LAS VEGAS – Vaginal trial of labor is safe after myomectomy, at least if the uterine cavity wasn’t entered, according to investigators from Northwestern University, Chicago.

M. Alexander Otto/MDedge News

The American College of Obstetricians and Gynecologists lists prior myomectomy as a medically-indicated reason for delivery before 39 weeks. The advice reflects a traditional concern that uterine scars will rupture during labor, with potentially devastating consequences for both mother and infant.

Reviews have put the risk at less than 1%, so ob.gyns. have shied away from ACOG’s blanket advice and now use uterine-cavity entry during myomectomy as their talisman for deciding whether or not to offer women vaginal delivery. The assumption is that uterine entry makes rupture more likely, but there’s not much evidence to support that idea, and it’s become clear in recent years that women who have a significant full-thickness insult to uterine integrity – a prior C-section – can usually deliver vaginally with no problem. In short, the uterus seems to have a remarkable ability to heal itself.

Even so, there are still ob.gyns. who pressure women into having premature babies if they’ve had a fibroid removed even without cavity entry. Barring additional indications, that doesn’t happen anymore at Northwestern University, said lead investigator Nathan King, MD, an ob.gyn. resident at the university.

The Northwestern team wanted to clear the fog. What they found adds to “literature that demonstrates the overall low risk of undergoing VTOL [vaginal trial of labor] after a prior myomectomy. We hope providers will feel more comfortable talking to their patients about delivery [options] and the success of VTOL after myomectomy,” Dr. King said at a meeting sponsored by AAGL.*

He and his team analyzed pregnancy outcomes in 112 women who had a live birth after non–cavity-entering myomectomies. Forty-nine women (44%) were allowed to undergo VTOL; 63 others had C-sections, most at term.

Thirty-two VTOL women (65%) had vaginal deliveries, a success rate similar to that of labor after C-section. There was just one uterine rupture in the VTOL group, for an incidence of 2%, which also was comparable to the rupture risk after a low-transverse C-section.

The rupture was discovered after spontaneous vaginal delivery, and an addressed by laparotomy. Both mother and infant were fine.

Adverse events were less likely in the VTOL group, regardless if they ultimately delivered vaginally or by C-section. The lower adverse event rate was driven by fewer postpartum hemorrhages (odds ratio, 0.441, 95% confidence interval, 0.2002-0.9722, P = .042).

There were no demographic difference between women who were allowed to undergo VTOL and those who were not. For most, it was their first delivery.

Women who had their uterine cavities entered during myomectomy weren’t allowed to undergo VTOL at Northwestern, and were not included in the analysis. Also, the study did not include women who became pregnant after myomectomy, but did not have a live delivery. The incidence of uterine rupture among them, if any, was not reported.

There was no external funding for the work, and Dr. King didn’t have any disclosures.

aotto@mdedge.com

SOURCE: King N et al. 2018 AAGL Global Congress, Abstract 162.

*Correction, 12/11/2018: An earlier version of this story misstated the name of the meeting sponsor. It is AAGL.
 

LAS VEGAS – Vaginal trial of labor is safe after myomectomy, at least if the uterine cavity wasn’t entered, according to investigators from Northwestern University, Chicago.

M. Alexander Otto/MDedge News

The American College of Obstetricians and Gynecologists lists prior myomectomy as a medically-indicated reason for delivery before 39 weeks. The advice reflects a traditional concern that uterine scars will rupture during labor, with potentially devastating consequences for both mother and infant.

Reviews have put the risk at less than 1%, so ob.gyns. have shied away from ACOG’s blanket advice and now use uterine-cavity entry during myomectomy as their talisman for deciding whether or not to offer women vaginal delivery. The assumption is that uterine entry makes rupture more likely, but there’s not much evidence to support that idea, and it’s become clear in recent years that women who have a significant full-thickness insult to uterine integrity – a prior C-section – can usually deliver vaginally with no problem. In short, the uterus seems to have a remarkable ability to heal itself.

Even so, there are still ob.gyns. who pressure women into having premature babies if they’ve had a fibroid removed even without cavity entry. Barring additional indications, that doesn’t happen anymore at Northwestern University, said lead investigator Nathan King, MD, an ob.gyn. resident at the university.

The Northwestern team wanted to clear the fog. What they found adds to “literature that demonstrates the overall low risk of undergoing VTOL [vaginal trial of labor] after a prior myomectomy. We hope providers will feel more comfortable talking to their patients about delivery [options] and the success of VTOL after myomectomy,” Dr. King said at a meeting sponsored by AAGL.*

He and his team analyzed pregnancy outcomes in 112 women who had a live birth after non–cavity-entering myomectomies. Forty-nine women (44%) were allowed to undergo VTOL; 63 others had C-sections, most at term.

Thirty-two VTOL women (65%) had vaginal deliveries, a success rate similar to that of labor after C-section. There was just one uterine rupture in the VTOL group, for an incidence of 2%, which also was comparable to the rupture risk after a low-transverse C-section.

The rupture was discovered after spontaneous vaginal delivery, and an addressed by laparotomy. Both mother and infant were fine.

Adverse events were less likely in the VTOL group, regardless if they ultimately delivered vaginally or by C-section. The lower adverse event rate was driven by fewer postpartum hemorrhages (odds ratio, 0.441, 95% confidence interval, 0.2002-0.9722, P = .042).

There were no demographic difference between women who were allowed to undergo VTOL and those who were not. For most, it was their first delivery.

Women who had their uterine cavities entered during myomectomy weren’t allowed to undergo VTOL at Northwestern, and were not included in the analysis. Also, the study did not include women who became pregnant after myomectomy, but did not have a live delivery. The incidence of uterine rupture among them, if any, was not reported.

There was no external funding for the work, and Dr. King didn’t have any disclosures.

aotto@mdedge.com

SOURCE: King N et al. 2018 AAGL Global Congress, Abstract 162.

*Correction, 12/11/2018: An earlier version of this story misstated the name of the meeting sponsor. It is AAGL.
 

LAS VEGAS – Vaginal trial of labor is safe after myomectomy, at least if the uterine cavity wasn’t entered, according to investigators from Northwestern University, Chicago.

M. Alexander Otto/MDedge News

The American College of Obstetricians and Gynecologists lists prior myomectomy as a medically-indicated reason for delivery before 39 weeks. The advice reflects a traditional concern that uterine scars will rupture during labor, with potentially devastating consequences for both mother and infant.

Reviews have put the risk at less than 1%, so ob.gyns. have shied away from ACOG’s blanket advice and now use uterine-cavity entry during myomectomy as their talisman for deciding whether or not to offer women vaginal delivery. The assumption is that uterine entry makes rupture more likely, but there’s not much evidence to support that idea, and it’s become clear in recent years that women who have a significant full-thickness insult to uterine integrity – a prior C-section – can usually deliver vaginally with no problem. In short, the uterus seems to have a remarkable ability to heal itself.

Even so, there are still ob.gyns. who pressure women into having premature babies if they’ve had a fibroid removed even without cavity entry. Barring additional indications, that doesn’t happen anymore at Northwestern University, said lead investigator Nathan King, MD, an ob.gyn. resident at the university.

The Northwestern team wanted to clear the fog. What they found adds to “literature that demonstrates the overall low risk of undergoing VTOL [vaginal trial of labor] after a prior myomectomy. We hope providers will feel more comfortable talking to their patients about delivery [options] and the success of VTOL after myomectomy,” Dr. King said at a meeting sponsored by AAGL.*

He and his team analyzed pregnancy outcomes in 112 women who had a live birth after non–cavity-entering myomectomies. Forty-nine women (44%) were allowed to undergo VTOL; 63 others had C-sections, most at term.

Thirty-two VTOL women (65%) had vaginal deliveries, a success rate similar to that of labor after C-section. There was just one uterine rupture in the VTOL group, for an incidence of 2%, which also was comparable to the rupture risk after a low-transverse C-section.

The rupture was discovered after spontaneous vaginal delivery, and an addressed by laparotomy. Both mother and infant were fine.

Adverse events were less likely in the VTOL group, regardless if they ultimately delivered vaginally or by C-section. The lower adverse event rate was driven by fewer postpartum hemorrhages (odds ratio, 0.441, 95% confidence interval, 0.2002-0.9722, P = .042).

There were no demographic difference between women who were allowed to undergo VTOL and those who were not. For most, it was their first delivery.

Women who had their uterine cavities entered during myomectomy weren’t allowed to undergo VTOL at Northwestern, and were not included in the analysis. Also, the study did not include women who became pregnant after myomectomy, but did not have a live delivery. The incidence of uterine rupture among them, if any, was not reported.

There was no external funding for the work, and Dr. King didn’t have any disclosures.

aotto@mdedge.com

SOURCE: King N et al. 2018 AAGL Global Congress, Abstract 162.

*Correction, 12/11/2018: An earlier version of this story misstated the name of the meeting sponsor. It is AAGL.
 

Whenever the principles of effective medical consultation are discussed, a classic article published in 1983 by Lee Goldman et al. is invariably referenced. In the “Ten Commandments for Effective Consultation,” Goldman argued that internists should “determine the question, establish urgency, look for yourself, be as brief as appropriate, be specific, provide contingency plans, honor thy turf, teach with tact, provide direct personal contact, and follow up.”¹ If these Ten Commandments were followed, then the consultation would be more effective and satisfactory for both the consultant and the referring provider. However, with the advent of comanagement in 1994 where internists and surgeons have a “shared responsibility and accountability,”² there has been a shift, and the once-concrete definitions of a specific reason for consult and the nature of “turf” have become blurred. Since 1994, the use of medical consultation and comanagement has skyrocketed, and today, more than 50% of surgical patients have a medical consultation or comanagement.³ This may be due to increased time pressures on surgeons and better outcomes of comanaged patients (eg, fewer postoperative complications, fewer transfers to an intensive care unit for acute medical deterioration, and increased likelihood to discharge to home).⁴

Medical management of surgical patients in the hospital involves a different skill set than that required to manage general medical patients. Accordingly, in 2012, the Accreditation Council for Graduate Medical Education (ACGME) made medical consultation and perioperative care an End of Training Entrustable Professional Activities and ACGME subcompetency. Earlier this year, a nationwide perioperative curriculum for graduate medical education was consisting of eight objective and core topic modules and pretest/posttest questions selected from SHMConsults.com, including assessment and management of perioperative cardiac and pulmonary risk and management of diabetes, perioperative fever, and anticoagulants. Trainees were assessed using the multiple-choice questions, observed mini-cex, and written evaluation of a consultation report. Despite this encouraging development of curricula and competencies for trainees, there are still important gaps in our knowledge of basic patterns for consultation practices. For example, the type of patients and medical conditions currently encountered on our medical consultation and comanagement services had been previously unknown.

In the December issue of the Journal of Hospital Medicine, Wang et al. answer this question through the first cross-sectional multicenter prospective survey to examine medical consultation/comanagement practices since observational studies in the 1970-1990s.⁶ In a sample of 1,264 consultation requests from 11 academic medical centers over four two-week periods from July 2014 through July 2015, they found that the most common requests for consultation were medical management/comanagement, preoperative evaluation, blood pressure management, and other common postoperative complications, including postoperative atrial fibrillation, heart failure, renal failure, hyponatremia, anemia, hypoxia, and altered mental status.⁹ The majority of referrals were from orthopedic surgery and neurosurgery. They also found that medical consultants and comanagers provided comprehensive evaluations where more than a third of encounters addressed issues that were not stated in the initial reason for consult (RFC) and that consultants addressed more than two RFCs per encounter.⁹

These findings illustrate the paradigm shift of medical consultation focusing on a single specific question to addressing and optimizing the entire patient. This shift toward a broader, more open-ended reason for consultation may present some challenges such as “dumping” where referring surgeons and other specialists signoff their patients after surgery is completed, with internists processing the surgeons’ patients through the hospitalization. These challenges can be mitigated with predefined comanagement agreements with clearly defined roles and collaborative professional relationships.

Nonetheless, given the recent developments in curricula and training competencies mentioned above, internists are better equipped than ever before to put everything together and take care of the medical conditions of the increasingly complex and older surgical patient. For example, if one is consulted to see a patient for postoperative hypertension, it is difficult to not address the patient’s blood sugars in the 300s, lack of venous thromboembolism prophylaxis, delirium, acute renal failure, and acute blood loss anemia. The authors are correct to assert it is critically important to ensure that this input is desired by the referring physician either via verbal communication or comanagement agreements.

The findings of Wang et al. suggest some important future steps in medical consultation to ensure that our trainees and colleagues are prepared to take care of the entire patient regardless of whether the patient is on a consultant or comanagement agreement. This study shows that trainees are exposed to a diverse clinical experience on our medical consultation and comanagement services, which is in accordance with the objectives, assessment tools, and modules of the nationwide curriculum. It is likely that comanagement services will continue to expand as more of our medically complex patients will need either elective or emergency surgeries and surgeons have become less comfortable managing these patients on their own. We also may be asked to participate in quality improvement initiatives in the management of surgical patients, including the “perioperative surgical home programs,” where physicians work on a patient-centered approach to the surgical patient using evidence-based standard clinical care pathways and transitions from before surgery to postdischarge.⁷ We should share our experiences in quality improvement and the patient-centered medical home to ensure that our patients are optimized for surgery and beyond. As Lee Goldman et al. stated in the “Ten Commandments for Effective Consultations,¹” consultative medicine is an important part of an internal medicine practice. Today, more than ever, the consultant or comanagement role or roles need to be carefully defined and clear communication and follow-up are important.

Whenever the principles of effective medical consultation are discussed, a classic article published in 1983 by Lee Goldman et al. is invariably referenced. In the “Ten Commandments for Effective Consultation,” Goldman argued that internists should “determine the question, establish urgency, look for yourself, be as brief as appropriate, be specific, provide contingency plans, honor thy turf, teach with tact, provide direct personal contact, and follow up.”¹ If these Ten Commandments were followed, then the consultation would be more effective and satisfactory for both the consultant and the referring provider. However, with the advent of comanagement in 1994 where internists and surgeons have a “shared responsibility and accountability,”² there has been a shift, and the once-concrete definitions of a specific reason for consult and the nature of “turf” have become blurred. Since 1994, the use of medical consultation and comanagement has skyrocketed, and today, more than 50% of surgical patients have a medical consultation or comanagement.³ This may be due to increased time pressures on surgeons and better outcomes of comanaged patients (eg, fewer postoperative complications, fewer transfers to an intensive care unit for acute medical deterioration, and increased likelihood to discharge to home).⁴

Medical management of surgical patients in the hospital involves a different skill set than that required to manage general medical patients. Accordingly, in 2012, the Accreditation Council for Graduate Medical Education (ACGME) made medical consultation and perioperative care an End of Training Entrustable Professional Activities and ACGME subcompetency. Earlier this year, a nationwide perioperative curriculum for graduate medical education was consisting of eight objective and core topic modules and pretest/posttest questions selected from SHMConsults.com, including assessment and management of perioperative cardiac and pulmonary risk and management of diabetes, perioperative fever, and anticoagulants. Trainees were assessed using the multiple-choice questions, observed mini-cex, and written evaluation of a consultation report. Despite this encouraging development of curricula and competencies for trainees, there are still important gaps in our knowledge of basic patterns for consultation practices. For example, the type of patients and medical conditions currently encountered on our medical consultation and comanagement services had been previously unknown.

In the December issue of the Journal of Hospital Medicine, Wang et al. answer this question through the first cross-sectional multicenter prospective survey to examine medical consultation/comanagement practices since observational studies in the 1970-1990s.⁶ In a sample of 1,264 consultation requests from 11 academic medical centers over four two-week periods from July 2014 through July 2015, they found that the most common requests for consultation were medical management/comanagement, preoperative evaluation, blood pressure management, and other common postoperative complications, including postoperative atrial fibrillation, heart failure, renal failure, hyponatremia, anemia, hypoxia, and altered mental status.⁹ The majority of referrals were from orthopedic surgery and neurosurgery. They also found that medical consultants and comanagers provided comprehensive evaluations where more than a third of encounters addressed issues that were not stated in the initial reason for consult (RFC) and that consultants addressed more than two RFCs per encounter.⁹

These findings illustrate the paradigm shift of medical consultation focusing on a single specific question to addressing and optimizing the entire patient. This shift toward a broader, more open-ended reason for consultation may present some challenges such as “dumping” where referring surgeons and other specialists signoff their patients after surgery is completed, with internists processing the surgeons’ patients through the hospitalization. These challenges can be mitigated with predefined comanagement agreements with clearly defined roles and collaborative professional relationships.

Nonetheless, given the recent developments in curricula and training competencies mentioned above, internists are better equipped than ever before to put everything together and take care of the medical conditions of the increasingly complex and older surgical patient. For example, if one is consulted to see a patient for postoperative hypertension, it is difficult to not address the patient’s blood sugars in the 300s, lack of venous thromboembolism prophylaxis, delirium, acute renal failure, and acute blood loss anemia. The authors are correct to assert it is critically important to ensure that this input is desired by the referring physician either via verbal communication or comanagement agreements.

The findings of Wang et al. suggest some important future steps in medical consultation to ensure that our trainees and colleagues are prepared to take care of the entire patient regardless of whether the patient is on a consultant or comanagement agreement. This study shows that trainees are exposed to a diverse clinical experience on our medical consultation and comanagement services, which is in accordance with the objectives, assessment tools, and modules of the nationwide curriculum. It is likely that comanagement services will continue to expand as more of our medically complex patients will need either elective or emergency surgeries and surgeons have become less comfortable managing these patients on their own. We also may be asked to participate in quality improvement initiatives in the management of surgical patients, including the “perioperative surgical home programs,” where physicians work on a patient-centered approach to the surgical patient using evidence-based standard clinical care pathways and transitions from before surgery to postdischarge.⁷ We should share our experiences in quality improvement and the patient-centered medical home to ensure that our patients are optimized for surgery and beyond. As Lee Goldman et al. stated in the “Ten Commandments for Effective Consultations,¹” consultative medicine is an important part of an internal medicine practice. Today, more than ever, the consultant or comanagement role or roles need to be carefully defined and clear communication and follow-up are important.

Whenever the principles of effective medical consultation are discussed, a classic article published in 1983 by Lee Goldman et al. is invariably referenced. In the “Ten Commandments for Effective Consultation,” Goldman argued that internists should “determine the question, establish urgency, look for yourself, be as brief as appropriate, be specific, provide contingency plans, honor thy turf, teach with tact, provide direct personal contact, and follow up.”¹ If these Ten Commandments were followed, then the consultation would be more effective and satisfactory for both the consultant and the referring provider. However, with the advent of comanagement in 1994 where internists and surgeons have a “shared responsibility and accountability,”² there has been a shift, and the once-concrete definitions of a specific reason for consult and the nature of “turf” have become blurred. Since 1994, the use of medical consultation and comanagement has skyrocketed, and today, more than 50% of surgical patients have a medical consultation or comanagement.³ This may be due to increased time pressures on surgeons and better outcomes of comanaged patients (eg, fewer postoperative complications, fewer transfers to an intensive care unit for acute medical deterioration, and increased likelihood to discharge to home).⁴

Medical management of surgical patients in the hospital involves a different skill set than that required to manage general medical patients. Accordingly, in 2012, the Accreditation Council for Graduate Medical Education (ACGME) made medical consultation and perioperative care an End of Training Entrustable Professional Activities and ACGME subcompetency. Earlier this year, a nationwide perioperative curriculum for graduate medical education was consisting of eight objective and core topic modules and pretest/posttest questions selected from SHMConsults.com, including assessment and management of perioperative cardiac and pulmonary risk and management of diabetes, perioperative fever, and anticoagulants. Trainees were assessed using the multiple-choice questions, observed mini-cex, and written evaluation of a consultation report. Despite this encouraging development of curricula and competencies for trainees, there are still important gaps in our knowledge of basic patterns for consultation practices. For example, the type of patients and medical conditions currently encountered on our medical consultation and comanagement services had been previously unknown.

In the December issue of the Journal of Hospital Medicine, Wang et al. answer this question through the first cross-sectional multicenter prospective survey to examine medical consultation/comanagement practices since observational studies in the 1970-1990s.⁶ In a sample of 1,264 consultation requests from 11 academic medical centers over four two-week periods from July 2014 through July 2015, they found that the most common requests for consultation were medical management/comanagement, preoperative evaluation, blood pressure management, and other common postoperative complications, including postoperative atrial fibrillation, heart failure, renal failure, hyponatremia, anemia, hypoxia, and altered mental status.⁹ The majority of referrals were from orthopedic surgery and neurosurgery. They also found that medical consultants and comanagers provided comprehensive evaluations where more than a third of encounters addressed issues that were not stated in the initial reason for consult (RFC) and that consultants addressed more than two RFCs per encounter.⁹

These findings illustrate the paradigm shift of medical consultation focusing on a single specific question to addressing and optimizing the entire patient. This shift toward a broader, more open-ended reason for consultation may present some challenges such as “dumping” where referring surgeons and other specialists signoff their patients after surgery is completed, with internists processing the surgeons’ patients through the hospitalization. These challenges can be mitigated with predefined comanagement agreements with clearly defined roles and collaborative professional relationships.

Nonetheless, given the recent developments in curricula and training competencies mentioned above, internists are better equipped than ever before to put everything together and take care of the medical conditions of the increasingly complex and older surgical patient. For example, if one is consulted to see a patient for postoperative hypertension, it is difficult to not address the patient’s blood sugars in the 300s, lack of venous thromboembolism prophylaxis, delirium, acute renal failure, and acute blood loss anemia. The authors are correct to assert it is critically important to ensure that this input is desired by the referring physician either via verbal communication or comanagement agreements.

The findings of Wang et al. suggest some important future steps in medical consultation to ensure that our trainees and colleagues are prepared to take care of the entire patient regardless of whether the patient is on a consultant or comanagement agreement. This study shows that trainees are exposed to a diverse clinical experience on our medical consultation and comanagement services, which is in accordance with the objectives, assessment tools, and modules of the nationwide curriculum. It is likely that comanagement services will continue to expand as more of our medically complex patients will need either elective or emergency surgeries and surgeons have become less comfortable managing these patients on their own. We also may be asked to participate in quality improvement initiatives in the management of surgical patients, including the “perioperative surgical home programs,” where physicians work on a patient-centered approach to the surgical patient using evidence-based standard clinical care pathways and transitions from before surgery to postdischarge.⁷ We should share our experiences in quality improvement and the patient-centered medical home to ensure that our patients are optimized for surgery and beyond. As Lee Goldman et al. stated in the “Ten Commandments for Effective Consultations,¹” consultative medicine is an important part of an internal medicine practice. Today, more than ever, the consultant or comanagement role or roles need to be carefully defined and clear communication and follow-up are important.

Decreased insulin clearance may be the first step on the path to insulin resistance. Also today, tender joint count may confound assessment of RA inflammation, common AEDs confer moderately increased risk of major congenital malformations, and the ACR and the NPF unveil new treatment guidelines for psoriatic arthritis.

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Decreased insulin clearance may be the first step on the path to insulin resistance. Also today, tender joint count may confound assessment of RA inflammation, common AEDs confer moderately increased risk of major congenital malformations, and the ACR and the NPF unveil new treatment guidelines for psoriatic arthritis.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Decreased insulin clearance may be the first step on the path to insulin resistance. Also today, tender joint count may confound assessment of RA inflammation, common AEDs confer moderately increased risk of major congenital malformations, and the ACR and the NPF unveil new treatment guidelines for psoriatic arthritis.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

© ASH/Rodney White 2018

SAN DIEGO—A phase 1 study suggests lymphodepletion can improve the efficacy of CD30-directed chimeric antigen receptor (CAR) T-cell therapy in patients with Hodgkin lymphoma (HL).

Researchers observed improved responses in HL patients treated with fludarabine and cyclophosphamide prior to CD30.CAR T-cell therapy.

This lymphodepleting regimen was also associated with increased toxicity, compared to no lymphodepletion. However, researchers consider the regimen safe.

Carlos A. Ramos, MD, of Baylor College of Medicine in Houston, Texas, presented these results at the 2018 ASH Annual Meeting (abstract 680*).

Without lymphodepletion

Dr. Ramos first discussed a previous phase 1 trial (NCT01316146), which was published in The Journal of Clinical Investigation in 2017.

In this trial, he and his colleagues had tested CD30.CAR T-cell therapy in patients with relapsed/refractory, CD30+ HL or T-cell non-Hodgkin lymphoma. None of these patients underwent lymphodepletion.

There were no dose-limiting toxicities in this trial—including no neurotoxicity or cytokine release syndrome—but responses were “limited,” according to Dr. Ramos.

Three patients achieved a complete response (CR), three had stable disease, and three progressed.

“Although we saw no significant toxicities and some good clinical responses . . ., the bottom line is that the responses were still quite limited, with several patients having, at most, stable disease or progressive disease,” Dr. Ramos said.

With lymphodepletion

Results from the previous trial prompted Dr. Ramos and his colleagues to conduct the RELY-30 trial (NCT02917083) and investigate whether lymphodepletion would improve responses to CD30.CAR T-cell therapy.

Thus far, 11 patients have been treated on this trial. All had relapsed, CD30+ HL at baseline. Six patients are male, and their median age at baseline was 30 (range, 17-69).

The patients had a median of 5 prior treatments (range, 2-9). This included PD-1 inhibitors (n=10), brentuximab vedotin (n=8), and transplant (n=6).

All patients received lymphodepletion with cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² daily for 3 days. They then received CD30.CAR T-cell therapy at 2×10⁷ cells/m² or 1×10⁸ cells/m².

Dr. Ramos noted that CD30.CAR T-cell expansion was dose-dependent and increased by lymphodepleting chemotherapy.

“The peak expansion is much higher [with lymphodepletion], probably in the order of two to three logs higher than what we see without lymphodepleting chemotherapy,” he said. “So chemotherapy makes a difference.”

Increased CD30.CAR T-cell expansion was associated with improved response. Of the nine evaluable patients, six achieved a CR, and three progressed.

Four complete responders were still in CR at last follow-up, one of them for more than a year. However, two complete responders ultimately progressed.

In addition to improved responses, the researchers observed increased toxicity in this trial. Dr. Ramos said some of these toxicities are “probably attributable” to the lymphodepleting chemotherapy.

Toxicities included grade 1 cytokine release syndrome (no tocilizumab required), maculopapular rash, transient cytopenias, nausea, vomiting, and alopecia.

Dr. Ramos said these results suggest adoptive transfer of CD30.CAR T cells is “safe, even with chemotherapy.”

He noted that the duration of response with this treatment is unknown, but trial enrollment and follow-up are ongoing.

RELY-30 was sponsored by Baylor College of Medicine. Dr. Ramos reported relationships with Novartis, Celgene, Bluebird Bio, and Tessa Therapeutics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.

A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.

However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.

Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*

This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.

Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.

The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).

Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).

In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.

Bendamustine alone

Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m². Three of these patients received CD30.CAR T-cell therapy at 1×10⁸ cells/m², and all three progressed.

Of the five patients who received CAR T-cell therapy at a dose of 2×10⁸ cells/m², one progressed, one had stable disease, and three had a complete response (CR).

However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.

“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”

When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.

Bendamustine plus fludarabine

Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m² and fludarabine at 30 mg/m².

All 16 patients received CAR T cells at 2×10⁸ cells/m², which was the recommended phase 2 dose.

“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.

Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.

Two patients had a partial response, one had stable disease, and one progressed.

PFS and toxicity

Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.

The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).

There was no neurotoxicity in this trial.

Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.

Eight patients had a mild rash, one of whom had a rash at baseline.

“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.

“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”

This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.

A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.

However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.

Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*

This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.

Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.

The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).

Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).

In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.

Bendamustine alone

Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m². Three of these patients received CD30.CAR T-cell therapy at 1×10⁸ cells/m², and all three progressed.

Of the five patients who received CAR T-cell therapy at a dose of 2×10⁸ cells/m², one progressed, one had stable disease, and three had a complete response (CR).

However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.

“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”

When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.

Bendamustine plus fludarabine

Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m² and fludarabine at 30 mg/m².

All 16 patients received CAR T cells at 2×10⁸ cells/m², which was the recommended phase 2 dose.

“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.

Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.

Two patients had a partial response, one had stable disease, and one progressed.

PFS and toxicity

Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.

The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).

There was no neurotoxicity in this trial.

Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.

Eight patients had a mild rash, one of whom had a rash at baseline.

“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.

“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”

This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.

A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.

However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.

Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*

This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.

Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.

The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).

Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).

In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.

Bendamustine alone

Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m². Three of these patients received CD30.CAR T-cell therapy at 1×10⁸ cells/m², and all three progressed.

Of the five patients who received CAR T-cell therapy at a dose of 2×10⁸ cells/m², one progressed, one had stable disease, and three had a complete response (CR).

However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.

“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”

When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.

Bendamustine plus fludarabine

Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m² and fludarabine at 30 mg/m².

All 16 patients received CAR T cells at 2×10⁸ cells/m², which was the recommended phase 2 dose.

“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.

Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.

Two patients had a partial response, one had stable disease, and one progressed.

PFS and toxicity

Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.

The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).

There was no neurotoxicity in this trial.

Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.

Eight patients had a mild rash, one of whom had a rash at baseline.

“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.

“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”

This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.

*Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—Patients who develop metabolic syndrome (MetS) after hematopoietic stem cell transplant (HSCT) have an increased risk of cardiovascular (CV) events and second malignancies, according to research presented at the 2018 ASH Annual Meeting.

Researchers found that HSCT recipients had a higher prevalence of MetS than the general population, and the incidence of MetS increased with age.

In addition, MetS was a predictor of CV events, and these events were associated with second malignancy.

“Our data support metabolic syndrome being an age-related late effect of transplant that is strongly associated with not only cardiovascular events but also the occurrence of second cancers, and this is a novel finding,” said Diana M. Greenfield, RN, PhD, of Sheffield Teaching Hospitals NHS Foundation Trust in Sheffield, United Kingdom.

Dr. Greenfield presented the data at ASH as abstract 251.

She noted that previous studies have reported rates of MetS after HSCT ranging from 31% to 49%. Intensive chemotherapy and radiation have been associated with MetS, and proposed mechanisms of MetS after HSCT include:

• Conditioning regimen-mediated damage to the neuro-hormonal system and vascular endothelium
• Immunological and inflammatory effects of allo-grafting, including graft-vs-host disease (GVHD) and treatment.

“Those with metabolic syndrome in the general population are already known to be twice as likely to develop cardiovascular disease as those without metabolic syndrome,” Dr. Greenfield noted. “The risk of cardiovascular hospitalizations and mortality is 3.6-fold higher in transplant patients vs the general population.”

With all this in mind, she and her colleagues set out to determine the prevalence of MetS and associated complications among HSCT recipients treated at 9 European centers in Belgium, France, Germany, Turkey, and the United Kingdom.

The researchers analyzed 462 patients—375 who had received an allogeneic HSCT and 87 who had undergone autologous HSCT. All patients were at least 18 years of age and at least 2 years post-HSCT.

The median age at transplant was 43 (interquartile range, 32-53), and 57.4% of patients were male.

Patients’ diagnoses included acute leukemia (37.9%), lymphoma (27.3%), myelodysplastic syndromes/myeloproliferative neoplasms (13%), chronic leukemia (12.3%), plasma cell disorders (5%), bone marrow failure (4.1%), solid tumors (0.2%), and inherited disorders (0.2%).

Results

The prevalence of MetS in this population was 30.4%. This is higher than the prevalence in the general population in Europe, which is 25%, according to the World Health Organization.

There was no significant difference in MetS prevalence between allogeneic and autologous HSCT recipients—29% and 35.6%, respectively.

However, there was a significant difference in MetS prevalence by age (P<0.001 with increasing age).

Among allogeneic HSCT recipients, there was no relationship between MetS prevalence and the presence or degree of acute or chronic GVHD, current use of immunosuppressive therapy, or conditioning intensity.

There was a significantly higher prevalence of CV events in patients with MetS than in patients without the syndrome—22.6% and 10.7%, respectively (P=0.006).

And logistic regression analysis confirmed that MetS is a predictor of CV events (odds ratio [OR]=4.72; 95% confidence interval [CI], 2.11-10.57).

The researchers also found that increasing age influenced the prevalence of MetS (OR=7.3; 95% CI, 3.2-16.8) and CV events (OR=3; 95% CI, 0.8-11.32) for patients older than 50, compared to patients in the 18-29 age group.

And CV events were associated with second malignancy (OR=7.93; 95% CI, 2.91-21.61).

“Early intervention of reversible features of metabolic syndrome with lifestyle and medical management may reduce the risk of cardiovascular events,” Dr. Greenfield said. “Meanwhile, screening and management should be robustly integrated within routine transplant long-term follow-up care.”

She added that the CIBMTR and EBMT guidelines on MetS and CV disease after HSCT should help in that regard.

Dr. Greenfield reported no conflicts of interest. However, her fellow researchers reported relationships with a range of pharmaceutical companies.

Photo courtesy of ASH

SAN DIEGO—Patients who develop metabolic syndrome (MetS) after hematopoietic stem cell transplant (HSCT) have an increased risk of cardiovascular (CV) events and second malignancies, according to research presented at the 2018 ASH Annual Meeting.

Researchers found that HSCT recipients had a higher prevalence of MetS than the general population, and the incidence of MetS increased with age.

In addition, MetS was a predictor of CV events, and these events were associated with second malignancy.

“Our data support metabolic syndrome being an age-related late effect of transplant that is strongly associated with not only cardiovascular events but also the occurrence of second cancers, and this is a novel finding,” said Diana M. Greenfield, RN, PhD, of Sheffield Teaching Hospitals NHS Foundation Trust in Sheffield, United Kingdom.

Dr. Greenfield presented the data at ASH as abstract 251.

She noted that previous studies have reported rates of MetS after HSCT ranging from 31% to 49%. Intensive chemotherapy and radiation have been associated with MetS, and proposed mechanisms of MetS after HSCT include:

• Conditioning regimen-mediated damage to the neuro-hormonal system and vascular endothelium
• Immunological and inflammatory effects of allo-grafting, including graft-vs-host disease (GVHD) and treatment.

“Those with metabolic syndrome in the general population are already known to be twice as likely to develop cardiovascular disease as those without metabolic syndrome,” Dr. Greenfield noted. “The risk of cardiovascular hospitalizations and mortality is 3.6-fold higher in transplant patients vs the general population.”

With all this in mind, she and her colleagues set out to determine the prevalence of MetS and associated complications among HSCT recipients treated at 9 European centers in Belgium, France, Germany, Turkey, and the United Kingdom.

The researchers analyzed 462 patients—375 who had received an allogeneic HSCT and 87 who had undergone autologous HSCT. All patients were at least 18 years of age and at least 2 years post-HSCT.

The median age at transplant was 43 (interquartile range, 32-53), and 57.4% of patients were male.

Patients’ diagnoses included acute leukemia (37.9%), lymphoma (27.3%), myelodysplastic syndromes/myeloproliferative neoplasms (13%), chronic leukemia (12.3%), plasma cell disorders (5%), bone marrow failure (4.1%), solid tumors (0.2%), and inherited disorders (0.2%).

Results

The prevalence of MetS in this population was 30.4%. This is higher than the prevalence in the general population in Europe, which is 25%, according to the World Health Organization.

There was no significant difference in MetS prevalence between allogeneic and autologous HSCT recipients—29% and 35.6%, respectively.

However, there was a significant difference in MetS prevalence by age (P<0.001 with increasing age).

Among allogeneic HSCT recipients, there was no relationship between MetS prevalence and the presence or degree of acute or chronic GVHD, current use of immunosuppressive therapy, or conditioning intensity.

There was a significantly higher prevalence of CV events in patients with MetS than in patients without the syndrome—22.6% and 10.7%, respectively (P=0.006).

And logistic regression analysis confirmed that MetS is a predictor of CV events (odds ratio [OR]=4.72; 95% confidence interval [CI], 2.11-10.57).

The researchers also found that increasing age influenced the prevalence of MetS (OR=7.3; 95% CI, 3.2-16.8) and CV events (OR=3; 95% CI, 0.8-11.32) for patients older than 50, compared to patients in the 18-29 age group.

And CV events were associated with second malignancy (OR=7.93; 95% CI, 2.91-21.61).

“Early intervention of reversible features of metabolic syndrome with lifestyle and medical management may reduce the risk of cardiovascular events,” Dr. Greenfield said. “Meanwhile, screening and management should be robustly integrated within routine transplant long-term follow-up care.”

She added that the CIBMTR and EBMT guidelines on MetS and CV disease after HSCT should help in that regard.

Dr. Greenfield reported no conflicts of interest. However, her fellow researchers reported relationships with a range of pharmaceutical companies.

Photo courtesy of ASH

SAN DIEGO—Patients who develop metabolic syndrome (MetS) after hematopoietic stem cell transplant (HSCT) have an increased risk of cardiovascular (CV) events and second malignancies, according to research presented at the 2018 ASH Annual Meeting.

Researchers found that HSCT recipients had a higher prevalence of MetS than the general population, and the incidence of MetS increased with age.

In addition, MetS was a predictor of CV events, and these events were associated with second malignancy.

“Our data support metabolic syndrome being an age-related late effect of transplant that is strongly associated with not only cardiovascular events but also the occurrence of second cancers, and this is a novel finding,” said Diana M. Greenfield, RN, PhD, of Sheffield Teaching Hospitals NHS Foundation Trust in Sheffield, United Kingdom.

Dr. Greenfield presented the data at ASH as abstract 251.

She noted that previous studies have reported rates of MetS after HSCT ranging from 31% to 49%. Intensive chemotherapy and radiation have been associated with MetS, and proposed mechanisms of MetS after HSCT include:

• Conditioning regimen-mediated damage to the neuro-hormonal system and vascular endothelium
• Immunological and inflammatory effects of allo-grafting, including graft-vs-host disease (GVHD) and treatment.

“Those with metabolic syndrome in the general population are already known to be twice as likely to develop cardiovascular disease as those without metabolic syndrome,” Dr. Greenfield noted. “The risk of cardiovascular hospitalizations and mortality is 3.6-fold higher in transplant patients vs the general population.”

With all this in mind, she and her colleagues set out to determine the prevalence of MetS and associated complications among HSCT recipients treated at 9 European centers in Belgium, France, Germany, Turkey, and the United Kingdom.

The researchers analyzed 462 patients—375 who had received an allogeneic HSCT and 87 who had undergone autologous HSCT. All patients were at least 18 years of age and at least 2 years post-HSCT.

The median age at transplant was 43 (interquartile range, 32-53), and 57.4% of patients were male.

Patients’ diagnoses included acute leukemia (37.9%), lymphoma (27.3%), myelodysplastic syndromes/myeloproliferative neoplasms (13%), chronic leukemia (12.3%), plasma cell disorders (5%), bone marrow failure (4.1%), solid tumors (0.2%), and inherited disorders (0.2%).

Results

The prevalence of MetS in this population was 30.4%. This is higher than the prevalence in the general population in Europe, which is 25%, according to the World Health Organization.

There was no significant difference in MetS prevalence between allogeneic and autologous HSCT recipients—29% and 35.6%, respectively.

However, there was a significant difference in MetS prevalence by age (P<0.001 with increasing age).

Among allogeneic HSCT recipients, there was no relationship between MetS prevalence and the presence or degree of acute or chronic GVHD, current use of immunosuppressive therapy, or conditioning intensity.

There was a significantly higher prevalence of CV events in patients with MetS than in patients without the syndrome—22.6% and 10.7%, respectively (P=0.006).

And logistic regression analysis confirmed that MetS is a predictor of CV events (odds ratio [OR]=4.72; 95% confidence interval [CI], 2.11-10.57).

The researchers also found that increasing age influenced the prevalence of MetS (OR=7.3; 95% CI, 3.2-16.8) and CV events (OR=3; 95% CI, 0.8-11.32) for patients older than 50, compared to patients in the 18-29 age group.

And CV events were associated with second malignancy (OR=7.93; 95% CI, 2.91-21.61).

“Early intervention of reversible features of metabolic syndrome with lifestyle and medical management may reduce the risk of cardiovascular events,” Dr. Greenfield said. “Meanwhile, screening and management should be robustly integrated within routine transplant long-term follow-up care.”

She added that the CIBMTR and EBMT guidelines on MetS and CV disease after HSCT should help in that regard.

Dr. Greenfield reported no conflicts of interest. However, her fellow researchers reported relationships with a range of pharmaceutical companies.

ABSTRACT

Systemic corticosteroids are used to treat a number of medical conditions; however, they are associated with numerous adverse effects. The impact of preoperative chronic corticosteroid use on postoperative outcomes following total hip arthroplasty (THA) is unclear. The purpose of this study was to assess the independent effect of chronic systemic preoperative steroid use on short-term perioperative complications and readmissions after THA.

All patients undergoing primary THA in the American College of Surgeons National Surgical Quality Improvement Program registry from 2005 to -–2015 were identified. Patients were considered chronic steroid users if they used any dosage of oral or parenteral steroids for >10 of the preceding 30 days before THA. Two equally sized propensity-matched groups based on preoperative steroid use were generated to account for differences in operative and baseline characteristics between the groups. Thirty-day complications and hospital readmissions rates were compared using bivariate analysis.

Of 101,532 THA patients who underwent primary THA, 3714 (3.7%) were identified as chronic corticosteroid users. Comparison of propensity-matched cohorts identified an increased rate of any complication (odds ratio [OR] 1.30, P = .003), sepsis (OR 2.07, P = .022), urinary tract infection (OR 1.61, P = .020), superficial surgical site infection (OR 1.73, P = .038), and hospital readmission (OR 1.50, P < .001) in patients who used systemic steroids preoperatively. Readmissions in preoperative steroid users were most commonly for infectious reasons.

Patients prescribed chronic corticosteroids are at a significantly increased risk of both 30-day periopative complications and hospital readmissions. This finding has important implications for pre- and postoperative patient counseling as well as preoperative risk stratification.

Continue to: Corticosteroids are powerful...

Corticosteroids are powerful anti-inflammatory steroid hormones that have many indications in the treatment of medical diseases, including advanced or poorly controlled asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, allergic conditions, among other indications.^1-4 In orthopedics and rheumatology, systemic steroids are, at times, used in patients with rheumatoid arthritis, systemic lupus erythematosus, and vasculitides.^5-7 Overman and colleagues,⁸ using data from the National Health and Nutrition Examination Survey between 1999 and 2008 identified both a 1.2% prevalence of chronic corticosteroid usage in the United States across all age groups and a positive correlation between steroid use prevalence and increasing age. In that study, nearly two-thirds of survey respondents reported using corticosteroids chronically for >90 days. Another observational study in the United Kingdom found that long-term steroid prescriptions increased between 1989 to 2008 and that 13.6% of patients with rheumatoid arthritis and 66.5% of patients with polymyalgia rheumatica or giant cell arteritis used long-term steroids.⁹

Enterally- or parenterally-administered corticosteroids have numerous systemic effects that are of particular relevance to orthopedic surgeons. Corticosteroids induce osteoporosis by preferentially inducing osteoclastic activity while inhibiting the differentiation of osteoblasts, ultimately leading to decreased bone quality and mass.¹⁰ As a consequence, patients who have previously used corticosteroids are more than twice as likely to have a hip fracture.¹¹ Steroids also increase the risk of both osteonecrosis and myopathy, among other musculoskeletal effects.¹² In addition to orthopedic complications, steroids have broad inhibitory effects on both acquired and innate immunity, which significantly increases the risk of infections.¹³ This increased risk of infection is dose-dependent¹⁴ and synergistic with other immunosuppressive drugs.¹⁵

Patients with hip pain may receive localized corticosteroid hip joint injections during the nonoperative management of various hip pathologies, including arthritis, bursitis, and labral tears.^16,17 Outcomes of patients who received intra-articular corticosteroid injections before total hip arthroplasty (THA) were evaluated in a systematic review of 9 studies by Pereira and colleagues.¹⁷ These authors found that the infection rate (both superficial and deep surgical site infections [SSI]) after THA in patients who received local steroid injection into the hip before surgery was between 0% and 30%.¹⁷ However, similar studies assessing the impact that systemic steroids have on outcomes after THA are lacking. Patients who undergo THA for conditions associated with higher lifetime steroid usage have worse outcomes than those who do not. For instance, in patients undergoing THA for rheumatoid arthritis, the rates of both postoperative periprosthetic joint infection and hip dislocation are higher, when compared with osteoarthritis.^18,19 However, it is unclear how much of this difference in outcomes is due to the underlying disease, adverse effects of steroids, or both. Given the high prevalence of chronic systemic steroid use, it is essential to elucidate more clearly the impact that these medications have on perioperative outcomes after THA.  

Therefore, the purpose of this study was to characterize short-term perioperative outcomes, including complication and readmission rates in patients undergoing THA while taking chronic preoperative corticosteroids. We also sought to identify the most common reasons for hospital readmission in patients who did and did not use long-term steroids.

MATERIALS AND METHODS

STUDY DESIGN AND SETTING

This investigation was a retrospective cohort study that utilized the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry.²⁰ The ACS-NSQIP is a prospectively collected, multi-institutional database that collects demographical information, operative variables, and both postoperative complications and hospital readmission data. Data is collected for up to 30 days after the index procedure, and patients are contacted by telephone if they are discharged before 30 days. Patient data is entered by specially trained surgical clinical reviewers and is routinely audited by the ACS-NSQIP, leading to more accurate data when compared with administrative research databases.^21,22 The ACS-NSQIP has been used in orthopedic surgery outcomes-based studies.^23-25

Continue to: All patients undergoing...

All patients undergoing THA between 2005 and 2015 were identified in the registry using primary Current Procedural Terminology code 27130. Patients were split into 2 groups based on whether or not they chronically used corticosteroids preoperatively for a medical condition. A patient was considered a chronic corticosteroid user if he/she used oral or parenteral corticosteroids within 30 days before the index procedure for >10 of the preceding 30 days. Those who received a 1-time steroid pulse or those who used topical or inhaled steroids were not considered as steroid users in this study.

BASELINE CHARACTERISTICS AND PERIOPERATIVE OUTCOMES

Baseline patient and operative characteristics, including patient age, gender, body mass index (BMI), functional status, American Society of Anesthesiologists (ASA) class, anesthesia type, operative duration, and medical comorbidities including hypertension, COPD, diabetes mellitus, and smoking history, were compared between both groups. Perioperative outcomes that were assessed in this study include death, renal, respiratory, and cardiac complications, deep vein thrombosis or pulmonary embolism, stroke, sepsis, return to the operating room, urinary tract infection (UTI), wound dehiscence, superficial and deep SSI, need for a blood transfusion within 72 hours of index surgical procedure, and hospital readmissions. Renal complications were defined as acute or progressive renal insufficiency; respiratory complications were defined as failure to wean from the ventilator, need for intubation after the index procedure, and the occurrence of pneumonia; and cardiac complications were defined as myocardial infarction or cardiac arrest requiring cardiopulmonary resuscitation. Patients were excluded if they had missing baseline or operative characteristic data, an unclean wound classification at the time of admission, or if their THA was considered emergent.

STATISTICAL ANALYSIS

A propensity score-matched comparison was performed to adjust for differences in baseline and operative characteristics between the 2 cohorts in this study. In the current study, the propensity score was defined as the conditional probability that a patient chronically used preoperative corticosteroids for a medical condition, as a function of age, BMI, gender, ASA class, functional status, medical comorbidities, anesthesia type, and operative duration. A 1:1 matching with tight calipers (0.0001), and nearest-neighbor matching was used to generate 2 equally-sized, propensity-matched cohorts based on steroid status.²⁶ Nearest-neighbor matching identifies patients in both cohorts with the closest propensity scores for inclusion in propensity-matched cohorts. This matching is continued until 1 group runs out of patients to match. Baseline patient and operative characteristics for the unadjusted and propensity-matched groups were compared using Pearson’s χ² analysis. Outcomes after THA by steroid status were also compared in both unadjusted and propensity-matched groups. Finally, all patients who were readmitted were identified, and the reason for readmission was determined using the International Classification of Disease Ninth (ICD-9) and Tenth (ICD-10) edition codes. Patients were classified as having an infectious readmission only if the ICD code clearly stated an infectious etiology. For instance, a patient with an intestinal infection due to Clostridium difficile (ICD-9 008.45) was counted as a gastrointestinal infection, whereas diarrhea without a distinctly specified etiology (ICD-9 787.91, ICD-10 R19.7) was counted as a gastrointestinal medical complication. Readmission data was only available in ACS-NSQIP from 2011 to 2015, constituting 92.5% of all patients included in this study. We used SPSS version 23 (IBM Corporation) for all statistical analyses, and defined a significant P value as <.05.

RESULTS

BASELINE PATIENTS AND OPERATIVE CHARACTERISTICS

In total, we identified 101,532 patients who underwent THA (Table 1). O these, 3714 (3.7%) chronically used corticosteroids preoperatively, whereas 97,818 (96.3%) did not. 

When the unadjusted cohorts were compared, patients using corticosteroids were more likely to be female, less likely to obese, more likely to have hypertension, diabetes mellitus, COPD, higher ASA class, undergone THA with general anesthesia, and have a dependent functional status (P < .001 for all comparisons). After propensity matching, 2 equally sized cohorts of 3618 patients each were generated based on steroid status and no differences in baseline and operative characteristics were identified between the 2 groups.

Continue to: CLINICAL OUTCOMES BY STEROID STATUS

CLINCIAL OUTCOMES BY STEROID STATUS

A comparison of unadjusted cohorts showed that patients who used preoperative steroids had an increased rate of any complication (7.89%) when compared with those who did not (4.87%) (Table 2). 

Similarly, those who used corticosteroids preoperatively had an increased rate of renal complications, respiratory complications, return to the operating room, sepsis, UTI, superficial and deep SSI, and perioperative blood transfusions. They also were more likely to have a 30-day hospital readmission (P < .05 for all comparisons).

When propensity-matched cohorts were compared, patients who used steroids preoperatively were found to have higher rates of any complication (odds Ratio [OR] 1.30, P = .003), sepsis (OR 2.07, P = .022), UTI (OR 1.61, P = .020), superficial SSI (OR 1.73, P = .038), and hospital readmission (OR 1.50, P < .001; Table 3).

REASONS FOR HOSPITAL READMISSION

In total, 3397 patients were readmitted to the hospital within thirty days. Of these, 226 used steroids preoperatively, and 3171 did not (Table 4). 

The most common reason for hospital readmission in patients who used preoperative corticosteroids was infectious complications (72 patients, 31.9% of all readmitted patients in this cohort), followed by medical complications (59 patients, 26.1%), and hip-related complications (48 patients, 21.2%). In those who did not use steroids preoperatively, the most common reason for hospital readmission was medical complications (932 patients, 29.4% of all readmitted patients in this cohort), followed by infectious complications (792 patients, 25.0%), and hip-related complications (763 patients, 24.1%).

Continue to: DISCUSSION

Nearly 3% of individuals >80 years in the US population chronically use corticosteroids for a medical condition,⁸ and this rate is likely higher in specific subsets of patients, such as those with rheumatoid arthritis.⁹ While some studies have assessed the impact of intra-articular corticosteroid hip injections on perioperative outcomes in THA,¹⁷ similar studies assessing systemic corticosteroid usage are lacking. The purpose of this study was to characterize short-term perioperative outcomes in patients undergoing THA who chronically use systemic steroids when compared with those who do not. We found that the prevalence of preoperative chronic steroid use in this cohort of THA patients was 3.7%. We also identified increased rates of infectious complications, including sepsis, UTI, and superficial SSI, in patients who used preoperative corticosteroids. Furthermore, we found an increased rate of hospital readmissions in corticosteroid users and identified the most common reason for hospital readmission as infectious complications in this cohort.

The primary finding of this study was an increase in postoperative infections in patients who use preoperative steroids chronically for medical conditions. Immunosuppression has previously been identified as a risk factor for developing periprosthetic joint infections. Tannenbaum and colleagues²⁷ performed a retrospective study of 19 patients who underwent either a kidney or liver transplant and were maintained on an induction regimen of either prednisone and azathioprine or cyclosporine. These 19 patients also underwent either a THA or total knee arthroplasty, and 5 of these patients (26.3%) developed a periprosthetic joint infection after an average of 3.4 years following the arthroplasty procedure. In another study of 37 renal transplant and dialysis patients who underwent a total of 45 THA procedures, there were 3 instances of superficial SSI and 2 instances of deep SSI.²⁸ However, reported infection rates in transplant patients undergoing THA vary significantly, and studies have been unable to assess the true impact that chronic immunosuppression has on perioperative infection rates.²⁹ In this study, patients who used preoperative corticosteroids chronically were at increased risk of perioperative infections, including sepsis, UTI, and superficial SSI.

Deep vein thrombosis is another postoperative complication that has been associated with chronic steroid use.³⁰ In a case-control study of 38,765 patients who developed a venous thromboembolism and 387,650 control patients who did not, Johannesdottir and colleagues³⁰ found an increased thromboembolic risk in current users of systemic glucocorticoids, but not former users, as well as an increased risk as the dose of glucocorticoids increased. We were not able to identify a similar increase in DVT/PE in chronic corticosteroid users, perhaps due to our sample size, or because we could not do subgroup analyses based on the type or dosage of steroid that a patient was taking. Future studies that identify the highest risk patients among those using systemic corticosteroids are important because parenteral corticosteroids are being increasingly used in THA to alleviate postoperative pain as an opioid-sparing measure.^31,32

Finally, we also found that patients who use chronic, systemic corticosteroids are at an increased risk for hospital readmission, when compared with those patients who are not using steroids and are most likely to be readmitted for an infectious complication. Schairer and colleagues³³ assessed readmission rates after THA and found 30- and 90-day readmission rate of 4% and 7%, respectively. These authors also found that medical complications accounted for approximately 25% of readmissions, and hip-related complications (eg, dislocation, SSI) accounted for >50%. In our study, we found a 30-day readmission rate in non-steroid users of 3.53% and a rate of 6.52% in chronic steroid users. More than 30% of patients using a steroid were readmitted for infectious complications. As THA is becoming increasingly reimbursed under a bundled payments model by Medicare and Medicaid,^34-36 reducing short-term readmissions is imperative. Therefore, discharge counseling that emphasizes how to recognize both the signs and symptoms of infection as well as how to prevent infections, such as reducing SSIs through appropriate wound care, may be warranted in higher risk chronic steroid users.

This study has a number of limitations that are inherent to ACS-NSQIP. First, we lacked specific information on a patient’s steroid history, including which corticosteroid they were using, dosage, frequency, and the indication for corticosteroid therapy. Therefore, we were unable to establish a dose-dependent relationship between steroid exposure and postoperative complications after THA. Second, we were able to assess only 30-day rates of complications and readmissions, and therefore, we were unable to identify intermediate- and long-term effects of systemic corticosteroid use on THA. Finally, we could not determine orthopedic- or hip-specific postoperative outcomes, such as functional scores and range of motion.

Continue to: CONCLUSION

In conclusion, this study quantified the increased risk for perioperative complications and hospital readmissions in patients who chronically use corticosteroids and are undergoing THA, when compared with those who do not use corticosteroids. These results suggest that patients who are on long-term steroids are at an increased risk for complications, primarily infectious complications. This finding has important implications for patient counseling, preoperative risk stratification, and suggests that higher risk patients, such as chronic steroid users, may benefit from improved discharge care to decrease complication rates.

ABSTRACT

Systemic corticosteroids are used to treat a number of medical conditions; however, they are associated with numerous adverse effects. The impact of preoperative chronic corticosteroid use on postoperative outcomes following total hip arthroplasty (THA) is unclear. The purpose of this study was to assess the independent effect of chronic systemic preoperative steroid use on short-term perioperative complications and readmissions after THA.

All patients undergoing primary THA in the American College of Surgeons National Surgical Quality Improvement Program registry from 2005 to -–2015 were identified. Patients were considered chronic steroid users if they used any dosage of oral or parenteral steroids for >10 of the preceding 30 days before THA. Two equally sized propensity-matched groups based on preoperative steroid use were generated to account for differences in operative and baseline characteristics between the groups. Thirty-day complications and hospital readmissions rates were compared using bivariate analysis.

Of 101,532 THA patients who underwent primary THA, 3714 (3.7%) were identified as chronic corticosteroid users. Comparison of propensity-matched cohorts identified an increased rate of any complication (odds ratio [OR] 1.30, P = .003), sepsis (OR 2.07, P = .022), urinary tract infection (OR 1.61, P = .020), superficial surgical site infection (OR 1.73, P = .038), and hospital readmission (OR 1.50, P < .001) in patients who used systemic steroids preoperatively. Readmissions in preoperative steroid users were most commonly for infectious reasons.

Patients prescribed chronic corticosteroids are at a significantly increased risk of both 30-day periopative complications and hospital readmissions. This finding has important implications for pre- and postoperative patient counseling as well as preoperative risk stratification.

Continue to: Corticosteroids are powerful...

Corticosteroids are powerful anti-inflammatory steroid hormones that have many indications in the treatment of medical diseases, including advanced or poorly controlled asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, allergic conditions, among other indications.^1-4 In orthopedics and rheumatology, systemic steroids are, at times, used in patients with rheumatoid arthritis, systemic lupus erythematosus, and vasculitides.^5-7 Overman and colleagues,⁸ using data from the National Health and Nutrition Examination Survey between 1999 and 2008 identified both a 1.2% prevalence of chronic corticosteroid usage in the United States across all age groups and a positive correlation between steroid use prevalence and increasing age. In that study, nearly two-thirds of survey respondents reported using corticosteroids chronically for >90 days. Another observational study in the United Kingdom found that long-term steroid prescriptions increased between 1989 to 2008 and that 13.6% of patients with rheumatoid arthritis and 66.5% of patients with polymyalgia rheumatica or giant cell arteritis used long-term steroids.⁹

Enterally- or parenterally-administered corticosteroids have numerous systemic effects that are of particular relevance to orthopedic surgeons. Corticosteroids induce osteoporosis by preferentially inducing osteoclastic activity while inhibiting the differentiation of osteoblasts, ultimately leading to decreased bone quality and mass.¹⁰ As a consequence, patients who have previously used corticosteroids are more than twice as likely to have a hip fracture.¹¹ Steroids also increase the risk of both osteonecrosis and myopathy, among other musculoskeletal effects.¹² In addition to orthopedic complications, steroids have broad inhibitory effects on both acquired and innate immunity, which significantly increases the risk of infections.¹³ This increased risk of infection is dose-dependent¹⁴ and synergistic with other immunosuppressive drugs.¹⁵

Patients with hip pain may receive localized corticosteroid hip joint injections during the nonoperative management of various hip pathologies, including arthritis, bursitis, and labral tears.^16,17 Outcomes of patients who received intra-articular corticosteroid injections before total hip arthroplasty (THA) were evaluated in a systematic review of 9 studies by Pereira and colleagues.¹⁷ These authors found that the infection rate (both superficial and deep surgical site infections [SSI]) after THA in patients who received local steroid injection into the hip before surgery was between 0% and 30%.¹⁷ However, similar studies assessing the impact that systemic steroids have on outcomes after THA are lacking. Patients who undergo THA for conditions associated with higher lifetime steroid usage have worse outcomes than those who do not. For instance, in patients undergoing THA for rheumatoid arthritis, the rates of both postoperative periprosthetic joint infection and hip dislocation are higher, when compared with osteoarthritis.^18,19 However, it is unclear how much of this difference in outcomes is due to the underlying disease, adverse effects of steroids, or both. Given the high prevalence of chronic systemic steroid use, it is essential to elucidate more clearly the impact that these medications have on perioperative outcomes after THA.  

Therefore, the purpose of this study was to characterize short-term perioperative outcomes, including complication and readmission rates in patients undergoing THA while taking chronic preoperative corticosteroids. We also sought to identify the most common reasons for hospital readmission in patients who did and did not use long-term steroids.

MATERIALS AND METHODS

STUDY DESIGN AND SETTING

This investigation was a retrospective cohort study that utilized the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry.²⁰ The ACS-NSQIP is a prospectively collected, multi-institutional database that collects demographical information, operative variables, and both postoperative complications and hospital readmission data. Data is collected for up to 30 days after the index procedure, and patients are contacted by telephone if they are discharged before 30 days. Patient data is entered by specially trained surgical clinical reviewers and is routinely audited by the ACS-NSQIP, leading to more accurate data when compared with administrative research databases.^21,22 The ACS-NSQIP has been used in orthopedic surgery outcomes-based studies.^23-25

Continue to: All patients undergoing...

All patients undergoing THA between 2005 and 2015 were identified in the registry using primary Current Procedural Terminology code 27130. Patients were split into 2 groups based on whether or not they chronically used corticosteroids preoperatively for a medical condition. A patient was considered a chronic corticosteroid user if he/she used oral or parenteral corticosteroids within 30 days before the index procedure for >10 of the preceding 30 days. Those who received a 1-time steroid pulse or those who used topical or inhaled steroids were not considered as steroid users in this study.

BASELINE CHARACTERISTICS AND PERIOPERATIVE OUTCOMES

Baseline patient and operative characteristics, including patient age, gender, body mass index (BMI), functional status, American Society of Anesthesiologists (ASA) class, anesthesia type, operative duration, and medical comorbidities including hypertension, COPD, diabetes mellitus, and smoking history, were compared between both groups. Perioperative outcomes that were assessed in this study include death, renal, respiratory, and cardiac complications, deep vein thrombosis or pulmonary embolism, stroke, sepsis, return to the operating room, urinary tract infection (UTI), wound dehiscence, superficial and deep SSI, need for a blood transfusion within 72 hours of index surgical procedure, and hospital readmissions. Renal complications were defined as acute or progressive renal insufficiency; respiratory complications were defined as failure to wean from the ventilator, need for intubation after the index procedure, and the occurrence of pneumonia; and cardiac complications were defined as myocardial infarction or cardiac arrest requiring cardiopulmonary resuscitation. Patients were excluded if they had missing baseline or operative characteristic data, an unclean wound classification at the time of admission, or if their THA was considered emergent.

STATISTICAL ANALYSIS

A propensity score-matched comparison was performed to adjust for differences in baseline and operative characteristics between the 2 cohorts in this study. In the current study, the propensity score was defined as the conditional probability that a patient chronically used preoperative corticosteroids for a medical condition, as a function of age, BMI, gender, ASA class, functional status, medical comorbidities, anesthesia type, and operative duration. A 1:1 matching with tight calipers (0.0001), and nearest-neighbor matching was used to generate 2 equally-sized, propensity-matched cohorts based on steroid status.²⁶ Nearest-neighbor matching identifies patients in both cohorts with the closest propensity scores for inclusion in propensity-matched cohorts. This matching is continued until 1 group runs out of patients to match. Baseline patient and operative characteristics for the unadjusted and propensity-matched groups were compared using Pearson’s χ² analysis. Outcomes after THA by steroid status were also compared in both unadjusted and propensity-matched groups. Finally, all patients who were readmitted were identified, and the reason for readmission was determined using the International Classification of Disease Ninth (ICD-9) and Tenth (ICD-10) edition codes. Patients were classified as having an infectious readmission only if the ICD code clearly stated an infectious etiology. For instance, a patient with an intestinal infection due to Clostridium difficile (ICD-9 008.45) was counted as a gastrointestinal infection, whereas diarrhea without a distinctly specified etiology (ICD-9 787.91, ICD-10 R19.7) was counted as a gastrointestinal medical complication. Readmission data was only available in ACS-NSQIP from 2011 to 2015, constituting 92.5% of all patients included in this study. We used SPSS version 23 (IBM Corporation) for all statistical analyses, and defined a significant P value as <.05.

RESULTS

BASELINE PATIENTS AND OPERATIVE CHARACTERISTICS

In total, we identified 101,532 patients who underwent THA (Table 1). O these, 3714 (3.7%) chronically used corticosteroids preoperatively, whereas 97,818 (96.3%) did not. 

When the unadjusted cohorts were compared, patients using corticosteroids were more likely to be female, less likely to obese, more likely to have hypertension, diabetes mellitus, COPD, higher ASA class, undergone THA with general anesthesia, and have a dependent functional status (P < .001 for all comparisons). After propensity matching, 2 equally sized cohorts of 3618 patients each were generated based on steroid status and no differences in baseline and operative characteristics were identified between the 2 groups.

Continue to: CLINICAL OUTCOMES BY STEROID STATUS

CLINCIAL OUTCOMES BY STEROID STATUS

A comparison of unadjusted cohorts showed that patients who used preoperative steroids had an increased rate of any complication (7.89%) when compared with those who did not (4.87%) (Table 2). 

Similarly, those who used corticosteroids preoperatively had an increased rate of renal complications, respiratory complications, return to the operating room, sepsis, UTI, superficial and deep SSI, and perioperative blood transfusions. They also were more likely to have a 30-day hospital readmission (P < .05 for all comparisons).

When propensity-matched cohorts were compared, patients who used steroids preoperatively were found to have higher rates of any complication (odds Ratio [OR] 1.30, P = .003), sepsis (OR 2.07, P = .022), UTI (OR 1.61, P = .020), superficial SSI (OR 1.73, P = .038), and hospital readmission (OR 1.50, P < .001; Table 3).

REASONS FOR HOSPITAL READMISSION

In total, 3397 patients were readmitted to the hospital within thirty days. Of these, 226 used steroids preoperatively, and 3171 did not (Table 4). 

The most common reason for hospital readmission in patients who used preoperative corticosteroids was infectious complications (72 patients, 31.9% of all readmitted patients in this cohort), followed by medical complications (59 patients, 26.1%), and hip-related complications (48 patients, 21.2%). In those who did not use steroids preoperatively, the most common reason for hospital readmission was medical complications (932 patients, 29.4% of all readmitted patients in this cohort), followed by infectious complications (792 patients, 25.0%), and hip-related complications (763 patients, 24.1%).

Continue to: DISCUSSION

Nearly 3% of individuals >80 years in the US population chronically use corticosteroids for a medical condition,⁸ and this rate is likely higher in specific subsets of patients, such as those with rheumatoid arthritis.⁹ While some studies have assessed the impact of intra-articular corticosteroid hip injections on perioperative outcomes in THA,¹⁷ similar studies assessing systemic corticosteroid usage are lacking. The purpose of this study was to characterize short-term perioperative outcomes in patients undergoing THA who chronically use systemic steroids when compared with those who do not. We found that the prevalence of preoperative chronic steroid use in this cohort of THA patients was 3.7%. We also identified increased rates of infectious complications, including sepsis, UTI, and superficial SSI, in patients who used preoperative corticosteroids. Furthermore, we found an increased rate of hospital readmissions in corticosteroid users and identified the most common reason for hospital readmission as infectious complications in this cohort.

The primary finding of this study was an increase in postoperative infections in patients who use preoperative steroids chronically for medical conditions. Immunosuppression has previously been identified as a risk factor for developing periprosthetic joint infections. Tannenbaum and colleagues²⁷ performed a retrospective study of 19 patients who underwent either a kidney or liver transplant and were maintained on an induction regimen of either prednisone and azathioprine or cyclosporine. These 19 patients also underwent either a THA or total knee arthroplasty, and 5 of these patients (26.3%) developed a periprosthetic joint infection after an average of 3.4 years following the arthroplasty procedure. In another study of 37 renal transplant and dialysis patients who underwent a total of 45 THA procedures, there were 3 instances of superficial SSI and 2 instances of deep SSI.²⁸ However, reported infection rates in transplant patients undergoing THA vary significantly, and studies have been unable to assess the true impact that chronic immunosuppression has on perioperative infection rates.²⁹ In this study, patients who used preoperative corticosteroids chronically were at increased risk of perioperative infections, including sepsis, UTI, and superficial SSI.

Deep vein thrombosis is another postoperative complication that has been associated with chronic steroid use.³⁰ In a case-control study of 38,765 patients who developed a venous thromboembolism and 387,650 control patients who did not, Johannesdottir and colleagues³⁰ found an increased thromboembolic risk in current users of systemic glucocorticoids, but not former users, as well as an increased risk as the dose of glucocorticoids increased. We were not able to identify a similar increase in DVT/PE in chronic corticosteroid users, perhaps due to our sample size, or because we could not do subgroup analyses based on the type or dosage of steroid that a patient was taking. Future studies that identify the highest risk patients among those using systemic corticosteroids are important because parenteral corticosteroids are being increasingly used in THA to alleviate postoperative pain as an opioid-sparing measure.^31,32

Finally, we also found that patients who use chronic, systemic corticosteroids are at an increased risk for hospital readmission, when compared with those patients who are not using steroids and are most likely to be readmitted for an infectious complication. Schairer and colleagues³³ assessed readmission rates after THA and found 30- and 90-day readmission rate of 4% and 7%, respectively. These authors also found that medical complications accounted for approximately 25% of readmissions, and hip-related complications (eg, dislocation, SSI) accounted for >50%. In our study, we found a 30-day readmission rate in non-steroid users of 3.53% and a rate of 6.52% in chronic steroid users. More than 30% of patients using a steroid were readmitted for infectious complications. As THA is becoming increasingly reimbursed under a bundled payments model by Medicare and Medicaid,^34-36 reducing short-term readmissions is imperative. Therefore, discharge counseling that emphasizes how to recognize both the signs and symptoms of infection as well as how to prevent infections, such as reducing SSIs through appropriate wound care, may be warranted in higher risk chronic steroid users.

This study has a number of limitations that are inherent to ACS-NSQIP. First, we lacked specific information on a patient’s steroid history, including which corticosteroid they were using, dosage, frequency, and the indication for corticosteroid therapy. Therefore, we were unable to establish a dose-dependent relationship between steroid exposure and postoperative complications after THA. Second, we were able to assess only 30-day rates of complications and readmissions, and therefore, we were unable to identify intermediate- and long-term effects of systemic corticosteroid use on THA. Finally, we could not determine orthopedic- or hip-specific postoperative outcomes, such as functional scores and range of motion.

Continue to: CONCLUSION

In conclusion, this study quantified the increased risk for perioperative complications and hospital readmissions in patients who chronically use corticosteroids and are undergoing THA, when compared with those who do not use corticosteroids. These results suggest that patients who are on long-term steroids are at an increased risk for complications, primarily infectious complications. This finding has important implications for patient counseling, preoperative risk stratification, and suggests that higher risk patients, such as chronic steroid users, may benefit from improved discharge care to decrease complication rates.

ABSTRACT

Systemic corticosteroids are used to treat a number of medical conditions; however, they are associated with numerous adverse effects. The impact of preoperative chronic corticosteroid use on postoperative outcomes following total hip arthroplasty (THA) is unclear. The purpose of this study was to assess the independent effect of chronic systemic preoperative steroid use on short-term perioperative complications and readmissions after THA.

All patients undergoing primary THA in the American College of Surgeons National Surgical Quality Improvement Program registry from 2005 to -–2015 were identified. Patients were considered chronic steroid users if they used any dosage of oral or parenteral steroids for >10 of the preceding 30 days before THA. Two equally sized propensity-matched groups based on preoperative steroid use were generated to account for differences in operative and baseline characteristics between the groups. Thirty-day complications and hospital readmissions rates were compared using bivariate analysis.

Of 101,532 THA patients who underwent primary THA, 3714 (3.7%) were identified as chronic corticosteroid users. Comparison of propensity-matched cohorts identified an increased rate of any complication (odds ratio [OR] 1.30, P = .003), sepsis (OR 2.07, P = .022), urinary tract infection (OR 1.61, P = .020), superficial surgical site infection (OR 1.73, P = .038), and hospital readmission (OR 1.50, P < .001) in patients who used systemic steroids preoperatively. Readmissions in preoperative steroid users were most commonly for infectious reasons.

Patients prescribed chronic corticosteroids are at a significantly increased risk of both 30-day periopative complications and hospital readmissions. This finding has important implications for pre- and postoperative patient counseling as well as preoperative risk stratification.

Continue to: Corticosteroids are powerful...

Corticosteroids are powerful anti-inflammatory steroid hormones that have many indications in the treatment of medical diseases, including advanced or poorly controlled asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, allergic conditions, among other indications.^1-4 In orthopedics and rheumatology, systemic steroids are, at times, used in patients with rheumatoid arthritis, systemic lupus erythematosus, and vasculitides.^5-7 Overman and colleagues,⁸ using data from the National Health and Nutrition Examination Survey between 1999 and 2008 identified both a 1.2% prevalence of chronic corticosteroid usage in the United States across all age groups and a positive correlation between steroid use prevalence and increasing age. In that study, nearly two-thirds of survey respondents reported using corticosteroids chronically for >90 days. Another observational study in the United Kingdom found that long-term steroid prescriptions increased between 1989 to 2008 and that 13.6% of patients with rheumatoid arthritis and 66.5% of patients with polymyalgia rheumatica or giant cell arteritis used long-term steroids.⁹

Enterally- or parenterally-administered corticosteroids have numerous systemic effects that are of particular relevance to orthopedic surgeons. Corticosteroids induce osteoporosis by preferentially inducing osteoclastic activity while inhibiting the differentiation of osteoblasts, ultimately leading to decreased bone quality and mass.¹⁰ As a consequence, patients who have previously used corticosteroids are more than twice as likely to have a hip fracture.¹¹ Steroids also increase the risk of both osteonecrosis and myopathy, among other musculoskeletal effects.¹² In addition to orthopedic complications, steroids have broad inhibitory effects on both acquired and innate immunity, which significantly increases the risk of infections.¹³ This increased risk of infection is dose-dependent¹⁴ and synergistic with other immunosuppressive drugs.¹⁵

Patients with hip pain may receive localized corticosteroid hip joint injections during the nonoperative management of various hip pathologies, including arthritis, bursitis, and labral tears.^16,17 Outcomes of patients who received intra-articular corticosteroid injections before total hip arthroplasty (THA) were evaluated in a systematic review of 9 studies by Pereira and colleagues.¹⁷ These authors found that the infection rate (both superficial and deep surgical site infections [SSI]) after THA in patients who received local steroid injection into the hip before surgery was between 0% and 30%.¹⁷ However, similar studies assessing the impact that systemic steroids have on outcomes after THA are lacking. Patients who undergo THA for conditions associated with higher lifetime steroid usage have worse outcomes than those who do not. For instance, in patients undergoing THA for rheumatoid arthritis, the rates of both postoperative periprosthetic joint infection and hip dislocation are higher, when compared with osteoarthritis.^18,19 However, it is unclear how much of this difference in outcomes is due to the underlying disease, adverse effects of steroids, or both. Given the high prevalence of chronic systemic steroid use, it is essential to elucidate more clearly the impact that these medications have on perioperative outcomes after THA.  

Therefore, the purpose of this study was to characterize short-term perioperative outcomes, including complication and readmission rates in patients undergoing THA while taking chronic preoperative corticosteroids. We also sought to identify the most common reasons for hospital readmission in patients who did and did not use long-term steroids.

MATERIALS AND METHODS

STUDY DESIGN AND SETTING

This investigation was a retrospective cohort study that utilized the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry.²⁰ The ACS-NSQIP is a prospectively collected, multi-institutional database that collects demographical information, operative variables, and both postoperative complications and hospital readmission data. Data is collected for up to 30 days after the index procedure, and patients are contacted by telephone if they are discharged before 30 days. Patient data is entered by specially trained surgical clinical reviewers and is routinely audited by the ACS-NSQIP, leading to more accurate data when compared with administrative research databases.^21,22 The ACS-NSQIP has been used in orthopedic surgery outcomes-based studies.^23-25

Continue to: All patients undergoing...

All patients undergoing THA between 2005 and 2015 were identified in the registry using primary Current Procedural Terminology code 27130. Patients were split into 2 groups based on whether or not they chronically used corticosteroids preoperatively for a medical condition. A patient was considered a chronic corticosteroid user if he/she used oral or parenteral corticosteroids within 30 days before the index procedure for >10 of the preceding 30 days. Those who received a 1-time steroid pulse or those who used topical or inhaled steroids were not considered as steroid users in this study.

BASELINE CHARACTERISTICS AND PERIOPERATIVE OUTCOMES

Baseline patient and operative characteristics, including patient age, gender, body mass index (BMI), functional status, American Society of Anesthesiologists (ASA) class, anesthesia type, operative duration, and medical comorbidities including hypertension, COPD, diabetes mellitus, and smoking history, were compared between both groups. Perioperative outcomes that were assessed in this study include death, renal, respiratory, and cardiac complications, deep vein thrombosis or pulmonary embolism, stroke, sepsis, return to the operating room, urinary tract infection (UTI), wound dehiscence, superficial and deep SSI, need for a blood transfusion within 72 hours of index surgical procedure, and hospital readmissions. Renal complications were defined as acute or progressive renal insufficiency; respiratory complications were defined as failure to wean from the ventilator, need for intubation after the index procedure, and the occurrence of pneumonia; and cardiac complications were defined as myocardial infarction or cardiac arrest requiring cardiopulmonary resuscitation. Patients were excluded if they had missing baseline or operative characteristic data, an unclean wound classification at the time of admission, or if their THA was considered emergent.

STATISTICAL ANALYSIS

A propensity score-matched comparison was performed to adjust for differences in baseline and operative characteristics between the 2 cohorts in this study. In the current study, the propensity score was defined as the conditional probability that a patient chronically used preoperative corticosteroids for a medical condition, as a function of age, BMI, gender, ASA class, functional status, medical comorbidities, anesthesia type, and operative duration. A 1:1 matching with tight calipers (0.0001), and nearest-neighbor matching was used to generate 2 equally-sized, propensity-matched cohorts based on steroid status.²⁶ Nearest-neighbor matching identifies patients in both cohorts with the closest propensity scores for inclusion in propensity-matched cohorts. This matching is continued until 1 group runs out of patients to match. Baseline patient and operative characteristics for the unadjusted and propensity-matched groups were compared using Pearson’s χ² analysis. Outcomes after THA by steroid status were also compared in both unadjusted and propensity-matched groups. Finally, all patients who were readmitted were identified, and the reason for readmission was determined using the International Classification of Disease Ninth (ICD-9) and Tenth (ICD-10) edition codes. Patients were classified as having an infectious readmission only if the ICD code clearly stated an infectious etiology. For instance, a patient with an intestinal infection due to Clostridium difficile (ICD-9 008.45) was counted as a gastrointestinal infection, whereas diarrhea without a distinctly specified etiology (ICD-9 787.91, ICD-10 R19.7) was counted as a gastrointestinal medical complication. Readmission data was only available in ACS-NSQIP from 2011 to 2015, constituting 92.5% of all patients included in this study. We used SPSS version 23 (IBM Corporation) for all statistical analyses, and defined a significant P value as <.05.

RESULTS

BASELINE PATIENTS AND OPERATIVE CHARACTERISTICS

In total, we identified 101,532 patients who underwent THA (Table 1). O these, 3714 (3.7%) chronically used corticosteroids preoperatively, whereas 97,818 (96.3%) did not. 

When the unadjusted cohorts were compared, patients using corticosteroids were more likely to be female, less likely to obese, more likely to have hypertension, diabetes mellitus, COPD, higher ASA class, undergone THA with general anesthesia, and have a dependent functional status (P < .001 for all comparisons). After propensity matching, 2 equally sized cohorts of 3618 patients each were generated based on steroid status and no differences in baseline and operative characteristics were identified between the 2 groups.

Continue to: CLINICAL OUTCOMES BY STEROID STATUS

CLINCIAL OUTCOMES BY STEROID STATUS

A comparison of unadjusted cohorts showed that patients who used preoperative steroids had an increased rate of any complication (7.89%) when compared with those who did not (4.87%) (Table 2). 

Similarly, those who used corticosteroids preoperatively had an increased rate of renal complications, respiratory complications, return to the operating room, sepsis, UTI, superficial and deep SSI, and perioperative blood transfusions. They also were more likely to have a 30-day hospital readmission (P < .05 for all comparisons).

When propensity-matched cohorts were compared, patients who used steroids preoperatively were found to have higher rates of any complication (odds Ratio [OR] 1.30, P = .003), sepsis (OR 2.07, P = .022), UTI (OR 1.61, P = .020), superficial SSI (OR 1.73, P = .038), and hospital readmission (OR 1.50, P < .001; Table 3).

REASONS FOR HOSPITAL READMISSION

In total, 3397 patients were readmitted to the hospital within thirty days. Of these, 226 used steroids preoperatively, and 3171 did not (Table 4). 

The most common reason for hospital readmission in patients who used preoperative corticosteroids was infectious complications (72 patients, 31.9% of all readmitted patients in this cohort), followed by medical complications (59 patients, 26.1%), and hip-related complications (48 patients, 21.2%). In those who did not use steroids preoperatively, the most common reason for hospital readmission was medical complications (932 patients, 29.4% of all readmitted patients in this cohort), followed by infectious complications (792 patients, 25.0%), and hip-related complications (763 patients, 24.1%).

Continue to: DISCUSSION

Nearly 3% of individuals >80 years in the US population chronically use corticosteroids for a medical condition,⁸ and this rate is likely higher in specific subsets of patients, such as those with rheumatoid arthritis.⁹ While some studies have assessed the impact of intra-articular corticosteroid hip injections on perioperative outcomes in THA,¹⁷ similar studies assessing systemic corticosteroid usage are lacking. The purpose of this study was to characterize short-term perioperative outcomes in patients undergoing THA who chronically use systemic steroids when compared with those who do not. We found that the prevalence of preoperative chronic steroid use in this cohort of THA patients was 3.7%. We also identified increased rates of infectious complications, including sepsis, UTI, and superficial SSI, in patients who used preoperative corticosteroids. Furthermore, we found an increased rate of hospital readmissions in corticosteroid users and identified the most common reason for hospital readmission as infectious complications in this cohort.

The primary finding of this study was an increase in postoperative infections in patients who use preoperative steroids chronically for medical conditions. Immunosuppression has previously been identified as a risk factor for developing periprosthetic joint infections. Tannenbaum and colleagues²⁷ performed a retrospective study of 19 patients who underwent either a kidney or liver transplant and were maintained on an induction regimen of either prednisone and azathioprine or cyclosporine. These 19 patients also underwent either a THA or total knee arthroplasty, and 5 of these patients (26.3%) developed a periprosthetic joint infection after an average of 3.4 years following the arthroplasty procedure. In another study of 37 renal transplant and dialysis patients who underwent a total of 45 THA procedures, there were 3 instances of superficial SSI and 2 instances of deep SSI.²⁸ However, reported infection rates in transplant patients undergoing THA vary significantly, and studies have been unable to assess the true impact that chronic immunosuppression has on perioperative infection rates.²⁹ In this study, patients who used preoperative corticosteroids chronically were at increased risk of perioperative infections, including sepsis, UTI, and superficial SSI.

Deep vein thrombosis is another postoperative complication that has been associated with chronic steroid use.³⁰ In a case-control study of 38,765 patients who developed a venous thromboembolism and 387,650 control patients who did not, Johannesdottir and colleagues³⁰ found an increased thromboembolic risk in current users of systemic glucocorticoids, but not former users, as well as an increased risk as the dose of glucocorticoids increased. We were not able to identify a similar increase in DVT/PE in chronic corticosteroid users, perhaps due to our sample size, or because we could not do subgroup analyses based on the type or dosage of steroid that a patient was taking. Future studies that identify the highest risk patients among those using systemic corticosteroids are important because parenteral corticosteroids are being increasingly used in THA to alleviate postoperative pain as an opioid-sparing measure.^31,32

Finally, we also found that patients who use chronic, systemic corticosteroids are at an increased risk for hospital readmission, when compared with those patients who are not using steroids and are most likely to be readmitted for an infectious complication. Schairer and colleagues³³ assessed readmission rates after THA and found 30- and 90-day readmission rate of 4% and 7%, respectively. These authors also found that medical complications accounted for approximately 25% of readmissions, and hip-related complications (eg, dislocation, SSI) accounted for >50%. In our study, we found a 30-day readmission rate in non-steroid users of 3.53% and a rate of 6.52% in chronic steroid users. More than 30% of patients using a steroid were readmitted for infectious complications. As THA is becoming increasingly reimbursed under a bundled payments model by Medicare and Medicaid,^34-36 reducing short-term readmissions is imperative. Therefore, discharge counseling that emphasizes how to recognize both the signs and symptoms of infection as well as how to prevent infections, such as reducing SSIs through appropriate wound care, may be warranted in higher risk chronic steroid users.

This study has a number of limitations that are inherent to ACS-NSQIP. First, we lacked specific information on a patient’s steroid history, including which corticosteroid they were using, dosage, frequency, and the indication for corticosteroid therapy. Therefore, we were unable to establish a dose-dependent relationship between steroid exposure and postoperative complications after THA. Second, we were able to assess only 30-day rates of complications and readmissions, and therefore, we were unable to identify intermediate- and long-term effects of systemic corticosteroid use on THA. Finally, we could not determine orthopedic- or hip-specific postoperative outcomes, such as functional scores and range of motion.

Continue to: CONCLUSION

In conclusion, this study quantified the increased risk for perioperative complications and hospital readmissions in patients who chronically use corticosteroids and are undergoing THA, when compared with those who do not use corticosteroids. These results suggest that patients who are on long-term steroids are at an increased risk for complications, primarily infectious complications. This finding has important implications for patient counseling, preoperative risk stratification, and suggests that higher risk patients, such as chronic steroid users, may benefit from improved discharge care to decrease complication rates.

To the Editor:

Although relatively uncommon, hypersensitivity reactions to tattoo pigment are on the rise due to the increasing popularity and prevalence of tattoos.¹ Multiple adverse events have been described in association with tattoos, including inflammatory, infectious, and neoplastic responses.² An id reaction (also known as autoeczematization or autosensitization) develops distant to an initial site of infection or sensitization. We describe a unique case of an id reaction and subsequent development of prurigo nodules associated with contact allergy to red tattoo ink.

A 40-year-old woman was referred to the New York University Skin and Cancer Unit (New York, New York) for evaluation of a pruritic eruption arising on and near sites of tattooed skin on the right foot and right upper arm of 8 months’ duration. The patient reported that she had obtained a polychromatic tattoo on the right dorsal foot 9 months prior to the current presentation. Approximately 1 month later, she developed pruritic papulonodular lesions localized to the red-pigmented areas of the tattoo. Concomitantly, the patient developed a similar eruption confined to areas of red pigment in a polychromatic tattoo on the right upper arm that she had obtained 10 years prior. She was treated with intralesional triamcinolone to several of the lesions on the right dorsal foot with some benefit; however, a few days later she developed a generalized, erythematous, pruritic eruption on the back, abdomen, arms, and legs. Her medical history was remarkable only for mild iron-deficiency anemia. She had no known drug allergies or history of atopy and was not taking any medications prior to the onset of the eruption.

Skin examination revealed multiple, well-demarcated, eczematous papulonodules with surrounding erythema confined to the red-pigmented areas of the tattoo on the right dorsal foot, with several similar lesions on the surrounding nontattooed skin (Figure 1). Linear, well-demarcated, eczematous, hyperpigmented plaques also were noted on the red-pigmented areas of the tattoo on the patient’s right upper arm (Figure 2). Eczematous plaques and scattered excoriations were noted on the back, abdomen, flanks, arms, and legs.

Patch testing with the North American Standard Series, metal series, and samples of the red pigments used in the tattoo on the foot were negative. A punch biopsy of a lesion on the dorsal right foot showed a psoriasiform spongiotic dermatitis with eosinophils (Figure 3). Periodic acid–Schiff staining with diastase failed to reveal fungal hyphae. The histologic findings were consistent with allergic contact dermatitis. A punch biopsy of the eczematous reaction on nontattooed skin on the trunk demonstrated a perivascular dermatitis with eosinophils and subtle spongiosis consistent with an id reaction.

The patient was treated with fluocinonide ointment for several months with no effect. Subsequently, she received several short courses of oral prednisone, after which the affected areas of the tattoo on the arm and foot flattened and the id reaction resolved; however, after several months, the red-pigmented areas of the tattoo on the foot again became elevated and pruritic, and the patient developed widespread prurigo nodules on nontattooed skin on the trunk, arms, and legs. She was subsequently referred to a laser specialist for a trial of fractional laser treatment to cautiously remove the red tattoo pigment. After 2 treatments, the pruritus improved and the papular lesions appeared slightly flatter; however, the prurigo nodules remained. The tattoo on the patient’s foot was surgically removed; however, the prurigo nodules remained. Ultimately, the lesions cleared with a several-month course of mycophenolate mofetil.

Systemic allergic reactions to tattoo ink are rare but can cause considerable morbidity. An id reaction, also known as autoeczematization or autosensitization, is a reaction that develops distant to an initial site of infection or sensitization. Although the pathogenesis of this reaction is not certain, it has been hypothesized that autoimmunity to skin antigens might play a role.³ Autologous epidermal cells are thought to become antigenic in the presence of acute inflammation at the primary cutaneous site. These antigenic autologous epidermal cells are postulated to enter the circulation and cause secondary eczematous lesions at distant sites. This proposed mechanism is supported by the development of positive skin reactions to autologous extracts of epidermal scaling in patients with active id reaction.³

Hematogenous dissemination of cytokines has been implicated in id reactions.⁴ Keratinocytes produce cytokines in response to conditions that are known to trigger id reactions.⁵ Epidermal cytokines released from the primary site of sensitization are thought to heighten sensitivity at distant skin areas.⁴ These cytokines regulate both cell-mediated and humoral cutaneous immune responses. Increased levels of activated HLA-DR isotype–positive T cells in patients with active autoeczemization favors a cellular-mediated immune mechanism. The presence of activated antigen-specific T cells also supports the role of allergic contact dermatitis in triggering id reactions.⁶

Allergic contact dermatitis is the most common hypersensitivity reaction to tattoo ink, with red pigments representing the most common cause of tattoo-related allergic contact dermatitis. Historically, cinnabar (mercuric sulfide) has been the most common red pigment to cause allergic contact dermatitis.⁷ More recently, mercury-free organic pigments (eg, azo dyes) have been used in polychromatic tattoos due to their ability to retain color over long periods of time⁸; however, these organic red tattoo pigments also have been implicated in allergic reactions.^8-11 The composition of these new organic red tattoo pigments varies, but chemical analysis has revealed a mixture of aromatic azo compounds (eg, quinacridone),¹⁰ heavy metals (eg, aluminum, lead, cadmium, chromium, cobalt, iron, titanium),^9,12 and intermediate reactive compounds (eg, naphthalene, 2-naphthol, chlorobenzene, benzene).⁸ Allergic contact dermatitis to red tattoo ink is well documented^8,13; however, a PubMed search of articles indexed for MEDLINE using the terms tattoo and dermatitis, tattoo and allergy, tattoo and autosensitization, tattoo and id reaction, and tattoo and autoeczematization yielded only 3 other reports of a concomitant id reaction.^11,14,15

The diagnosis of id reaction associated with allergic contact dermatitis is made on the basis of clinical history, physical examination, and histopathology. Patch testing usually is not positive in cases of tattoo allergy; it is thought that the allergen is a tattoo ink byproduct possibly caused by photoinduced or metabolic change of the tattoo pigment and a haptenization process.^1,8,16 Histologically, variable reaction patterns, including eczematous, lichenoid, granulomatous, and pseudolymphomatous reactions have been reported in association with delayed-type inflammatory reactions to tattoo pigments, but the lichenoid pattern is most commonly observed.⁸

Treatment options for allergic contact dermatitis to tattoo ink include topical, intralesional, and oral steroids; topical calcineurin inhibitors; and surgical excision of the tattoo. Q-switched lasers—ruby, Nd:YAG, and alexandrite—are the gold standard for removing tattoo pigments¹⁷; however, these lasers remove tattoo pigment by selective photothermolysis, resulting in extracellular extravasation of pigment, which can precipitate a heightened immune response that can lead to localized and generalized allergic reactions.¹⁸ Therefore, Q-switched lasers should be avoided in the setting of an allergic reaction to tattoo ink. Fractional ablative laser resurfacing may be a safer alternative for removal of tattoos in the setting of an allergic reaction.¹⁷ Further studies are needed to confirm the safety and efficacy of this modality for allergic tattoo ink removal.^17,18

Our case illustrates a rare cause of id reaction and the subsequent development of prurigo nodules associated with contact allergy to red tattoo ink. We present this case to raise awareness of the potential health and iatrogenic risks associated with tattoo placement. Further investigation of these color additives is warranted to better elucidate ink components responsible for these cutaneous allergic reactions.

Acknowledgments
We would like to thank Vitaly Terushkin, MD (West Orange, New Jersey, and New York, New York), and Arielle Kauvar, MD (New York, New York), for their contributions to the patient’s clinical care.

To the Editor:

Although relatively uncommon, hypersensitivity reactions to tattoo pigment are on the rise due to the increasing popularity and prevalence of tattoos.¹ Multiple adverse events have been described in association with tattoos, including inflammatory, infectious, and neoplastic responses.² An id reaction (also known as autoeczematization or autosensitization) develops distant to an initial site of infection or sensitization. We describe a unique case of an id reaction and subsequent development of prurigo nodules associated with contact allergy to red tattoo ink.

A 40-year-old woman was referred to the New York University Skin and Cancer Unit (New York, New York) for evaluation of a pruritic eruption arising on and near sites of tattooed skin on the right foot and right upper arm of 8 months’ duration. The patient reported that she had obtained a polychromatic tattoo on the right dorsal foot 9 months prior to the current presentation. Approximately 1 month later, she developed pruritic papulonodular lesions localized to the red-pigmented areas of the tattoo. Concomitantly, the patient developed a similar eruption confined to areas of red pigment in a polychromatic tattoo on the right upper arm that she had obtained 10 years prior. She was treated with intralesional triamcinolone to several of the lesions on the right dorsal foot with some benefit; however, a few days later she developed a generalized, erythematous, pruritic eruption on the back, abdomen, arms, and legs. Her medical history was remarkable only for mild iron-deficiency anemia. She had no known drug allergies or history of atopy and was not taking any medications prior to the onset of the eruption.

Skin examination revealed multiple, well-demarcated, eczematous papulonodules with surrounding erythema confined to the red-pigmented areas of the tattoo on the right dorsal foot, with several similar lesions on the surrounding nontattooed skin (Figure 1). Linear, well-demarcated, eczematous, hyperpigmented plaques also were noted on the red-pigmented areas of the tattoo on the patient’s right upper arm (Figure 2). Eczematous plaques and scattered excoriations were noted on the back, abdomen, flanks, arms, and legs.

Patch testing with the North American Standard Series, metal series, and samples of the red pigments used in the tattoo on the foot were negative. A punch biopsy of a lesion on the dorsal right foot showed a psoriasiform spongiotic dermatitis with eosinophils (Figure 3). Periodic acid–Schiff staining with diastase failed to reveal fungal hyphae. The histologic findings were consistent with allergic contact dermatitis. A punch biopsy of the eczematous reaction on nontattooed skin on the trunk demonstrated a perivascular dermatitis with eosinophils and subtle spongiosis consistent with an id reaction.

The patient was treated with fluocinonide ointment for several months with no effect. Subsequently, she received several short courses of oral prednisone, after which the affected areas of the tattoo on the arm and foot flattened and the id reaction resolved; however, after several months, the red-pigmented areas of the tattoo on the foot again became elevated and pruritic, and the patient developed widespread prurigo nodules on nontattooed skin on the trunk, arms, and legs. She was subsequently referred to a laser specialist for a trial of fractional laser treatment to cautiously remove the red tattoo pigment. After 2 treatments, the pruritus improved and the papular lesions appeared slightly flatter; however, the prurigo nodules remained. The tattoo on the patient’s foot was surgically removed; however, the prurigo nodules remained. Ultimately, the lesions cleared with a several-month course of mycophenolate mofetil.

Systemic allergic reactions to tattoo ink are rare but can cause considerable morbidity. An id reaction, also known as autoeczematization or autosensitization, is a reaction that develops distant to an initial site of infection or sensitization. Although the pathogenesis of this reaction is not certain, it has been hypothesized that autoimmunity to skin antigens might play a role.³ Autologous epidermal cells are thought to become antigenic in the presence of acute inflammation at the primary cutaneous site. These antigenic autologous epidermal cells are postulated to enter the circulation and cause secondary eczematous lesions at distant sites. This proposed mechanism is supported by the development of positive skin reactions to autologous extracts of epidermal scaling in patients with active id reaction.³

Hematogenous dissemination of cytokines has been implicated in id reactions.⁴ Keratinocytes produce cytokines in response to conditions that are known to trigger id reactions.⁵ Epidermal cytokines released from the primary site of sensitization are thought to heighten sensitivity at distant skin areas.⁴ These cytokines regulate both cell-mediated and humoral cutaneous immune responses. Increased levels of activated HLA-DR isotype–positive T cells in patients with active autoeczemization favors a cellular-mediated immune mechanism. The presence of activated antigen-specific T cells also supports the role of allergic contact dermatitis in triggering id reactions.⁶

Allergic contact dermatitis is the most common hypersensitivity reaction to tattoo ink, with red pigments representing the most common cause of tattoo-related allergic contact dermatitis. Historically, cinnabar (mercuric sulfide) has been the most common red pigment to cause allergic contact dermatitis.⁷ More recently, mercury-free organic pigments (eg, azo dyes) have been used in polychromatic tattoos due to their ability to retain color over long periods of time⁸; however, these organic red tattoo pigments also have been implicated in allergic reactions.^8-11 The composition of these new organic red tattoo pigments varies, but chemical analysis has revealed a mixture of aromatic azo compounds (eg, quinacridone),¹⁰ heavy metals (eg, aluminum, lead, cadmium, chromium, cobalt, iron, titanium),^9,12 and intermediate reactive compounds (eg, naphthalene, 2-naphthol, chlorobenzene, benzene).⁸ Allergic contact dermatitis to red tattoo ink is well documented^8,13; however, a PubMed search of articles indexed for MEDLINE using the terms tattoo and dermatitis, tattoo and allergy, tattoo and autosensitization, tattoo and id reaction, and tattoo and autoeczematization yielded only 3 other reports of a concomitant id reaction.^11,14,15

The diagnosis of id reaction associated with allergic contact dermatitis is made on the basis of clinical history, physical examination, and histopathology. Patch testing usually is not positive in cases of tattoo allergy; it is thought that the allergen is a tattoo ink byproduct possibly caused by photoinduced or metabolic change of the tattoo pigment and a haptenization process.^1,8,16 Histologically, variable reaction patterns, including eczematous, lichenoid, granulomatous, and pseudolymphomatous reactions have been reported in association with delayed-type inflammatory reactions to tattoo pigments, but the lichenoid pattern is most commonly observed.⁸

Treatment options for allergic contact dermatitis to tattoo ink include topical, intralesional, and oral steroids; topical calcineurin inhibitors; and surgical excision of the tattoo. Q-switched lasers—ruby, Nd:YAG, and alexandrite—are the gold standard for removing tattoo pigments¹⁷; however, these lasers remove tattoo pigment by selective photothermolysis, resulting in extracellular extravasation of pigment, which can precipitate a heightened immune response that can lead to localized and generalized allergic reactions.¹⁸ Therefore, Q-switched lasers should be avoided in the setting of an allergic reaction to tattoo ink. Fractional ablative laser resurfacing may be a safer alternative for removal of tattoos in the setting of an allergic reaction.¹⁷ Further studies are needed to confirm the safety and efficacy of this modality for allergic tattoo ink removal.^17,18

Our case illustrates a rare cause of id reaction and the subsequent development of prurigo nodules associated with contact allergy to red tattoo ink. We present this case to raise awareness of the potential health and iatrogenic risks associated with tattoo placement. Further investigation of these color additives is warranted to better elucidate ink components responsible for these cutaneous allergic reactions.

Acknowledgments
We would like to thank Vitaly Terushkin, MD (West Orange, New Jersey, and New York, New York), and Arielle Kauvar, MD (New York, New York), for their contributions to the patient’s clinical care.

To the Editor:

Although relatively uncommon, hypersensitivity reactions to tattoo pigment are on the rise due to the increasing popularity and prevalence of tattoos.¹ Multiple adverse events have been described in association with tattoos, including inflammatory, infectious, and neoplastic responses.² An id reaction (also known as autoeczematization or autosensitization) develops distant to an initial site of infection or sensitization. We describe a unique case of an id reaction and subsequent development of prurigo nodules associated with contact allergy to red tattoo ink.

A 40-year-old woman was referred to the New York University Skin and Cancer Unit (New York, New York) for evaluation of a pruritic eruption arising on and near sites of tattooed skin on the right foot and right upper arm of 8 months’ duration. The patient reported that she had obtained a polychromatic tattoo on the right dorsal foot 9 months prior to the current presentation. Approximately 1 month later, she developed pruritic papulonodular lesions localized to the red-pigmented areas of the tattoo. Concomitantly, the patient developed a similar eruption confined to areas of red pigment in a polychromatic tattoo on the right upper arm that she had obtained 10 years prior. She was treated with intralesional triamcinolone to several of the lesions on the right dorsal foot with some benefit; however, a few days later she developed a generalized, erythematous, pruritic eruption on the back, abdomen, arms, and legs. Her medical history was remarkable only for mild iron-deficiency anemia. She had no known drug allergies or history of atopy and was not taking any medications prior to the onset of the eruption.

Skin examination revealed multiple, well-demarcated, eczematous papulonodules with surrounding erythema confined to the red-pigmented areas of the tattoo on the right dorsal foot, with several similar lesions on the surrounding nontattooed skin (Figure 1). Linear, well-demarcated, eczematous, hyperpigmented plaques also were noted on the red-pigmented areas of the tattoo on the patient’s right upper arm (Figure 2). Eczematous plaques and scattered excoriations were noted on the back, abdomen, flanks, arms, and legs.

Patch testing with the North American Standard Series, metal series, and samples of the red pigments used in the tattoo on the foot were negative. A punch biopsy of a lesion on the dorsal right foot showed a psoriasiform spongiotic dermatitis with eosinophils (Figure 3). Periodic acid–Schiff staining with diastase failed to reveal fungal hyphae. The histologic findings were consistent with allergic contact dermatitis. A punch biopsy of the eczematous reaction on nontattooed skin on the trunk demonstrated a perivascular dermatitis with eosinophils and subtle spongiosis consistent with an id reaction.

The patient was treated with fluocinonide ointment for several months with no effect. Subsequently, she received several short courses of oral prednisone, after which the affected areas of the tattoo on the arm and foot flattened and the id reaction resolved; however, after several months, the red-pigmented areas of the tattoo on the foot again became elevated and pruritic, and the patient developed widespread prurigo nodules on nontattooed skin on the trunk, arms, and legs. She was subsequently referred to a laser specialist for a trial of fractional laser treatment to cautiously remove the red tattoo pigment. After 2 treatments, the pruritus improved and the papular lesions appeared slightly flatter; however, the prurigo nodules remained. The tattoo on the patient’s foot was surgically removed; however, the prurigo nodules remained. Ultimately, the lesions cleared with a several-month course of mycophenolate mofetil.

Systemic allergic reactions to tattoo ink are rare but can cause considerable morbidity. An id reaction, also known as autoeczematization or autosensitization, is a reaction that develops distant to an initial site of infection or sensitization. Although the pathogenesis of this reaction is not certain, it has been hypothesized that autoimmunity to skin antigens might play a role.³ Autologous epidermal cells are thought to become antigenic in the presence of acute inflammation at the primary cutaneous site. These antigenic autologous epidermal cells are postulated to enter the circulation and cause secondary eczematous lesions at distant sites. This proposed mechanism is supported by the development of positive skin reactions to autologous extracts of epidermal scaling in patients with active id reaction.³

Hematogenous dissemination of cytokines has been implicated in id reactions.⁴ Keratinocytes produce cytokines in response to conditions that are known to trigger id reactions.⁵ Epidermal cytokines released from the primary site of sensitization are thought to heighten sensitivity at distant skin areas.⁴ These cytokines regulate both cell-mediated and humoral cutaneous immune responses. Increased levels of activated HLA-DR isotype–positive T cells in patients with active autoeczemization favors a cellular-mediated immune mechanism. The presence of activated antigen-specific T cells also supports the role of allergic contact dermatitis in triggering id reactions.⁶

Allergic contact dermatitis is the most common hypersensitivity reaction to tattoo ink, with red pigments representing the most common cause of tattoo-related allergic contact dermatitis. Historically, cinnabar (mercuric sulfide) has been the most common red pigment to cause allergic contact dermatitis.⁷ More recently, mercury-free organic pigments (eg, azo dyes) have been used in polychromatic tattoos due to their ability to retain color over long periods of time⁸; however, these organic red tattoo pigments also have been implicated in allergic reactions.^8-11 The composition of these new organic red tattoo pigments varies, but chemical analysis has revealed a mixture of aromatic azo compounds (eg, quinacridone),¹⁰ heavy metals (eg, aluminum, lead, cadmium, chromium, cobalt, iron, titanium),^9,12 and intermediate reactive compounds (eg, naphthalene, 2-naphthol, chlorobenzene, benzene).⁸ Allergic contact dermatitis to red tattoo ink is well documented^8,13; however, a PubMed search of articles indexed for MEDLINE using the terms tattoo and dermatitis, tattoo and allergy, tattoo and autosensitization, tattoo and id reaction, and tattoo and autoeczematization yielded only 3 other reports of a concomitant id reaction.^11,14,15

The diagnosis of id reaction associated with allergic contact dermatitis is made on the basis of clinical history, physical examination, and histopathology. Patch testing usually is not positive in cases of tattoo allergy; it is thought that the allergen is a tattoo ink byproduct possibly caused by photoinduced or metabolic change of the tattoo pigment and a haptenization process.^1,8,16 Histologically, variable reaction patterns, including eczematous, lichenoid, granulomatous, and pseudolymphomatous reactions have been reported in association with delayed-type inflammatory reactions to tattoo pigments, but the lichenoid pattern is most commonly observed.⁸

Treatment options for allergic contact dermatitis to tattoo ink include topical, intralesional, and oral steroids; topical calcineurin inhibitors; and surgical excision of the tattoo. Q-switched lasers—ruby, Nd:YAG, and alexandrite—are the gold standard for removing tattoo pigments¹⁷; however, these lasers remove tattoo pigment by selective photothermolysis, resulting in extracellular extravasation of pigment, which can precipitate a heightened immune response that can lead to localized and generalized allergic reactions.¹⁸ Therefore, Q-switched lasers should be avoided in the setting of an allergic reaction to tattoo ink. Fractional ablative laser resurfacing may be a safer alternative for removal of tattoos in the setting of an allergic reaction.¹⁷ Further studies are needed to confirm the safety and efficacy of this modality for allergic tattoo ink removal.^17,18

Our case illustrates a rare cause of id reaction and the subsequent development of prurigo nodules associated with contact allergy to red tattoo ink. We present this case to raise awareness of the potential health and iatrogenic risks associated with tattoo placement. Further investigation of these color additives is warranted to better elucidate ink components responsible for these cutaneous allergic reactions.

Acknowledgments
We would like to thank Vitaly Terushkin, MD (West Orange, New Jersey, and New York, New York), and Arielle Kauvar, MD (New York, New York), for their contributions to the patient’s clinical care.

To the Editor:

Disseminated cryptococcosis is a well-known opportunistic infection in patients with advanced human immunodeficiency virus (HIV) infection, but it is not frequently seen as a primary infection of the skin in immunocompetent hosts. We report a case of primary cutaneous cryptococcosis (PCC) of the lower legs in an immunocompetent Iraq War veteran.

A 28-year-old female service member presented to the dermatology clinic with progressively enlarging plaquelike lesions on the shins of 6 months’ duration. The patient had resided and worked as a deployed soldier in the lower level of a bullet hole–laden, pigeon-infested observation tower in southern Iraq 9 months prior to the current presentation. During her 7-month deployment, she reported daily exposure to pigeon excreta on equipment and frequently sustained superficial abrasions and lacerations to the legs due to the cramped and hazardous working environment. The patient noticed intensely pruritic, bugbitelike papular lesions on the shins and calves 1 month after residing in the observation tower. She sought medical treatment and was given hydrocortisone cream 1% and calamine lotion for a presumed irritant dermatitis. Over the ensuing 3 months, the pruritus worsened, and the primary lesions coalesced into annular erythematous plaques (Figure).

After returning to the United States, the patient presented again for medical care and was given ketoconazole cream 1% for presumed tinea corporis, which resulted in no improvement. A dermatologic consultation and evaluation ensued with subsequent microbial workup showing no bacterial growth on wound culture and no fungal elements on a potassium hydroxide preparation. Hematoxylin and eosin, periodic acid–Schiff, and Grocott-Gomori methenamine-silver staining did not demonstrate any organisms. Tissue cultures for bacteria and acid-fast bacilli showed no growth. A fungal tissue culture ultimately confirmed the presence of Cryptococcus neoformans. A lumbar puncture showed no evidence of Cryptococcus on DNA probe testing. Serologic testing for HIV was negative, and brain magnetic resonance imaging showed no lesions. Sputum culture and staining showed no fungal elements, and a chest radiograph was normal. A diagnosis of PCC was made and therapy with oral fluconazole 200 mg twice daily was initiated, with the intention of completing a 6-month course. During the treatment, the pruritus resolved within 3 weeks and the lesions involuted over 3 months. From the time of onset of the lesions throughout treatment, the patient showed no pulmonary, neurologic, or other systemic symptoms. She currently is healthy with no evidence of recurrence.

Primary cutaneous cryptococcosis mainly affects individuals with underlying immunosuppression, most commonly due to advanced HIV, prolonged treatment with immunosuppressive medications, or organ transplantation.¹ The most common route of inoculation is by inhalation of Cryptococcus spores with subsequent hematogenous dissemination.² Primary cutaneous cryptococcosis with skin lesions and no concomitant systemic involvement has rarely been reported, and when encountered, it usually is associated with environments that predispose patients to skin wounds with simultaneous exposure to soil or vegetative debris contaminated with bird excreta.³ Primary cutaneous cryptococcosis can present in a myriad of ways, including papules, nodules, plaques, and even necrotizing fasciitis–like skin lesions.^4,5 This variable presentation often creates clinical confusion and diagnostic delay; therefore, a high index of suspicion is required for timely diagnosis.

Due to the worldwide deployment of US military service members, exotic cutaneous infectious diseases such as PCC may be encountered in dermatology practice. Prompt clinical and histologic diagnosis is imperative to assess for systemic disease and avoid cutaneous spread and morbidity in US service members and travelers returning home from the Middle East.

To the Editor:

Disseminated cryptococcosis is a well-known opportunistic infection in patients with advanced human immunodeficiency virus (HIV) infection, but it is not frequently seen as a primary infection of the skin in immunocompetent hosts. We report a case of primary cutaneous cryptococcosis (PCC) of the lower legs in an immunocompetent Iraq War veteran.

A 28-year-old female service member presented to the dermatology clinic with progressively enlarging plaquelike lesions on the shins of 6 months’ duration. The patient had resided and worked as a deployed soldier in the lower level of a bullet hole–laden, pigeon-infested observation tower in southern Iraq 9 months prior to the current presentation. During her 7-month deployment, she reported daily exposure to pigeon excreta on equipment and frequently sustained superficial abrasions and lacerations to the legs due to the cramped and hazardous working environment. The patient noticed intensely pruritic, bugbitelike papular lesions on the shins and calves 1 month after residing in the observation tower. She sought medical treatment and was given hydrocortisone cream 1% and calamine lotion for a presumed irritant dermatitis. Over the ensuing 3 months, the pruritus worsened, and the primary lesions coalesced into annular erythematous plaques (Figure).

After returning to the United States, the patient presented again for medical care and was given ketoconazole cream 1% for presumed tinea corporis, which resulted in no improvement. A dermatologic consultation and evaluation ensued with subsequent microbial workup showing no bacterial growth on wound culture and no fungal elements on a potassium hydroxide preparation. Hematoxylin and eosin, periodic acid–Schiff, and Grocott-Gomori methenamine-silver staining did not demonstrate any organisms. Tissue cultures for bacteria and acid-fast bacilli showed no growth. A fungal tissue culture ultimately confirmed the presence of Cryptococcus neoformans. A lumbar puncture showed no evidence of Cryptococcus on DNA probe testing. Serologic testing for HIV was negative, and brain magnetic resonance imaging showed no lesions. Sputum culture and staining showed no fungal elements, and a chest radiograph was normal. A diagnosis of PCC was made and therapy with oral fluconazole 200 mg twice daily was initiated, with the intention of completing a 6-month course. During the treatment, the pruritus resolved within 3 weeks and the lesions involuted over 3 months. From the time of onset of the lesions throughout treatment, the patient showed no pulmonary, neurologic, or other systemic symptoms. She currently is healthy with no evidence of recurrence.

Primary cutaneous cryptococcosis mainly affects individuals with underlying immunosuppression, most commonly due to advanced HIV, prolonged treatment with immunosuppressive medications, or organ transplantation.¹ The most common route of inoculation is by inhalation of Cryptococcus spores with subsequent hematogenous dissemination.² Primary cutaneous cryptococcosis with skin lesions and no concomitant systemic involvement has rarely been reported, and when encountered, it usually is associated with environments that predispose patients to skin wounds with simultaneous exposure to soil or vegetative debris contaminated with bird excreta.³ Primary cutaneous cryptococcosis can present in a myriad of ways, including papules, nodules, plaques, and even necrotizing fasciitis–like skin lesions.^4,5 This variable presentation often creates clinical confusion and diagnostic delay; therefore, a high index of suspicion is required for timely diagnosis.

Due to the worldwide deployment of US military service members, exotic cutaneous infectious diseases such as PCC may be encountered in dermatology practice. Prompt clinical and histologic diagnosis is imperative to assess for systemic disease and avoid cutaneous spread and morbidity in US service members and travelers returning home from the Middle East.

To the Editor:

Disseminated cryptococcosis is a well-known opportunistic infection in patients with advanced human immunodeficiency virus (HIV) infection, but it is not frequently seen as a primary infection of the skin in immunocompetent hosts. We report a case of primary cutaneous cryptococcosis (PCC) of the lower legs in an immunocompetent Iraq War veteran.

A 28-year-old female service member presented to the dermatology clinic with progressively enlarging plaquelike lesions on the shins of 6 months’ duration. The patient had resided and worked as a deployed soldier in the lower level of a bullet hole–laden, pigeon-infested observation tower in southern Iraq 9 months prior to the current presentation. During her 7-month deployment, she reported daily exposure to pigeon excreta on equipment and frequently sustained superficial abrasions and lacerations to the legs due to the cramped and hazardous working environment. The patient noticed intensely pruritic, bugbitelike papular lesions on the shins and calves 1 month after residing in the observation tower. She sought medical treatment and was given hydrocortisone cream 1% and calamine lotion for a presumed irritant dermatitis. Over the ensuing 3 months, the pruritus worsened, and the primary lesions coalesced into annular erythematous plaques (Figure).

After returning to the United States, the patient presented again for medical care and was given ketoconazole cream 1% for presumed tinea corporis, which resulted in no improvement. A dermatologic consultation and evaluation ensued with subsequent microbial workup showing no bacterial growth on wound culture and no fungal elements on a potassium hydroxide preparation. Hematoxylin and eosin, periodic acid–Schiff, and Grocott-Gomori methenamine-silver staining did not demonstrate any organisms. Tissue cultures for bacteria and acid-fast bacilli showed no growth. A fungal tissue culture ultimately confirmed the presence of Cryptococcus neoformans. A lumbar puncture showed no evidence of Cryptococcus on DNA probe testing. Serologic testing for HIV was negative, and brain magnetic resonance imaging showed no lesions. Sputum culture and staining showed no fungal elements, and a chest radiograph was normal. A diagnosis of PCC was made and therapy with oral fluconazole 200 mg twice daily was initiated, with the intention of completing a 6-month course. During the treatment, the pruritus resolved within 3 weeks and the lesions involuted over 3 months. From the time of onset of the lesions throughout treatment, the patient showed no pulmonary, neurologic, or other systemic symptoms. She currently is healthy with no evidence of recurrence.

Primary cutaneous cryptococcosis mainly affects individuals with underlying immunosuppression, most commonly due to advanced HIV, prolonged treatment with immunosuppressive medications, or organ transplantation.¹ The most common route of inoculation is by inhalation of Cryptococcus spores with subsequent hematogenous dissemination.² Primary cutaneous cryptococcosis with skin lesions and no concomitant systemic involvement has rarely been reported, and when encountered, it usually is associated with environments that predispose patients to skin wounds with simultaneous exposure to soil or vegetative debris contaminated with bird excreta.³ Primary cutaneous cryptococcosis can present in a myriad of ways, including papules, nodules, plaques, and even necrotizing fasciitis–like skin lesions.^4,5 This variable presentation often creates clinical confusion and diagnostic delay; therefore, a high index of suspicion is required for timely diagnosis.

Due to the worldwide deployment of US military service members, exotic cutaneous infectious diseases such as PCC may be encountered in dermatology practice. Prompt clinical and histologic diagnosis is imperative to assess for systemic disease and avoid cutaneous spread and morbidity in US service members and travelers returning home from the Middle East.

The Diagnosis: Tinea Faciei

Given the morphology of the plaque, a potassium hydroxide preparation was performed and was positive for hyphal elements consistent with dermatophyte infection (Figure).

Tinea faciei is a fungal infection of the face caused by a dermatophyte that invades the stratum corneum.¹ It is transmitted through direct contact with an infected individual or fomite.² Infections typically are characterized by annular or serpiginous erythematous plaques with a scaly appearance and advancing edge. There may be associated vesicles, papules, or pustules with crusting around the advancing border.³ Tinea faciei can occur concomitantly with other dermatophytic infections and frequently presents atypically due to different characteristics of facial anatomy when compared to other tinea infections. As a result, it often is misdiagnosed.¹

Tinea faciei represents roughly 19% of all superficial fungal infections and occurs more commonly in temperate humid regions.⁴ It can occur at any age but has bimodal peaks in incidence during childhood and early adulthood.⁵ The most common causative dermatophytes are Trichophyton tonsurans, Microsporum canis, Trichophyton mentagrophytes, and Trichophyton rubrum.¹ Transmission is mainly through direct contact with infected individuals, animals, or soil, which likely occurred during the close quarters and exercises our patient experienced during basic training in the military.

Tinea faciei often is misdiagnosed and treated with topical corticosteroids. The steroids can give a false impression that the rash is resolving by initially decreasing the inflammatory component and reducing scale, which is referred to as tinea incognito. Once the steroid is stopped, however, the fungal infection often returns worse than the original presentation. The differential diagnosis includes subacute cutaneous lupus erythematosus, periorificial dermatitis, seborrheic dermatitis, psoriasis, rosacea, erythema annulare centrifugum, granuloma annulare, sarcoidosis, and contact dermatitis.^1,3,6

Diagnosis of tinea faciei is best made with skin scraping of the active border of the lesion. The scraping is treated with potassium hydroxide 10%. Visualizing branching or curving hyphae confirms the diagnosis. Fungal speciation often is not performed due to the long time needed to culture. Wood lamp may fluoresce blue-green if tinea faciei is caused by Microsporum species; however, diagnosis in this manner is limited because other common species do not fluoresce.⁷

Options for treatment of tinea faciei include topical antifungals for 2 to 6 weeks for localized disease or oral antifungals for more extensive or unresponsive infections for 1 to 8 weeks depending on the agent that is used. If fungal folliculitis is present, oral medication should be given.¹ Our patient was treated with oral terbinafine 250 mg once daily for 4 weeks with follow-up after that time to ensure resolution.

The Diagnosis: Tinea Faciei

Given the morphology of the plaque, a potassium hydroxide preparation was performed and was positive for hyphal elements consistent with dermatophyte infection (Figure).

Tinea faciei is a fungal infection of the face caused by a dermatophyte that invades the stratum corneum.¹ It is transmitted through direct contact with an infected individual or fomite.² Infections typically are characterized by annular or serpiginous erythematous plaques with a scaly appearance and advancing edge. There may be associated vesicles, papules, or pustules with crusting around the advancing border.³ Tinea faciei can occur concomitantly with other dermatophytic infections and frequently presents atypically due to different characteristics of facial anatomy when compared to other tinea infections. As a result, it often is misdiagnosed.¹

Tinea faciei represents roughly 19% of all superficial fungal infections and occurs more commonly in temperate humid regions.⁴ It can occur at any age but has bimodal peaks in incidence during childhood and early adulthood.⁵ The most common causative dermatophytes are Trichophyton tonsurans, Microsporum canis, Trichophyton mentagrophytes, and Trichophyton rubrum.¹ Transmission is mainly through direct contact with infected individuals, animals, or soil, which likely occurred during the close quarters and exercises our patient experienced during basic training in the military.

Tinea faciei often is misdiagnosed and treated with topical corticosteroids. The steroids can give a false impression that the rash is resolving by initially decreasing the inflammatory component and reducing scale, which is referred to as tinea incognito. Once the steroid is stopped, however, the fungal infection often returns worse than the original presentation. The differential diagnosis includes subacute cutaneous lupus erythematosus, periorificial dermatitis, seborrheic dermatitis, psoriasis, rosacea, erythema annulare centrifugum, granuloma annulare, sarcoidosis, and contact dermatitis.^1,3,6

Diagnosis of tinea faciei is best made with skin scraping of the active border of the lesion. The scraping is treated with potassium hydroxide 10%. Visualizing branching or curving hyphae confirms the diagnosis. Fungal speciation often is not performed due to the long time needed to culture. Wood lamp may fluoresce blue-green if tinea faciei is caused by Microsporum species; however, diagnosis in this manner is limited because other common species do not fluoresce.⁷

Options for treatment of tinea faciei include topical antifungals for 2 to 6 weeks for localized disease or oral antifungals for more extensive or unresponsive infections for 1 to 8 weeks depending on the agent that is used. If fungal folliculitis is present, oral medication should be given.¹ Our patient was treated with oral terbinafine 250 mg once daily for 4 weeks with follow-up after that time to ensure resolution.

The Diagnosis: Tinea Faciei

Given the morphology of the plaque, a potassium hydroxide preparation was performed and was positive for hyphal elements consistent with dermatophyte infection (Figure).

Tinea faciei is a fungal infection of the face caused by a dermatophyte that invades the stratum corneum.¹ It is transmitted through direct contact with an infected individual or fomite.² Infections typically are characterized by annular or serpiginous erythematous plaques with a scaly appearance and advancing edge. There may be associated vesicles, papules, or pustules with crusting around the advancing border.³ Tinea faciei can occur concomitantly with other dermatophytic infections and frequently presents atypically due to different characteristics of facial anatomy when compared to other tinea infections. As a result, it often is misdiagnosed.¹

Tinea faciei represents roughly 19% of all superficial fungal infections and occurs more commonly in temperate humid regions.⁴ It can occur at any age but has bimodal peaks in incidence during childhood and early adulthood.⁵ The most common causative dermatophytes are Trichophyton tonsurans, Microsporum canis, Trichophyton mentagrophytes, and Trichophyton rubrum.¹ Transmission is mainly through direct contact with infected individuals, animals, or soil, which likely occurred during the close quarters and exercises our patient experienced during basic training in the military.

Tinea faciei often is misdiagnosed and treated with topical corticosteroids. The steroids can give a false impression that the rash is resolving by initially decreasing the inflammatory component and reducing scale, which is referred to as tinea incognito. Once the steroid is stopped, however, the fungal infection often returns worse than the original presentation. The differential diagnosis includes subacute cutaneous lupus erythematosus, periorificial dermatitis, seborrheic dermatitis, psoriasis, rosacea, erythema annulare centrifugum, granuloma annulare, sarcoidosis, and contact dermatitis.^1,3,6

Diagnosis of tinea faciei is best made with skin scraping of the active border of the lesion. The scraping is treated with potassium hydroxide 10%. Visualizing branching or curving hyphae confirms the diagnosis. Fungal speciation often is not performed due to the long time needed to culture. Wood lamp may fluoresce blue-green if tinea faciei is caused by Microsporum species; however, diagnosis in this manner is limited because other common species do not fluoresce.⁷

Options for treatment of tinea faciei include topical antifungals for 2 to 6 weeks for localized disease or oral antifungals for more extensive or unresponsive infections for 1 to 8 weeks depending on the agent that is used. If fungal folliculitis is present, oral medication should be given.¹ Our patient was treated with oral terbinafine 250 mg once daily for 4 weeks with follow-up after that time to ensure resolution.