Pulmonary pathology in culture-negative sepsis: a potential confounder for sepsis treatment and research

Abstract

The recent study by Chang et al. observed differences between sepsis with positive cultures and sepsis with negative cultures [1]. Given the significant frequency and mortality of sepsis associated with pulmonary infection [2], there remains a need to explain why pulmonary infection and respiratory failure were more common in the culture-negative sepsis cohort than the culture-positive cohort. Two hypotheses may help explain these findings.

First, the imperfect sensitivity of culture data can make identifying bacterial pulmonary pathogens challenging. Lack of hematogenous spread from the lungs may limit the utility of blood cultures in diagnosing bacterial pneumonia [3]. Even when sputum cultures are obtained, only a minority of samples may be diagnostic due to limitations of sample yield, contamination, or sensitivity [4].

Second, a number of these culture-negative “pulmonary infections” may have been misdiagnosed. Many non-infectious conditions can mimic pneumonia on chest radiography, including pulmonary edema, malignancy, interstitial lung disease, and pneumonitis from aspiration or medication. These pulmonary pathologies can also cause respiratory compromise and, therefore, the worsened PaO2/FiO2 ratios observed by the authors in their culture-negative cohort. In our own prior analysis of culture-positive sepsis vs. culture negative sepsis, we, too, found diagnosis of pneumonia and initiation of mechanical ventilation were more common in our culture-negative cohort, offering validation of the authors’ findings [5]. However, when we completed a post-hoc review of chest imaging from culture-negative sepsis patients with presumed pulmonary infection, we found their chest imaging was commonly interpreted by radiologists as having equivocal findings. In the absence of true infection, many of these patients may not have had sepsis at all.

Pulmonary pathology in culture-negative sepsis may therefore represent a confounding factor in sepsis treatment and investigation: a subset of patients who either have infectious pathogens that are difficult to identify, or who lack infection altogether and therefore won’t respond to antibiotics.

I thank the authors for their valuable contribution and hope this perspective aids in the interpretation of their findings.

No datasets were generated or analysed during the current study.

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Michael Filbin, MD, MPH, for thoughtful review and feedback.

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Authors and Affiliations

1. Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA

   Brett Biebelberg

2. Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

   Brett Biebelberg

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BB is a sepsis researcher and has previously published on related topics including the heterogeneity of sepsis and differences in sepsis with or without positive cultures

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Biebelberg, B. Pulmonary pathology in culture-negative sepsis: a potential confounder for sepsis treatment and research. Crit Care 29, 44 (2025). https://doi.org/10.1186/s13054-025-05267-0

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• Received: 06 January 2025

• Accepted: 08 January 2025

• Published: 24 January 2025

• DOI: https://doi.org/10.1186/s13054-025-05267-0

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