When the Pathogen Shapes the Host: Metabolic Divergence in COVID-19 and Community-Acquired Pneumonia

A patient is admitted with fever, hypoxemia, and a new lobar consolidation.Blood cultures grow Streptococcus pneumoniae, and she promptly receives appropriate antibiotics.She may recover uneventfully.She may also progress to respiratory failure, shock, and death.For most of the modern era, our therapeutics for pneumonia have had the singular aim of destroying the pathogen.That strategy is necessary yet insufficient, as evidenced by the mortality that persists among critically ill adults with pneumonia despite adequate antimicrobial therapy (1).We have long known that much of the harm in sepsis comes not from the pathogen itself but from the host response to it and that distinct host-response signatures shared across syndromes of critical illness track with poor outcomes (2, 3).It was not until COVID-19, however, that host-directed therapy first demonstrated an unambiguous benefit, when dexamethasone and interleukin-6 receptor antagonists reduced mortality among patients requiring respiratory support (4-6).Whether such therapies benefit patients with other viral or bacterial infections remains uncertain.For corticosteroids in particular, the evidence has been markedly heterogeneous.This raises a mechanistic question: how much of the dysregulated host response is pathogen-specific?In this issue of Critical Care Explorations, Rapti et al (7) take up part of this question.Using untargeted serum metabolomics, they compared 46 patients with COVID-19 enrolled in the suPAR-guided Anakinra Treatment for Validation of the Risk and Management of Respiratory Failure by COVID-19 (SAVE) trial with 46 patients with non-COVID-19 community-acquired pneumonia (CAP) enrolled in the A randomized clinical trial of oral Clarithromycin in Community-acquired pneumonia to attenuatE inflammatory responseS and improve outcomeS (ACCESS) trial, matched on age, sex, and Charlson Comorbidity Index.Both parent studies, it is worth noting, were trials of hostdirected therapy (8, 9).Of 3555 detected metabolites, 73% differed between groups.CAP was characterized by enrichment of tricarboxylic acid (TCA) cycle intermediates (pyruvate, isocitrate, cis-aconitate, and malate) and of arachidonic acid metabolism.COVID-19 demonstrated elevations in uric acid, palmitoylcarnitine, lactate, and kynurenine, with pathway-level alterations in amino acid, purine, and mitochondrial metabolism.The principal signatures were preserved after adjustment for Sequential Organ Failure Assessment score and after stratification by corticosteroid exposure.Samples were processed Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, UCSF, San Francisco, CA.Dr. Alipanah-Lechner has disclosed that she does not have any potential conflicts of interest.