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In this opinion article, we discuss a serendipitous observation we made in a study investigating survival in aged mice after bacterial infection. This observation involved a non-invasive ventilation approach that led to variable and higher survival in male and female mice with different genetic backgrounds for the innate immune molecule, surfactant protein A (SP-A). We suggest that employing the best ventilatory modality, whether that be HFNC or another method, may augment the role of other factors such as SP-A genetics and sex in a personalized approach, and may ultimately improve the outcome.