Vitamin D Status and Incident Acute Respiratory Failure
Vitamin D Status and Incident Acute Respiratory Failure
The present, two-centre study aimed to determine whether suboptimal vitamin D status prior to hospital admission was associated with acute respiratory failure in the critically ill. In unadjusted and adjusted analyses, we found increased odds of acute respiratory failure in patients with preadmission 25(OH)D <20 ng/mL. In addition, our mortality analysis suggests that patients with 25(OH)D levels <20 ng/mL before hospital admission who develop acute respiratory failure have a higher risk for mortality compared to patients with prehospital 25(OH)D levels ≥30 ng/mL.
ARDS is due to diffuse alveolar damage mediated by inflammatory cytokines such as tumour-necrosis factor, interleukin (IL)-1, IL-6 and IL-8 and subsequent neutrophil recruitment and release of oxygen free radicals that damage capillary endothelium and alveolar epithelium. Immunomodulatory and proinflammatory associations of vitamin D deficiency are well known. Vitamin D induces expression of the gene for cathelicidin, which promotes intracellular killing of bacteria. In the lung, cathelicidin likely plays a role in mucosal defence as it is produced by neutrophils, macrophages and airway epithelium, and upregulated in response to infection and inflammation. These biological observations indicate the potential importance of vitamin D status to innate immunity and ARDS.
Prior studies have reported robust associations of low vitamin D and sepsis, bloodstream infections and mortality in critically ill adults. The VITdAL-ICU trial secondary outcome data shows high-dose vitamin D supplementation reduces mortality in patients with severe vitamin D deficiency (25(OH)D≤12 ng/mL), but was not designed to study respiratory outcomes. In the current study, the reason for an increase in mortality in acute respiratory failure patients with vitamin D inadequacy is likely to be multifactorial. Other issues that may be important for critical illness outcomes include vitamin D related effects on vascular endothelial growth factor, endothelin and the renin-angiotensin-aldosterone system. Further, comorbidities including incident hypertension, glucose intolerance, the metabolic syndrome, obesity and cardiovascular disease are all associated with low 25(OH)D and higher mortality.
The present study is not without potential limitations. Observational studies may be limited by bias, confounding, and/or reverse causation. Importantly, causality cannot be determined in our study. Our utilisation of ICD-9 and CPT coding likely reflects the measured incidence of acute respiratory failure in the cohort rather than the actual incidence. Ascertainment bias may exist in our study as the patient cohort under study had vitamin D status measurements for reasons that may be absent in other critically ill patients. Despite adjustment for multiple potential confounders, residual confounding may contribute to the observed differences in outcomes and vitamin D status could simply be a marker of baseline healthy behaviours. Specifically, we are unable to adjust for immobilisation, excessive alcohol intake, smoking status, genetic factors, hypertension, low-density lipoprotein-cholesterol, education level and low milk consumption all of which can alter 25(OH)D. The percentage of cohort patients who are female is 55% while the percentage of African-Americans is only 6%, which may limit generalisability. The 25(OH)D-mortality association appears to be preserved when 25(OH)D is obtained within 30 days of admission. Despite this observation, vitamin D levels at the time of hospitalisation may be different from the levels when prehospital values were drawn. We also do not have any information as to why 25(OH)D concentrations were obtained in the cohort. Finally, our observations may represent a healthy user effect rather than causality.
The present study has several strengths. To the best of our knowledge, our study is the first large sample study to evaluate an association between prehospital vitamin D and incident acute respiratory failure. Crucially, we have sufficient statistical power to detect a clinically relevant difference in acute respiratory failure between the vitamin D groups. The exclusion of ICD-9 codes related to heart failure and requirement of mechanical ventilation ICD-9 codes for our exposure increases the specificity of the codes for ARDS. The Deyo-Charlson Index allowed us to account for chronic medical comorbidities. Finally, by measuring vitamin D status at least 7 days prior to hospitalisation, we attempted to uncouple the influence of acute illness and inflammation on 25(OH)D levels.
Discussion
The present, two-centre study aimed to determine whether suboptimal vitamin D status prior to hospital admission was associated with acute respiratory failure in the critically ill. In unadjusted and adjusted analyses, we found increased odds of acute respiratory failure in patients with preadmission 25(OH)D <20 ng/mL. In addition, our mortality analysis suggests that patients with 25(OH)D levels <20 ng/mL before hospital admission who develop acute respiratory failure have a higher risk for mortality compared to patients with prehospital 25(OH)D levels ≥30 ng/mL.
ARDS is due to diffuse alveolar damage mediated by inflammatory cytokines such as tumour-necrosis factor, interleukin (IL)-1, IL-6 and IL-8 and subsequent neutrophil recruitment and release of oxygen free radicals that damage capillary endothelium and alveolar epithelium. Immunomodulatory and proinflammatory associations of vitamin D deficiency are well known. Vitamin D induces expression of the gene for cathelicidin, which promotes intracellular killing of bacteria. In the lung, cathelicidin likely plays a role in mucosal defence as it is produced by neutrophils, macrophages and airway epithelium, and upregulated in response to infection and inflammation. These biological observations indicate the potential importance of vitamin D status to innate immunity and ARDS.
Prior studies have reported robust associations of low vitamin D and sepsis, bloodstream infections and mortality in critically ill adults. The VITdAL-ICU trial secondary outcome data shows high-dose vitamin D supplementation reduces mortality in patients with severe vitamin D deficiency (25(OH)D≤12 ng/mL), but was not designed to study respiratory outcomes. In the current study, the reason for an increase in mortality in acute respiratory failure patients with vitamin D inadequacy is likely to be multifactorial. Other issues that may be important for critical illness outcomes include vitamin D related effects on vascular endothelial growth factor, endothelin and the renin-angiotensin-aldosterone system. Further, comorbidities including incident hypertension, glucose intolerance, the metabolic syndrome, obesity and cardiovascular disease are all associated with low 25(OH)D and higher mortality.
The present study is not without potential limitations. Observational studies may be limited by bias, confounding, and/or reverse causation. Importantly, causality cannot be determined in our study. Our utilisation of ICD-9 and CPT coding likely reflects the measured incidence of acute respiratory failure in the cohort rather than the actual incidence. Ascertainment bias may exist in our study as the patient cohort under study had vitamin D status measurements for reasons that may be absent in other critically ill patients. Despite adjustment for multiple potential confounders, residual confounding may contribute to the observed differences in outcomes and vitamin D status could simply be a marker of baseline healthy behaviours. Specifically, we are unable to adjust for immobilisation, excessive alcohol intake, smoking status, genetic factors, hypertension, low-density lipoprotein-cholesterol, education level and low milk consumption all of which can alter 25(OH)D. The percentage of cohort patients who are female is 55% while the percentage of African-Americans is only 6%, which may limit generalisability. The 25(OH)D-mortality association appears to be preserved when 25(OH)D is obtained within 30 days of admission. Despite this observation, vitamin D levels at the time of hospitalisation may be different from the levels when prehospital values were drawn. We also do not have any information as to why 25(OH)D concentrations were obtained in the cohort. Finally, our observations may represent a healthy user effect rather than causality.
The present study has several strengths. To the best of our knowledge, our study is the first large sample study to evaluate an association between prehospital vitamin D and incident acute respiratory failure. Crucially, we have sufficient statistical power to detect a clinically relevant difference in acute respiratory failure between the vitamin D groups. The exclusion of ICD-9 codes related to heart failure and requirement of mechanical ventilation ICD-9 codes for our exposure increases the specificity of the codes for ARDS. The Deyo-Charlson Index allowed us to account for chronic medical comorbidities. Finally, by measuring vitamin D status at least 7 days prior to hospitalisation, we attempted to uncouple the influence of acute illness and inflammation on 25(OH)D levels.