Patient With Leukocytosis and Persistent Dry Cough

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Discussion

An interdisciplinary discussion regarding the diagnosis considered the clinical features of the patient along with the imaging characteristics. The histological examination demonstrating sarcomatoid features with the supporting immunohistochemistry that confirmed both mesenchymal and epithelioid presence and was used to make the diagnosis of pulmonary sarcomatoid carcinoma (PSC).

table
PSC is a very rare aggressive subtype of poorly differentiated non–small cell lung carcinoma (NSCLC). This tumor is clinically characterized by tumor cells with molecular, histological, and cytological properties of epithelial and mesenchymal tumors, distinguishing it from other types of NSCLC. PSC has a sarcoma-like differentiation (spindle and/or giant cell) or a component of sarcoma (malignant bone, cartilage, or skeletal muscle).1-5 The World Health Organization (WHO) has classified PSC based on morphological characteristics (Table).

The incidence of PSC ranges between 0.1% and 0.4% of all lung malignancies.1,4-7 PSC usually occurs in older men whose weight is moderate to heavy and who smoke. PSC appears to have an upper lobe predilection; also, these tumors tend to be bulky with invasive tendency, early recurrence, and systemic metastases. PSC frequently involves the adjacent lung, chest wall, diaphragm, pericardium, and other tissues.1-5 The source of the sarcoma component of the PSC remains uncertain. However, prior research suggests that it is associated with a clonal evolution that induces epidermal and mesenchymal tumor histological characteristics.1,8,9 The tumor cell epithelial-mesenchymal transition may induce transformation of the carcinoma component of PSC to into a sarcoma component. The epithelial-mesenchymal transition is associated with the PSC high risk for invasiveness and induces metastasis sites, such as the esophagus, colon, rectum, kidneys, and the common sites of NSCLC.

The most common symptoms include productive cough, chest congestion, and chest pain.1,7 In view of PSC’s clinical presentation and imaging, numerous differential diagnoses should be considered, such as sarcomatoid carcinomas, primary or secondary metastatic sarcomas, malignant melanoma, and pleural mesothelioma.6,10

The tumor is initially identified by a chest CT, confirmed by histology and immunohistochemistry. Several biomarkers are useful for diagnosis and classification of an undifferentiated neoplasm/tumor of uncertain origin. Those biomarkers help to understand the tumor pathobiology, to select the therapeutic regimen, and to predict the patient’s outcome. Although immunohistochemical staining of epithelial and mesenchymal markers can be helpful, a reliable diagnosis requires a precise histopathological examination. This is often difficult on small biopsy samples, such as fine-needle aspiration, as all the histological elements of PSC required to make the correct evaluation may not be present. Adequate sampling to generate a considerable number of histological slides is essential for an accurate diagnosis, which can be reached only with surgical resection.5

Due to rarity, rapid progression, short survival, and heterogeneous pathological qualities, PSC has been difficult to formulate treatment recommendations. Compared with other histological subtypes of NSCLC, PSC is more aggressive and has a poor prognosis. Survival time on average is about 13.3 months due to early metastasis, lower than other types of NSCLC. The greatest overall survival (OS) benefit has been shown with surgery in early-stage operable PSC, which remains the standard of care. Because most patients with PSC present in the advanced stage, they lose their opportunity for curative surgery. Auxiliary methods of treatment include radiotherapy and chemotherapy. Prior studies have shown that systemic chemotherapy efficacy has varied, some showing no OS benefit; others showing a modest benefit. It has also been noted that advanced-stage PSC has minimal response to chemotherapy. Further larger prospective studies are needed to outline the efficacy and role of systemic chemotherapy and other therapeutic agents, including targeted therapies and immunotherapy.1,4,11-13 However, two-thirds of patients are not sensitive to conventional chemotherapy. In comparison with other types of NSCLC, PSC carries a poor prognosis even in early-stage disease or if tumor metastasis is present. Therefore, further research on novel treatment options is needed to improve long-term survival.1,3-8

Conclusions

PSC is diagnostically challenging because it is rare and has an aggressive progression. Identification of this tumor requires knowledge of histological criteria to identify their subtypes. Immunohistochemistry has an important role in the classification and to rule out differential diagnoses, including metastatic spread. Nevertheless, a reliable diagnosis requires precise histopathological examination, reached with surgical resection. Therefore, a detailed history, physical examination, systematic investigation, and correlation with chest imaging are needed to avoid misdiagnosis.

Our case highlights the importance of keeping this rare, aggressive tumor as part of the differential diagnosis. In view of its natural history, heterogeneity, and low incidence, published cases of PSC are limited. Thus, further investigation could optimize rapid identification and treatment options.

References

1. Qin Z, Huang B, Yu G, Zheng Y, Zhao K. Gingival metastasis of a mediastinal pulmonary sarcomatoid carcinoma: a case report. J Cardiothorac Surg. 2019;14(1):161. Published 2019 Sep 9. doi:10.1186/s13019-019-0991-y

2. Travis WD, Brambilla E, Nicholson AG, et al; WHO Panel. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10(9):1243-1260. doi:10.1097/JTO.0000000000000630

3. Yendamuri S, Caty L, Pine M, et al. Outcomes of sarcomatoid carcinoma of the lung: a Surveillance, Epidemiology, and End Results Database analysis. Surgery. 2012;152(3):397-402. doi:10.1016/j.surg.2012.05.007

4. Karim NA, Schuster J, Eldessouki I, et al. Pulmonary sarcomatoid carcinoma: University of Cincinnati experience. Oncotarget. 2017;9(3):4102-4108. Published 2017 Dec 18. doi:10.18632/oncotarget.23468

5. Weissferdt A. Pulmonary sarcomatoid carcinomas: a review. Adv Anat Pathol. 2018;25(5):304-313. doi:10.1097/PAP.0000000000000202

6. Roesel C, Terjung S, Weinreich G, et al. Sarcomatoid carcinoma of the lung: a rare histological subtype of non-small cell lung cancer with a poor prognosis even at earlier tumour stages. Interact Cardiovasc Thorac Surg. 2017;24(3):407-413. doi:10.1093/icvts/ivw392

7. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med. 2010;134(1):49-54. doi:10.5858/2008-0547-RAR.1

8. Thomas VT, Hinson S, Konduri K. Epithelial-mesenchymal transition in pulmonary carcinosarcoma: case report and literature review. Ther Adv Med Oncol. 2012;4(1):31-37. doi:10.1177/1758834011421949

9. Chang YL, Wu CT, Shih JY, Lee YC. EGFR and p53 status of pulmonary pleomorphic carcinoma: implications for EGFR tyrosine kinase inhibitors therapy of an aggressive lung malignancy. Ann Surg Oncol. 2011;18(10):2952-2960. doi:10.1245/s10434-011-1621-7

10. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. International Agency for Research on Cancer; 2015:88-94.

11. Huang SY, Shen SJ, Li XY. Pulmonary sarcomatoid carcinoma: a clinicopathologic study and prognostic analysis of 51 cases. World J Surg Oncol. 2013;11:252. Published 2013 Oct 2. doi:10.1186/1477-7819-11-252

12. Pelosi G, Sonzogni A, De Pas T, et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol. 2010;18(2):103-120. doi:10.1177/1066896908330049

13. Lin F, Liu H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138(12):1583-1610. doi:10.5858/arpa.2014-0061-RA

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Mariela M. Rivera-Agosto, MDa; Onix Cantres-Fonseca, MDa; Luis E. Irizarry-Nievesa; William Rodríguez-Cintrón, MD, MACPa

Correspondence:  William Rodríguez-Cintrón  ([email protected])

aVeterans Affairs Caribbean Healthcare System, San Juan, Puerto Rico

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The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

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The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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The patient died before he could provide written consent and relatives were unavailable despite attempts. No personal identifiers were used to maintain the patient's privacy.

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aVeterans Affairs Caribbean Healthcare System, San Juan, Puerto Rico

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

The patient died before he could provide written consent and relatives were unavailable despite attempts. No personal identifiers were used to maintain the patient's privacy.

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Mariela M. Rivera-Agosto, MDa; Onix Cantres-Fonseca, MDa; Luis E. Irizarry-Nievesa; William Rodríguez-Cintrón, MD, MACPa

Correspondence:  William Rodríguez-Cintrón  ([email protected])

aVeterans Affairs Caribbean Healthcare System, San Juan, Puerto Rico

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

The patient died before he could provide written consent and relatives were unavailable despite attempts. No personal identifiers were used to maintain the patient's privacy.

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Discussion

An interdisciplinary discussion regarding the diagnosis considered the clinical features of the patient along with the imaging characteristics. The histological examination demonstrating sarcomatoid features with the supporting immunohistochemistry that confirmed both mesenchymal and epithelioid presence and was used to make the diagnosis of pulmonary sarcomatoid carcinoma (PSC).

table
PSC is a very rare aggressive subtype of poorly differentiated non–small cell lung carcinoma (NSCLC). This tumor is clinically characterized by tumor cells with molecular, histological, and cytological properties of epithelial and mesenchymal tumors, distinguishing it from other types of NSCLC. PSC has a sarcoma-like differentiation (spindle and/or giant cell) or a component of sarcoma (malignant bone, cartilage, or skeletal muscle).1-5 The World Health Organization (WHO) has classified PSC based on morphological characteristics (Table).

The incidence of PSC ranges between 0.1% and 0.4% of all lung malignancies.1,4-7 PSC usually occurs in older men whose weight is moderate to heavy and who smoke. PSC appears to have an upper lobe predilection; also, these tumors tend to be bulky with invasive tendency, early recurrence, and systemic metastases. PSC frequently involves the adjacent lung, chest wall, diaphragm, pericardium, and other tissues.1-5 The source of the sarcoma component of the PSC remains uncertain. However, prior research suggests that it is associated with a clonal evolution that induces epidermal and mesenchymal tumor histological characteristics.1,8,9 The tumor cell epithelial-mesenchymal transition may induce transformation of the carcinoma component of PSC to into a sarcoma component. The epithelial-mesenchymal transition is associated with the PSC high risk for invasiveness and induces metastasis sites, such as the esophagus, colon, rectum, kidneys, and the common sites of NSCLC.

The most common symptoms include productive cough, chest congestion, and chest pain.1,7 In view of PSC’s clinical presentation and imaging, numerous differential diagnoses should be considered, such as sarcomatoid carcinomas, primary or secondary metastatic sarcomas, malignant melanoma, and pleural mesothelioma.6,10

The tumor is initially identified by a chest CT, confirmed by histology and immunohistochemistry. Several biomarkers are useful for diagnosis and classification of an undifferentiated neoplasm/tumor of uncertain origin. Those biomarkers help to understand the tumor pathobiology, to select the therapeutic regimen, and to predict the patient’s outcome. Although immunohistochemical staining of epithelial and mesenchymal markers can be helpful, a reliable diagnosis requires a precise histopathological examination. This is often difficult on small biopsy samples, such as fine-needle aspiration, as all the histological elements of PSC required to make the correct evaluation may not be present. Adequate sampling to generate a considerable number of histological slides is essential for an accurate diagnosis, which can be reached only with surgical resection.5

Due to rarity, rapid progression, short survival, and heterogeneous pathological qualities, PSC has been difficult to formulate treatment recommendations. Compared with other histological subtypes of NSCLC, PSC is more aggressive and has a poor prognosis. Survival time on average is about 13.3 months due to early metastasis, lower than other types of NSCLC. The greatest overall survival (OS) benefit has been shown with surgery in early-stage operable PSC, which remains the standard of care. Because most patients with PSC present in the advanced stage, they lose their opportunity for curative surgery. Auxiliary methods of treatment include radiotherapy and chemotherapy. Prior studies have shown that systemic chemotherapy efficacy has varied, some showing no OS benefit; others showing a modest benefit. It has also been noted that advanced-stage PSC has minimal response to chemotherapy. Further larger prospective studies are needed to outline the efficacy and role of systemic chemotherapy and other therapeutic agents, including targeted therapies and immunotherapy.1,4,11-13 However, two-thirds of patients are not sensitive to conventional chemotherapy. In comparison with other types of NSCLC, PSC carries a poor prognosis even in early-stage disease or if tumor metastasis is present. Therefore, further research on novel treatment options is needed to improve long-term survival.1,3-8

Conclusions

PSC is diagnostically challenging because it is rare and has an aggressive progression. Identification of this tumor requires knowledge of histological criteria to identify their subtypes. Immunohistochemistry has an important role in the classification and to rule out differential diagnoses, including metastatic spread. Nevertheless, a reliable diagnosis requires precise histopathological examination, reached with surgical resection. Therefore, a detailed history, physical examination, systematic investigation, and correlation with chest imaging are needed to avoid misdiagnosis.

Our case highlights the importance of keeping this rare, aggressive tumor as part of the differential diagnosis. In view of its natural history, heterogeneity, and low incidence, published cases of PSC are limited. Thus, further investigation could optimize rapid identification and treatment options.

Discussion

An interdisciplinary discussion regarding the diagnosis considered the clinical features of the patient along with the imaging characteristics. The histological examination demonstrating sarcomatoid features with the supporting immunohistochemistry that confirmed both mesenchymal and epithelioid presence and was used to make the diagnosis of pulmonary sarcomatoid carcinoma (PSC).

table
PSC is a very rare aggressive subtype of poorly differentiated non–small cell lung carcinoma (NSCLC). This tumor is clinically characterized by tumor cells with molecular, histological, and cytological properties of epithelial and mesenchymal tumors, distinguishing it from other types of NSCLC. PSC has a sarcoma-like differentiation (spindle and/or giant cell) or a component of sarcoma (malignant bone, cartilage, or skeletal muscle).1-5 The World Health Organization (WHO) has classified PSC based on morphological characteristics (Table).

The incidence of PSC ranges between 0.1% and 0.4% of all lung malignancies.1,4-7 PSC usually occurs in older men whose weight is moderate to heavy and who smoke. PSC appears to have an upper lobe predilection; also, these tumors tend to be bulky with invasive tendency, early recurrence, and systemic metastases. PSC frequently involves the adjacent lung, chest wall, diaphragm, pericardium, and other tissues.1-5 The source of the sarcoma component of the PSC remains uncertain. However, prior research suggests that it is associated with a clonal evolution that induces epidermal and mesenchymal tumor histological characteristics.1,8,9 The tumor cell epithelial-mesenchymal transition may induce transformation of the carcinoma component of PSC to into a sarcoma component. The epithelial-mesenchymal transition is associated with the PSC high risk for invasiveness and induces metastasis sites, such as the esophagus, colon, rectum, kidneys, and the common sites of NSCLC.

The most common symptoms include productive cough, chest congestion, and chest pain.1,7 In view of PSC’s clinical presentation and imaging, numerous differential diagnoses should be considered, such as sarcomatoid carcinomas, primary or secondary metastatic sarcomas, malignant melanoma, and pleural mesothelioma.6,10

The tumor is initially identified by a chest CT, confirmed by histology and immunohistochemistry. Several biomarkers are useful for diagnosis and classification of an undifferentiated neoplasm/tumor of uncertain origin. Those biomarkers help to understand the tumor pathobiology, to select the therapeutic regimen, and to predict the patient’s outcome. Although immunohistochemical staining of epithelial and mesenchymal markers can be helpful, a reliable diagnosis requires a precise histopathological examination. This is often difficult on small biopsy samples, such as fine-needle aspiration, as all the histological elements of PSC required to make the correct evaluation may not be present. Adequate sampling to generate a considerable number of histological slides is essential for an accurate diagnosis, which can be reached only with surgical resection.5

Due to rarity, rapid progression, short survival, and heterogeneous pathological qualities, PSC has been difficult to formulate treatment recommendations. Compared with other histological subtypes of NSCLC, PSC is more aggressive and has a poor prognosis. Survival time on average is about 13.3 months due to early metastasis, lower than other types of NSCLC. The greatest overall survival (OS) benefit has been shown with surgery in early-stage operable PSC, which remains the standard of care. Because most patients with PSC present in the advanced stage, they lose their opportunity for curative surgery. Auxiliary methods of treatment include radiotherapy and chemotherapy. Prior studies have shown that systemic chemotherapy efficacy has varied, some showing no OS benefit; others showing a modest benefit. It has also been noted that advanced-stage PSC has minimal response to chemotherapy. Further larger prospective studies are needed to outline the efficacy and role of systemic chemotherapy and other therapeutic agents, including targeted therapies and immunotherapy.1,4,11-13 However, two-thirds of patients are not sensitive to conventional chemotherapy. In comparison with other types of NSCLC, PSC carries a poor prognosis even in early-stage disease or if tumor metastasis is present. Therefore, further research on novel treatment options is needed to improve long-term survival.1,3-8

Conclusions

PSC is diagnostically challenging because it is rare and has an aggressive progression. Identification of this tumor requires knowledge of histological criteria to identify their subtypes. Immunohistochemistry has an important role in the classification and to rule out differential diagnoses, including metastatic spread. Nevertheless, a reliable diagnosis requires precise histopathological examination, reached with surgical resection. Therefore, a detailed history, physical examination, systematic investigation, and correlation with chest imaging are needed to avoid misdiagnosis.

Our case highlights the importance of keeping this rare, aggressive tumor as part of the differential diagnosis. In view of its natural history, heterogeneity, and low incidence, published cases of PSC are limited. Thus, further investigation could optimize rapid identification and treatment options.

References

1. Qin Z, Huang B, Yu G, Zheng Y, Zhao K. Gingival metastasis of a mediastinal pulmonary sarcomatoid carcinoma: a case report. J Cardiothorac Surg. 2019;14(1):161. Published 2019 Sep 9. doi:10.1186/s13019-019-0991-y

2. Travis WD, Brambilla E, Nicholson AG, et al; WHO Panel. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10(9):1243-1260. doi:10.1097/JTO.0000000000000630

3. Yendamuri S, Caty L, Pine M, et al. Outcomes of sarcomatoid carcinoma of the lung: a Surveillance, Epidemiology, and End Results Database analysis. Surgery. 2012;152(3):397-402. doi:10.1016/j.surg.2012.05.007

4. Karim NA, Schuster J, Eldessouki I, et al. Pulmonary sarcomatoid carcinoma: University of Cincinnati experience. Oncotarget. 2017;9(3):4102-4108. Published 2017 Dec 18. doi:10.18632/oncotarget.23468

5. Weissferdt A. Pulmonary sarcomatoid carcinomas: a review. Adv Anat Pathol. 2018;25(5):304-313. doi:10.1097/PAP.0000000000000202

6. Roesel C, Terjung S, Weinreich G, et al. Sarcomatoid carcinoma of the lung: a rare histological subtype of non-small cell lung cancer with a poor prognosis even at earlier tumour stages. Interact Cardiovasc Thorac Surg. 2017;24(3):407-413. doi:10.1093/icvts/ivw392

7. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med. 2010;134(1):49-54. doi:10.5858/2008-0547-RAR.1

8. Thomas VT, Hinson S, Konduri K. Epithelial-mesenchymal transition in pulmonary carcinosarcoma: case report and literature review. Ther Adv Med Oncol. 2012;4(1):31-37. doi:10.1177/1758834011421949

9. Chang YL, Wu CT, Shih JY, Lee YC. EGFR and p53 status of pulmonary pleomorphic carcinoma: implications for EGFR tyrosine kinase inhibitors therapy of an aggressive lung malignancy. Ann Surg Oncol. 2011;18(10):2952-2960. doi:10.1245/s10434-011-1621-7

10. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. International Agency for Research on Cancer; 2015:88-94.

11. Huang SY, Shen SJ, Li XY. Pulmonary sarcomatoid carcinoma: a clinicopathologic study and prognostic analysis of 51 cases. World J Surg Oncol. 2013;11:252. Published 2013 Oct 2. doi:10.1186/1477-7819-11-252

12. Pelosi G, Sonzogni A, De Pas T, et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol. 2010;18(2):103-120. doi:10.1177/1066896908330049

13. Lin F, Liu H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138(12):1583-1610. doi:10.5858/arpa.2014-0061-RA

References

1. Qin Z, Huang B, Yu G, Zheng Y, Zhao K. Gingival metastasis of a mediastinal pulmonary sarcomatoid carcinoma: a case report. J Cardiothorac Surg. 2019;14(1):161. Published 2019 Sep 9. doi:10.1186/s13019-019-0991-y

2. Travis WD, Brambilla E, Nicholson AG, et al; WHO Panel. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10(9):1243-1260. doi:10.1097/JTO.0000000000000630

3. Yendamuri S, Caty L, Pine M, et al. Outcomes of sarcomatoid carcinoma of the lung: a Surveillance, Epidemiology, and End Results Database analysis. Surgery. 2012;152(3):397-402. doi:10.1016/j.surg.2012.05.007

4. Karim NA, Schuster J, Eldessouki I, et al. Pulmonary sarcomatoid carcinoma: University of Cincinnati experience. Oncotarget. 2017;9(3):4102-4108. Published 2017 Dec 18. doi:10.18632/oncotarget.23468

5. Weissferdt A. Pulmonary sarcomatoid carcinomas: a review. Adv Anat Pathol. 2018;25(5):304-313. doi:10.1097/PAP.0000000000000202

6. Roesel C, Terjung S, Weinreich G, et al. Sarcomatoid carcinoma of the lung: a rare histological subtype of non-small cell lung cancer with a poor prognosis even at earlier tumour stages. Interact Cardiovasc Thorac Surg. 2017;24(3):407-413. doi:10.1093/icvts/ivw392

7. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis. Arch Pathol Lab Med. 2010;134(1):49-54. doi:10.5858/2008-0547-RAR.1

8. Thomas VT, Hinson S, Konduri K. Epithelial-mesenchymal transition in pulmonary carcinosarcoma: case report and literature review. Ther Adv Med Oncol. 2012;4(1):31-37. doi:10.1177/1758834011421949

9. Chang YL, Wu CT, Shih JY, Lee YC. EGFR and p53 status of pulmonary pleomorphic carcinoma: implications for EGFR tyrosine kinase inhibitors therapy of an aggressive lung malignancy. Ann Surg Oncol. 2011;18(10):2952-2960. doi:10.1245/s10434-011-1621-7

10. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. International Agency for Research on Cancer; 2015:88-94.

11. Huang SY, Shen SJ, Li XY. Pulmonary sarcomatoid carcinoma: a clinicopathologic study and prognostic analysis of 51 cases. World J Surg Oncol. 2013;11:252. Published 2013 Oct 2. doi:10.1186/1477-7819-11-252

12. Pelosi G, Sonzogni A, De Pas T, et al. Review article: pulmonary sarcomatoid carcinomas: a practical overview. Int J Surg Pathol. 2010;18(2):103-120. doi:10.1177/1066896908330049

13. Lin F, Liu H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138(12):1583-1610. doi:10.5858/arpa.2014-0061-RA

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Supplements Are Not a Synonym for Safe: Suspected Liver Injury From Ashwagandha

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Many patients take herbals as alternative supplements to boost energy and mood. There are increasing reports of unintended adverse effects related to these supplements, particularly to the liver.1-3 A study by the Drug-Induced Liver Injury Network found that liver injury caused by herbals and dietary supplements has increased from 7% in 2004 to 20% in 2013.4

The supplement ashwagandha has become increasingly popular. Ashwagandha is extracted from the root of Withania somnifera (W somnifera). It is purported to have health benefits, such as improving men’s health and increasing strength, memory, and learning abilities while decreasing anxiety and counteracting chronic fatigue.5,6W somnifera generally has been considered safe, though recently, a few case reports suggest that it may lead to a cholestatic pattern of injury.5-7

To date, the factors defining the population at risk for ashwagandha toxicity are unclear, and an understanding of how to diagnose drug-induced liver injury is still immature in clinical practice. The regulation and study of the herbal and dietary supplement industry remain challenging. While many so-called natural substances are well tolerated, others can have unanticipated and harmful adverse effects and drug interactions. Future research should not only identify potentially harmful substances, but also which patients may be at greatest risk.

Case Presentation

A 48-year-old man with a history of severe alcohol use disorder (AUD) complicated by fatty liver and withdrawal seizures and delirium tremens, hypertension, depression, and anxiety presented to the emergency department (ED) after 4 days of having jaundice, epigastric abdominal pain, dark urine, and pale stools. In the preceding months, he had increased his alcohol use to as many as 12 drinks daily due to depression. After experiencing a blackout, he stopped drinking 7 days before presenting to the ED. He felt withdrawal symptoms, including tremors, diaphoresis, abdominal pain, nausea, and vomiting. On the third day of withdrawals, he reported that he had started taking an over-the-counter testosterone-boosting supplement to increase his energy, which he referred to as TestBoost—a mix of 8 ingredients, including ashwagandha, eleuthero root, Hawthorn berry, longjack, ginseng root, mushroom extract, bindii, and horny goat weed. After taking the supplement for 2 days, he noticed that his urine darkened, his stools became paler, his abdominal pain worsened, and he became jaundiced. After 2 additional days without improvement, and still taking the supplement, he presented to the ED. He reported having no fever, chills, recent illness, chest pain, shortness of breath, melena, lower extremity swelling, recent travel, or any changes in medications.

 

 

The patient had a 100.1 °F temperature, 102 beats per minute pulse; 129/94 mm Hg blood pressure, 18 beats per minute respiratory rate, and 97% oxygen saturation on room air on admission. He was in no acute distress, though his examination was notable for generalized jaundice and scleral icterus. He was mildly tender to palpation in the epigastric and right upper quadrant region. He was alert and oriented without confusion. He did not have any asterixis or spider angiomas, though he had scattered bruises on his left flank and left calf. His laboratory results were notable for mildly elevated aspartate aminotransferase (AST), 58 U/L (reference range, 13-35); alanine transaminase (ALT), 49 U/L (reference range, 7-45); and alkaline phosphatase (ALP), 98 U/L (reference range 33-94); total bilirubin, 13.6 mg/dL (reference range, 0.2-1.0); direct bilirubin, 8.4 mg/dL (reference range, 0.2-1); and international normalized ratio (INR), 1.11 (reference range, 2-3). His white blood cell and platelet counts were not remarkable at 9790/μL (reference range, 4500-11,000) and 337,000/μL (reference range, 150,000-440,000), respectively. Abdominal ultrasound and computed tomography (CT) revealed fatty liver with contracted gallbladder and no biliary dilatation. Urine ethanol levels were negative. The gastrointestinal (GI) service was consulted and agreed that his cholestatic injury was nonobstructive and likely related to the ashwagandha component of his supplement. The recommendation was cessation with close outpatient follow-up.

table 1

The patient was not prescribed any additional medications, such as steroids or ursodiol. He ceased supplement use following hospitalization; but relapsed into alcohol use 1 month after his discharge. Within 3 weeks, his total bilirubin had improved to 2.87 mg/dL, though AST, ALT, and ALP worsened to 127 U/L, 152 U/L, and 140 U/L, respectively. According to the notes of his psychiatrist who saw him at the time the laboratory tests were drawn, he had remained sober since discharge. His acute hepatitis panel drawn on admission was negative, and he demonstrated immunity to hepatitis A and B. Urine toxicology was negative. Antinuclear antibody (ANA) test was negative 1 year prior to discharge. Epstein-Barr virus (EBV), cytomegalovirus (CMV), ANA, antismooth muscle antibody, and immunoglobulins were not checked as suspicion for these etiologies was low. The Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated as 6 (+1 for timing, +2 for drop in total bilirubin, +1 for ethanol risk factor, 0 for no other drugs, 0 for rule out of other diseases, +2 for known hepatotoxicity, 0 no repeat administration) for this patient indicating probable adverse drug reaction liver injury (Tables 1 and 2). However, we acknowledge that CMV, EBV, and herpes simplex virus status were not tested.

table 2

The 8 ingredients contained in TestBoost aside from ashwagandha did not have any major known liver adverse effects per a major database of medications. The other ingredients include eleuthero root, Hawthorn berry (crataegus laevigata), longjack (eurycoma longifolla) root, American ginseng root (American panax ginseng—panax quinquefolius), and Cordyceps mycelium (mushroom) extract, bindii (Tribulus terrestris), and epimedium grandiflorum (horny goat weed).6 No assays were performed to confirm purity of the ingredients in the patient’s supplement container.

Alcoholic hepatitis is an important consideration in this patient with AUD, though the timing of symptoms with supplement use and the cholestatic injury pattern with normal INR seems more consistent with drug-induced injury. Viral, infectious, and obstructive etiologies also were investigated. Acute viral hepatitis was ruled out based on bloodwork. The normal hepatobiliary tree on both ultrasound and CT effectively ruled out acute cholecystitis, cholangitis, and choledocholithiasis and there was no further indication for magnetic resonance cholangiopancreatography. There was no hepatic vein clot suggestive of Budd-Chiari syndrome. Autoimmune hepatitis was thought to be unlikely given that the etiology of injury seemed cholestatic in nature. Given the timing of the liver injury relative to supplement use it is likely that ashwagandha was a causative factor of this patient’s liver injury overlaid on an already strained liver from increased alcohol abuse.

The patient did not follow up with the GI service as an outpatient. There are no reports that the patient continued using the testosterone booster. His bilirubin improved dramatically within 1.5 months while his liver enzymes peaked 3 weeks later, with ALT ≥ AST. During his next admission 3 months later, he had relapsed, and his liver enzymes had the classic 2:1 AST to ALT ratio.

 

 

Discussion

Generally, ashwagandha has been thought to be well tolerated and possibly hepatoprotective.7-10 However, recent studies suggest potential for hepatotoxicity, though without clear guidance about which patients are most at risk.5,11,12 A study by Inagaki and colleagues suggests the potential for dose-dependent mechanism of liver injury, and this is supported by in vitro CYP450 inhibition with high doses of W Somnifera extract.11,13 We hypothesize that there may be a multihit process that makes some patients more susceptible to supplement harm, particularly those with repeated exposures and with ongoing exposure to hepatic toxins, such as AUD.14 Supplements should be used with more caution in these individuals.

Additionally, although there are no validated guidelines to confirm the diagnosis of drug-induced liver injury (DILI) from a manufactured medication or herbal remedy, the Council for International Organizations of Medical Sciences (CIOMS) developed RUCAM, a set of diagnostic criteria for DILI, which can be used to determine the probability of DILI based on pattern of injury.15 Although not widely used in clinical practice, RUCAM can help identify the possibility of DILI outside of expert consensus.16 It seems to have better discriminative ability than the Maria and Victorino scale, also used to identify DILI.16,17 While there is no replacement for clinical judgment, these scales may aid in identifying potential causes of DILI. The National Institutes of Health also has a LiverTox online tool that can assist health care professionals in identifying potentially hepatotoxic substances.6

Conclusions

We present a patient with AUD who developed cholestatic liver injury after ashwagandha use. Crucial to the diagnostic process is quantifying the amount ingested before presentation and the presence of contaminants, which is currently difficult to quantify given the lack of mechanisms to test supplements expediently in this manner in the clinical setting, which also requires the patient to bring in the supplements directly. There is also a lack of regulation and uniformity in these products. A clinician may be inclined to measure ashwagandha serum levels; however, such a test is not available to our knowledge. Nonetheless, using clinical tools such as RUCAM and utilizing databases, such as LiverTox, may help clinicians identify and remove potentially unsafe supplements. While there are many possible synergies between current medical practice and herbal remedies, practitioners must take care to first do no harm, as outlined in our Hippocratic Oath.

References

1. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis. 2009;29(4):373-382. doi:10.1055/s-0029-1240006

2. Suk KT, Kim DJ, Kim CH, et al. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol. 2012;107(9):1380-1387. doi:10.1038/ajg.2012.138

3. Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in mainland China. Gastroenterology. 2019;156(8):2230-2241.e11. doi:10.1053/j.gastro.2019.02.002

4. Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60(4):1399-1408. doi:10.1002/hep.27317

5. Björnsson HK, Björnsson, Avula B, et al. (2020). Ashwagandha‐induced liver injury: a case series from Iceland and the US Drug‐Induced Liver Injury Network. Liver Int. 2020;40(4):825-829. doi:10.1111/liv.14393

6. National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: clinical and research information on drug-induced liver injury [internet]. Ashwagandha. Updated May 2, 2019. Accessed August 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK548536

7. Kumar G, Srivastava A, Sharma SK, Rao TD, Gupta YK. Efficacy and safety evaluation of Ayurvedic treatment (ashwagandha powder & Sidh Makardhwaj) in rheumatoid arthritis patients: a pilot prospective study. Indian J Med Res. 2015;141(1):100-106. doi:10.4103/0971-5916.154510

8. Kumar G, Srivastava A, Sharma SK, Gupta YK. Safety and efficacy evaluation of Ayurvedic treatment (arjuna powder and Arogyavardhini Vati) in dyslipidemia patients: a pilot prospective cohort clinical study. 2012;33(2):197-201. doi:10.4103/0974-8520.105238

9. Sultana N, Shimmi S, Parash MT, Akhtar J. Effects of ashwagandha (Withania somnifera) root extract on some serum liver marker enzymes (AST, ALT) in gentamicin intoxicated rats. J Bangladesh Soc Physiologist. 2012;7(1): 1-7. doi:10.3329/JBSP.V7I1.11152

10. Patel DP, Yan T, Kim D, et al. Withaferin A improves nonalcoholic steatohepatitis in mice. J Pharmacol Exp Ther. 2019;371(2):360-374. doi:10.1124/jpet.119.256792

11. Inagaki K, Mori N, Honda Y, Takaki S, Tsuji K, Chayama K. A case of drug-induced liver injury with prolonged severe intrahepatic cholestasis induced by ashwagandha. Kanzo. 2017;58(8):448-454. doi:10.2957/kanzo.58.448

12. Alali F, Hermez K, Ullah N. Acute hepatitis induced by a unique combination of herbal supplements. Am J Gastroenterol. 2018;113:S1661.

13. Sava J, Varghese A, Pandita N. Lack of the cytochrome P450 3A interaction of methanolic extract of Withania somnifera, Withaferin A, Withanolide A and Withanoside IV. J Pharm Negative Results. 2013;4(1):26.

14. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474-485. doi:10.1056/NEJMra021844.

15. Danan G, Benichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of International Consensus Meeting: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323–1333. doi:10.1016/0895-4356(93)90101-6

16. Hayashi PH. Causality assessment in drug-induced liver injury. Semin Liver Dis. 2009;29(4):348-356. doi.10.1002/cld.615

17. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 2001;33(1):123-130. doi:10.1053/jhep.2001.20645

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Sondra Vazirani, MD, MPHa; Amit Kothari, MDa; Jeffrey Fujimoto, MD, MBAb; Mariana Gomez, MD, MBAb

Correspondence:  Sondra Vazirani  ([email protected])

aVeterans Affairs Greater Los Angeles Healthcare System, California

bUniversity of California, Los Angeles

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

The patient gave verbal consent to Dr. Fujimoto. The patient would not return to hospital or accept an email to sign a paper consent. There is no identifiable patient information in this case report.

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Sondra Vazirani, MD, MPHa; Amit Kothari, MDa; Jeffrey Fujimoto, MD, MBAb; Mariana Gomez, MD, MBAb

Correspondence:  Sondra Vazirani  ([email protected])

aVeterans Affairs Greater Los Angeles Healthcare System, California

bUniversity of California, Los Angeles

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

The patient gave verbal consent to Dr. Fujimoto. The patient would not return to hospital or accept an email to sign a paper consent. There is no identifiable patient information in this case report.

Author and Disclosure Information

Sondra Vazirani, MD, MPHa; Amit Kothari, MDa; Jeffrey Fujimoto, MD, MBAb; Mariana Gomez, MD, MBAb

Correspondence:  Sondra Vazirani  ([email protected])

aVeterans Affairs Greater Los Angeles Healthcare System, California

bUniversity of California, Los Angeles

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

The patient gave verbal consent to Dr. Fujimoto. The patient would not return to hospital or accept an email to sign a paper consent. There is no identifiable patient information in this case report.

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Article PDF

Many patients take herbals as alternative supplements to boost energy and mood. There are increasing reports of unintended adverse effects related to these supplements, particularly to the liver.1-3 A study by the Drug-Induced Liver Injury Network found that liver injury caused by herbals and dietary supplements has increased from 7% in 2004 to 20% in 2013.4

The supplement ashwagandha has become increasingly popular. Ashwagandha is extracted from the root of Withania somnifera (W somnifera). It is purported to have health benefits, such as improving men’s health and increasing strength, memory, and learning abilities while decreasing anxiety and counteracting chronic fatigue.5,6W somnifera generally has been considered safe, though recently, a few case reports suggest that it may lead to a cholestatic pattern of injury.5-7

To date, the factors defining the population at risk for ashwagandha toxicity are unclear, and an understanding of how to diagnose drug-induced liver injury is still immature in clinical practice. The regulation and study of the herbal and dietary supplement industry remain challenging. While many so-called natural substances are well tolerated, others can have unanticipated and harmful adverse effects and drug interactions. Future research should not only identify potentially harmful substances, but also which patients may be at greatest risk.

Case Presentation

A 48-year-old man with a history of severe alcohol use disorder (AUD) complicated by fatty liver and withdrawal seizures and delirium tremens, hypertension, depression, and anxiety presented to the emergency department (ED) after 4 days of having jaundice, epigastric abdominal pain, dark urine, and pale stools. In the preceding months, he had increased his alcohol use to as many as 12 drinks daily due to depression. After experiencing a blackout, he stopped drinking 7 days before presenting to the ED. He felt withdrawal symptoms, including tremors, diaphoresis, abdominal pain, nausea, and vomiting. On the third day of withdrawals, he reported that he had started taking an over-the-counter testosterone-boosting supplement to increase his energy, which he referred to as TestBoost—a mix of 8 ingredients, including ashwagandha, eleuthero root, Hawthorn berry, longjack, ginseng root, mushroom extract, bindii, and horny goat weed. After taking the supplement for 2 days, he noticed that his urine darkened, his stools became paler, his abdominal pain worsened, and he became jaundiced. After 2 additional days without improvement, and still taking the supplement, he presented to the ED. He reported having no fever, chills, recent illness, chest pain, shortness of breath, melena, lower extremity swelling, recent travel, or any changes in medications.

 

 

The patient had a 100.1 °F temperature, 102 beats per minute pulse; 129/94 mm Hg blood pressure, 18 beats per minute respiratory rate, and 97% oxygen saturation on room air on admission. He was in no acute distress, though his examination was notable for generalized jaundice and scleral icterus. He was mildly tender to palpation in the epigastric and right upper quadrant region. He was alert and oriented without confusion. He did not have any asterixis or spider angiomas, though he had scattered bruises on his left flank and left calf. His laboratory results were notable for mildly elevated aspartate aminotransferase (AST), 58 U/L (reference range, 13-35); alanine transaminase (ALT), 49 U/L (reference range, 7-45); and alkaline phosphatase (ALP), 98 U/L (reference range 33-94); total bilirubin, 13.6 mg/dL (reference range, 0.2-1.0); direct bilirubin, 8.4 mg/dL (reference range, 0.2-1); and international normalized ratio (INR), 1.11 (reference range, 2-3). His white blood cell and platelet counts were not remarkable at 9790/μL (reference range, 4500-11,000) and 337,000/μL (reference range, 150,000-440,000), respectively. Abdominal ultrasound and computed tomography (CT) revealed fatty liver with contracted gallbladder and no biliary dilatation. Urine ethanol levels were negative. The gastrointestinal (GI) service was consulted and agreed that his cholestatic injury was nonobstructive and likely related to the ashwagandha component of his supplement. The recommendation was cessation with close outpatient follow-up.

table 1

The patient was not prescribed any additional medications, such as steroids or ursodiol. He ceased supplement use following hospitalization; but relapsed into alcohol use 1 month after his discharge. Within 3 weeks, his total bilirubin had improved to 2.87 mg/dL, though AST, ALT, and ALP worsened to 127 U/L, 152 U/L, and 140 U/L, respectively. According to the notes of his psychiatrist who saw him at the time the laboratory tests were drawn, he had remained sober since discharge. His acute hepatitis panel drawn on admission was negative, and he demonstrated immunity to hepatitis A and B. Urine toxicology was negative. Antinuclear antibody (ANA) test was negative 1 year prior to discharge. Epstein-Barr virus (EBV), cytomegalovirus (CMV), ANA, antismooth muscle antibody, and immunoglobulins were not checked as suspicion for these etiologies was low. The Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated as 6 (+1 for timing, +2 for drop in total bilirubin, +1 for ethanol risk factor, 0 for no other drugs, 0 for rule out of other diseases, +2 for known hepatotoxicity, 0 no repeat administration) for this patient indicating probable adverse drug reaction liver injury (Tables 1 and 2). However, we acknowledge that CMV, EBV, and herpes simplex virus status were not tested.

table 2

The 8 ingredients contained in TestBoost aside from ashwagandha did not have any major known liver adverse effects per a major database of medications. The other ingredients include eleuthero root, Hawthorn berry (crataegus laevigata), longjack (eurycoma longifolla) root, American ginseng root (American panax ginseng—panax quinquefolius), and Cordyceps mycelium (mushroom) extract, bindii (Tribulus terrestris), and epimedium grandiflorum (horny goat weed).6 No assays were performed to confirm purity of the ingredients in the patient’s supplement container.

Alcoholic hepatitis is an important consideration in this patient with AUD, though the timing of symptoms with supplement use and the cholestatic injury pattern with normal INR seems more consistent with drug-induced injury. Viral, infectious, and obstructive etiologies also were investigated. Acute viral hepatitis was ruled out based on bloodwork. The normal hepatobiliary tree on both ultrasound and CT effectively ruled out acute cholecystitis, cholangitis, and choledocholithiasis and there was no further indication for magnetic resonance cholangiopancreatography. There was no hepatic vein clot suggestive of Budd-Chiari syndrome. Autoimmune hepatitis was thought to be unlikely given that the etiology of injury seemed cholestatic in nature. Given the timing of the liver injury relative to supplement use it is likely that ashwagandha was a causative factor of this patient’s liver injury overlaid on an already strained liver from increased alcohol abuse.

The patient did not follow up with the GI service as an outpatient. There are no reports that the patient continued using the testosterone booster. His bilirubin improved dramatically within 1.5 months while his liver enzymes peaked 3 weeks later, with ALT ≥ AST. During his next admission 3 months later, he had relapsed, and his liver enzymes had the classic 2:1 AST to ALT ratio.

 

 

Discussion

Generally, ashwagandha has been thought to be well tolerated and possibly hepatoprotective.7-10 However, recent studies suggest potential for hepatotoxicity, though without clear guidance about which patients are most at risk.5,11,12 A study by Inagaki and colleagues suggests the potential for dose-dependent mechanism of liver injury, and this is supported by in vitro CYP450 inhibition with high doses of W Somnifera extract.11,13 We hypothesize that there may be a multihit process that makes some patients more susceptible to supplement harm, particularly those with repeated exposures and with ongoing exposure to hepatic toxins, such as AUD.14 Supplements should be used with more caution in these individuals.

Additionally, although there are no validated guidelines to confirm the diagnosis of drug-induced liver injury (DILI) from a manufactured medication or herbal remedy, the Council for International Organizations of Medical Sciences (CIOMS) developed RUCAM, a set of diagnostic criteria for DILI, which can be used to determine the probability of DILI based on pattern of injury.15 Although not widely used in clinical practice, RUCAM can help identify the possibility of DILI outside of expert consensus.16 It seems to have better discriminative ability than the Maria and Victorino scale, also used to identify DILI.16,17 While there is no replacement for clinical judgment, these scales may aid in identifying potential causes of DILI. The National Institutes of Health also has a LiverTox online tool that can assist health care professionals in identifying potentially hepatotoxic substances.6

Conclusions

We present a patient with AUD who developed cholestatic liver injury after ashwagandha use. Crucial to the diagnostic process is quantifying the amount ingested before presentation and the presence of contaminants, which is currently difficult to quantify given the lack of mechanisms to test supplements expediently in this manner in the clinical setting, which also requires the patient to bring in the supplements directly. There is also a lack of regulation and uniformity in these products. A clinician may be inclined to measure ashwagandha serum levels; however, such a test is not available to our knowledge. Nonetheless, using clinical tools such as RUCAM and utilizing databases, such as LiverTox, may help clinicians identify and remove potentially unsafe supplements. While there are many possible synergies between current medical practice and herbal remedies, practitioners must take care to first do no harm, as outlined in our Hippocratic Oath.

Many patients take herbals as alternative supplements to boost energy and mood. There are increasing reports of unintended adverse effects related to these supplements, particularly to the liver.1-3 A study by the Drug-Induced Liver Injury Network found that liver injury caused by herbals and dietary supplements has increased from 7% in 2004 to 20% in 2013.4

The supplement ashwagandha has become increasingly popular. Ashwagandha is extracted from the root of Withania somnifera (W somnifera). It is purported to have health benefits, such as improving men’s health and increasing strength, memory, and learning abilities while decreasing anxiety and counteracting chronic fatigue.5,6W somnifera generally has been considered safe, though recently, a few case reports suggest that it may lead to a cholestatic pattern of injury.5-7

To date, the factors defining the population at risk for ashwagandha toxicity are unclear, and an understanding of how to diagnose drug-induced liver injury is still immature in clinical practice. The regulation and study of the herbal and dietary supplement industry remain challenging. While many so-called natural substances are well tolerated, others can have unanticipated and harmful adverse effects and drug interactions. Future research should not only identify potentially harmful substances, but also which patients may be at greatest risk.

Case Presentation

A 48-year-old man with a history of severe alcohol use disorder (AUD) complicated by fatty liver and withdrawal seizures and delirium tremens, hypertension, depression, and anxiety presented to the emergency department (ED) after 4 days of having jaundice, epigastric abdominal pain, dark urine, and pale stools. In the preceding months, he had increased his alcohol use to as many as 12 drinks daily due to depression. After experiencing a blackout, he stopped drinking 7 days before presenting to the ED. He felt withdrawal symptoms, including tremors, diaphoresis, abdominal pain, nausea, and vomiting. On the third day of withdrawals, he reported that he had started taking an over-the-counter testosterone-boosting supplement to increase his energy, which he referred to as TestBoost—a mix of 8 ingredients, including ashwagandha, eleuthero root, Hawthorn berry, longjack, ginseng root, mushroom extract, bindii, and horny goat weed. After taking the supplement for 2 days, he noticed that his urine darkened, his stools became paler, his abdominal pain worsened, and he became jaundiced. After 2 additional days without improvement, and still taking the supplement, he presented to the ED. He reported having no fever, chills, recent illness, chest pain, shortness of breath, melena, lower extremity swelling, recent travel, or any changes in medications.

 

 

The patient had a 100.1 °F temperature, 102 beats per minute pulse; 129/94 mm Hg blood pressure, 18 beats per minute respiratory rate, and 97% oxygen saturation on room air on admission. He was in no acute distress, though his examination was notable for generalized jaundice and scleral icterus. He was mildly tender to palpation in the epigastric and right upper quadrant region. He was alert and oriented without confusion. He did not have any asterixis or spider angiomas, though he had scattered bruises on his left flank and left calf. His laboratory results were notable for mildly elevated aspartate aminotransferase (AST), 58 U/L (reference range, 13-35); alanine transaminase (ALT), 49 U/L (reference range, 7-45); and alkaline phosphatase (ALP), 98 U/L (reference range 33-94); total bilirubin, 13.6 mg/dL (reference range, 0.2-1.0); direct bilirubin, 8.4 mg/dL (reference range, 0.2-1); and international normalized ratio (INR), 1.11 (reference range, 2-3). His white blood cell and platelet counts were not remarkable at 9790/μL (reference range, 4500-11,000) and 337,000/μL (reference range, 150,000-440,000), respectively. Abdominal ultrasound and computed tomography (CT) revealed fatty liver with contracted gallbladder and no biliary dilatation. Urine ethanol levels were negative. The gastrointestinal (GI) service was consulted and agreed that his cholestatic injury was nonobstructive and likely related to the ashwagandha component of his supplement. The recommendation was cessation with close outpatient follow-up.

table 1

The patient was not prescribed any additional medications, such as steroids or ursodiol. He ceased supplement use following hospitalization; but relapsed into alcohol use 1 month after his discharge. Within 3 weeks, his total bilirubin had improved to 2.87 mg/dL, though AST, ALT, and ALP worsened to 127 U/L, 152 U/L, and 140 U/L, respectively. According to the notes of his psychiatrist who saw him at the time the laboratory tests were drawn, he had remained sober since discharge. His acute hepatitis panel drawn on admission was negative, and he demonstrated immunity to hepatitis A and B. Urine toxicology was negative. Antinuclear antibody (ANA) test was negative 1 year prior to discharge. Epstein-Barr virus (EBV), cytomegalovirus (CMV), ANA, antismooth muscle antibody, and immunoglobulins were not checked as suspicion for these etiologies was low. The Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated as 6 (+1 for timing, +2 for drop in total bilirubin, +1 for ethanol risk factor, 0 for no other drugs, 0 for rule out of other diseases, +2 for known hepatotoxicity, 0 no repeat administration) for this patient indicating probable adverse drug reaction liver injury (Tables 1 and 2). However, we acknowledge that CMV, EBV, and herpes simplex virus status were not tested.

table 2

The 8 ingredients contained in TestBoost aside from ashwagandha did not have any major known liver adverse effects per a major database of medications. The other ingredients include eleuthero root, Hawthorn berry (crataegus laevigata), longjack (eurycoma longifolla) root, American ginseng root (American panax ginseng—panax quinquefolius), and Cordyceps mycelium (mushroom) extract, bindii (Tribulus terrestris), and epimedium grandiflorum (horny goat weed).6 No assays were performed to confirm purity of the ingredients in the patient’s supplement container.

Alcoholic hepatitis is an important consideration in this patient with AUD, though the timing of symptoms with supplement use and the cholestatic injury pattern with normal INR seems more consistent with drug-induced injury. Viral, infectious, and obstructive etiologies also were investigated. Acute viral hepatitis was ruled out based on bloodwork. The normal hepatobiliary tree on both ultrasound and CT effectively ruled out acute cholecystitis, cholangitis, and choledocholithiasis and there was no further indication for magnetic resonance cholangiopancreatography. There was no hepatic vein clot suggestive of Budd-Chiari syndrome. Autoimmune hepatitis was thought to be unlikely given that the etiology of injury seemed cholestatic in nature. Given the timing of the liver injury relative to supplement use it is likely that ashwagandha was a causative factor of this patient’s liver injury overlaid on an already strained liver from increased alcohol abuse.

The patient did not follow up with the GI service as an outpatient. There are no reports that the patient continued using the testosterone booster. His bilirubin improved dramatically within 1.5 months while his liver enzymes peaked 3 weeks later, with ALT ≥ AST. During his next admission 3 months later, he had relapsed, and his liver enzymes had the classic 2:1 AST to ALT ratio.

 

 

Discussion

Generally, ashwagandha has been thought to be well tolerated and possibly hepatoprotective.7-10 However, recent studies suggest potential for hepatotoxicity, though without clear guidance about which patients are most at risk.5,11,12 A study by Inagaki and colleagues suggests the potential for dose-dependent mechanism of liver injury, and this is supported by in vitro CYP450 inhibition with high doses of W Somnifera extract.11,13 We hypothesize that there may be a multihit process that makes some patients more susceptible to supplement harm, particularly those with repeated exposures and with ongoing exposure to hepatic toxins, such as AUD.14 Supplements should be used with more caution in these individuals.

Additionally, although there are no validated guidelines to confirm the diagnosis of drug-induced liver injury (DILI) from a manufactured medication or herbal remedy, the Council for International Organizations of Medical Sciences (CIOMS) developed RUCAM, a set of diagnostic criteria for DILI, which can be used to determine the probability of DILI based on pattern of injury.15 Although not widely used in clinical practice, RUCAM can help identify the possibility of DILI outside of expert consensus.16 It seems to have better discriminative ability than the Maria and Victorino scale, also used to identify DILI.16,17 While there is no replacement for clinical judgment, these scales may aid in identifying potential causes of DILI. The National Institutes of Health also has a LiverTox online tool that can assist health care professionals in identifying potentially hepatotoxic substances.6

Conclusions

We present a patient with AUD who developed cholestatic liver injury after ashwagandha use. Crucial to the diagnostic process is quantifying the amount ingested before presentation and the presence of contaminants, which is currently difficult to quantify given the lack of mechanisms to test supplements expediently in this manner in the clinical setting, which also requires the patient to bring in the supplements directly. There is also a lack of regulation and uniformity in these products. A clinician may be inclined to measure ashwagandha serum levels; however, such a test is not available to our knowledge. Nonetheless, using clinical tools such as RUCAM and utilizing databases, such as LiverTox, may help clinicians identify and remove potentially unsafe supplements. While there are many possible synergies between current medical practice and herbal remedies, practitioners must take care to first do no harm, as outlined in our Hippocratic Oath.

References

1. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis. 2009;29(4):373-382. doi:10.1055/s-0029-1240006

2. Suk KT, Kim DJ, Kim CH, et al. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol. 2012;107(9):1380-1387. doi:10.1038/ajg.2012.138

3. Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in mainland China. Gastroenterology. 2019;156(8):2230-2241.e11. doi:10.1053/j.gastro.2019.02.002

4. Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60(4):1399-1408. doi:10.1002/hep.27317

5. Björnsson HK, Björnsson, Avula B, et al. (2020). Ashwagandha‐induced liver injury: a case series from Iceland and the US Drug‐Induced Liver Injury Network. Liver Int. 2020;40(4):825-829. doi:10.1111/liv.14393

6. National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: clinical and research information on drug-induced liver injury [internet]. Ashwagandha. Updated May 2, 2019. Accessed August 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK548536

7. Kumar G, Srivastava A, Sharma SK, Rao TD, Gupta YK. Efficacy and safety evaluation of Ayurvedic treatment (ashwagandha powder & Sidh Makardhwaj) in rheumatoid arthritis patients: a pilot prospective study. Indian J Med Res. 2015;141(1):100-106. doi:10.4103/0971-5916.154510

8. Kumar G, Srivastava A, Sharma SK, Gupta YK. Safety and efficacy evaluation of Ayurvedic treatment (arjuna powder and Arogyavardhini Vati) in dyslipidemia patients: a pilot prospective cohort clinical study. 2012;33(2):197-201. doi:10.4103/0974-8520.105238

9. Sultana N, Shimmi S, Parash MT, Akhtar J. Effects of ashwagandha (Withania somnifera) root extract on some serum liver marker enzymes (AST, ALT) in gentamicin intoxicated rats. J Bangladesh Soc Physiologist. 2012;7(1): 1-7. doi:10.3329/JBSP.V7I1.11152

10. Patel DP, Yan T, Kim D, et al. Withaferin A improves nonalcoholic steatohepatitis in mice. J Pharmacol Exp Ther. 2019;371(2):360-374. doi:10.1124/jpet.119.256792

11. Inagaki K, Mori N, Honda Y, Takaki S, Tsuji K, Chayama K. A case of drug-induced liver injury with prolonged severe intrahepatic cholestasis induced by ashwagandha. Kanzo. 2017;58(8):448-454. doi:10.2957/kanzo.58.448

12. Alali F, Hermez K, Ullah N. Acute hepatitis induced by a unique combination of herbal supplements. Am J Gastroenterol. 2018;113:S1661.

13. Sava J, Varghese A, Pandita N. Lack of the cytochrome P450 3A interaction of methanolic extract of Withania somnifera, Withaferin A, Withanolide A and Withanoside IV. J Pharm Negative Results. 2013;4(1):26.

14. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474-485. doi:10.1056/NEJMra021844.

15. Danan G, Benichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of International Consensus Meeting: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323–1333. doi:10.1016/0895-4356(93)90101-6

16. Hayashi PH. Causality assessment in drug-induced liver injury. Semin Liver Dis. 2009;29(4):348-356. doi.10.1002/cld.615

17. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 2001;33(1):123-130. doi:10.1053/jhep.2001.20645

References

1. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis. 2009;29(4):373-382. doi:10.1055/s-0029-1240006

2. Suk KT, Kim DJ, Kim CH, et al. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol. 2012;107(9):1380-1387. doi:10.1038/ajg.2012.138

3. Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in mainland China. Gastroenterology. 2019;156(8):2230-2241.e11. doi:10.1053/j.gastro.2019.02.002

4. Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60(4):1399-1408. doi:10.1002/hep.27317

5. Björnsson HK, Björnsson, Avula B, et al. (2020). Ashwagandha‐induced liver injury: a case series from Iceland and the US Drug‐Induced Liver Injury Network. Liver Int. 2020;40(4):825-829. doi:10.1111/liv.14393

6. National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: clinical and research information on drug-induced liver injury [internet]. Ashwagandha. Updated May 2, 2019. Accessed August 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK548536

7. Kumar G, Srivastava A, Sharma SK, Rao TD, Gupta YK. Efficacy and safety evaluation of Ayurvedic treatment (ashwagandha powder & Sidh Makardhwaj) in rheumatoid arthritis patients: a pilot prospective study. Indian J Med Res. 2015;141(1):100-106. doi:10.4103/0971-5916.154510

8. Kumar G, Srivastava A, Sharma SK, Gupta YK. Safety and efficacy evaluation of Ayurvedic treatment (arjuna powder and Arogyavardhini Vati) in dyslipidemia patients: a pilot prospective cohort clinical study. 2012;33(2):197-201. doi:10.4103/0974-8520.105238

9. Sultana N, Shimmi S, Parash MT, Akhtar J. Effects of ashwagandha (Withania somnifera) root extract on some serum liver marker enzymes (AST, ALT) in gentamicin intoxicated rats. J Bangladesh Soc Physiologist. 2012;7(1): 1-7. doi:10.3329/JBSP.V7I1.11152

10. Patel DP, Yan T, Kim D, et al. Withaferin A improves nonalcoholic steatohepatitis in mice. J Pharmacol Exp Ther. 2019;371(2):360-374. doi:10.1124/jpet.119.256792

11. Inagaki K, Mori N, Honda Y, Takaki S, Tsuji K, Chayama K. A case of drug-induced liver injury with prolonged severe intrahepatic cholestasis induced by ashwagandha. Kanzo. 2017;58(8):448-454. doi:10.2957/kanzo.58.448

12. Alali F, Hermez K, Ullah N. Acute hepatitis induced by a unique combination of herbal supplements. Am J Gastroenterol. 2018;113:S1661.

13. Sava J, Varghese A, Pandita N. Lack of the cytochrome P450 3A interaction of methanolic extract of Withania somnifera, Withaferin A, Withanolide A and Withanoside IV. J Pharm Negative Results. 2013;4(1):26.

14. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474-485. doi:10.1056/NEJMra021844.

15. Danan G, Benichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of International Consensus Meeting: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323–1333. doi:10.1016/0895-4356(93)90101-6

16. Hayashi PH. Causality assessment in drug-induced liver injury. Semin Liver Dis. 2009;29(4):348-356. doi.10.1002/cld.615

17. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 2001;33(1):123-130. doi:10.1053/jhep.2001.20645

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Upadacitinib an effective treatment option in AD patients with recent discontinuation of dupilumab

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Changed
Wed, 10/04/2023 - 13:02

Key clinical point: Upadacitinib was safe and effective in patients with atopic dermatitis (AD) who recently discontinued dupilumab therapy due to lack of desired efficacy or an adverse event (AE).

Major finding: By week 16, a ≥75% improvement in the Eczema Area and Severity Index score or an Investigator’s Global Assessment score of 0 or 1 was achieved by 75% and 81.8% of patients receiving 15 mg and 30 mg upadacitinib, respectively. The treatment-related AE rate was 30.7%, and none of the patients discontinued treatment during the 16-week treatment period.

Study details: Findings are from a real-world multicenter retrospective study that included 39 adult patients with AD who were treated with upadacitinib after discontinuing treatment with dupilumab due to inefficacy or an AE.

Disclosures: This study did not receive any funding. Two authors declared serving as advisors, consultants, speakers, or investigators for various organizations. The other authors declared no conflicts of interest.

Source: Georgakopoulos JR et al. Real-world effectiveness and safety of upadacitinib for the treatment of atopic dermatitis in adult patients switched from dupilumab: A multicenter retrospective study. J Am Acad Dermatol. 2023 (Aug 28). doi: 10.1016/j.jaad.2023.08.059

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Key clinical point: Upadacitinib was safe and effective in patients with atopic dermatitis (AD) who recently discontinued dupilumab therapy due to lack of desired efficacy or an adverse event (AE).

Major finding: By week 16, a ≥75% improvement in the Eczema Area and Severity Index score or an Investigator’s Global Assessment score of 0 or 1 was achieved by 75% and 81.8% of patients receiving 15 mg and 30 mg upadacitinib, respectively. The treatment-related AE rate was 30.7%, and none of the patients discontinued treatment during the 16-week treatment period.

Study details: Findings are from a real-world multicenter retrospective study that included 39 adult patients with AD who were treated with upadacitinib after discontinuing treatment with dupilumab due to inefficacy or an AE.

Disclosures: This study did not receive any funding. Two authors declared serving as advisors, consultants, speakers, or investigators for various organizations. The other authors declared no conflicts of interest.

Source: Georgakopoulos JR et al. Real-world effectiveness and safety of upadacitinib for the treatment of atopic dermatitis in adult patients switched from dupilumab: A multicenter retrospective study. J Am Acad Dermatol. 2023 (Aug 28). doi: 10.1016/j.jaad.2023.08.059

Key clinical point: Upadacitinib was safe and effective in patients with atopic dermatitis (AD) who recently discontinued dupilumab therapy due to lack of desired efficacy or an adverse event (AE).

Major finding: By week 16, a ≥75% improvement in the Eczema Area and Severity Index score or an Investigator’s Global Assessment score of 0 or 1 was achieved by 75% and 81.8% of patients receiving 15 mg and 30 mg upadacitinib, respectively. The treatment-related AE rate was 30.7%, and none of the patients discontinued treatment during the 16-week treatment period.

Study details: Findings are from a real-world multicenter retrospective study that included 39 adult patients with AD who were treated with upadacitinib after discontinuing treatment with dupilumab due to inefficacy or an AE.

Disclosures: This study did not receive any funding. Two authors declared serving as advisors, consultants, speakers, or investigators for various organizations. The other authors declared no conflicts of interest.

Source: Georgakopoulos JR et al. Real-world effectiveness and safety of upadacitinib for the treatment of atopic dermatitis in adult patients switched from dupilumab: A multicenter retrospective study. J Am Acad Dermatol. 2023 (Aug 28). doi: 10.1016/j.jaad.2023.08.059

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No association between dupilumab treatment and risk for arthralgia in atopic dermatitis

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Wed, 10/04/2023 - 12:59

Key clinical point: Treatment with dupilumab vs cyclosporine or mycophenolate is not associated with an increased risk for arthralgia in patients with atopic dermatitis (AD).

Major finding: The pooled 180-day incidence rate of arthralgia for dupilumab vs cyclosporine or mycophenolate was 100.7 vs 65.4/1000 person-years (adjusted hazard ratio 1.27; 95% CI 0.93-1.72).

Study details: Findings are from a cohort study that included patients age < 50 years with AD who initiated treatment with either dupilumab (n = 4011) or cyclosporine/mycophenolate (n = 2220).

Disclosures: This study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, USA. Some authors declared serving as consultants or investigators for or receiving research grants from various sources.

Source: Schneeweiss MC et al. Joint pain in patients with atopic dermatitis receiving treatment with dupilumab: A US nation-wide cohort study. J Am Acad Dermatol. 2023 (Aug 18). doi: 10.1016/j.jaad.2023.08.025

 

 

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Key clinical point: Treatment with dupilumab vs cyclosporine or mycophenolate is not associated with an increased risk for arthralgia in patients with atopic dermatitis (AD).

Major finding: The pooled 180-day incidence rate of arthralgia for dupilumab vs cyclosporine or mycophenolate was 100.7 vs 65.4/1000 person-years (adjusted hazard ratio 1.27; 95% CI 0.93-1.72).

Study details: Findings are from a cohort study that included patients age < 50 years with AD who initiated treatment with either dupilumab (n = 4011) or cyclosporine/mycophenolate (n = 2220).

Disclosures: This study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, USA. Some authors declared serving as consultants or investigators for or receiving research grants from various sources.

Source: Schneeweiss MC et al. Joint pain in patients with atopic dermatitis receiving treatment with dupilumab: A US nation-wide cohort study. J Am Acad Dermatol. 2023 (Aug 18). doi: 10.1016/j.jaad.2023.08.025

 

 

Key clinical point: Treatment with dupilumab vs cyclosporine or mycophenolate is not associated with an increased risk for arthralgia in patients with atopic dermatitis (AD).

Major finding: The pooled 180-day incidence rate of arthralgia for dupilumab vs cyclosporine or mycophenolate was 100.7 vs 65.4/1000 person-years (adjusted hazard ratio 1.27; 95% CI 0.93-1.72).

Study details: Findings are from a cohort study that included patients age < 50 years with AD who initiated treatment with either dupilumab (n = 4011) or cyclosporine/mycophenolate (n = 2220).

Disclosures: This study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, USA. Some authors declared serving as consultants or investigators for or receiving research grants from various sources.

Source: Schneeweiss MC et al. Joint pain in patients with atopic dermatitis receiving treatment with dupilumab: A US nation-wide cohort study. J Am Acad Dermatol. 2023 (Aug 18). doi: 10.1016/j.jaad.2023.08.025

 

 

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Patients with non-alcoholic fatty liver disease have a lower risk for atopic dermatitis

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Changed
Wed, 10/04/2023 - 12:55

Key clinical point: Patients with non-alcoholic fatty liver disease (NAFLD), especially younger patients, have a significantly decreased risk of developing atopic dermatitis (AD).

Major finding: The risk for AD was significantly lower among patients with NAFLD (adjusted hazard ratio [aHR] 0.93; P = .024), particularly those age ≤ 40 years (aHR 0.80; P < .001), compared with control individuals without NAFLD.

Study details: This retrospective cohort study included 307,743 patients with NAFLD and 1,230,972 matched control individuals without NAFLD.

Disclosures: This study was funded by the Chung Shan Medical University Hospital and China Medical University, Taiwan. The authors declared no conflicts of interest.

Source: Gau SY et al. The association between non-alcoholic fatty liver disease and atopic dermatitis: A population-based cohort study. Front Immunol. 2023;14:1171804 (Aug 18). doi: 10.3389/fimmu.2023.1171804

 

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Key clinical point: Patients with non-alcoholic fatty liver disease (NAFLD), especially younger patients, have a significantly decreased risk of developing atopic dermatitis (AD).

Major finding: The risk for AD was significantly lower among patients with NAFLD (adjusted hazard ratio [aHR] 0.93; P = .024), particularly those age ≤ 40 years (aHR 0.80; P < .001), compared with control individuals without NAFLD.

Study details: This retrospective cohort study included 307,743 patients with NAFLD and 1,230,972 matched control individuals without NAFLD.

Disclosures: This study was funded by the Chung Shan Medical University Hospital and China Medical University, Taiwan. The authors declared no conflicts of interest.

Source: Gau SY et al. The association between non-alcoholic fatty liver disease and atopic dermatitis: A population-based cohort study. Front Immunol. 2023;14:1171804 (Aug 18). doi: 10.3389/fimmu.2023.1171804

 

Key clinical point: Patients with non-alcoholic fatty liver disease (NAFLD), especially younger patients, have a significantly decreased risk of developing atopic dermatitis (AD).

Major finding: The risk for AD was significantly lower among patients with NAFLD (adjusted hazard ratio [aHR] 0.93; P = .024), particularly those age ≤ 40 years (aHR 0.80; P < .001), compared with control individuals without NAFLD.

Study details: This retrospective cohort study included 307,743 patients with NAFLD and 1,230,972 matched control individuals without NAFLD.

Disclosures: This study was funded by the Chung Shan Medical University Hospital and China Medical University, Taiwan. The authors declared no conflicts of interest.

Source: Gau SY et al. The association between non-alcoholic fatty liver disease and atopic dermatitis: A population-based cohort study. Front Immunol. 2023;14:1171804 (Aug 18). doi: 10.3389/fimmu.2023.1171804

 

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Reduction in S aureus skin infections may reduce the risk for eczema herpeticum in atopic dermatitis

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Wed, 10/04/2023 - 12:52
Display Headline
Reduction in S aureus skin infections may reduce the risk for eczema herpeticum in atopic dermatitis

Key clinical point: Among patients with atopic dermatitis (AD), those with vs without a history of Staphylococcus aureus skin infections have significantly higher odds of having a history of eczema herpeticum (EH).

Major finding: Patients with AD and with vs without a history of S aureus skin infections had a 6.60-fold increased risk of having a history of EH (adjusted odds ratio 6.60; P = .002).

Study details: This multicenter, clinical registry study included 112 patients with AD and with (n = 56) or without (n = 56) a history of EH, matched by age and AD severity.

Disclosures: This study was supported partly by a National Eczema Association Engagement Research Grant. Several authors declared serving as consultants or investigator for or receiving grants, personal fees, or clinical trial support from various organizations.

Source: Moran MC et al. History of S. aureus skin infection significantly associates with history of eczema herpeticum in patients with atopic dermatitis. Dermatol Ther (Heidelb). 2023 (Aug 24). doi: 10.1007/s13555-023-00996-y

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Key clinical point: Among patients with atopic dermatitis (AD), those with vs without a history of Staphylococcus aureus skin infections have significantly higher odds of having a history of eczema herpeticum (EH).

Major finding: Patients with AD and with vs without a history of S aureus skin infections had a 6.60-fold increased risk of having a history of EH (adjusted odds ratio 6.60; P = .002).

Study details: This multicenter, clinical registry study included 112 patients with AD and with (n = 56) or without (n = 56) a history of EH, matched by age and AD severity.

Disclosures: This study was supported partly by a National Eczema Association Engagement Research Grant. Several authors declared serving as consultants or investigator for or receiving grants, personal fees, or clinical trial support from various organizations.

Source: Moran MC et al. History of S. aureus skin infection significantly associates with history of eczema herpeticum in patients with atopic dermatitis. Dermatol Ther (Heidelb). 2023 (Aug 24). doi: 10.1007/s13555-023-00996-y

Key clinical point: Among patients with atopic dermatitis (AD), those with vs without a history of Staphylococcus aureus skin infections have significantly higher odds of having a history of eczema herpeticum (EH).

Major finding: Patients with AD and with vs without a history of S aureus skin infections had a 6.60-fold increased risk of having a history of EH (adjusted odds ratio 6.60; P = .002).

Study details: This multicenter, clinical registry study included 112 patients with AD and with (n = 56) or without (n = 56) a history of EH, matched by age and AD severity.

Disclosures: This study was supported partly by a National Eczema Association Engagement Research Grant. Several authors declared serving as consultants or investigator for or receiving grants, personal fees, or clinical trial support from various organizations.

Source: Moran MC et al. History of S. aureus skin infection significantly associates with history of eczema herpeticum in patients with atopic dermatitis. Dermatol Ther (Heidelb). 2023 (Aug 24). doi: 10.1007/s13555-023-00996-y

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Reduction in S aureus skin infections may reduce the risk for eczema herpeticum in atopic dermatitis
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Dupilumab rapidly controls atopic dermatitis symptoms in children

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Wed, 10/04/2023 - 12:46

Key clinical point: Dupilumab rapidly improves the severity of atopic dermatitis (AD) symptoms and shows a favorable safety profile in children with moderate-to-severe AD.

Major finding: Dupilumab significantly reduced the mean Eczema Area and Severity Index (EASI) score at weeks 16, 24, and 52 (all P < .0001) and from weeks 16 to 24 (P < .01) and weeks 16 to 52 (P < .001). By week 52, 86.8% of patients had achieved a ≥ 75% improvement in the EASI score. No serious adverse events were observed, and none of the children discontinued treatment.

Study details: Findings are from a retrospective, observational, real-life study including 96 children (age 6-11 years) with moderate-to-severe AD inadequately controlled with conventional topical therapies who received dupilumab (300 mg on days 1 and 15 and 300 mg every 4 weeks).

Disclosures: This study did not receive any funding. Several authors reported receiving honoraria, travel support, or personal fees from or serving as consultants, investigators, speakers, or advisory board members for or having other ties with various sources.

Source: Patruno C et al. A 52-week multicenter retrospective real-world study on effectiveness and safety of dupilumab in children with atopic dermatitis aged from 6 to 11 years. J Dermatolog Treat. 2023;34:2246602 (Aug 14). doi: 10.1080/09546634.2023.2246602

 

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Key clinical point: Dupilumab rapidly improves the severity of atopic dermatitis (AD) symptoms and shows a favorable safety profile in children with moderate-to-severe AD.

Major finding: Dupilumab significantly reduced the mean Eczema Area and Severity Index (EASI) score at weeks 16, 24, and 52 (all P < .0001) and from weeks 16 to 24 (P < .01) and weeks 16 to 52 (P < .001). By week 52, 86.8% of patients had achieved a ≥ 75% improvement in the EASI score. No serious adverse events were observed, and none of the children discontinued treatment.

Study details: Findings are from a retrospective, observational, real-life study including 96 children (age 6-11 years) with moderate-to-severe AD inadequately controlled with conventional topical therapies who received dupilumab (300 mg on days 1 and 15 and 300 mg every 4 weeks).

Disclosures: This study did not receive any funding. Several authors reported receiving honoraria, travel support, or personal fees from or serving as consultants, investigators, speakers, or advisory board members for or having other ties with various sources.

Source: Patruno C et al. A 52-week multicenter retrospective real-world study on effectiveness and safety of dupilumab in children with atopic dermatitis aged from 6 to 11 years. J Dermatolog Treat. 2023;34:2246602 (Aug 14). doi: 10.1080/09546634.2023.2246602

 

Key clinical point: Dupilumab rapidly improves the severity of atopic dermatitis (AD) symptoms and shows a favorable safety profile in children with moderate-to-severe AD.

Major finding: Dupilumab significantly reduced the mean Eczema Area and Severity Index (EASI) score at weeks 16, 24, and 52 (all P < .0001) and from weeks 16 to 24 (P < .01) and weeks 16 to 52 (P < .001). By week 52, 86.8% of patients had achieved a ≥ 75% improvement in the EASI score. No serious adverse events were observed, and none of the children discontinued treatment.

Study details: Findings are from a retrospective, observational, real-life study including 96 children (age 6-11 years) with moderate-to-severe AD inadequately controlled with conventional topical therapies who received dupilumab (300 mg on days 1 and 15 and 300 mg every 4 weeks).

Disclosures: This study did not receive any funding. Several authors reported receiving honoraria, travel support, or personal fees from or serving as consultants, investigators, speakers, or advisory board members for or having other ties with various sources.

Source: Patruno C et al. A 52-week multicenter retrospective real-world study on effectiveness and safety of dupilumab in children with atopic dermatitis aged from 6 to 11 years. J Dermatolog Treat. 2023;34:2246602 (Aug 14). doi: 10.1080/09546634.2023.2246602

 

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Implementation of an Automated Phone Call Distribution System in an Inpatient Pharmacy Setting

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Changed
Fri, 09/15/2023 - 19:45

Pharmacy call centers have been successfully implemented in outpatient and specialty pharmacy settings.1 A centralized pharmacy call center gives patients immediate access to a pharmacist who can view their health records to answer specific questions or fulfill medication renewal requests.2-4 Little literature exists to describe its use in an inpatient setting.

Inpatient pharmacies receive numerous calls from health care professionals and patients. Challenges related to phone calls in the inpatient pharmacy setting may include interruptions, distractions, low accountability, poor efficiency, lack of optimal resources, and staffing.5 An unequal distribution and lack of accountability may exist when answering phone calls for the inpatient pharmacy team, which may contribute to long hold times and call abandonment rates. Phone calls also may be directed inefficiently between clinical pharmacists (CPs) and pharmacy technicians. Team member time related to answering phone calls may not be captured or measured.

The Edward Hines, Jr. Veterans Affairs Hospital (EHJVAH) in Illinois offers primary, extended, and specialty care and is a tertiary care referral center. The facility operates 483 beds and serves 6 community-based outpatient clinics.

table 1
The pharmacy leadership team decided to evaluate accountability, efficiency, and resources related to phone calls through the implementation of an automated call distribution (ACD) phone system in the inpatient pharmacy setting and capture potential workload metrics (Table 1).

Implementation

A new inpatient pharmacy service phone line extension was implemented. Data used to report quality metrics were obtained from the Global Navigator (GNAV), an information system that records calls, tracks the performance of agents, and coordinates personnel scheduling. The effectiveness of the ACD system was evaluated by quality metric goals of mean speed to answer ≤ 30 seconds and mean abandonment rate ≤ 5%. This project was determined to be quality improvement and was not reviewed by the EHJVAH Institutional Review Board.

The ACD system was set up in December 2020. After a 1-month implementation period, metrics were reported to the inpatient pharmacy team and leadership. By January 2021, EHJVAH fully implemented an ACD phone system operated by inpatient pharmacy technicians and CPs. EHJVAH inpatient pharmacy includes CPs who practice without a scope of practice and board-certified pharmacy technicians in 3 shifts. The CPs and pharmacy technicians work in the central pharmacy (the main pharmacy and inpatient pharmacy vault) or are decentralized with responsibility for answering phone calls and making deliveries (pharmacy technicians).

The pharmacy leadership team decided to implement 1 phone line with 2 ACD splits. The first split was directed to pharmacy technicians and the second to CPs. The intention was to streamline calls to be directed to proper team members within the inpatient pharmacy. The CP line also was designed to back up the pharmacy technician line. These calls were equally distributed among staff based on a standard algorithm. The pharmacy greeting stated, “Thank you for contacting the inpatient pharmacy at Hines VA Hospital. For missing doses, unit stock requests, or to speak with a pharmacy technician, please press 1. For clinical questions, order verification, or to speak with a pharmacist, please press 2.” Each inpatient pharmacy team member had a unique system login.

Fourteen ACD phone stations were established in the main pharmacy and in decentralized locations for order verification. The stations were distributed across the pharmacy service to optimize workload, space, and resources.

 

 

Training and Communication

Before implementing the inpatient pharmacy ACD phone system, the CPs and pharmacy technicians received mandatory ACD training. After the training, pharmacy team members were required to sign off on the training document to indicate that they had completed the course. The pharmacy team was trained on the importance of staffing the phones continuously. As a 24-hour pharmacy service in the acute care setting, any call may be critical for patient care.

A hospital-wide memorandum was distributed via email to all unit managers and hospital staff to educate them on the new ACD phone system, which included a new phone line extension for the inpatient pharmacy. Additionally, the inpatient pharmacy team was trained on the proper way of communicating the ACD phone system process with the hospital staff. The inpatient pharmacy team was notified that there would be an educational period to explain the queue process to hospital staff. Occasionally, hospital staff believed they were speaking to an automated system and hung up before their call was answered. The inpatient pharmacy team was instructed to notify the hospital staff to stay on the line since their call would be answered in the order it was received. Once the inpatient pharmacy team received proper training and felt comfortable with the phone system, it was set up and integrated into the workflow.

Postimplementation Evaluation

Inpatient pharmacy ACD phone system data were collected for 2021. To evaluate the effectiveness of an ACD system, the pharmacy leadership team set up the following metrics and goals for inpatient CPs and inpatient pharmacy technicians for monthly call volume/abandonment rate, mean speed to answer, mean call volume by shift, and the mean abandonment rate by shift.

table 2
Inpatient CPs answered 24,075 calls with a mean call abandonment rate of 4.7%. and a mean 13.1 seconds to answer (Table 2). The highest call volume for inpatient CPs was during the first shift (8 AM to 4 PM) (Figure 1).
figure 1
The highest abandonment rate for inpatient CPs was during the third shift (midnight to 8 AM) (Figure 2).

Inpatient pharmacy technicians answered 27,655 calls with a mean call abandonment rate of 4.7%. and a mean 15.6 seconds to answer.
figure 2
Besides January 2021, the highest call volume for inpatient pharmacy technicians was during the first shift. The highest abandonment rate for inpatient pharmacy technicians was during the third shift.

Discussion

Since implementing the inpatient pharmacy ACD phone system in January 2021, there have been successes and challenges. The implementation increased accountability and efficiency when answering pharmacy phone calls. An ACD uses an algorithm that ensures equitable distribution of phone calls between CPs and pharmacy technicians. Through this algorithm, the pharmacy team is held more accountable when answering incoming calls. Distributing phone calls equally allows for optimization and balances the workload. The ACD phone system also improved efficiency when answering incoming calls. By incorporating splits when a patient or health care professional calls, ACD routes the question to the appropriate staff member. As a result, CPs spend less time answering questions meant for pharmacy technicians and instead can answer clinical or order verification questions more efficiently.

 

 

ACD data also allow pharmacy leadership to assess staffing needs, depending on the call volume. Based on ACD data, the busiest time of day was 8:00 AM to 4:00 PM. Based on this information, pharmacy leadership plans to staff more appropriately to have more pharmacy technicians working during the first shift to attend to phone calls.

The mean call abandonment rate was 4.7% for both CPs and pharmacy technicians, which met the ≤ 5% goal. The highest call abandonment rate was from midnight to 8 AM, though this shift also experienced the lowest call volume. This trend may be attributed to fewer pharmacy team members available to meet the demands of the overnight shift.

Pharmacy technicians handled a higher total call volume, which may be attributed to more phone calls related to missing doses or unit stock requests compared with clinical questions or order verifications. This information may be beneficial to identify opportunities to improve pharmacy operations.

The main challenges encountered in the ACD implementation process were hardware installation and communication with hospital staff about the changes in the inpatient pharmacy phone system. To implement the new inpatient pharmacy ACD phone system, previous telephones and hardware were removed and replaced. Initially, hardware and installation delays made it difficult for the ACD phone system to operate efficiently in the early months of its implementation. The inpatient pharmacy team depends on the telecommunications system and computers for their daily activities. Delays and issues with the hardware and ACD phone system made it more difficult to provide patient care.

Communication is a continuous challenge to ensure that hospital staff are notified of the new inpatient pharmacy ACD phone number. Over time, the understanding and use of the new ACD phone system have increased dramatically, but there are still opportunities to capture any misdirected calls. Informal feedback was obtained at pharmacy huddles and 1-on-1 discussions with pharmacy staff, and the opinions were mixed. Members of the pharmacy staff expressed that the ACD phone system set up an effective way to triage phone calls. Another positive comment was that the system created a means of accountability for pharmacy phone calls. Critical feedback included challenges with triaging phone calls to appropriate pharmacists, because calls are assigned based on an algorithm, whereas clinical coverage is determined by designated unit daily assignments.

Limitations

There are potential limitations to this quality improvement project. This phone system may not apply to all inpatient hospital pharmacy settings. Potential limitations for implementation at other institutions may include but are not limited to, differing pharmacy practice models (centralized vs decentralized), implementation costs, and internal resources.

Future Goals

To improve the quality of service provided to patients and other hospital staff, the pharmacy leadership team can use the data to ensure that inpatient pharmacy technician resources are being used effectively during times of day with the greatest number of incoming ACD calls. The ACD phone system helps determine whether current resources are being used most efficiently and if they are not, can help identify areas of improvement.

 

 

The pharmacy leadership team plans on using reports for pharmacy team members to monitor performance. Reports on individual agent activity capture workload; this may be used as a performance-related metric for future performance plans.

Conclusions

The inpatient pharmacy ACD phone system at EHJVAH is a promising application of available technology. The implementation of the ACD system improved accountability, efficiency, work distribution, and the allocation of resources in the inpatient pharmacy service. The ACD phone system has yielded positive performance metrics including mean speed to answer ≤ 30 seconds and abandonment rate ≤ 5% over 12 months after implementation. With time, users of the inpatient pharmacy ACD phone system will become more comfortable with the technology, thus further improving the patient health care quality.

References

1. Rim MH, Thomas KC, Chandramouli J, Barrus SA, Nickman NA. Implementation and quality assessment of a pharmacy services call center for outpatient pharmacies and specialty pharmacy services in an academic health system. Am J Health Syst Pharm. 2018;75(10):633-641. doi:10.2146/ajhp170319

2. Patterson BJ, Doucette WR, Urmie JM, McDonough RP. Exploring relationships among pharmacy service use, patronage motives, and patient satisfaction. J Am Pharm Assoc (2003). 2013;53(4):382-389. doi:10.1331/JAPhA.2013.12100

3. Walker DM, Sieck CJ, Menser T, Huerta TR, Scheck McAlearney A. Information technology to support patient engagement: where do we stand and where can we go?. J Am Med Inform Assoc. 2017;24(6):1088-1094. doi:10.1093/jamia/ocx043

4. Menichetti J, Libreri C, Lozza E, Graffigna G. Giving patients a starring role in their own care: a bibliometric analysis of the on-going literature debate. Health Expect. 2016;19(3):516-526. doi:10.1111/hex.12299

5. Raimbault M, Guérin A, Caron É, Lebel D, Bussières J-F. Identifying and reducing distractions and interruptions in a pharmacy department. Am J Health Syst Pharm. 2013;70(3):186-190. doi:10.2146/ajhp120344

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Samaneh Ghassemi, PharmDa; Freddy Tadros, PharmD, DPLAb; Elizabeth Stone, PharmDc; Joelle Farano, PharmD, MBAc

Correspondence:  Joelle Farano  ([email protected])

aVeterans Affairs Center for Medication Safety (VA MedSAFE), Hines, Illinois

bUS Department of Veterans Affairs Great Lakes Consolidated Mail Outpatient Pharmacy and Veterans Affairs Emergency Pharmacy Service, Hines, Illinois

cEdward Hines Jr. Veterans Affairs Hospital, Hines, Illinois

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Ethics and consent

The Edward Hines Veterans Affairs Hospital Institutional Review Board (IRB) formally determined that this project was not considered research, and thus was exempt from IRB review.

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aVeterans Affairs Center for Medication Safety (VA MedSAFE), Hines, Illinois

bUS Department of Veterans Affairs Great Lakes Consolidated Mail Outpatient Pharmacy and Veterans Affairs Emergency Pharmacy Service, Hines, Illinois

cEdward Hines Jr. Veterans Affairs Hospital, Hines, Illinois

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Ethics and consent

The Edward Hines Veterans Affairs Hospital Institutional Review Board (IRB) formally determined that this project was not considered research, and thus was exempt from IRB review.

Author and Disclosure Information

Samaneh Ghassemi, PharmDa; Freddy Tadros, PharmD, DPLAb; Elizabeth Stone, PharmDc; Joelle Farano, PharmD, MBAc

Correspondence:  Joelle Farano  ([email protected])

aVeterans Affairs Center for Medication Safety (VA MedSAFE), Hines, Illinois

bUS Department of Veterans Affairs Great Lakes Consolidated Mail Outpatient Pharmacy and Veterans Affairs Emergency Pharmacy Service, Hines, Illinois

cEdward Hines Jr. Veterans Affairs Hospital, Hines, Illinois

Author disclosures

The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Ethics and consent

The Edward Hines Veterans Affairs Hospital Institutional Review Board (IRB) formally determined that this project was not considered research, and thus was exempt from IRB review.

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Article PDF

Pharmacy call centers have been successfully implemented in outpatient and specialty pharmacy settings.1 A centralized pharmacy call center gives patients immediate access to a pharmacist who can view their health records to answer specific questions or fulfill medication renewal requests.2-4 Little literature exists to describe its use in an inpatient setting.

Inpatient pharmacies receive numerous calls from health care professionals and patients. Challenges related to phone calls in the inpatient pharmacy setting may include interruptions, distractions, low accountability, poor efficiency, lack of optimal resources, and staffing.5 An unequal distribution and lack of accountability may exist when answering phone calls for the inpatient pharmacy team, which may contribute to long hold times and call abandonment rates. Phone calls also may be directed inefficiently between clinical pharmacists (CPs) and pharmacy technicians. Team member time related to answering phone calls may not be captured or measured.

The Edward Hines, Jr. Veterans Affairs Hospital (EHJVAH) in Illinois offers primary, extended, and specialty care and is a tertiary care referral center. The facility operates 483 beds and serves 6 community-based outpatient clinics.

table 1
The pharmacy leadership team decided to evaluate accountability, efficiency, and resources related to phone calls through the implementation of an automated call distribution (ACD) phone system in the inpatient pharmacy setting and capture potential workload metrics (Table 1).

Implementation

A new inpatient pharmacy service phone line extension was implemented. Data used to report quality metrics were obtained from the Global Navigator (GNAV), an information system that records calls, tracks the performance of agents, and coordinates personnel scheduling. The effectiveness of the ACD system was evaluated by quality metric goals of mean speed to answer ≤ 30 seconds and mean abandonment rate ≤ 5%. This project was determined to be quality improvement and was not reviewed by the EHJVAH Institutional Review Board.

The ACD system was set up in December 2020. After a 1-month implementation period, metrics were reported to the inpatient pharmacy team and leadership. By January 2021, EHJVAH fully implemented an ACD phone system operated by inpatient pharmacy technicians and CPs. EHJVAH inpatient pharmacy includes CPs who practice without a scope of practice and board-certified pharmacy technicians in 3 shifts. The CPs and pharmacy technicians work in the central pharmacy (the main pharmacy and inpatient pharmacy vault) or are decentralized with responsibility for answering phone calls and making deliveries (pharmacy technicians).

The pharmacy leadership team decided to implement 1 phone line with 2 ACD splits. The first split was directed to pharmacy technicians and the second to CPs. The intention was to streamline calls to be directed to proper team members within the inpatient pharmacy. The CP line also was designed to back up the pharmacy technician line. These calls were equally distributed among staff based on a standard algorithm. The pharmacy greeting stated, “Thank you for contacting the inpatient pharmacy at Hines VA Hospital. For missing doses, unit stock requests, or to speak with a pharmacy technician, please press 1. For clinical questions, order verification, or to speak with a pharmacist, please press 2.” Each inpatient pharmacy team member had a unique system login.

Fourteen ACD phone stations were established in the main pharmacy and in decentralized locations for order verification. The stations were distributed across the pharmacy service to optimize workload, space, and resources.

 

 

Training and Communication

Before implementing the inpatient pharmacy ACD phone system, the CPs and pharmacy technicians received mandatory ACD training. After the training, pharmacy team members were required to sign off on the training document to indicate that they had completed the course. The pharmacy team was trained on the importance of staffing the phones continuously. As a 24-hour pharmacy service in the acute care setting, any call may be critical for patient care.

A hospital-wide memorandum was distributed via email to all unit managers and hospital staff to educate them on the new ACD phone system, which included a new phone line extension for the inpatient pharmacy. Additionally, the inpatient pharmacy team was trained on the proper way of communicating the ACD phone system process with the hospital staff. The inpatient pharmacy team was notified that there would be an educational period to explain the queue process to hospital staff. Occasionally, hospital staff believed they were speaking to an automated system and hung up before their call was answered. The inpatient pharmacy team was instructed to notify the hospital staff to stay on the line since their call would be answered in the order it was received. Once the inpatient pharmacy team received proper training and felt comfortable with the phone system, it was set up and integrated into the workflow.

Postimplementation Evaluation

Inpatient pharmacy ACD phone system data were collected for 2021. To evaluate the effectiveness of an ACD system, the pharmacy leadership team set up the following metrics and goals for inpatient CPs and inpatient pharmacy technicians for monthly call volume/abandonment rate, mean speed to answer, mean call volume by shift, and the mean abandonment rate by shift.

table 2
Inpatient CPs answered 24,075 calls with a mean call abandonment rate of 4.7%. and a mean 13.1 seconds to answer (Table 2). The highest call volume for inpatient CPs was during the first shift (8 AM to 4 PM) (Figure 1).
figure 1
The highest abandonment rate for inpatient CPs was during the third shift (midnight to 8 AM) (Figure 2).

Inpatient pharmacy technicians answered 27,655 calls with a mean call abandonment rate of 4.7%. and a mean 15.6 seconds to answer.
figure 2
Besides January 2021, the highest call volume for inpatient pharmacy technicians was during the first shift. The highest abandonment rate for inpatient pharmacy technicians was during the third shift.

Discussion

Since implementing the inpatient pharmacy ACD phone system in January 2021, there have been successes and challenges. The implementation increased accountability and efficiency when answering pharmacy phone calls. An ACD uses an algorithm that ensures equitable distribution of phone calls between CPs and pharmacy technicians. Through this algorithm, the pharmacy team is held more accountable when answering incoming calls. Distributing phone calls equally allows for optimization and balances the workload. The ACD phone system also improved efficiency when answering incoming calls. By incorporating splits when a patient or health care professional calls, ACD routes the question to the appropriate staff member. As a result, CPs spend less time answering questions meant for pharmacy technicians and instead can answer clinical or order verification questions more efficiently.

 

 

ACD data also allow pharmacy leadership to assess staffing needs, depending on the call volume. Based on ACD data, the busiest time of day was 8:00 AM to 4:00 PM. Based on this information, pharmacy leadership plans to staff more appropriately to have more pharmacy technicians working during the first shift to attend to phone calls.

The mean call abandonment rate was 4.7% for both CPs and pharmacy technicians, which met the ≤ 5% goal. The highest call abandonment rate was from midnight to 8 AM, though this shift also experienced the lowest call volume. This trend may be attributed to fewer pharmacy team members available to meet the demands of the overnight shift.

Pharmacy technicians handled a higher total call volume, which may be attributed to more phone calls related to missing doses or unit stock requests compared with clinical questions or order verifications. This information may be beneficial to identify opportunities to improve pharmacy operations.

The main challenges encountered in the ACD implementation process were hardware installation and communication with hospital staff about the changes in the inpatient pharmacy phone system. To implement the new inpatient pharmacy ACD phone system, previous telephones and hardware were removed and replaced. Initially, hardware and installation delays made it difficult for the ACD phone system to operate efficiently in the early months of its implementation. The inpatient pharmacy team depends on the telecommunications system and computers for their daily activities. Delays and issues with the hardware and ACD phone system made it more difficult to provide patient care.

Communication is a continuous challenge to ensure that hospital staff are notified of the new inpatient pharmacy ACD phone number. Over time, the understanding and use of the new ACD phone system have increased dramatically, but there are still opportunities to capture any misdirected calls. Informal feedback was obtained at pharmacy huddles and 1-on-1 discussions with pharmacy staff, and the opinions were mixed. Members of the pharmacy staff expressed that the ACD phone system set up an effective way to triage phone calls. Another positive comment was that the system created a means of accountability for pharmacy phone calls. Critical feedback included challenges with triaging phone calls to appropriate pharmacists, because calls are assigned based on an algorithm, whereas clinical coverage is determined by designated unit daily assignments.

Limitations

There are potential limitations to this quality improvement project. This phone system may not apply to all inpatient hospital pharmacy settings. Potential limitations for implementation at other institutions may include but are not limited to, differing pharmacy practice models (centralized vs decentralized), implementation costs, and internal resources.

Future Goals

To improve the quality of service provided to patients and other hospital staff, the pharmacy leadership team can use the data to ensure that inpatient pharmacy technician resources are being used effectively during times of day with the greatest number of incoming ACD calls. The ACD phone system helps determine whether current resources are being used most efficiently and if they are not, can help identify areas of improvement.

 

 

The pharmacy leadership team plans on using reports for pharmacy team members to monitor performance. Reports on individual agent activity capture workload; this may be used as a performance-related metric for future performance plans.

Conclusions

The inpatient pharmacy ACD phone system at EHJVAH is a promising application of available technology. The implementation of the ACD system improved accountability, efficiency, work distribution, and the allocation of resources in the inpatient pharmacy service. The ACD phone system has yielded positive performance metrics including mean speed to answer ≤ 30 seconds and abandonment rate ≤ 5% over 12 months after implementation. With time, users of the inpatient pharmacy ACD phone system will become more comfortable with the technology, thus further improving the patient health care quality.

Pharmacy call centers have been successfully implemented in outpatient and specialty pharmacy settings.1 A centralized pharmacy call center gives patients immediate access to a pharmacist who can view their health records to answer specific questions or fulfill medication renewal requests.2-4 Little literature exists to describe its use in an inpatient setting.

Inpatient pharmacies receive numerous calls from health care professionals and patients. Challenges related to phone calls in the inpatient pharmacy setting may include interruptions, distractions, low accountability, poor efficiency, lack of optimal resources, and staffing.5 An unequal distribution and lack of accountability may exist when answering phone calls for the inpatient pharmacy team, which may contribute to long hold times and call abandonment rates. Phone calls also may be directed inefficiently between clinical pharmacists (CPs) and pharmacy technicians. Team member time related to answering phone calls may not be captured or measured.

The Edward Hines, Jr. Veterans Affairs Hospital (EHJVAH) in Illinois offers primary, extended, and specialty care and is a tertiary care referral center. The facility operates 483 beds and serves 6 community-based outpatient clinics.

table 1
The pharmacy leadership team decided to evaluate accountability, efficiency, and resources related to phone calls through the implementation of an automated call distribution (ACD) phone system in the inpatient pharmacy setting and capture potential workload metrics (Table 1).

Implementation

A new inpatient pharmacy service phone line extension was implemented. Data used to report quality metrics were obtained from the Global Navigator (GNAV), an information system that records calls, tracks the performance of agents, and coordinates personnel scheduling. The effectiveness of the ACD system was evaluated by quality metric goals of mean speed to answer ≤ 30 seconds and mean abandonment rate ≤ 5%. This project was determined to be quality improvement and was not reviewed by the EHJVAH Institutional Review Board.

The ACD system was set up in December 2020. After a 1-month implementation period, metrics were reported to the inpatient pharmacy team and leadership. By January 2021, EHJVAH fully implemented an ACD phone system operated by inpatient pharmacy technicians and CPs. EHJVAH inpatient pharmacy includes CPs who practice without a scope of practice and board-certified pharmacy technicians in 3 shifts. The CPs and pharmacy technicians work in the central pharmacy (the main pharmacy and inpatient pharmacy vault) or are decentralized with responsibility for answering phone calls and making deliveries (pharmacy technicians).

The pharmacy leadership team decided to implement 1 phone line with 2 ACD splits. The first split was directed to pharmacy technicians and the second to CPs. The intention was to streamline calls to be directed to proper team members within the inpatient pharmacy. The CP line also was designed to back up the pharmacy technician line. These calls were equally distributed among staff based on a standard algorithm. The pharmacy greeting stated, “Thank you for contacting the inpatient pharmacy at Hines VA Hospital. For missing doses, unit stock requests, or to speak with a pharmacy technician, please press 1. For clinical questions, order verification, or to speak with a pharmacist, please press 2.” Each inpatient pharmacy team member had a unique system login.

Fourteen ACD phone stations were established in the main pharmacy and in decentralized locations for order verification. The stations were distributed across the pharmacy service to optimize workload, space, and resources.

 

 

Training and Communication

Before implementing the inpatient pharmacy ACD phone system, the CPs and pharmacy technicians received mandatory ACD training. After the training, pharmacy team members were required to sign off on the training document to indicate that they had completed the course. The pharmacy team was trained on the importance of staffing the phones continuously. As a 24-hour pharmacy service in the acute care setting, any call may be critical for patient care.

A hospital-wide memorandum was distributed via email to all unit managers and hospital staff to educate them on the new ACD phone system, which included a new phone line extension for the inpatient pharmacy. Additionally, the inpatient pharmacy team was trained on the proper way of communicating the ACD phone system process with the hospital staff. The inpatient pharmacy team was notified that there would be an educational period to explain the queue process to hospital staff. Occasionally, hospital staff believed they were speaking to an automated system and hung up before their call was answered. The inpatient pharmacy team was instructed to notify the hospital staff to stay on the line since their call would be answered in the order it was received. Once the inpatient pharmacy team received proper training and felt comfortable with the phone system, it was set up and integrated into the workflow.

Postimplementation Evaluation

Inpatient pharmacy ACD phone system data were collected for 2021. To evaluate the effectiveness of an ACD system, the pharmacy leadership team set up the following metrics and goals for inpatient CPs and inpatient pharmacy technicians for monthly call volume/abandonment rate, mean speed to answer, mean call volume by shift, and the mean abandonment rate by shift.

table 2
Inpatient CPs answered 24,075 calls with a mean call abandonment rate of 4.7%. and a mean 13.1 seconds to answer (Table 2). The highest call volume for inpatient CPs was during the first shift (8 AM to 4 PM) (Figure 1).
figure 1
The highest abandonment rate for inpatient CPs was during the third shift (midnight to 8 AM) (Figure 2).

Inpatient pharmacy technicians answered 27,655 calls with a mean call abandonment rate of 4.7%. and a mean 15.6 seconds to answer.
figure 2
Besides January 2021, the highest call volume for inpatient pharmacy technicians was during the first shift. The highest abandonment rate for inpatient pharmacy technicians was during the third shift.

Discussion

Since implementing the inpatient pharmacy ACD phone system in January 2021, there have been successes and challenges. The implementation increased accountability and efficiency when answering pharmacy phone calls. An ACD uses an algorithm that ensures equitable distribution of phone calls between CPs and pharmacy technicians. Through this algorithm, the pharmacy team is held more accountable when answering incoming calls. Distributing phone calls equally allows for optimization and balances the workload. The ACD phone system also improved efficiency when answering incoming calls. By incorporating splits when a patient or health care professional calls, ACD routes the question to the appropriate staff member. As a result, CPs spend less time answering questions meant for pharmacy technicians and instead can answer clinical or order verification questions more efficiently.

 

 

ACD data also allow pharmacy leadership to assess staffing needs, depending on the call volume. Based on ACD data, the busiest time of day was 8:00 AM to 4:00 PM. Based on this information, pharmacy leadership plans to staff more appropriately to have more pharmacy technicians working during the first shift to attend to phone calls.

The mean call abandonment rate was 4.7% for both CPs and pharmacy technicians, which met the ≤ 5% goal. The highest call abandonment rate was from midnight to 8 AM, though this shift also experienced the lowest call volume. This trend may be attributed to fewer pharmacy team members available to meet the demands of the overnight shift.

Pharmacy technicians handled a higher total call volume, which may be attributed to more phone calls related to missing doses or unit stock requests compared with clinical questions or order verifications. This information may be beneficial to identify opportunities to improve pharmacy operations.

The main challenges encountered in the ACD implementation process were hardware installation and communication with hospital staff about the changes in the inpatient pharmacy phone system. To implement the new inpatient pharmacy ACD phone system, previous telephones and hardware were removed and replaced. Initially, hardware and installation delays made it difficult for the ACD phone system to operate efficiently in the early months of its implementation. The inpatient pharmacy team depends on the telecommunications system and computers for their daily activities. Delays and issues with the hardware and ACD phone system made it more difficult to provide patient care.

Communication is a continuous challenge to ensure that hospital staff are notified of the new inpatient pharmacy ACD phone number. Over time, the understanding and use of the new ACD phone system have increased dramatically, but there are still opportunities to capture any misdirected calls. Informal feedback was obtained at pharmacy huddles and 1-on-1 discussions with pharmacy staff, and the opinions were mixed. Members of the pharmacy staff expressed that the ACD phone system set up an effective way to triage phone calls. Another positive comment was that the system created a means of accountability for pharmacy phone calls. Critical feedback included challenges with triaging phone calls to appropriate pharmacists, because calls are assigned based on an algorithm, whereas clinical coverage is determined by designated unit daily assignments.

Limitations

There are potential limitations to this quality improvement project. This phone system may not apply to all inpatient hospital pharmacy settings. Potential limitations for implementation at other institutions may include but are not limited to, differing pharmacy practice models (centralized vs decentralized), implementation costs, and internal resources.

Future Goals

To improve the quality of service provided to patients and other hospital staff, the pharmacy leadership team can use the data to ensure that inpatient pharmacy technician resources are being used effectively during times of day with the greatest number of incoming ACD calls. The ACD phone system helps determine whether current resources are being used most efficiently and if they are not, can help identify areas of improvement.

 

 

The pharmacy leadership team plans on using reports for pharmacy team members to monitor performance. Reports on individual agent activity capture workload; this may be used as a performance-related metric for future performance plans.

Conclusions

The inpatient pharmacy ACD phone system at EHJVAH is a promising application of available technology. The implementation of the ACD system improved accountability, efficiency, work distribution, and the allocation of resources in the inpatient pharmacy service. The ACD phone system has yielded positive performance metrics including mean speed to answer ≤ 30 seconds and abandonment rate ≤ 5% over 12 months after implementation. With time, users of the inpatient pharmacy ACD phone system will become more comfortable with the technology, thus further improving the patient health care quality.

References

1. Rim MH, Thomas KC, Chandramouli J, Barrus SA, Nickman NA. Implementation and quality assessment of a pharmacy services call center for outpatient pharmacies and specialty pharmacy services in an academic health system. Am J Health Syst Pharm. 2018;75(10):633-641. doi:10.2146/ajhp170319

2. Patterson BJ, Doucette WR, Urmie JM, McDonough RP. Exploring relationships among pharmacy service use, patronage motives, and patient satisfaction. J Am Pharm Assoc (2003). 2013;53(4):382-389. doi:10.1331/JAPhA.2013.12100

3. Walker DM, Sieck CJ, Menser T, Huerta TR, Scheck McAlearney A. Information technology to support patient engagement: where do we stand and where can we go?. J Am Med Inform Assoc. 2017;24(6):1088-1094. doi:10.1093/jamia/ocx043

4. Menichetti J, Libreri C, Lozza E, Graffigna G. Giving patients a starring role in their own care: a bibliometric analysis of the on-going literature debate. Health Expect. 2016;19(3):516-526. doi:10.1111/hex.12299

5. Raimbault M, Guérin A, Caron É, Lebel D, Bussières J-F. Identifying and reducing distractions and interruptions in a pharmacy department. Am J Health Syst Pharm. 2013;70(3):186-190. doi:10.2146/ajhp120344

References

1. Rim MH, Thomas KC, Chandramouli J, Barrus SA, Nickman NA. Implementation and quality assessment of a pharmacy services call center for outpatient pharmacies and specialty pharmacy services in an academic health system. Am J Health Syst Pharm. 2018;75(10):633-641. doi:10.2146/ajhp170319

2. Patterson BJ, Doucette WR, Urmie JM, McDonough RP. Exploring relationships among pharmacy service use, patronage motives, and patient satisfaction. J Am Pharm Assoc (2003). 2013;53(4):382-389. doi:10.1331/JAPhA.2013.12100

3. Walker DM, Sieck CJ, Menser T, Huerta TR, Scheck McAlearney A. Information technology to support patient engagement: where do we stand and where can we go?. J Am Med Inform Assoc. 2017;24(6):1088-1094. doi:10.1093/jamia/ocx043

4. Menichetti J, Libreri C, Lozza E, Graffigna G. Giving patients a starring role in their own care: a bibliometric analysis of the on-going literature debate. Health Expect. 2016;19(3):516-526. doi:10.1111/hex.12299

5. Raimbault M, Guérin A, Caron É, Lebel D, Bussières J-F. Identifying and reducing distractions and interruptions in a pharmacy department. Am J Health Syst Pharm. 2013;70(3):186-190. doi:10.2146/ajhp120344

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Severe atopic dermatitis raises risks for cardiovascular disease and venous thromboembolism

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Key clinical point: Severe atopic dermatitis (AD) is associated with higher risks for venous thromboembolism and cardiovascular diseases in both children and adults.

Major finding: Children with severe AD vs those without AD had a significantly increased risk (adjusted hazard ratio; 95% CI) for cerebrovascular accidents (2.43; 1.13-5.22), diabetes (1.46; 1.06-2.01), and deep vein thrombosis (DVT; 2.13; 1.17-3.87). Among adults, the severe AD vs non-AD group had a significantly higher risk for cerebrovascular accidents (1.21; 1.13-1.30), diabetes (1.15; 1.09-1.22), dyslipidemia (1.11; 1.06-1.17), myocardial infarction (1.27; 1.15-1.39), DVT (1.64; 1.49-1.82), and pulmonary embolism (1.39; 1.21-1.60).

Study details: This population-based cohort study included 409,431 children (age < 18 years) and 625,083 adults with AD who were matched with 1,809,029 children and 2,678,888 adults without AD, respectively.

Disclosures: This study was supported by a contract from Pfizer, Inc. Some authors declared serving as consultants for or receiving research grants, honoraria, or consulting fees from various sources, including Pfizer. AR Lemeshow declared being an employee of Pfizer, Inc.

Source: Wan J, Chiesa Fuxench  ZC, et al. Incidence of cardiovascular disease and venous thromboembolism in patients with atopic dermatitis. J Allergy Clin Immunol Pract. 2023 (Aug 10). doi: 10.1016/j.jaip.2023.08.007

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Key clinical point: Severe atopic dermatitis (AD) is associated with higher risks for venous thromboembolism and cardiovascular diseases in both children and adults.

Major finding: Children with severe AD vs those without AD had a significantly increased risk (adjusted hazard ratio; 95% CI) for cerebrovascular accidents (2.43; 1.13-5.22), diabetes (1.46; 1.06-2.01), and deep vein thrombosis (DVT; 2.13; 1.17-3.87). Among adults, the severe AD vs non-AD group had a significantly higher risk for cerebrovascular accidents (1.21; 1.13-1.30), diabetes (1.15; 1.09-1.22), dyslipidemia (1.11; 1.06-1.17), myocardial infarction (1.27; 1.15-1.39), DVT (1.64; 1.49-1.82), and pulmonary embolism (1.39; 1.21-1.60).

Study details: This population-based cohort study included 409,431 children (age < 18 years) and 625,083 adults with AD who were matched with 1,809,029 children and 2,678,888 adults without AD, respectively.

Disclosures: This study was supported by a contract from Pfizer, Inc. Some authors declared serving as consultants for or receiving research grants, honoraria, or consulting fees from various sources, including Pfizer. AR Lemeshow declared being an employee of Pfizer, Inc.

Source: Wan J, Chiesa Fuxench  ZC, et al. Incidence of cardiovascular disease and venous thromboembolism in patients with atopic dermatitis. J Allergy Clin Immunol Pract. 2023 (Aug 10). doi: 10.1016/j.jaip.2023.08.007

Key clinical point: Severe atopic dermatitis (AD) is associated with higher risks for venous thromboembolism and cardiovascular diseases in both children and adults.

Major finding: Children with severe AD vs those without AD had a significantly increased risk (adjusted hazard ratio; 95% CI) for cerebrovascular accidents (2.43; 1.13-5.22), diabetes (1.46; 1.06-2.01), and deep vein thrombosis (DVT; 2.13; 1.17-3.87). Among adults, the severe AD vs non-AD group had a significantly higher risk for cerebrovascular accidents (1.21; 1.13-1.30), diabetes (1.15; 1.09-1.22), dyslipidemia (1.11; 1.06-1.17), myocardial infarction (1.27; 1.15-1.39), DVT (1.64; 1.49-1.82), and pulmonary embolism (1.39; 1.21-1.60).

Study details: This population-based cohort study included 409,431 children (age < 18 years) and 625,083 adults with AD who were matched with 1,809,029 children and 2,678,888 adults without AD, respectively.

Disclosures: This study was supported by a contract from Pfizer, Inc. Some authors declared serving as consultants for or receiving research grants, honoraria, or consulting fees from various sources, including Pfizer. AR Lemeshow declared being an employee of Pfizer, Inc.

Source: Wan J, Chiesa Fuxench  ZC, et al. Incidence of cardiovascular disease and venous thromboembolism in patients with atopic dermatitis. J Allergy Clin Immunol Pract. 2023 (Aug 10). doi: 10.1016/j.jaip.2023.08.007

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Atopic dermatitis increases the risk for type 2 diabetes mellitus in adults

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Wed, 10/04/2023 - 12:35

Key clinical point: Adults with newly diagnosed atopic dermatitis (AD) have a 44% increased risk of subsequently developing type 2 diabetes (T2D).

Major finding: The risk for new-onset T2D was significantly higher in adults with newly diagnosed AD vs control individuals without AD (adjusted hazard ratio 1.44; P < .001), with the risk being significantly greater in both men and women with AD (both P < .001).

Study details: Findings are from a retrospective cohort study including 36,692 adult patients with AD and 36,692 matched control individuals who had never been diagnosed with AD.

Disclosures: This study was supported by the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology and others. The authors declared no conflicts of interest.

Source: Won Lee S et al. Risk of type 2 diabetes mellitus in adult patients with atopic dermatitis. Diabetes Res Clin Pract. 2023;110883 (Aug 16). doi: 10.1016/j.diabres.2023.110883

 

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Key clinical point: Adults with newly diagnosed atopic dermatitis (AD) have a 44% increased risk of subsequently developing type 2 diabetes (T2D).

Major finding: The risk for new-onset T2D was significantly higher in adults with newly diagnosed AD vs control individuals without AD (adjusted hazard ratio 1.44; P < .001), with the risk being significantly greater in both men and women with AD (both P < .001).

Study details: Findings are from a retrospective cohort study including 36,692 adult patients with AD and 36,692 matched control individuals who had never been diagnosed with AD.

Disclosures: This study was supported by the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology and others. The authors declared no conflicts of interest.

Source: Won Lee S et al. Risk of type 2 diabetes mellitus in adult patients with atopic dermatitis. Diabetes Res Clin Pract. 2023;110883 (Aug 16). doi: 10.1016/j.diabres.2023.110883

 

Key clinical point: Adults with newly diagnosed atopic dermatitis (AD) have a 44% increased risk of subsequently developing type 2 diabetes (T2D).

Major finding: The risk for new-onset T2D was significantly higher in adults with newly diagnosed AD vs control individuals without AD (adjusted hazard ratio 1.44; P < .001), with the risk being significantly greater in both men and women with AD (both P < .001).

Study details: Findings are from a retrospective cohort study including 36,692 adult patients with AD and 36,692 matched control individuals who had never been diagnosed with AD.

Disclosures: This study was supported by the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology and others. The authors declared no conflicts of interest.

Source: Won Lee S et al. Risk of type 2 diabetes mellitus in adult patients with atopic dermatitis. Diabetes Res Clin Pract. 2023;110883 (Aug 16). doi: 10.1016/j.diabres.2023.110883

 

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