Federal Practitioner

Posttraumatic stress disorder (PTSD) is a common psychiatric condition in the veteran population and is associated with significant sleep disturbances and trauma-related nightmares.¹ PTSD can present with intrusive symptoms, such as recurrent memories or dreams, which are associated with traumatic events.² Clinical studies have described an increase in central nervous system (CNS) noradrenergic activity in PTSD; specifically, noradrenergic outflow and/or postsynaptic adrenoreceptor responsiveness is increased.^3,4 Targeting a reduction in noradrenergic activity via antagonism of noradrenergic receptors has been a therapeutic treatment strategy in PTSD.

Prazosin crosses the blood-brain barrier and works to antagonize α-1 adrenoreceptors to decrease noradrenergic outflow.⁵ It has been shown in multiple trials to effectively reduce nightmares and improve sleep quality in the veteran population.^6-12 However, a recent negative trial contributed to a downgraded recommendation for prazosin in the treatment of PTSD-related nightmares in the joint PTSD guideline from the US Department of Veterans Affairs (VA) and US Department of Defense (DoD).^13,14

The diagnosis of PTSD in veterans aged ≥ 65 years has been increasing due to improved recognition.¹⁵ As a result, prazosin may be considered more frequently as a treatment option for those patients who report PTSD-related nightmares. It is important to recognize that the normal physiologic process of aging is associated with increased noradrenergic outflow, which may change the pharmacodynamics of prazosin in geriatric patients.^12,16 This may necessitate increased doses to adequately antagonize the α-1 adenoreceptor.¹⁷ High doses of prazosin may increase the risk of hypotension in older patients.¹² This increased risk is especially concerning for patients who already receive multiple medications or have comorbid conditions that impact blood pressure (BP).

The existing literature has few studies that have reported on outcomes with prazosin use in older veterans.^11,12 The few existing reports provide clinically valuable descriptions of tolerability and efficacy with prazosin. For example, Peskind and colleagues showed prazosin to be an effective agent in the treatment of PTSD-related nightmares.¹² However, in older veterans prazosin dosing > 4 mg has not been described or reported in the literature.

There appears to be a lack of clinical guidance with regards to dosing of prazosin in older patients. The goal of the current study was to assess the outcomes of older veterans with PTSD under pharmacist management of prazosin at our outpatient Prazosin Titration Clinic (PTC) in order to contribute to the minimal, yet valuable, existing clinical literature.

Methods

This study was approved by the University of Iowa Institutional Review Board and Iowa City Veterans Affairs Health Care System (ICVAHCS) research and development committee. The study was a retrospective chart review of older patients with consultations referred to the ICVAHCS PTC. To be eligible for inclusion, veterans with a PTSD diagnosis must have been evaluated at an initial consult appointment with a mental health clinical pharmacy specialist (MH CPS) from February 1, 2016 to August 31, 2018, and had at least 1 follow-up appointment. Follow-up visits were conducted either by telephone or in a face-to-face clinic visit.

Prazosin Titration Clinics

VA health care systems use pharmacists to manage veterans prescribed prazosin through PTC consultations. PTCs provide a process for close follow-up and assessment of PTSD-related outcomes. Due to the frequency of follow-up, this service may be beneficial for older veterans with more complex comorbidities and medication regimens. Any veteran with PTSD-related nightmares may be referred to the PTC for a consultation by any health care provider. Once referred to the clinic, MH CPSs assume responsibility for the prazosin prescription, including dose adjustments. For example, if a veteran reported no issues with tolerability but continued to have frequent and distressing nightmares, the dose may be increased, typically by 1-mg to 2-mg increments. Once the veteran reaches a stable and tolerable dose of prazosin, they are discharged from the PTC, and the referring health care provider resumes responsibility for the prazosin prescription.

Clinically Measured Outcomes

Nightmare frequency and intensity were measured using the Recurrent Distressing Dreams item B2 of the Clinician Administered PTSD Scale (CAPS) (Table 1). The PTSD Checklist (PCL-5), Insomnia Severity Index (ISI), and total sleep hours were used to determine the effect of prazosin on symptom severity (Table 2). The PCL-5 is a 20-item self-report used to monitor and quantify symptom level and change over time. It evaluates the frequency over the past month that a patient was bothered by any of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) PTSD criterion.² Scores range from 0 (not at all) to 4 (extreme), with a maximum score of 80. The ISI is a 7-item self-report of sleep symptoms, with a total score of 28, where increasing scores indicate increasing severity of insomnia (Table 3).

Clinically measured outcome scales were performed and assessed by MH CPSs. CAPS frequency and intensity were measured at each clinic visit. PCL-5 and ISI scores were assessed at baseline and at the endpoint of study or discharge from clinic (Table 4). Patients who continued in the PTC after the end of the study date or who were lost to follow-up did not complete these measures at time of discharge.

Data Analysis

The primary outcome was change in CAPS nightmare frequency and intensity from time of initial clinic visit to time of discharge or end of study. The secondary outcomes included change in PCL-5, ISI, and sleep hours. Other secondary outcomes included measures of tolerability: BP changes, adverse effects (AEs) reported, and outcome of prazosin therapy when AEs were reported. Change in PTSD symptoms, PCL-5, and ISI were assessed using the Wilcoxon signed rank tests. Findings were considered to be statistically significant at P ≤ .05. Other variables were reported descriptively.

Results

Thirty-two veterans, aged ≥ 65 years, with clinical diagnosis of PTSD at the time of referral to the PTC were reviewed (Table 5). All patients were male and 93.8% were white. Thirty were Vietnam era veterans, 1 served in the Persian Gulf era, and 2 served in the post-Korean War era. Twenty-eight veterans had a combat history. Severe PTSD symptoms were reported as indicated by baseline PCL-5 scores, and moderate severity insomnia symptoms as indicated by baseline ISI scores.

All veterans had at least 1 comorbid medical condition, and the majority had multiple medical comorbidities. All were taking multiple medical and psychiatric medications. More than 80% of veterans were taking antihypertensive agents at baseline (Table 6). Twenty-two of the 32 veterans were prescribed a VA/DoD PTSD guideline-recommended antidepressant.

Primary Outcomes

The baseline, final, and changes in the primary outcomes are included in the Figure. Treatment with prazosin was associated with significant improvement in median scores from baseline to endpoint for CAPS nightmare frequency (-2, P = .0001), CAPS nightmare intensity (-2, P = .001), and total CAPS item score (-4, P < .001).

Secondary Outcomes

Of the 32 patients included in the study, PCL-5 was obtained from 20 veterans and ISI from 17 veterans at discharge from clinic. Thirty veterans reported final sleep hours, 2 veterans were unable to quantify average sleep hours per night at their final visit. PTSD symptom severity showed significant median change from baseline to endpoint of management in PTC for PCL-5 (-20.5, P = .0002) and ISI (-6.5, P = .002). Total sleep hours also showed significant improvement from baseline to endpoint (1.5, P = .003) (Table 7).

Prazosin Dosing

Maximum prazosin total daily doses were evaluated from the study baseline to the endpoint (Table 8). The mean (SD) maximum total daily dose of prazosin reached was 5.6 (5.1) mg (median, 3.5 mg; range, 1-17 mg). The mean (SD) total daily dose of prazosin at endpoint of study was 5.1 (5.3) mg (median, 2.5 mg; range, 0-17 mg). The average (SD) change of prazosin dose from baseline to endpoint was 3.5 (4.6) mg (median, 2 mg; range, -2 to 15 mg).

Tolerability

The average (SD) baseline systolic BP (SBP) was 135.8 (20.5) mm Hg and diastolic BP (DBP) was 77.2 (11.0) mm Hg. The average SBP and DBP at study endpoint were 131.8 (16.6) mm Hg and 75.9 (13.7) mm Hg, respectively. Endpoint BP values were missing for 6 patients.

Nine of 32 veterans reported AEs during PTC management of prazosin. Dizziness was the most common AE reported. Other AEs noted included orthostatic hypotension, headache, and falls. Of 12 reported AEs, 8 were related to dizziness, 5 of which were transient or tolerable. One veteran had a dose reduction of prazosin due to dizziness, and 3 veterans discontinued prazosin due to orthostasis. Several veterans had changes made to their antihypertensive medication regimen during prazosin titration, including dose reductions and/or decreased number of medications. If indicated, the MH CPS collaborated with the antihypertensive prescriber to make dosing adjustments. Two veterans reported a fall during prazosin titration; 1 veteran had other mobility-related factors thought to precipitate to their fall, and neither veterans were injured because of the falls.

Discussion

The existing literature reports few outcomes for older veterans prescribed prazosin for PTSD. One report included a 75-year-old otherwise-healthy veteran, who received 2-mg prazosin at bedtime. At this dose, he reported good tolerability and response, as indicated by a reduction in his CAPS nightmare severity score.¹¹ An open-label trial assessed prazosin in 9 geriatric men with chronic PTSD and found low-dose prazosin (average [SD] maximum prazosin dose reported was 2.3 [0.7] mg, range 2-4 mg per day) greatly reduced nightmares and overall PTSD severity in 8 of 9 subjects.¹² Despite the veterans in that study having multiple medical comorbid conditions and taking concomitant medications, prazosin was reported to be well tolerated, and changes in BP were determined to be clinically insignificant.¹² A recent study of middle-aged veterans (average [SD] age 52 [14] years) reported prazosin did not significantly alleviate PTSD-related nightmares.¹³ However, we observed prazosin therapy significantly reduced nightmares and sleep disturbances, and significantly improved PTSD severity in our older veteran population.

To our knowledge, the current study is the largest retrospective study that evaluates prazosin therapy for the treatment of PTSD-related nightmares in older veterans. The findings of this study are similar to a previous study in older veterans as well as studies of prazosin in younger and middle-aged adult veterans, with the average age ranging from 30 to 56 years.^6-12 Like the previously reported studies, prazosin also was well tolerated in our sample of veterans with multiple comorbidities and concomitant medications. Changes in BP were not clinically significant.

Studies have demonstrated increased noradrenergic activity as a component of the normal aging process.^16,17 This may require utilizing caution during prazosin dose titration and frequent patient assessment, due to the concern for risk of hypotension in older patients and in particular those who may require increased doses to achieve efficacy. In our study, favorable outcomes were achieved at an average (SD) total daily dose of 5.1 (5.3) mg (median, 2.5 mg; range 0-17 mg). A previous report showed efficacy of prazosin around an average (SD) maximum dose of 2.3 (0.7) mg, which is lower than the doses reported in the current study.¹² In addition, 13 veterans (40.6%) from our sample reached doses of ≥ 5 mg per day, and 8 veterans (25.0%) reached doses of ≥ 10 mg per day.

The doses reached in this study were reflective of a management approach using assessment of patient-reported symptoms at weekly to biweekly follow-up visits. The individualized management approach applied in the PTC by MH CPSs aids in uncovering the most efficacious and tolerated dose of prazosin for each veteran. Evaluation of symptom change during treatment in PTC was facilitated use of objective rating scales, which helped measure nightmare frequency and intensity, sleep satisfaction, and global PTSD severity. Given the variability in dosing of prazosin reported in the literature, further studies may be warranted to provide more definitive clinical guidance as far as dosing prazosin in older patients.

The study by Peskind and colleaguesrationalized that lower doses of prazosin may be used in older patients given pharmacokinetic effects of aging, age-associated changes in PTSD pathophysiology, and effects and interactions of concomitant medications.¹² However, our study found that prazosin could be well tolerated at higher doses. The rate of discontinuation due to intolerable AEs was low. AEs reported were consistent with the established AE profile of prazosin, with dizziness, orthostasis, and headache most commonly reported. Similar to the Peskind and colleagues study, BP had a tendency to decrease in this current study; however, the change was not clinically significant.¹² That study also reported transient dizziness with prazosin titration, which was shown to be tolerable in the majority of our veterans reporting dizziness.¹² Other common AEs with prazosin, such as rash, priapism, sedation, syncope, other cardiac AEs, and sleep disturbance were not reported in our study population.

MH CPS-managed PTCs are one venue that may allow veterans to achieve favorable outcomes through frequent follow-up. As prazosin dosing is specific to each individual patient, frequent follow-up visits are helpful in determining optimal doses that maximize efficacy while minimizing intolerable AEs. The majority of veterans treated in our PTC continued use of prazosin 6 months postdischarge, while 3 veterans required a postdischarge dose change.

The 2017 VA/DoD PTSD guidelines recommend individual, trauma-focused psychotherapy over pharmacologic therapy for the primary treatment of PTSD.¹⁴ About half of the veterans in the current study participated in either group or individual psychotherapy during enrollment in the PTC. A systematic review of psychotherapy in older veterans reported mixed results, with 4 studies indicating positive effects of therapy, while the other 3 studies reported no benefit or mixed effects for PTSD symptoms. The review concluded that fewer older adults experience complete remission of symptoms with psychotherapy alone.¹⁸ A previous study of older veterans described improvement in PTSD-related symptoms with prazosin without concurrent psychotherapy.¹²

Limitations and Strengths

While this study is the largest study to evaluate outcomes of prazosin in older patients with PTSD, there are several important limitations. The study population was small and all were male. The results of this study may not be applicable to women. Another limitation was several missing values in our data set, as some secondary outcomes were not collected via telephone follow-up visits. This could potentially contribute a measurement bias in the reported secondary outcomes results, specifically for the PCL-5 and ISI. Additionally, some veterans in this study may have reported symptomatic improvement based on the additional supportive intervention that clinical pharmacists were able to offer, as well as concomitant participation in psychotherapy. This may be reflected in the study results. This study did not have a true placebo group, as we may find a reduction in symptoms with placebo.

Strengths of this study include multiple data points for assessment of prazosin tolerability and a pre- and poststudy design, which allowed for the veterans to serve as their own control. Another strength of this study is that data were complete for primary outcome measures, including the CAPS Recurrent and Distressing Dreams Item, where prazosin showed significant benefit in reduction of PTSD-related nightmares. While the results of this study are reassuring, further randomized, double-blind, placebo-controlled trials are likely needed in order to establish efficacy and tolerability of prazosin in older veterans for PTSD related nightmares.

Conclusion

These results demonstrate prazosin therapy in older veterans can significantly improve PTSD-related nightmares and PTSD severity. Prazosin was well tolerated in this population at doses higher than previously reported in other studies. This study shows that prazosin therapy can be effectively managed and tolerated in older veterans with complex medical and psychiatric comorbidities to provide favorable patient outcomes.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Iowa City VA Health Care System and by the Health Services Research and Development Service, US Department of Veterans Affairs.

Posttraumatic stress disorder (PTSD) is a common psychiatric condition in the veteran population and is associated with significant sleep disturbances and trauma-related nightmares.¹ PTSD can present with intrusive symptoms, such as recurrent memories or dreams, which are associated with traumatic events.² Clinical studies have described an increase in central nervous system (CNS) noradrenergic activity in PTSD; specifically, noradrenergic outflow and/or postsynaptic adrenoreceptor responsiveness is increased.^3,4 Targeting a reduction in noradrenergic activity via antagonism of noradrenergic receptors has been a therapeutic treatment strategy in PTSD.

Prazosin crosses the blood-brain barrier and works to antagonize α-1 adrenoreceptors to decrease noradrenergic outflow.⁵ It has been shown in multiple trials to effectively reduce nightmares and improve sleep quality in the veteran population.^6-12 However, a recent negative trial contributed to a downgraded recommendation for prazosin in the treatment of PTSD-related nightmares in the joint PTSD guideline from the US Department of Veterans Affairs (VA) and US Department of Defense (DoD).^13,14

The diagnosis of PTSD in veterans aged ≥ 65 years has been increasing due to improved recognition.¹⁵ As a result, prazosin may be considered more frequently as a treatment option for those patients who report PTSD-related nightmares. It is important to recognize that the normal physiologic process of aging is associated with increased noradrenergic outflow, which may change the pharmacodynamics of prazosin in geriatric patients.^12,16 This may necessitate increased doses to adequately antagonize the α-1 adenoreceptor.¹⁷ High doses of prazosin may increase the risk of hypotension in older patients.¹² This increased risk is especially concerning for patients who already receive multiple medications or have comorbid conditions that impact blood pressure (BP).

The existing literature has few studies that have reported on outcomes with prazosin use in older veterans.^11,12 The few existing reports provide clinically valuable descriptions of tolerability and efficacy with prazosin. For example, Peskind and colleagues showed prazosin to be an effective agent in the treatment of PTSD-related nightmares.¹² However, in older veterans prazosin dosing > 4 mg has not been described or reported in the literature.

There appears to be a lack of clinical guidance with regards to dosing of prazosin in older patients. The goal of the current study was to assess the outcomes of older veterans with PTSD under pharmacist management of prazosin at our outpatient Prazosin Titration Clinic (PTC) in order to contribute to the minimal, yet valuable, existing clinical literature.

Methods

This study was approved by the University of Iowa Institutional Review Board and Iowa City Veterans Affairs Health Care System (ICVAHCS) research and development committee. The study was a retrospective chart review of older patients with consultations referred to the ICVAHCS PTC. To be eligible for inclusion, veterans with a PTSD diagnosis must have been evaluated at an initial consult appointment with a mental health clinical pharmacy specialist (MH CPS) from February 1, 2016 to August 31, 2018, and had at least 1 follow-up appointment. Follow-up visits were conducted either by telephone or in a face-to-face clinic visit.

Prazosin Titration Clinics

VA health care systems use pharmacists to manage veterans prescribed prazosin through PTC consultations. PTCs provide a process for close follow-up and assessment of PTSD-related outcomes. Due to the frequency of follow-up, this service may be beneficial for older veterans with more complex comorbidities and medication regimens. Any veteran with PTSD-related nightmares may be referred to the PTC for a consultation by any health care provider. Once referred to the clinic, MH CPSs assume responsibility for the prazosin prescription, including dose adjustments. For example, if a veteran reported no issues with tolerability but continued to have frequent and distressing nightmares, the dose may be increased, typically by 1-mg to 2-mg increments. Once the veteran reaches a stable and tolerable dose of prazosin, they are discharged from the PTC, and the referring health care provider resumes responsibility for the prazosin prescription.

Clinically Measured Outcomes

Nightmare frequency and intensity were measured using the Recurrent Distressing Dreams item B2 of the Clinician Administered PTSD Scale (CAPS) (Table 1). The PTSD Checklist (PCL-5), Insomnia Severity Index (ISI), and total sleep hours were used to determine the effect of prazosin on symptom severity (Table 2). The PCL-5 is a 20-item self-report used to monitor and quantify symptom level and change over time. It evaluates the frequency over the past month that a patient was bothered by any of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) PTSD criterion.² Scores range from 0 (not at all) to 4 (extreme), with a maximum score of 80. The ISI is a 7-item self-report of sleep symptoms, with a total score of 28, where increasing scores indicate increasing severity of insomnia (Table 3).

Clinically measured outcome scales were performed and assessed by MH CPSs. CAPS frequency and intensity were measured at each clinic visit. PCL-5 and ISI scores were assessed at baseline and at the endpoint of study or discharge from clinic (Table 4). Patients who continued in the PTC after the end of the study date or who were lost to follow-up did not complete these measures at time of discharge.

Data Analysis

The primary outcome was change in CAPS nightmare frequency and intensity from time of initial clinic visit to time of discharge or end of study. The secondary outcomes included change in PCL-5, ISI, and sleep hours. Other secondary outcomes included measures of tolerability: BP changes, adverse effects (AEs) reported, and outcome of prazosin therapy when AEs were reported. Change in PTSD symptoms, PCL-5, and ISI were assessed using the Wilcoxon signed rank tests. Findings were considered to be statistically significant at P ≤ .05. Other variables were reported descriptively.

Results

Thirty-two veterans, aged ≥ 65 years, with clinical diagnosis of PTSD at the time of referral to the PTC were reviewed (Table 5). All patients were male and 93.8% were white. Thirty were Vietnam era veterans, 1 served in the Persian Gulf era, and 2 served in the post-Korean War era. Twenty-eight veterans had a combat history. Severe PTSD symptoms were reported as indicated by baseline PCL-5 scores, and moderate severity insomnia symptoms as indicated by baseline ISI scores.

All veterans had at least 1 comorbid medical condition, and the majority had multiple medical comorbidities. All were taking multiple medical and psychiatric medications. More than 80% of veterans were taking antihypertensive agents at baseline (Table 6). Twenty-two of the 32 veterans were prescribed a VA/DoD PTSD guideline-recommended antidepressant.

Primary Outcomes

The baseline, final, and changes in the primary outcomes are included in the Figure. Treatment with prazosin was associated with significant improvement in median scores from baseline to endpoint for CAPS nightmare frequency (-2, P = .0001), CAPS nightmare intensity (-2, P = .001), and total CAPS item score (-4, P < .001).

Secondary Outcomes

Of the 32 patients included in the study, PCL-5 was obtained from 20 veterans and ISI from 17 veterans at discharge from clinic. Thirty veterans reported final sleep hours, 2 veterans were unable to quantify average sleep hours per night at their final visit. PTSD symptom severity showed significant median change from baseline to endpoint of management in PTC for PCL-5 (-20.5, P = .0002) and ISI (-6.5, P = .002). Total sleep hours also showed significant improvement from baseline to endpoint (1.5, P = .003) (Table 7).

Prazosin Dosing

Maximum prazosin total daily doses were evaluated from the study baseline to the endpoint (Table 8). The mean (SD) maximum total daily dose of prazosin reached was 5.6 (5.1) mg (median, 3.5 mg; range, 1-17 mg). The mean (SD) total daily dose of prazosin at endpoint of study was 5.1 (5.3) mg (median, 2.5 mg; range, 0-17 mg). The average (SD) change of prazosin dose from baseline to endpoint was 3.5 (4.6) mg (median, 2 mg; range, -2 to 15 mg).

Tolerability

The average (SD) baseline systolic BP (SBP) was 135.8 (20.5) mm Hg and diastolic BP (DBP) was 77.2 (11.0) mm Hg. The average SBP and DBP at study endpoint were 131.8 (16.6) mm Hg and 75.9 (13.7) mm Hg, respectively. Endpoint BP values were missing for 6 patients.

Nine of 32 veterans reported AEs during PTC management of prazosin. Dizziness was the most common AE reported. Other AEs noted included orthostatic hypotension, headache, and falls. Of 12 reported AEs, 8 were related to dizziness, 5 of which were transient or tolerable. One veteran had a dose reduction of prazosin due to dizziness, and 3 veterans discontinued prazosin due to orthostasis. Several veterans had changes made to their antihypertensive medication regimen during prazosin titration, including dose reductions and/or decreased number of medications. If indicated, the MH CPS collaborated with the antihypertensive prescriber to make dosing adjustments. Two veterans reported a fall during prazosin titration; 1 veteran had other mobility-related factors thought to precipitate to their fall, and neither veterans were injured because of the falls.

Discussion

The existing literature reports few outcomes for older veterans prescribed prazosin for PTSD. One report included a 75-year-old otherwise-healthy veteran, who received 2-mg prazosin at bedtime. At this dose, he reported good tolerability and response, as indicated by a reduction in his CAPS nightmare severity score.¹¹ An open-label trial assessed prazosin in 9 geriatric men with chronic PTSD and found low-dose prazosin (average [SD] maximum prazosin dose reported was 2.3 [0.7] mg, range 2-4 mg per day) greatly reduced nightmares and overall PTSD severity in 8 of 9 subjects.¹² Despite the veterans in that study having multiple medical comorbid conditions and taking concomitant medications, prazosin was reported to be well tolerated, and changes in BP were determined to be clinically insignificant.¹² A recent study of middle-aged veterans (average [SD] age 52 [14] years) reported prazosin did not significantly alleviate PTSD-related nightmares.¹³ However, we observed prazosin therapy significantly reduced nightmares and sleep disturbances, and significantly improved PTSD severity in our older veteran population.

To our knowledge, the current study is the largest retrospective study that evaluates prazosin therapy for the treatment of PTSD-related nightmares in older veterans. The findings of this study are similar to a previous study in older veterans as well as studies of prazosin in younger and middle-aged adult veterans, with the average age ranging from 30 to 56 years.^6-12 Like the previously reported studies, prazosin also was well tolerated in our sample of veterans with multiple comorbidities and concomitant medications. Changes in BP were not clinically significant.

Studies have demonstrated increased noradrenergic activity as a component of the normal aging process.^16,17 This may require utilizing caution during prazosin dose titration and frequent patient assessment, due to the concern for risk of hypotension in older patients and in particular those who may require increased doses to achieve efficacy. In our study, favorable outcomes were achieved at an average (SD) total daily dose of 5.1 (5.3) mg (median, 2.5 mg; range 0-17 mg). A previous report showed efficacy of prazosin around an average (SD) maximum dose of 2.3 (0.7) mg, which is lower than the doses reported in the current study.¹² In addition, 13 veterans (40.6%) from our sample reached doses of ≥ 5 mg per day, and 8 veterans (25.0%) reached doses of ≥ 10 mg per day.

The doses reached in this study were reflective of a management approach using assessment of patient-reported symptoms at weekly to biweekly follow-up visits. The individualized management approach applied in the PTC by MH CPSs aids in uncovering the most efficacious and tolerated dose of prazosin for each veteran. Evaluation of symptom change during treatment in PTC was facilitated use of objective rating scales, which helped measure nightmare frequency and intensity, sleep satisfaction, and global PTSD severity. Given the variability in dosing of prazosin reported in the literature, further studies may be warranted to provide more definitive clinical guidance as far as dosing prazosin in older patients.

The study by Peskind and colleaguesrationalized that lower doses of prazosin may be used in older patients given pharmacokinetic effects of aging, age-associated changes in PTSD pathophysiology, and effects and interactions of concomitant medications.¹² However, our study found that prazosin could be well tolerated at higher doses. The rate of discontinuation due to intolerable AEs was low. AEs reported were consistent with the established AE profile of prazosin, with dizziness, orthostasis, and headache most commonly reported. Similar to the Peskind and colleagues study, BP had a tendency to decrease in this current study; however, the change was not clinically significant.¹² That study also reported transient dizziness with prazosin titration, which was shown to be tolerable in the majority of our veterans reporting dizziness.¹² Other common AEs with prazosin, such as rash, priapism, sedation, syncope, other cardiac AEs, and sleep disturbance were not reported in our study population.

MH CPS-managed PTCs are one venue that may allow veterans to achieve favorable outcomes through frequent follow-up. As prazosin dosing is specific to each individual patient, frequent follow-up visits are helpful in determining optimal doses that maximize efficacy while minimizing intolerable AEs. The majority of veterans treated in our PTC continued use of prazosin 6 months postdischarge, while 3 veterans required a postdischarge dose change.

The 2017 VA/DoD PTSD guidelines recommend individual, trauma-focused psychotherapy over pharmacologic therapy for the primary treatment of PTSD.¹⁴ About half of the veterans in the current study participated in either group or individual psychotherapy during enrollment in the PTC. A systematic review of psychotherapy in older veterans reported mixed results, with 4 studies indicating positive effects of therapy, while the other 3 studies reported no benefit or mixed effects for PTSD symptoms. The review concluded that fewer older adults experience complete remission of symptoms with psychotherapy alone.¹⁸ A previous study of older veterans described improvement in PTSD-related symptoms with prazosin without concurrent psychotherapy.¹²

Limitations and Strengths

While this study is the largest study to evaluate outcomes of prazosin in older patients with PTSD, there are several important limitations. The study population was small and all were male. The results of this study may not be applicable to women. Another limitation was several missing values in our data set, as some secondary outcomes were not collected via telephone follow-up visits. This could potentially contribute a measurement bias in the reported secondary outcomes results, specifically for the PCL-5 and ISI. Additionally, some veterans in this study may have reported symptomatic improvement based on the additional supportive intervention that clinical pharmacists were able to offer, as well as concomitant participation in psychotherapy. This may be reflected in the study results. This study did not have a true placebo group, as we may find a reduction in symptoms with placebo.

Strengths of this study include multiple data points for assessment of prazosin tolerability and a pre- and poststudy design, which allowed for the veterans to serve as their own control. Another strength of this study is that data were complete for primary outcome measures, including the CAPS Recurrent and Distressing Dreams Item, where prazosin showed significant benefit in reduction of PTSD-related nightmares. While the results of this study are reassuring, further randomized, double-blind, placebo-controlled trials are likely needed in order to establish efficacy and tolerability of prazosin in older veterans for PTSD related nightmares.

Conclusion

These results demonstrate prazosin therapy in older veterans can significantly improve PTSD-related nightmares and PTSD severity. Prazosin was well tolerated in this population at doses higher than previously reported in other studies. This study shows that prazosin therapy can be effectively managed and tolerated in older veterans with complex medical and psychiatric comorbidities to provide favorable patient outcomes.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Iowa City VA Health Care System and by the Health Services Research and Development Service, US Department of Veterans Affairs.

Posttraumatic stress disorder (PTSD) is a common psychiatric condition in the veteran population and is associated with significant sleep disturbances and trauma-related nightmares.¹ PTSD can present with intrusive symptoms, such as recurrent memories or dreams, which are associated with traumatic events.² Clinical studies have described an increase in central nervous system (CNS) noradrenergic activity in PTSD; specifically, noradrenergic outflow and/or postsynaptic adrenoreceptor responsiveness is increased.^3,4 Targeting a reduction in noradrenergic activity via antagonism of noradrenergic receptors has been a therapeutic treatment strategy in PTSD.

Prazosin crosses the blood-brain barrier and works to antagonize α-1 adrenoreceptors to decrease noradrenergic outflow.⁵ It has been shown in multiple trials to effectively reduce nightmares and improve sleep quality in the veteran population.^6-12 However, a recent negative trial contributed to a downgraded recommendation for prazosin in the treatment of PTSD-related nightmares in the joint PTSD guideline from the US Department of Veterans Affairs (VA) and US Department of Defense (DoD).^13,14

The diagnosis of PTSD in veterans aged ≥ 65 years has been increasing due to improved recognition.¹⁵ As a result, prazosin may be considered more frequently as a treatment option for those patients who report PTSD-related nightmares. It is important to recognize that the normal physiologic process of aging is associated with increased noradrenergic outflow, which may change the pharmacodynamics of prazosin in geriatric patients.^12,16 This may necessitate increased doses to adequately antagonize the α-1 adenoreceptor.¹⁷ High doses of prazosin may increase the risk of hypotension in older patients.¹² This increased risk is especially concerning for patients who already receive multiple medications or have comorbid conditions that impact blood pressure (BP).

The existing literature has few studies that have reported on outcomes with prazosin use in older veterans.^11,12 The few existing reports provide clinically valuable descriptions of tolerability and efficacy with prazosin. For example, Peskind and colleagues showed prazosin to be an effective agent in the treatment of PTSD-related nightmares.¹² However, in older veterans prazosin dosing > 4 mg has not been described or reported in the literature.

There appears to be a lack of clinical guidance with regards to dosing of prazosin in older patients. The goal of the current study was to assess the outcomes of older veterans with PTSD under pharmacist management of prazosin at our outpatient Prazosin Titration Clinic (PTC) in order to contribute to the minimal, yet valuable, existing clinical literature.

Methods

This study was approved by the University of Iowa Institutional Review Board and Iowa City Veterans Affairs Health Care System (ICVAHCS) research and development committee. The study was a retrospective chart review of older patients with consultations referred to the ICVAHCS PTC. To be eligible for inclusion, veterans with a PTSD diagnosis must have been evaluated at an initial consult appointment with a mental health clinical pharmacy specialist (MH CPS) from February 1, 2016 to August 31, 2018, and had at least 1 follow-up appointment. Follow-up visits were conducted either by telephone or in a face-to-face clinic visit.

Prazosin Titration Clinics

VA health care systems use pharmacists to manage veterans prescribed prazosin through PTC consultations. PTCs provide a process for close follow-up and assessment of PTSD-related outcomes. Due to the frequency of follow-up, this service may be beneficial for older veterans with more complex comorbidities and medication regimens. Any veteran with PTSD-related nightmares may be referred to the PTC for a consultation by any health care provider. Once referred to the clinic, MH CPSs assume responsibility for the prazosin prescription, including dose adjustments. For example, if a veteran reported no issues with tolerability but continued to have frequent and distressing nightmares, the dose may be increased, typically by 1-mg to 2-mg increments. Once the veteran reaches a stable and tolerable dose of prazosin, they are discharged from the PTC, and the referring health care provider resumes responsibility for the prazosin prescription.

Clinically Measured Outcomes

Nightmare frequency and intensity were measured using the Recurrent Distressing Dreams item B2 of the Clinician Administered PTSD Scale (CAPS) (Table 1). The PTSD Checklist (PCL-5), Insomnia Severity Index (ISI), and total sleep hours were used to determine the effect of prazosin on symptom severity (Table 2). The PCL-5 is a 20-item self-report used to monitor and quantify symptom level and change over time. It evaluates the frequency over the past month that a patient was bothered by any of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) PTSD criterion.² Scores range from 0 (not at all) to 4 (extreme), with a maximum score of 80. The ISI is a 7-item self-report of sleep symptoms, with a total score of 28, where increasing scores indicate increasing severity of insomnia (Table 3).

Clinically measured outcome scales were performed and assessed by MH CPSs. CAPS frequency and intensity were measured at each clinic visit. PCL-5 and ISI scores were assessed at baseline and at the endpoint of study or discharge from clinic (Table 4). Patients who continued in the PTC after the end of the study date or who were lost to follow-up did not complete these measures at time of discharge.

Data Analysis

The primary outcome was change in CAPS nightmare frequency and intensity from time of initial clinic visit to time of discharge or end of study. The secondary outcomes included change in PCL-5, ISI, and sleep hours. Other secondary outcomes included measures of tolerability: BP changes, adverse effects (AEs) reported, and outcome of prazosin therapy when AEs were reported. Change in PTSD symptoms, PCL-5, and ISI were assessed using the Wilcoxon signed rank tests. Findings were considered to be statistically significant at P ≤ .05. Other variables were reported descriptively.

Results

Thirty-two veterans, aged ≥ 65 years, with clinical diagnosis of PTSD at the time of referral to the PTC were reviewed (Table 5). All patients were male and 93.8% were white. Thirty were Vietnam era veterans, 1 served in the Persian Gulf era, and 2 served in the post-Korean War era. Twenty-eight veterans had a combat history. Severe PTSD symptoms were reported as indicated by baseline PCL-5 scores, and moderate severity insomnia symptoms as indicated by baseline ISI scores.

All veterans had at least 1 comorbid medical condition, and the majority had multiple medical comorbidities. All were taking multiple medical and psychiatric medications. More than 80% of veterans were taking antihypertensive agents at baseline (Table 6). Twenty-two of the 32 veterans were prescribed a VA/DoD PTSD guideline-recommended antidepressant.

Primary Outcomes

The baseline, final, and changes in the primary outcomes are included in the Figure. Treatment with prazosin was associated with significant improvement in median scores from baseline to endpoint for CAPS nightmare frequency (-2, P = .0001), CAPS nightmare intensity (-2, P = .001), and total CAPS item score (-4, P < .001).

Secondary Outcomes

Of the 32 patients included in the study, PCL-5 was obtained from 20 veterans and ISI from 17 veterans at discharge from clinic. Thirty veterans reported final sleep hours, 2 veterans were unable to quantify average sleep hours per night at their final visit. PTSD symptom severity showed significant median change from baseline to endpoint of management in PTC for PCL-5 (-20.5, P = .0002) and ISI (-6.5, P = .002). Total sleep hours also showed significant improvement from baseline to endpoint (1.5, P = .003) (Table 7).

Prazosin Dosing

Maximum prazosin total daily doses were evaluated from the study baseline to the endpoint (Table 8). The mean (SD) maximum total daily dose of prazosin reached was 5.6 (5.1) mg (median, 3.5 mg; range, 1-17 mg). The mean (SD) total daily dose of prazosin at endpoint of study was 5.1 (5.3) mg (median, 2.5 mg; range, 0-17 mg). The average (SD) change of prazosin dose from baseline to endpoint was 3.5 (4.6) mg (median, 2 mg; range, -2 to 15 mg).

Tolerability

The average (SD) baseline systolic BP (SBP) was 135.8 (20.5) mm Hg and diastolic BP (DBP) was 77.2 (11.0) mm Hg. The average SBP and DBP at study endpoint were 131.8 (16.6) mm Hg and 75.9 (13.7) mm Hg, respectively. Endpoint BP values were missing for 6 patients.

Nine of 32 veterans reported AEs during PTC management of prazosin. Dizziness was the most common AE reported. Other AEs noted included orthostatic hypotension, headache, and falls. Of 12 reported AEs, 8 were related to dizziness, 5 of which were transient or tolerable. One veteran had a dose reduction of prazosin due to dizziness, and 3 veterans discontinued prazosin due to orthostasis. Several veterans had changes made to their antihypertensive medication regimen during prazosin titration, including dose reductions and/or decreased number of medications. If indicated, the MH CPS collaborated with the antihypertensive prescriber to make dosing adjustments. Two veterans reported a fall during prazosin titration; 1 veteran had other mobility-related factors thought to precipitate to their fall, and neither veterans were injured because of the falls.

Discussion

The existing literature reports few outcomes for older veterans prescribed prazosin for PTSD. One report included a 75-year-old otherwise-healthy veteran, who received 2-mg prazosin at bedtime. At this dose, he reported good tolerability and response, as indicated by a reduction in his CAPS nightmare severity score.¹¹ An open-label trial assessed prazosin in 9 geriatric men with chronic PTSD and found low-dose prazosin (average [SD] maximum prazosin dose reported was 2.3 [0.7] mg, range 2-4 mg per day) greatly reduced nightmares and overall PTSD severity in 8 of 9 subjects.¹² Despite the veterans in that study having multiple medical comorbid conditions and taking concomitant medications, prazosin was reported to be well tolerated, and changes in BP were determined to be clinically insignificant.¹² A recent study of middle-aged veterans (average [SD] age 52 [14] years) reported prazosin did not significantly alleviate PTSD-related nightmares.¹³ However, we observed prazosin therapy significantly reduced nightmares and sleep disturbances, and significantly improved PTSD severity in our older veteran population.

To our knowledge, the current study is the largest retrospective study that evaluates prazosin therapy for the treatment of PTSD-related nightmares in older veterans. The findings of this study are similar to a previous study in older veterans as well as studies of prazosin in younger and middle-aged adult veterans, with the average age ranging from 30 to 56 years.^6-12 Like the previously reported studies, prazosin also was well tolerated in our sample of veterans with multiple comorbidities and concomitant medications. Changes in BP were not clinically significant.

Studies have demonstrated increased noradrenergic activity as a component of the normal aging process.^16,17 This may require utilizing caution during prazosin dose titration and frequent patient assessment, due to the concern for risk of hypotension in older patients and in particular those who may require increased doses to achieve efficacy. In our study, favorable outcomes were achieved at an average (SD) total daily dose of 5.1 (5.3) mg (median, 2.5 mg; range 0-17 mg). A previous report showed efficacy of prazosin around an average (SD) maximum dose of 2.3 (0.7) mg, which is lower than the doses reported in the current study.¹² In addition, 13 veterans (40.6%) from our sample reached doses of ≥ 5 mg per day, and 8 veterans (25.0%) reached doses of ≥ 10 mg per day.

The doses reached in this study were reflective of a management approach using assessment of patient-reported symptoms at weekly to biweekly follow-up visits. The individualized management approach applied in the PTC by MH CPSs aids in uncovering the most efficacious and tolerated dose of prazosin for each veteran. Evaluation of symptom change during treatment in PTC was facilitated use of objective rating scales, which helped measure nightmare frequency and intensity, sleep satisfaction, and global PTSD severity. Given the variability in dosing of prazosin reported in the literature, further studies may be warranted to provide more definitive clinical guidance as far as dosing prazosin in older patients.

The study by Peskind and colleaguesrationalized that lower doses of prazosin may be used in older patients given pharmacokinetic effects of aging, age-associated changes in PTSD pathophysiology, and effects and interactions of concomitant medications.¹² However, our study found that prazosin could be well tolerated at higher doses. The rate of discontinuation due to intolerable AEs was low. AEs reported were consistent with the established AE profile of prazosin, with dizziness, orthostasis, and headache most commonly reported. Similar to the Peskind and colleagues study, BP had a tendency to decrease in this current study; however, the change was not clinically significant.¹² That study also reported transient dizziness with prazosin titration, which was shown to be tolerable in the majority of our veterans reporting dizziness.¹² Other common AEs with prazosin, such as rash, priapism, sedation, syncope, other cardiac AEs, and sleep disturbance were not reported in our study population.

MH CPS-managed PTCs are one venue that may allow veterans to achieve favorable outcomes through frequent follow-up. As prazosin dosing is specific to each individual patient, frequent follow-up visits are helpful in determining optimal doses that maximize efficacy while minimizing intolerable AEs. The majority of veterans treated in our PTC continued use of prazosin 6 months postdischarge, while 3 veterans required a postdischarge dose change.

The 2017 VA/DoD PTSD guidelines recommend individual, trauma-focused psychotherapy over pharmacologic therapy for the primary treatment of PTSD.¹⁴ About half of the veterans in the current study participated in either group or individual psychotherapy during enrollment in the PTC. A systematic review of psychotherapy in older veterans reported mixed results, with 4 studies indicating positive effects of therapy, while the other 3 studies reported no benefit or mixed effects for PTSD symptoms. The review concluded that fewer older adults experience complete remission of symptoms with psychotherapy alone.¹⁸ A previous study of older veterans described improvement in PTSD-related symptoms with prazosin without concurrent psychotherapy.¹²

Limitations and Strengths

While this study is the largest study to evaluate outcomes of prazosin in older patients with PTSD, there are several important limitations. The study population was small and all were male. The results of this study may not be applicable to women. Another limitation was several missing values in our data set, as some secondary outcomes were not collected via telephone follow-up visits. This could potentially contribute a measurement bias in the reported secondary outcomes results, specifically for the PCL-5 and ISI. Additionally, some veterans in this study may have reported symptomatic improvement based on the additional supportive intervention that clinical pharmacists were able to offer, as well as concomitant participation in psychotherapy. This may be reflected in the study results. This study did not have a true placebo group, as we may find a reduction in symptoms with placebo.

Strengths of this study include multiple data points for assessment of prazosin tolerability and a pre- and poststudy design, which allowed for the veterans to serve as their own control. Another strength of this study is that data were complete for primary outcome measures, including the CAPS Recurrent and Distressing Dreams Item, where prazosin showed significant benefit in reduction of PTSD-related nightmares. While the results of this study are reassuring, further randomized, double-blind, placebo-controlled trials are likely needed in order to establish efficacy and tolerability of prazosin in older veterans for PTSD related nightmares.

Conclusion

These results demonstrate prazosin therapy in older veterans can significantly improve PTSD-related nightmares and PTSD severity. Prazosin was well tolerated in this population at doses higher than previously reported in other studies. This study shows that prazosin therapy can be effectively managed and tolerated in older veterans with complex medical and psychiatric comorbidities to provide favorable patient outcomes.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Iowa City VA Health Care System and by the Health Services Research and Development Service, US Department of Veterans Affairs.

Sporadic porphyria cutanea tarda (PCT) is the most common cause of porphyria worldwide.^1,2 Unlike other forms of porphyria, PCT usually is an acquired disease precipitated by extrinsic risk factors that commonly include excessive alcohol consumption, smoking, and chronic hepatitis C virus (HCV) infection. Additional risk factors include myeloproliferative disorders, exposure to polyhalogenated compounds, estrogen therapy, diseases of iron overload like hereditary hemochromatosis (HH), and potentially, HIV infection.^1-3

In this case report, we present a patient with an iron overload (due in part to an HFE gene mutation) and concomitant PCT, HCV infection, and coronary artery disease (CAD). We will discuss the relationship that his iron overload may play in each of these disease states.

Case Presentation

Mr. M is a 59-year-old white male of Irish background with a medical history that includes coronary artery disease. He is status post ST-elevation myocardial infarction and percutaneous coronary intervention with placement of 2 drug-eluting stents. Additional medical issues include PCT and HCV infection with cirrhosis. He is an active smoker.

The patient has a long history of developing blisters with minor trauma, such as rubbing against his mattress/bed sheets or bumping into doors. These blisters primarily occur on his upper extremities, but also can occur on his face after shaving. Mr. M was diagnosed with HCV infection in 1979 while on active military duty. At that time, he had an acute HCV infection and jaundice that required a prolonged hospitalization. He reported no IV drug use and that many others on his military base had similar manifestations. He drinks 1 to 2 beers daily, but reports no binge drinking.

Porphyria Cutanea Tarda

The pathogenesis of PCT is related to the intrahepatic deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme in the heme biosynthetic pathway (Figure 1). Decreased activity of UROD leads to accumulation of uroporphyrinogen and its derivatives, which most likely are oxidized in presence of cytochrome P450 1A2. Up to 80% of PCT cases are sporadic, in which the deficiency of UROD is acquired by exogenous risk factors as mentioned above. However, the remaining 20% of PCT cases are due to an autosomal dominant mutation of UROD that causes the partial deficiency (up to 50%) of UROD. In these cases, additional risk factors are needed to decrease UROD activity to < 75% for symptoms to occur.

Clinical Manifestation

Patients with PCT typically develop blisters, skin fragility, and peeling with sun exposure or minor trauma. They also may experience delayed wound healing in sun-exposed skin.³ The photosensitivity of PCT is believed to be related to the saturation of highly carboxylated uroporphyrins in the liver, which are then released into the circulation. Sun exposure then activates these products facilitating an immune reaction and subsequent skin damage.² In chronic cases, fibrotic reactions and scaring occur which can be mistaken for scleroderma. Other skin manifestations include hyperpigmentation, hypertrichosis, alopecia due to scaring and purplish heliotrope suffusion of periorbital areas.

Patients can develop cirrhosis due to accumulation of porphyria in the hepatocytes and subsequent parenchymal damage. Hepatocellular carcinoma surveillance is recommended for patients with PCT, although its incidence is rare in those patients.

Diagnosis and Treatment

PCT is mainly a clinical diagnosis. Physicians should consider PCT in patients with photosensitivity and blisters after minor trauma (Figure 2). The urine of a patient with PCT is often pink or red when exposed to air or light due to its high concentration of porphyrin products. Mild elevation of liver enzymes and fatty liver on ultrasound are also noted. Evidence of iron overload is seen in most cases. Screening for risk factors like HCV, HIV, hepatitis B virus, and HH is recommended. Confirmation of PCT typically requires measurement of the porphyria level in a 24-hour urine collection.

Avoiding sun exposure is fundamental in decreasing the development of skin lesions and scaring. Additionally, patients should be advised about the adverse effects of alcohol, smoking, and estrogen therapy on PCT. Treatment of PCT is frequently focused on iron overload and subsequent increased porphyrin oxidation.^1,2 Iron can increase reactive oxygen species (ROS), which, in turn, increases the rate of oxidation of uroporphyrinogens. Excess iron also decreases the activity of UROD and increases δ-aminolevulinic acid (ALA) production (the precursor of uroporphyrinogen). Phlebotomy to treat iron overload should be done to a target ferritin level of 20 ng/mL. Clinical manifestations, including skin lesions, typically will normalize before the laboratory findings. Therapeutic remission is expected after 6 to 7 phlebotomy attempts, while clinical improvement can occur after 2 to 3 phlebotomies.

In addition to phlebotomy, 4-aminoquinoline medications (chloroquine and hydroxychloroquine) can be used effectively to treat PCT. Hydroxychloroquine is generally preferred due to its better safety profile. Although the exact mechanism of action of 4-aminoquinolines is not clear, it has been suggested that they bind to porphyrins and form water-soluble products, which are then excreted in the urine. Again, clinical remission occurs much sooner than chemical remission, (3 months vs 12 months). A 4-aminoquinoline should not be used in patients with severe liver disease, renal insufficiency, pregnancy, or G6PD deficiency. When used, they should be used in lower than typical doses due to the rapid removal of accumulated porphyrin from the hepatocytes potentially causing necrosis and acute hepatitis.

Iron chelation also is effective, but it is slower in achieving remission and more expensive than phlebotomy. Treatment of PCT should be individualized. For example, 4-aminoquinolines are contraindicated for patients with end-stage renal disease (ESRD), while phlebotomy could present a problem for patients with preexisting anemia. In this instance, removing 50 cc of blood every 2 weeks may be safe and effective. Furthermore, 4-aminoquinolines in patients with severe iron overload and phlebotomy have been used together. Plasmapheresis is still another option in patients with ESRD.

The use of direct antiviral agents (DAA) in the treatment of HCV has shown promising results in maintaining undetectable viral loads and concurrent remission of PCT. Several studies have shown that treatment of HCV with a DAA obviates the need for treatment PCT.^3-5 Treatment of HCV with interferon (IFN) and ribavirin have shown mixed results in controlling PCT, possibly due to their ineffectiveness in maintaining a suppressed viral load. Some studies even showed worsening of PCT with IFN/ribavirin.⁶

Hemochromatosis

Human cells need iron for aerobic respiration. The intestinal mucosa controls iron uptake and its transfer to the blood stream. Aside from variations in intestinal absorption with fecal excretion, humans do not have another pathway to excrete excess iron. HH is the most common genetic disorder in whites.⁷ It is an autosomal recessive disorder that increases the intestinal absorption of iron. The most common mutation in the hemochromatosis (HFE) gene results in a substitution of tyrosine for cysteine at amino acid number 282 and is referred to as the C282Y mutation. A second mutation changes histidine at position 63 to aspartic acid and is referred to as a H63D mutation. H63D is present in a minority of the patients with phenotypically expressed HH and its clinical impact is unknown.

Homozygosity of the C282Y mutation is the most common genotype associated with clinical hemochromatosis. While carriers of the C282Y gene heterozygote mutation typically do not develop enough iron overload to cause clinical hemochromatosis, they can if other risk factors, such as PCT, excess alcohol use, liver disease, or HCV, are present.⁸ Additionally, an associated genetic defect, like a compound heterozygotes C282Y/H63D mutation, a private HFE mutation in trans, or other iron-related genes, can cause manifestations of iron overload. Lastly, about 20% of patients that are heterozygous for both mutations can express the HH phenotype.⁸

Clinical Manifestation

Patients with HH absorb only a few extra milligrams of iron daily. The clinical manifestation begins to occur when the total body iron store reaches 15-40 g (normal, 4 g). While the genetic mutation is present from birth, iron stores start to rise slowly to around 10 g > age 15 years, at which point serum iron levels are elevated. After age 20 years, the speed with which the iron is stored increases, and by 30 years, liver damage and tissue injury will occur. Cirrhosis is possible by 40 years.⁷ Age, sex, dietary iron intake, blood loss (menstruation), pregnancy, and other unknown factors greatly influence the disease progression. Homozygote C282Y mutation is as common in women as it is in men, but women are less likely to express the HH phenotype, presumably due, in part, to menstruation. When diagnosed early, most of the clinical manifestations of HH are preventable. Additional manifestations of HH include hyperpigmentation, cardiomyopathy, diabetes mellitus, hypogonadism, hypothyroidism, and arthropathy due to pseudogout.

Iron overload due to HH should be distinguished from other causes of iron overload including exogenous iron overload, anemia (thalassemia, sideroblastic), and chronic liver diseases like PCT, viral hepatitis, nonalcoholic steatohepatitis, and alcoholic liver disease.

Diagnosis

HH should be suspected in patients with a high serum transferrin saturation and elevated serum ferritin concentrations. Typically, transferrin saturation is > 50% and ferritin levels are > 300 ng/mL in men and > 200 ng/mL in women. In early stages of the disease, transferrin saturation can be normal. Additionally, in patients with chronic inflammation, ferritin may be high due to acute-phase reactants and the iron panel should be interpreted with caution. When the secondary causes of abnormalities in a patient’s iron studies are excluded, genetic testing for HFE gene is recommended.

The majority of patients (60-93%) with clinically evident hemochromatosis are homozygous for C282Y mutation. In a heterozygous C282Y mutation with a high transferrin saturation and HH phenotype, additional genetic testing for a heterozygous compound mutation C282Y/H63D is recommended.⁸ Additional studies could include evaluation for a private HFE mutation in trans or other iron-related genes. Liver biopsy is the gold standard for assessing the degree of hepatic fibrosis. Determining the degree of fibrosis by some means is needed due to the increased risk of hepatocellular carcinoma (HCC) in HH patients with advanced fibrosis and cirrhosis.⁹

Treatment

Iron depletion with phlebotomy is the cornerstone of treatment in HH. Phlebotomy initially is done weekly with goal of achieving a transferrin saturation < 50%, a serum ferritin level < 50 ng/mL, and a hemoglobin of 12 to 13 ng/mL. When these goals are achieved, patients typically need 4 to 8 phlebotomies per year to maintain a transferrin saturation < 50% (Figure 3).

Hemochromatosis and PCT

Many studies have investigated the relevance of C282Y and/or H63D mutations in patients with PCT.^9,10 It appears that ≥ 1 mutation of the HFE gene in PCT may be an important susceptibility factor in the development of clinical PCT. Various studies have shown an incidence of C282Y mutations of 44 to 47% in patients with PCT, compared with 9 to 12% in control populations.^9,10 The incidence of the H63D mutation in PCT has been more variable, with some studies showing no difference between patients with PCT and a control group, while other studies showed 31% incidence of H63D mutation in patients with PCT.^9,10 A higher incidence of C282Y and H63D mutations in PCT may be a sign that the HFE mutation could be an important factor in developing PCT.

Hemochromatosis and Hepatitis C

Transferrin saturation is frequently elevated in patients with HCV. It is yet unclear whether the pathology of liver disease in patients with HCV is influenced by iron overload or limited to the direct cell damage from replication of the virus and subsequent inflammation. It is believed that the pathology of iron overload in the patients with HCV is different from HH. Like other secondary causes of iron overload, the excess iron is stored in the Kupffer cells of patients with HCV. In HH, excess iron is stored in hepatocytes.

The prevalence of the HFE mutation is the same in the patients with chronic HCV and healthy individuals.^10,11 However, HFE mutations are more prevalent in 30 to 60% of the patients with chronic HCV who have elevated transferrin saturations. Alone, C282Y heterozygosity, H63D heterozygosity, or C282Y/H63D compound heterozygosity could not lead to clinically significant iron overload in otherwise healthy individuals; however, these could be a significant cause of iron overload in patients with chronic HCV. Theoretically, the combination of iron overload and HFE gene mutations could increase the rate of advanced fibrosis/cirrhosis in chronic HCV. An increase serum ferritin level of 200 ng/dL in women and 250 ng/dL in men has been observed in 32% of patients with chronic HCV. In this subset of patients, phlebotomy reduced the progression of their liver disease and reduction in their liver enzymes.

Iron Overload and Cardiovascular Risk

In 1987, a Framingham cohort of > 2,800 patients showed a higher incident of CAD in postmenopausal women when compared with premenopausal women.¹² In the 1980s, Sullivan hypothesized that the reason for higher incidence of CAD in men when compared with premenopausal women was due to their higher body iron storage.^13-16 A study of 1,930 Finnish men reported that the men with ferritin level ≥ 200 ng/dL had a risk 2.2 times higher of acute myocardial infarction when compared to men with lower serum ferritin level.¹⁷

A prospective study published in 1997 by Klechl showed the role of iron stores in early atherogenesis via promotion of lipid oxidation.¹⁸ Other epidemiological studies have shown a decreased risk of myocardial infarction in blood donors, and while arguments have been made that the blood donors tend to be healthier individuals, 2 studies were published in 1997 matching healthy blood donors to healthy nonblood donors, and both showed a lower risk of CVD in the donors when compared with nondonors.^19,20 Furthermore, in an animal model of atherosclerosis, an iron depleted diet showed a reduction of atherosclerosis progression.²¹ Multiple studies have shown that the heterozygosity for HFE is significantly linked to the risk of cardiovascular events, including the fact that heterozygosity for C282Y has been shown to be a risk factor for myocardial infarction in men and cerebrovascular death in women.^22-25

Conclusion

Multiple studies have shown an association between the elevated iron levels associated with the HFE genotype and the disease states of our patient. These include an increased risk of CAD, the increased risk of cirrhosis in HCV and the development of PCT. Indeed, in this case, our patient likely acquired PCT from the combined risks of HCV and his heterozygous HFE genetic mutation.

With regard to Mr. M’s treatment, the use of an antiviral agent in the treatment of his HCV is fundamental, along with avoidance of alcohol and smoking. If he were to accept HCV treatment, we would anticipate resolution of the PCT, but the ongoing progression of his liver and cardiovascular conditions, due perhaps in part, to relative iron overload from his heterozygous HFE mutation. In this situation, we expect that an ongoing course of therapeutic phlebotomy could help to delay the progression of his chronic liver and cardiovascular diseases.

Sporadic porphyria cutanea tarda (PCT) is the most common cause of porphyria worldwide.^1,2 Unlike other forms of porphyria, PCT usually is an acquired disease precipitated by extrinsic risk factors that commonly include excessive alcohol consumption, smoking, and chronic hepatitis C virus (HCV) infection. Additional risk factors include myeloproliferative disorders, exposure to polyhalogenated compounds, estrogen therapy, diseases of iron overload like hereditary hemochromatosis (HH), and potentially, HIV infection.^1-3

In this case report, we present a patient with an iron overload (due in part to an HFE gene mutation) and concomitant PCT, HCV infection, and coronary artery disease (CAD). We will discuss the relationship that his iron overload may play in each of these disease states.

Case Presentation

Mr. M is a 59-year-old white male of Irish background with a medical history that includes coronary artery disease. He is status post ST-elevation myocardial infarction and percutaneous coronary intervention with placement of 2 drug-eluting stents. Additional medical issues include PCT and HCV infection with cirrhosis. He is an active smoker.

The patient has a long history of developing blisters with minor trauma, such as rubbing against his mattress/bed sheets or bumping into doors. These blisters primarily occur on his upper extremities, but also can occur on his face after shaving. Mr. M was diagnosed with HCV infection in 1979 while on active military duty. At that time, he had an acute HCV infection and jaundice that required a prolonged hospitalization. He reported no IV drug use and that many others on his military base had similar manifestations. He drinks 1 to 2 beers daily, but reports no binge drinking.

Porphyria Cutanea Tarda

The pathogenesis of PCT is related to the intrahepatic deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme in the heme biosynthetic pathway (Figure 1). Decreased activity of UROD leads to accumulation of uroporphyrinogen and its derivatives, which most likely are oxidized in presence of cytochrome P450 1A2. Up to 80% of PCT cases are sporadic, in which the deficiency of UROD is acquired by exogenous risk factors as mentioned above. However, the remaining 20% of PCT cases are due to an autosomal dominant mutation of UROD that causes the partial deficiency (up to 50%) of UROD. In these cases, additional risk factors are needed to decrease UROD activity to < 75% for symptoms to occur.

Clinical Manifestation

Patients with PCT typically develop blisters, skin fragility, and peeling with sun exposure or minor trauma. They also may experience delayed wound healing in sun-exposed skin.³ The photosensitivity of PCT is believed to be related to the saturation of highly carboxylated uroporphyrins in the liver, which are then released into the circulation. Sun exposure then activates these products facilitating an immune reaction and subsequent skin damage.² In chronic cases, fibrotic reactions and scaring occur which can be mistaken for scleroderma. Other skin manifestations include hyperpigmentation, hypertrichosis, alopecia due to scaring and purplish heliotrope suffusion of periorbital areas.

Patients can develop cirrhosis due to accumulation of porphyria in the hepatocytes and subsequent parenchymal damage. Hepatocellular carcinoma surveillance is recommended for patients with PCT, although its incidence is rare in those patients.

Diagnosis and Treatment

PCT is mainly a clinical diagnosis. Physicians should consider PCT in patients with photosensitivity and blisters after minor trauma (Figure 2). The urine of a patient with PCT is often pink or red when exposed to air or light due to its high concentration of porphyrin products. Mild elevation of liver enzymes and fatty liver on ultrasound are also noted. Evidence of iron overload is seen in most cases. Screening for risk factors like HCV, HIV, hepatitis B virus, and HH is recommended. Confirmation of PCT typically requires measurement of the porphyria level in a 24-hour urine collection.

Avoiding sun exposure is fundamental in decreasing the development of skin lesions and scaring. Additionally, patients should be advised about the adverse effects of alcohol, smoking, and estrogen therapy on PCT. Treatment of PCT is frequently focused on iron overload and subsequent increased porphyrin oxidation.^1,2 Iron can increase reactive oxygen species (ROS), which, in turn, increases the rate of oxidation of uroporphyrinogens. Excess iron also decreases the activity of UROD and increases δ-aminolevulinic acid (ALA) production (the precursor of uroporphyrinogen). Phlebotomy to treat iron overload should be done to a target ferritin level of 20 ng/mL. Clinical manifestations, including skin lesions, typically will normalize before the laboratory findings. Therapeutic remission is expected after 6 to 7 phlebotomy attempts, while clinical improvement can occur after 2 to 3 phlebotomies.

In addition to phlebotomy, 4-aminoquinoline medications (chloroquine and hydroxychloroquine) can be used effectively to treat PCT. Hydroxychloroquine is generally preferred due to its better safety profile. Although the exact mechanism of action of 4-aminoquinolines is not clear, it has been suggested that they bind to porphyrins and form water-soluble products, which are then excreted in the urine. Again, clinical remission occurs much sooner than chemical remission, (3 months vs 12 months). A 4-aminoquinoline should not be used in patients with severe liver disease, renal insufficiency, pregnancy, or G6PD deficiency. When used, they should be used in lower than typical doses due to the rapid removal of accumulated porphyrin from the hepatocytes potentially causing necrosis and acute hepatitis.

Iron chelation also is effective, but it is slower in achieving remission and more expensive than phlebotomy. Treatment of PCT should be individualized. For example, 4-aminoquinolines are contraindicated for patients with end-stage renal disease (ESRD), while phlebotomy could present a problem for patients with preexisting anemia. In this instance, removing 50 cc of blood every 2 weeks may be safe and effective. Furthermore, 4-aminoquinolines in patients with severe iron overload and phlebotomy have been used together. Plasmapheresis is still another option in patients with ESRD.

The use of direct antiviral agents (DAA) in the treatment of HCV has shown promising results in maintaining undetectable viral loads and concurrent remission of PCT. Several studies have shown that treatment of HCV with a DAA obviates the need for treatment PCT.^3-5 Treatment of HCV with interferon (IFN) and ribavirin have shown mixed results in controlling PCT, possibly due to their ineffectiveness in maintaining a suppressed viral load. Some studies even showed worsening of PCT with IFN/ribavirin.⁶

Hemochromatosis

Human cells need iron for aerobic respiration. The intestinal mucosa controls iron uptake and its transfer to the blood stream. Aside from variations in intestinal absorption with fecal excretion, humans do not have another pathway to excrete excess iron. HH is the most common genetic disorder in whites.⁷ It is an autosomal recessive disorder that increases the intestinal absorption of iron. The most common mutation in the hemochromatosis (HFE) gene results in a substitution of tyrosine for cysteine at amino acid number 282 and is referred to as the C282Y mutation. A second mutation changes histidine at position 63 to aspartic acid and is referred to as a H63D mutation. H63D is present in a minority of the patients with phenotypically expressed HH and its clinical impact is unknown.

Homozygosity of the C282Y mutation is the most common genotype associated with clinical hemochromatosis. While carriers of the C282Y gene heterozygote mutation typically do not develop enough iron overload to cause clinical hemochromatosis, they can if other risk factors, such as PCT, excess alcohol use, liver disease, or HCV, are present.⁸ Additionally, an associated genetic defect, like a compound heterozygotes C282Y/H63D mutation, a private HFE mutation in trans, or other iron-related genes, can cause manifestations of iron overload. Lastly, about 20% of patients that are heterozygous for both mutations can express the HH phenotype.⁸

Clinical Manifestation

Patients with HH absorb only a few extra milligrams of iron daily. The clinical manifestation begins to occur when the total body iron store reaches 15-40 g (normal, 4 g). While the genetic mutation is present from birth, iron stores start to rise slowly to around 10 g > age 15 years, at which point serum iron levels are elevated. After age 20 years, the speed with which the iron is stored increases, and by 30 years, liver damage and tissue injury will occur. Cirrhosis is possible by 40 years.⁷ Age, sex, dietary iron intake, blood loss (menstruation), pregnancy, and other unknown factors greatly influence the disease progression. Homozygote C282Y mutation is as common in women as it is in men, but women are less likely to express the HH phenotype, presumably due, in part, to menstruation. When diagnosed early, most of the clinical manifestations of HH are preventable. Additional manifestations of HH include hyperpigmentation, cardiomyopathy, diabetes mellitus, hypogonadism, hypothyroidism, and arthropathy due to pseudogout.

Iron overload due to HH should be distinguished from other causes of iron overload including exogenous iron overload, anemia (thalassemia, sideroblastic), and chronic liver diseases like PCT, viral hepatitis, nonalcoholic steatohepatitis, and alcoholic liver disease.

Diagnosis

HH should be suspected in patients with a high serum transferrin saturation and elevated serum ferritin concentrations. Typically, transferrin saturation is > 50% and ferritin levels are > 300 ng/mL in men and > 200 ng/mL in women. In early stages of the disease, transferrin saturation can be normal. Additionally, in patients with chronic inflammation, ferritin may be high due to acute-phase reactants and the iron panel should be interpreted with caution. When the secondary causes of abnormalities in a patient’s iron studies are excluded, genetic testing for HFE gene is recommended.

The majority of patients (60-93%) with clinically evident hemochromatosis are homozygous for C282Y mutation. In a heterozygous C282Y mutation with a high transferrin saturation and HH phenotype, additional genetic testing for a heterozygous compound mutation C282Y/H63D is recommended.⁸ Additional studies could include evaluation for a private HFE mutation in trans or other iron-related genes. Liver biopsy is the gold standard for assessing the degree of hepatic fibrosis. Determining the degree of fibrosis by some means is needed due to the increased risk of hepatocellular carcinoma (HCC) in HH patients with advanced fibrosis and cirrhosis.⁹

Treatment

Iron depletion with phlebotomy is the cornerstone of treatment in HH. Phlebotomy initially is done weekly with goal of achieving a transferrin saturation < 50%, a serum ferritin level < 50 ng/mL, and a hemoglobin of 12 to 13 ng/mL. When these goals are achieved, patients typically need 4 to 8 phlebotomies per year to maintain a transferrin saturation < 50% (Figure 3).

Hemochromatosis and PCT

Many studies have investigated the relevance of C282Y and/or H63D mutations in patients with PCT.^9,10 It appears that ≥ 1 mutation of the HFE gene in PCT may be an important susceptibility factor in the development of clinical PCT. Various studies have shown an incidence of C282Y mutations of 44 to 47% in patients with PCT, compared with 9 to 12% in control populations.^9,10 The incidence of the H63D mutation in PCT has been more variable, with some studies showing no difference between patients with PCT and a control group, while other studies showed 31% incidence of H63D mutation in patients with PCT.^9,10 A higher incidence of C282Y and H63D mutations in PCT may be a sign that the HFE mutation could be an important factor in developing PCT.

Hemochromatosis and Hepatitis C

Transferrin saturation is frequently elevated in patients with HCV. It is yet unclear whether the pathology of liver disease in patients with HCV is influenced by iron overload or limited to the direct cell damage from replication of the virus and subsequent inflammation. It is believed that the pathology of iron overload in the patients with HCV is different from HH. Like other secondary causes of iron overload, the excess iron is stored in the Kupffer cells of patients with HCV. In HH, excess iron is stored in hepatocytes.

The prevalence of the HFE mutation is the same in the patients with chronic HCV and healthy individuals.^10,11 However, HFE mutations are more prevalent in 30 to 60% of the patients with chronic HCV who have elevated transferrin saturations. Alone, C282Y heterozygosity, H63D heterozygosity, or C282Y/H63D compound heterozygosity could not lead to clinically significant iron overload in otherwise healthy individuals; however, these could be a significant cause of iron overload in patients with chronic HCV. Theoretically, the combination of iron overload and HFE gene mutations could increase the rate of advanced fibrosis/cirrhosis in chronic HCV. An increase serum ferritin level of 200 ng/dL in women and 250 ng/dL in men has been observed in 32% of patients with chronic HCV. In this subset of patients, phlebotomy reduced the progression of their liver disease and reduction in their liver enzymes.

Iron Overload and Cardiovascular Risk

In 1987, a Framingham cohort of > 2,800 patients showed a higher incident of CAD in postmenopausal women when compared with premenopausal women.¹² In the 1980s, Sullivan hypothesized that the reason for higher incidence of CAD in men when compared with premenopausal women was due to their higher body iron storage.^13-16 A study of 1,930 Finnish men reported that the men with ferritin level ≥ 200 ng/dL had a risk 2.2 times higher of acute myocardial infarction when compared to men with lower serum ferritin level.¹⁷

A prospective study published in 1997 by Klechl showed the role of iron stores in early atherogenesis via promotion of lipid oxidation.¹⁸ Other epidemiological studies have shown a decreased risk of myocardial infarction in blood donors, and while arguments have been made that the blood donors tend to be healthier individuals, 2 studies were published in 1997 matching healthy blood donors to healthy nonblood donors, and both showed a lower risk of CVD in the donors when compared with nondonors.^19,20 Furthermore, in an animal model of atherosclerosis, an iron depleted diet showed a reduction of atherosclerosis progression.²¹ Multiple studies have shown that the heterozygosity for HFE is significantly linked to the risk of cardiovascular events, including the fact that heterozygosity for C282Y has been shown to be a risk factor for myocardial infarction in men and cerebrovascular death in women.^22-25

Conclusion

Multiple studies have shown an association between the elevated iron levels associated with the HFE genotype and the disease states of our patient. These include an increased risk of CAD, the increased risk of cirrhosis in HCV and the development of PCT. Indeed, in this case, our patient likely acquired PCT from the combined risks of HCV and his heterozygous HFE genetic mutation.

With regard to Mr. M’s treatment, the use of an antiviral agent in the treatment of his HCV is fundamental, along with avoidance of alcohol and smoking. If he were to accept HCV treatment, we would anticipate resolution of the PCT, but the ongoing progression of his liver and cardiovascular conditions, due perhaps in part, to relative iron overload from his heterozygous HFE mutation. In this situation, we expect that an ongoing course of therapeutic phlebotomy could help to delay the progression of his chronic liver and cardiovascular diseases.

Sporadic porphyria cutanea tarda (PCT) is the most common cause of porphyria worldwide.^1,2 Unlike other forms of porphyria, PCT usually is an acquired disease precipitated by extrinsic risk factors that commonly include excessive alcohol consumption, smoking, and chronic hepatitis C virus (HCV) infection. Additional risk factors include myeloproliferative disorders, exposure to polyhalogenated compounds, estrogen therapy, diseases of iron overload like hereditary hemochromatosis (HH), and potentially, HIV infection.^1-3

In this case report, we present a patient with an iron overload (due in part to an HFE gene mutation) and concomitant PCT, HCV infection, and coronary artery disease (CAD). We will discuss the relationship that his iron overload may play in each of these disease states.

Case Presentation

Mr. M is a 59-year-old white male of Irish background with a medical history that includes coronary artery disease. He is status post ST-elevation myocardial infarction and percutaneous coronary intervention with placement of 2 drug-eluting stents. Additional medical issues include PCT and HCV infection with cirrhosis. He is an active smoker.

The patient has a long history of developing blisters with minor trauma, such as rubbing against his mattress/bed sheets or bumping into doors. These blisters primarily occur on his upper extremities, but also can occur on his face after shaving. Mr. M was diagnosed with HCV infection in 1979 while on active military duty. At that time, he had an acute HCV infection and jaundice that required a prolonged hospitalization. He reported no IV drug use and that many others on his military base had similar manifestations. He drinks 1 to 2 beers daily, but reports no binge drinking.

Porphyria Cutanea Tarda

The pathogenesis of PCT is related to the intrahepatic deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme in the heme biosynthetic pathway (Figure 1). Decreased activity of UROD leads to accumulation of uroporphyrinogen and its derivatives, which most likely are oxidized in presence of cytochrome P450 1A2. Up to 80% of PCT cases are sporadic, in which the deficiency of UROD is acquired by exogenous risk factors as mentioned above. However, the remaining 20% of PCT cases are due to an autosomal dominant mutation of UROD that causes the partial deficiency (up to 50%) of UROD. In these cases, additional risk factors are needed to decrease UROD activity to < 75% for symptoms to occur.

Clinical Manifestation

Patients with PCT typically develop blisters, skin fragility, and peeling with sun exposure or minor trauma. They also may experience delayed wound healing in sun-exposed skin.³ The photosensitivity of PCT is believed to be related to the saturation of highly carboxylated uroporphyrins in the liver, which are then released into the circulation. Sun exposure then activates these products facilitating an immune reaction and subsequent skin damage.² In chronic cases, fibrotic reactions and scaring occur which can be mistaken for scleroderma. Other skin manifestations include hyperpigmentation, hypertrichosis, alopecia due to scaring and purplish heliotrope suffusion of periorbital areas.

Patients can develop cirrhosis due to accumulation of porphyria in the hepatocytes and subsequent parenchymal damage. Hepatocellular carcinoma surveillance is recommended for patients with PCT, although its incidence is rare in those patients.

Diagnosis and Treatment

PCT is mainly a clinical diagnosis. Physicians should consider PCT in patients with photosensitivity and blisters after minor trauma (Figure 2). The urine of a patient with PCT is often pink or red when exposed to air or light due to its high concentration of porphyrin products. Mild elevation of liver enzymes and fatty liver on ultrasound are also noted. Evidence of iron overload is seen in most cases. Screening for risk factors like HCV, HIV, hepatitis B virus, and HH is recommended. Confirmation of PCT typically requires measurement of the porphyria level in a 24-hour urine collection.

Avoiding sun exposure is fundamental in decreasing the development of skin lesions and scaring. Additionally, patients should be advised about the adverse effects of alcohol, smoking, and estrogen therapy on PCT. Treatment of PCT is frequently focused on iron overload and subsequent increased porphyrin oxidation.^1,2 Iron can increase reactive oxygen species (ROS), which, in turn, increases the rate of oxidation of uroporphyrinogens. Excess iron also decreases the activity of UROD and increases δ-aminolevulinic acid (ALA) production (the precursor of uroporphyrinogen). Phlebotomy to treat iron overload should be done to a target ferritin level of 20 ng/mL. Clinical manifestations, including skin lesions, typically will normalize before the laboratory findings. Therapeutic remission is expected after 6 to 7 phlebotomy attempts, while clinical improvement can occur after 2 to 3 phlebotomies.

In addition to phlebotomy, 4-aminoquinoline medications (chloroquine and hydroxychloroquine) can be used effectively to treat PCT. Hydroxychloroquine is generally preferred due to its better safety profile. Although the exact mechanism of action of 4-aminoquinolines is not clear, it has been suggested that they bind to porphyrins and form water-soluble products, which are then excreted in the urine. Again, clinical remission occurs much sooner than chemical remission, (3 months vs 12 months). A 4-aminoquinoline should not be used in patients with severe liver disease, renal insufficiency, pregnancy, or G6PD deficiency. When used, they should be used in lower than typical doses due to the rapid removal of accumulated porphyrin from the hepatocytes potentially causing necrosis and acute hepatitis.

Iron chelation also is effective, but it is slower in achieving remission and more expensive than phlebotomy. Treatment of PCT should be individualized. For example, 4-aminoquinolines are contraindicated for patients with end-stage renal disease (ESRD), while phlebotomy could present a problem for patients with preexisting anemia. In this instance, removing 50 cc of blood every 2 weeks may be safe and effective. Furthermore, 4-aminoquinolines in patients with severe iron overload and phlebotomy have been used together. Plasmapheresis is still another option in patients with ESRD.

The use of direct antiviral agents (DAA) in the treatment of HCV has shown promising results in maintaining undetectable viral loads and concurrent remission of PCT. Several studies have shown that treatment of HCV with a DAA obviates the need for treatment PCT.^3-5 Treatment of HCV with interferon (IFN) and ribavirin have shown mixed results in controlling PCT, possibly due to their ineffectiveness in maintaining a suppressed viral load. Some studies even showed worsening of PCT with IFN/ribavirin.⁶

Hemochromatosis

Human cells need iron for aerobic respiration. The intestinal mucosa controls iron uptake and its transfer to the blood stream. Aside from variations in intestinal absorption with fecal excretion, humans do not have another pathway to excrete excess iron. HH is the most common genetic disorder in whites.⁷ It is an autosomal recessive disorder that increases the intestinal absorption of iron. The most common mutation in the hemochromatosis (HFE) gene results in a substitution of tyrosine for cysteine at amino acid number 282 and is referred to as the C282Y mutation. A second mutation changes histidine at position 63 to aspartic acid and is referred to as a H63D mutation. H63D is present in a minority of the patients with phenotypically expressed HH and its clinical impact is unknown.

Homozygosity of the C282Y mutation is the most common genotype associated with clinical hemochromatosis. While carriers of the C282Y gene heterozygote mutation typically do not develop enough iron overload to cause clinical hemochromatosis, they can if other risk factors, such as PCT, excess alcohol use, liver disease, or HCV, are present.⁸ Additionally, an associated genetic defect, like a compound heterozygotes C282Y/H63D mutation, a private HFE mutation in trans, or other iron-related genes, can cause manifestations of iron overload. Lastly, about 20% of patients that are heterozygous for both mutations can express the HH phenotype.⁸

Clinical Manifestation

Patients with HH absorb only a few extra milligrams of iron daily. The clinical manifestation begins to occur when the total body iron store reaches 15-40 g (normal, 4 g). While the genetic mutation is present from birth, iron stores start to rise slowly to around 10 g > age 15 years, at which point serum iron levels are elevated. After age 20 years, the speed with which the iron is stored increases, and by 30 years, liver damage and tissue injury will occur. Cirrhosis is possible by 40 years.⁷ Age, sex, dietary iron intake, blood loss (menstruation), pregnancy, and other unknown factors greatly influence the disease progression. Homozygote C282Y mutation is as common in women as it is in men, but women are less likely to express the HH phenotype, presumably due, in part, to menstruation. When diagnosed early, most of the clinical manifestations of HH are preventable. Additional manifestations of HH include hyperpigmentation, cardiomyopathy, diabetes mellitus, hypogonadism, hypothyroidism, and arthropathy due to pseudogout.

Iron overload due to HH should be distinguished from other causes of iron overload including exogenous iron overload, anemia (thalassemia, sideroblastic), and chronic liver diseases like PCT, viral hepatitis, nonalcoholic steatohepatitis, and alcoholic liver disease.

Diagnosis

HH should be suspected in patients with a high serum transferrin saturation and elevated serum ferritin concentrations. Typically, transferrin saturation is > 50% and ferritin levels are > 300 ng/mL in men and > 200 ng/mL in women. In early stages of the disease, transferrin saturation can be normal. Additionally, in patients with chronic inflammation, ferritin may be high due to acute-phase reactants and the iron panel should be interpreted with caution. When the secondary causes of abnormalities in a patient’s iron studies are excluded, genetic testing for HFE gene is recommended.

The majority of patients (60-93%) with clinically evident hemochromatosis are homozygous for C282Y mutation. In a heterozygous C282Y mutation with a high transferrin saturation and HH phenotype, additional genetic testing for a heterozygous compound mutation C282Y/H63D is recommended.⁸ Additional studies could include evaluation for a private HFE mutation in trans or other iron-related genes. Liver biopsy is the gold standard for assessing the degree of hepatic fibrosis. Determining the degree of fibrosis by some means is needed due to the increased risk of hepatocellular carcinoma (HCC) in HH patients with advanced fibrosis and cirrhosis.⁹

Treatment

Iron depletion with phlebotomy is the cornerstone of treatment in HH. Phlebotomy initially is done weekly with goal of achieving a transferrin saturation < 50%, a serum ferritin level < 50 ng/mL, and a hemoglobin of 12 to 13 ng/mL. When these goals are achieved, patients typically need 4 to 8 phlebotomies per year to maintain a transferrin saturation < 50% (Figure 3).

Hemochromatosis and PCT

Many studies have investigated the relevance of C282Y and/or H63D mutations in patients with PCT.^9,10 It appears that ≥ 1 mutation of the HFE gene in PCT may be an important susceptibility factor in the development of clinical PCT. Various studies have shown an incidence of C282Y mutations of 44 to 47% in patients with PCT, compared with 9 to 12% in control populations.^9,10 The incidence of the H63D mutation in PCT has been more variable, with some studies showing no difference between patients with PCT and a control group, while other studies showed 31% incidence of H63D mutation in patients with PCT.^9,10 A higher incidence of C282Y and H63D mutations in PCT may be a sign that the HFE mutation could be an important factor in developing PCT.

Hemochromatosis and Hepatitis C

Transferrin saturation is frequently elevated in patients with HCV. It is yet unclear whether the pathology of liver disease in patients with HCV is influenced by iron overload or limited to the direct cell damage from replication of the virus and subsequent inflammation. It is believed that the pathology of iron overload in the patients with HCV is different from HH. Like other secondary causes of iron overload, the excess iron is stored in the Kupffer cells of patients with HCV. In HH, excess iron is stored in hepatocytes.

The prevalence of the HFE mutation is the same in the patients with chronic HCV and healthy individuals.^10,11 However, HFE mutations are more prevalent in 30 to 60% of the patients with chronic HCV who have elevated transferrin saturations. Alone, C282Y heterozygosity, H63D heterozygosity, or C282Y/H63D compound heterozygosity could not lead to clinically significant iron overload in otherwise healthy individuals; however, these could be a significant cause of iron overload in patients with chronic HCV. Theoretically, the combination of iron overload and HFE gene mutations could increase the rate of advanced fibrosis/cirrhosis in chronic HCV. An increase serum ferritin level of 200 ng/dL in women and 250 ng/dL in men has been observed in 32% of patients with chronic HCV. In this subset of patients, phlebotomy reduced the progression of their liver disease and reduction in their liver enzymes.

Iron Overload and Cardiovascular Risk

In 1987, a Framingham cohort of > 2,800 patients showed a higher incident of CAD in postmenopausal women when compared with premenopausal women.¹² In the 1980s, Sullivan hypothesized that the reason for higher incidence of CAD in men when compared with premenopausal women was due to their higher body iron storage.^13-16 A study of 1,930 Finnish men reported that the men with ferritin level ≥ 200 ng/dL had a risk 2.2 times higher of acute myocardial infarction when compared to men with lower serum ferritin level.¹⁷

A prospective study published in 1997 by Klechl showed the role of iron stores in early atherogenesis via promotion of lipid oxidation.¹⁸ Other epidemiological studies have shown a decreased risk of myocardial infarction in blood donors, and while arguments have been made that the blood donors tend to be healthier individuals, 2 studies were published in 1997 matching healthy blood donors to healthy nonblood donors, and both showed a lower risk of CVD in the donors when compared with nondonors.^19,20 Furthermore, in an animal model of atherosclerosis, an iron depleted diet showed a reduction of atherosclerosis progression.²¹ Multiple studies have shown that the heterozygosity for HFE is significantly linked to the risk of cardiovascular events, including the fact that heterozygosity for C282Y has been shown to be a risk factor for myocardial infarction in men and cerebrovascular death in women.^22-25

Conclusion

Multiple studies have shown an association between the elevated iron levels associated with the HFE genotype and the disease states of our patient. These include an increased risk of CAD, the increased risk of cirrhosis in HCV and the development of PCT. Indeed, in this case, our patient likely acquired PCT from the combined risks of HCV and his heterozygous HFE genetic mutation.

With regard to Mr. M’s treatment, the use of an antiviral agent in the treatment of his HCV is fundamental, along with avoidance of alcohol and smoking. If he were to accept HCV treatment, we would anticipate resolution of the PCT, but the ongoing progression of his liver and cardiovascular conditions, due perhaps in part, to relative iron overload from his heterozygous HFE mutation. In this situation, we expect that an ongoing course of therapeutic phlebotomy could help to delay the progression of his chronic liver and cardiovascular diseases.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

Amid the rising spread of the 2019 Novel Coronavirus (2019-nCoV), the World Health Organization (WHO) has declared the virus outbreak a public health emergency of international concern (PHEIC).

WHO.int

The declaration was made during a press briefing on Jan. 30 after a week of growing concern and pressure on WHO to designate the virus at a higher emergency level. WHO’s Emergency Committee made the nearly unanimous decision after considering the increasing number of coronavirus cases in China, the rising infections outside of China, and the questionable measures some countries are taking regarding travel, said committee chair Didier Houssin, MD, said during the press conference.

As of Jan. 30, there were 8,236 confirmed cases of the coronavirus in China and 171 deaths, with another 112 cases identified outside of China in 21 other countries.

“Declaring a Public Health Emergency of International Concern is likely to facilitate [WHO’s] leadership role for public health measures, holding countries to account concerning additional measures they may take regarding travel, trade, quarantine or screening, research efforts, global coordination and anticipation of economic impact [and] support to vulnerable states,” Dr. Houssin said during the press conference. “Declaring a PHEIC should certainly not be seen as manifestation of distrust in the Chinese authorities and people which are doing tremendous efforts on the frontlines of this outbreak, with transparency, and let us hope, with success.”
 

What happens next?

Once a PHEIC is declared, WHO launches a series of steps, including the release of temporary recommendations for the affected country on health measures to implement and guidance for other countries on preventing and reducing the international spread of the disease, WHO spokesman Tarik Jasarevic said in an interview.

“The purpose of declaring a PHEIC is to advise the world on what measures need to be taken to enhance global health security by preventing international transmission of an infectious hazard,” he said.

Following the Jan. 30 press conference, WHO released temporary guidance for China and for other countries regarding identifying, managing, containing, and preventing the virus. China is advised to continue updating the population about the outbreak, continue enhancing its public health measures for containment and surveillance of cases, and to continue collaboration with WHO and other partners to investigate the epidemiology and evolution of the outbreak and share data on all human cases.

Other countries should be prepared for containment, including the active surveillance, early detection, isolation, case management, and prevention of virus transmission and to share full data with WHO, according to the recommendations.

Under the International Health Regulations (IHR), countries are required to share information and data with WHO. Additionally, WHO leaders advised the global community to support low- and middle-income countries with their response to the coronavirus and to facilitate diagnostics, potential vaccines, and therapeutics in these areas.

The IHR requires that countries implementing health measures that go beyond what WHO recommends must send to WHO the public health rationale and justification within 48 hours of their implementation for WHO review, Mr. Jasarevic noted.

“WHO is obliged to share the information about measures and the justification received with other countries involved,” he said.
 

PHEIC travel and resource impact

Declaration of a PHEIC means WHO will now oversee any travel restrictions made by other countries in response to 2019-nCoV. The agency recommends that countries conduct a risk and cost-benefit analysis before enacting travel restrictions and other countries are required to inform WHO about any travel measures taken.

“Countries will be asked to provide public health justification for any travel or trade measures that are not scientifically based, such as refusal of entry of suspect cases or unaffected persons to affected areas,” Mr. Jasarevic said in an interview.

As far as resources, the PHEIC mechanism is not a fundraising mechanism, but some donors might consider a PHEIC declaration as a trigger for releasing additional funding to respond to the health threat, he said.

Allison T. Chamberlain, PhD, acting director for the Emory Center for Public Health Preparedness and Research at the Emory Rollins School of Public Health in Atlanta, said national governments and nongovernmental aid organizations are among the most affected by a PHEIC because they are looked at to provide assistance to the most heavily affected areas and to bolster public health preparedness within their own borders.

“In terms of resources that are deployed, a Public Health Emergency of International Concern raises levels of international support and commitment to stopping the emergency,” Dr. Chamberlain said in an interview. “By doing so, it gives countries the needed flexibility to release financial resources of their own accord to support things like response teams that might go into heavily affected areas to assist, for instance.”

WHO Director-General Dr. Tedros Adhanom Ghebreyesus stressed that cooperation among countries is key during the PHEIC.

“We can only stop it together,” he said during the press conference. “This is the time for facts, not fear. This is the time for science, not rumors. This is the time for solidarity, not stigma.”

This is the sixth PHEIC declared by WHO in the last 10 years. Such declarations were made for the 2009 H1NI influenza pandemic, the 2014 polio resurgence, the 2014 Ebola outbreak in West Africa, the 2016 Zika virus, and the 2019 Kivu Ebola outbreak in the Democratic Republic of Congo.

[email protected]

Amid the rising spread of the 2019 Novel Coronavirus (2019-nCoV), the World Health Organization (WHO) has declared the virus outbreak a public health emergency of international concern (PHEIC).

WHO.int

The declaration was made during a press briefing on Jan. 30 after a week of growing concern and pressure on WHO to designate the virus at a higher emergency level. WHO’s Emergency Committee made the nearly unanimous decision after considering the increasing number of coronavirus cases in China, the rising infections outside of China, and the questionable measures some countries are taking regarding travel, said committee chair Didier Houssin, MD, said during the press conference.

As of Jan. 30, there were 8,236 confirmed cases of the coronavirus in China and 171 deaths, with another 112 cases identified outside of China in 21 other countries.

“Declaring a Public Health Emergency of International Concern is likely to facilitate [WHO’s] leadership role for public health measures, holding countries to account concerning additional measures they may take regarding travel, trade, quarantine or screening, research efforts, global coordination and anticipation of economic impact [and] support to vulnerable states,” Dr. Houssin said during the press conference. “Declaring a PHEIC should certainly not be seen as manifestation of distrust in the Chinese authorities and people which are doing tremendous efforts on the frontlines of this outbreak, with transparency, and let us hope, with success.”
 

What happens next?

Once a PHEIC is declared, WHO launches a series of steps, including the release of temporary recommendations for the affected country on health measures to implement and guidance for other countries on preventing and reducing the international spread of the disease, WHO spokesman Tarik Jasarevic said in an interview.

“The purpose of declaring a PHEIC is to advise the world on what measures need to be taken to enhance global health security by preventing international transmission of an infectious hazard,” he said.

Following the Jan. 30 press conference, WHO released temporary guidance for China and for other countries regarding identifying, managing, containing, and preventing the virus. China is advised to continue updating the population about the outbreak, continue enhancing its public health measures for containment and surveillance of cases, and to continue collaboration with WHO and other partners to investigate the epidemiology and evolution of the outbreak and share data on all human cases.

Other countries should be prepared for containment, including the active surveillance, early detection, isolation, case management, and prevention of virus transmission and to share full data with WHO, according to the recommendations.

Under the International Health Regulations (IHR), countries are required to share information and data with WHO. Additionally, WHO leaders advised the global community to support low- and middle-income countries with their response to the coronavirus and to facilitate diagnostics, potential vaccines, and therapeutics in these areas.

The IHR requires that countries implementing health measures that go beyond what WHO recommends must send to WHO the public health rationale and justification within 48 hours of their implementation for WHO review, Mr. Jasarevic noted.

“WHO is obliged to share the information about measures and the justification received with other countries involved,” he said.
 

PHEIC travel and resource impact

Declaration of a PHEIC means WHO will now oversee any travel restrictions made by other countries in response to 2019-nCoV. The agency recommends that countries conduct a risk and cost-benefit analysis before enacting travel restrictions and other countries are required to inform WHO about any travel measures taken.

“Countries will be asked to provide public health justification for any travel or trade measures that are not scientifically based, such as refusal of entry of suspect cases or unaffected persons to affected areas,” Mr. Jasarevic said in an interview.

As far as resources, the PHEIC mechanism is not a fundraising mechanism, but some donors might consider a PHEIC declaration as a trigger for releasing additional funding to respond to the health threat, he said.

Allison T. Chamberlain, PhD, acting director for the Emory Center for Public Health Preparedness and Research at the Emory Rollins School of Public Health in Atlanta, said national governments and nongovernmental aid organizations are among the most affected by a PHEIC because they are looked at to provide assistance to the most heavily affected areas and to bolster public health preparedness within their own borders.

“In terms of resources that are deployed, a Public Health Emergency of International Concern raises levels of international support and commitment to stopping the emergency,” Dr. Chamberlain said in an interview. “By doing so, it gives countries the needed flexibility to release financial resources of their own accord to support things like response teams that might go into heavily affected areas to assist, for instance.”

WHO Director-General Dr. Tedros Adhanom Ghebreyesus stressed that cooperation among countries is key during the PHEIC.

“We can only stop it together,” he said during the press conference. “This is the time for facts, not fear. This is the time for science, not rumors. This is the time for solidarity, not stigma.”

This is the sixth PHEIC declared by WHO in the last 10 years. Such declarations were made for the 2009 H1NI influenza pandemic, the 2014 polio resurgence, the 2014 Ebola outbreak in West Africa, the 2016 Zika virus, and the 2019 Kivu Ebola outbreak in the Democratic Republic of Congo.

[email protected]

Amid the rising spread of the 2019 Novel Coronavirus (2019-nCoV), the World Health Organization (WHO) has declared the virus outbreak a public health emergency of international concern (PHEIC).

WHO.int

The declaration was made during a press briefing on Jan. 30 after a week of growing concern and pressure on WHO to designate the virus at a higher emergency level. WHO’s Emergency Committee made the nearly unanimous decision after considering the increasing number of coronavirus cases in China, the rising infections outside of China, and the questionable measures some countries are taking regarding travel, said committee chair Didier Houssin, MD, said during the press conference.

As of Jan. 30, there were 8,236 confirmed cases of the coronavirus in China and 171 deaths, with another 112 cases identified outside of China in 21 other countries.

“Declaring a Public Health Emergency of International Concern is likely to facilitate [WHO’s] leadership role for public health measures, holding countries to account concerning additional measures they may take regarding travel, trade, quarantine or screening, research efforts, global coordination and anticipation of economic impact [and] support to vulnerable states,” Dr. Houssin said during the press conference. “Declaring a PHEIC should certainly not be seen as manifestation of distrust in the Chinese authorities and people which are doing tremendous efforts on the frontlines of this outbreak, with transparency, and let us hope, with success.”
 

What happens next?

Once a PHEIC is declared, WHO launches a series of steps, including the release of temporary recommendations for the affected country on health measures to implement and guidance for other countries on preventing and reducing the international spread of the disease, WHO spokesman Tarik Jasarevic said in an interview.

“The purpose of declaring a PHEIC is to advise the world on what measures need to be taken to enhance global health security by preventing international transmission of an infectious hazard,” he said.

Following the Jan. 30 press conference, WHO released temporary guidance for China and for other countries regarding identifying, managing, containing, and preventing the virus. China is advised to continue updating the population about the outbreak, continue enhancing its public health measures for containment and surveillance of cases, and to continue collaboration with WHO and other partners to investigate the epidemiology and evolution of the outbreak and share data on all human cases.

Other countries should be prepared for containment, including the active surveillance, early detection, isolation, case management, and prevention of virus transmission and to share full data with WHO, according to the recommendations.

Under the International Health Regulations (IHR), countries are required to share information and data with WHO. Additionally, WHO leaders advised the global community to support low- and middle-income countries with their response to the coronavirus and to facilitate diagnostics, potential vaccines, and therapeutics in these areas.

The IHR requires that countries implementing health measures that go beyond what WHO recommends must send to WHO the public health rationale and justification within 48 hours of their implementation for WHO review, Mr. Jasarevic noted.

“WHO is obliged to share the information about measures and the justification received with other countries involved,” he said.
 

PHEIC travel and resource impact

Declaration of a PHEIC means WHO will now oversee any travel restrictions made by other countries in response to 2019-nCoV. The agency recommends that countries conduct a risk and cost-benefit analysis before enacting travel restrictions and other countries are required to inform WHO about any travel measures taken.

“Countries will be asked to provide public health justification for any travel or trade measures that are not scientifically based, such as refusal of entry of suspect cases or unaffected persons to affected areas,” Mr. Jasarevic said in an interview.

As far as resources, the PHEIC mechanism is not a fundraising mechanism, but some donors might consider a PHEIC declaration as a trigger for releasing additional funding to respond to the health threat, he said.

Allison T. Chamberlain, PhD, acting director for the Emory Center for Public Health Preparedness and Research at the Emory Rollins School of Public Health in Atlanta, said national governments and nongovernmental aid organizations are among the most affected by a PHEIC because they are looked at to provide assistance to the most heavily affected areas and to bolster public health preparedness within their own borders.

“In terms of resources that are deployed, a Public Health Emergency of International Concern raises levels of international support and commitment to stopping the emergency,” Dr. Chamberlain said in an interview. “By doing so, it gives countries the needed flexibility to release financial resources of their own accord to support things like response teams that might go into heavily affected areas to assist, for instance.”

WHO Director-General Dr. Tedros Adhanom Ghebreyesus stressed that cooperation among countries is key during the PHEIC.

“We can only stop it together,” he said during the press conference. “This is the time for facts, not fear. This is the time for science, not rumors. This is the time for solidarity, not stigma.”

This is the sixth PHEIC declared by WHO in the last 10 years. Such declarations were made for the 2009 H1NI influenza pandemic, the 2014 polio resurgence, the 2014 Ebola outbreak in West Africa, the 2016 Zika virus, and the 2019 Kivu Ebola outbreak in the Democratic Republic of Congo.

[email protected]

A Chicago woman in her 60s who tested positive for the 2019 Novel Coronavirus (2019-nCoV) after returning from Wuhan, China, earlier this month has infected her husband, becoming the first known instance of person-to-person transmission of the 2019-nCoV in the United States.

James Gathany/Centers for Disease Control and Prevention

“Limited person-to-person spread of this new virus outside of China has already been seen in nine close contacts, where travelers were infected and transmitted the virus to someone else,” Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention, said during a press briefing on Jan. 30, 2020. “However, the full picture of how easy and how sustainable this virus can spread is unclear. Today’s news underscores the important risk-dependent exposure. The vast majority of Americans have not had recent travel to China, where sustained human-to-human transmission is occurring. Individuals who are close personal contacts of cases, though, could have a risk.”

The affected man, also in his 60s, is the spouse of the first confirmed travel-associated case of 2019-nCoV to be reported in the state of Illinois, according to Ngozi O. Ezike, MD, director of the Illinois Department of Public Health. The man had no history of recent travel to China. “This person-to-person spread was between two very close contacts: a wife and husband,” said Dr. Ezike, who added that 21 individuals in the state are under investigation for 2019-nCoV. “The virus is not spreading widely across the community. At this time, we are not recommending that people in the general public take additional precautions such as canceling activities or avoiding going out. While there is concern with this second case, public health officials are actively monitoring close contacts, including health care workers, and we believe that people in Illinois are at low risk.”

Jennifer Layden, MD, state epidemiologist at the Illinois Department of Public Health, said that the infected Chicago woman returned from Wuhan, China on Jan. 13, 2020. She is hospitalized in stable condition “and continues to do well,” Dr. Layden said. “Public health officials have been actively and closely monitoring individuals who had contacts with her, including her husband, who had close contact for symptoms. He recently began reporting symptoms and was immediately admitted to the hospital and placed in an isolation room, where he is in stable condition. We are actively monitoring individuals such as health care workers, household contacts, and others who were in contact with either of the confirmed cases in the goal to contain and reduce the risk of additional transmission.”

Nancy Messonnier, MD, director, National Center for Immunization and Respiratory Diseases, expects that more cases of 2019-nCoV will transpire in the United States.

“More cases means the potential for more person-to-person spread,” Dr. Messonnier said. “We’re trying to strike a balance in our response right now. We want to be aggressive, but we want our actions to be evidence-based and appropriate for the current circumstance. For example, CDC does not currently recommend use of face masks for the general public. The virus is not spreading in the general community.”

[email protected]

A Chicago woman in her 60s who tested positive for the 2019 Novel Coronavirus (2019-nCoV) after returning from Wuhan, China, earlier this month has infected her husband, becoming the first known instance of person-to-person transmission of the 2019-nCoV in the United States.

James Gathany/Centers for Disease Control and Prevention

“Limited person-to-person spread of this new virus outside of China has already been seen in nine close contacts, where travelers were infected and transmitted the virus to someone else,” Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention, said during a press briefing on Jan. 30, 2020. “However, the full picture of how easy and how sustainable this virus can spread is unclear. Today’s news underscores the important risk-dependent exposure. The vast majority of Americans have not had recent travel to China, where sustained human-to-human transmission is occurring. Individuals who are close personal contacts of cases, though, could have a risk.”

The affected man, also in his 60s, is the spouse of the first confirmed travel-associated case of 2019-nCoV to be reported in the state of Illinois, according to Ngozi O. Ezike, MD, director of the Illinois Department of Public Health. The man had no history of recent travel to China. “This person-to-person spread was between two very close contacts: a wife and husband,” said Dr. Ezike, who added that 21 individuals in the state are under investigation for 2019-nCoV. “The virus is not spreading widely across the community. At this time, we are not recommending that people in the general public take additional precautions such as canceling activities or avoiding going out. While there is concern with this second case, public health officials are actively monitoring close contacts, including health care workers, and we believe that people in Illinois are at low risk.”

Jennifer Layden, MD, state epidemiologist at the Illinois Department of Public Health, said that the infected Chicago woman returned from Wuhan, China on Jan. 13, 2020. She is hospitalized in stable condition “and continues to do well,” Dr. Layden said. “Public health officials have been actively and closely monitoring individuals who had contacts with her, including her husband, who had close contact for symptoms. He recently began reporting symptoms and was immediately admitted to the hospital and placed in an isolation room, where he is in stable condition. We are actively monitoring individuals such as health care workers, household contacts, and others who were in contact with either of the confirmed cases in the goal to contain and reduce the risk of additional transmission.”

Nancy Messonnier, MD, director, National Center for Immunization and Respiratory Diseases, expects that more cases of 2019-nCoV will transpire in the United States.

“More cases means the potential for more person-to-person spread,” Dr. Messonnier said. “We’re trying to strike a balance in our response right now. We want to be aggressive, but we want our actions to be evidence-based and appropriate for the current circumstance. For example, CDC does not currently recommend use of face masks for the general public. The virus is not spreading in the general community.”

[email protected]

A Chicago woman in her 60s who tested positive for the 2019 Novel Coronavirus (2019-nCoV) after returning from Wuhan, China, earlier this month has infected her husband, becoming the first known instance of person-to-person transmission of the 2019-nCoV in the United States.

James Gathany/Centers for Disease Control and Prevention

“Limited person-to-person spread of this new virus outside of China has already been seen in nine close contacts, where travelers were infected and transmitted the virus to someone else,” Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention, said during a press briefing on Jan. 30, 2020. “However, the full picture of how easy and how sustainable this virus can spread is unclear. Today’s news underscores the important risk-dependent exposure. The vast majority of Americans have not had recent travel to China, where sustained human-to-human transmission is occurring. Individuals who are close personal contacts of cases, though, could have a risk.”

The affected man, also in his 60s, is the spouse of the first confirmed travel-associated case of 2019-nCoV to be reported in the state of Illinois, according to Ngozi O. Ezike, MD, director of the Illinois Department of Public Health. The man had no history of recent travel to China. “This person-to-person spread was between two very close contacts: a wife and husband,” said Dr. Ezike, who added that 21 individuals in the state are under investigation for 2019-nCoV. “The virus is not spreading widely across the community. At this time, we are not recommending that people in the general public take additional precautions such as canceling activities or avoiding going out. While there is concern with this second case, public health officials are actively monitoring close contacts, including health care workers, and we believe that people in Illinois are at low risk.”

Jennifer Layden, MD, state epidemiologist at the Illinois Department of Public Health, said that the infected Chicago woman returned from Wuhan, China on Jan. 13, 2020. She is hospitalized in stable condition “and continues to do well,” Dr. Layden said. “Public health officials have been actively and closely monitoring individuals who had contacts with her, including her husband, who had close contact for symptoms. He recently began reporting symptoms and was immediately admitted to the hospital and placed in an isolation room, where he is in stable condition. We are actively monitoring individuals such as health care workers, household contacts, and others who were in contact with either of the confirmed cases in the goal to contain and reduce the risk of additional transmission.”

Nancy Messonnier, MD, director, National Center for Immunization and Respiratory Diseases, expects that more cases of 2019-nCoV will transpire in the United States.

“More cases means the potential for more person-to-person spread,” Dr. Messonnier said. “We’re trying to strike a balance in our response right now. We want to be aggressive, but we want our actions to be evidence-based and appropriate for the current circumstance. For example, CDC does not currently recommend use of face masks for the general public. The virus is not spreading in the general community.”

[email protected]

 What happens to patients at risk for suicide after they leave the emergency department (ED)? According to a new study funded by the National Institute of Mental Health and published in JAMA Network Open, people who presented to California EDs with deliberate self-harm or suicidal ideation were not just at risk for a future suicide—they were at extreme risk.

The researchers divided patients into 3 groups: 83,507 who had deliberately self-harmed with or without co-occurring suicidal ideation; 67,379 presenting with suicidal ideation but without deliberate self-harm; and 497,760 without either self-harm or suicidal ideation.

In the first year after the ED visit, the patients who had presented with deliberate self-harm had a suicide rate almost 57 times higher than that of demographically similar Californians. Among those with suicidal ideation, the suicide rate was about 31 times higher. The suicide rate for the reference group, while the lowest of the 3 groups, was still twice the rate among Californians overall.

The researchers found certain clinical and demographic characteristics predicted subsequent suicide. Men and patients aged > 65 years had higher rates of suicide when compared with women or people aged 10 to 24 years. In all groups, suicide rates were higher for non-Hispanic, white patients.

Comorbid diagnoses were associated with suicide risk but with “striking differences” among the groups, the researchers say. Among patients presenting with deliberate self-harm, those with a comorbid diagnosis of bipolar disorder, anxiety disorder, or a psychotic disorder were more likely to die of suicide. Among reference patients, those with bipolar disorder, depression, or alcohol use disorder had a higher risk.

Of note, the researchers say, patients in the deliberate self-harm group who presented with a firearm-related injury had a subsequent suicide rate of 4.4% in the following year, a far higher rate than that in any other patient group. The researchers urge ED physicians to be aware that patients who present with self-harm who use high-lethality methods at a nonfatal event remain at highly increased risk for future suicide.

To the researchers’ knowledge, this is the first US population-based study to examine 12-month suicide rates after an index ED visit. These findings reinforce the importance of universal screening for suicide risk in EDs and the need for follow-up care, the researchers add, “an approach that has been found to increase the number of ED patients identified as warranting treatment for suicide risk by approximately 2-fold, but which is also not yet widespread.”

 What happens to patients at risk for suicide after they leave the emergency department (ED)? According to a new study funded by the National Institute of Mental Health and published in JAMA Network Open, people who presented to California EDs with deliberate self-harm or suicidal ideation were not just at risk for a future suicide—they were at extreme risk.

The researchers divided patients into 3 groups: 83,507 who had deliberately self-harmed with or without co-occurring suicidal ideation; 67,379 presenting with suicidal ideation but without deliberate self-harm; and 497,760 without either self-harm or suicidal ideation.

In the first year after the ED visit, the patients who had presented with deliberate self-harm had a suicide rate almost 57 times higher than that of demographically similar Californians. Among those with suicidal ideation, the suicide rate was about 31 times higher. The suicide rate for the reference group, while the lowest of the 3 groups, was still twice the rate among Californians overall.

The researchers found certain clinical and demographic characteristics predicted subsequent suicide. Men and patients aged > 65 years had higher rates of suicide when compared with women or people aged 10 to 24 years. In all groups, suicide rates were higher for non-Hispanic, white patients.

Comorbid diagnoses were associated with suicide risk but with “striking differences” among the groups, the researchers say. Among patients presenting with deliberate self-harm, those with a comorbid diagnosis of bipolar disorder, anxiety disorder, or a psychotic disorder were more likely to die of suicide. Among reference patients, those with bipolar disorder, depression, or alcohol use disorder had a higher risk.

Of note, the researchers say, patients in the deliberate self-harm group who presented with a firearm-related injury had a subsequent suicide rate of 4.4% in the following year, a far higher rate than that in any other patient group. The researchers urge ED physicians to be aware that patients who present with self-harm who use high-lethality methods at a nonfatal event remain at highly increased risk for future suicide.

To the researchers’ knowledge, this is the first US population-based study to examine 12-month suicide rates after an index ED visit. These findings reinforce the importance of universal screening for suicide risk in EDs and the need for follow-up care, the researchers add, “an approach that has been found to increase the number of ED patients identified as warranting treatment for suicide risk by approximately 2-fold, but which is also not yet widespread.”

 What happens to patients at risk for suicide after they leave the emergency department (ED)? According to a new study funded by the National Institute of Mental Health and published in JAMA Network Open, people who presented to California EDs with deliberate self-harm or suicidal ideation were not just at risk for a future suicide—they were at extreme risk.

The researchers divided patients into 3 groups: 83,507 who had deliberately self-harmed with or without co-occurring suicidal ideation; 67,379 presenting with suicidal ideation but without deliberate self-harm; and 497,760 without either self-harm or suicidal ideation.

In the first year after the ED visit, the patients who had presented with deliberate self-harm had a suicide rate almost 57 times higher than that of demographically similar Californians. Among those with suicidal ideation, the suicide rate was about 31 times higher. The suicide rate for the reference group, while the lowest of the 3 groups, was still twice the rate among Californians overall.

The researchers found certain clinical and demographic characteristics predicted subsequent suicide. Men and patients aged > 65 years had higher rates of suicide when compared with women or people aged 10 to 24 years. In all groups, suicide rates were higher for non-Hispanic, white patients.

Comorbid diagnoses were associated with suicide risk but with “striking differences” among the groups, the researchers say. Among patients presenting with deliberate self-harm, those with a comorbid diagnosis of bipolar disorder, anxiety disorder, or a psychotic disorder were more likely to die of suicide. Among reference patients, those with bipolar disorder, depression, or alcohol use disorder had a higher risk.

Of note, the researchers say, patients in the deliberate self-harm group who presented with a firearm-related injury had a subsequent suicide rate of 4.4% in the following year, a far higher rate than that in any other patient group. The researchers urge ED physicians to be aware that patients who present with self-harm who use high-lethality methods at a nonfatal event remain at highly increased risk for future suicide.

To the researchers’ knowledge, this is the first US population-based study to examine 12-month suicide rates after an index ED visit. These findings reinforce the importance of universal screening for suicide risk in EDs and the need for follow-up care, the researchers add, “an approach that has been found to increase the number of ED patients identified as warranting treatment for suicide risk by approximately 2-fold, but which is also not yet widespread.”

A total of 165 persons in the United States are under investigation for infection with the 2019 Novel Coronavirus (2019-nCoV), with 68 testing negative and only 5 confirming positive, according to data presented Jan. 29 during a Centers for Disease Control and Prevention (CDC) briefing. 

The remaining samples are in transit or are being processed at the CDC for testing, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the briefing.

“The genetic sequence for all five viruses detected in the United States to date has been uploaded to the CDC website,” she said. “We are working quickly through the process to get the CDC-developed test into the hands of public health partners in the U.S. and internationally.”

Dr. Messonnier reported that the CDC is expanding screening efforts to U.S. ports of entry that house CDC quarantine stations. Also, in collaboration with U.S. Customs and Border Protection, the agency is expanding distribution of travel health education materials to all travelers from China.

“The good news here is that, despite an aggressive public health investigation to find new cases [of 2019-nCoV], we have not,” she said. “The situation in China is concerning, however, we are looking hard here in the U.S. We will continue to be proactive. I still expect that we will find additional cases.”

In another development, the federal government facilitated the return of a plane full of U.S. citizens living in Wuhan, China, to March Air Reserve Force Base in Riverside County, Calif. “We have taken every precaution to ensure their safety while also continuing to protect the health of our nation and the people around them,” Dr. Messonnier said.

All 195 passengers have been screened, monitored, and evaluated by medical personnel “every step of the way,” including before takeoff, during the flight, during a refueling stop in Alaska, and again upon landing at March Air Reserve Force Base on Jan. 28. “All 195 patients are without the symptoms of the novel coronavirus, and all have been assigned living quarters at the Air Force base,” Dr. Messonnier said.

The CDC has launched a second stage of further screening and information gathering from the passengers, who will be offered testing as part of a thorough risk assessment.

“I understand that many people in the U.S. are worried about this virus and whether it will affect them,” Dr. Messonnier said. “Outbreaks like this are always concerning, particularly when a new virus is emerging. But we are well prepared and working closely with federal, state, and local partners to protect our communities and others nationwide from this public health threat. At this time, we continue to believe that the immediate health risk from this new virus to the general American public is low.”

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A total of 165 persons in the United States are under investigation for infection with the 2019 Novel Coronavirus (2019-nCoV), with 68 testing negative and only 5 confirming positive, according to data presented Jan. 29 during a Centers for Disease Control and Prevention (CDC) briefing. 

The remaining samples are in transit or are being processed at the CDC for testing, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the briefing.

“The genetic sequence for all five viruses detected in the United States to date has been uploaded to the CDC website,” she said. “We are working quickly through the process to get the CDC-developed test into the hands of public health partners in the U.S. and internationally.”

Dr. Messonnier reported that the CDC is expanding screening efforts to U.S. ports of entry that house CDC quarantine stations. Also, in collaboration with U.S. Customs and Border Protection, the agency is expanding distribution of travel health education materials to all travelers from China.

“The good news here is that, despite an aggressive public health investigation to find new cases [of 2019-nCoV], we have not,” she said. “The situation in China is concerning, however, we are looking hard here in the U.S. We will continue to be proactive. I still expect that we will find additional cases.”

In another development, the federal government facilitated the return of a plane full of U.S. citizens living in Wuhan, China, to March Air Reserve Force Base in Riverside County, Calif. “We have taken every precaution to ensure their safety while also continuing to protect the health of our nation and the people around them,” Dr. Messonnier said.

All 195 passengers have been screened, monitored, and evaluated by medical personnel “every step of the way,” including before takeoff, during the flight, during a refueling stop in Alaska, and again upon landing at March Air Reserve Force Base on Jan. 28. “All 195 patients are without the symptoms of the novel coronavirus, and all have been assigned living quarters at the Air Force base,” Dr. Messonnier said.

The CDC has launched a second stage of further screening and information gathering from the passengers, who will be offered testing as part of a thorough risk assessment.

“I understand that many people in the U.S. are worried about this virus and whether it will affect them,” Dr. Messonnier said. “Outbreaks like this are always concerning, particularly when a new virus is emerging. But we are well prepared and working closely with federal, state, and local partners to protect our communities and others nationwide from this public health threat. At this time, we continue to believe that the immediate health risk from this new virus to the general American public is low.”

[email protected]

A total of 165 persons in the United States are under investigation for infection with the 2019 Novel Coronavirus (2019-nCoV), with 68 testing negative and only 5 confirming positive, according to data presented Jan. 29 during a Centers for Disease Control and Prevention (CDC) briefing. 

The remaining samples are in transit or are being processed at the CDC for testing, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the briefing.

“The genetic sequence for all five viruses detected in the United States to date has been uploaded to the CDC website,” she said. “We are working quickly through the process to get the CDC-developed test into the hands of public health partners in the U.S. and internationally.”

Dr. Messonnier reported that the CDC is expanding screening efforts to U.S. ports of entry that house CDC quarantine stations. Also, in collaboration with U.S. Customs and Border Protection, the agency is expanding distribution of travel health education materials to all travelers from China.

“The good news here is that, despite an aggressive public health investigation to find new cases [of 2019-nCoV], we have not,” she said. “The situation in China is concerning, however, we are looking hard here in the U.S. We will continue to be proactive. I still expect that we will find additional cases.”

In another development, the federal government facilitated the return of a plane full of U.S. citizens living in Wuhan, China, to March Air Reserve Force Base in Riverside County, Calif. “We have taken every precaution to ensure their safety while also continuing to protect the health of our nation and the people around them,” Dr. Messonnier said.

All 195 passengers have been screened, monitored, and evaluated by medical personnel “every step of the way,” including before takeoff, during the flight, during a refueling stop in Alaska, and again upon landing at March Air Reserve Force Base on Jan. 28. “All 195 patients are without the symptoms of the novel coronavirus, and all have been assigned living quarters at the Air Force base,” Dr. Messonnier said.

The CDC has launched a second stage of further screening and information gathering from the passengers, who will be offered testing as part of a thorough risk assessment.

“I understand that many people in the U.S. are worried about this virus and whether it will affect them,” Dr. Messonnier said. “Outbreaks like this are always concerning, particularly when a new virus is emerging. But we are well prepared and working closely with federal, state, and local partners to protect our communities and others nationwide from this public health threat. At this time, we continue to believe that the immediate health risk from this new virus to the general American public is low.”

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CT scan screening of older people with heavy smoking histories – using lesion volume, not diameter, as a trigger for further work-up – reduced lung cancer deaths by about 30% in a randomized trial from the Netherlands and Belgium with almost 16,000 current and former smokers, investigators reported in the New England Journal of Medicine.

The Dutch-Belgian lung-cancer screening trial (Nederlands-Leuvens Longkanker Screenings Onderzoek [NELSON]) is “arguably the only adequately powered trial other than the” National Lung Screening Trial (NLST) in the United States to assess the role of CT scan screening among smokers, wrote University of London cancer epidemiologist Stephen Duffy, MSc, and University of Liverpool molecular oncology professor John Field, PhD, in an accompanying editorial.

NLST, which used lesion diameter, found an approximately 20% lower lung cancer mortality than screening with chest x-rays among 53,454 heavy smokers after a median follow-up of 6.5 years. The trial ultimately led the U.S. Preventive Services Task Force to recommend annual screening for people aged 55-80 years with a history of at least 30 pack-years.

European countries have considered similar programs but have hesitated “partly due to doubts fostered by the early publication of inconclusive results of a number of smaller trials in Europe. These doubts should be laid to rest,” Mr. Duffy and Dr. Field wrote.

“With the NELSON results, the efficacy of low-dose CT screening for lung cancer is confirmed. Our job is no longer to assess whether low-dose CT screening for lung cancer works; it does. Our job is to identify the target population in which it will be acceptable and cost effective,” they added.

The 15,789 NELSON participants (84% men, with a median age of 58 years and 38 pack-year history) were randomized about 1:1 to either low-dose CT scan screening at baseline and 1, 3, and 5.5 years, or to no screening.

At 10 years follow-up, there were 5.58 lung cancer cases and 2.5 deaths per 1,000 person-years in the screened group versus 4.91 cases and 3.3 deaths per 1,000 person-years among controls. Lung-cancer mortality was 24% lower among screened subjects overall, and 33% lower among screened women. The team estimated that screening prevented about 60 lung cancer deaths.

Using volume instead of diameter “resulted in low[er] referral rates” – 2.1% with a positive predictive value of 43.5% versus 24% with a positive predictive value of 3.8% in NLST – for additional work-up, explained investigators led by H.J. de Koning, MD, PhD, of the department of public health at Erasmus University Medical Center in Rotterdam, the Netherlands.

The upper limit of overdiagnosis risk – a major concern with any screening program – was 18.5% with NLST versus 8.9% with NELSON, they wrote.

In short: “Volume CT screening enabled a significant reduction of harms (e.g., false positive tests and unnecessary work-up procedures) without jeopardizing favorable outcomes,” the investigators wrote. Indeed, an ad hoc analysis suggested “more-favorable effects on lung-cancer mortality than in the NLST, despite lower referral rates for suspicious lesions” and the fact that NLST used annual screening.

“Recently,” Mr. Duffy and Dr. Field explained in their editorial, “the NELSON investigators evaluated both diameter and volume measurement to estimate lung-nodule size as an imaging biomarker for nodule management; this provided evidence that using mean or maximum axial diameter to assess nodule volume led to a substantial overestimation of nodule volume.” Direct measurement of volume “resulted in a substantial number of early-stage cancers identified at the time of diagnosis and avoided false positives from the overestimation incurred by management based on diameter.”

“The lung-nodule management system used in the NELSON trial has been advocated in the European position statement on lung-cancer screening. This will improve the acceptability of the intervention, because the rate of further investigation has been a major concern in lung cancer screening,” they wrote.

Baseline characteristics did not differ significantly between the screened and unscreened in NELSON, except for a slightly longer duration of smoking in the screened group.

The work was funded by the Netherlands Organization of Health Research and Development, among others. Mr. Duffy and Dr. de Koning didn’t report any disclosures. Dr. Field is an advisor for AstraZeneca, Epigenomics, and Nucleix, and has a research grant to his university from Janssen.
 

SOURCE: de Honing HJ et al. N Engl J Med. 2020 Jan 29. doi: 10.1056/NEJMoa1911793.

CT scan screening of older people with heavy smoking histories – using lesion volume, not diameter, as a trigger for further work-up – reduced lung cancer deaths by about 30% in a randomized trial from the Netherlands and Belgium with almost 16,000 current and former smokers, investigators reported in the New England Journal of Medicine.

The Dutch-Belgian lung-cancer screening trial (Nederlands-Leuvens Longkanker Screenings Onderzoek [NELSON]) is “arguably the only adequately powered trial other than the” National Lung Screening Trial (NLST) in the United States to assess the role of CT scan screening among smokers, wrote University of London cancer epidemiologist Stephen Duffy, MSc, and University of Liverpool molecular oncology professor John Field, PhD, in an accompanying editorial.

NLST, which used lesion diameter, found an approximately 20% lower lung cancer mortality than screening with chest x-rays among 53,454 heavy smokers after a median follow-up of 6.5 years. The trial ultimately led the U.S. Preventive Services Task Force to recommend annual screening for people aged 55-80 years with a history of at least 30 pack-years.

European countries have considered similar programs but have hesitated “partly due to doubts fostered by the early publication of inconclusive results of a number of smaller trials in Europe. These doubts should be laid to rest,” Mr. Duffy and Dr. Field wrote.

“With the NELSON results, the efficacy of low-dose CT screening for lung cancer is confirmed. Our job is no longer to assess whether low-dose CT screening for lung cancer works; it does. Our job is to identify the target population in which it will be acceptable and cost effective,” they added.

The 15,789 NELSON participants (84% men, with a median age of 58 years and 38 pack-year history) were randomized about 1:1 to either low-dose CT scan screening at baseline and 1, 3, and 5.5 years, or to no screening.

At 10 years follow-up, there were 5.58 lung cancer cases and 2.5 deaths per 1,000 person-years in the screened group versus 4.91 cases and 3.3 deaths per 1,000 person-years among controls. Lung-cancer mortality was 24% lower among screened subjects overall, and 33% lower among screened women. The team estimated that screening prevented about 60 lung cancer deaths.

Using volume instead of diameter “resulted in low[er] referral rates” – 2.1% with a positive predictive value of 43.5% versus 24% with a positive predictive value of 3.8% in NLST – for additional work-up, explained investigators led by H.J. de Koning, MD, PhD, of the department of public health at Erasmus University Medical Center in Rotterdam, the Netherlands.

The upper limit of overdiagnosis risk – a major concern with any screening program – was 18.5% with NLST versus 8.9% with NELSON, they wrote.

In short: “Volume CT screening enabled a significant reduction of harms (e.g., false positive tests and unnecessary work-up procedures) without jeopardizing favorable outcomes,” the investigators wrote. Indeed, an ad hoc analysis suggested “more-favorable effects on lung-cancer mortality than in the NLST, despite lower referral rates for suspicious lesions” and the fact that NLST used annual screening.

“Recently,” Mr. Duffy and Dr. Field explained in their editorial, “the NELSON investigators evaluated both diameter and volume measurement to estimate lung-nodule size as an imaging biomarker for nodule management; this provided evidence that using mean or maximum axial diameter to assess nodule volume led to a substantial overestimation of nodule volume.” Direct measurement of volume “resulted in a substantial number of early-stage cancers identified at the time of diagnosis and avoided false positives from the overestimation incurred by management based on diameter.”

“The lung-nodule management system used in the NELSON trial has been advocated in the European position statement on lung-cancer screening. This will improve the acceptability of the intervention, because the rate of further investigation has been a major concern in lung cancer screening,” they wrote.

Baseline characteristics did not differ significantly between the screened and unscreened in NELSON, except for a slightly longer duration of smoking in the screened group.

The work was funded by the Netherlands Organization of Health Research and Development, among others. Mr. Duffy and Dr. de Koning didn’t report any disclosures. Dr. Field is an advisor for AstraZeneca, Epigenomics, and Nucleix, and has a research grant to his university from Janssen.
 

SOURCE: de Honing HJ et al. N Engl J Med. 2020 Jan 29. doi: 10.1056/NEJMoa1911793.

CT scan screening of older people with heavy smoking histories – using lesion volume, not diameter, as a trigger for further work-up – reduced lung cancer deaths by about 30% in a randomized trial from the Netherlands and Belgium with almost 16,000 current and former smokers, investigators reported in the New England Journal of Medicine.

The Dutch-Belgian lung-cancer screening trial (Nederlands-Leuvens Longkanker Screenings Onderzoek [NELSON]) is “arguably the only adequately powered trial other than the” National Lung Screening Trial (NLST) in the United States to assess the role of CT scan screening among smokers, wrote University of London cancer epidemiologist Stephen Duffy, MSc, and University of Liverpool molecular oncology professor John Field, PhD, in an accompanying editorial.

NLST, which used lesion diameter, found an approximately 20% lower lung cancer mortality than screening with chest x-rays among 53,454 heavy smokers after a median follow-up of 6.5 years. The trial ultimately led the U.S. Preventive Services Task Force to recommend annual screening for people aged 55-80 years with a history of at least 30 pack-years.

European countries have considered similar programs but have hesitated “partly due to doubts fostered by the early publication of inconclusive results of a number of smaller trials in Europe. These doubts should be laid to rest,” Mr. Duffy and Dr. Field wrote.

“With the NELSON results, the efficacy of low-dose CT screening for lung cancer is confirmed. Our job is no longer to assess whether low-dose CT screening for lung cancer works; it does. Our job is to identify the target population in which it will be acceptable and cost effective,” they added.

The 15,789 NELSON participants (84% men, with a median age of 58 years and 38 pack-year history) were randomized about 1:1 to either low-dose CT scan screening at baseline and 1, 3, and 5.5 years, or to no screening.

At 10 years follow-up, there were 5.58 lung cancer cases and 2.5 deaths per 1,000 person-years in the screened group versus 4.91 cases and 3.3 deaths per 1,000 person-years among controls. Lung-cancer mortality was 24% lower among screened subjects overall, and 33% lower among screened women. The team estimated that screening prevented about 60 lung cancer deaths.

Using volume instead of diameter “resulted in low[er] referral rates” – 2.1% with a positive predictive value of 43.5% versus 24% with a positive predictive value of 3.8% in NLST – for additional work-up, explained investigators led by H.J. de Koning, MD, PhD, of the department of public health at Erasmus University Medical Center in Rotterdam, the Netherlands.

The upper limit of overdiagnosis risk – a major concern with any screening program – was 18.5% with NLST versus 8.9% with NELSON, they wrote.

In short: “Volume CT screening enabled a significant reduction of harms (e.g., false positive tests and unnecessary work-up procedures) without jeopardizing favorable outcomes,” the investigators wrote. Indeed, an ad hoc analysis suggested “more-favorable effects on lung-cancer mortality than in the NLST, despite lower referral rates for suspicious lesions” and the fact that NLST used annual screening.

“Recently,” Mr. Duffy and Dr. Field explained in their editorial, “the NELSON investigators evaluated both diameter and volume measurement to estimate lung-nodule size as an imaging biomarker for nodule management; this provided evidence that using mean or maximum axial diameter to assess nodule volume led to a substantial overestimation of nodule volume.” Direct measurement of volume “resulted in a substantial number of early-stage cancers identified at the time of diagnosis and avoided false positives from the overestimation incurred by management based on diameter.”

“The lung-nodule management system used in the NELSON trial has been advocated in the European position statement on lung-cancer screening. This will improve the acceptability of the intervention, because the rate of further investigation has been a major concern in lung cancer screening,” they wrote.

Baseline characteristics did not differ significantly between the screened and unscreened in NELSON, except for a slightly longer duration of smoking in the screened group.

The work was funded by the Netherlands Organization of Health Research and Development, among others. Mr. Duffy and Dr. de Koning didn’t report any disclosures. Dr. Field is an advisor for AstraZeneca, Epigenomics, and Nucleix, and has a research grant to his university from Janssen.