Moderate to Severe Impairment of D <scp>l</scp>  CO and Iso↓D <scp>l</scp>  CO Are Associated with All-Cause Mortality in People with Human Immunodeficiency Virus

<b>Rationale:</b> The most common lung function abnormality in people with human immunodeficiency virus (HIV) (PWH) is a low diffusing capacity of the lung for carbon monoxide (Dl_CO), which is associated with distinct plasma biomarker patterns, increased symptom burden, and increased mortality. In PWH undergoing spirometry and Dl_CO measurement, the most common abnormality is an abnormal Dl_CO with normal spirometry (iso↓Dl_CO), which is associated with distinct biomarkers and increased symptom burden but whose association with mortality is unknown. <b>Objectives:</b> To investigate the relationship between abnormal Dl_CO, including iso↓Dl_CO, and mortality in PWH. <b>Methods:</b> Adult PWH underwent pre and postbronchodilator spirometry and single-breath Dl_CO measurements from April 2013 to January 2023. Dl_CO was categorized as normal (Dl_CO greater than or equal to the lower limit of normal [LLN]), mildly abnormal (60% predicted < Dl_CO < LLN), or moderately to severely abnormal (Dl_CO ≤60% predicted). Iso↓Dl_CO was defined as abnormal Dl_CO with normal spirometry (forced expiratory volume in 1 second/forced vital capacity ⩾ LLN, forced expiratory volume in 1 second ⩾ LLN, forced vital capacity ⩾ LLN). Participants' present vital status was assessed through electronic health record review and the National Death Index. Multivariable Cox proportional hazards models adjusted for age, smoking status, history of bacterial pneumonia, and CD4 count were used to estimate associations between Dl_CO and all-cause mortality. <b>Results:</b> Among 241 participants, 205 (85%) were male and 26 (11%) died during follow-up of 1,055 person-years. Among 178 participants with normal spirometry, 16 (9%) died over 770 person-years. Both moderate to severe Dl_CO impairment (adjusted hazard ratio, 4.67; 95% confidence interval, 1.69-12.9; <i>P</i> = 0.003) and moderate to severe iso↓Dl_CO (adjusted hazard ratio, 11.0; 95% confidence interval, 2.20-55.1; <i>P</i> = 0.004) were significantly associated with increased mortality. <b>Conclusions:</b> Moderate to severe impairment of Dl_CO and iso↓Dl_CO are associated with all-cause mortality in PWH. Further studies evaluating mechanistic pathways and cause-specific mortality are warranted.