MANILA — Countries should “test, test, test,” the chief of the World Health Organization has reiterated, in a bid to contain the novel coronavirus outbreak.
“You cannot fight a fire blindfolded. And we cannot stop this pandemic if we don’t know who is infected,” WHO Director-General Tedros Adhanom Ghebreyesus said during a press briefing.
“If you don't look for cases, your numbers will always be zero.”— Dr. Cassandra Kelly-Cirino, director of emerging threats, FIND
Populations around the world are demanding the same, and are expressing frustration against their own governments for failing to do so.
But widespread testing, even in high-income economies, is just not feasible at the moment, for several reasons. There are issues, for example, on laboratory and processing capacity, high demand for certain items critical to testing such as reagents, and countries’ financial capacity.
What are the different COVID-19 tests?
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There are several testing kits available in the market, or in development, Dr. Cassandra Kelly-Cirino, director of emerging threats at the Foundation for Innovative New Diagnostics, told Devex.
The most commonly used tests are manual molecular assays, which detect the virus’ genetic material in the liquid sample taken from a patient suspected of being infected with SARS-CoV-2, which causes COVID-19. The sample is taken using a swab, which looks like an elongated cotton bud, inserted into a patient’s nose.
This test requires three individual steps: an RNA extraction kit, a PCR assay mixture, and a polymerase chain reaction or PCR machine that runs the test to determine if a patient is SARS-CoV-2 positive or negative.
“We call it manual because you have to do each step individually and it's all user-operated. So there has to be a laboratorian in a laboratory with the right biosafety precautions, handling the specimens and doing all the work,” Kelli-Cirino said.
There are also automated molecular assays. Meaning, after the swab is collected, the whole process is done by a machine. The four most common platforms are Cepheid's GeneXpert system, Roche’s cobas 6800/8800 systems, Abbott’s m2000 RealTime system, and the BD MAX System.
Then there are rapid diagnostic tests, which look like a pregnancy test. There are two types: one that detects viral particles from nasal secretions, and one that detects antibodies in the blood of someone who’s been infected with the virus.
“One is detecting that you're actively infected with the virus, and the other one is detecting that you've, at some point, been exposed to the virus,” Kelly-Cirino said.
There are also antibody-based or antigen-based tests that use enzyme-linked immunosorbent assays or ELISAs. But these are laboratory-based assays and not for point-of-care use.
What are the bottlenecks for widespread testing?
Different countries use a different mix of these testing kits. This can depend on their financial capability, laboratory capacity, and access.
While there are few rapid test options, there is an abundance of manual molecular tests out in the market, and several more awaiting evaluations and regulatory approval. FIND has received applications to review over 200 manual molecular tests, some of which are now under evaluation.
But manual molecular tests require complex infrastructure and systems in place, and operating them can be quite cumbersome in countries with limited resource capacities. There’s also a layer of logistical challenge, as the different kits needed to run this test can come from different manufacturers.
These tests also require chemical reagents that countries are now struggling to secure. Manufacturers of these reagents are located only in a handful of high-income countries, and some are being asked by their home countries to first ensure domestic supply, Kelly-Cirino said.
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“[That is] extremely understandable given that every country is struggling to try to keep up with the demand on testing. But of course by default that's going to leave other countries behind. And I'm not talking just about low- and middle-income countries,” she said, adding high-income countries that don’t have a huge manufacturing footprint will also struggle for access.
Automated molecular test systems can reduce these complexities, but they can be costly to purchase and maintain.
Some of these machines, such as Cepheid's GeneXpert system, are already in use for other diseases by several countries, including LMICs.
But other instruments needed to run the test add to the cost. The cartridges for Cepheid’s SARS-CoV-2 test, for example, cost $19.80 each, twice the price for tuberculosis tests.
Lucica Ditiu, executive secretary at the Stop TB Partnership, told Devex it has now started negotiations for reduced pricing for the test. The Global Drug Facility, which helps countries access TB drugs and diagnostics at lower costs, announced on March 27 that it is including Cepheid’s SARS-CoV-2 test cartridge in its catalog.
Organizations such as Médecins Sans Frontières have raised concerns about “business profiteering” in the current pandemic. Pricing is one of the largest barriers for LMICs to increase their testing capacities against COVID-19, said Stijn Deborggraeve, diagnostics advisor for MSF’s Access Campaign.
“In countries where people often live with $1 a day, it is clear commercial tests with sky-high prices are out of reach of many,” Deborggraeve told Devex. This blocks the capacity of LMICs to scale up and maintain testing capacities
Tests vary in turnaround time for results. Manual molecular assay tests can take 3-4 hours, but the number of machines, personnel, and testing volume can affect this. The automated tests promise a turnaround time of under an hour. Some as short as 5 minutes.
Rapid test kits appear to be the best options for countries aiming to do large-scale, mass testing, and there’s a long list of these types of kits waiting for validation and regulatory approval. Some are already being used.
But data is still limited on the sensitivity of these tests in determining SARS-CoV-2 infection, Kelly-Cirino said.
“Our question really isn't are they being used? Because we think that they're starting to be used. It's how do they perform and do we know if they perform well enough, which is why at FIND, we're really focusing on rapidly assessing the performance so that you understand if there's any limitations to it, [and] how to interpret your data based on those limitations,” she said.
“We're waiting for our orders of the rapid test kits to come into our laboratories so that we can generate the data, and we'll make that publicly available as soon as it's ready, which I'm hoping is no more than a couple of weeks depending on when the actual test kits hit our labs,” she added.
Several countries are discovering the variability of these test kits. Last week, the Spanish daily newspaper El País reported that rapid test kits the government purchased from Bioeasy, a Shenzhen-based biotechnology company, are only able to correctly identify 30% of people infected with SARS-CoV-2.
In places such as South Korea, which has been portrayed in the media as a model for COVID-19 testing, the government used a combination of rapid testing and PCR-based tests initially. This meant results from the rapid tests were verified by laboratory tests simultaneously to ensure accuracy.
What are WHO’s testing guidelines?
It’s difficult to paint a picture of how many people have been tested to date globally. Numbers put out by countries are either based on the number of tests done, or the number of people tested. It’s important to note that an individual is often tested multiple times.
Testing guidelines also vary per country, which then can affect their testing rates.
Iceland, for instance, has started offering free testing to its general public, even those with no symptoms and are not under quarantine. Whereas in South Korea, the Korean Centers for Disease Control and Prevention only recommends testing for symptomatic patients who have come into contact with a patient who tested positive for COVID-19 and those with travel history to a country with known local transmission. Asymptomatic patients are not advised for testing.
WHO’s technical guidance for countries on laboratory testing of suspected COVID-19 patients recommends countries with no confirmed cases, with sporadic cases, and clusters of cases to test all individuals suspected of having COVID-19 disease.
But countries already dealing with large scale local transmission are likely to face constraints in testing every suspected case. In such situations and where testing capacity and resources are limited, WHO recommends prioritizing vulnerable populations at risk of developing severe disease, symptomatic health care workers — regardless of contact with a confirmed case — and the first symptomatic individuals in closed settings such as schools, prisons, and hospitals.
Focusing testing on symptomatic people can miss those who are already infected but are asymptomatic, but WHO said the risk of getting COVID-19 from an asymptomatic individual is very low.
Why do false-negatives happen?
It depends on a number of factors, but Kelly-Cirino highlighted two reasons — it depends on the test being used, and when it is used.
It may be that when a health worker takes a swab, the patient is still in his or her early days of infection, and so the level of virus present is too low to trigger detection, revealing a negative result. This can happen when using a molecular-based test.
It’s the same for antibody-based tests. When the test is done in the early days of the infection, there’s a possibility that the body has not produced enough antibodies that allow for detection.
“There's a lag time between when your body sees the virus and when it mounts an actual antibody response. It takes about seven to 14 days … and sometimes our bodies don't mount very strong responses to certain viruses, and certain people behave differently than others,” she said.
Why should countries increase testing against COVID-19?
As countries test, it’s normal to see a spike in the number of confirmed cases. But Kelly-Cirino said this should even out. If it doesn’t, then that means the virus is continuously spreading to communities and new infections are being detected, which is what’s happening now in Italy, she said.
“It's not that they're just ramping up scaling or testing. Those increases that they're seeing are new infections every day that they're picking up,” she said.
Not testing and not knowing who is infected would allow for infections to spread undetected, later on, spelling catastrophe for a country’s health care system.
“If you don't look for cases, your numbers will always be zero,” said Kelly-Cirino.
“I personally believe that the more you test, the more you know what's happening in your country, the better you can actually implement those other precautions around ... to be able to try to curb the spread and start to flatten the curve and take the pressure off of the health care system,” she said.
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Update, April 1, 2020: This article has been updated to clarify that FIND is evaluating some molecular tests from the hundreds of applications it received for review.