key to diagnosis, hence the medical training required.

But I digress.

In the case of Dr Ashcroft, he was tested as part of the routine and probably blanket screening of medical staff in the emergency department (ED) for SARS-COV-2 using RT-PCR (presumably via nasopharyngeal- there are other methods). He did not reveal if he declared his previous COVID-19 infection nor if it was properly recorded in the test request accompanying the sample being tested.

Dr Ashcroft states he was tested positive for IgG antibodies to SARS-COV-2 in early June 2020, but he did not state if he was ever tested as negative for RT-PCR since his COVID-19 infection earlier in the year.

The routine testing of healthcare staff especially the frontline (emergency) areas is probably relating to the news of some hospital ED had 50% tested positive for COVID-19 (ref 2) and speculation that up to 20% COVID-19 cases are related to healthcare settings (ref 3). Also, some speculated as much as 30% of daily COVID-19 cases in April 2020 were healthcare workers (ref 4).

While Dr Ashcroft has referenced some research relating to RT-PCR positive people not infectious, this phenomenon was described as early as April 2020 (ref 5) and there had been in fact international recommendations published (ref 6-9) including the World Health Organisation (ref 10-11) on how to discharge COVID-19 patient from isolation based on symptoms (or lack of), although I am not able to find one published for UK including one for NHS staff.

Thus the possible scenarios relating to directions to Dr Ashcroft to isolate can be as follows:

1. Clinical staff providing direction to isolate not aware of Dr Ashcroft’s previous infection or serology results

2. Clinical staff aware of Dr Ashcroft’s previous infection or serology results, but in absence of formal NHS guidelines, is treated as a newly infected case

3. Clinical staff aware of Dr Ashcroft’s previous infection or serology results, considered formal NHS guidelines consistent with WHO recommendation, but in view of his healthcare worker status in the frontline, erred on the side of caution in decision making

4. Staff contacting Dr Ashcroft were not adequately trained or authorized to deviate from the written script and action plan

Dr Ashcroft’s dilemma will not be unique, since at least 3% of asymptomatic NHS staff at work tested positive to SARS-COV-2 (ref 12); this does not include NHS staff who were isolating at home during the study due to symptoms or previously tested positive. If the direction to isolate healthcare workers is based solely on a single RT-PCR positive test, the NHS will be at risk of further loss of staff from the current pandemic shortage.

References
1. https://www.bmj.com/content/369/bmj.m2241/rr
2. https://www.bbc.com/news/uk-wales-52263285
3. https://www.theguardian.com/world/2020/may/17/hospital-patients-england-...
4. https://www.cebm.net/covid-19/covid-19-how-many-healthcare-workers-are-i...
5. https://www.nature.com/articles/s41586-020-2196-x.pdf
6. https://www.ams.edu.sg/view-pdf.aspx?file=media%5C5556_fi_331.pdf&ofile=...(final)+23-5-20+(logos).pdf
7. https://www.theladders.com/career-advice/new-study-finds-covid-19-patien...
8. https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-guidan...
9. https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html
10. https://www.who.int/news-room/commentaries/detail/criteria-for-releasing...
11. https://apps.who.int/iris/rest/bitstreams/1282284/retrieve
12. https://elifesciences.org/articles/58728

Competing interests: No competing interests

28 July 2020
Shyan Goh
Orthopaedic Surgeon
Sydney, Australia