2024 Top Story in Respiratory Medicine: Effect of Metagenomic Sequencing on Clinical Outcomes of Patients With Severe Community-Acquired Pneumonia

Despite advances in medicine, pneumonia remains one of the leading causes of morbidity and mortality in the US and beyond. Community-acquired pneumonia (CAP) refers to a type of pneumonia that is acquired outside of the hospital or long-term care settings. In the US, the annual incidence of CAP is estimated at 24.8 per 10,000 adults, with rates increasing with older age. For those with severe CAP who require admission to the ICU, mortality may be as high as 23.0%.¹ Although estimates vary, in at least one-third to half of the cases, no causative pathogen is identified despite multimodal assessment, which may include collection of sputum and respiratory tract samples for culture, blood cultures, PCR testing, and urine antigen tests.

To improve the efficiency and accuracy of pathogen identification, newer tools such as metagenomic sequencing have been developed. Compared with our historical tools, metagenomic sequencing is significantly more sensitive and may help identify rare or unexpected pathogens to refine antimicrobial choice and, in some situations, help reduce use or appropriately narrow down the spectrum of antibiotic coverage. Despite its promising test characteristics, whether metagenomic sequencing will have a meaningful clinical impact for patient care in the real-world setting is unclear.²

In a multicenter randomized controlled study by Wu et al,³ a total of 349 adults with suspected or confirmed severe CAP were randomized in a 1:1 ratio to undergo metagenomic sequencing of bronchoalveolar lavage (BAL) fluid assessment or conventional microbiological testing of BAL fluid. The primary endpoint was the time to clinical improvement, defined as a decline (ie, clinical improvement) by 2 from the category score assigned at the time of randomization within 28 days or at time of discharge from the ICU. The six categories of clinical status were: 1) discharge from the ICU or hospital; 2) in the ICU, requiring noninvasive oxygen therapy at FiO₂ <50% without vasopressors; 3) in the ICU, requiring noninvasive oxygen therapy at FiO₂ >50% or using vasopressors; 4) in the ICU, requiring invasive mechanical ventilation; 5) in the ICU, requiring extracorporeal membrane oxygenation; and 6) death.

The study showed a positive pathogen identification rate that was substantially improved among patients in the metagenomic sequencing group (79.9%) compared with those in the conventional testing group (38.8%), as expected. Importantly, a higher proportion of patients in the intervention group saw a change in antibiotics, primarily in the form of de-escalation (20.7% vs 10.6%). Among the subset of immunocompromised patients, there was also a trend toward more escalations (46.0% vs 38.1%). The median time to clinical improvement (defined above) was shorter in the intervention group (10.0 days vs 13.0 days). Additionally, 63.9% of patients in the intervention group compared with 59.4% of those in the control group achieved the prespecified metric of clinical improvement within 28 days. Using a 14-day threshold, 62.0% of the patients in the intervention group as opposed to 46.5% of the patients in the conventional testing group met the definition of "clinical improvement." Subgroup analysis suggested more benefit for immunocompromised patients and those not on invasive mechanical ventilation. Mortality rates (at 28 days, in ICU, or in the hospital) were not different.

With this promising study highlighting a meaningful patient-centric outcome improvement, we are on the verge of adopting a new tool into our armamentarium for the treatment of patients with severe CAP. Before widespread adoption, a few remaining questions need to be answered. First, it is not yet clear whether a bronchoscopically acquired sample is required. The benefit of metagenomic data needs to be weighed against the risk of an invasive procedure. Some studies have suggested that a tracheal aspirate compared with a mini-BAL may provide similar outcomes.⁴ Additional larger studies are needed to answer this question. Second, given the sensitivity of metagenomic analysis, some have raised concerns regarding the overuse of antibiotics. This study shows the opposite — de-escalation of antibiotics was the most frequently made clinical decision. However, interpretation and adjudication of data in this study were performed using expert-guided group discussions for every patient to help distinguish among colonizers, contaminants, and pathogenic overgrowth. Such expertise and structures are not available widely. A simplified decision tree is much needed. Finally, the trial did not achieve the sample size within 2 years, and this may have impacted the likelihood of observing a difference in mortality or length of stay. Since this study began, the benefits of other interventions, such as steroids for the treatment of patients with severe CAP, have been published. Further study is needed to quantify the benefit, if any, in terms of other metrics, such as mortality, ventilator days, and length of stay, using a larger cohort incorporating other best practices holistically.