COVID-19: The Problem of a high False Negative test rate and single testing

I received notes taken from a ZOOM session with Dr. Wen Hong Zang, chair of the Society of Infectious Diseases, China Medical Association. About 7000 attendees, mostly US listeners, including Stanford Health Care, Santa Clara County hospitals, and NYC hospitals.

First the most salient points, then comparison to US approach, then the full notes from the COVID CRITICAL CARE GROUP.

  • Key to mitigating spread in Shanghai was doing diagnostic COVID test on every suspected case. (anyone with symptoms)
  • Tests are done within 4 hours in China, or frozen at -20C, otherwise there is increased false negative.
  • False negative rate of COVID PCR even with two serial swabs was 10-30%!  Next Generation Sequencing for COVID was used as the gold standard.
  • Molecular diagnostics was needed, and even two negative PCRs, for suspected cases on CT – they sent Next Gen Sequencing, a PCR to National Lab, a 3rd local PCR, and local PCR in another swab location (e.g. anal) (e.g. sent all 4) before they would rule out COVID. Thus SIX TESTS: SAMPLING DIFFERENT LOCATIONS, using DIFFERENT LABS, multiple METHODS and multiple SITES WERE REQUIRED to absolutely identify all positives.
  • All patients with positive COVID PCR were admitted to a designated COVID hospital regardless of their level of illness. (ACHIEVING GUARANTEED ISOLATION FROM FAMILY/COMMUNITY) 
  • Cases went down to zero or near zero by late-Feb, and there is now a small second wave from imported cases.

Compare this with the US situation.

  • Testing is usually done once (Missing many positives because of high FN rate)
  • Testing is NOT done on all symptomatic people, in most areas criteria for testing include symptoms AND exposure to a known case (BUT WITH LOW TESTING RATES THE SECOND CRITERIA WILL NOT BE MET FOR MANY who have actually been EXPOSURED)
  •  Only very sick patients are hospitalized, so mildly symptomatic are sent home where their families/communites will be exposed, enhancing spread of the virus, hampering containment.
  •  Our guidelines are to stay home for mild symptoms so we are testing even fewer patients and exposing more households to symptomatic patients.
  • Test turnaround at Quest and Labcorp is as high as 10 days in some areas.
  •  LabCorp and Quest are not accepting specimens in some locations because of the tremendous backlog. (therefore turn around time > 10 days (indefinite) when a sample is refused)
  • With delays in testing, and long turn around times, the false negative rate increases (viral decay in sample over time) thereby sending more positive cases back to family/community and under-reporting positives.
  •  US is not routinely employing CT scan, which can be positive in the face of a negative PCR.

With very stringent widespread multiple testing for everyone with symptoms, utilization of chest CT scan, and hospitalization of all positives, China achieved near zero growth within 2 months with subsequent small second wave from imported cases.

The US approach thus far has clearly been TOO LITTLE, TOO LATE, and appears destined to fail unless significant changes are immediately instituted.

Based on the experience in China, in order to achieve adequate control, we need:

  1. Intensive widespread testing (multiple tests for every symptomatic person)
  2. If CT scan is positive, even if two PCRs are negative, further repeat testing is required to discover all positives.
  3. rapid turn-around and frozen samples for remote testing
  4. complete isolation of all positives, away from family/community.
  5.  we cannot send symptomatic patients home or let them remain in the community unless they repeatedly test negative.
  6. Aggressive use of CT scan for evaluation.

Here is the full set of notes I received.

From Physician anesthesia group on FB…

Posted in Covid Critical Care Group & to be shared : 

Predicted number of cases in Shanghai with exponential growth was calculated to be nearly one million by March 1, but social distancing avoided this. (editorial Bob Hansen MD: Along with stringent testing of all symptomatic individuals, multiple testing, CT scan part of workup, isolation of all positives in hospital)

Cases went down to zero or near zero by late-Feb, and there is now a small second wave from imported cases.

Key to mitigating spread in Shanghai was doing *diagnostic COVID test on every suspected case* .

All patients with positve COVID PCR were *admitted to a designated* *COVID* *hospital* *regardless* *of their level of illness.* 

Coinfection was very common with other respiratory bacteria and common cold viruses, and >50% patients were positive for a co-infection with a respiratory organism.

False negative rate of COVID PCR even with two serial swabs was 10-30%!  Next Generation Sequencing for COVID was used as the gold standard.

RSV, Mycoplasma and Parainfluenza virus also caused similar bilateral CT findings to COVID.  Molecular diagnostics was needed, and even two negative PCRs, for suspected cases on CT – they sent Next Gen Sequencing, a PCR to National Lab, a 3rd local PCR, and local PCR in another swab location (e.g. anal) (e.g. sent all 4) before they would r/o COVID.

Mean incubation was 6.4 days, and patients were quarantined mean 5.5 days from symptom onset, with this approach the “curve” was 1 month in duration.

Hydroxychloroquine is in a multicentre RCT in China and will be published “very soon”.

LDH and D-Dimer was associated with development of ARDS.

He felt there is a narrow window between positive CT findings and deterioration to ARDS, where corticosteroids have been helpful and further studies are required to investigate this.

Approxiatemately 5% of patients will need ICU level care, and mortality depends on availability of ICU.

How to protect medical personnel* – China protocol:

1) Standardized process in terms of patient care areas and flow.

2) PPE – double-layer gloves, double-layer shoe covers, isolation gown, masks, googles, etc.  “The most important is to cover the head”

3) Positive pressure masks – for aerosol generating procedures.

Q&A:

Time window until infection and test positive? 3d by PCR, and 7d by Serological.

Who did you test?  They abandoned risk factor criteria quickly and just tested anyone with symptoms.

What is the best test?  PCR is better than Antibody test for sensitivity.  But the Antibody test is helpful, as PCR can have false negative by week 3.  Antibody test is helpful to see the overall population prevalence in terms of patients with mild or no symptoms.

Does viral RNA degradation of samples happen?  Tests are done within 4 hours in China, or frozen at -20C otherwise there is increased false negative.

What is risk for pregnant women?  These cases were mild, and no severe/intubated cases were seen so far in Shanghai (no Wuhan data presented).

What is the underlying medical conditions that are high risk?  Heart disease do the worst – the virus causes myocarditis as well.

 What percentage of patients have antibodies?  Every recovered patient tested have found to have antibodies on testing but it is unclear if these are actually protective.

What is the dosage for hydroxychloroquine? 400mg bid x1d, 400mg po qd.  They did not treat with azithromycin due to hepatotoxicity observed.

 What is the risk to health care workers? There were none of his colleagues who went to Wuhan to help that became infected with COVID, and this is attributed to PPE.

What is the outcome of COVID survivors?  Lung fibrosis is definitely less than SARS and most patients had a good long-term outcome.

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

 

 

 

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