Northwestern University scientists have uncovered what they say may potentially be a previously unknown, hidden player in pneumonia. In their newly reported study, the scientists found that the lungs’ own microbial community, or microbiome, appears to influence how the illness evolves, who responds well to treatment, and whether a patient will recover successfully or continue to deteriorate.
Using lung samples from pneumonia patients, the team applied multiomics techniques to uncover clinically relevant drivers of pneumonia progression and identify how microbial ecosystems and immune responses evolved over time. Among their findings, the investigators discovered that patients most likely to recover shared two characteristics: that their lung microbiomes resembled oral microbiomes, and that their microbial communities were dynamic rather than stable. The findings eventually could help physicians predict patient outcomes, tailor personalized antibiotic treatment plans, and develop therapies that nurture beneficial microbes in the lungs. The new findings could also help improve understanding of pneumonia.
“Most people are familiar with the gut microbiome or skin microbiome but are surprised to learn the respiratory tract also has a microbiome,” said study lead Erica Hartmann, PhD, associate professor of civil and environmental engineering at Northwestern’s McCormick School of Engineering. “For a long time, people actually thought the lungs were sterile, and microbes were present only during an infection. It turns out that’s not the case. We wondered if the microbiome might help explain why some pneumonia patients respond to treatment, and others do not. Ultimately, we hope this leads to better diagnostics and improved patient outcomes.”
Hartmann and colleagues reported on their findings in Cell Host & Microbe, in a paper titled “Transitions in lung microbiota landscape associate with distinct patterns of pneumonia progression,” in which they concluded, “In summary, we show that host and microbiota landscapes change in unison with clinical phenotypes and that microbiota state dynamics reflect pneumonia progression. We suggest that distinct pathways of lung microbial community succession mediate pneumonia progression.”
Each year, pneumonia sends roughly 1.2 million people to emergency departments in the United States, according to CDC figures. But despite its prevalence, pneumonia remains surprisingly difficult to predict and treat. Even if two patients have the same diagnosis and receive the same antibiotic, they can have vastly different outcomes. “The three general categories, ventilator-associated pneumonia (VAP), hospital-acquired pneumonia (HAP), and community-acquired pneumonia (CAP), are associated each with a specific pathogen,” the authors wrote. “The precise microbial determinants driving clinical outcomes in severe pneumonia are unknown.”
“Pneumonia is defined by its symptoms, not by its cause,” Hartmann further explained. “There is a huge proportion of pneumonia patients for which doctors can’t tell if it’s bacterial, viral, or fungal. Hospital-acquired pneumonia and community-acquired pneumonia also are quite different. Depending on the type of bacterial infection the patient has, the antibiotics may or may not be effective.”
Added study co-author Richard Wunderink, MD, PhD, a professor of medicine at Northwestern University Feinberg School of Medicine, “This unpredictability has significantly hampered research efforts to understand pneumonia pathogenesis. For way too long, we have used the 19th-century tool of bacterial cultures to study an important 21st-century problem.”
To better understand the illness, the researchers aimed to identify the microbes present in pneumonia patients. Together with Wunderink and colleagues, Hartmann collected multiple lung samples from more than 200 critically ill pneumonia patients in hospitals’ intensive care units. Then, they identified the microbes within the samples and measured how many bacteria were present.
They combined 16S rRNA gene, metagenomic, and metatranscriptomic sequencing with bacterial-load quantification to track the microbiomes over time. Their results uncovered four distinct microbial patterns, or “pneumotypes,” associated with different types of pneumonia, including community-acquired, hospital-acquired, and ventilator-acquired. To determine the microbial signatures implicated in pneumonia pathogenesis and clinical outcome, we implement a comprehensive multiomics approach, involving systematic and serial bronchoscopic sampling of over 200 critically ill patients across various pneumonia subtypes (CAP, HAP, and VAP) and non-pneumonia (NP) states,” the authors wrote.
They found that patients’ lungs were either dominated by microbes typically found in the mouth, on the skin, or a mix of both. The fourth pneumotype was dominated by the common pathogen Staphylococcus aureus. The results indicated that the lung microbiomes and the host’s immune response were intertwined and changed together. The team also found that patients with oral-like pneumotypes were more likely to recover successfully. “Pneumotypes were predictive of therapeutic success in a category-dependent manner,” the authors stated. “Although rare in patients with HAP … an oral-like microbiota state (pneumotypeOL) was indicative of successful pneumonia therapy in patients with HAP and CAP.” Skin-like and mixed pneumotypes were not clearly associated with recovery, but also not clearly associated with decline. The patients with Staphylococcus-dominated pneumotypes tended to have the worst outcomes.
Wunderink added, “Sequencing data like this will allow greater understanding of how patients get pneumonia, what microbes are actually causing pneumonia, and ultimately, what pathogen is causing the pneumonia in the patient I am caring for right now.”
Hartmann acknowledged, “We’re still trying to understand what this means. One speculative hypothesis is that the lungs already have constant exposure to oral-like microbes. The upper respiratory tract includes the mouth and throat, so saliva is constantly moving down and getting coughed back up. The immune system might already be adapted to those oral-like microbes, so it knows how to respond when it encounters them.”
The scientists also found that the worst outcomes were associated with the most stable lung microbiomes. “We hypothesize that microbiota state transition is an underlying mechanism of successful response to pneumonia therapy,” they wrote. “Moreover, ecologically resistant states may challenge therapy success.” Hartmann said, “Lungs are like any other ecosystem. When an ecosystem is perturbed, it shifts. Those shifts might give it the potential to kick out a pathogen. But if the community is too stable, then it might not be flexible enough to defend itself. Again, though, we don’t really know, so this is all highly speculative.”
To help confirm these speculations, Hartmann and her collaborators plan to conduct experiments in cellular cultures. The team could only obtain lung samples through bronchoscopy, which requires patients to already be using ventilators. Although the experiments included ventilated patients without pneumonia as controls, they could not include healthy controls.
“Going forward, we want to culture these organisms and put them in a flask together to see how they interact,” Hartmann said. “But it does seem that the microbial communities and different pneumotypes do matter. And whether or not that pneumotype remains stable also matters. And that’s fascinating.”
The authors concluded, “As research focusing on large-scale center-wide studies emerges, our understanding of the temporal dynamics of the lung microbiome will continue to expand.” This will further help to redefine what is understood about pneumonia and disease states, they suggested. “Eventually, information about the lung microbiome will enable finer diagnostics and mid-treatment evaluation of prognosis, eventually leading to radically improved pneumonia therapies.”
