SARS-CoV-2, a coronavirus that humans have never before encountered, is causing hundreds of thousands of deaths around the globe. The emergence of new infectious agents is tragically part of the cycle of infectious disease. What is not part of that cycle are the many Covid-19-related deaths that occur because of our systemic failure to employ rapid diagnostic tools, something that health systems have long neglected — to our peril.
Many deaths from Covid-19 mirror deaths from sepsis, which are also largely preventable with better diagnostic tools. Sepsis, the immune system’s out-of-control response to infection, often leads to organ failure and death. In the United States alone, sepsis is responsible for more than 250,000 deaths a year and accounts for 1 in 3 hospital-based deaths. Globally, sepsis kills 6 million people a year, and leaves many survivors with lingering physical and mental health issues.
It is also linked to Covid-19. In a retrospective study from China’s Jinyintan Hospital and Wuhan Pulmonary Hospital, among 191 patients with laboratory confirmed Covid-19, sepsis was the second leading cause of death.
The treatment for sepsis goes something like this: When a clinician suspects sepsis based on a patient’s signs and symptoms, he or she orders a blood culture. It takes two to 10 days to culture blood for bacteria, and up to 30 days for fungi. While waiting for the results, the clinician begins empirical treatment based on his or her education, training, and experience. Simply stated, the treatment chosen is the clinician’s best guess and usually involves the administration of broad-spectrum antimicrobials.
This is the antithesis of evidence-based medical practice. It works inefficiently — if it works at all — and threatens more than just the individual patient’s health but also contributes to the development of antimicrobial resistance.
As we confront Covid-19 and the growing list of pathogens resistant to standard antimicrobial therapy, it is time to replace outdated, ineffective, and inefficient therapies with more enlightened, effective, and efficient modalities based on rapid and accurate diagnostic tools.
This call for action is not meant to diminish the importance of developing vaccines against SARS-CoV-2. The number of lives saved by other advances in medicine pale in comparison to the number saved by vaccines. Yet Ebola, H1N1, SARS, MERS, and HIV have taught us we also need effective first-line treatments.
Government leaders, medical researchers, and providers in the United States and around the world are seeking the coordinated development, distribution, and administration of Covid-19-specific diagnostics. This is an important step. Diagnostic tools to quickly and accurately identify sepsis are equally essential. Dr. Julie Geberding, the former director of the Centers for Disease Control and Prevention, has called attention to sepsis as the cause of death among thousands of Covid-19 patients suffering from secondary bacterial pneumonia.
Time is of the essence in diagnosing and treating sepsis, yet we continue to rely on outdated blood culture technology. That’s unacceptable. There are alternatives available as documented in several papers describing advances in diagnosing sepsis.
For more than three years, in an attempt to address this issue, we and other colleagues have submitted articles for peer review to JAMA, Clinical Infectious Diseases, Lancet Infectious Diseases, and many other journals detailing the shortcomings of the current empirical therapeutic treatment system for sepsis and the need for rapid diagnosis of bloodstream infections. All were rejected. Understanding that it is not unusual for manuscripts to be rejected, we assumed reviewers were pressed by competing submissions with equally strong messages.
We quickly changed our minds when an editor parroted the system’s bias: “Unfortunately, although there is always room for improvement, the Editor did not agree with your assertion that the health care system lacks rapid and effective infectious disease diagnostics.”
If that is true, then why is “Treat first, diagnose later” the current protocol for sepsis? Why do we still encourage practitioners to administer best-guess or shotgun therapy in the form of broad-spectrum antimicrobials as the first line of treatment while awaiting culture and sensitivity results? Once results do arrive, practitioners use them to validate, modify, or reject their initial treatment plan.
This approach provides a false sense of security and leads practitioners to overuse low-cost, broad-spectrum antimicrobials for 50% to 70% of septic patients. Unfortunately, when using this method, nearly half of all patients receive inappropriate therapy while awaiting accurate diagnosis. The problem is compounded when a patient recovers after receiving an incorrect empirical treatment because the approach appeared to work, further reinforcing the behavior.
Some currently available rapid diagnostic tools detect the presence of resistance genes. Others involving whole-genome sequencing are not yet rapid enough to affect treatment because they require a pathogen isolated from a blood culture. Still others base their diagnostics on the polymerase chain reaction (PCR) such as Unyvero from Curetis AG and Biofire from bioMérieux. These deliver results in less than six hours using samples taken directly from patients with pulmonary, abdominal, urinary tract, and implant infections. The only FDA cleared system that works directly from blood samples, without upfront culture is the T2Dx from T2 Biosystems, which uses magnetic resonance to deliver results in three to five hours from whole blood samples without isolating the pathogen.
A major concern is the cost of these innovative technologies. Yet how does one measure the cost of something versus the cost of nothing? Because of their portability and rapid results, some of these technologies are ideally suited for use in underserved communities where testing is absent or impractical. The value accrued through lives saved, morbidity reduction, restored productivity, and societal stabilization is incalculable.
In medical centers, savings from the adoption of these technologies are more easily calculated. The average cost of a day in an intensive care unit requiring ventilatory support starts at $10,794 on day one and stabilizes at $3,968 by day three. Rapid, accurate, diagnosis enables targeted treatment to begin two to many days sooner, reducing ICU time. Add to this the reduction in use of inappropriate/ineffective antimicrobials as well as the immeasurable benefit of lower patient morbidity and mortality. The savings would be expected to far outweigh initial costs.
A big barrier for the introduction of new diagnostics is that clinical trials for their approval do not compare their projected cost and cost saving to the cost expenditures incurred with current technologies. Such studies must be carefully designed, will take a long time, and are expensive, but they are worth doing and must be done if we have any expectation that our treatments will evolve along with — or ahead of — pathogens.
Practitioners, hospitals, and payers look for outcome data that justify the adoption of new diagnostic systems. The Biodefense Advanced Research and Development Authority (BARDA) supported the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms Act (DISARM ACT) as part of its mission to prepare for a pandemic. It could not have known it would be needed so soon.
BARDA is a dominant medical research and development governmental entity in the U.S. and abroad. It has also supported the Centers for Medicare and Medicaid Services approval of payments based on value, having realized the high, hidden costs of older diagnostic tests when compared to the cost/benefit savings that accrue from using rapid diagnostics. BARDA was, and continues to be, a leading advocate for the adoption of rapid diagnostics.
Those who must decide whether or not to adopt new diagnostic tools traditionally strive to maximize local cost benefit in individual hospitals based solely on local analyses. This myopic approach fails to consider the effects of such actions on optimal patient outcomes. With the advent of Covid-19, sepsis can no longer be disguised as a local problem. It is part of a global pandemic that requires a global response. There needs to be a broader analysis of total cost, both financial and social, to determine a global cost-benefit assessment.
Diagnostic tests aim to increase certainty by producing accurate and useful information. Pathogens evolve, increasing uncertainty. Diagnostics must evolve to keep pace. Up to date rapid diagnostic tools provide ways to reduce this uncertainty and help ensure that patients receive the right treatment as quickly and efficiently as possible.
Prabhavathi Fernandes chairs the scientific advisory board of the Global Antibiotic Research and Development Partnership in Geneva, Switzerland, and chairs the National Biodefense Science Board in Chapel Hill, North Carolina. Steve Brozak is president and managing director of WBB Securities in Cranford, New Jersey.