Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia
Marilia Sanches Santos Rizzo Zuttion, … , David M. Underhill, Peter Chen
Marilia Sanches Santos Rizzo Zuttion, … , David M. Underhill, Peter Chen
Published September 10, 2024
Citation Information: J Clin Invest. 2024;134(21):e180986. https://doi.org/10.1172/JCI180986.
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Research Article Infectious disease Pulmonology

Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia

Abstract

A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated that antibiotic treatment during influenza infection caused a fungal dysbiosis that drove lung eosinophilia and impaired MRSA clearance. Finally, we evaluated 3 cohorts of hospitalized patients and found that eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs, thereby increasing the risk of developing a secondary bacterial infection.

Authors

Marilia Sanches Santos Rizzo Zuttion, Tanyalak Parimon, Stephanie A. Bora, Changfu Yao, Katherine Lagree, Catherine A. Gao, Richard G. Wunderink, Georgios D. Kitsios, Alison Morris, Yingze Zhang, Bryan J. McVerry, Matthew E. Modes, Alberto M. Marchevsky, Barry R. Stripp, Christopher M. Soto, Ying Wang, Kimberly Merene, Silvia Cho, Blandine L. Victor, Ivan Vujkovic-Cvijin, Suman Gupta, Suzanne L. Cassel, Fayyaz S. Sutterwala, Suzanne Devkota, David M. Underhill, Peter Chen

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Figure 7

Eosinophils correlate with antibiotic use and worsen clinical outcomes in hospitalized patients.

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Eosinophils correlate with antibiotic use and worsen clinical outcomes i...
(A) Lungs from an uninfected patient and one who died from influenza followed by MRSA infection were immunostained for MBP-1 to identify eosinophils (green fluorescence) and counterstained with DAPI (blue). See Supplemental Figure 12 for a representative image of the lungs from a patient who died from influenza with S. pneumoniae superinfection. Scale bars: 100 μm. (B) Initial and final eosinophil levels in peripheral blood of patients hospitalized for influenza infection on antibiotics for more than 4 days (n = 131). (C) Initial and final eosinophil levels in peripheral blood of ICU patients requiring mechanical ventilation and on antibiotics for more than 4 days (n = 121). (D and E) Mean eosinophils in peripheral blood (n = 175) (D) and BAL (E) correlated with days of antibiotic use in the ICU (n = 186). (F) Mean eosinophils in peripheral blood correlated with hospital length of stay for influenza patients (n = 229). (G and H) Mean eosinophils in peripheral blood (n = 175) (G) and BAL (n = 186) (H) correlated with length of stay in the ICU. (I–N) Eosinophil peroxidase (EPX) was measured in plasma of ICU patients. (I and J) Violin plot of EPX levels in ICU patients with ARDS (n = 51) compared with those at risk (n = 67) (I) and with pneumonia (PNA; n = 96) compared with those without pneumonia (No PNA; n = 23) (J). (K–N) EPX levels were correlated with plasma levels (n = 119) of IL-6 (K), CX3CL1 (L), ANG-2 (M), and soluble TNFR1 (N). Data presented from Cedars-Sinai Medical Center (CSMC) (B and F), Northwestern University (NU) (C–E, G, and H), and University of Pittsburgh (Pitt) (I–N). The data presented include all the patients within respective cohorts. Patient demographics for each cohort are described in Supplemental Table 7. **P < 0.01, ***P < 0.001, ****P < 0.0001 by 2-tailed Student’s t test (B, C, I, and J). Spearman’s correlation was used to determine association between various parameters (D–H and K–N).