PARIS – An accelerated rule-out pathway, reliant upon a single high-sensitivity cardiac troponin test upon presentation to the ED with suspected acute coronary syndrome, reduced length of stay and hospital admission rates without increasing cardiac events at 30 days or 1 year in a major Scottish study.

“We conclude that implementation of this early rule-out pathway is both effective and safe, and adoption of this pathway will have major benefits for patients and health care systems,” Nicholas L. Mills, MBChB, PhD, said in presenting the results of the HiSTORIC (High-Sensitivity Cardiac Troponin at Presentation to Rule Out Myocardial Infarction) trial at the annual congress of the European Society of Cardiology.

Indeed, in the Unites States, where more than 20 million people per year present to EDs with suspected ACS, the 3.3-hour reduction in length of stay achieved in the HiSTORIC trial by implementing the accelerated rule-out pathway would add up to a $3.6 billion annual savings in bed occupancy alone, according to Dr. Mills, who is chair of cardiology at the University of Edinburgh.

The HiSTORIC pathway incorporates separate thresholds for risk stratification and diagnosis. This strategy is based on an accumulation of persuasive evidence that the major advantage of high-sensitivity cardiac troponin testing is to rule out MI, rather than to rule it in, Dr. Mills explained.

HiSTORIC was a 2-year, prospective, stepped-wedge, cluster-randomized, controlled trial including 31,492 consecutive patients with suspected ACS who presented to seven participating hospitals in Scotland. Patients were randomized, at the hospital level, to one of two management pathways. The control group got a standard guideline-recommended strategy involving high-sensitivity cardiac troponin I testing upon presentation and again 6-12 hours later, with MI being ruled out if the troponin levels were not above the 99th percentile.

In contrast, the novel early rule-out strategy worked as follows: If the patient presented with at least 2 hours of symptoms and the initial troponin I level was below 5 ng/L, then MI was ruled out and the patient was triaged straightaway for outpatient management. If the level was above the 99th percentile, the patient was admitted for serial testing to be done 6-12 hours after symptom onset. And for an intermediate test result – that is, a troponin level between 5 ng/L and the 99th percentile – patients remained in the ED for retesting 3 hours from the time of presentation, and were subsequently admitted only if their troponin level was rising.

Using the accelerated rule-out strategy, two-thirds of patients were quickly discharged from the ED on the basis of a troponin level below 5 ng/mL, and another 7% were ruled out for MI and discharged from the ED after a 3-hour stay on the basis of their second test.

The primary efficacy outcome was length of stay from initial presentation to the ED to discharge. The duration was 10.1 hours with the guideline-recommended pathway and 6.8 hours with the accelerated rule-out pathway, for a statistically significant and clinically meaningful 3.3-hour difference. Moreover, the proportion of patients discharged directly from the ED without hospital admission increased from 53% to 74%, a 57% jump.

The primary safety outcome was the rate of MI or cardiac death post discharge. The rates at 30 days and 1 year were 0.4% and 2.6%, respectively, in the standard-pathway group, compared with 0.3% and 1.8% with the early rule-out pathway. Those between-group differences favoring the accelerated rule-out pathway weren’t statistically significant, but they provided reassurance that the novel pathway was safe.

Of note, this was the first-ever randomized trial to evaluate the safety and efficacy of an early rule-out pathway. Other rapid diagnostic pathways are largely based on observational experience and expert opinion, Dr. Mills said.

The assay utilized in the HiSTORIC trial was the Abbott Diagnostics Architect high sensitivity assay. The 5-ng/L threshold for early rule-out was chosen for the trial because an earlier study by Dr. Mills and coinvestigators showed that a level below that cutoff had a 99.6% negative predictive value for MI (Lancet. 2015 Dec 19;386[10012]:2481-8)

The early rule-out pathway was deliberately designed to be simple and pragmatic, according to the cardiologist. “One of the most remarkable observations in this trial was the adherence to the pathway. We prespecified three criteria to evaluate this and demonstrated adherence rates of 86%-92% for each of these criteria. This was despite the pathway being implemented in all consecutive patients at seven different hospitals and used by many hundreds of different clinicians.”

Discussant Hugo A. Katus, MD, called the HiSTORIC study “a really urgently needed and very well-conducted trial.”

Bruce Jancin/MDedge News

“There were very consistently low MI and cardiac death rates at 30 days and 1 year. So this really works,” commented Dr. Katus, who is chief of internal medicine and director of the department of cardiovascular medicine at Heidelberg (Germany) University.

“Accelerated rule-out high-sensitivity cardiac troponin protocols are here to stay,” he declared.

However, Dr. Katus voiced a concern: “By early discharge as rule out, are other life-threatening conditions ignored?”

He raised this issue because of what he views as the substantial 1-year all-cause mortality and return-to-hospital rates of 5.8% and 39.2% in the standard-pathway group and 5.2% and 38.9% in the accelerated rule-out patients in HiSTORIC. An accelerated rule-out strategy should not prohibit a careful clinical work-up, he emphasized.

Dr. Mills discussed the results in a video interview.

The HiSTORIC trial was funded by the British Heart Foundation. Dr. Mills reported receiving research grants from Abbott Diagnostics and Siemens.

Simultaneous with Dr. Mills’ presentation of the HiSTORIC trial results at the ESC congress, an earlier study that formed the scientific basis for the investigators’ decision to employ distinct risk stratification and diagnostic thresholds for cardiac troponin testing was published online (Circulation. 2019 Sep 1. doi: 10.1161/CIRCULATIONAHA.119.042866). The actual HiSTORIC trial results will be published later.

Dr. Katus reported holding a patent for a cardiac troponin T test and serving as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk.

[email protected]

PARIS – An accelerated rule-out pathway, reliant upon a single high-sensitivity cardiac troponin test upon presentation to the ED with suspected acute coronary syndrome, reduced length of stay and hospital admission rates without increasing cardiac events at 30 days or 1 year in a major Scottish study.

“We conclude that implementation of this early rule-out pathway is both effective and safe, and adoption of this pathway will have major benefits for patients and health care systems,” Nicholas L. Mills, MBChB, PhD, said in presenting the results of the HiSTORIC (High-Sensitivity Cardiac Troponin at Presentation to Rule Out Myocardial Infarction) trial at the annual congress of the European Society of Cardiology.

Indeed, in the Unites States, where more than 20 million people per year present to EDs with suspected ACS, the 3.3-hour reduction in length of stay achieved in the HiSTORIC trial by implementing the accelerated rule-out pathway would add up to a $3.6 billion annual savings in bed occupancy alone, according to Dr. Mills, who is chair of cardiology at the University of Edinburgh.

The HiSTORIC pathway incorporates separate thresholds for risk stratification and diagnosis. This strategy is based on an accumulation of persuasive evidence that the major advantage of high-sensitivity cardiac troponin testing is to rule out MI, rather than to rule it in, Dr. Mills explained.

HiSTORIC was a 2-year, prospective, stepped-wedge, cluster-randomized, controlled trial including 31,492 consecutive patients with suspected ACS who presented to seven participating hospitals in Scotland. Patients were randomized, at the hospital level, to one of two management pathways. The control group got a standard guideline-recommended strategy involving high-sensitivity cardiac troponin I testing upon presentation and again 6-12 hours later, with MI being ruled out if the troponin levels were not above the 99th percentile.

In contrast, the novel early rule-out strategy worked as follows: If the patient presented with at least 2 hours of symptoms and the initial troponin I level was below 5 ng/L, then MI was ruled out and the patient was triaged straightaway for outpatient management. If the level was above the 99th percentile, the patient was admitted for serial testing to be done 6-12 hours after symptom onset. And for an intermediate test result – that is, a troponin level between 5 ng/L and the 99th percentile – patients remained in the ED for retesting 3 hours from the time of presentation, and were subsequently admitted only if their troponin level was rising.

Using the accelerated rule-out strategy, two-thirds of patients were quickly discharged from the ED on the basis of a troponin level below 5 ng/mL, and another 7% were ruled out for MI and discharged from the ED after a 3-hour stay on the basis of their second test.

The primary efficacy outcome was length of stay from initial presentation to the ED to discharge. The duration was 10.1 hours with the guideline-recommended pathway and 6.8 hours with the accelerated rule-out pathway, for a statistically significant and clinically meaningful 3.3-hour difference. Moreover, the proportion of patients discharged directly from the ED without hospital admission increased from 53% to 74%, a 57% jump.

The primary safety outcome was the rate of MI or cardiac death post discharge. The rates at 30 days and 1 year were 0.4% and 2.6%, respectively, in the standard-pathway group, compared with 0.3% and 1.8% with the early rule-out pathway. Those between-group differences favoring the accelerated rule-out pathway weren’t statistically significant, but they provided reassurance that the novel pathway was safe.

Of note, this was the first-ever randomized trial to evaluate the safety and efficacy of an early rule-out pathway. Other rapid diagnostic pathways are largely based on observational experience and expert opinion, Dr. Mills said.

The assay utilized in the HiSTORIC trial was the Abbott Diagnostics Architect high sensitivity assay. The 5-ng/L threshold for early rule-out was chosen for the trial because an earlier study by Dr. Mills and coinvestigators showed that a level below that cutoff had a 99.6% negative predictive value for MI (Lancet. 2015 Dec 19;386[10012]:2481-8)

The early rule-out pathway was deliberately designed to be simple and pragmatic, according to the cardiologist. “One of the most remarkable observations in this trial was the adherence to the pathway. We prespecified three criteria to evaluate this and demonstrated adherence rates of 86%-92% for each of these criteria. This was despite the pathway being implemented in all consecutive patients at seven different hospitals and used by many hundreds of different clinicians.”

Discussant Hugo A. Katus, MD, called the HiSTORIC study “a really urgently needed and very well-conducted trial.”

Bruce Jancin/MDedge News

“There were very consistently low MI and cardiac death rates at 30 days and 1 year. So this really works,” commented Dr. Katus, who is chief of internal medicine and director of the department of cardiovascular medicine at Heidelberg (Germany) University.

“Accelerated rule-out high-sensitivity cardiac troponin protocols are here to stay,” he declared.

However, Dr. Katus voiced a concern: “By early discharge as rule out, are other life-threatening conditions ignored?”

He raised this issue because of what he views as the substantial 1-year all-cause mortality and return-to-hospital rates of 5.8% and 39.2% in the standard-pathway group and 5.2% and 38.9% in the accelerated rule-out patients in HiSTORIC. An accelerated rule-out strategy should not prohibit a careful clinical work-up, he emphasized.

Dr. Mills discussed the results in a video interview.

The HiSTORIC trial was funded by the British Heart Foundation. Dr. Mills reported receiving research grants from Abbott Diagnostics and Siemens.

Simultaneous with Dr. Mills’ presentation of the HiSTORIC trial results at the ESC congress, an earlier study that formed the scientific basis for the investigators’ decision to employ distinct risk stratification and diagnostic thresholds for cardiac troponin testing was published online (Circulation. 2019 Sep 1. doi: 10.1161/CIRCULATIONAHA.119.042866). The actual HiSTORIC trial results will be published later.

Dr. Katus reported holding a patent for a cardiac troponin T test and serving as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk.

[email protected]

PARIS – An accelerated rule-out pathway, reliant upon a single high-sensitivity cardiac troponin test upon presentation to the ED with suspected acute coronary syndrome, reduced length of stay and hospital admission rates without increasing cardiac events at 30 days or 1 year in a major Scottish study.

“We conclude that implementation of this early rule-out pathway is both effective and safe, and adoption of this pathway will have major benefits for patients and health care systems,” Nicholas L. Mills, MBChB, PhD, said in presenting the results of the HiSTORIC (High-Sensitivity Cardiac Troponin at Presentation to Rule Out Myocardial Infarction) trial at the annual congress of the European Society of Cardiology.

Indeed, in the Unites States, where more than 20 million people per year present to EDs with suspected ACS, the 3.3-hour reduction in length of stay achieved in the HiSTORIC trial by implementing the accelerated rule-out pathway would add up to a $3.6 billion annual savings in bed occupancy alone, according to Dr. Mills, who is chair of cardiology at the University of Edinburgh.

The HiSTORIC pathway incorporates separate thresholds for risk stratification and diagnosis. This strategy is based on an accumulation of persuasive evidence that the major advantage of high-sensitivity cardiac troponin testing is to rule out MI, rather than to rule it in, Dr. Mills explained.

HiSTORIC was a 2-year, prospective, stepped-wedge, cluster-randomized, controlled trial including 31,492 consecutive patients with suspected ACS who presented to seven participating hospitals in Scotland. Patients were randomized, at the hospital level, to one of two management pathways. The control group got a standard guideline-recommended strategy involving high-sensitivity cardiac troponin I testing upon presentation and again 6-12 hours later, with MI being ruled out if the troponin levels were not above the 99th percentile.

In contrast, the novel early rule-out strategy worked as follows: If the patient presented with at least 2 hours of symptoms and the initial troponin I level was below 5 ng/L, then MI was ruled out and the patient was triaged straightaway for outpatient management. If the level was above the 99th percentile, the patient was admitted for serial testing to be done 6-12 hours after symptom onset. And for an intermediate test result – that is, a troponin level between 5 ng/L and the 99th percentile – patients remained in the ED for retesting 3 hours from the time of presentation, and were subsequently admitted only if their troponin level was rising.

Using the accelerated rule-out strategy, two-thirds of patients were quickly discharged from the ED on the basis of a troponin level below 5 ng/mL, and another 7% were ruled out for MI and discharged from the ED after a 3-hour stay on the basis of their second test.

The primary efficacy outcome was length of stay from initial presentation to the ED to discharge. The duration was 10.1 hours with the guideline-recommended pathway and 6.8 hours with the accelerated rule-out pathway, for a statistically significant and clinically meaningful 3.3-hour difference. Moreover, the proportion of patients discharged directly from the ED without hospital admission increased from 53% to 74%, a 57% jump.

The primary safety outcome was the rate of MI or cardiac death post discharge. The rates at 30 days and 1 year were 0.4% and 2.6%, respectively, in the standard-pathway group, compared with 0.3% and 1.8% with the early rule-out pathway. Those between-group differences favoring the accelerated rule-out pathway weren’t statistically significant, but they provided reassurance that the novel pathway was safe.

Of note, this was the first-ever randomized trial to evaluate the safety and efficacy of an early rule-out pathway. Other rapid diagnostic pathways are largely based on observational experience and expert opinion, Dr. Mills said.

The assay utilized in the HiSTORIC trial was the Abbott Diagnostics Architect high sensitivity assay. The 5-ng/L threshold for early rule-out was chosen for the trial because an earlier study by Dr. Mills and coinvestigators showed that a level below that cutoff had a 99.6% negative predictive value for MI (Lancet. 2015 Dec 19;386[10012]:2481-8)

The early rule-out pathway was deliberately designed to be simple and pragmatic, according to the cardiologist. “One of the most remarkable observations in this trial was the adherence to the pathway. We prespecified three criteria to evaluate this and demonstrated adherence rates of 86%-92% for each of these criteria. This was despite the pathway being implemented in all consecutive patients at seven different hospitals and used by many hundreds of different clinicians.”

Discussant Hugo A. Katus, MD, called the HiSTORIC study “a really urgently needed and very well-conducted trial.”

Bruce Jancin/MDedge News

“There were very consistently low MI and cardiac death rates at 30 days and 1 year. So this really works,” commented Dr. Katus, who is chief of internal medicine and director of the department of cardiovascular medicine at Heidelberg (Germany) University.

“Accelerated rule-out high-sensitivity cardiac troponin protocols are here to stay,” he declared.

However, Dr. Katus voiced a concern: “By early discharge as rule out, are other life-threatening conditions ignored?”

He raised this issue because of what he views as the substantial 1-year all-cause mortality and return-to-hospital rates of 5.8% and 39.2% in the standard-pathway group and 5.2% and 38.9% in the accelerated rule-out patients in HiSTORIC. An accelerated rule-out strategy should not prohibit a careful clinical work-up, he emphasized.

Dr. Mills discussed the results in a video interview.

The HiSTORIC trial was funded by the British Heart Foundation. Dr. Mills reported receiving research grants from Abbott Diagnostics and Siemens.

Simultaneous with Dr. Mills’ presentation of the HiSTORIC trial results at the ESC congress, an earlier study that formed the scientific basis for the investigators’ decision to employ distinct risk stratification and diagnostic thresholds for cardiac troponin testing was published online (Circulation. 2019 Sep 1. doi: 10.1161/CIRCULATIONAHA.119.042866). The actual HiSTORIC trial results will be published later.

Dr. Katus reported holding a patent for a cardiac troponin T test and serving as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk.

[email protected]

The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.¹ Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.²

The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.

It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.³ A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.

Background

The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.

Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.

Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.

Methods

The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.

These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.

Results

The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.⁴ Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.

DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A_1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.

In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.

HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.

Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. ⁵ Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.

Discussion

These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.

Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.

Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.

Conclusion

The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.² The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.

Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.

The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.¹ Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.²

The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.

It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.³ A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.

Background

The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.

Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.

Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.

Methods

The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.

These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.

Results

The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.⁴ Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.

DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A_1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.

In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.

HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.

Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. ⁵ Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.

Discussion

These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.

Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.

Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.

Conclusion

The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.² The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.

Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.

The US is in the midst of a chronic disease crisis. According to the latest published data available, 60% of Americans have at least 1 chronic condition, and 42% have ≥ 2 chronic conditions.¹ Estimates by the Health Resources and Services Administration (HRSA) indicate a current shortfall of 13 800 primary care physicians and a projected escalation of that shortage to be between 14 800 and 49 300 physicians by the year 2030.²

The US Public Health Service (USPHS) has used pharmacists since 1930 to provide direct patient care to underserved and vulnerable populations. Clinical pharmacists currently serve in direct patient care roles within the Indian Health Service (IHS), Federal Bureau of Prisons (BOP), Immigration and Customs Enforcement (ICE), and the United States Coast Guard (USCG) in many states (Figure). These pharmacists play a vital role in improving access to care and delivering quality care by managing acute and chronic diseases in collaborative practice settings and pharmacist-managed clinics.

It has previously been reported that in the face of physician shortages and growing demand for primary health care providers, pharmacists are well-equipped and motivated to meet this demand.³ A review of the previous 2 years of outcomes reported by clinical pharmacists certified through the USPHS National Clinical Pharmacy Specialist (NCPS) Committee are presented to demonstrate the impact of pharmacists in advancing the health of the populations they serve and to showcase a model for ameliorating the ongoing physician shortage.

Background

The USPHS NCPS Committee serves to promote uniform competency among clinical pharmacists by establishing national standards for protocols, collaborative practice agreements (CPAs), credentialing and privileging of pharmacists, and by collecting, reviewing, and publishing health care outcomes. The committee, whose constituents include pharmacist and physician subject matter experts from across USPHS agencies, reviews applications and protocols and certifies pharmacists (civilian and uniformed) to recognize an advanced scope of practice in managing various diseases and optimizing medication therapy. NCPScertified pharmacists manage a wide spectrum of diseases, including coagulopathy, asthma, diabetes mellitus (DM), hepatitis C, HIV, hypertension, pain, seizure disorders, and tobacco use disorders.

Clinical pharmacists practicing chronic disease management establish a clinical service in collaboration with 1 or more physicians, physician assistants, or nurse practitioners. In this collaborative practice, the health care practitioner(s) refer patients to be managed by a pharmacist for specific medical needs, such as anticoagulation management, or for holistic medication- focused care (eg, cardiovascular risk reduction, DM management, HIV, hepatitis, or mental health). The pharmacist may order and interpret laboratory tests, check vital signs, perform a limited physical examination, and gather other pertinent information from the patient and the medical record in order to provide the best possible care to the patient.

Medications may be started, stopped, or adjusted, education is provided, and therapeutic lifestyle interventions may be recommended. The pharmacist-run clinic provides the patient more frequent interaction with a health care professional (pharmacist) and focused disease management. As a result, pharmacists increase access to care and allow the medical team to handle a larger panel of patients as the practitioner delegates specified diseases to the pharmacist- managed clinic(s). The number of NCPS-certified pharmacists grew 46% from 2012 (n = 230) to 2017 (n = 336), reflecting an evolution of pharmacists’ practice to better meet the need of patients across the nation.

Methods

The NCPS Committee requires NCPS pharmacists to report data annually from all patients referred for pharmacist management for specific diseases in which they have been certified. The data reflect the patient’s clinical outcome goal status at the time of referral as well as the same status at the end of the reporting period or on release from the pharmacist-run clinic. These data describe the impact prescribing pharmacists have on patients reaching clinical outcome goals acting as the team member specializing in the medication selection and dosing aspect of care.

These records were reviewed for the fiscal year (FY) periods of October 1, 2015 to September 30, 2016 (FY 2016) and October 1, 2016 to September 30, 2017 (FY 2017). A systematic review of submitted reports resulted in 181 reports that included all requested data points for the disease as published here for FYs 2016 and 2017. These include 66 reports from FY 2016 and 115 reports from FY 2017; they cover 76 BOP and IHS facilities located across 24 states. Table 1 shows the number of outcome reports collected from 104 075 patient visits in pharmacist-run clinics in FYs 2016 and 2017.

Results

The following tables represent the standardized outcomes collected by NCPS-certified pharmacists providing direct patient care. Patients on anticoagulants (eg, warfarin) require special monitoring and education for drug interactions and adverse effects. NCPS-certified pharmacists were able to achieve a mean patient time in therapeutic range (TTR) of 67.6% (regardless of indication) over the 2 years (calculated per each facility by Rosendaal method of linear interpolation then combined in a weighted average per visit). The TTR produced by NCPS-certified pharmacists are consistent with Chest Guidelines and Expert Panel Report suggesting that TTR should be between 65% and 70%.⁴ Table 2 shows data from 100 reports with 68 255 patient visits for anticoagulation management.

DM management can be complex and time-intensive. NCPS data indicate pharmacist intervention resulted in a mean decrease in hemoglobin A_1c (HbA1c) of 1.8% from a baseline of 10.2% (decrease calculated per each facility then combined by weighted average per visit). Table 3 shows data from 30 reports with 16 518 patient visits for DM care.

In addition to diet and exercise, medication management plays a vital role in managing hypertension. Patients managed by an NCPS-certified pharmacist experienced a mean decrease in blood pressure from 144/83 to 133/77, putting them in goal for both systolic and diastolic ranges (decrease calculated per each facility then combined by weighted average per visit). Table 4 shows data from 16 reports and 7997 patient visits for treatment of hypertension.

HIV viral suppression is vital in order to best manage patients with HIV and reduce the risk of transmission. Pharmacistled clinics have shown a 32.9% absolute improvement in patients at goal (viral load < 50 copies/mL), from a mean baseline of 46.0% to a mean final assessment of 71.6% of patients at goal (combined by weighted average visits). Table 5 shows data from 6 reports covering 1532 patient encounters for management of HIV.

Nicotine dependence includes the use of cigarettes, cigars, pipe tobacco, chewing tobacco, and vaping products containing nicotine. NCPS-certified pharmacists have successfully helped patients improve their chance of quitting, with a 6-month quit rate of 22.2% (quit rate calculated per each facility then combined by weighted average by visits), which is higher than the national average of 9.4% as reported by the Centers for Disease and Control and Prevention. ⁵ Table 6 shows 29 reports covering 9773 patient visits for treatment of nicotine dependence.

Discussion

These data demonstrate the ability of advanced practice pharmacists in multiple locations within the federal sector to improve targeted clinical outcomes in patients with varying diseases. These results are strengthened by their varied origins as well as the improvements observed across the board. Limitations include the general lack of a comparable dataset, manual method of selfreporting by the individual facilities, and the relatively limited array of diseases reported. Although NCPS-certified pharmacists are currently providing care for patients with hepatitis C, asthma, seizure, pain and other diseases not reported here, there are insufficient data collected for FYs 2016 and 2017 to merit inclusion within this report.

Pharmacists are trusted, readily available medication experts. In a clinical role, NCPS-certified pharmacists have increased access to primary care services and demonstrated beneficial impact on important health outcomes as exhibited by the data reported above. Clinical pharmacy is a growing field, and NCPS has displayed continual growth in both the number of NCPS-certified pharmacists and the number of patient encounters performed by these providers. As more pharmacists in all settings collaborate with medical providers to offer high-quality clinical care, these providers will have more opportunity to delegate disease management. Continued reporting of clinical pharmacy outcomes is expected to increase confidence in pharmacists as primary care providers, increase utilization of pharmacy clinical services, and assist in easing the burden of primary care provider shortages across our nation.

Although these outcomes indicate demonstrable benefit in patient-centered outcomes, the need for ongoing assessment and continued improvement is not obviated. Future efforts may benefit from a comparison of alternative approaches to better facilitate the establishment of best practices. Alignment of clinical outcomes with the Centers for Medicare and Medicaid Services (CMS) Electronic Clinical Quality Measures, where applicable, also may prove beneficial by automating the reporting process and thereby decreasing the burden of reporting as well as providing an avenue for standard comparison across multiple populations. Clinical pharmacy interventions have positive outcomes based on the NCPS model, and the NCPS Committee invites other clinical settings to report outcomes data with which to compare.

Conclusion

The NCPS Committee has documented positive outcomes of clinical pharmacy intervention and anticipates growth of the pharmacy profession as additional states and health systems recognize the capacity of the pharmacist to provide high-quality, multidisciplinary patient care. Clinical pharmacists are prepared to address critical health care needs as the US continues to face a PCP shortage.² The NCPS Committee challenges those participating in clinical pharmacy practice to report outcomes to amplify this body of evidence.

Acknowledgments
NCPS-certified pharmacists provided the outcomes detailed in this report. For document review and edits: Federal Bureau of Prison Publication Review Workgroup; RADM Ty Bingham, USPHS; CAPT Cindy Gunderson, USPHS; CAPT Kevin Brooks, USPHS.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

There are 4 variants of psoriasis: plaque, guttate, pustular, and erythroderma (in order of prevalence).² Guttate psoriasis is characterized by small, 2- to 10-mm, raindroplike lesions on the skin.¹ It accounts for approximately 2% of total psoriasis cases and is commonly triggered by group A streptococcal pharyngitis or tonsillitis.^3,4

Hand-foot-and-mouth disease (HFMD) is an illness most commonly caused by a coxsackievirus A infection but also can be caused by other enteroviruses.^5,6 Coxsackievirus is a serotype of the Enterovirus species within the Picornaviridae family.⁷ Hand-foot-and-mouth disease is characterized by a brief fever and vesicular rashes on the palms, soles, or buttocks, as well as oropharyngeal ulcers.⁸ Typically, the rash is benign and short-lived.⁹ In rare cases, neurologic complications develop. There have been no reported cases of guttate psoriasis following a coxsackievirus A infection.

The involvement of coxsackievirus B in the etiopathogenesis of psoriasis has been previously reported.¹⁰ We report the case of guttate psoriasis following presumed coxsackievirus A HFMD.

Case Report

A 56-year-old woman presented with a vesicular rash on the hands, feet, and lips. The patient reported having a sore throat that started around the same time that the rash developed. The severity of the sore throat was rated as moderate. No fever was reported. One day prior, the patient’s primary care physician prescribed a tapered course of prednisone for the rash. The patient reported a medical history of herpes zoster virus, sunburn, and genital herpes. She was taking clonazepam and had a known allergy to penicillin.

Physical examination revealed erythematous vesicular and papular lesions on the extensor surfaces of the hands and feet. Vesicles also were noted on the vermilion border of the lip. Examination of the patient’s mouth showed blisters and shallow ulcerations in the oral cavity. A clinical diagnosis of coxsackievirus A HFMD was made, and the treatment plan included triamcinolone acetonide ointment 0.025% applied twice daily for 2 weeks and oral valacyclovir hydrochloride 1 g taken 3 times daily for 7 days. A topical emollient also was recommended for the lips when necessary. The lesions all resolved within a 2-week period with no sequela.

The patient returned 1 month later, citing newer red abdominal skin lesions. Fever was denied. She reported that both prescribed treatments had not been helping for the newer lesions. She noticed similar lesions on the groin and brought them to the attention of her gynecologist. Physical examination revealed salmon pink papules and plaques with silvery scaling involving the abdomen, bilateral upper extremities and ears, and scalp. The patient was then clinically diagnosed with guttate psoriasis. A shave biopsy of a representative lesion on the abdomen was performed. The treatment plan included betamethasone dipropionate cream 0.05% applied twice daily for 2 weeks, clobetasol propionate solution 0.05% applied twice daily for 14 days (for the scalp), and hydrocortisone valerate cream 0.2% applied twice daily for 14 days (for the groin).

The skin biopsy shown in the Figure was received in 10% buffered formalin, measuring 5×4×1 mm of skin. Sections showed an acanthotic epidermis with foci of spongiosis and hypergranulosis covered by mounds of parakeratosis infiltrated by neutrophils. Superficial perivascular and interstitial lymphocytic inflammation was present. Tortuous blood vessels within the papillary dermis also were present. Results showed psoriasiform dermatitis with mild spongiosis. Periodic acid–Schiff stain did not reveal any fungal organisms. These findings were consistent with a diagnosis of guttate psoriasis.

Comment

Enterovirus-derived HFMD likely is caused by coxsackie-virus A. Current evidence supports the theory that guttate psoriasis can be environmentally triggered in genetically susceptible individuals, often but not exclusively by a streptococcal infection. The causative agent elicits a T-cell–mediated reaction leading to increased type 1 helper T cells, IFN-γ, and IL-2 cytokine levels. HLA-Cw^∗0602–positive patients are considered genetically susceptible and more likely to develop guttate psoriasis following an environmental trigger. Based on the coincidence in timing of both diagnoses, this reported case of guttate psoriasis may have been triggered by a coxsackievirus A infection.

There are 4 variants of psoriasis: plaque, guttate, pustular, and erythroderma (in order of prevalence).² Guttate psoriasis is characterized by small, 2- to 10-mm, raindroplike lesions on the skin.¹ It accounts for approximately 2% of total psoriasis cases and is commonly triggered by group A streptococcal pharyngitis or tonsillitis.^3,4

Hand-foot-and-mouth disease (HFMD) is an illness most commonly caused by a coxsackievirus A infection but also can be caused by other enteroviruses.^5,6 Coxsackievirus is a serotype of the Enterovirus species within the Picornaviridae family.⁷ Hand-foot-and-mouth disease is characterized by a brief fever and vesicular rashes on the palms, soles, or buttocks, as well as oropharyngeal ulcers.⁸ Typically, the rash is benign and short-lived.⁹ In rare cases, neurologic complications develop. There have been no reported cases of guttate psoriasis following a coxsackievirus A infection.

The involvement of coxsackievirus B in the etiopathogenesis of psoriasis has been previously reported.¹⁰ We report the case of guttate psoriasis following presumed coxsackievirus A HFMD.

Case Report

A 56-year-old woman presented with a vesicular rash on the hands, feet, and lips. The patient reported having a sore throat that started around the same time that the rash developed. The severity of the sore throat was rated as moderate. No fever was reported. One day prior, the patient’s primary care physician prescribed a tapered course of prednisone for the rash. The patient reported a medical history of herpes zoster virus, sunburn, and genital herpes. She was taking clonazepam and had a known allergy to penicillin.

Physical examination revealed erythematous vesicular and papular lesions on the extensor surfaces of the hands and feet. Vesicles also were noted on the vermilion border of the lip. Examination of the patient’s mouth showed blisters and shallow ulcerations in the oral cavity. A clinical diagnosis of coxsackievirus A HFMD was made, and the treatment plan included triamcinolone acetonide ointment 0.025% applied twice daily for 2 weeks and oral valacyclovir hydrochloride 1 g taken 3 times daily for 7 days. A topical emollient also was recommended for the lips when necessary. The lesions all resolved within a 2-week period with no sequela.

The patient returned 1 month later, citing newer red abdominal skin lesions. Fever was denied. She reported that both prescribed treatments had not been helping for the newer lesions. She noticed similar lesions on the groin and brought them to the attention of her gynecologist. Physical examination revealed salmon pink papules and plaques with silvery scaling involving the abdomen, bilateral upper extremities and ears, and scalp. The patient was then clinically diagnosed with guttate psoriasis. A shave biopsy of a representative lesion on the abdomen was performed. The treatment plan included betamethasone dipropionate cream 0.05% applied twice daily for 2 weeks, clobetasol propionate solution 0.05% applied twice daily for 14 days (for the scalp), and hydrocortisone valerate cream 0.2% applied twice daily for 14 days (for the groin).

The skin biopsy shown in the Figure was received in 10% buffered formalin, measuring 5×4×1 mm of skin. Sections showed an acanthotic epidermis with foci of spongiosis and hypergranulosis covered by mounds of parakeratosis infiltrated by neutrophils. Superficial perivascular and interstitial lymphocytic inflammation was present. Tortuous blood vessels within the papillary dermis also were present. Results showed psoriasiform dermatitis with mild spongiosis. Periodic acid–Schiff stain did not reveal any fungal organisms. These findings were consistent with a diagnosis of guttate psoriasis.

Comment

Enterovirus-derived HFMD likely is caused by coxsackie-virus A. Current evidence supports the theory that guttate psoriasis can be environmentally triggered in genetically susceptible individuals, often but not exclusively by a streptococcal infection. The causative agent elicits a T-cell–mediated reaction leading to increased type 1 helper T cells, IFN-γ, and IL-2 cytokine levels. HLA-Cw^∗0602–positive patients are considered genetically susceptible and more likely to develop guttate psoriasis following an environmental trigger. Based on the coincidence in timing of both diagnoses, this reported case of guttate psoriasis may have been triggered by a coxsackievirus A infection.

There are 4 variants of psoriasis: plaque, guttate, pustular, and erythroderma (in order of prevalence).² Guttate psoriasis is characterized by small, 2- to 10-mm, raindroplike lesions on the skin.¹ It accounts for approximately 2% of total psoriasis cases and is commonly triggered by group A streptococcal pharyngitis or tonsillitis.^3,4

Hand-foot-and-mouth disease (HFMD) is an illness most commonly caused by a coxsackievirus A infection but also can be caused by other enteroviruses.^5,6 Coxsackievirus is a serotype of the Enterovirus species within the Picornaviridae family.⁷ Hand-foot-and-mouth disease is characterized by a brief fever and vesicular rashes on the palms, soles, or buttocks, as well as oropharyngeal ulcers.⁸ Typically, the rash is benign and short-lived.⁹ In rare cases, neurologic complications develop. There have been no reported cases of guttate psoriasis following a coxsackievirus A infection.

The involvement of coxsackievirus B in the etiopathogenesis of psoriasis has been previously reported.¹⁰ We report the case of guttate psoriasis following presumed coxsackievirus A HFMD.

Case Report

A 56-year-old woman presented with a vesicular rash on the hands, feet, and lips. The patient reported having a sore throat that started around the same time that the rash developed. The severity of the sore throat was rated as moderate. No fever was reported. One day prior, the patient’s primary care physician prescribed a tapered course of prednisone for the rash. The patient reported a medical history of herpes zoster virus, sunburn, and genital herpes. She was taking clonazepam and had a known allergy to penicillin.

Physical examination revealed erythematous vesicular and papular lesions on the extensor surfaces of the hands and feet. Vesicles also were noted on the vermilion border of the lip. Examination of the patient’s mouth showed blisters and shallow ulcerations in the oral cavity. A clinical diagnosis of coxsackievirus A HFMD was made, and the treatment plan included triamcinolone acetonide ointment 0.025% applied twice daily for 2 weeks and oral valacyclovir hydrochloride 1 g taken 3 times daily for 7 days. A topical emollient also was recommended for the lips when necessary. The lesions all resolved within a 2-week period with no sequela.

The patient returned 1 month later, citing newer red abdominal skin lesions. Fever was denied. She reported that both prescribed treatments had not been helping for the newer lesions. She noticed similar lesions on the groin and brought them to the attention of her gynecologist. Physical examination revealed salmon pink papules and plaques with silvery scaling involving the abdomen, bilateral upper extremities and ears, and scalp. The patient was then clinically diagnosed with guttate psoriasis. A shave biopsy of a representative lesion on the abdomen was performed. The treatment plan included betamethasone dipropionate cream 0.05% applied twice daily for 2 weeks, clobetasol propionate solution 0.05% applied twice daily for 14 days (for the scalp), and hydrocortisone valerate cream 0.2% applied twice daily for 14 days (for the groin).

The skin biopsy shown in the Figure was received in 10% buffered formalin, measuring 5×4×1 mm of skin. Sections showed an acanthotic epidermis with foci of spongiosis and hypergranulosis covered by mounds of parakeratosis infiltrated by neutrophils. Superficial perivascular and interstitial lymphocytic inflammation was present. Tortuous blood vessels within the papillary dermis also were present. Results showed psoriasiform dermatitis with mild spongiosis. Periodic acid–Schiff stain did not reveal any fungal organisms. These findings were consistent with a diagnosis of guttate psoriasis.

Comment

Enterovirus-derived HFMD likely is caused by coxsackie-virus A. Current evidence supports the theory that guttate psoriasis can be environmentally triggered in genetically susceptible individuals, often but not exclusively by a streptococcal infection. The causative agent elicits a T-cell–mediated reaction leading to increased type 1 helper T cells, IFN-γ, and IL-2 cytokine levels. HLA-Cw^∗0602–positive patients are considered genetically susceptible and more likely to develop guttate psoriasis following an environmental trigger. Based on the coincidence in timing of both diagnoses, this reported case of guttate psoriasis may have been triggered by a coxsackievirus A infection.

Photolichenoid dermatitis is an uncommon eruptive dermatitis of variable clinical presentation. It has a histopathologic pattern of lichenoid inflammation and is best characterized as a photoallergic reaction.¹ Photolichenoid dermatitis was first described in 1954 in association with the use of quinidine in the treatment of malaria.² Subsequently, it has been associated with various medications, including trimethoprim-sulfamethoxazole, azithromycin, and nonsteroidal anti-inflammatory drugs.^1,2 Photolichenoid dermatitis has been documented in patients with human immunodeficiency virus (HIV) with variable clinical presentations. Photolichenoid dermatitis in patients with HIV has been described both with and without an associated photosensitizing systemic agent, suggesting that HIV infection is an independent risk factor for the development of this eruption in patients with HIV.^3-6

Case Report

A 62-year-old African man presented for evaluation of asymptomatic hypopigmented and depigmented patches in a photodistributed pattern. The eruption began the preceding summer when he noted a pink patch on the right side of the forehead. It progressed over 2 months to involve the face, ears, neck, and arms. His medical history was negative. The only medication he was taking was hydroxychloroquine, which was prescribed by another dermatologist when the patient first developed the eruption. The patient was unsure of the indication for the medication and admitted to poor compliance. A review of systems was negative. There was no personal or family history of autoimmune disease. A detailed sexual history and illicit drug history were not obtained. Physical examination revealed hypopigmented and depigmented patches, some with overlying erythema and collarettes of fine scale. The patches were photodistributed on the face, conchal bowls, neck, dorsal aspect of the hands, and extensor forearms (Figures 1 and 2). Macules of repigmentation were noted within some of the patches. There also were large hyperpigmented patches with peripheral hypopigmentation on the legs.

A punch biopsy taken from the left posterior neck revealed a patchy bandlike lymphocytic infiltrate in the superficial dermis with lymphocytes present at the dermoepidermal junction and scattered dyskeratotic keratinocytes extending into the mid spinous layer (Figure 3). Histopathologic findings were consistent with photolichenoid dermatitis.

Comment

Prevalence of Photosensitive Eruptions
Photodermatitis is an uncommon clinical manifestation of HIV occurring in approximately 5% of patients who are HIV positive.³ Photosensitive eruptions previously described in association with HIV include porphyria cutanea tarda, pseudoporphyria, chronic actinic dermatitis, granuloma annulare, photodistributed dyspigmentation, and lichenoid photodermatitis.⁷ These HIV-associated photosensitive eruptions have been found to disproportionally affect patients of African and Native American descent.^5,7,8 Therefore, a new photodistributed eruption in a patient of African or Native American descent should prompt evaluation of possible underlying HIV infection.

Presenting Sign of HIV Infection
We report a case of photolichenoid dermatitis presenting with loss of pigmentation as a presenting sign of HIV. The patient had no known history of HIV or prior opportunistic infections and was not taking any medications at the time of onset or presentation to clinic. Similar cases of photodistributed depigmentation with lichenoid inflammation on histopathology occurring in patients with HIV have been previously described.^4-6,9 In these cases, most patients were of African descent with previously diagnosed advanced HIV and CD4 counts of less than 50 cells/mL³. The additional clinical findings of lichenoid papules and plaques were noted in several of these cases.^5,6

Exposure to Photosensitizing Drugs
Photodermatitis in patients with HIV often is attributed to exposure to a photosensitizing drug. Many reported cases are retrospective and identify a temporal association between the onset of photodermatitis following the initiation of a photosensitizing drug. The most commonly implicated drugs have included nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, and azithromycin. Other potential offenders may include saquinavir, dapsone, ketoconazole, and efavirenz.^3,5 In cases in which temporal association with a new medication could not be identified, the photodermatitis often has been presumed to be due to polypharmacy and the potential synergistic effect of multiple photosensitizing drugs.^3,5-8

Advanced HIV
There are several reported cases of photodermatitis occurring in patients who were not exposed to systemic photosensitizers. These patients had advanced HIV, meeting criteria for AIDS with a CD4 count of less than 200 cells/mL³. The majority of patients had an even lower CD4 count of less than 50 cells/mL³. Clinical presentations have included photodistributed lichenoid papules and plaques as well as depigmented patches.^4,5,8,10

Evaluating HIV as a Risk Factor for Photodermatitis
Discerning the validity of the correlation between photodermatitis and HIV is difficult, as all previously reported cases are case reports and small retrospective case series. One study of 34 patients with HIV and photodermatitis showed that there was no significant increase in incidence of photodermatitis in patients who were exposed to a photosensitizing drug vs those who were not,³ which further validates that HIV infection may be an independent risk factor in the development of photodermatitis.

Conclusion

This case represents an uncommon presentation of photolichenoid dermatitis as the presenting sign of HIV infection.¹⁰ Although most reported cases of photodermatitis in HIV are attributed to photosensitizing drugs, we propose that HIV may be an independent risk factor for the development of photodermatitis. We recommend consideration of HIV testing in patients who present with photodistributed depigmenting eruptions, even in the absence of a photosensitizing drug, particularly in patients of African and Native American descent.

Photolichenoid dermatitis is an uncommon eruptive dermatitis of variable clinical presentation. It has a histopathologic pattern of lichenoid inflammation and is best characterized as a photoallergic reaction.¹ Photolichenoid dermatitis was first described in 1954 in association with the use of quinidine in the treatment of malaria.² Subsequently, it has been associated with various medications, including trimethoprim-sulfamethoxazole, azithromycin, and nonsteroidal anti-inflammatory drugs.^1,2 Photolichenoid dermatitis has been documented in patients with human immunodeficiency virus (HIV) with variable clinical presentations. Photolichenoid dermatitis in patients with HIV has been described both with and without an associated photosensitizing systemic agent, suggesting that HIV infection is an independent risk factor for the development of this eruption in patients with HIV.^3-6

Case Report

A 62-year-old African man presented for evaluation of asymptomatic hypopigmented and depigmented patches in a photodistributed pattern. The eruption began the preceding summer when he noted a pink patch on the right side of the forehead. It progressed over 2 months to involve the face, ears, neck, and arms. His medical history was negative. The only medication he was taking was hydroxychloroquine, which was prescribed by another dermatologist when the patient first developed the eruption. The patient was unsure of the indication for the medication and admitted to poor compliance. A review of systems was negative. There was no personal or family history of autoimmune disease. A detailed sexual history and illicit drug history were not obtained. Physical examination revealed hypopigmented and depigmented patches, some with overlying erythema and collarettes of fine scale. The patches were photodistributed on the face, conchal bowls, neck, dorsal aspect of the hands, and extensor forearms (Figures 1 and 2). Macules of repigmentation were noted within some of the patches. There also were large hyperpigmented patches with peripheral hypopigmentation on the legs.

A punch biopsy taken from the left posterior neck revealed a patchy bandlike lymphocytic infiltrate in the superficial dermis with lymphocytes present at the dermoepidermal junction and scattered dyskeratotic keratinocytes extending into the mid spinous layer (Figure 3). Histopathologic findings were consistent with photolichenoid dermatitis.

Comment

Prevalence of Photosensitive Eruptions
Photodermatitis is an uncommon clinical manifestation of HIV occurring in approximately 5% of patients who are HIV positive.³ Photosensitive eruptions previously described in association with HIV include porphyria cutanea tarda, pseudoporphyria, chronic actinic dermatitis, granuloma annulare, photodistributed dyspigmentation, and lichenoid photodermatitis.⁷ These HIV-associated photosensitive eruptions have been found to disproportionally affect patients of African and Native American descent.^5,7,8 Therefore, a new photodistributed eruption in a patient of African or Native American descent should prompt evaluation of possible underlying HIV infection.

Presenting Sign of HIV Infection
We report a case of photolichenoid dermatitis presenting with loss of pigmentation as a presenting sign of HIV. The patient had no known history of HIV or prior opportunistic infections and was not taking any medications at the time of onset or presentation to clinic. Similar cases of photodistributed depigmentation with lichenoid inflammation on histopathology occurring in patients with HIV have been previously described.^4-6,9 In these cases, most patients were of African descent with previously diagnosed advanced HIV and CD4 counts of less than 50 cells/mL³. The additional clinical findings of lichenoid papules and plaques were noted in several of these cases.^5,6

Exposure to Photosensitizing Drugs
Photodermatitis in patients with HIV often is attributed to exposure to a photosensitizing drug. Many reported cases are retrospective and identify a temporal association between the onset of photodermatitis following the initiation of a photosensitizing drug. The most commonly implicated drugs have included nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, and azithromycin. Other potential offenders may include saquinavir, dapsone, ketoconazole, and efavirenz.^3,5 In cases in which temporal association with a new medication could not be identified, the photodermatitis often has been presumed to be due to polypharmacy and the potential synergistic effect of multiple photosensitizing drugs.^3,5-8

Advanced HIV
There are several reported cases of photodermatitis occurring in patients who were not exposed to systemic photosensitizers. These patients had advanced HIV, meeting criteria for AIDS with a CD4 count of less than 200 cells/mL³. The majority of patients had an even lower CD4 count of less than 50 cells/mL³. Clinical presentations have included photodistributed lichenoid papules and plaques as well as depigmented patches.^4,5,8,10

Evaluating HIV as a Risk Factor for Photodermatitis
Discerning the validity of the correlation between photodermatitis and HIV is difficult, as all previously reported cases are case reports and small retrospective case series. One study of 34 patients with HIV and photodermatitis showed that there was no significant increase in incidence of photodermatitis in patients who were exposed to a photosensitizing drug vs those who were not,³ which further validates that HIV infection may be an independent risk factor in the development of photodermatitis.

Conclusion

This case represents an uncommon presentation of photolichenoid dermatitis as the presenting sign of HIV infection.¹⁰ Although most reported cases of photodermatitis in HIV are attributed to photosensitizing drugs, we propose that HIV may be an independent risk factor for the development of photodermatitis. We recommend consideration of HIV testing in patients who present with photodistributed depigmenting eruptions, even in the absence of a photosensitizing drug, particularly in patients of African and Native American descent.

Photolichenoid dermatitis is an uncommon eruptive dermatitis of variable clinical presentation. It has a histopathologic pattern of lichenoid inflammation and is best characterized as a photoallergic reaction.¹ Photolichenoid dermatitis was first described in 1954 in association with the use of quinidine in the treatment of malaria.² Subsequently, it has been associated with various medications, including trimethoprim-sulfamethoxazole, azithromycin, and nonsteroidal anti-inflammatory drugs.^1,2 Photolichenoid dermatitis has been documented in patients with human immunodeficiency virus (HIV) with variable clinical presentations. Photolichenoid dermatitis in patients with HIV has been described both with and without an associated photosensitizing systemic agent, suggesting that HIV infection is an independent risk factor for the development of this eruption in patients with HIV.^3-6

Case Report

A 62-year-old African man presented for evaluation of asymptomatic hypopigmented and depigmented patches in a photodistributed pattern. The eruption began the preceding summer when he noted a pink patch on the right side of the forehead. It progressed over 2 months to involve the face, ears, neck, and arms. His medical history was negative. The only medication he was taking was hydroxychloroquine, which was prescribed by another dermatologist when the patient first developed the eruption. The patient was unsure of the indication for the medication and admitted to poor compliance. A review of systems was negative. There was no personal or family history of autoimmune disease. A detailed sexual history and illicit drug history were not obtained. Physical examination revealed hypopigmented and depigmented patches, some with overlying erythema and collarettes of fine scale. The patches were photodistributed on the face, conchal bowls, neck, dorsal aspect of the hands, and extensor forearms (Figures 1 and 2). Macules of repigmentation were noted within some of the patches. There also were large hyperpigmented patches with peripheral hypopigmentation on the legs.

A punch biopsy taken from the left posterior neck revealed a patchy bandlike lymphocytic infiltrate in the superficial dermis with lymphocytes present at the dermoepidermal junction and scattered dyskeratotic keratinocytes extending into the mid spinous layer (Figure 3). Histopathologic findings were consistent with photolichenoid dermatitis.

Comment

Prevalence of Photosensitive Eruptions
Photodermatitis is an uncommon clinical manifestation of HIV occurring in approximately 5% of patients who are HIV positive.³ Photosensitive eruptions previously described in association with HIV include porphyria cutanea tarda, pseudoporphyria, chronic actinic dermatitis, granuloma annulare, photodistributed dyspigmentation, and lichenoid photodermatitis.⁷ These HIV-associated photosensitive eruptions have been found to disproportionally affect patients of African and Native American descent.^5,7,8 Therefore, a new photodistributed eruption in a patient of African or Native American descent should prompt evaluation of possible underlying HIV infection.

Presenting Sign of HIV Infection
We report a case of photolichenoid dermatitis presenting with loss of pigmentation as a presenting sign of HIV. The patient had no known history of HIV or prior opportunistic infections and was not taking any medications at the time of onset or presentation to clinic. Similar cases of photodistributed depigmentation with lichenoid inflammation on histopathology occurring in patients with HIV have been previously described.^4-6,9 In these cases, most patients were of African descent with previously diagnosed advanced HIV and CD4 counts of less than 50 cells/mL³. The additional clinical findings of lichenoid papules and plaques were noted in several of these cases.^5,6

Exposure to Photosensitizing Drugs
Photodermatitis in patients with HIV often is attributed to exposure to a photosensitizing drug. Many reported cases are retrospective and identify a temporal association between the onset of photodermatitis following the initiation of a photosensitizing drug. The most commonly implicated drugs have included nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, and azithromycin. Other potential offenders may include saquinavir, dapsone, ketoconazole, and efavirenz.^3,5 In cases in which temporal association with a new medication could not be identified, the photodermatitis often has been presumed to be due to polypharmacy and the potential synergistic effect of multiple photosensitizing drugs.^3,5-8

Advanced HIV
There are several reported cases of photodermatitis occurring in patients who were not exposed to systemic photosensitizers. These patients had advanced HIV, meeting criteria for AIDS with a CD4 count of less than 200 cells/mL³. The majority of patients had an even lower CD4 count of less than 50 cells/mL³. Clinical presentations have included photodistributed lichenoid papules and plaques as well as depigmented patches.^4,5,8,10

Evaluating HIV as a Risk Factor for Photodermatitis
Discerning the validity of the correlation between photodermatitis and HIV is difficult, as all previously reported cases are case reports and small retrospective case series. One study of 34 patients with HIV and photodermatitis showed that there was no significant increase in incidence of photodermatitis in patients who were exposed to a photosensitizing drug vs those who were not,³ which further validates that HIV infection may be an independent risk factor in the development of photodermatitis.

Conclusion

This case represents an uncommon presentation of photolichenoid dermatitis as the presenting sign of HIV infection.¹⁰ Although most reported cases of photodermatitis in HIV are attributed to photosensitizing drugs, we propose that HIV may be an independent risk factor for the development of photodermatitis. We recommend consideration of HIV testing in patients who present with photodistributed depigmenting eruptions, even in the absence of a photosensitizing drug, particularly in patients of African and Native American descent.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.