Thursday, February 27, 2020

Here's what we need to know about COVID-19 testing

The problem of highly restricted testing in the US

The COVID-19 virus is quite deadly (mortality appears to be between 2 and 10% as discussed in my last post) though since we don't know how many asymptomatic or mildly symptomatic cases there are, we still can't be sure of this.

Why don't we know the number of cases?  In the US, so far you can't order the PCR (or any other test) without CDC approval.  Approval is contingent upon meeting a high bar, including known exposure.

Thus we are missing lots of cases, who are not being asked to self-quarantine if the cases are mild, and are thus likely to spread disease.

Why aren't we testing broadly to get a sense of actual case numbers?  The best guess is that CDC does not trust its own test, and that by restricting testing to those who are almost certainly positive to start with, they will make fewer diagnostic errors.  

Tests kits were sent to state labs by CDC, then recalled, with the excuse that there was a problem with a "reagent".  A reagent could be any component of the test. CDC has not replaced the reagent or the test kits.  States are begging for them.

Dr. Messonier (head of Vaccines and Respiratory Diseases at CDC) says CDC is keeping up with testing, there is no backlog, they can test 400 samples together, and turnaround is overnight.  That should clue you in that relatively few are being tested.

Some other countries are reporting large numbers of new cases daily.  Do they have better tests?  Has any journalist looked into the relative sensitivity and specificity of tests being used around the world?

PCR is a rapid screening test, which when positive almost always connotes a true positive.  Negatives may actually be positive if the sample does not contain enough virus or is collected or transported incorrectly.

What is also needed are viral culture tests, which could theoretically pick up cases missed by PCR.  Such cultures might also be used to test the effects of drugs on the virus.  What work is being done to develop COVID  viral culture techniques?  Might such tests already exist, since they would probably be very similar to those for SARS and MERS?

Update March 30:  FDA says it is not their fault that tests were not available for novel coronavirus.  Between the lines, I am reading, "It was the CDC, not us, and we accept none of their blame."

Update Feb. 27:  Australia developed viral cultures; so has CDC:

Akst J. Australian Lab Cultures New Coronavirus as Infections Climb. The Scientist.
CDC has grown the COVID-19 virus in cell culture, which is necessary for further studies, including for additional genetic characterization. The cell-grown virus was sent to NIH’s BEI Resources Repository for use by the broad scientific community.
If there is a bat or other animal model for this virus, so much the better for testing drugs that might show efficacy against COVID-19.  What work is being done on developing or using animal models?

I assume one gains immunity after infection with COVID-19, which usually occurs after infections, but not always.  The next test needed is an antibody or T-cell test that will accurately identify immunity to the virus.  People who have recovered should be studied to identify markers of immunity.  Then, we will be able to identify those who can safely care for infected individuals without catching the disease themselves.

Let me reiterate:  with the limited testing now being performed in the US, we are definitely missing many cases, and missing the opportunity to appropriately use quarantines to limit the rapidity of spread.  Slowing spread is critical to producing enough masks, gowns, ventilators, ECMO machines, training hospital staff, building hospitals just for COVID-19 cases, etc.   

We need an accurate test, probably a PCR test, NOW.  What is holding it up?

Update Feb. 27, from WHO:

Ensuring ongoing test availability. WHO has procured a commercial assay (manufactured under ISO:13485) with strong performance data and shipped to over 150 laboratories globally as an interim measure for Member States requesting support. The main goal is to strengthen global diagnostic capacity for detection of the COVID-19 virus. Support is now also provided to ensure the quality of testing through the implementation of an External Quality Assurance mechanism.
Update March 27:  China has a monkey animal model of disease as well as antibody tests
Update:  New CDC Testing Criteria, issued 2/27
Criteria to Guide Evaluation of PUI for COVID-19
Local health departments, in consultation with clinicians, should determine whether a patient is a PUI for COVID-2019. The CDC clinical criteria for COVID-19 PUIs have been developed based on available information about this novel virus, as well as what is known about Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). These criteria are subject to change as additional information becomes available.

Clinical features and epidemiologic risk
Clinical Features&Epidemiologic Risk
Fever1 or signs/symptoms of lower respiratory illness (e.g. cough or shortness of breath)ANDAny person, including health care workers2, who has had close contact3with a laboratory-confirmed4 COVID-19 patient within 14 days of symptom onset
Fever1 and signs/symptoms of a lower respiratory illness (e.g., cough or shortness of breath) requiring hospitalizationANDA history of travel from affected geographic areas5 (see below) within 14 days of symptom onset
Fever1 with severe acute lower respiratory illness (e.g., pneumonia, ARDS) requiring hospitalization4 and without alternative explanatory diagnosis (e.g., influenza)6ANDNo source of exposure has been identified
Update 2/28:  Initial CDC testing info and interpretation protocol:

2019-nCoV rRT-PCR Diagnostic Panel Results Interpretation
2019 nCoV_N12019 nCoV_N22019 nCoV_N3RPResult Interpretationa
+++±2019-nCoV detected
If only one, or two, of three targets is positive±Inconclusive Result
+2019-nCoV not detected
Invalid Result

Assay Limitations

  • Analysts should be trained and familiar with testing procedures and interpretation of results prior to performing the assay.
  • A false negative result may occur if inadequate numbers of organisms are present in the specimen due to improper collection, transport or handling.
  • RNA viruses in particular show substantial genetic variability. Although efforts were made to design rRT-PCR assays to conserved regions of the viral genomes, variability resulting in mis-matches between the primers and probes and the target sequences can result in diminished assay performance and possible false negative results.
Update 2/28:  NPR reports that China and Singapore have an antibody test they are using to detect recovered or asymptomatic cases.  ZeroHedge reports that CDC has only tested a total of 466 people in the US, as of past 2 days, while UK has tested 6,000.  If so, CDC needs to get off its behind and get a reliable test and make it available to all labs in the US with rtPCR capability.  Who knows how much community spread is ongoing when CDC refused to test people unless they had a close association with China and were sick with an illness consistent with COVID.

Is Trump aware that the head of the COVID response at CDC, Lisa Messonier, is the sister of Rod Rosenstein, the Deputy AG who suggested secretly recording Trump?

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