Thursday, February 13, 2020

Problematic Lab Testing For The Novel Coronavirus


For several weeks there have been murmurs - first in Chinese social media - and more recently from more official sources, that the lab tests being used to detect the novel coronavirus in China - and elsewhere - aren't as sensitive as we'd hope. 
Patients - even those with overt symptoms - sometimes test negative, even though they are actually infected. 
This isn't a new problem, and we've seen it in the past with avian flu (H5N1 in particular), and with MERS-CoV.  Nearly two weeks ago, on February 1st, I wrote:
While the rapid development of an RT-PCR test for the novel coronavirus has provided doctors and public health officials an important tool in the fight against this epidemic, no lab test is 100% perfect, and there are unanswered questions over the current test's sensitivity and specificity.
  • Sensitivity is defined as the ability of a test to correctly identify individuals who have a given disease or condition.
  • Specificity is defined as the ability of a test to exclude someone from having a disease or illness.
It isn't known exactly when an infected person - who may be exhibiting no, or few symptoms - will likely begin to test positive. How the patient's samples are taken, and transported to the lab, can affect impact reliability. And viral shedding - at least with MERS-CoV - has been shown to be intermittent, which may sometimes foil lab testing.
Yesterday, the CDC announced they had uncovered some problems with the test kits they have recently sent out to all 50 states and to 30 countries; the test failed to consistently identify positive samples.  This from quote from a statement by Dr. Nancy Messonnier yesterday.
As you know, this is a dynamic, rapidly evolving situation, and our response continues to be based on the latest science. We continue to be flexible to meet the public health challenges that the virus presents, and clearly a success is the CDC rapid development of a diagnostic and rapid deployments to the states, which was clearly important to try to bring the testing closer to patients to avoid delays that have been inherent in sending samples to CDC. When the state receives these test kits, their procedure is to do quality control themselves in their own laboratories.
Again, that is part of the normal procedures, but in doing it, some of the states identified some inconclusive laboratory results. We are working closely with them to correct the issues and as we’ve said all along, speed is important, but equally or more important in this situation is making sure that the laboratory results are correct. During a response like this, we know things may not always go as smoothly as we would like. We have multiple levels of quality control to detect issues just like this one. We’re looking into all of these issues to understand what went wrong, and to prevent these same things from happening in the future.
With any new test, hiccups are to be expected, particularly given how little we know about this novel coronavirus, and how quickly the test was developed.

But in October of 2017, a full 5 years after MERS-CoV was first identified, we look at study in AJIC: Intermittent Positive Testing For MERS-CoV, that found intermittent positive results for MERS-CoV on reverse-transcription polymerase chain reaction (RT-PCR) tests were still a problem. The authors (including Memish and Al-Tawfiq) wrote:
Our data indicate that 2 to 3 nasopharyngeal samples are needed to produce the highest yield of positive results for MERS-CoV. In addition, 2 negative results 48 hours apart with clinical improvement or stabilization are needed to clear patients from MERS-CoV. Evaluation of the yield of sputum samples is needed to assess the effectiveness against nasopharyngeal swabs.
Accordingly, the CDC's interim recommendations for specimen collection for MERS are more rigorous, calling for `Collection of all three specimen types (not just one or two of the three), lower respiratory, upper respiratory and serum specimens for testing using the CDC MERS rRT-PCR assay is recommended.'
In recent day there have been reports out of China that their test kits may only pick up 30% to 50% of infected cases, and last night's inclusion of nearly 15,000 clinically diagnosed cases (without a positive lab test) would seem to bolster those claims. 
Two days ago, in Japan MOH: 2 Wuhan Evacuees Test Positive For Coronavirus 10 Days After Returnwe saw a report on two cases who initially tested negative - one tested negative twice (once even after a fever and cough appeared) - who developed COVID-19 more than 10 days after returning from Wuhan.

To all of this we can add a study - published yesterday - in Radiology, that found multiple patients with positive chest CTs and other symptoms who continued to test negative for the novel coronavirus.

Radiology. 2020 Feb 12:200343. doi: 10.1148/radiol.2020200343. [Epub ahead of print]
Chest CT for Typical 2019-nCoV Pneumonia: Relationship to Negative RT-PCR Testing.
Xie X1, Zhong Z1, Zhao W1, Zheng C1, Wang F1, Liu J1.

Some patients with positive chest CT findings may present with negative results of real time reverse-transcription-polymerase chain- reaction (RT-PCR) for 2019 novel coronavirus (2019-nCoV)
In this report, we present chest CT findings from five patients with 2019-nCoV infection who had initial negative RT-PCR results. All five patients had typical imaging findings, including ground-glass opacity (GGO) (5 patients) and/or mixed GGO and mixed consolidation (2 patients).
After isolation for presumed 2019-nCoV pneumonia, all patients were eventually confirmed with 2019-nCoV infection by repeated swab tests. A combination of repeated swab tests and CT scanning may be helpful when for individuals with high clinical suspicion of nCoV infection but negative RT-PCR screening.
Given the challenges we've seen in the past with obtaining accurate lab tests on deep lung infections from avian flu and MERS-CoV,  the limitations and problems with our current lab tests are not surprising.
While I expect testing will improve in the days and weeks ahead, there will likely never be a 100% reliable test for this novel coronavirus 
Between sub-optimal sample collection, intermittent viral shedding by the host, sample degradation during transport, and the limitations of the test itself, some false negatives are inevitable.
While expected, this does make this novel coronavirus harder to contain. No matter how diligently countries test, some infected cases will get through the screening process. 
Which means that when we hear that Country X has only 5 cases, or that Country Z has none, we need to take that information with a sizable grain of salt.