HOW I FOUND MY RHYTHM WHEN THE MUSIC STOPPED

At a time in everyone’s life, we come to find ourselves in a situation where the music stops, and we must go on.  The unfortunate truth about life is that the unexpected will happen. Some of us learn from it, some of us change because of it and some of us find our life’s calling because of it. The latter was the case for me.  After our dad picked us up from middle school, we spent that afternoon like we had every afternoon that month. We went to the oncology unit at the hospital, where my brother was admitted.

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THE MAN IN A BLUE SARONG

I remember him. I remember the man in the dark blue sarong the same way I remember the lines on back of my own hand. He was hunched over next to a column on a dirty platform at a railway station in Calcutta, India in the middle of the harsh summer sun. His hands were withered, his fingers and toes looked like tiny nubs, and he was completely malnourished and alone. He had opaque blue eyes, as if fog had taken place of his irises and pupils.

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PATIENT “OWNERSHIP”

I studied insects in college; my favorite insects were the bees (I found them diligent and so helpful to humankind).  One of my favorite classes was about medical diseases caused by insects. My professors noticed my interest in the medical side of things and connected me with a professor who did clinical research. Our work focused on a clinical trial for children with intractable epilepsy and exposed me early on to patient care and patients.

….FULL ARTICLE

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“positive” on one machine but “negative” on another.   This can be also be due to repeat testing at later days, sampling techniques, delays in transport, or conditions of transport to the testing lab. Additionally, most large labs use more than one brand of PCR test. Testing supplies continue to be seriously limited, and this allows labs to have at least one machine with all the components needed to be up and running. This means even within the same laboratory; discrepant results sometimes occur when virus load is low. The tests do not distinguish infectious virus from “dead” virus or RNA fragments present in later stages of disease. This causes uncertainty as to whether the PCR test can be used to tell if a patient is actively contagious during a patient’s recovery phase.


In order to test large numbers of specimens efficiently, most machines run samples in batches and require 4-6 hours for each batch. One large reference lab tests 200,000 specimens daily. National reference laboratory turn-around times currently range from 2 to 6 days. Longer delays, once common, are now infrequent but do occur. Unfortunately, traditional PCR turnaround times are too long for diagnosis of symptomatic patients in the ER.


Faster methods of PCR are now available; one test within 15 minutes. Many large hospitals (and the White House) have these machines. Unfortunately, clinical sensitivity has been questioned with one study finding up to 30% false negative rates. (3) Other laboratories have seen similar possible false negative rates. Most false negative cases are thought to be due to inadequate sampling, perhaps due to dry nasal passages, excessive mucus or inflammation, timing of the sampling or delays in transport rather than significant analytic failings. Still, there remains an urgent need for rapid testing in ERs and other point-of-care (POC) settings, especially given the shortage of rapid PCR testing capacity and PCR supplies in general. Currently machines, as well as other testing supplies, are distributed under the control of the White House Coronavirus Task Force, through the Health and Human Services Department (HHS).


Rapid tests for SARS CoV2 using viral antigen detection rather than nucleic acid sequences by PCR are now available. It is hoped these may help expand national rapid on-site testing capacity. These antigen tests are inexpensive and can be done in a wide variety of settings with results in 5-15 minutes. Some can be read visually. There are four that have received EUA from the FDA. Sensitivity is not felt to be as high as PCR methods, most reported as 80-90% analytic sensitivity. Most of the antigen tests are not reliably positive after 5-7 days of symptoms, so physicians will often order confirmation of negative tests by PCR as soon as possible. Again, I do not find independent, peer-reviewed clinical evaluation in asymptomatic individuals published. Their utility is predominantly speed in urgent settings without rapid PCR availability and their low cost.


Recently, HHS has contracted for purchase of one rapid antigen test.  The company claims 97.5% positive analytic sensitivity in SARS CoV2 infections. (4) To my knowledge details of those studies have not been published in any medical journal. The contract calls for 150 million tests by the end of December, to be produced at a cost of $5 per test. There appear to be government plans to have these rapid antigen tests available for screening in schools and long term care facilities. Private sector employer on-site use as well as point-of-care clinical use is promoted by the company. The company also markets a phone app which interfaces with the test. They anticipate that eventually some entities will require negative Covid status for entry and the app will serve as documentation.


In summary, SARS CoV2 testing capacity in the US continues to grow rapidly. Current testing is at about 1 million tests per day.  Most epidemiologists estimate at least 2 million tests per day are needed under current infection rates. Expectations are that during the fall and winter the need may reach 7 million per day, partly because of influenza presenting with almost identical clinical features. Testing is also increasing due to lessening of the restrictions on social and business interactions which will result in more new infections, contact tracing is expanding, and elective surgeries resume.  Businesses in general, long term care facility staff, prisons, the military, universities, professional and college sports are now using or investigating frequent testing programs. Testing in K-12 schools presents special problems. Pediatric cases in the US have been kept to a minimum due to spring school closings, so the real epidemiology in those age groups is still unclear. CDC guidelines for in-person school does not include any recommendations for or against testing at the time of research for this article.


References


  1. Titus, K., College of American Pathology Magazine, The Laboratory Tests of Pandemic Summer.  CAP Today, 2020 08:1, College of American Pathology Publishing Co.
  2. Prinzi, Andrea. False Negatives and Reinfections: The Challenges of SARS- CoV-2 RT-PCR Testing.
  3. A. Bassu, et al. Performance of Abbott ID Now Rapid Nucleic Acid Test….,DOI:  10.1128/JCM.01136-20
  4. Abbott Laboratories, press release. Aug 26, 2020.  

The technology and applications for SARS CoV2 testing is changing so rapidly that it is impossible for community physicians and the general public to get a clear picture of testing realities.


There is a morass of media coverage, corporate product promotion and government information that is often contradictory and incomplete. Since there are few independent clinical evaluations of testing products in peer-reviewed journals, it is even difficult for specialists in the field to stay current.  This article is an attempt to present the most current information available as of September 8th. The material is summarized predominantly from a review article in the August issue of the College of American Pathology Today magazine. (1)   I have included additional information gleaned from multiple specialist webinars and test manufacturer technical documents as well. It is important to note that all of the tests were released outside of the usual FDA approval process for diagnostic tests. They were instead released under Emergency Use Authorization (EUA) after March. There was an urgent need for tests to confirm SARS CoV2 infection as U.S. cases overwhelmed the testing capacity of the Center for Disease Control and Prevention (CDC) laboratories.


Polymerase Chain Reaction (PCR) for SARS CoV2 RNA is the most frequent test type used to confirm diagnosis of Covid-19 disease. This is the most sensitive and specific method of testing to date. Several commercial PCR platforms had years ago received formal FDA approval for use in diagnosing many infectious agents.

BY TERRY CLARK, MD, FCAP

With this experience, several established testing companies were able to rapidly adapt their instruments to Covid testing.  Many less experienced companies and research institutions also developed new tests and applied for EUA. The FDA website currently lists 163 laboratory developed PCR tests with EUA approval for diagnostic use. The PCR process generates many copies of the virus nucleic acid code. This enables the method to detect what was originally very low concentrations of virus. Results are qualitative; with a positive, negative or equivocal result.


How good are these PCR tests? In their EUA application most companies document analytic sensitivity at the lowest limit of detection (LOD) of 97% or greater.  However, LODs for different brands of PCR are listed from about 100- 6000 viral genomes/ml of assayed fluid. (2)  Symptomatic patients usually shed virus for about 5-7 days at levels well above these LODs.  However, levels drop markedly after that, although some patients remain positive for weeks. Asymptomatic patients often shed virus at numbers equal to early symptomatic patients, but many show lower levels. Methods target variably 2 to 4 gene sequences that are thought to be rare sites of mutation. Thus, it is not surprising that occasionally specimens with low virus load may result as qualitatively