Delays in testing as a source of COVID-19 false negative results
(Manuscript submitted on June 2, 2020)
As Canada moves out of full public health lockdown to restart the economy, it is projected that flares of additional “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) virus infections causing “coronavirus disease 2019” (COVID-19) will need to be promptly detected to mitigate second and third outbreak waves in the coming months. Development, testing and production of effective vaccines and antiviral drugs to combat this pandemic will not likely be fully implemented for the foreseeable future, while the infection continues to spread globally over the coming year or two. Reliable and valid testing of acute cases will remain an important means to control community spread during this vulnerable period.
Yet current COVID-19 results from nasopharyngeal and oropharyngeal swabbing suggest improvements are needed in the overall testing procedures within Canada. As of 1st of June 2020; 263,074 tests were conducted on 237,747 persons in Alberta1. And yet for having one the highest per capita testing rates in North America, Alberta has only 7,044 confirmed cases of COVID-19 (or a 3 % positive rate), including those cases that were initially imported from outside the country. While the surge of cases in the Province (mostly in Calgary) reached an apex on 23rd of April 2020, steady daily cases continue to be reported since 3rd of May 2020 suggesting ongoing undetected community spread2. So why are we not finding more of these cases?
There are many reasons for a patient to have a negative test using a reverse transcriptase polymerase chain reaction (RT-PCR), as outlined in Table 1. In Canada, true negative tests are certainly plausible in a minority of cases at this time of the year. During the period from April to June, it is unlikely that a majority of mild to moderate flu-like illnesses are due to something other than a SARS-CoV-2 virus infection in the current year. Typically, viral respiratory infections in Canada are at a low ebb outside the annual influenza season (i.e., November to March). Domestic arbovirus infections that can create similar COVID-19 symptoms (e.g., Jamestown Canyon Virus, West Nile Virus or Spotted Fever) are not common in Canada and occur primarily in late spring and summer months3.
Though other foreign jurisdictions have cited false negative rates varying up to 50%4, provincial systems such as Alberta’s provincial laboratory testing process yielded 100% accuracy as per the Canadian National Microbiology Lab (NML)5. Moreover, the local-provincial-federal system of specimen collection and transport to centralized lab sites has been reliable for those of us using it regularly for other infectious diseases testing over several decades. Thus, the factors prone to potential improvement involve the timing and technique of sampling during clinical encounters with moderately ill patients. Those with severe acute COVID-19 will be hospitalized and tested immediately. However, testing in the community is another story.
While nasopharyngeal (NP) swabbing requires greater confidence between provider and patients to perform, a NP swab is unlikely to miss sampling the infected mucosa compared with a deep nasal or oropharyngeal (OP)/throat swab6. Canadian family physicians have had a long history of competently conducting NP testing during the annual influenza season, including formal participation in the FluWatch Sentinel Practitioner ILI Surveillance Program7. Deep nasal swabbing was quickly abandoned by Alberta Health Services (AHS) following a preliminary study showing it to be less reliable6, especially in the hands of non-physicians at large drive-through assessment centres. Due to a global shortage of nasopharyngeal swabs, Canadian jurisdictions have been forced to use the alternative swabbing techniques8. Until there is improvement in the supply of nasopharyngeal swabs within Canada, this factor cannot be currently addressed.
The only factor that can be substantially improved at the population level is to reduce the time between the onset of illness and quality OP testing, which ensures sampling occurs during the optimal time for detecting the virus in the upper respiratory tract9-11. Though there has been limited published information on the lowest false negative testing period, Kucirka and colleagues have modeled the best testing period from the onset of any symptoms is within the first 7-10 days12. Testing someone prior to symptoms or after 10 days following symptoms risks a higher likelihood of false negative testing. Systemic delays in the booking of patients for testing unnecessarily increases the number of false negative results, and can be addressed by returning to a decentralized process reintroducing family medicine clinics as testing sites for moderately ill cases (see Figure 1).
The following scenario illustrates the problem with systemic delays, when one remains reliant on an ad hoc centralized process for COVID-19 testing such as currently exists in Alberta13. Over the first three weeks of April 2020, one encountered patients with several symptoms characteristic of mild to moderate COVID-1914. Many had been waiting between 3-14 days (averaging 5 days) to be tested from the time of contacting 811 (Health Link) to book an appointment. The results from all these patients were negative. Thus, suspected mild to moderate COVID-19 cases were consistently being tested beyond 7 days from onset of symptoms, when the risk of a false negative RT-PCR test increases substantially12. Up to this point in the outbreak, the only positive COVID-19 cases encountered were those discharged from hospital following a severe clinical course and requiring follow-up in the community. All suspect cases sent to the drive-through testing centres were tested negative.
During the third week of April 2020, three patients called our medical clinic requesting testing for possible SARS-CoV-2 viral infection. All three were unrelated community cases with moderate symptoms including fever, sweats, myalgias and mild cough or chest congestion without shortness of breath. The onset of symptoms was within the previous 6 days. All had previously called 811 and were still waiting for an appointment to have a throat (OP) swab at one of the government-run assessment centres. Though family medicine clinics in Alberta were not provided viral testing kits for COVID-19 screening, our clinic had residual NP testing kits from the previous annual influenza season’s surveillance program. All three cases were brought into the clinic immediately for testing, and 2 of 3 patients were positive for SARS-CoV-2 virus infection reported the following day.
One of the confirmed cases was a parent with a spouse and two children at home with similar flu-like symptoms. The positive case and the older child had symptoms on the same day. The spouse developed symptoms a few days later, and the younger child shortly thereafter. Because of a limited supply of remaining swab kits, we were unable to test the rest of the family suggesting that they assume to be COVID-19 infected and self-isolate. The parent booked remaining family members through the 811 centralized booking process, and waited seven more days to be tested at a drive-through assessment centre. The older child with the most severe symptoms was tested negative, the spouse was tested indeterminate (then later classified as positive), and the smaller child with the mildest symptoms was tested positive. This situation reinforces the observation of there being a short window for reliably using RT-PCR testing within the first 7-10 days from onset of illness to avoid false negative testing9-12.
There are a number of factors leading to unnecessary delays in testing through a centralized booking system including but not limited to: a communication choke point (811) leading to long wait times, problems with surge capacity for doing tests (e.g., insufficient staff at different times of day or week), and ineffectual triaging to exclude inappropriate cases for testing. The last factor has been well documented, when debriefing patients who had received testing in the past. Several patients with chronic sinus congestion, allergic rhinosinusitis, mild asthma, or other non-specific upper respiratory symptoms for the previous 2 to 8 weeks were still triaged to be tested at an assessment centre. None of these chronic cases should have been booked for COVID-19 swabs, and probably contribute to those with acute symptoms having to wait longer than is appropriate.
What is worse than randomly testing a group of asymptomatic people with no recent cold or flu-like illness is to systemically test all symptomatic patients beyond the window period when a COVID-19 RT-PCR test would likely be positive. While one may pick up asymptomatic infections in the first group, there will likely be no cases found in those with resolving COVID-19 infections. If one is testing symptomatic patients beyond 7-10 days from onset of illness, then the RT-PCR test has a greater probability of being negative due to clearance of the SARS-CoV-2 virus from the upper airway (see Figure 1). The current approach of testing with systemic delays will help to ensure community spread continues to occur mostly undetected in the coming months.
As the first wave of the COVID-19 pandemic passes over various Canadian communities, it seems appropriate to consider moving from a centralized to a decentralized approach to coronavirus testing that is better aligned with community-based family practices. Sporadic cases will present at primary care with non-specific upper respiratory infection symptoms, where physicians should be able to immediately test their patients as part of normal medical care. This was the normal approach prior to the onset of the pandemic, and one that has worked quite well during annual influenza seasons over several decades. Public health officials will still want to do widespread surveillance testing of staff and residents living or working in close quarters in high-risk locations such as nursing homes, hospitals, prisons, group homes, meat packing plants, fulfillment centres, etc.
But if we want to better characterize community spread during the lull following the first wave of the COVID-19 outbreak, then we need to test more patients in a timely manner within 7-10 days from the onset of any flu-like symptoms. When an approved serology test is disseminated throughout Canada15, only then will we be able to determine the full extent to which the current testing strategy has missed a majority of mild and asymptomatic community cases. Until then, centralized assessment centres could reduce unnecessary delays by declining to test anyone who will have had symptoms longer than 7 days at the time of their booking. This would slash the backlog and move acutely ill patients up the queue with a goal of testing them within 24-48 hours from calling 811.
In addition, provincial governments could restock medical offices with viral (OP and/or NP) swabs and media kits to allow same day testing. Though this analysis has focused on Alberta, the basic premise is the same for all Canadian provinces. We need to return to a less centralized process of patient testing by increasing the number of access points within the health care system to improve the timeliness and reduce the number of COVID-19 RT-PCR false negative tests yet to be confirmed by future seroprevalence studies.
Dr. Zimmer is a clinical assistant professor in the Department of Community Health Sciences, University of Calgary. He is a practicing public health specialist and family physician with a wide array of past experiences including emergency medicine, remote rural care, medical officer of health, HIV prevention and tropical medicine. He currently practices at the Richmond Square Medical Centre in Calgary, Alberta.
References
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