Impaired immune responses in the airways are associated with poor outcome in critically ill COVID-19 patients

Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. Here, we investigate the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), broncheoalveolar lavage (BAL) and blood specimen antibody levels, and BAL viral load. While there was heterogeneity in the levels of the SARS-CoV-2 specific antibodies, we unexpectedly found that some BAL specimens displayed higher levels than in paired concurrent plasma samples, despite the known dilutional effects common in BAL samples. We found that survivors had higher levels of anti-Spike, anti-Spike-NTD, and anti-Spike-RBD IgG antibodies in their BAL (6684 [258–13 148]versus15 899 [8958–22 629], 5336 [256–10 343]versus13 494 [8028–19 414], and 1620 [199–6637]versus8466 [5144–16 157] median fluorescent intensity units, for deceasedversussurvivors, respectively, p<0.05), while there was no such association with antibody levels in the systemic circulation. Thus, our data highlight the critical role of local adaptive immunity in the airways as a key defense mechanism against primary SARS-CoV-2 infection.