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First Author:  Laura Pandolfi 

Journal/preprint name: Research Square preprint under consideration at BMC Pulmonary Medicine  

Tags: COVID-19 associated alveolitis, bronchoalveolar lavage, IL-6 and IL-8 

Summary

Pandolfi et al. assess and compare the broncho-alveolar inflammatory environment between COVID-19 patients admitted to Intensive Care Unit (ICU) and Intermediate Medicine Ward (IMW) at two main COVID-19 centers of Italy (located in Pavia/Milan). Inflammatory cell and cytokine analysis of bronchoalveolar lavage (BAL) samples suggest that hyperactivation of innate immune effectors, particularly neutrophil infiltration, contribute to COVID-19 associated alveolitis in severe cases. Furthermore, elevated levels of pro-inflammatory cytokines (IL-6 and 8) correlate with alveolar inflammatory status and patient clinical outcome.  

Research Highlights 

  1. ICU patients showed a significant increase in neutrophilsand relatively lower lymphocyte and macrophage levelscompared to IMW patients.  Neutrophil infiltration at alveolar level did not correlate with clinical outcome.   

  1. BAL collected from COVID-19 ICU patients revealed extensive cytopathic damage in all cell types, including loss of nuclear & plasma membrane integrity, pseudopodia formation and cytoplasm vacuolization.  Presence of viral particles were also observed in cytopathic epithelial and mononuclear cells.   

  1. Pro-inflammatory IL-6 and IL-8 cytokines were significantly higher in BAL samples derived from ICU compared to IMW COVID-19 patients.  Additionally, non-survivors (N=12) had higher IL-6/IL-8 BAL levels compared to survivors (N=16) 

  1. Patients treated with steroids had lower BAL IL-6 compared to patients on tocilizumab or antivirals (remdesivir, lopinavir/ritonavir or hydroxychloroquine).   

  1. Direct correlation between BAL IL-6/IL-8 and neutrophil count.  In contrast, IL-6/IL-8 levels inversely correlated with percentage of macrophages.  BAL IL-8 also inversely correlated with lymphocyte count.   

Impact for COVID-19 research:  

  • Increased IL-6 and IL-8 levels in broncho-alveolar environment of COVID-19 patients correlates with neutrophil infiltration and is associated with clinical outcome. Steroid treatment could reduce IL-6 levels in severe COVID-19 cases, potentially leading to better outcome.  

Methodologies: 

  • Study TypePatient cohort  

  • Key Techniques: Assessment of BAL cell differentials, ultrastructural cell analysis and cytokine profiling  

Limitations: 

  • Small patient cohort (N=33; 28 ICU and 5 IMW)Majority of patients were male.  

  • Small sample size limited the possibility of additional analysis (e.g. flow cytometric evaluation cell surface activation markers).  

  • The study is specific to a particular time & place and cannot be generalised.  

  • Paired assessment of inflammatory cytokines in peripheral blood was not possible due to lack of stored serum samples from acute COVID-19 patients/healthy donors.  

  • Pre-existing comorbidities may have influenced cellular infiltration and cytokine levels