When Viruses Pair: The Dynamics of Co-Infections

Viral co-infections appear to impact clinical outcomes

Viral co-infections infections are about six times more common in children than adults and changes clinical outcomes, a new study finds.

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Investigating five years of respiratory virus infections, the Cleveland Clinic research team, led by pediatric infectious disease specialist Frank Esper, MD, examined all co-infection pairings to determine if specific viral pairings were occurring more often than expected and what was the clinical significance of those pairings. This data set included more than 30,000 samples, and of those, almost 10,000 of them were positive for a virus, and more than 1,000 were positive for a co-infection.

“This is one of the first studies to look specifically into virus pairings,” says Dr. Esper. “Previous studies poorly describe co-infections and often do not look at specific virus pairings. We’re still at the beginning of understanding what happens when two viral pathogens infect together — compared with one single pathogen acting alone — we are finding that co-infections do impact outcomes.”

All co-infections are not created equal

Detecting multiple infectious agents in one test is possible with the use of very advanced multiplex polymerase chain reaction (PCR) testing. The researchers were able to screen for 14 different viruses in 132 pairing permutations.

Pediatric patients had substantially higher co-infection rates than adults: 35% percent of all viruses infecting children had co-infections, compared with only about 6% of viruses infecting adults. Although they had similar numbers of positive samples, the pediatric samples were much more likely to be co-infected with a second virus. Pediatric patients were also less likely to be hospitalized than adults.

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Certain pairings occur more frequently than others

“This is one of the first studies that takes analyzes co-infection based on the community circulation patterns of the viruses,” Dr. Esper explains. “As opposed to tabulating the numbers as whole over a five-year period, we analyzed the data month-to-month. The result was a much more robust model, which finds that several viral pairings were happening much more than we would expect, while others were less likely to occur.”

Specifically, three pairings were happening more than would be expected: Adenovirus C (ADVC) —rhinovirus (hRV), respiratory syncytial virus (RSV) A—hRV and RSVB—hRV. These findings  suggest that these viruses may either directly help each other infect a person simultaneously, or that one virus produces conditions which are beneficial for the second virus.

Impact on clinical disease

One goal of this project was to determine whether or not co-infections had a significant impact on clinical severity. The team used data for hospitalization within 48 hours of sample procurement as  a broad marker of severity of illness.

“Surprisingly, we found that patients who were co-infected with certain pairings had less severe illness than those patients with mono-infections. This effect was most prominent in the ADVC—hRV pairing; that is, children infected with both ADVC and hRV at the same time were less likely to be hospitalized than a child infected with ADVC-only or hRV-only. This seems a bit counterintuitive. Although we are uncertain as to whether the co-infection minimizes the immune response or the ability of another pathogen to cause more harm, it does seem that co-infections alleviate illness severity. Our next step is to use indicators other than hospitalization — such as oxygen use, mechanical ventilation, etc. — to really figure out exactly how polymicrobial infections affect clinical severity,” Dr. Esper says.

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Next, the team will look more closely at the clinical outcomes focusing on those with higher risk for more severe disease, such as patients who have underlying immunologic issues, cancer patients, transplant patients and those with underlying lung disease like asthma, chronic obstructive pulmonary disease or cystic fibrosis.

“We are now looking at the immunologic response of the co-infection pairings we found – specifically at cytokines and chemokines – to figure out how the immunologic response of the co-infection differs from that of mono-infections,” Dr. Esper states.