The COVID-19 pandemic has forced medical science to revisit the question of co-infection in connection with respiratory viruses, which is responsible for a conspicuous share of fatalities in this pandemic. However, next-generation sequencing may help provide clinicians with a speedier answer as to the identity of the second pathogen, a service that may prove critical to suppressing the fatality rate in this and in future pandemics, according to Robert Schlaberg, chief medical officer of IDbyDNA Inc., of Salt Lake City.

The U.S. CDC has recently updated its tip sheet for health care providers, which states that patients with COVID-19 may suffer from co-infection with bacterial, fungal or other viral pathogens. CDC said clinicians should consider treating patients for both COVID-19 and the flu if symptoms are compatible with both diagnoses, adding that a number of patients have presented with concurrent community-acquired bacterial pneumonia. However, the agency offers little insight as to how to efficiently diagnose these co-infections.

Schlaberg said there are few publicly available data points to render a clear picture for the nationwide rate of co-infections in hospitals. There are multiplex assays for use in polymerase chain reaction (PCR) testing, but the current state of testing for co-infections by bacteria and fungi is limited.

Mutations rarely affect diagnostics

Another potentially complicating factor is that this version of the coronavirus is mutating, although Schlaberg said it does not appear to do so in a manner that is conspicuous relative to other versions of the virus. “There are at least five [strains], by some counts more, circulating globally,” he said, adding that as is often the case, this virus’s evolution is somewhat specific to a given region. Any mutation might represent nothing more than a minor tweaking of a nucleotide, and thus the impact on testing is likely to be modest at worst.

The indication for testing of a given patient will determine whether testing for co-infection is undertaken serially vs. simultaneously, and the factors start with whether the patient exhibits symptoms that are strongly suggestive of multiple infections. Whether the patient poses a significant risk to others is another element the clinician will consider, but Schlaberg said a patient who is symptomatic for co-infection might be evaluated by a culture for the co-infecting pathogen. However, some of these approaches also suffer from a significant rate of false negatives, leaving clinicians with a difficult dilemma to address.

Schlaberg said next-generation sequencing (NGS) might be the best solution for these co-infection scenarios since the technology is agnostic for pathogens. NGS can be used on multiple sample types, and the results can be digitized and then analyzed digitally, which allows the lab technician to detect virtually any type of pathogen. “You don’t have to know what you’re looking for” to find a specific infection, he said.

PCR has evolved in the past decade or so such that a series of reactions can be run in parallel, providing a large volume of throughput compared to the first generation of PCR systems. PCR systems can be scaled up to handle as many as thousands of samples per day, but pushing such systems much beyond that figure is difficult, thus inviting the prospect that a lab would have to purchase multiple systems to acquire the volume needed to keep up with a fast-moving pathogen like the SARS-CoV-2.

Schlaberg said NGS system operating costs have fallen significantly in recent years, although this has been largely accomplished by boosting system throughput. Still, lab operators must prepare each of the samples, although this step can be at least somewhat automated.

Schlaberg pointed out that co-infection is often due to an interaction between a novel pathogen and a virus or bacteria that is routinely present in the human body, but which reacts to the strain on the immune system. Medical science’s ability to predict these kinds of interactions is to some extent limited by the technology that would allow a lab to more clearly map out the proliferation of the native pathogen. He said the ability to generate a comprehensive result “is really what’s going to drive a paradigm shift, and our ability to understand the importance of co-infection.”

Avian flu a looming possibility

The FDA has granted emergency use authorizations for multiplex assays that cover the SARS-CoV-2 virus along with influenza types A and B, but Schlaberg noted that a resurgence of avian flu could further impede efforts to corral the pandemic. This, too, is a scenario that might lend itself to NGS analysis, given its ability to indiscriminately detect any microbial life forms in a sample.

Schlaberg said the company’s Explify platform is an example of how NGS systems can help health care professionals overcome the issues they’re seeing in the clinic. The Explify can identify more than 50,000 microorganisms and more than 6,000 known pathogens, some rare and some more commonplace. The list includes more than 35,000 viruses, 13,000 bacteria and 4,000 species of fungi. The Explify also picks up more than 150 types of parasites, and features a workflow manager to ensure that lab personnel have to perform a step once and only once, thus simplifying clinical workflow, a particularly important consideration in labs that are working under a severe strain.

Schlaberg said the Explify system processes samples based on a standard extraction process, but can also process samples that are subjected to more recently developed and streamlined extraction methods. He also noted that IDbyDNA had teamed up with Illumina Inc., of San Diego, to pair the Explify platform with Illumina’s NGS systems for detection of microorganisms, a partnership that arrived just in time to address the most dangerous pathogen the world has seen in a century.

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