Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid found naturally in apples, waxy berries, rosemary, oregano, and several other plants and herbs used in medicine and the diet.^1,2 It is known to have significant antioxidant, anti-inflammatory, and antiproliferative properties, and has also been associated with a wider range of biologic activities, including anticancer, antimicrobial, antitumor, antiwrinkle, anti-HIV, cytotoxic, and hepatoprotective.^3,4 In addition, ursolic acid is the focus of human clinical trials for potential uses in cancer and skin wrinkles.⁴ While this triterpenoid is known to suppress tumor formation and viability in various kinds of cancer, including skin cancer, several forms of cancer are resistant to ursolic acid.

RobinCraigPhoto/Thinkstock

Anti-inflammatory activity

In a 2013 study of the antibacterial and anti-inflammatory effects of Syzygium jambos on acne, Sharma et al. found that ursolic acid was one of the constituents of the leaf extracts that contributed to a significant suppression of the release of inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha.⁵

In 2010, Yang et al. identified ursolic acid as a key constituent of Acanthopanax koreanum fruit, a popular fruit in Jeju Island, South Korea, extracts of which they found to exhibit significant anti-inflammatory activity and suitability as a topical agent.⁶

Yasukawa et al. conducted an in vivo two-stage carcinogenesis test in mice in 2009 in which extracts of the branches of Hippophae rhamnoides displayed significant antitumor activity after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Ursolic acid and (-)-epigallocatechin were the constituents found to have the greatest inhibitory effects on TPA-induced inflammation.⁷

Anticancer activity

In 2015, Cho et al. reported on the inhibitory effects on skin tumor promotion from the topical application of ursolic acid, resveratrol, or the combination of the two prior to TPA treatment on mouse skin. The combination of the two botanical agents yielded the strongest suppression of TPA-induced epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion.¹¹

In another study that year buttressing the combination of the two botanical agents, Junco et al. demonstrated that chloroquine could be used to sensitize B16F10 metastatic mouse melanoma to the anticancer activities of ursolic acid and resveratrol. The investigators concluded that the combination of ursolic acid or resveratrol with chloroquine has potential for inclusion in melanoma treatment in humans.¹² Previously, Junco et al. observed that the anti–skin cancer effects of ursolic acid are augmented by P-glycoprotein inhibitors, and that ursolic acid and the stilbene resveratrol, a potent antioxidant, work synergistically, although not by blocking P-glycoprotein. The investigators suggested that ursolic acid along with resveratrol and/or P-glycoprotein inhibitors have potential as effective anti–skin cancer regimens.

In 2014, Lee et al. showed that ursolic acid can differentially modulate apoptosis in cutaneous melanoma and retinal pigment epithelial cells exposed to ultraviolet to visible broadband radiation, exhibiting the potential to protect normal cells while sensitizing melanoma cells to the effects of UV radiation.¹³ These findings supported earlier work by the team showing that pretreatment of human cells derived from a malignant skin melanoma markedly enhanced the sensitivity of melanoma cells to UV radiation, while providing some photoprotection to retinal pigment epithelium.

Also that year, Soica et al. demonstrated, using in vitro tests and in vivo skin cancer models, that the mixture of oleanolic and ursolic acids and in complex with cyclodextrin rendered a synergistic antitumor activity.¹⁴

A year earlier, Kowalczyk et al. showed that the combined action of phytochemicals – dietary calcium D-glucarate and topical ursolic acid and resveratrol – was effective in suppressing the initiation (with 7,12-dimethylbenz[a]anthracene [DMBA]) and promotion (with TPA) of skin tumorigenesis in SENCAR mice. Ursolic acid alone or in combination with calcium D-glucarate significantly diminished epidermal hyperplasia when applied during promotion. All of the antipromotion protocols led to significant decreases in cyclooxygenase-2 and interleukin (IL)-6 expression. The researchers concluded that ursolic acid strongly inhibits skin tumor promotion and inflammatory signaling, and warrants attention as a potential preventive agent against skin and other epithelial cancers.¹⁵ Kowalczyk et al. had previously found that ursolic acid and other phytochemicals displayed significant in vitro and in vivo antioxidant and antitumorigenic activity, inhibiting murine skin carcinogenesis by blunting tumor initiation and tumor promotion/progression.¹⁶

In 2006, beta-ursolic acid isolated from Salvia officinalis was found by Jedinák et al. to be effective in suppressing lung colonization of beta16 mouse melanoma cells in vivo.¹⁷

Huang et al. showed in 1994 that extracts of the leaves of Rosmarinus officinalis (rosemary) were effective in suppressing tumor initiation and promotion in a two-stage skin tumorigenesis mouse model. Topically applied ursolic acid isolated from the leaves was found to hinder TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. The number of tumors per mouse also declined significantly due to the topical application of ursolic acid concurrent with twice weekly application of the tumor-promoter TPA in DMBA-initiated mice.¹⁸

Antiaging and other activities

In 2015, Herndon et al. conducted an open-label clinical trial in 37 females (aged 35-60 years) to ascertain the effectiveness of an anti-aging moisturizer containing Astragalus membranaceus root extract, a peptide blend including palmitoyl tripeptide-38, standardized rosemary leaf extract (ursolic acid), tetrahexyldecyl ascorbate (THD ascorbate), and ubiquinone (coenzyme Q10). Subjects were instructed to apply the moisturizer once in the morning and once in the evening, and were assessed at baseline, and after 4, 8, and 12 weeks of twice daily application. Clinical evaluations after 8 weeks revealed a statistically significant improvement in all grading parameters (fine lines and wrinkles, clarity/brightness, visual roughness, tactile roughness, redness, hyperpigmentation, and overall appearance), with even more pronounced improvement at 12 weeks. The product was found to be mild and well tolerated, and digital photography reinforced clinical assessments and self-evaluations.¹⁹

Lee et al. reported in 2012 on in vitro results suggesting that ursolic acid was effective as an inhibitor of matrix metalloproteinase (MMP)-1 after UVB exposure and was more effective than retinoic acid.²⁰

Based on studies with hairless mice, Lim et al. found in 2007 that ursolic and oleanolic acids can enhance the recovery of skin barrier function and, via peroxisome proliferator-activated receptor-alpha, spur epidermal keratinocyte differentiation. They concluded that both acids have potential for use as agents to promote epidermal permeability barrier function.²¹

In 2003, Soo et al. observed that pretreatment with ursolic acid inhibited UVA-induced oxidative stress and activation and expression of MMP-2 in HaCaT human keratinocytes. They concluded that ursolic acid may merit attention for the prevention of UVA-induced photoaging.²²

Three years earlier, Yarosh et al. showed that liposomes containing ursolic acid augmented ceramide content in cultured normal human epidermal keratinocytes and collagen content in cultured normal human dermal fibroblasts. Over an 11-day period, clinical tests with the ursolic acid–containing liposome (Merotaine) revealed increases in the ceramide content in human skin.²³ Two years later, many of the same researchers duplicated their results. This new study also demonstrated that ursolic acid liposomes raise ceramide levels in normal human epidermal keratinocytes, in contrast to the effects of retinoic acid, earlier shown to reduce such levels. They concluded that ursolic acid liposomes show promise for use alone or in combination to replenish or maintain cutaneous ceramide and collagen levels.²⁴ Notably, ursolic acid is incorporated into topical oils and creams intended to confer rejuvenating effects to the skin.
 

Conclusion

Ursolic acid is a compelling ingredient. I especially will be interested in the results of ongoing human clinical trials of this triterpenoid for treating cancer and skin wrinkles. As it is, ursolic acid is known to exert significant inhibitory activity against tumor formation and tumor cell viability in the laboratory. Given its wide range of biologic activity, and some promising cutaneous results, there is reason to believe that ursolic acid has the potential to play an increasingly useful role in topical skin care agents and dermatologic practice.

References

1. J Dermatol. 2007 Sep;34(9):625-34.

2. Folia Histochem Cytobiol. 2011;49(4):664-9.

3. J Cosmet Dermatol. 2004 Jan;3(1):26-34.

4. J Enzyme Inhib Med Chem. 2011 Oct;26(5):616-42.

5. BMC Complement Altern Med. 2013 Oct 29;13:292.

6. J Biomed Biotechnol. 2010;2010:715739.

7. Fitoterapia. 2009 Apr;80(3):164-7.

8. Biosci Biotechnol Biochem. 2004 Jan;68(1):85-90.

9. J Ethnopharmacol. 2002 Oct;82(2-3):229-37.

10. Eur J Pharmacol. 1997 Sep 3;334(1):103-5.

11. Cancer Prev Res (Phila). 2015 Sep;8(9):817-25.

12. Melanoma Res. 2015 Apr;25(2):103-12.

13. Apoptosis. 2014 May;19(5):816-28.

14. Molecules. 2014 Apr 17;19(4):4924-40.

15. Int J Oncol. 2013 Sep;43(3):911-8.

16. Carcinogenesis. 2009 Jun;30(6):1008-15.

17. Z Naturforsch C. 2006 Nov-Dec;61(11-12):777-82.

18. Cancer Res. 1994 Feb 1;54(3):701-8.

19. J Drugs Dermatol. 2015 Jul;14(7):699-704.

20. Bioorg Khim. 2012 May-Jun;38(3):374-81.

21. J Dermatol. 2007;34(9):625-34.

22. Eur J Pharmacol. 2003 Aug 29;476(3):173-8.

23. Horm Res. 2000;54(5-6):318-21.

24. Arch Dermatol Res. 2002 Jan;293(11):569-75.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid found naturally in apples, waxy berries, rosemary, oregano, and several other plants and herbs used in medicine and the diet.^1,2 It is known to have significant antioxidant, anti-inflammatory, and antiproliferative properties, and has also been associated with a wider range of biologic activities, including anticancer, antimicrobial, antitumor, antiwrinkle, anti-HIV, cytotoxic, and hepatoprotective.^3,4 In addition, ursolic acid is the focus of human clinical trials for potential uses in cancer and skin wrinkles.⁴ While this triterpenoid is known to suppress tumor formation and viability in various kinds of cancer, including skin cancer, several forms of cancer are resistant to ursolic acid.

RobinCraigPhoto/Thinkstock

Anti-inflammatory activity

In a 2013 study of the antibacterial and anti-inflammatory effects of Syzygium jambos on acne, Sharma et al. found that ursolic acid was one of the constituents of the leaf extracts that contributed to a significant suppression of the release of inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha.⁵

In 2010, Yang et al. identified ursolic acid as a key constituent of Acanthopanax koreanum fruit, a popular fruit in Jeju Island, South Korea, extracts of which they found to exhibit significant anti-inflammatory activity and suitability as a topical agent.⁶

Yasukawa et al. conducted an in vivo two-stage carcinogenesis test in mice in 2009 in which extracts of the branches of Hippophae rhamnoides displayed significant antitumor activity after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Ursolic acid and (-)-epigallocatechin were the constituents found to have the greatest inhibitory effects on TPA-induced inflammation.⁷

Anticancer activity

In 2015, Cho et al. reported on the inhibitory effects on skin tumor promotion from the topical application of ursolic acid, resveratrol, or the combination of the two prior to TPA treatment on mouse skin. The combination of the two botanical agents yielded the strongest suppression of TPA-induced epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion.¹¹

In another study that year buttressing the combination of the two botanical agents, Junco et al. demonstrated that chloroquine could be used to sensitize B16F10 metastatic mouse melanoma to the anticancer activities of ursolic acid and resveratrol. The investigators concluded that the combination of ursolic acid or resveratrol with chloroquine has potential for inclusion in melanoma treatment in humans.¹² Previously, Junco et al. observed that the anti–skin cancer effects of ursolic acid are augmented by P-glycoprotein inhibitors, and that ursolic acid and the stilbene resveratrol, a potent antioxidant, work synergistically, although not by blocking P-glycoprotein. The investigators suggested that ursolic acid along with resveratrol and/or P-glycoprotein inhibitors have potential as effective anti–skin cancer regimens.

In 2014, Lee et al. showed that ursolic acid can differentially modulate apoptosis in cutaneous melanoma and retinal pigment epithelial cells exposed to ultraviolet to visible broadband radiation, exhibiting the potential to protect normal cells while sensitizing melanoma cells to the effects of UV radiation.¹³ These findings supported earlier work by the team showing that pretreatment of human cells derived from a malignant skin melanoma markedly enhanced the sensitivity of melanoma cells to UV radiation, while providing some photoprotection to retinal pigment epithelium.

Also that year, Soica et al. demonstrated, using in vitro tests and in vivo skin cancer models, that the mixture of oleanolic and ursolic acids and in complex with cyclodextrin rendered a synergistic antitumor activity.¹⁴

A year earlier, Kowalczyk et al. showed that the combined action of phytochemicals – dietary calcium D-glucarate and topical ursolic acid and resveratrol – was effective in suppressing the initiation (with 7,12-dimethylbenz[a]anthracene [DMBA]) and promotion (with TPA) of skin tumorigenesis in SENCAR mice. Ursolic acid alone or in combination with calcium D-glucarate significantly diminished epidermal hyperplasia when applied during promotion. All of the antipromotion protocols led to significant decreases in cyclooxygenase-2 and interleukin (IL)-6 expression. The researchers concluded that ursolic acid strongly inhibits skin tumor promotion and inflammatory signaling, and warrants attention as a potential preventive agent against skin and other epithelial cancers.¹⁵ Kowalczyk et al. had previously found that ursolic acid and other phytochemicals displayed significant in vitro and in vivo antioxidant and antitumorigenic activity, inhibiting murine skin carcinogenesis by blunting tumor initiation and tumor promotion/progression.¹⁶

In 2006, beta-ursolic acid isolated from Salvia officinalis was found by Jedinák et al. to be effective in suppressing lung colonization of beta16 mouse melanoma cells in vivo.¹⁷

Huang et al. showed in 1994 that extracts of the leaves of Rosmarinus officinalis (rosemary) were effective in suppressing tumor initiation and promotion in a two-stage skin tumorigenesis mouse model. Topically applied ursolic acid isolated from the leaves was found to hinder TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. The number of tumors per mouse also declined significantly due to the topical application of ursolic acid concurrent with twice weekly application of the tumor-promoter TPA in DMBA-initiated mice.¹⁸

Antiaging and other activities

In 2015, Herndon et al. conducted an open-label clinical trial in 37 females (aged 35-60 years) to ascertain the effectiveness of an anti-aging moisturizer containing Astragalus membranaceus root extract, a peptide blend including palmitoyl tripeptide-38, standardized rosemary leaf extract (ursolic acid), tetrahexyldecyl ascorbate (THD ascorbate), and ubiquinone (coenzyme Q10). Subjects were instructed to apply the moisturizer once in the morning and once in the evening, and were assessed at baseline, and after 4, 8, and 12 weeks of twice daily application. Clinical evaluations after 8 weeks revealed a statistically significant improvement in all grading parameters (fine lines and wrinkles, clarity/brightness, visual roughness, tactile roughness, redness, hyperpigmentation, and overall appearance), with even more pronounced improvement at 12 weeks. The product was found to be mild and well tolerated, and digital photography reinforced clinical assessments and self-evaluations.¹⁹

Lee et al. reported in 2012 on in vitro results suggesting that ursolic acid was effective as an inhibitor of matrix metalloproteinase (MMP)-1 after UVB exposure and was more effective than retinoic acid.²⁰

Based on studies with hairless mice, Lim et al. found in 2007 that ursolic and oleanolic acids can enhance the recovery of skin barrier function and, via peroxisome proliferator-activated receptor-alpha, spur epidermal keratinocyte differentiation. They concluded that both acids have potential for use as agents to promote epidermal permeability barrier function.²¹

In 2003, Soo et al. observed that pretreatment with ursolic acid inhibited UVA-induced oxidative stress and activation and expression of MMP-2 in HaCaT human keratinocytes. They concluded that ursolic acid may merit attention for the prevention of UVA-induced photoaging.²²

Three years earlier, Yarosh et al. showed that liposomes containing ursolic acid augmented ceramide content in cultured normal human epidermal keratinocytes and collagen content in cultured normal human dermal fibroblasts. Over an 11-day period, clinical tests with the ursolic acid–containing liposome (Merotaine) revealed increases in the ceramide content in human skin.²³ Two years later, many of the same researchers duplicated their results. This new study also demonstrated that ursolic acid liposomes raise ceramide levels in normal human epidermal keratinocytes, in contrast to the effects of retinoic acid, earlier shown to reduce such levels. They concluded that ursolic acid liposomes show promise for use alone or in combination to replenish or maintain cutaneous ceramide and collagen levels.²⁴ Notably, ursolic acid is incorporated into topical oils and creams intended to confer rejuvenating effects to the skin.
 

Conclusion

Ursolic acid is a compelling ingredient. I especially will be interested in the results of ongoing human clinical trials of this triterpenoid for treating cancer and skin wrinkles. As it is, ursolic acid is known to exert significant inhibitory activity against tumor formation and tumor cell viability in the laboratory. Given its wide range of biologic activity, and some promising cutaneous results, there is reason to believe that ursolic acid has the potential to play an increasingly useful role in topical skin care agents and dermatologic practice.

References

1. J Dermatol. 2007 Sep;34(9):625-34.

2. Folia Histochem Cytobiol. 2011;49(4):664-9.

3. J Cosmet Dermatol. 2004 Jan;3(1):26-34.

4. J Enzyme Inhib Med Chem. 2011 Oct;26(5):616-42.

5. BMC Complement Altern Med. 2013 Oct 29;13:292.

6. J Biomed Biotechnol. 2010;2010:715739.

7. Fitoterapia. 2009 Apr;80(3):164-7.

8. Biosci Biotechnol Biochem. 2004 Jan;68(1):85-90.

9. J Ethnopharmacol. 2002 Oct;82(2-3):229-37.

10. Eur J Pharmacol. 1997 Sep 3;334(1):103-5.

11. Cancer Prev Res (Phila). 2015 Sep;8(9):817-25.

12. Melanoma Res. 2015 Apr;25(2):103-12.

13. Apoptosis. 2014 May;19(5):816-28.

14. Molecules. 2014 Apr 17;19(4):4924-40.

15. Int J Oncol. 2013 Sep;43(3):911-8.

16. Carcinogenesis. 2009 Jun;30(6):1008-15.

17. Z Naturforsch C. 2006 Nov-Dec;61(11-12):777-82.

18. Cancer Res. 1994 Feb 1;54(3):701-8.

19. J Drugs Dermatol. 2015 Jul;14(7):699-704.

20. Bioorg Khim. 2012 May-Jun;38(3):374-81.

21. J Dermatol. 2007;34(9):625-34.

22. Eur J Pharmacol. 2003 Aug 29;476(3):173-8.

23. Horm Res. 2000;54(5-6):318-21.

24. Arch Dermatol Res. 2002 Jan;293(11):569-75.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid found naturally in apples, waxy berries, rosemary, oregano, and several other plants and herbs used in medicine and the diet.^1,2 It is known to have significant antioxidant, anti-inflammatory, and antiproliferative properties, and has also been associated with a wider range of biologic activities, including anticancer, antimicrobial, antitumor, antiwrinkle, anti-HIV, cytotoxic, and hepatoprotective.^3,4 In addition, ursolic acid is the focus of human clinical trials for potential uses in cancer and skin wrinkles.⁴ While this triterpenoid is known to suppress tumor formation and viability in various kinds of cancer, including skin cancer, several forms of cancer are resistant to ursolic acid.

RobinCraigPhoto/Thinkstock

Anti-inflammatory activity

In a 2013 study of the antibacterial and anti-inflammatory effects of Syzygium jambos on acne, Sharma et al. found that ursolic acid was one of the constituents of the leaf extracts that contributed to a significant suppression of the release of inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha.⁵

In 2010, Yang et al. identified ursolic acid as a key constituent of Acanthopanax koreanum fruit, a popular fruit in Jeju Island, South Korea, extracts of which they found to exhibit significant anti-inflammatory activity and suitability as a topical agent.⁶

Yasukawa et al. conducted an in vivo two-stage carcinogenesis test in mice in 2009 in which extracts of the branches of Hippophae rhamnoides displayed significant antitumor activity after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Ursolic acid and (-)-epigallocatechin were the constituents found to have the greatest inhibitory effects on TPA-induced inflammation.⁷

Anticancer activity

In 2015, Cho et al. reported on the inhibitory effects on skin tumor promotion from the topical application of ursolic acid, resveratrol, or the combination of the two prior to TPA treatment on mouse skin. The combination of the two botanical agents yielded the strongest suppression of TPA-induced epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion.¹¹

In another study that year buttressing the combination of the two botanical agents, Junco et al. demonstrated that chloroquine could be used to sensitize B16F10 metastatic mouse melanoma to the anticancer activities of ursolic acid and resveratrol. The investigators concluded that the combination of ursolic acid or resveratrol with chloroquine has potential for inclusion in melanoma treatment in humans.¹² Previously, Junco et al. observed that the anti–skin cancer effects of ursolic acid are augmented by P-glycoprotein inhibitors, and that ursolic acid and the stilbene resveratrol, a potent antioxidant, work synergistically, although not by blocking P-glycoprotein. The investigators suggested that ursolic acid along with resveratrol and/or P-glycoprotein inhibitors have potential as effective anti–skin cancer regimens.

In 2014, Lee et al. showed that ursolic acid can differentially modulate apoptosis in cutaneous melanoma and retinal pigment epithelial cells exposed to ultraviolet to visible broadband radiation, exhibiting the potential to protect normal cells while sensitizing melanoma cells to the effects of UV radiation.¹³ These findings supported earlier work by the team showing that pretreatment of human cells derived from a malignant skin melanoma markedly enhanced the sensitivity of melanoma cells to UV radiation, while providing some photoprotection to retinal pigment epithelium.

Also that year, Soica et al. demonstrated, using in vitro tests and in vivo skin cancer models, that the mixture of oleanolic and ursolic acids and in complex with cyclodextrin rendered a synergistic antitumor activity.¹⁴

A year earlier, Kowalczyk et al. showed that the combined action of phytochemicals – dietary calcium D-glucarate and topical ursolic acid and resveratrol – was effective in suppressing the initiation (with 7,12-dimethylbenz[a]anthracene [DMBA]) and promotion (with TPA) of skin tumorigenesis in SENCAR mice. Ursolic acid alone or in combination with calcium D-glucarate significantly diminished epidermal hyperplasia when applied during promotion. All of the antipromotion protocols led to significant decreases in cyclooxygenase-2 and interleukin (IL)-6 expression. The researchers concluded that ursolic acid strongly inhibits skin tumor promotion and inflammatory signaling, and warrants attention as a potential preventive agent against skin and other epithelial cancers.¹⁵ Kowalczyk et al. had previously found that ursolic acid and other phytochemicals displayed significant in vitro and in vivo antioxidant and antitumorigenic activity, inhibiting murine skin carcinogenesis by blunting tumor initiation and tumor promotion/progression.¹⁶

In 2006, beta-ursolic acid isolated from Salvia officinalis was found by Jedinák et al. to be effective in suppressing lung colonization of beta16 mouse melanoma cells in vivo.¹⁷

Huang et al. showed in 1994 that extracts of the leaves of Rosmarinus officinalis (rosemary) were effective in suppressing tumor initiation and promotion in a two-stage skin tumorigenesis mouse model. Topically applied ursolic acid isolated from the leaves was found to hinder TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. The number of tumors per mouse also declined significantly due to the topical application of ursolic acid concurrent with twice weekly application of the tumor-promoter TPA in DMBA-initiated mice.¹⁸

Antiaging and other activities

In 2015, Herndon et al. conducted an open-label clinical trial in 37 females (aged 35-60 years) to ascertain the effectiveness of an anti-aging moisturizer containing Astragalus membranaceus root extract, a peptide blend including palmitoyl tripeptide-38, standardized rosemary leaf extract (ursolic acid), tetrahexyldecyl ascorbate (THD ascorbate), and ubiquinone (coenzyme Q10). Subjects were instructed to apply the moisturizer once in the morning and once in the evening, and were assessed at baseline, and after 4, 8, and 12 weeks of twice daily application. Clinical evaluations after 8 weeks revealed a statistically significant improvement in all grading parameters (fine lines and wrinkles, clarity/brightness, visual roughness, tactile roughness, redness, hyperpigmentation, and overall appearance), with even more pronounced improvement at 12 weeks. The product was found to be mild and well tolerated, and digital photography reinforced clinical assessments and self-evaluations.¹⁹

Lee et al. reported in 2012 on in vitro results suggesting that ursolic acid was effective as an inhibitor of matrix metalloproteinase (MMP)-1 after UVB exposure and was more effective than retinoic acid.²⁰

Based on studies with hairless mice, Lim et al. found in 2007 that ursolic and oleanolic acids can enhance the recovery of skin barrier function and, via peroxisome proliferator-activated receptor-alpha, spur epidermal keratinocyte differentiation. They concluded that both acids have potential for use as agents to promote epidermal permeability barrier function.²¹

In 2003, Soo et al. observed that pretreatment with ursolic acid inhibited UVA-induced oxidative stress and activation and expression of MMP-2 in HaCaT human keratinocytes. They concluded that ursolic acid may merit attention for the prevention of UVA-induced photoaging.²²

Three years earlier, Yarosh et al. showed that liposomes containing ursolic acid augmented ceramide content in cultured normal human epidermal keratinocytes and collagen content in cultured normal human dermal fibroblasts. Over an 11-day period, clinical tests with the ursolic acid–containing liposome (Merotaine) revealed increases in the ceramide content in human skin.²³ Two years later, many of the same researchers duplicated their results. This new study also demonstrated that ursolic acid liposomes raise ceramide levels in normal human epidermal keratinocytes, in contrast to the effects of retinoic acid, earlier shown to reduce such levels. They concluded that ursolic acid liposomes show promise for use alone or in combination to replenish or maintain cutaneous ceramide and collagen levels.²⁴ Notably, ursolic acid is incorporated into topical oils and creams intended to confer rejuvenating effects to the skin.
 

Conclusion

Ursolic acid is a compelling ingredient. I especially will be interested in the results of ongoing human clinical trials of this triterpenoid for treating cancer and skin wrinkles. As it is, ursolic acid is known to exert significant inhibitory activity against tumor formation and tumor cell viability in the laboratory. Given its wide range of biologic activity, and some promising cutaneous results, there is reason to believe that ursolic acid has the potential to play an increasingly useful role in topical skin care agents and dermatologic practice.

References

1. J Dermatol. 2007 Sep;34(9):625-34.

2. Folia Histochem Cytobiol. 2011;49(4):664-9.

3. J Cosmet Dermatol. 2004 Jan;3(1):26-34.

4. J Enzyme Inhib Med Chem. 2011 Oct;26(5):616-42.

5. BMC Complement Altern Med. 2013 Oct 29;13:292.

6. J Biomed Biotechnol. 2010;2010:715739.

7. Fitoterapia. 2009 Apr;80(3):164-7.

8. Biosci Biotechnol Biochem. 2004 Jan;68(1):85-90.

9. J Ethnopharmacol. 2002 Oct;82(2-3):229-37.

10. Eur J Pharmacol. 1997 Sep 3;334(1):103-5.

11. Cancer Prev Res (Phila). 2015 Sep;8(9):817-25.

12. Melanoma Res. 2015 Apr;25(2):103-12.

13. Apoptosis. 2014 May;19(5):816-28.

14. Molecules. 2014 Apr 17;19(4):4924-40.

15. Int J Oncol. 2013 Sep;43(3):911-8.

16. Carcinogenesis. 2009 Jun;30(6):1008-15.

17. Z Naturforsch C. 2006 Nov-Dec;61(11-12):777-82.

18. Cancer Res. 1994 Feb 1;54(3):701-8.

19. J Drugs Dermatol. 2015 Jul;14(7):699-704.

20. Bioorg Khim. 2012 May-Jun;38(3):374-81.

21. J Dermatol. 2007;34(9):625-34.

22. Eur J Pharmacol. 2003 Aug 29;476(3):173-8.

23. Horm Res. 2000;54(5-6):318-21.

24. Arch Dermatol Res. 2002 Jan;293(11):569-75.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

People with cystic fibrosis (CF) survive an average of 10 years longer if they live in Canada than if they live in the United States, according to a report published online March 14 in Annals of Internal Medicine.

Differences between the two nations’ health care systems, including access to insurance, “may, in part, explain the Canadian survival advantage,” said Anne L. Stephenson, MD, PhD, of St. Michael’s Hospital, Toronto, and her associates.

People with cystic fibrosis (CF) survive an average of 10 years longer if they live in Canada than if they live in the United States, according to a report published online March 14 in Annals of Internal Medicine.

Differences between the two nations’ health care systems, including access to insurance, “may, in part, explain the Canadian survival advantage,” said Anne L. Stephenson, MD, PhD, of St. Michael’s Hospital, Toronto, and her associates.

People with cystic fibrosis (CF) survive an average of 10 years longer if they live in Canada than if they live in the United States, according to a report published online March 14 in Annals of Internal Medicine.

Differences between the two nations’ health care systems, including access to insurance, “may, in part, explain the Canadian survival advantage,” said Anne L. Stephenson, MD, PhD, of St. Michael’s Hospital, Toronto, and her associates.

Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.¹ Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.² Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.³ A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.⁴

The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.⁵ Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.⁶

Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.⁶

The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.⁷ A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.⁶ Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.⁷

In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.⁸ In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.

Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.⁶ A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.⁹

Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.¹⁰ Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.¹⁰ Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.

Methods

The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.

All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.

Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.

The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹

In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²

Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).

Patient Descriptions

Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.

Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.

On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).

Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV₁); forced vital capacity (FVC), FEV₁/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV₁ ratio—available in 60 of 98 PFTs.

Interventions

All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.

Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.

Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.

Results

Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.

The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.

PFT Data

Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV₁ of 3.6, a median FVC of 4.5, with ratio of 0.80.

Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV₁, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.

Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.

Discussion

This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.¹ The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.

The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.

Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.

Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.

Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.

The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV₁, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.

Limitations

Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.⁸

This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.

Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.

It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.

Conclusion

Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.

Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.¹ Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.² Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.³ A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.⁴

The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.⁵ Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.⁶

Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.⁶

The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.⁷ A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.⁶ Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.⁷

In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.⁸ In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.

Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.⁶ A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.⁹

Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.¹⁰ Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.¹⁰ Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.

Methods

The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.

All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.

Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.

The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹

In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²

Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).

Patient Descriptions

Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.

Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.

On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).

Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV₁); forced vital capacity (FVC), FEV₁/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV₁ ratio—available in 60 of 98 PFTs.

Interventions

All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.

Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.

Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.

Results

Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.

The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.

PFT Data

Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV₁ of 3.6, a median FVC of 4.5, with ratio of 0.80.

Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV₁, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.

Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.

Discussion

This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.¹ The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.

The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.

Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.

Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.

Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.

The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV₁, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.

Limitations

Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.⁸

This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.

Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.

It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.

Conclusion

Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.

Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.¹ Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.² Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.³ A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.⁴

The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.⁵ Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.⁶

Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.⁶

The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.⁷ A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.⁶ Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.⁷

In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.⁸ In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.

Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.⁶ A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.⁹

Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.¹⁰ Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.¹⁰ Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.

Methods

The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.

All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.

Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.

The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹

In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²

Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).

Patient Descriptions

Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.

Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.

On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).

Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV₁); forced vital capacity (FVC), FEV₁/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV₁ ratio—available in 60 of 98 PFTs.

Interventions

All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.

Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.

Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.

Results

Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.

The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.

PFT Data

Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV₁ of 3.6, a median FVC of 4.5, with ratio of 0.80.

Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV₁, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.

Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.

Discussion

This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.¹ The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.

The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.

Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.

Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.

Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.

The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV₁, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.

Limitations

Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.⁸

This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.

Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.

It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.

Conclusion

Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).

Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.

While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.

However, no new patients may be enrolled in selinexor trials until the hold is lifted.

The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.

As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold.  By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.

Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.

About selinexor

Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.

One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.

The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.

STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.

Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.

Additional phase 1, 2, and 3 studies are ongoing or currently planned. 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).

Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.

While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.

However, no new patients may be enrolled in selinexor trials until the hold is lifted.

The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.

As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold.  By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.

Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.

About selinexor

Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.

One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.

The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.

STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.

Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.

Additional phase 1, 2, and 3 studies are ongoing or currently planned. 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).

Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.

While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.

However, no new patients may be enrolled in selinexor trials until the hold is lifted.

The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.

As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold.  By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.

Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.

About selinexor

Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.

One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.

The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.

STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.

Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.

Additional phase 1, 2, and 3 studies are ongoing or currently planned. 

Image by Spencer Phillips

Black individuals with sickle cell trait (SCT) have an increased risk of developing end-stage renal disease (ESRD), according to new research.

The study indicates that having SCT actually doubles the risk of ESRD.

And the trait confers a similar degree of risk as APOL1 gene variants, which are currently the most widely recognized genetic contributors to kidney disease in blacks.

Researchers believe this finding may have important public policy implications for genetic counseling for individuals with SCT.

Rakhi P. Naik, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and her colleagues reported this finding in the Journal of the American Society of Nephrology.

Previous research suggested there is an association between SCT and chronic kidney disease, but it hasn’t been clear if that extends to ESRD. Studies have also suggested a possible association between kidney disease and hemoglobin C trait, but the link has not been confirmed.

So Dr Naik and her colleagues decided to investigate these potential links. To do so, the researchers analyzed data from a large, population-based study, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.

The team evaluated information on 9909 black individuals, 739 of whom had SCT and 243 of whom had hemoglobin C trait.

The data indicate that individuals with SCT have a 2-fold higher risk of developing ESRD when compared to those without SCT. But there is no association between hemoglobin C trait and ESRD.

At a median follow-up of 6.5 years, the incidence of ESRD was 5.4% (40/739) in participants with SCT, 2.5% (6/243) in subjects with hemoglobin C trait, and 2.6% (234/8927) in individuals without either trait.

The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT, 3.9 per 1000 person-years for subjects with hemoglobin C trait, and 4.0 per 1000 person-years for individuals without either trait.

The researchers noted that SCT conferred a similar degree of ESRD risk as APOL1 gene variants. The hazard ratio for subjects with SCT was 2.03, and the hazard ratio for those with APOL1 high-risk genotypes was 1.77.

“Although you cannot change the genes you are born with, doctors can use this information to start screening for kidney disease earlier and to aggressively treat any other risk factors you may have, such as diabetes or high blood pressure,” Dr Naik said.

“We still need more studies to determine if there are other treatments that can be used to slow the progression of kidney disease, specifically in individuals with sickle cell trait.”

Image by Spencer Phillips

Black individuals with sickle cell trait (SCT) have an increased risk of developing end-stage renal disease (ESRD), according to new research.

The study indicates that having SCT actually doubles the risk of ESRD.

And the trait confers a similar degree of risk as APOL1 gene variants, which are currently the most widely recognized genetic contributors to kidney disease in blacks.

Researchers believe this finding may have important public policy implications for genetic counseling for individuals with SCT.

Rakhi P. Naik, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and her colleagues reported this finding in the Journal of the American Society of Nephrology.

Previous research suggested there is an association between SCT and chronic kidney disease, but it hasn’t been clear if that extends to ESRD. Studies have also suggested a possible association between kidney disease and hemoglobin C trait, but the link has not been confirmed.

So Dr Naik and her colleagues decided to investigate these potential links. To do so, the researchers analyzed data from a large, population-based study, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.

The team evaluated information on 9909 black individuals, 739 of whom had SCT and 243 of whom had hemoglobin C trait.

The data indicate that individuals with SCT have a 2-fold higher risk of developing ESRD when compared to those without SCT. But there is no association between hemoglobin C trait and ESRD.

At a median follow-up of 6.5 years, the incidence of ESRD was 5.4% (40/739) in participants with SCT, 2.5% (6/243) in subjects with hemoglobin C trait, and 2.6% (234/8927) in individuals without either trait.

The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT, 3.9 per 1000 person-years for subjects with hemoglobin C trait, and 4.0 per 1000 person-years for individuals without either trait.

The researchers noted that SCT conferred a similar degree of ESRD risk as APOL1 gene variants. The hazard ratio for subjects with SCT was 2.03, and the hazard ratio for those with APOL1 high-risk genotypes was 1.77.

“Although you cannot change the genes you are born with, doctors can use this information to start screening for kidney disease earlier and to aggressively treat any other risk factors you may have, such as diabetes or high blood pressure,” Dr Naik said.

“We still need more studies to determine if there are other treatments that can be used to slow the progression of kidney disease, specifically in individuals with sickle cell trait.”

Image by Spencer Phillips

Black individuals with sickle cell trait (SCT) have an increased risk of developing end-stage renal disease (ESRD), according to new research.

The study indicates that having SCT actually doubles the risk of ESRD.

And the trait confers a similar degree of risk as APOL1 gene variants, which are currently the most widely recognized genetic contributors to kidney disease in blacks.

Researchers believe this finding may have important public policy implications for genetic counseling for individuals with SCT.

Rakhi P. Naik, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and her colleagues reported this finding in the Journal of the American Society of Nephrology.

Previous research suggested there is an association between SCT and chronic kidney disease, but it hasn’t been clear if that extends to ESRD. Studies have also suggested a possible association between kidney disease and hemoglobin C trait, but the link has not been confirmed.

So Dr Naik and her colleagues decided to investigate these potential links. To do so, the researchers analyzed data from a large, population-based study, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.

The team evaluated information on 9909 black individuals, 739 of whom had SCT and 243 of whom had hemoglobin C trait.

The data indicate that individuals with SCT have a 2-fold higher risk of developing ESRD when compared to those without SCT. But there is no association between hemoglobin C trait and ESRD.

At a median follow-up of 6.5 years, the incidence of ESRD was 5.4% (40/739) in participants with SCT, 2.5% (6/243) in subjects with hemoglobin C trait, and 2.6% (234/8927) in individuals without either trait.

The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT, 3.9 per 1000 person-years for subjects with hemoglobin C trait, and 4.0 per 1000 person-years for individuals without either trait.

The researchers noted that SCT conferred a similar degree of ESRD risk as APOL1 gene variants. The hazard ratio for subjects with SCT was 2.03, and the hazard ratio for those with APOL1 high-risk genotypes was 1.77.

“Although you cannot change the genes you are born with, doctors can use this information to start screening for kidney disease earlier and to aggressively treat any other risk factors you may have, such as diabetes or high blood pressure,” Dr Naik said.

“We still need more studies to determine if there are other treatments that can be used to slow the progression of kidney disease, specifically in individuals with sickle cell trait.”

MRI scan

The European Medicines Agency’s (EMA) Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended suspending marketing authorizations for 4 linear gadolinium contrast agents because of evidence that small amounts of the gadolinium they contain are deposited in the brain.

The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide, which are given to patients to enhance images from magnetic resonance imaging (MRI) body scans.

The PRAC’s review of gadolinium agents found “convincing evidence” of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal intensity seen on MRI scan images many months after the last injection of a gadolinium contrast agent.

Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC took a precautionary approach, noting that data on the long-term effects in the brain are limited.

Companies concerned by this review have the right to request that the PRAC re-examine its recommendations.

The PRAC’s recommendations will be sent to the Committee for Medicinal Products for Human Use (CHMP) for its opinion. Further details will be published at the time of the CHMP opinion.

The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all European Union member states.

Details of the review, recommendations

The PRAC’s review was initiated on March 17, 2016, at the request of the European Commission, under Article 31 of Directive 2001/83/EC.

The review covers agents containing the following active substances: gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid, gadoteric acid, gadoteridol, gadoversetamide, and gadoxetic acid.

The 4 agents recommended for suspension (gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide) are linear agents. They have a structure more likely to release gadolinium, which can build up in body tissues.

Other agents, known as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium.

The PRAC recommends that macrocyclic agents (gadobutrol, gadoteric acid, and gadoteridol) be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable.

The PRAC has recommended that some linear agents remain available. The committee said that gadoxetic acid, a linear agent used at a low dose for liver scans, can remain on the market as it meets an important diagnostic need in patients with few alternatives.

In addition, a formulation of gadopentetic acid injected directly into joints should remain available because its gadolinium concentration is very low—around 200 times lower than those of intravenous products.

Both agents should be used at the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable.

For those marketing authorizations recommended for suspension, the suspensions can be lifted if the respective companies provide evidence of new benefits in an identified patient group that outweigh its risks or show that their product (modified or not) does not release gadolinium significantly or lead to its retention in tissues.

MRI scan

The European Medicines Agency’s (EMA) Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended suspending marketing authorizations for 4 linear gadolinium contrast agents because of evidence that small amounts of the gadolinium they contain are deposited in the brain.

The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide, which are given to patients to enhance images from magnetic resonance imaging (MRI) body scans.

The PRAC’s review of gadolinium agents found “convincing evidence” of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal intensity seen on MRI scan images many months after the last injection of a gadolinium contrast agent.

Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC took a precautionary approach, noting that data on the long-term effects in the brain are limited.

Companies concerned by this review have the right to request that the PRAC re-examine its recommendations.

The PRAC’s recommendations will be sent to the Committee for Medicinal Products for Human Use (CHMP) for its opinion. Further details will be published at the time of the CHMP opinion.

The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all European Union member states.

Details of the review, recommendations

The PRAC’s review was initiated on March 17, 2016, at the request of the European Commission, under Article 31 of Directive 2001/83/EC.

The review covers agents containing the following active substances: gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid, gadoteric acid, gadoteridol, gadoversetamide, and gadoxetic acid.

The 4 agents recommended for suspension (gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide) are linear agents. They have a structure more likely to release gadolinium, which can build up in body tissues.

Other agents, known as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium.

The PRAC recommends that macrocyclic agents (gadobutrol, gadoteric acid, and gadoteridol) be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable.

The PRAC has recommended that some linear agents remain available. The committee said that gadoxetic acid, a linear agent used at a low dose for liver scans, can remain on the market as it meets an important diagnostic need in patients with few alternatives.

In addition, a formulation of gadopentetic acid injected directly into joints should remain available because its gadolinium concentration is very low—around 200 times lower than those of intravenous products.

Both agents should be used at the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable.

For those marketing authorizations recommended for suspension, the suspensions can be lifted if the respective companies provide evidence of new benefits in an identified patient group that outweigh its risks or show that their product (modified or not) does not release gadolinium significantly or lead to its retention in tissues.

MRI scan

The European Medicines Agency’s (EMA) Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended suspending marketing authorizations for 4 linear gadolinium contrast agents because of evidence that small amounts of the gadolinium they contain are deposited in the brain.

The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide, which are given to patients to enhance images from magnetic resonance imaging (MRI) body scans.

The PRAC’s review of gadolinium agents found “convincing evidence” of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal intensity seen on MRI scan images many months after the last injection of a gadolinium contrast agent.

Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC took a precautionary approach, noting that data on the long-term effects in the brain are limited.

Companies concerned by this review have the right to request that the PRAC re-examine its recommendations.

The PRAC’s recommendations will be sent to the Committee for Medicinal Products for Human Use (CHMP) for its opinion. Further details will be published at the time of the CHMP opinion.

The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all European Union member states.

Details of the review, recommendations

The PRAC’s review was initiated on March 17, 2016, at the request of the European Commission, under Article 31 of Directive 2001/83/EC.

The review covers agents containing the following active substances: gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid, gadoteric acid, gadoteridol, gadoversetamide, and gadoxetic acid.

The 4 agents recommended for suspension (gadobenic acid, gadodiamide, gadopentetic acid, and gadoversetamide) are linear agents. They have a structure more likely to release gadolinium, which can build up in body tissues.

Other agents, known as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium.

The PRAC recommends that macrocyclic agents (gadobutrol, gadoteric acid, and gadoteridol) be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable.

The PRAC has recommended that some linear agents remain available. The committee said that gadoxetic acid, a linear agent used at a low dose for liver scans, can remain on the market as it meets an important diagnostic need in patients with few alternatives.

In addition, a formulation of gadopentetic acid injected directly into joints should remain available because its gadolinium concentration is very low—around 200 times lower than those of intravenous products.

Both agents should be used at the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable.

For those marketing authorizations recommended for suspension, the suspensions can be lifted if the respective companies provide evidence of new benefits in an identified patient group that outweigh its risks or show that their product (modified or not) does not release gadolinium significantly or lead to its retention in tissues.

Q) What is the role of vitamin D in multiple sclerosis? Is it beneficial?

The exact etiology and pathophysiology of multiple sclerosis (MS) is still not fully understood. Research strongly suggests that there are two major causative factors: one genetic, and the other, environmental. From an environmental standpoint, multiple studies have shown that living farther from the equator, not being exposed to sunlight, and having a low vitamin D level are all correlated with increased risk for MS and MS relapse.¹

Our bodies need sunlight to successfully synthesize vitamin D in the skin. Research has found that individuals with lightly pigmented skin are five times more efficient at synthesizing vitamin D in the presence of sunlight than those with darker skin.² However, the ability to absorb sunlight is also correlated with the earth’s latitude; worse absorption occurs in areas beyond the 40th parallel (in either hemisphere), where UVB levels are too low to synthesize vitamin D four to six months out of the year.²

When exposed to UVB rays, our bodies start to synthesize vitamin D; it undergoes a transformation in the liver and then the kidneys and ultimately becomes the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol).² Calcitriol is recognized by multiple tissues throughout the body that contain vitamin D receptors. Specifically, in the central nervous system, receptors are located on microglia, activated monocytes, and B and T lymphocytes.¹ In MS, myelin (the coating around the nerves) is destroyed by an immune-mediated inflammatory process involving the microglia and B and T lymphocytes. Vitamin D quiets down this inflammation, thereby reducing disability accumulation and relapse risk and resulting in fewer changes on MRI.

Vitamin D is also believed to shift the immune response to an anti-inflammatory state by focusing the response on the cytotoxic T cells often found in MS lesions, which attack neurons and oligodendrocytes.² This theory was tested by Munger and colleagues, who used a pooled cohort of 187,000 women from the Nurses’ Health Study and Nurses’ Health Study II to assess vitamin D intake and risk for MS. Compared to women with lower vitamin D intake, those who took 700 IU/d had a 41% lower incidence of MS. Women who took ≥ 400 IU/d had a 33% lower risk for MS, compared to nonusers.³ In another evaluation of 7 million US military personnel, individuals with a serum vitamin D level of 40 ng/mL were 62% less likely to develop MS.⁴

In light of the anti-inflammatory effects of vitamin D and its purported reduction of MS risk, it is possible that patients with MS should begin vitamin D supplementation early to obtain maximum anti-inflammatory effects. While an optimal vitamin D goal has not been established in the literature, some studies suggest 30 to 55 ng/mL as a target range for serum vitamin D level.¹

While vitamin D has been found to be well-tolerated, patients should be cautioned that very high doses can cause fatigue, abdominal cramps, nausea, vomiting, kidney damage, hypertension, hypercalcemia, and other toxic effects.¹ Additional research is needed to determine the exact dosage MS patients need to gain the optimal anti-inflammatory benefits. What we do know is that the Institute of Medicine’s current guidelines recommend a daily allowance of 600 IU/d of vitamin D for the general public.⁵ —LMF

Lisa Marie Fox, MSPAS, PA-C
Division of Multiple Sclerosis, Department of Neurology, Johns Hopkins Hosptial, Baltimore

Q) What is the role of vitamin D in multiple sclerosis? Is it beneficial?

The exact etiology and pathophysiology of multiple sclerosis (MS) is still not fully understood. Research strongly suggests that there are two major causative factors: one genetic, and the other, environmental. From an environmental standpoint, multiple studies have shown that living farther from the equator, not being exposed to sunlight, and having a low vitamin D level are all correlated with increased risk for MS and MS relapse.¹

Our bodies need sunlight to successfully synthesize vitamin D in the skin. Research has found that individuals with lightly pigmented skin are five times more efficient at synthesizing vitamin D in the presence of sunlight than those with darker skin.² However, the ability to absorb sunlight is also correlated with the earth’s latitude; worse absorption occurs in areas beyond the 40th parallel (in either hemisphere), where UVB levels are too low to synthesize vitamin D four to six months out of the year.²

When exposed to UVB rays, our bodies start to synthesize vitamin D; it undergoes a transformation in the liver and then the kidneys and ultimately becomes the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol).² Calcitriol is recognized by multiple tissues throughout the body that contain vitamin D receptors. Specifically, in the central nervous system, receptors are located on microglia, activated monocytes, and B and T lymphocytes.¹ In MS, myelin (the coating around the nerves) is destroyed by an immune-mediated inflammatory process involving the microglia and B and T lymphocytes. Vitamin D quiets down this inflammation, thereby reducing disability accumulation and relapse risk and resulting in fewer changes on MRI.

Vitamin D is also believed to shift the immune response to an anti-inflammatory state by focusing the response on the cytotoxic T cells often found in MS lesions, which attack neurons and oligodendrocytes.² This theory was tested by Munger and colleagues, who used a pooled cohort of 187,000 women from the Nurses’ Health Study and Nurses’ Health Study II to assess vitamin D intake and risk for MS. Compared to women with lower vitamin D intake, those who took 700 IU/d had a 41% lower incidence of MS. Women who took ≥ 400 IU/d had a 33% lower risk for MS, compared to nonusers.³ In another evaluation of 7 million US military personnel, individuals with a serum vitamin D level of 40 ng/mL were 62% less likely to develop MS.⁴

In light of the anti-inflammatory effects of vitamin D and its purported reduction of MS risk, it is possible that patients with MS should begin vitamin D supplementation early to obtain maximum anti-inflammatory effects. While an optimal vitamin D goal has not been established in the literature, some studies suggest 30 to 55 ng/mL as a target range for serum vitamin D level.¹

While vitamin D has been found to be well-tolerated, patients should be cautioned that very high doses can cause fatigue, abdominal cramps, nausea, vomiting, kidney damage, hypertension, hypercalcemia, and other toxic effects.¹ Additional research is needed to determine the exact dosage MS patients need to gain the optimal anti-inflammatory benefits. What we do know is that the Institute of Medicine’s current guidelines recommend a daily allowance of 600 IU/d of vitamin D for the general public.⁵ —LMF

Lisa Marie Fox, MSPAS, PA-C
Division of Multiple Sclerosis, Department of Neurology, Johns Hopkins Hosptial, Baltimore

Q) What is the role of vitamin D in multiple sclerosis? Is it beneficial?

The exact etiology and pathophysiology of multiple sclerosis (MS) is still not fully understood. Research strongly suggests that there are two major causative factors: one genetic, and the other, environmental. From an environmental standpoint, multiple studies have shown that living farther from the equator, not being exposed to sunlight, and having a low vitamin D level are all correlated with increased risk for MS and MS relapse.¹

Our bodies need sunlight to successfully synthesize vitamin D in the skin. Research has found that individuals with lightly pigmented skin are five times more efficient at synthesizing vitamin D in the presence of sunlight than those with darker skin.² However, the ability to absorb sunlight is also correlated with the earth’s latitude; worse absorption occurs in areas beyond the 40th parallel (in either hemisphere), where UVB levels are too low to synthesize vitamin D four to six months out of the year.²

When exposed to UVB rays, our bodies start to synthesize vitamin D; it undergoes a transformation in the liver and then the kidneys and ultimately becomes the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol).² Calcitriol is recognized by multiple tissues throughout the body that contain vitamin D receptors. Specifically, in the central nervous system, receptors are located on microglia, activated monocytes, and B and T lymphocytes.¹ In MS, myelin (the coating around the nerves) is destroyed by an immune-mediated inflammatory process involving the microglia and B and T lymphocytes. Vitamin D quiets down this inflammation, thereby reducing disability accumulation and relapse risk and resulting in fewer changes on MRI.

Vitamin D is also believed to shift the immune response to an anti-inflammatory state by focusing the response on the cytotoxic T cells often found in MS lesions, which attack neurons and oligodendrocytes.² This theory was tested by Munger and colleagues, who used a pooled cohort of 187,000 women from the Nurses’ Health Study and Nurses’ Health Study II to assess vitamin D intake and risk for MS. Compared to women with lower vitamin D intake, those who took 700 IU/d had a 41% lower incidence of MS. Women who took ≥ 400 IU/d had a 33% lower risk for MS, compared to nonusers.³ In another evaluation of 7 million US military personnel, individuals with a serum vitamin D level of 40 ng/mL were 62% less likely to develop MS.⁴

In light of the anti-inflammatory effects of vitamin D and its purported reduction of MS risk, it is possible that patients with MS should begin vitamin D supplementation early to obtain maximum anti-inflammatory effects. While an optimal vitamin D goal has not been established in the literature, some studies suggest 30 to 55 ng/mL as a target range for serum vitamin D level.¹

While vitamin D has been found to be well-tolerated, patients should be cautioned that very high doses can cause fatigue, abdominal cramps, nausea, vomiting, kidney damage, hypertension, hypercalcemia, and other toxic effects.¹ Additional research is needed to determine the exact dosage MS patients need to gain the optimal anti-inflammatory benefits. What we do know is that the Institute of Medicine’s current guidelines recommend a daily allowance of 600 IU/d of vitamin D for the general public.⁵ —LMF

Lisa Marie Fox, MSPAS, PA-C
Division of Multiple Sclerosis, Department of Neurology, Johns Hopkins Hosptial, Baltimore

Readmission to the hospital after acute GI bleeding in children is most often associated with an initial diagnosis of portal hypertension or esophageal variceal hemorrhage, based on data from a retrospective study of 9,902 patients.

Rebleeding in adults may be predicted by endoscopic characteristics of the bleeding source in some cases, but “there is still a considerable subgroup of children admitted with acute gastrointestinal bleeding and not endoscoped but in whom we do not have any measure to predict rebleeding including after discharge,” Thomas M. Attard, MD, Children’s Mercy Hospital, Kansas City, Mo., and his colleagues said.

The study included children aged 1-21 years with upper or indeterminate GI bleeding who were discharged from 49 pediatric hospitals between January 1, 2007 and September 30, 2015. Overall, 1,460 children (16%) were readmitted at least once within 30 days, with 72 readmitted twice and an average of 10 days’ time to readmission.

Readmission for recurrent bleeding was most frequently associated with an initial diagnosis of portal hypertension (20%) or esophageal variceal hemorrhage (20%). Children who had undergone endoscopy (odds ratio, 0.77) or Meckel’s scan (OR, 0.51) on initial admission were least likely to require readmission.

Children with one or two complex chronic conditions were almost twice as likely to be readmitted than were those with no complex chronic conditions, and a longer initial hospital stay and early treatment with proton pump inhibitors were associated with increased likelihood of readmission. “These may be indicative of more medically frail patients and greater severity of initial illness, respectively,” the researchers said. They found no association between increased risk of readmission and demographic factors including age, sex, race, and urban vs. rural residence (J Pediatr. 2017 Feb. doi: 10.1016/j.jpeds.2017.01.044).

Readmission to the hospital after acute GI bleeding in children is most often associated with an initial diagnosis of portal hypertension or esophageal variceal hemorrhage, based on data from a retrospective study of 9,902 patients.

Rebleeding in adults may be predicted by endoscopic characteristics of the bleeding source in some cases, but “there is still a considerable subgroup of children admitted with acute gastrointestinal bleeding and not endoscoped but in whom we do not have any measure to predict rebleeding including after discharge,” Thomas M. Attard, MD, Children’s Mercy Hospital, Kansas City, Mo., and his colleagues said.

The study included children aged 1-21 years with upper or indeterminate GI bleeding who were discharged from 49 pediatric hospitals between January 1, 2007 and September 30, 2015. Overall, 1,460 children (16%) were readmitted at least once within 30 days, with 72 readmitted twice and an average of 10 days’ time to readmission.

Readmission for recurrent bleeding was most frequently associated with an initial diagnosis of portal hypertension (20%) or esophageal variceal hemorrhage (20%). Children who had undergone endoscopy (odds ratio, 0.77) or Meckel’s scan (OR, 0.51) on initial admission were least likely to require readmission.

Children with one or two complex chronic conditions were almost twice as likely to be readmitted than were those with no complex chronic conditions, and a longer initial hospital stay and early treatment with proton pump inhibitors were associated with increased likelihood of readmission. “These may be indicative of more medically frail patients and greater severity of initial illness, respectively,” the researchers said. They found no association between increased risk of readmission and demographic factors including age, sex, race, and urban vs. rural residence (J Pediatr. 2017 Feb. doi: 10.1016/j.jpeds.2017.01.044).

Readmission to the hospital after acute GI bleeding in children is most often associated with an initial diagnosis of portal hypertension or esophageal variceal hemorrhage, based on data from a retrospective study of 9,902 patients.

Rebleeding in adults may be predicted by endoscopic characteristics of the bleeding source in some cases, but “there is still a considerable subgroup of children admitted with acute gastrointestinal bleeding and not endoscoped but in whom we do not have any measure to predict rebleeding including after discharge,” Thomas M. Attard, MD, Children’s Mercy Hospital, Kansas City, Mo., and his colleagues said.

The study included children aged 1-21 years with upper or indeterminate GI bleeding who were discharged from 49 pediatric hospitals between January 1, 2007 and September 30, 2015. Overall, 1,460 children (16%) were readmitted at least once within 30 days, with 72 readmitted twice and an average of 10 days’ time to readmission.

Readmission for recurrent bleeding was most frequently associated with an initial diagnosis of portal hypertension (20%) or esophageal variceal hemorrhage (20%). Children who had undergone endoscopy (odds ratio, 0.77) or Meckel’s scan (OR, 0.51) on initial admission were least likely to require readmission.

Children with one or two complex chronic conditions were almost twice as likely to be readmitted than were those with no complex chronic conditions, and a longer initial hospital stay and early treatment with proton pump inhibitors were associated with increased likelihood of readmission. “These may be indicative of more medically frail patients and greater severity of initial illness, respectively,” the researchers said. They found no association between increased risk of readmission and demographic factors including age, sex, race, and urban vs. rural residence (J Pediatr. 2017 Feb. doi: 10.1016/j.jpeds.2017.01.044).