Diagnosing pneumonia in patients hospitalized for respiratory failure can be challenging, particularly when the patients are children.
Children frequently carry bacterial pathogens in the upper throat and airways that could cause pneumonia. But just because those bacteria are present doesn’t necessarily mean there’s an infection, according to Emily Lydon, MD, an infectious disease (ID) physician and clinical fellow at the University of California, San Francisco (UCSF).
Those pathogens might just be taking up residence.
“The respiratory tract is a non-sterile environment directly connected to the outside world into your mouth. And you know, there are tons of microbes in there,” Lydon told CIDRAP News.
That’s especially true when a child is in the hospital—an environment teeming with potentially pathogenic microbes. Studies have found that, in nearly half of the patients who are intubated for non-infectious indications, their airways are found to be colonized with potential pathogenic bacteria within 24 hours.
But when a child who’s been intubated tests positive for Staphylococcus aureus, for example, clinicians don’t have a way of definitively knowing whether it’s causing pneumonia. Those tests don’t exist.
Detection of a pathogen in the airways can lead to premature diagnosis of pneumonia and unnecessary antibiotic exposure. It can also result in overlooking other, non-infectious causes of respiratory failure, like a heart or autoimmune condition, Lydon said.
“All of our diagnostic tests are based on identifying the pathogen,” she said. “They cannot distinguish whether that pathogen is causing an infection or it’s just a pathogen that’s along for the ride.
A collapse of microbial diversity with true infection
To get a better understanding of what’s going in the lower airway when there truly is an infection, Lydon and a team of researchers sequenced the RNA of tracheal aspirates collected from 326 critically ill, mechanically ventilated children at eight US hospitals from February 2015 through December 2017. The findings from their study were published last week in Nature Communications.
Their aim was to see if there were any differences in the composition and function of the lung microbiome between children who had a lower respiratory tract infection (LRTI) and those with incidental pathogen carriage (IPC).
“To understand these differences, you need to look holistically at the community of organisms in the lower respiratory tract,” said co-author Charles Langelier, MD, PhD, an ID physician and professor at UCSF.
In a separate retrospective analysis of clinical data from the children conducted by a team of adjudicators, 207 were determined to have a clinically diagnosed LRTI with a respiratory pathogen and 119 had a non-infectious cause of respiratory failure. Of those children, 70 had IPC, and 49 had no pathogen detected (the control group).
All of our diagnostic tests are based on identifying the pathogen...They cannot distinguish whether that pathogen is causing an infection or it’s just a pathogen that’s along for the ride.
Respiratory syncytial virus (RSV) was the most common respiratory pathogen detected, identified in 53% of the LRTI and 13% of the IPC group. Other detected pathogens included Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, and S aureus.
The sequencing of RNA from the tracheal aspirates revealed the different ways true infection and IPC affected the lung microbiome. In children with a diagnosed LRTI, there was a collapse of microbial diversity, with the infectious pathogen crowding other microbes out and becoming the dominant player, Lydon explained.
In the children with IPC, however, “it was a relatively balanced microbiome, where the pathogen was one of many different bacteria that were detected,” she said.
A promising biomarker
They also found that the host response was different in children with pneumonia than in those with IPC. This was reflected by “markedly different” expression of FABP4, a protein that plays a role in inflammation, in lower respiratory tract fluid. No difference was observed in FABP4 levels between the IPC and control group.
“We found that the levels of this gene in the lower respiratory tract were highly accurate in terms of distinguishing true infection from incidental pathogen carriage,” Langelier said. “This gene has emerged as a very promising biomarker to distinguish these two states.”
Langelier said the findings underscore the fact that pneumonia and LRTIs represent a “dynamic relationship between host and microbe.”
Lydon and Langelier said they plan to conduct similar research in adults to see if the microbial and hosts differences are similar to what they found in children. Ultimately, they hope that, as RNA sequencing technology gets cheaper and faster, the findings could be translated into a rapid diagnostic test that could combine host and microbial features to help clinicians accurately identify true respiratory infections and properly treat them.
“That’s the goal,” said Lydon.
