In the absence of a “gold standard,” researchers are finding a high frequency of false negatives among SARS-CoV-2 RT-PCR tests
Serology tests designed to detect antibodies to the SARS-CoV-2 coronavirus that causes the COVID-19 illness have been dogged by well-publicized questions about accuracy. However, researchers also are raising concerns about the accuracy of molecular diagnostics which claim to detect the actual presence of the coronavirus itself.
“Diagnostic tests, typically involving a nasopharyngeal swab, can be inaccurate in two ways,” said Steven Woloshin, MD, MS, in a news release announcing a new report that “examines challenges and implications of false-negative COVID-19 tests.” Woloshin is an internist, a professor at Dartmouth Institute, and co-director of the Geisel School of Medicine at Dartmouth.
“A false-positive result mistakenly labels a person infected, with consequences including unnecessary quarantine and contact tracing,” he stated in the news release. “False-negative results are far more consequential, because infected persons who might be asymptomatic may not be isolated and can infect others.”
Woloshin led a team of Dartmouth researchers who analyzed two studies from Wuhan, China, and a literature review by researchers in Europe and South America that indicated diagnostic tests for COVID-19 are frequently generating false negatives. The team published their results in the June 5 New England Journal of Medicine (NEJM).
For example, one research team in Wuhan collected samples from 213 hospitalized COVID-19 patients and found that an approved RT-PCR test produced false negatives in 11% of sputum samples, 27% of nasal samples, and 40% of throat samples. Their research was published on the medRxiv preprint server and has not been peer-reviewed.
The literature review Woloshin’s team studied was also published on medRxiv, titled, “False-Negative Results of Initial Rt-PCR Assays for COVID-19: A Systematic Review.” It indicated that the rate of false negatives could be as high as 29%. The authors of the review looked at five studies that had enrolled a total of 957 patients. “The collected evidence has several limitations, including risk of bias issues, high heterogeneity, and concerns about its applicability,” they wrote. “Nonetheless, our findings reinforce the need for repeated testing in patients with suspicion of SARS-Cov-2 infection.”
Another literature review, published in the Annals of Internal Medicine, titled, “Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure,” estimated the probability of false negatives in RT-PCR tests at varying intervals from the time of exposure and symptom onset. For example, the authors found that the median false-negative rate was 38% if a test was performed on the day of symptom onset, versus 20% three days after onset. Their analysis was based on seven studies, five of which were peer-reviewed, with a total of 1330 test samples.
Doctors also are seeing anecdotal evidence of false negatives. For example, clinicians at UC San Diego Health medical center treated a patient with obvious symptoms of COVID-19, but two tests performed on throat samples were negative. However, a third test, using a sample from a bronchial wash, identified the virus, reported Medscape.
Sensitivity and Specificity of COVID-19 Clinical Laboratory Tests
The key measures of test accuracy are sensitivity, which refers to the ability to detect the presence of the virus, and specificity, the ability to determine that the targeted pathogen is not present. “So, a sensitive test is less likely to provide a false-negative result and a specific test is less likely to provide a false-positive result,” wrote Kirsten Meek, PhD, medical writer and editor, in an article for ARUP Laboratories.
“Analytic” sensitivity and specificity “represent the accuracy of a test under ideal conditions in which specimens have been collected from patients with either high viral loads or a complete absence of exposure,” she wrote. However, “sensitivity and specificity under real-world conditions, in which patients are more variable and specimen collection may not be ideal, can often be lower than reported numbers.”
In a statement defending its ID Now molecular point-of-care test, which came under scrutiny during a study of COVID-19 molecular tests by NYU Langone Health, Northwell Health, and Cleveland Clinic, according to MedTech Dive, Abbott Laboratories blamed improper sample collection and handling for highly-publicized false negatives produced by its rapid test. An FDA issued alert about the test on May 14 noted that Abbott had agreed to conduct post-market studies to identify the cause of the false negatives and suggest remedial actions.
Issues with Emergency Use Authorizations
In their NEJM analysis, Woloshin et al point to issues with the FDA’s process for issuing Emergency Use Authorizations (EUAs). For example, they noted variations in how manufacturers are conducting clinical evaluations to determine test performance. “The FDA prefers the use of ‘natural clinical specimens’ but has permitted the use of ‘contrived specimens’ produced by adding viral RNA or inactivated virus to leftover clinical material,” they wrote.
When evaluating clinical performance, manufacturers ordinarily conduct an index test of patients and compare the results with reference-standard test, according to the Dartmouth researchers. For people showing symptoms, the reference standard should be a clinical diagnosis performed by an independent adjudication panel. However, they wrote, “it is unclear whether the sensitivity of any FDA-authorized commercial test has been assessed in this way.” Additionally, a reference standard for determining sensitivity in asymptomatic people “is an unsolved problem that needs urgent attention to increase confidence in test results for contact-tracing or screening purposes.”
“To truly determine false negatives, you need a gold standard test, which is essentially as close to perfect as we can get,” Stephen Rawlings, MD, PhD, (above), a resident physician of internal medicine and infectious diseases fellow at UC San Diego’s Center for AIDS Research (CFAR), who has been working on SARS-CoV-2 test validation since March. “But there just isn’t one yet for coronavirus,” he told Medscape. (Photo copyright: University of California, San Diego.)
Continued adherence to current measures, such as physical distancing and surface disinfection.
Development of highly sensitive and specific tests or combinations of tests to minimize the risk of false-negative results and ongoing transmission based on a false sense of security.
Improved RT-PCR tests and serological assays.
Development and communication of clear risk-stratified protocols for management of negative COVID-19 test results.
“These protocols must evolve as diagnostic test, transmission, and outcome statistics become more available,” they wrote.
Meanwhile, clinical laboratories remain somewhat on their own at selecting which COVID-19 molecular and serology tests they want to purchase and run in their labs. Complicating such decisions is the fact that many of the nation’s most reputable in vitro diagnostics manufacturers cannot produce enough of their COVID-19 tests to meet demand.
Consequently, when looking to purchase tests for SARS-CoV-2, smaller medical laboratory organizations find themselves evaluating COVID-19 kits developed by little-known or even brand-new companies.
‘Aerosol and Surface Stability’ study shows that the virus can remain infectious in aerosol form for hours and on surfaces for days
By now, clinical laboratory workers, microbiologists, and phlebotomists should be fully aware of the potential for transmission on surfaces of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes Coronavirus disease 2019 (COVID-19). The CDC’s latest Morbidity and Mortality Weekly Report revealed that the coronavirus “was identified on a variety of surfaces in cabins of both symptomatic and asymptomatic infected passengers up to 17 days after cabins were vacated on the Diamond Princess, but before disinfection procedures had been conducted,” the New York Post reported. That means the virus can survive on surfaces significantly longer than CDC previously believed.
But did you know a recent study published in the New England Journal of Medicine (NEJM) found that SARS-CoV-2 can also survive in the air for many hours, potentially allowing aerosolized transmission of the virus as well?
The NEJM study also showed that the stability of SARS-CoV-2 to survive on surfaces and in aerosolized form mirrors the stability of the SARS coronavirus (SARS-CoV) that caused the severe acute respiratory syndrome (SARS) outbreak of 2003.
This is critically important information for clinical laboratory professionals in open-space laboratories, phlebotomists collecting medical laboratory specimens, and frontline healthcare workers who come in direct contact with potentially infected patients. They should be aware of every potential COVID-19 transmission pathway.
Hospital infection control teams will be particularly
interested in the possibility of airborne transmission, as they often visit
infected patients and are tasked with tracking both the source of the infection
as well as individuals who may be exposed to sick patients.
The NEJM study, titled “Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1” was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), an agency of the US Department of Health and Human Services (HHS), the Centers for Disease Control and Prevention (CDC), Princeton University, and University of California, Los Angeles. The researchers concluded that SARS-CoV-2 remains in the air “up to three hours post aerosolization.”
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They also found the virus was detectable for up to four
hours on copper and up to 24 hours on cardboard. The scientists concluded SARS-CoV-2
can remain on plastic and stainless-steel surfaces for two to three days,
though the amount of the virus on surfaces decreases over time.
“Our results indicate that aerosol and fomite transmission of SARS-CoV-2 is plausible, since the virus can remain viable and infectious in aerosols for hours and on surfaces up to days,” the study states. “These findings echo those with SARS-CoV-1, in which these forms of transmission were associated with nosocomial spread and super-spreading events, and they provide information for pandemic mitigation efforts.”
But Can COVID-19 Be Caught Through Air?
However, as noted in Wired, the researchers did not clearly state that infected persons can spread COVID-19 to others in the same airspace. Some experts have pointed out that there is a difference between a virus that can exist as an aerosol—defined as a liquid or solid suspended in gas under only limited conditions—and the measles virus, for example, which the CDC estimates “can live for up two hours in an airspace where the infected person has coughed or sneezed.”
“While the researchers tested how long the virus can survive
in aerosols suspended in the air, they didn’t actually sample the air around
infected people,” Wired noted. “Instead, they put the virus into a
nebulizer and puffed it into a rotating drum to keep it airborne. Then, they
tested how long the virus could survive in the air inside the drum.”
Neeltje van Doremalen, PhD, a research fellow at National Institutes of Health (NIH) and researcher at the NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, who coauthored the NEJM study, cautioned against an overreaction to this latest research. On Twitter she wrote, “Important: we experimentally generated [COVID-19] aerosols and kept them afloat in a drum. This is not evidence of aerosol transmission.”
Nonetheless, the World House Organization (WHO) took note of the study’s findings and on March 16, 2020, announced it was considering “airborne precautions” for healthcare workers, CNBC reported in its coverage of a virtual press conference on March 16, 2020, led by Maria Van Kerkhove, MS, PhD, Technical Lead for WHO’s Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Task Force.
Van Kerkhove emphasized that health officials were
monitoring results from other studies investigating how environmental
conditions such as humidity, temperature, and ultraviolet light affect
the disease and its ability to live on different surfaces.
“When you do an aerosol-generating procedure like in a medical care facility, you have the possibility to what we call aerosolize these particles, which means they can stay in the air a little bit longer,” said Maria Van Kerkhove, MS, PhD (above), Technical Lead for WHO’s Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Task Force during a virtual press conference, CNBC reported. “It’s very important that healthcare workers take additional precautions when they’re working on patients and doing these procedures,” she added. [Photo copyright: World Health Organization/YouTube.)
To Be or Not to Be an Airborne Pathogen
Stanley Perlman, MD, PhD, Professor of Microbiology and Immunology at the University of Iowa, believes aerosol transmission ultimately will be found not to play a large role in COVID-19 transmission.
“I think the answer will be, aerosolization occurs rarely, but not never,” Perlman told STAT. “You have to distinguish between what’s possible and what’s actually happening.”
In an NEJM editorial, Perlman expanded on those thoughts. “Although specific anti-coronaviral therapies are still in development, we now know much more about how to control such infections in the community and hospitals, which should alleviate some of this fear,” he wrote. “Transmission of [SARS-CoV-2] probably occurs by means of large droplets and contact and less so by means of aerosols and fomites, on the basis of our experience with SARS-CoV and MERS-CoV. Public health measures, including quarantining in the community as well as timely diagnosis and strict adherence to universal precautions in healthcare settings, were critical in controlling SARS and MERS. Institution of similar measures will be important and, it is hoped, successful in reducing the transmission of [SARS-CoV-2].”
An NIH news release announcing the SARS-CoV-2 stability study highlighted two additional observations:
“If the viability of the two coronaviruses is
similar, why is SARS-CoV-2 resulting in more cases? Emerging evidence suggest
that people infected with SARS-CoV-2 might be spreading virus without
recognizing, or prior to recognizing, symptoms. That would make disease control
measures that were effective against SARS-CoV-1 less effective against its
successor.
In contrast to SARS-CoV-1, most secondary cases
of virus transmission of SARS-CoV-2 appear to be occurring in community
settings rather than healthcare settings. However, healthcare settings are also
vulnerable to the introduction and spread of SARS-CoV-2, and the stability of
SARS-CoV-2 in aerosols and on surfaces likely contributes to transmission of
the virus in healthcare settings.”
Clearly, the scientific community has not agreed on
aerosolization as a definite source of infection. Nevertheless, clinical
laboratory workers in settings where potential exposure to SARS-CoV-2 exists
should take precautions against airborne transmission until scientists can
definitively determine whether this latest coronavirus can be acquired through
the airborne transmission.
Clinical laboratory test claims make up a substantial proportion of all claims filed each year. Thus, any effort to streamline or reform claims adjudication and administration in the US will alter how labs and pathologists conduct business
Clinical laboratory managers and anatomic pathologists know how costly and complex the US healthcare system can be. However, expenses associated with care and treatment are only part of the total picture. Resources devoted to paperwork and administrative costs apparently increase overall expenditures associated with healthcare to a much higher degree than is generally known.
That’s according to several studies The New York Times reported on in July.
US Administrative Costs Higher than All Other Nations
One study conducted by The New England Journal of Medicine (NEJM) in 2003 estimated administrative costs account for approximately 30% of all healthcare expenditures in the US. The researchers examined data from 1999 to reach those conclusions. In today’s economy, those numbers are higher. On average, $5,700 of every $19,000 that US workers and their employers pay for family coverage each year goes towards administrative costs.
A 2014 study published by Health Affairs compared administrative costs for US hospital expenditures to those of seven other countries: Canada, England, France, Germany, the Netherlands, Scotland, and Wales. This study evaluated data from 2010/2011 and found that hospital administrative costs in the US far exceed rates in other nations. According to the study, administrative costs accounted for:
25.3% of total hospital expenditures in the US;
19.8% in the Netherlands;
15.5% in England; and,
12% in Canada and Scotland.
According to the Health Affairs study, more than $150 billion could have been saved in 2011 by reducing per capita spending for administrative costs to the levels observed in Canada and Scotland.
“The extraordinary costs we see are not because of administrative slack or because healthcare leaders don’t try to economize,” Kevin Schulman, MD, Professor, Department of Medicine, Duke University, and co-author of the Health Affairs study told The New York Times. “The high administrative costs are functions of the system’s complexity.” (Photo copyright: Duke University.)
Complexity of Payer System Partly to Blame
One reason for the costliness in the US healthcare system is the myriad of payers that healthcare organizations have to grapple with to receive payment. Private health insurers and public health programs like Medicare and Medicaid, each have their own procedures, regulations, and forms that need to be submitted to receive payments. This translates to more employee time devoted to billing.
Another factor driving costs is the staff time devoted to the collection of debts. A 2017 Health Affairs study examined medical claims data from 88,000 healthcare providers contracted with Athenahealth to determine the percentage of bills paid within one year from the initial service.
The study found that 93.8% of patient bills under $35 were paid within a year. However, that percentage decreased as the patient obligation increased:
90.5% of patients paid bills between $35 and $75 within one year;
83.7% paid bills between $75 and $200 in the same time period; however,
When bills increase to $200 or more, just 66.7% were paid within a year’s time.
Providers wrote off approximately 16% as abandoned or bad debts, with an additional 17% going to collection agencies.
Another study, published in Health Affairs in 2009, surveyed 895 physicians about the time they spent dealing with administrative tasks. On average, physicians reported spending 43 minutes per workday interacting with health plans. This number is the equivalent of three hours/week and almost three weeks/year. Those numbers have reportedly increased since then.
EHRs Do Not Reduce Administrative Costs, Contrary to Belief
Efforts have been made to reduce administrative costs in the US healthcare industry. One such measure involved increased use of certified electronic health record (EHR) systems, which the federal government spent billions of dollars promoting and incentivizing providers to adopt on the claim that EHRs would reduce healthcare costs, in part by removing most of the paperwork.
However, a 2018 study published in the Journal of the American Medical Association (JAMA) reported the adoption of EHRs did not reduce administration costs. Researchers at Duke University and Harvard Business School utilized a cutting-edge accounting method to determine the administrative costs within a large academic healthcare system that was using a certified EHR.
Their study determined the administrative costs for processing a single medical bill ranged from $20 for a doctor visit to $215 for an inpatient surgical procedure. These costs accounted for 3%-25% of total professional revenue for the provided services.
“We need to understand better how complexity is driving these enormous costs within the system, costs that do not add value to patients, employers, or providers,” noted Barak Richman, JD, PhD, Duke University School of Law and Margolis Center for Health Policy, one of the study’s authors.
Clinical Lab Test Claims a Major Portion of Administrative Costs
Nevertheless, administrative costs are a necessary part of doing business and not always as negative as perceived. An article published by Health Affairs in 1992 divided administrative costs in the healthcare industry into four categories:
Transaction-related: claims processing, billing, admissions, and tracking employee hiring/terminations;
Benefits Management: quality assurance, plan design, statistical and internal analyses, and management information systems;
Selling and Marketing: strategic planning, underwriting, and advertising; and,
Regulatory and Compliance: waste management, licensing requirements, and discharge planning.
“We hope that this work is the first step toward informing policy solutions that could reduce these non-value-added costs largely hidden within the healthcare system,” Schulman stated in a Duke University news release.
The issue of costly paperwork and administrative expenditures is significant for the clinical laboratory profession as lab test claims make up a substantial portion of all medical claims filed annually. Efforts to streamline or reform claims adjudication and administration will have an impact on the way clinical labs and anatomic pathology groups conduct business in the future.
Similar study of exome sequencing at UCLA produces findings that mirror the diagnostic outcomes produced by researchers at the three Houston organizations
In this expanded study, published in the November 12, 2014, issue of the Journal of the American Medical Association (JAMA), 504 patients (25.2%) received a molecular diagnosis and 92 patients (4.6%) benefitted from medical intervention to ameliorate or eliminate negative symptoms. (more…)
Some physicians fear disclosure of payments by drug and medical device companies could damage patient confidence and physician-patient relationships
Over the course of 2014, pathologists and medical laboratory managers will experience a different relationship with in vitro diagnostic (IVD) manufacturers and other lab industry vendors. That’s because a new federal law requires vendors to publicly disclose financial and other arrangements they have with providers.
That law is the Physician Payment Sunshine Act, and it became effective on August 21, 2013. The intent of this new law is to shed light on financial aspects of relationships between physicians and healthcare vendors.
Vendors Must Disclose All ‘Transfers of Value’ They Made to Providers
Vendors are now required to publicly disclose all payments—or “transfers of value”—to providers where the value is more than $10 or an aggregate amount of $100 annually. Manufacturers and providers, therefore, must report payments for speaking engagements, consulting fees, research grants, travel reimbursements, stock, and even small trinkets and meals during routine sales visits.
This includes medical device and medical equipment manufacturers, group purchasing organizations, pharmaceutical firms, software companies, physicians, and teaching hospitals, noted an article published in the New England Journal of Medicine (NEJM). The Sunshine Act also requires manufacturers and group purchasing organizations to report certain information regarding ownership or investment interests of physicians in their companies.
Data collected must be reported to the Centers for Medicare & Medicaid Services (CMS) and will be compiled into a database. The U.S. Department of Health and Human Services (HHS) is expected to publish the information on a public website for the first time in September 2014. HHS also will include this information in an annual report to Congress.
Study Revealed Extent of Physician-Vendor Financial Relationships
The NEJM article noted the extent of vendor-physician financial relationships by citing a 2007 study. This study revealed that 94% of U.S. physicians had an industry financial relationship. The study found that 83% of physicians received gifts and 28% received payments for professional services, such as consulting or research participation. Of physicians reporting industry relationships, 60% were involved in medical education and 40% in creating clinical practice guidelines.
By 2001, commercial vendors had also become the major source of research and development funding, accounting for 55% to 60% of the $100 billion annually spent on these activities. Additionally, commercial funding for continuing medical education (CME) has also increased, with the industry now paying for more than a third of all CME offerings.
Requirements of the Sunshine Act are particularly familiar to companies that have been sued by the federal government for allegedly making payments to physicians to encourage them to improperly market drugs for off-label uses or as kickbacks to get them to use specific devices. In settlements with the government to resolve the charges, these companies have signed corporate integrity agreements, noted a report in Modern Healthcare. Under these settlements, dozens of companies, including Eli Lilly and Co., Novartis, and Pfizer, disclosed their financial arrangements with physicians.
Will Disclosure of Payments Hurt Physician-Patient Relationships?
Congress passed this law in 2010 as part of the Affordable Care Act (ACA) to thwart the influence of financial perks on physician choice of vendor products and healthcare costs. Research has indicated that disclosure of physician-vendor financial relationships may bring down healthcare costs.
Patients “might be less inclined to accept treatment recommendations from these physicians or even to receive care from them,” noted authors of the NEJM article. “Given the evidence that greater physician financial involvement with manufacturers is associated with higher utilization of expensive, brand-name products, such dynamics could reduce costs.”
Attorney David Hoffmeister is a partner in the law firm of Wilson Sonsi Goodrich & Rosati. When it comes to public reporting about vendor payments to physicians, he believes a significant number of computer-savvy patients will look for such information about their physicians’ financial relationships with commercial vendors and judge them accordingly. (Photo copyright Wilson Sonsi Goodrich & Rosati)
In light of the number of people seeking healthcare information on websites, such as WebMD, it is apparent “there are some folks who are going to be very interested in what type of remuneration their physicians receive from medical device companies,” said Hoffmeister. He noted that, if undergoing a hip replacement or knee replacement, for example, smart patients might look at the HHS website to determine whether or not their physicians have received significant remuneration from the manufacturers of those devices.
Will Transparency End Cozy Physician-Vendor Relationships?
Although HHS intends the website to inform the general public, Hoffmeister noted that the information may not be useful to anyone other than prosecutors or investigators. The concern of physicians about disclosure was voiced at the American Medical Association’s (AMA) annual meeting in June. The greatest fear about the new law expressed by physicians was that it would cause patients to question their reasons for prescribing a certain drug if the HHS data links them to a drug company. In turn, that may ultimately affect the patient-physician relationship.
“Whether transparency will lead to fewer relationships is really the million-dollar question,” said Daniel Carla, M.D., Director of the Pew Charitable Trusts Prescription Project. “The kinds of relationships that may drop off may well be the most inappropriate relationships.” He suggested, however, that drug and device companies are expected to seek new ways to keep frustrated doctors from walking away from valued consulting and research relationships.
Daniel Carla, M.D., (pictured here) is Director of the Pew Charitable Trusts Prescription Project. He is unsure if disclosure will actually end or limit physician financial relationships with commercial vendors. He suggested that drug and device companies will find loop holes in the new law to retain valued research and consulting relationships. (Photo copyright of National Physicians Alliance.)
AMA Encourages Doctors to Take Advantage of Disclosure Review Period
Though the burden for collecting and reporting data falls on industry vendors, the AMA is encouraging doctors to review vendor disclosures and demand correction of inaccuracies. The law provides 45 days for physicians to review industry disclosures before submission to the CMS. The CMS will indicate the data is in dispute, but it’s up to vendors to make corrections, noted the Modern Healthcare report.
Some hospitals are educating their physicians about the potential impact of the Sunshine Act. The University of Arkansas for Medical Sciences in Little Rock, for instance, began strengthening its conflict-of-interest policy more than two years ago to address relationships between physicians and commercial interests.
Medical Laboratory Professionals Affected by ‘Sunshine Act’ Too
The law has already changed policies and practices of in vitro diagnostics (IVD) companies and other lab industry vendors. Because this law calls for tracking and public reporting of the various types of incentives and remuneration provided by IVD manufacturing and supply firms, every pathologist and medical laboratory professional should be aware of this law’s requirements. They will also want to follow guidelines established by their parent organizations or hospital institutions regarding vendor remuneration.
It is also important to know that the Advanced Medical Technology Association (AdvaMed) introduced stricter new ethics guidelines for its members in recent years. This combination of industry guidelines and federal legislation is why many IVD manufacturers, healthcare informatics companies, and other lab industry vendors have revised their policies for remunerating pathologists and clinical laboratory professionals for various technology development and evaluation services. It is also why lab industry vendors have changed the policies that govern how they provide sponsorships and grants in support of medical lab industry meetings and conferences.