LETTERS of 31.958 S, even greater variations in seasonal levels might be expected with the potential to misclassify cases of maternal vitamin D deficiency. The Avon Longitudinal Study of Parents and Children, which prospectively measured 25-hydroxyvitamin D levels from a subset of at least 7,700 pregnant women in the southwest of England, found seasonal effects with regard to lung function outcomes for offspring with a mean age of 8.7 years (3). Reductions in the minimally adjusted mean difference for FEV1 and FVC were observed for the lowest compared with the highest quintile of 25-hydroxyvitamin D; however, no differences remained after adjusting for seasonality. The adjustment did not change the null result for asthma. In addition, it is now appreciated that estimated levels of bioavailable 25-hydroxyvitamin D may be more appropriate than the total level, at least with regard to bone homeostasis. Between 85% and 90% of the total 25-hydroxyvitamin D is bound to vitamin D-binding protein, in contrast to the lesser but more functional non–vitamin D–binding protein fraction (4). Compared with white Americans, black Americans were estimated to have similar concentrations of this bioavailable fraction, as well as greater bone mineral density, in spite of the lower total and the correspondingly lower vitamin D–binding protein levels, which might be largely explained by two genetic polymorphisms. Although ethnicity-related data for native-born and migrant Australians are not yet available, a description of the ethnic mix of the Raine study participants might have been informative. This bioavailable form, which is likely to have a genetic basis and is unlikely to be proportionally related to total levels (4), raises the possibility of measurement error and a further source of misclassification of exposure categories. Bioavailable 25hydroxyvitamin D is distinct from the biologically active form, 1,25-dihydroxyvitamin D, and the influence of the latter with regard to the bioavailable form and mineral metabolism has not yet been established (4). A possible benefit of using the active metabolite over total 25-hydroxyvitamin D levels was acknowledged by the authors.
Adopting the use of bioavailable 25-hydroxyvitamin D levels with seasonal adjustment for exposure may prove advantageous when examining, for lung health, the effects of prenatal vitamin D deficiency. The inconsistencies of the current literature may relate in part to the variation of definitions for total 25-hydroxyvitamin D deficiency and variable inclusion of seasonality as a confounder (5) through its influence on the estimated strengths of association for asthma and lung function outcomes.
Reply
variations in ultraviolet radiation exposure, leading to annual fluctuations in circulating 25(OH)D levels (2). Seasonal fluctuations in population 25(OH)D levels have been used by many groups as a justification for seasonal adjustment of vitamin D levels in population health studies. However, for our study, seasonal adjustment of 25(OH)D is predicated on the assumption that it is a mother’s vitamin D levels relative to the population at a particular point during gestation, rather than the absolute values of vitamin D, that are important. We argue that normal physiological function requires an as-yetundetermined amount of circulating 25(OH)D to ensure the normal growth of the fetus. Our analysis was conducted with the understanding that having circulating levels of 25(OH)D , 25 nmol/L at 16–20 weeks’ gestation has an effect on postnatal lung function and the risk for asthma, irrespective of whether these low levels are experienced during summer, winter, autumn, or spring. This is consistent with international public health guidelines that specify a particular level of 25(OH)D for normal physiological function
From the Authors: We thank Perret and Lodge for considering the results of our study, in which we showed associations among maternal serum levels of 25-hydroxy vitamin D [25(OH)D], postnatal deficits in lung function, and asthma at 6 years of age (1). Perret and Lodge raised the possibility of two potential confounders that may have introduced additional variation and may explain between-study discrepancies in the link between maternal vitamin D levels and postnatal lung outcomes in children: no seasonal adjustment for 25(OH)D levels in our analysis and measurement of total 25(OH)D levels, as opposed to bioavailable levels. As pointed out by Perret and Lodge, our study was conducted in Perth, Australia, which experiences considerable seasonal Supported by National Health and Medical Research Council Project Grant 1042235 (G.R.Z.).
Letters
Author disclosures are available with the text of this letter at www.atsjournals.org. Jennifer L. Perret, M.B. B.S. Caroline J. Lodge, M.B. B.S., Ph.D. The University of Melbourne Melbourne, Victoria, Australia
References 1 Zosky GR, Hart PH, Whitehouse AJ, Kusel MM, Ang W, Foong RE, Chen L, Holt PG, Sly PD, Hall GL. Vitamin D deficiency at 16 to 20 weeks’ gestation is associated with impaired lung function and asthma at 6 years of age. Ann Am Thorac Soc 2014;11:571–577. 2 Levis S, Gomez A, Jimenez C, Veras L, Ma F, Lai S, Hollis B, Roos BA. Vitamin D deficiency and seasonal variation in an adult South Florida population. J Clin Endocrinol Metab 2005;90:1557–1562. 3 Wills AK, Shaheen SO, Granell R, Henderson AJ, Fraser WD, Lawlor DA. Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. Clin Exp Allergy 2013;43:1180– 1188. 4 Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369:1991–2000. 5 Sokol SI, Tsang P, Aggarwal V, Melamed ML, Srinivas VS. Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis. Cardiol Rev 2011;19:192–201. Copyright © 2014 by the American Thoracic Society
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LETTERS (3), rather than a seasonally adjusted value. It should also be pointed out that differences between studies could also reflect variations in the time of gestation when vitamin D levels were measured. For example, the Avon Longitudinal Study of Parents and Children study measured 25(OH)D at 34 weeks’ gestation (4), a time when the lung is relatively mature compared with 16–20 weeks’ gestation, as was the case in our study. Perret and Lodge raise an important point regarding the bioavailable fraction of 25(OH)D. We measured total 25(OH)D, which may have introduced an additional level of variation (error) into our data; however, it is unlikely to have changed the direction of our findings. The importance of considering ethnicity in population studies of vitamin D is also noted. The Western Australia Pregnancy cohort used for our study is known to have a high proportion of whites (.80%), so it is unlikely that ethnicity had a major effect on our analysis. Further analysis of the effect of vitamin D deficiency on postnatal lung outcome at different stages of gestation is certainly warranted, along with consideration of the effect of ethnicity and genetic polymorphisms on the bioavailability of circulating 25(OH)D. Author disclosures are available with the text of this letter at www.atsjournals.org.
Diffuse Alveolar Hemorrhage, Anesthesia, and Cannabis To the Editor: We read with interest the letter submitted by Kim and colleagues entitled “Diffuse Alveolar Hemorrhage Induced by Sevoflurane” (1). The letter reported and commented on the experience of a 31-year-old man with a past history of cannabis use who developed pulmonary edema and hemoptysis 45 minutes into the postoperative period after perirectal pilonidal cyst excision. The authors came to the ultimate conclusion that this was a case of diffuse alveolar hemorrhage related to sevoflurane administration. We propose that the patient’s alveolar hemorrhage is more likely attributable to negative pressure pulmonary edema in conjunction with the patient’s cannabis use. We have chosen to use the term cannabis in place of “marijuana,” in accordance with National Cannabis Prevention and Information Centre recommendations. Negative pressure pulmonary edema is a condition that occurs most frequently surrounding anesthesia, although a dyssynchrony between the patient and a ventilator has also been cited as a cause in the intensive care unit. The incidence of negative pressure pulmonary edema is believed to be 0.05–0.1% for patients undergoing general anesthesia. It has been suggested that 50% of these episodes occur in the postoperative recovery area (2). Edema develops as a consequence of an excessive pressure gradient between the capillary space and the alveolar space caused by a negative intrathoracic pressure-induced increase in right ventricular filling and a decrease in left ventricular ejection (3). Although rare, negative pressure pulmonary edema has been associated with hemoptysis (4). Use of the term negative pressure pulmonary hemorrhage has been suggested for this
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Graeme R. Zosky, Ph.D. University of Tasmania Hobart, Tasmania, Australia Prue H. Hart, Ph.D. Andrew J. O. Whitehouse, Ph.D. Graham L. Hall, Ph.D. University of Western Australia Crawley, Western Australia, Australia
References 1 Zosky GR, Hart PH, Whitehouse AJO, Kusel MM, Ang W, Foong RE, Chen L, Holt PG, Sly PD, Hall GL. Vitamin D deficiency at 16 to 20 weeks’ gestation is associated with impaired lung function and asthma at 6 years of age. Ann Am Thorac Soc 2014;11:571–577. 2 Ramankutty P, de Klerk NH, Miller M, Fenech M, O’Callaghan N, Armstrong BK, Milne E. Ultraviolet radiation exposure and serum vitamin D levels in young children. J Paediatr Child Health 2014;50:713–720. 3 Pramyothin P, Holick MF. Vitamin D supplementation: guidelines and evidence for subclinical deficiency. Curr Opin Gastroenterol 2012; 28:139–150. 4 Wills AK, Shaheen SO, Granell R, Henderson AJ, Fraser WD, Lawlor DA. Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. Clin Exp Allergy 2013;43:1180–1188. Copyright © 2014 by the American Thoracic Society
variant (3). For alveolar hemorrhage to develop, there must also be mechanical damage to the alveolar epithelial lining. We believe the patient’s cannabis use could have contributed to this damage, through both the pulmonary injury and anticoagulation. Similar to tobacco, cannabis smoking has been linked to visual and histological evidence of airway inflammation, edema, and increased alveolar permeability (5). In addition to this, cannabis has been implicated in anticoagulant effects. It has been shown that cannabis sativa, tetrahydrocannabinol, and cannabinol cause inhibition of thrombin-driven clot formation in a rat model (6). It should be noted that there are many variables in cannabis’ effects on lung function that remain understudied: the effect of tetrahydrocannabinol content in each use, the route of administration (cigarette vs. water pipe vs. vaporizer), and the complicated relationship between acute and chronic use on bronchodilation and constriction. The authors postulate that sevoflurane was the causative agent in their case but were able to find only one other case report in support of this hypothesis. The patients described in both case reports engaged in recreational drug use. Diffuse alveolar hemorrhage has been shown to occur with crack cocaine as well. In conclusion, we suggest that instead of the highly unlikely event of sevoflurane-induced pulmonary hemorrhage, the cause is more likely to be related to negative pressure pulmonary edema that was rendered hemorrhagic by antecedent lung injury and coagulopathy attributable to recreational drug use. The increase in legalized cannabis use in the United States may present an opportunity to further investigate functional coagulation effects in the setting of cannabis use. It would also be interesting to see whether there is an increased incidence of possible negative pressure pulmonary edema with the newer formulations of cannabis compared with traditional, naturally grown cannabis. AnnalsATS Volume 11 Number 8 | October 2014
Adopting the use of bioavailable 25-hydroxyvitamin D levels with seasonal adjustment for exposure may prove advantageous when examining, for lung health, the effects of prenatal vitamin D deficiency. The inconsistencies of the current literature may relate in part to the variation of definitions for total 25-hydroxyvitamin D deficiency and variable inclusion of seasonality as a confounder (5) through its influence on the estimated strengths of association for asthma and lung function outcomes.
Reply
variations in ultraviolet radiation exposure, leading to annual fluctuations in circulating 25(OH)D levels (2). Seasonal fluctuations in population 25(OH)D levels have been used by many groups as a justification for seasonal adjustment of vitamin D levels in population health studies. However, for our study, seasonal adjustment of 25(OH)D is predicated on the assumption that it is a mother’s vitamin D levels relative to the population at a particular point during gestation, rather than the absolute values of vitamin D, that are important. We argue that normal physiological function requires an as-yetundetermined amount of circulating 25(OH)D to ensure the normal growth of the fetus. Our analysis was conducted with the understanding that having circulating levels of 25(OH)D , 25 nmol/L at 16–20 weeks’ gestation has an effect on postnatal lung function and the risk for asthma, irrespective of whether these low levels are experienced during summer, winter, autumn, or spring. This is consistent with international public health guidelines that specify a particular level of 25(OH)D for normal physiological function
From the Authors: We thank Perret and Lodge for considering the results of our study, in which we showed associations among maternal serum levels of 25-hydroxy vitamin D [25(OH)D], postnatal deficits in lung function, and asthma at 6 years of age (1). Perret and Lodge raised the possibility of two potential confounders that may have introduced additional variation and may explain between-study discrepancies in the link between maternal vitamin D levels and postnatal lung outcomes in children: no seasonal adjustment for 25(OH)D levels in our analysis and measurement of total 25(OH)D levels, as opposed to bioavailable levels. As pointed out by Perret and Lodge, our study was conducted in Perth, Australia, which experiences considerable seasonal Supported by National Health and Medical Research Council Project Grant 1042235 (G.R.Z.).
Letters
Author disclosures are available with the text of this letter at www.atsjournals.org. Jennifer L. Perret, M.B. B.S. Caroline J. Lodge, M.B. B.S., Ph.D. The University of Melbourne Melbourne, Victoria, Australia
References 1 Zosky GR, Hart PH, Whitehouse AJ, Kusel MM, Ang W, Foong RE, Chen L, Holt PG, Sly PD, Hall GL. Vitamin D deficiency at 16 to 20 weeks’ gestation is associated with impaired lung function and asthma at 6 years of age. Ann Am Thorac Soc 2014;11:571–577. 2 Levis S, Gomez A, Jimenez C, Veras L, Ma F, Lai S, Hollis B, Roos BA. Vitamin D deficiency and seasonal variation in an adult South Florida population. J Clin Endocrinol Metab 2005;90:1557–1562. 3 Wills AK, Shaheen SO, Granell R, Henderson AJ, Fraser WD, Lawlor DA. Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. Clin Exp Allergy 2013;43:1180– 1188. 4 Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369:1991–2000. 5 Sokol SI, Tsang P, Aggarwal V, Melamed ML, Srinivas VS. Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis. Cardiol Rev 2011;19:192–201. Copyright © 2014 by the American Thoracic Society
1337
LETTERS (3), rather than a seasonally adjusted value. It should also be pointed out that differences between studies could also reflect variations in the time of gestation when vitamin D levels were measured. For example, the Avon Longitudinal Study of Parents and Children study measured 25(OH)D at 34 weeks’ gestation (4), a time when the lung is relatively mature compared with 16–20 weeks’ gestation, as was the case in our study. Perret and Lodge raise an important point regarding the bioavailable fraction of 25(OH)D. We measured total 25(OH)D, which may have introduced an additional level of variation (error) into our data; however, it is unlikely to have changed the direction of our findings. The importance of considering ethnicity in population studies of vitamin D is also noted. The Western Australia Pregnancy cohort used for our study is known to have a high proportion of whites (.80%), so it is unlikely that ethnicity had a major effect on our analysis. Further analysis of the effect of vitamin D deficiency on postnatal lung outcome at different stages of gestation is certainly warranted, along with consideration of the effect of ethnicity and genetic polymorphisms on the bioavailability of circulating 25(OH)D. Author disclosures are available with the text of this letter at www.atsjournals.org.
Diffuse Alveolar Hemorrhage, Anesthesia, and Cannabis To the Editor: We read with interest the letter submitted by Kim and colleagues entitled “Diffuse Alveolar Hemorrhage Induced by Sevoflurane” (1). The letter reported and commented on the experience of a 31-year-old man with a past history of cannabis use who developed pulmonary edema and hemoptysis 45 minutes into the postoperative period after perirectal pilonidal cyst excision. The authors came to the ultimate conclusion that this was a case of diffuse alveolar hemorrhage related to sevoflurane administration. We propose that the patient’s alveolar hemorrhage is more likely attributable to negative pressure pulmonary edema in conjunction with the patient’s cannabis use. We have chosen to use the term cannabis in place of “marijuana,” in accordance with National Cannabis Prevention and Information Centre recommendations. Negative pressure pulmonary edema is a condition that occurs most frequently surrounding anesthesia, although a dyssynchrony between the patient and a ventilator has also been cited as a cause in the intensive care unit. The incidence of negative pressure pulmonary edema is believed to be 0.05–0.1% for patients undergoing general anesthesia. It has been suggested that 50% of these episodes occur in the postoperative recovery area (2). Edema develops as a consequence of an excessive pressure gradient between the capillary space and the alveolar space caused by a negative intrathoracic pressure-induced increase in right ventricular filling and a decrease in left ventricular ejection (3). Although rare, negative pressure pulmonary edema has been associated with hemoptysis (4). Use of the term negative pressure pulmonary hemorrhage has been suggested for this
1338
Graeme R. Zosky, Ph.D. University of Tasmania Hobart, Tasmania, Australia Prue H. Hart, Ph.D. Andrew J. O. Whitehouse, Ph.D. Graham L. Hall, Ph.D. University of Western Australia Crawley, Western Australia, Australia
References 1 Zosky GR, Hart PH, Whitehouse AJO, Kusel MM, Ang W, Foong RE, Chen L, Holt PG, Sly PD, Hall GL. Vitamin D deficiency at 16 to 20 weeks’ gestation is associated with impaired lung function and asthma at 6 years of age. Ann Am Thorac Soc 2014;11:571–577. 2 Ramankutty P, de Klerk NH, Miller M, Fenech M, O’Callaghan N, Armstrong BK, Milne E. Ultraviolet radiation exposure and serum vitamin D levels in young children. J Paediatr Child Health 2014;50:713–720. 3 Pramyothin P, Holick MF. Vitamin D supplementation: guidelines and evidence for subclinical deficiency. Curr Opin Gastroenterol 2012; 28:139–150. 4 Wills AK, Shaheen SO, Granell R, Henderson AJ, Fraser WD, Lawlor DA. Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. Clin Exp Allergy 2013;43:1180–1188. Copyright © 2014 by the American Thoracic Society
variant (3). For alveolar hemorrhage to develop, there must also be mechanical damage to the alveolar epithelial lining. We believe the patient’s cannabis use could have contributed to this damage, through both the pulmonary injury and anticoagulation. Similar to tobacco, cannabis smoking has been linked to visual and histological evidence of airway inflammation, edema, and increased alveolar permeability (5). In addition to this, cannabis has been implicated in anticoagulant effects. It has been shown that cannabis sativa, tetrahydrocannabinol, and cannabinol cause inhibition of thrombin-driven clot formation in a rat model (6). It should be noted that there are many variables in cannabis’ effects on lung function that remain understudied: the effect of tetrahydrocannabinol content in each use, the route of administration (cigarette vs. water pipe vs. vaporizer), and the complicated relationship between acute and chronic use on bronchodilation and constriction. The authors postulate that sevoflurane was the causative agent in their case but were able to find only one other case report in support of this hypothesis. The patients described in both case reports engaged in recreational drug use. Diffuse alveolar hemorrhage has been shown to occur with crack cocaine as well. In conclusion, we suggest that instead of the highly unlikely event of sevoflurane-induced pulmonary hemorrhage, the cause is more likely to be related to negative pressure pulmonary edema that was rendered hemorrhagic by antecedent lung injury and coagulopathy attributable to recreational drug use. The increase in legalized cannabis use in the United States may present an opportunity to further investigate functional coagulation effects in the setting of cannabis use. It would also be interesting to see whether there is an increased incidence of possible negative pressure pulmonary edema with the newer formulations of cannabis compared with traditional, naturally grown cannabis. AnnalsATS Volume 11 Number 8 | October 2014
