Positive SARS-CoV-2 RT-PCR Test: Virus Dead Or Alive? — Dr Tan Poh Tin

A clinician’s dream and public health nightmare.

The Director General of Health, Malaysia announced on May 26 that Malaysia will change its Covid-19 protocol and discharge patients after 14 days even if their RT-PCR is positive. Patients will be advised to undergo home quarantine for another 14 days. This follows a WHO (World Health Organization) report that those who have been infected for more than 14 days will have zero infectivity.

The netizens’ comments on this Malaysiakini online article raised valid concerns: “Where is this report?”; “WHO has been proven wrong before”; “how do you count the 14 days?”; “heading for disaster”; “sending them home to die?”; “what if they infect others”; “quarantine them with a dog, see if the dog falls sick and test the sick dog”; “more lockdown?”; “We are broke”; “scary”; “Doesn’t Malaysia have experts? Tedros ain’t a medical doctor”. Jonah2’s spot diagnosis: “if you are following WHO, you are a confirmed idiot….”

Where is the science? Are netizens justified in throwing rocks at our rock star DG?

A Google search did not yield any WHO report on this issue. However, on May 23, the National Centre for Infectious Diseases and the Chapter of Infectious Disease Physicians, Academy of Medicine, Singapore had issued this Position Statement after carefully reviewing the latest publications. (research paper).

Period of Infectivity to Inform Strategies for De-isolation For Covid-19 Patients

The summary and conclusion is as follows:

“Based on the accumulated data since the start of the Covid-19 pandemic, the infectious period of SARS-CoV-2 in symptomatic individuals may begin around 2 days before the onset of symptoms, and persists for about 7-10 days after the onset of symptoms.

“Active viral replication drops quickly after the first week. Viable virus was not found after the second week of illness despite the persistence of PCR detection of RNA. These findings are supported by epidemiologic, microbiologic and clinical data.

These new findings allow for revised discharge criteria based on the data on the time course of infectiousness, rather than the absence of RNA detection by PCR testing, taking into consideration both the clinical and public health perspectives, including the individual patient’s physical and mental well-being.

In addition, given these findings, resources can focus on testing persons with acute respiratory symptoms and suspected Covid-19 in early presentation, allowing timelier public health intervention and containment”. All the references of the recent publications used to support this were listed.

RT-PCR Tests For SARS-CoV-2 RNA Gene Targets, Not Whole RNA Or Live Virus

So far, the most reliable test for the diagnosis of Covid-19 is the RT-PCR test using nasopharyngeal swabs or airway specimens, including throat swabs and saliva. A variety of RNA gene targets (viral envelop, nucleocapsid, spike etc) are used by different manufacturers.

On 11–12 February 2020, WHO organized a forum to identify research gaps and priorities for Covid-19, in collaboration with GloPID-R (Global Research Collaboration For Infectious Disease Preparedness). One of the eight immediate research needs agreed upon as part of the Forum was to “mobilize research on rapid point of care diagnostics for use at the community level”.

This recognition underscores the urgent need for access to accurate and standardised diagnostics for SARS-CoV-2 which can be deployed in decentralised settings.

WHO is continually updating technical guidance for Covid-19, including guidance on laboratory testing. The Geneva-based non-profit Foundation for Innovative New Diagnostics (FIND) is working closely with WHO and other partners to provide support on training, technical assistance and capacity building to ensure access to accurate and high-quality diagnostic testing for SARS-CoV-2.

On 19 February 2020, FIND launched an expression of interest (EOI) for test developers of in vitro diagnostics (IVDs) that detect SARS-CoV-2 nucleic acid (molecular tests). The EOI closed on 9 March 2020. A total of 220 submissions were received for evaluation.

FIND conducted independent evaluations at the University Hospitals of Geneva (HUG), to verify the limit of detection (LOD) and the clinical performance (as reported by the manufacturers) of these molecular test kits. Test results can be checked here.

SARS-CoV-2 RT-PCR tests for RNA fragments, not viable or infectious virus. To prove infectivity, viral culture and epidemiological studies are needed.

In most symptomatic Covid-19 individuals, nasopharyngeal swab viral RNA becomes detectable as early as day 1 of symptoms and peaks within the first week of symptom onset. This declines by week 3 when most mild cases yield a negative result. In severely ill hospitalised cases, positivity may persist beyond 3 weeks.

The time course of RT-PCR positivity may vary with children or immunosuppressed groups, and for asymptomatic undiagnosed individuals. It is not known how long potential immunity lasts.

Virus Culture Positive Till Day 8-11 Of Symptom Onset In Positive RT-PCR Cases

Wölfel et al (Virological assessment of hospitalized patients with COVID19.
Nature 2020. Published online April 1, 2020. doi:10.1038/s41586-020-2196-x
) reported a detailed virological analysis of nine cases that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak on day 4.

Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples, in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. The shedding of viral RNA from sputum outlasted the end of symptoms.

Seroconversion (positive antibody test) occurred after 7 days in 50% of patients and by day 14 in all patients, but was not followed by a rapid decline in viral load. Infectious virus was cultured from throat and lung specimens in the first week of symptoms, but none after day 8 in spite of high viral loads detected by regular PCR.

The Singapore NCID data, based on an analysis of 766 patients, showed that by day 15 from the onset of illness, 30% of all Covid-19 patients are PCR-negative on nasopharyngeal swab. This rises to 68% by day 21 and 88% by day 28. By day 33, 95% of all patients are negative by PCR.

The Singapore position paper quoted a local study from a multicenter cohort of 73 COVID-19 patients, virus could not be isolated or cultured after day 11 of illness.

Epidemiological Studies Of Infective period: 2 Days Before Till 5-7 Days After Onset Of Symptoms

A Hong Kong study of 77 infector-infectee pairs estimated that the infectious period started 2.3 days (0.8 to 3 days) before onset of symptoms, peaking at 0.7 days (0.2 to 2 days), and declining within 7 days. (He et al Temporal dynamics in viral shedding and transmissibility of COVID-19. Nature Med 2020; 26:672-675).

Taiwan traced 2,761 close contacts of 100 Covid-19 patients and identified 22 paired index-secondary cases. All 22 cases arose from contact with the index case within 5 days of symptom onset and none (0 cases from 852 contacts) arose from contact 5 days or after. (Cheng HY et al. Contact tracing assessment of COVID-19 transmission dynamics in Taiwan and risk at different exposure periods before and after symptom onset. JAMA Intern Med. 2020 May 1).

RT-PCR Test – Positive, Persistently Positive, Re-Positive and False Positive?

On 21 May, the Korean CDC revealed the findings from the investigation of 285 out of 447 cases who tested positive for RT-PCR after being discharged negative. Of the 285 re-positive cases, 44.7% were symptomatic for cough or sore throat.

Virus isolation in cell culture of respiratory samples of 108 re-positive cases, were all negative of their 790 close contacts, no secondary case has been found directly arising from this “re-positive period”.

On average, it took 44.9 days (8-82 days) from initial symptom onset to testing positive again after discharge. It took 14.3 days (1-37 days) from discharge to re-test positive.

While this study is ongoing, the Korea CDC was sufficiently confident to recommend a change to existing protocols effective 19 May. For confirmed cases after discharge from isolation, the 14-day self-isolation will no longer be needed, nor will PCR test be required if symptoms occur within 14 days of discharge from isolation. The cases that test positive after discharge from isolation will no longer be isolated as confirmed or quarantined as contacts of infected cases.

However, reporting and investigation of re positive cases and their contacts will continue as before for purpose of research and evaluation. So, they have changed the term “re-positive” to “PCR detected after discharge from isolation”.

In Singapore, 18 positive cases were found to be persistently positive for between 38-51 days while isolated in a community care facility. They were clinically well.

Discharge RT-PCR Positive Cases 2 Weeks After Symptom Onset — Home Quarantine Needed?

The Malaysian National Hammer thrower Jackie Wong who tested Covid positive on March 16 was admitted to the Sibu Hospital, Sarawak. Following the previous Ministry of Health Malaysia protocol, he could not be discharged till at least two consecutive nasal swabs tested negative for RT-PCR over 24 hours. His RT-PCR tests had been on and off positive over the 70 days, although he showed no symptoms. He (and his coach) was ecstatic to be finally discharged on 27th May following this new protocol.

As of 31 May, Sarawak has 552 confirmed cases (first case 13 March) with 508 discharged and 17 deaths. 27 are still hospitalised in the four quarantine hospitals. According to a statement by the SDMC (Sarawak Disaster Management Committee) secretariat, out of the 552 positive cases, 19 were those who were readmitted to the hospital because they had tested positive for the virus again.

More Covid-19 cases will discharged based on this new protocol, which will free up wards and staff who have been “drafted” into Covid duty. Certain sections of the hospitals, outpatient clinics, diagnostic and laboratory facilities can be safely reopened and staffed to handle the backlog of all the postponed operations, cancer cases, and all the other so called “non-urgent cases” which have been put on hold.

After all, hospitals are not safe places to “hold up” recovering patients who are asymptomatic but whose nasal swabs refuse to go negative or become positive weeks later. In their recovery stage they may pick up other hospital germs! (nosocomial infections). According to the Institute of Aging, you can lose up to 1% of lean muscle mass each day you spend in bed. Spending 3-5 weeks immobilised can lead to 50% decrease in muscle strength

Take Home Message: Recovery Phase RT-PCR Positive Doesn’t Mean Infectious

Viral cultures are usually negative from as early as the 10th-11th day of illness, even though the RT-PCR may remain positive for 2–6 weeks.

In re-positives or persistently positive cases, the RT-PCR test could be picking up dead viral components which are no longer transmissible nor infective to others.

The actual on-the-field performance and accuracy of all diagnostic tests for Covid-19, between brands, within countries and laboratories is being intensely scrutinised and audited. Interpreting findings of studies by different groups and extrapolating conclusions is, thus, a tough, calculated judgement call every country’s DG MOH has to make.

The jury is still out. Netizens, hold on to your rocks.

Dr Tan Poh Tin is a public health-trained paediatrician from Kuching, Sarawak, who retired from MOH and Unimas.

  • This is the personal opinion of the writer or publication and does not necessarily represent the views of CodeBlue.

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