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Less than a fifth of UK deaths in the last week of May were linked to coronavirus, Office for National Statistics figures show.

• New research from Dartmouth emphasises the implications of false negative tests

• Numerous false negatives have been reported in RT-PCR tests

• More emphasis on accuracy and a standardised process is needed 

On 29 May 2020 Health24 published an article on the possible repercussions that false negatives for coronavirus could have in containing the spread of Covid-19.

According to the latest research published in the Annals of Internal Medicine, the odds of a false negative through RT-PCR, the most commonly used test, is one in five.

Now, further research from the Geisel Medical School of Dartmouth suggests that even more emphasis should be placed on addressing these inaccuracies, as testing is crucial to containing the pandemic.

Testing inaccurate in two ways

According to lead author, Prof Steve Woloshin from the Geisel School of Medicine at Dartmouth and of the Dartmouth Institute for Health Policy and Clinical practice, there are two ways in which the current diagnostic tests, which involve a swab from the nasal passage, can be inaccurate:

“A false-positive result mistakenly labels a person infected, with consequences including unnecessary quarantine and contact tracing. [Secondly], false-negative results are far more consequential because infected persons who might be asymptomatic may not be isolated and can infect others,” he stated in a news release.

Lack of standard process

In the paper published in the New England Journal of Medicine, the team from Dartmouth refer to several current limitations of the RT-PCR tests. This includes a difference in the sensitivity of the tests and the lack of a standard process to validate the accuracy of the tests

The researchers also concluded that testing can only be part of an efficient strategy to contain the epidemic and that a standard should be set for all tests. Right now, there is no standard process, according to the study authors.

What can go wrong if tests are not accurate?

In a previous article, Health24 spoke to Dr Glenda Davison, laboratory expert and head of the Biomedical Sciences Department at the Cape Peninsula University of Technology about the implications in South Africa if we experience false negatives.

According to her, it’s a difficult situation as there are many factors that can contribute to false negatives and inaccuracies, including the fact that the sampling from a nose or throat swab isn’t always adequate.

She also stated that the inaccuracy of tests has negative consequences for the effectiveness of track and trace screening.

“In many cases, tests are being performed on people who do not have any symptoms, but who have been in contact with a positive individual. If it is in the early stages (days one to four), or the specimen is not processed properly, they could very well test negative and not go into quarantine. This could, of course, lead to increased spread unless all contacts are made to self-isolate irrespective of a test result,” she stated.

No laboratory test fool-proof

According to Dr Davison, the current limitations of tests shouldn’t be a reason for us to become complacent with the current efforts in place.

“However, these tests also have their pitfalls. In the meantime, it is important that we are all aware of the limitations of the RT PCR test and that false negative results are possible,” Professor Davison said.

More effort needed

The research team from Dartmouth drew several conclusions from their study. Diagnostic testing will help in safely reopening countries while controlling Covid-19, but this strategy can only work if the sensitivity and accuracy of tests are increased.

They also stated that there should be a standardised process and that the FDA should provide full details of the tests’ clinical sensitivity.

Dr Davison also stated that, as infections in South Africa increase, there should be more awareness of the fact that tests could result in false negatives. She stated that screeners should know that these false negatives can happen, as well as the reasons why they happen.

READ | Scientists warn of false-negative results with Covid-19 virus tests – what are the implications for SA?

READ | Latest on Covid-19 testing in SA: Public sector backlogs more than 6 days – an expert tells us more

South Africa’s testing strategy needs urgent fixing: here’s how to do it

^{Image credit: Gustavo Fring on Pexels}

Marelize Wilke

• More than 1 billion people worldwide suffer from hypertension

• New research shows hypertension patients with Covid-19 have a doubled risk of mortality

• Health professionals urge patients to continue taking their medication

High blood pressure, medically known as hypertension, is a serious medical condition that affects an estimated 1.13 billion people worldwide, according to the World Health Organization (WHO) – most of them in low- and middle-income countries.

According to new research published this month in the European Heart Journal, patients with this condition have a double risk of dying from Covid-19, the disease caused by the new coronavirus, than patients without it.

Hypertension patients ‘should take good care of themselves’

The study was carried out by researchers in China and Ireland who looked at data from 2 866 patients with Covid-19. The patients were admitted to Huo Shen Shan hospital in Wuhan, China, earlier this year. Out of these patients, 850 presented with a medical history of high blood pressure.

The researchers found that 34 out of 850 patients (4%) with Covid-19 died, compared to 22 out of 2 027 (1.1%) patients without hypertension. This was after they took into account factors that may have affected the results, such as age, sex and other medical conditions.

Among patients with hypertension who were not taking their medication, 11 out of 140 (7.9%) died, compared to 23 out of 710 (3.2%) patients who were taking medication. Researchers stressed that this only highlights that neglecting medication for hypertension places patients at an even higher risk of death due to Covid-19.

“It is important that patients with high blood pressure realise that they are at increased risk of dying from Covid-19. They should take good care of themselves during this pandemic and they need more attention if they are infected with the coronavirus,” said Professor Fei from Xijing Hospital, reported EurekAlert.

RAAS inhibitors do not increase risk of death

“There were 140 patients admitted to hospital with Covid-19 who had discontinued their anti-hypertensive treatment due to various reasons. We found that this was associated with a greater risk of dying from the coronavirus,” Li said.

The team looked at additional data from almost 2 300 patients in three other studies. Through a meta-analysis, they intended to analyse the death rates in these patients and determine whether patients being treated with medication to control blood pressure levels which targets the renin-angiotensin-aldosterone system (RAAS) can increase the risk of mortality.

Their findings revealed a lower risk of death among 183 patients that were treated with RAAS inhibitors, compared to 527 patients who were treated with other medication to control their blood pressure levels.

“In contrast to our initial hypothesis, we found that RAAS inhibitors, such as ACE inhibitors or angiotensin receptor blockers, were not linked to an increased risk of dying from Covid-19 and, in fact, may be protective,” Li said.

However, the researchers wrote that it is too early to make clinical recommendations based on these results, and that randomised controlled clinical trials (RCT) will offer better insight into the role played by RAAS inhibitors.

Health24 recently reported on another study, published in the New England Journal of Medicine in May, wherein researchers looked at the link between treatment with four drug classes for hypertension, and an increased risk of severe Covid-19. Their results proved that there is no link between substantial risk of severe Covid-19 (such as intensive care, use of a ventilator, or death) among patients and certain, common classes of antihypertensive medications. 

Patients urged to continue medication

The Heart and Stroke Foundation South Africa notes that 225 South Africans are killed by heart disease every day and that 13% of global deaths are caused by hypertension. An estimated 42% to 54% of South Africans were suffering from hypertension in 2018, Health-E News reported.

Minister of Health, Dr Zweli Mkhize said in a media release last month that data for patients who had been hospitalised with Covid-19 showed that hypertension, diabetes and cardiac disease are the three most common comorbidities associated with serious illness from Covid-19, and urged South Africans who live with these conditions to take extra precaution during this time.

Compiled by Zakiyah Ebrahim

Scientist across the world became interested in the drugs hydroxychloroquine and chloroquine after an in vitro study (done in a lab) in China in February showed promising results in combatting Covid-19. The drug which has anti-inflammatory and anti-viral properties, also showed promising signs in animal studies and in some small clinical studies done early in the Covid-19 pandemic. Soon the rush was on and countries like Australia and the US began stockpiling the drug previously best known as a treatment for malaria. 

Hydroxychloroquine has however to date not been proven effective to treat Covid-19 in humans, especially in placebo-controlled, randomised controlled clinical trials, considered the gold standard for medical evidence. 

While low-dose chloroquine has an extensive safety track record of long-term use for malaria prevention and treatment of auto-immune disorders like lupus, higher doses of chloroquine and hydroxychloroquine can be toxic and, among others, cause heart problems. Hydroxychloroquine is a less toxic version of its close cousin chloroquine.

Major blow for hydroxychloroquine

A major blow for hydroxychloroquine came on Friday when British scientists stopped the hydroxychloroquine arm of the RECOVERY trial. The RECOVERY trial is a multi-arm randomised controlled trial that is comparing several potential treatments for Covid-19.

In the trial a total of 1 542 patients were randomised to hydroxychloroquine and compared with 3 132 patients randomised to usual care alone.

There was no significant difference between the two groups in terms of deaths or in other key indicators such as how long patients stayed in hospital.

The researchers said that the drug does not work as a treatment for infected patients and that it should not be used to treat patients with Covid-19 in hospitals.

The findings have not yet been published in a medical journal.

WHO trial to continue testing hydroxychloroquine

Responding to the findings, the World Health Organisation (WHO) said on Friday the RECOVERY results would not change its plan to test hydroxychloroquine as part of its SOLIDARITY trial. Similar to RECOVERY, SOLIDARITY is a multi-arm randomised control trial comparing a number of different experimental treatments for Covid-19. 

South Africa is one of over 70 countries participating in the SOLIDARITY trial. (Spotlight previously reported on the SOLIDARITY trial here.) 

Dr Jeremy Nel, co-principal investigator of the SOLIDARITY trial in South Africa, confirmed that it is going ahead with the hydroxychloroquine arm of the trial. In South Africa, the trial is being conducted in 14 hospitals in most of South Africa’s provinces. According to Nel, recruitment of patients hospitalised with Covid-19 at these healthcare facilities will soon begin.

“Chloroquine can block SARS-CoV-2 from replicating, by a number of different mechanisms including stopping the virus from entering the cell and stopping new virus from being produced by the cell,” says Nel. Nel, head of the Infectious Diseases Division at Helen Joseph Hospital, University of the Witwatersrand, said the WHO is supplying the drug and has given the assurance that it has sufficient availability.

Another setback

Another disappointment for the drug’s use came on Thursday last week with the publication in the New England Journal of Medicine of findings from an eagerly awaited trial that tested the use of hydroxychloroquine to prevent Covid-19.

Researchers at the University of Minnesota in the United States found hydroxychloroquine did not prevent people, who’d been exposed to others with Covid-19, from developing the disease.

A total of 821 people were enrolled in this first double-blind randomised, placebo-controlled trial of hydroxychloroquine as a form of prevention. They were either living in the same household as someone with Covid-19 or were health care workers who had been exposed to someone with Covid-19 who had not worn adequate protection.

That trial did however have some shortcomings and some researchers remain hopeful of a role for hydroxychloroquine or chloroquine in the prevention of Covid-19.

SA participation in prevention trial

Researchers in South Africa taking part in a large international trial exploring the use of low-dose chloroquine as a form of Covid-19 prevention. The trial, called Crown Coronation, is expected to recruit healthy front-line healthcare workers soon. 

National co-principal investigator, Professor Bruce Biccard, makes an important distinction saying that it was a prophylaxis trial unlike the RECOVERY trial which was a treatment trial.

“There is good evidence that chloroquine should have good antiviral properties, and there is nothing to suggest that it can’t be used for prophylaxis,” said Biccard who is based in the department of anaesthesia and perioperative medicine at Cape Town’s Groote Schuur Hospital.

“The primary outcome of the trial is preventing infection but we are also looking at severity of infection. So either you don’t get infected or you get infected with a milder form of Covid-19,” he said.

Internationally the trial will recruit 30 000 volunteers, half of whom will be in Africa (Zambia, Zimbabwe and possibly Cameroon) with most health care workers enrolling in South Africa.He pointed out that a low dose of chloroquine will be given – 500mg twice weekly, and that there was no indication that low doses of chloroquine were harmful.

According to the National Department of Health, by 6 June 2 528 healthcare workers had already been infected and 23 died in South Africa’s public and private health sectors.

The ability to provide healthcare services is impacted by healthcare workers becoming infected, as is already being witnessed in the Western Cape. The province currently accounts for just over 65% of all infections in the country.

“We don’t have enough health care workers. Many are sick and this makes delivering a service really difficult. If we can decrease the rate of infection or decrease the severity of the disease, frontline health care workers can recover sooner and return to work sooner,” Biccard said.

“We are trying to recruit at a very high rate and hopefully to get a signal of benefit early. We want to make an impact during this pandemic which will be around for a while. But even if we don’t manage to impact this pandemic, then we will impact the next one because these coronavirus epidemics seem to come every few years,” he said.

Controversial study muddies the waters 

Controversy over the use of hydroxychloroquine intensified two weeks ago when the Lancet medical journal published a study that showed hydroxychloroquine was not effective in treating hospitalised patients with Covid-19 and that patients who got the drug were dying at higher rates and experiencing more heart-related complications than other infected patients. 

The large observational study analysed data from 15 000 patients with Covid-19 who received the drug alone or in combination with antibiotics and comparing this data with 81 000 controls who did not receive the drug. 

The WHO responded by temporarily suspending the hydroxychloroquine arm of its SOLIDARITY trial. It resumed its trials last week after the study was retracted on Thursday by its authors who could not vouch for its data.

The withdrawal of the study followed a statement to the Lancet from 150 clinicians who were concerned about the reliability of the data used in the study.

An investigation by the UK Guardian found serious flaws in the data and raised concerns about the reliability of the analytics company Surgisphere and its CEO who was a co-author of the study. It was revealed that the company had also provided data for a New England Journal of Medicine study which has also since been retracted.

Peter Horby, professor of emerging infectious diseases and global health at the University of Oxford, who was a chief investigator in the RECOVERY trial, was quoted in the UK Guardian pointing out that the retracted Lancet study was not a randomised controlled trial but a

n observational study – comparing patients in hospitals who had been treated with the drug with others who had not. “One of the key lessons we should learn historically is that making treatment decisions based on observational data is not the way forward,” he said.

Since the retraction of studies in two leading international medical journals, some researchers are concerned that perceptions of the potential benefits of hydroxychloroquine and chloroquine for Covid-19 have become negative and this could affect recruitment to future trials.  

Commenting on the retracted Lancet study, Nel said, “It’s unfortunate in that it has cast what appears to be an unjustified pall over the drug.” He hopes that this will not affect recruitment for the SOLIDARITY trial.

Professor Linda-Gail Bekker, who is on the Crown Coronation trial committee, said the study had a significant impact. “It has a knock-on effect” in that it “makes people nervous”. 

She said the team had been negotiating with the South African Health Products Regulatory Authority and their ethics committee when the article was published.

“We had to make it clear that our dose was a tenth of the dose quoted in the Lancet paper.

“It made us have to work harder to convince people. When doing a prophylaxis trial in healthy healthcare workers, you have to be sure that it won’t do more harm than good,” she said. 

Bekker, who is the deputy director of the Desmond Tutu HIV Centre at the University of Cape Town, said that the regulatory authorities in the United Kingdom did temporarily hold back consent for the arm of the trial in that country.

The two journals will have to work hard at regaining credibility, she said. 

“The pressure to get data out and to rapid peer review may have been the issue. These instruments of medical literature are incredibly powerful and with this comes huge accountability and when this is missing, they can become instruments of harm rather than good.

“It’s hard to find a balance, but we cannot compromise quality for speed,” she said.

*Adele Baleta is an independent science writer, media consultant and facilitator.

This article was produced by SPOTLIGHT – health journalism in the public interest. SIGN UP for our newsletter.

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